CN110870943A - Implantable two-section type microneedle patch and preparation method thereof - Google Patents
Implantable two-section type microneedle patch and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Abstract
The invention discloses an implantable two-section microneedle patch and a preparation method thereof. The invention discloses an implantable two-section type microneedle, which comprises an upper section needle point and a lower section integrated base; the upper section of the needle tip is formed by a biodegradable water-insoluble high polymer material matrix; the lower integrated susceptor is formed of a matrix comprising a water-soluble polymer material. The invention also discloses a preparation method of the microneedle. The microneedle is characterized in that an upper section of needle point is made of biodegradable water-insoluble high polymer material, a lower section of integrated base is made of water-soluble high polymer material, so that a two-section microneedle with the needle point being insoluble in water and the base being soluble in water is formed, after the microneedle acts on skin, the lower section of integrated base absorbs water in the skin to be quickly dissolved, the rapid separation is realized, the upper section of needle point can be embedded into the skin, and a user can ensure that the drug is released in vivo for a long time without pasting the microneedle for a long time. Meanwhile, the lower-section integrated base is made of water-soluble polymer materials, so that medical waste is avoided.
Description
Technical Field
The invention relates to the technical field of medicines. More particularly, relates to an implantable two-section type microneedle patch and a preparation method thereof.
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.
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(Advanced Functional materials.2013Jan 14; 23(2): 161-. In the method, firstly, a medicament is loaded in polylactic acid-glycolic acid copolymer (PLGA) microspheres by an emulsification method, and then the microspheres are directly loaded on a needle point or the microspheres are subjected to high-temperature hot melting at 140 ℃ to form the PLGA integrated microneedle needle body. In the method, the substrate material is polyacrylic acid which can be quickly dissolved in water, and when the microneedle acts on the skin, the polyacrylic acid quickly absorbs moisture in the skin and is quickly dissolved, so that PLGA microspheres or an integrated PLGA needle body is directly loaded into the skin, and the controllable release of the medicament is realized. However, the loading of the medicine in the method needs to prepare the PLGA microspheres firstly, the process is complex, the cost is high, and the integrated PLGA needle body needs to be prepared at a high temperature of 140 ℃, so that the application range of the medicine is greatly limited.
In recent years, a plurality of researchers are dedicated to research on two-section microneedles capable of being separated from skin quickly, and the microneedles can effectively shorten the microneedle operation time.
Chinese patent (CN 104707241 a) discloses a two-stage microneedle array and a method for preparing the same. The lower section base of the micro-needle in the patent adopts biodegradable water-insoluble high polymer material, the tip of the upper section is used for bearing the drug, and the preparation material is biodegradable soluble high polymer material. The microneedle array can effectively puncture the epidermis and realize the quick separation of the drug-loading section and the needle body. However, the microneedle prepared in this patent has no sustained release function since the tip loaded in the skin is made of a soluble polymer material.
A separable arrowhead microneedle that can rapidly release drugs and vaccines into the skin without pain was also reported in the document 3(Journal of Controlled Release.2011Feb 10; 149(3): 242-9). The microneedles are fabricated by attaching micron-sized arrows to metal arrow shafts. The arrow is divided into water-soluble arrow and water-insoluble arrow, wherein the insoluble arrow is prepared by blending the medicine and the molten PLGA, the manufacturing process is severe, the applicable medicine must resist high temperature (200 ℃), the medicine range is greatly limited, and meanwhile, the waste metal arrow shaft can bring medical waste.
In document 4 (biomaterials.2013Apr; 34(12): 3077-86), a PLA block microneedle containing chitosan needle points is reported, and intradermal implantation of a medicine-containing needle point is realized by dissolving water-soluble PVP coated on the outer surface of PLA, and the method has the advantage that the implanted chitosan has a slow release function, so that the sustained release of the medicine at the needle point is realized. However, this method is cumbersome to operate, requires a variety of molds in the manufacturing process, requires a PCL holder to be manufactured, and presses chitosan gel into the tip of the needle tip cavity of the mold, and also generates medical waste from the discarded PLA holder after the drug-containing needle tip is embedded in the skin.
In summary, the preparation process of polylactic acid microneedles at present can be divided into two categories, one is that polylactic acid is firstly made into microspheres, then the microspheres are added on a microneedle mould, and then the microneedles with certain mechanical strength are formed after heating, melting and cooling, and the microneedles can be loaded with drugs, but the microspheres are firstly made and then the microneedles are formed, so that the operation is complex and the cost is high; the other method is that polylactic acid powder is directly added on a microneedle mould, heated and melted (higher than 200 ℃) and cooled to form the microneedle, and the preparation method has narrow drug application range. In addition, most of the upper needle points of the two-section type microneedles at the present stage are made of water-soluble high polymer materials, so that the application of insoluble medicines is limited, and meanwhile, most of the needle points do not have a slow release function; the lower-section base is mostly prepared from metal or biodegradable high polymer materials such as polylactic acid, the metal materials can generate medical waste, and the preparation process of the polylactic acid materials needs a high-temperature process.
Therefore, an implantable two-stage microneedle with a long-acting sustained release polylactic acid, which has a simple process, high safety, no need of long-time application, rapid separation of a needle tip from a substrate, and short operation time, is needed.
Disclosure of Invention
The first purpose of the invention is to provide an implantable two-section type microneedle, which can be used for quickly implanting a polylactic acid needle tip into the skin, quickly separating the needle tip from a substrate, and realizing a biodegradable sustained-release microneedle patch with simple process, high safety and high efficiency, and convenient, safe and biodegradable administration.
The second objective of the present invention is to provide a method for preparing the implantable two-stage 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 implantable microneedles.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides an implantable two-section type microneedle, which comprises an upper section needle point and a lower section integrated base; the upper section of the needle tip is formed by a biodegradable water-insoluble high polymer material matrix; the lower integrated susceptor is formed of a matrix comprising a water-soluble polymer material.
The implantable two-section type microneedle has the advantages that the height of the needle point at the upper section is not more than two thirds of the whole height of the microneedle, and preferably not more than one half; the diameter or the side length of the edge of the bottom of the upper section needle point is more than or equal to the diameter or the side length of the joint of the lower section integrated base and the upper section needle point; after the microneedle enters the skin, the needle tip is not easy to take out when the basement membrane is peeled off; the overlapped height of the upper section needle point and the lower section integrated base is more than or equal to one half of the height of the upper section needle point, preferably more than two thirds of the height of the upper section needle point.
The biodegradable water-insoluble high polymer material of the upper segment needle point of the microneedle can also load 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.
Further, the biodegradable water-insoluble polymer material includes, but is not limited to, one or more of polyanhydrides, polyorthoesters (poly (ortho esters), POE), Polyphosphoesters (PPEs), aliphatic polyesters (aliphatics polyesters), and derivatives thereof. Wherein polyanhydrides include, but are not limited to, P (CPP-SA), P (FA-SA), P (FAD-SA); the aliphatic polyester and its derivatives include, but are not limited to, one or more of polyglycolide (PGA, also called polyglycolic acid or polyglycolic acid), polylactide (PLA, also called polylactic acid or polyhydroxypropionic acid), glycolide-lactide copolymer (PLGA or polylactic-co-glycolic acid), Polycaprolactone (PCL), levolactic acid (L-PLA), racemic polylactic acid, polyethylene glycol-polylactic acid copolymer and its derivatives.
In a preferred embodiment of the invention, the upper needle tip further comprises a pore-forming agent, and the pore-forming agent is used for helping intradermal water molecules to enter the inside of the upper needle tip matrix and regulating and controlling the release rate of the medicament. The pore-forming agent comprises one or more of sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, polyvinylpyrrolidone, hyaluronic acid and sodium salt thereof, cellulose derivatives, trehalose, maltose and cyclodextrin.
Preferably, the pore-foaming agent accounts for 0.1-20% of the total mass of the upper section of the needle tip.
In a preferred embodiment of the present invention, the upper needle tip further comprises a protective agent, and the protective agent includes, but is not limited to, one or more of polyhydroxy compounds (mannitol, sorbitol, polyethylene glycol, etc.), sugar compounds (trehalose, dextrin, lactose, sucrose, etc.), serum albumin, polyvinylpyrrolidone, chondroitin sulfate, and amino acids (proline, tryptophan, glutamic acid, glycine, etc.).
Preferably, the protective agent accounts for no more than 20% of the total mass of the needle tip at the upper section.
The lower-section integrated base is a microneedle which is integrally formed by water-soluble high polymer materials and comprises a needle body and a base.
Further, the water-soluble polymer material includes, but is not limited to, one or more of carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl chitosan, chitosan and derivatives thereof, polyvinyl alcohol and derivatives thereof, polyvinylpyrrolidone and derivatives thereof, sodium hyaluronate, chondroitin sulfate, dextran and derivatives thereof, sodium alginate, poly-gamma-glutamic acid, pullulan, gelatin, polydopamine, polyacrylamide or polyacrylamide.
The molecular weight of the water-soluble high molecular material is 10-1000 kDa.
Further, the needle body is conical or polygonal conical, preferably, the needle body is conical; when the micro-needle forms a micro-needle array, the density of the micro-needle bodies is as follows: each square centimeter of substrate is provided with 25-1000 needle bodies; the height of the needle body is 0.3-2 mm, the angle between the upper section needle point and the upper needle body of the lower section integrated base is 10-90 degrees, and the thickness of the base in the lower section integrated base is 10-500 mu m.
The invention also provides a preparation method of the implantable two-section type 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 an upper-section 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 upper-section needle point matrix material solution to obtain upper-section needle point injection molding liquid;
alternatively, the first and second electrodes may be,
mixing a biodegradable water-insoluble high polymer material with an organic solvent, adding or not adding a pore-foaming agent, adding or not adding a protective agent, adding an active ingredient, and uniformly mixing to obtain an upper-section needle point injection molding liquid;
2) mixing a water-soluble high polymer material with water to obtain lower-section integrated base injection molding liquid;
3) injecting the lower-section integrated base injection molding liquid into a microneedle mould, vacuumizing, drying, and demolding to prepare a lower-section integrated base; adding the injection molding liquid of the upper-section needle point into a microneedle mold, vacuumizing, heating to 30-80 ℃, and removing the organic solvent to obtain the upper-section needle point; and aligning the lower-section integrated base with the upper-section needle point for splicing, cooling, demolding and forming the needle.
Preferably, the organic solvent is one or more of acetone, ethyl acetate, dichloromethane, dimethyl sulfoxide or N-methylpyrrolidone.
The invention further provides an implantable two-section microneedle patch, which comprises a microneedle array and a lining, wherein the microneedle array is composed of the implantable two-section microneedles; preferably, the lining is a pressure sensitive adhesive lining or a silica gel lining or a hydrocolloid.
The preparation method of the implantable two-section microneedle patch comprises the steps of preparing the microneedle array on the basis of preparing the implantable two-section microneedle, further attaching a pressure-sensitive adhesive lining to the back surface of the lower section integrated base 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 microneedle or the microneedle patch is characterized in that the upper segment of the needle tip is made of biodegradable water-insoluble high polymer material, and the lower segment of the integrated base is made of water-soluble high polymer material, so that the two-segment microneedle with the needle tip being insoluble in water and the base being soluble in water is formed. After the microneedle acts on the skin, the lower integrated base absorbs moisture in the skin to be quickly dissolved, so that the lower integrated base is quickly separated from the upper needle point within 30s-60min, the upper biodegradable water-insoluble high polymer material needle point can be embedded into the skin after the base is removed, and a user can ensure long-term release of the drug in the body without pasting the microneedle patch for a long time. Meanwhile, the lower-section integrated base is made of water-soluble polymer materials, so that medical waste is avoided.
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 schematic structural diagram of a lower integrated base.
Fig. 3 shows a photograph under a stereomicroscope of the microneedle patch.
Fig. 4 shows a side view under a microscope of a microneedle patch.
Fig. 5 shows the effect of implanting the needle tip of the microneedle patch into the pigskin.
Fig. 6 shows a dissolution diagram of the integrated base of the lower section after the microneedle patch punctured the pigskin.
Fig. 7 shows a graph of the in vitro release results of microneedles without addition of a pore.
Figure 8 shows a graph of the in vitro release results of the modified pore (trehalose) microneedles.
Figure 9 shows a graph comparing in vitro release results of microneedles with and without the porogen (trehalose).
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 an implantable two-stage microneedle patch containing a fluorescent dye
1. Heating and swelling water serving as a solvent and polyvinyl alcohol (PVA) serving as a matrix to prepare a PVA aqueous solution with the mass fraction of 30%; preparing 30% PVP K120 aqueous solution by taking water as a solvent and polyvinylpyrrolidone PVP K120 as a matrix, mixing the 30% PVA aqueous solution and the 30% PVP K120 aqueous solution according to the mass ratio of 1:2, stirring uniformly, centrifuging to remove bubbles, and taking the mixture as lower-end integrated base injection molding liquid.
2. Preparing a PLGA (10KDa, 75/25) solution with the mass fraction of 30% by taking N-methylpyrrolidone as a solvent; preparing 10mg/mL fat-soluble simulated medicine fluorescent scarlet solution by taking N-methylpyrrolidone as a solvent; 0.5mL of the fluorescent scarlet solution and 0.5mL of the PLGA solution are uniformly mixed to prepare 15% PLGA (75/25) solution containing fluorescent scarlet (5mg/mL) as injection molding liquid of the upper section needle point.
3. Adding 100 mu L of the integrated base injection molding liquid into a mold with a pinhole depth of 700 micrometers and an area of 0.64 square centimeter, enabling the base injection molding liquid to enter the pinhole of the microneedle mold in a vacuumizing mode, drying for 6 hours at 25 ℃ under the humidity condition of 35%, and demolding to obtain the integrated base; adding 4 microlitres of the injection molding liquid with the needle point at the upper section into a microneedle mould with a pinhole depth of 500 micrometers and a step height of 300 micrometers, enabling the injection molding liquid with the needle point at the upper section to enter the pinhole of the microneedle mould in a vacuumizing mode, removing the redundant solution on the mould, and heating for 1 hour at 75 ℃; and transferring the heated mold containing the needle point to a heating table, aligning the prefabricated lower integrated base with the needle point for splicing, and then placing at room temperature for cooling for 3 min. And (3) sticking a pressure-sensitive adhesive lining on the back of the spliced microneedle substrate, and demolding. The microneedle with the upper section of the needle tip of 300 micrometers, the overlapping height of the upper section of the needle tip and the integrated needle base of 200 micrometers and the overall height of 800 micrometers is obtained.
The microneedle patch was prepared as shown in fig. 3, 117 needles/sheet. The side view of the prepared microneedle patch was observed under a microscope, as shown in fig. 4.
Example 2 skin puncture and needle tip implantation test of an implantable two-stage microneedle patch
The microneedle patch prepared in example 1 is applied to fresh pig skin, is pressed for 40s by a 30N needle inserter, is placed on agar hydrogel for moisture preservation for 20min, is then taken off, and is used for observing whether an implanted needle point exists in the skin, as shown in fig. 5, an implanted photo of the microneedle needle point in the pig skin is shown, so that the situation that the needle point containing fluorescent scarlet is left in the skin can be obviously seen, and the implantation rate of the needle point is close to 100%. At the same time, when the removed microneedle patch was observed under a stereomicroscope, the lower integrated base was dissolved as shown in fig. 6, and no residual needle tip was found, further demonstrating that the needle tip had remained in the skin.
Example 3 preparation of an implantable two-stage microneedle patch containing an insoluble drug
1. PVP K90 aqueous solution with solid content of 30% is prepared by taking water as a solvent and is used as the lower-section integrated base injection molding liquid.
2. Preparing a PLGA (15KDa, 50/50) solution with the mass fraction of 30% by taking N-methylpyrrolidone as a solvent; preparing 100mg/mL levonorgestrel solution by taking N-methylpyrrolidone as a solvent; 0.5mL of the levonorgestrel solution and 0.5mL of the PLGA solution are uniformly mixed to prepare a 15% PLGA solution containing levonorgestrel (50mg/mL) as an upper-section needle tip injection molding solution.
3. Adding 100 mu L of the integrated base injection molding liquid into a mold, enabling the base injection molding liquid to enter a microneedle mold pinhole in a vacuumizing mode, drying for 1h under the conditions of 25 ℃ and 35% humidity, and demolding to obtain an integrated base; adding the injection molding liquid with the upper needle point into a microneedle mould, enabling the injection molding liquid with the upper needle point to enter a pinhole of the microneedle mould in a vacuumizing mode, removing the redundant solution on the mould, and heating at 70 ℃ for 1.5 hours; transferring the heated mold containing the needle point to a heating table, splicing the lower integrated base which is manufactured in advance and is aligned to the needle point at the temperature of 70 ℃, and cooling for 2min at room temperature after splicing; and (3) attaching a pressure-sensitive adhesive lining to the back of the microneedle substrate, and demolding. The microneedle mould used in this example was the same size as in example 1, and the microneedle patch was prepared with 117 needles/sheet, with a total needle height of 800 μm.
4. Skin puncture tests are carried out on the prepared microneedle patch according to the method in the embodiment 2, and it is found that when the microneedle is detached after being attached for 5min, the needle point is almost 100% implanted in the skin, and the lower integrated base is dissolved, namely, the microneedle patch can be attached for 5min to separate the upper needle point from the lower integrated base.
5. And (3) testing the drug loading capacity: placing a microneedle into a centrifuge tube, adding 0.7mL of acetonitrile, adding 0.3mL of ultrapure water after vortex dissolution, carrying out vortex mixing, centrifuging, and taking supernatant for liquid chromatography analysis. In the experiment, 6 tablets are tested in parallel, and finally, the drug loading of each tablet is measured to be 60 +/-2.3 mu g.
6. In vitro release experiments: the micro-needle is placed in a dialysis bag and sealed, 40% PEG-PBS (pH: 7.4) is selected as a receiving solution, sampling is carried out once every 12h for the first 14d, sampling is carried out once every 24h for the second 9d, sampling is carried out completely, the receiving solution with the same amount is replaced, the concentration of the released drug in the receiving solution is measured by liquid chromatography, and the result shows that the cumulative release rate of the first 3d reaches 15.6% +/-0.9%, the cumulative release rate of the 23d reaches 56.1% +/-1.9%, and the experimental result is shown in figure 7, wherein the release rate of the micro-needle in three weeks is more than.
The levonorgestrel of this example can be substituted with other active ingredients to achieve similar sustained release effects. Wherein the temperature of the heating stage in step 3 can be controlled to 70 deg.C or lower.
Example 4 preparation of an implantable two-stage microneedle patch with a needle tip containing a porogen
1. The lower integrated susceptor molding liquid was the same as in example 3.
2. Preparing 10% and 30% solutions of trehalose and PLGA (50/50) respectively by using N-methylpyrrolidone as a solvent; preparing 100mg/mL levonorgestrel solution by using N-methylpyrrolidone as a solvent; 0.5mL of the levonorgestrel solution and 0.5mL of the solution containing 10% and 30% of trehalose and PLGA (50/50) are uniformly mixed to prepare a 15% PLGA solution containing levonorgestrel (50mg/mL) and trehalose (25mg/mL) as an upper-section needle point injection molding solution.
3. The manufacturing method of the lower integrated base and the upper needle point and the splicing method of the two-segment microneedle are the same as those in the embodiment 3.
4. Skin puncture tests are carried out on the prepared microneedle patch according to the method in the embodiment 2, and it is found that when the microneedle is detached after being attached for 5min, the needle point 90% is implanted into the skin, and the lower integrated base is also dissolved, namely, the microneedle patch can be attached for 5min to separate the upper needle point from the lower integrated base.
5. And (3) testing the drug loading capacity: the test method was the same as in example 3. In the experiment, 6 tablets are tested in parallel, and finally, the drug loading of each tablet is 57 +/-3.4 mu g.
6. In vitro release experiments: the micro-needle is placed in a dialysis bag and sealed, 40% PEG-PBS (pH: 7.4) is selected as a receiving solution, sampling is carried out once every 12 hours, sampling mode is fully carried out, the same amount of the receiving solution is replaced, the concentration of the released drug in the receiving solution is measured by liquid chromatography, the result shows that the cumulative release rate of the first 3d reaches 44.1% +/-1.0%, the cumulative release rate of the 8d reaches 92.2% +/-1.1%, and the experimental result is shown in figure 8. Examples 3 and 4 the experimental results are shown in figure 9. The addition of the porogen can shorten the release time to 6 days.
The active ingredients of this example may also be substituted with other active ingredients. The heating temperature of the active component with poor heat resistance can be controlled below 70 ℃.
Examples 5 to 9:
the preparation is as in example 1, with the parameters for the components of examples 5 to 9 being shown in Table 1.
Table 1: the proportion of each component and the process parameters
It should be noted that the lower one-piece susceptor in the above embodiments corresponds to more than one embodiment, and may be combined with the upper one-piece susceptor in other embodiments, wherein the separation time of the tip and the susceptor is determined by the composition of the lower one-piece susceptor, and the heating temperature and the splicing temperature of the tip are determined by the substrate of the tip.
Examples 10 to 15:
the preparation is as in example 1, with the parameters for the components of examples 10 to 15 being shown in Table 2.
Table 2: the proportion of each component and the process parameters
Examples 10-15 are also applicable to the preparation of microneedle patches for other small molecule drugs or active ingredients.
Examples 16 to 21:
the preparation is as in example 1, with the parameters for the components of examples 16 to 21 being shown in Table 3.
Table 3: the proportion of each component and the process parameters
Examples 16-21 are also applicable to the preparation of other biomacromolecule drugs or vaccine microneedle patches.
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. An implantable two-section type microneedle is characterized by comprising an upper section needle point and a lower section integrated base; the upper section of the needle tip is formed by a biodegradable water-insoluble high polymer material matrix; the lower integrated susceptor is formed of a matrix comprising a water-soluble polymer material.
2. The implantable sustained-release microneedle according to claim 1, wherein the upper-stage 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 implantable two-segment microneedle according to claim 1, wherein the biodegradable water-insoluble polymer material is one or more of polyanhydride, polyorthoester, polyphosphoester, aliphatic polyester and derivatives thereof.
4. The implantable two-segment microneedle according to claim 1, wherein the upper segment needle tip further comprises a porogen; wherein the pore-forming agent is one or more of sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, polymethyl pyrrolidone, hyaluronic acid and sodium salt thereof, cellulose derivatives, trehalose, maltose and cyclodextrin; preferably, the pore-foaming agent accounts for 0.1-20% of the total mass of the upper section of the needle tip; more preferably, the upper-section 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 less than or equal to 20% of the total mass of the needle tip at the upper section.
5. The implantable two-stage microneedle according to claim 1, wherein the water-soluble polymer material is one or more selected from carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, chitosan and its derivatives, polyvinyl alcohol and its derivatives, polyvinylpyrrolidone and its derivatives, hyaluronic acid and its derivatives, chondroitin sulfate, dextran and its derivatives, sodium alginate, poly-gamma-glutamic acid, pullulan, gelatin, polydopamine, polyacrylic acid or polyacrylamide; preferably, the molecular weight is 10-1000 kDa.
6. The implantable two-segment microneedle according to claim 1, wherein the microneedle body is conical or polygonal-conical.
7. The implantable two-segment microneedle according to claim 1, wherein the upper segment needle tip height is less than or equal to two-thirds of the overall microneedle height; the diameter or the side length of the edge of the bottom of the upper section needle point is more than or equal to the diameter or the side length of the joint of the lower section integrated base and the upper section needle point; the overlapping height of the upper section needle point and the lower section integrated base is more than or equal to one half of the height of the upper section needle point; the angle between the upper section needle point and the lower section integrated base upper needle body is 10-90 degrees.
8. A method of preparing an implantable two-segment 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 an upper-section 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 upper-section needle point matrix material solution to obtain upper-section needle point injection molding liquid;
alternatively, the first and second electrodes may be,
mixing a biodegradable water-insoluble high polymer material with an organic solvent, adding or not adding a pore-foaming agent, adding or not adding a protective agent, adding an active ingredient, and uniformly mixing to obtain an upper-section needle point injection molding liquid;
mixing a water-soluble high polymer material with water to obtain lower-section integrated base injection molding liquid;
injecting the lower-section integrated base injection molding liquid into a microneedle mould, vacuumizing, drying, and demolding to prepare a lower-section integrated base; adding the injection molding liquid of the upper-section needle point into a microneedle mould, vacuumizing, heating, and removing an organic solvent to obtain an upper-section needle point; and aligning the lower-section integrated base with the upper-section needle point for splicing, cooling, demolding and forming the needle.
9. An implantable two-stage microneedle patch comprising a microneedle array comprising the implantable two-stage microneedles according to any one of claims 1 to 7 and a backing.
10. The implantable two-stage 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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