CN113827723A - Parkinson disease micro-needle patch based on L-DOPA space-time controllable drug delivery strategy and preparation method - Google Patents
Parkinson disease micro-needle patch based on L-DOPA space-time controllable drug delivery strategy and preparation method Download PDFInfo
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- CN113827723A CN113827723A CN202111037294.1A CN202111037294A CN113827723A CN 113827723 A CN113827723 A CN 113827723A CN 202111037294 A CN202111037294 A CN 202111037294A CN 113827723 A CN113827723 A CN 113827723A
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- 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
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- 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
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- 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
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Abstract
The invention relates to a Parkinson disease microneedle patch based on an L-DOPA space-time controllable drug delivery strategy, which comprises a backing and a drug-carrying microneedle array attached to one side surface of the backing, wherein the drug-carrying microneedle array comprises a plurality of microneedles, each microneedle comprises a large number of up-conversion microrods coated by mesoporous silica, common drugs for treating Parkinson are loaded in the mesopores, and an azo compound is used as a hole sealing agent. Microneedle patch was applied to the skin using 1.56W/cm2After irradiation with near infrared light (980nm), both ultraviolet and visible light are emitted. Photons can be absorbed by photoresponsive azo molecules in mesoporous silica on the surface of UCMRs, and then reversible photoisomerization is immediately carried out, so that continuous rotation-reversal movement of azo is caused, and the controlled release of levodopa from the microneedle is triggered. Under the same administration condition, the drug has higher blood drug concentration and brain drug concentration, and has sensitive light-controlled drug release characteristic, and the drug concentration can be controlled in a proper range.
Description
Technical Field
The invention relates to the field of microneedle patches, in particular to a Parkinson microneedle patch based on an L-DOPA space-time controllable drug delivery strategy and a preparation method thereof. A light-controlled drug-loaded microneedle patch article comprising a microneedle patch and capable of treating parkinson's disease by controlling the release dose of L-DOPA from the microneedle patch. The invention also relates to a method for preparing the light-operated drug-loaded microneedle patch product and application of the light-operated drug-loaded microneedle patch product to treatment of Parkinson's disease.
Background
Parkinson's Disease (PD) is a common degenerative disease of the central nervous system in the elderly. Common symptoms are tremor, stiffness and slowness of movement. Currently, oral administration of L-DOPA is one of the most commonly used drugs for the treatment of Parkinson's disease. Although this approach is very effective in ameliorating parkinson's symptoms, it can lead to choking as patients often have serious motor problems, even swallowing difficulties, which can lead to the drug getting stuck in the throat or entering the lungs. Even if the medicine is taken successfully, the medicine needs to stay in the digestive tract for several hours before entering blood, which brings many adverse factors to the treatment of nerve-related diseases with quick onset, strong damage and great harm to the body, and brings many sequelae to patients. In addition, most parkinson's drugs have gastrointestinal side effects such as nausea, vomiting, abdominal distension, and loss of appetite. Many drugs are easily damaged by corrosive gastric acid, gastric juice, intestinal juice, etc. In addition, the presence of a large number of microorganisms in the gastrointestinal tract can degrade many drugs or stimulate the host to reduce drug absorption. Therefore, there is a need to develop a more convenient and rapid drug administration method for non-oral administration, which can reduce the side effects on the digestive system, avoid the decomposition of the digestive juice, and improve the utilization rate of the drug. Transdermal patch therapy, a typical non-oral administration method, has received much attention and use because it effectively avoids the disadvantages of poor taste, irritation to the digestive system, and destruction of digestive juices or intestinal microorganisms. Here, we developed a microneedle patch that can precisely release a drug in a controlled time and space, triggered by near infrared light, for treating parkinson's disease.
The microneedle takes methacrylate gelatin (methacrylate gelatin) as a matrix, and the therapeutic drug (L-DOPA) is stored in the mesopores of the upconversion micro rod (UCMRs) and dispersed in the methacrylate gelatin. The molecular motor acts as a pore blocker and gate switch and isomerizes under the excitation of UCMRs ultraviolet and visible light to control drug release. The microneedle patch penetrates the epidermis in a painless, non-invasive, and infection-free manner. At 1.56W/cm2Under near infrared (980nm) radiation, UCMRs emit ultraviolet and visible light. After the photons are absorbed by azo molecules in mesoporous silica on the surface of UCMRs, reversible photoisomerization is immediately carried out, so that the azo molecules continuously rotate and reversely move. Oscillation of the azo molecule results in controlled release of L-DOPA from the microneedles. The L-DOPA in the microneedles will be released as needed and then penetrate into the blood and brain, relieving the symptoms of PD. In thatThis protocol significantly restored motor function in the treatment of the parkinson mouse model, and further mechanistic studies showed that it reduced neuroinflammation and the death of nigral dopaminergic neurons. The released L-DOPA directly enters the blood, thereby reducing the side effect on the gastrointestinal tract and improving the utilization rate of the medicament. These advantages suggest that microneedle patch-controlled drug delivery systems may be candidate strategies for treating parkinson's disease and may be applied in relevant biomedical fields.
The microneedle drug delivery is a novel local transdermal drug delivery technology, combines the convenience of emplastrum and the effectiveness of subcutaneous injection drug delivery, avoids the defects of other drug delivery modes, and has the advantages of no contact with nerves, safety, no pain, high-efficiency permeation and the like.
Microneedle articles typically comprise a plurality of microneedles, typically no more than about 1mm in length, which are capable of forming microchannels in the stratum corneum, breaking through the barrier of the stratum corneum, and promoting drug penetration, thereby reducing the amount of drug accumulated in the stratum corneum and increasing the amount of drug delivered to the epidermis, dermis, and subcutaneous tissues. Therefore, the microneedle product is widely applied to promoting the transdermal absorption of micromolecular and macromolecular drugs, is used for treating obesity, diabetes, cancer, neurological diseases and other diseases, and has wide application prospect. In addition, the microneedle product is extremely convenient to use, does not need professional training, can be automatically administrated by patients, has low accidental needle stick injury risk and is easy to treat after use.
However, no document in the prior art discloses that the light-operated drug-loaded treatment of the Parkinson disease is combined with a microneedle technology, a microneedle patch system with the light-operated drug release rate is realized, the use efficiency of the Parkinson treatment drug is improved, and the treatment effect is enhanced.
Disclosure of Invention
The invention aims to provide a microneedle patch drug delivery product which has rapid onset, is not oral and can control the drug release rate by fully utilizing the advantages of microneedle patch technology and the advantages of light-operated time-space drug delivery, and can release a therapeutic drug L-DOPA loaded in a microneedle mesoporous according to the requirement through light control, so that the novel microneedle drug delivery system can have higher blood concentration and brain drug concentration under the same drug delivery condition, has sensitive light-operated drug release characteristics and can control the drug concentration in a proper range.
In order to solve the technical problem, the invention provides the following technical scheme: the Parkinson disease microneedle patch based on the L-DOPA space-time controllable drug delivery strategy comprises a backing and a light-controlled drug-loaded microneedle array attached to one side of the backing, wherein the light-controlled drug-loaded microneedle array comprises a plurality of microneedles, and the microneedles adopt methacrylate gelatin and a photoinitiator HMPP mixed as main materials. Wherein each microneedle comprises a large number of conversion micrometer rods on the mesoporous silica coating, L-DOPA is loaded in the mesopores, and azo is used as a pore sealing agent. The photo-responsive azo molecules in the mesoporous silica can undergo reversible photo-isomerization under the condition of absorbing photons, so that azo is continuously rotated and reversely moved, and the controlled release of L-DOPA from the micro-needle is triggered.
Furthermore, the up-conversion micron rod can emit blue light and ultraviolet light under the excitation of near infrared, and due to the impeller type rotation process of azo, the drug is loaded on the up-conversion micron rod, so that the drug release can be excited by infrared light, and the purpose of time-space control of the drug release is achieved.
Further wherein the matrix is formed by cross-linking and/or dry curing an aqueous solution comprising one or more of the following: polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinylpyrrolidone and polyvinyl alcohol, preferably methacrylate gelatin and/or hyaluronic acid, more preferably methacrylate gelatin.
Further wherein the backing is formed by cross-linking and/or dry curing an aqueous solution comprising one or more of the following: polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinylpyrrolidone and polyvinyl alcohol, preferably polyvinyl alcohol.
Further wherein each microneedle has a tip and a base, the tip being distal from the backing, the microneedle being attached to the backing via the base, the tip to base distance being from about 200 μm to about 1mm, the base having a base diameter of from about 100 μm to about 500 μm, and the spacing between adjacent microneedle tip ends being from about 300 μm to about 800 μm.
The second technical scheme of the present invention is a method for preparing the microneedle patch preparation, which comprises the steps of:
(1) and preparing the up-conversion micron rod, wherein the up-conversion micron rod can emit blue light and ultraviolet light under infrared excitation. Synthesis of lanthanide-substituted NaYF4: tm and Yb UCMRs successfully modify mesoporous silica by utilizing tetraethoxysilane and hexadecyl trimethyl ammonium bromide, azobenzene (azo) can be successfully modified in mesopores, and the materials are prepared into UCMRs @ mSiO2-azo. The prepared UCMRs @ mSiO2-azo and therapeutic drug (L-DOPA) were stirred at room temperature for 24h to give UCMRs @ mSiO2-azo-L-DOPA. Under near infrared light, the ultraviolet lamp emits ultraviolet light and visible light. Under ultraviolet light and visible light, trans-and cis-isomers of azo compounds can be reversibly converted into each other;
(2) the main material of the matrix is prepared, methacrylate gelatin is prepared and mixed with photoinitiator HMPP to be used as the main material of the matrix, and the content of the methacrylate gelatin in the tip material of the microneedle patch has important influence on the mechanical strength and permeability of the microneedle patch. The mechanical strength of the microneedle patches containing 10%, 15%, 20%, 25% and 30% methacrylate gelatin was tested, and it was found that the microneedle patches containing 30% methacrylate gelatin had the best mechanical strength. Addition of UCMRs @ mSiO2-azo-L-DOPA had little effect on the mechanical strength of the microneedle patch, and UCMRs @ mSiO prepared in (1)2-azo-L-DOPA and methacrylate gelatin and photoinitiator HMPP;
(3) providing a microneedle mould comprising an upper surface and a shaped aperture extending downwardly from the upper surface, wherein the shaped aperture has a tip end distal from the upper surface and a base end planar flush with the upper surface, the tip end to base end distance is preferably from about 200 μm to about 1mm, the base end preferably has a base end diameter of from about 100 μm to about 500 μm, and the spacing between adjacent tip ends is preferably from about 300 μm to about 800 μm;
(4) placing the mixed solution obtained from step (2) in the molding hole and filling at least a portion of the molding hole volume, preferably filling the molding hole;
(5) allowing said near-IR triggered anti-Parkinsonian drug delivery System UCMRs @ mSiO comprising said matrix material in said shaped wells2-azo-L-DOPA, and curing under an ultraviolet lamp for 12s after removing excessive materials, thereby forming the microneedles in the molding hole, wherein a plurality of the microneedles form the light-controlled drug-loaded microneedle array, each microneedle has a tip end and a bottom end, and the tip end of the microneedle is far away from the upper surface relative to the bottom end of the microneedle;
(6) applying a solution comprising a backing material, preferably selected from the group consisting of polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinylpyrrolidone, polyvinyl alcohol, or a mixture of two or more thereof, preferably polyvinyl alcohol, on the bottom end surface of the microneedles and the upper surface of the microneedle mould not covered by the microneedles to form a layer of backing solution, and optionally cross-linking the backing material to form a continuous backing layer, thereby attaching the light-controlled drug-loaded microneedle patch array to the layer of backing solution or the backing layer;
(7) and (3) covering the microneedle patch with the backing solution layer or the backing layer obtained in the step (6) as a lining material, drying at 50 ℃ for 12 hours, and finally demolding to obtain the complete microneedle patch.
Further, use of the microneedle patch preparation for alleviating and/or treating symptoms of parkinson's disease in an animal body.
Use of a light-controlled drug-loaded microneedle patch article for a medical device for alleviating and/or treating symptoms of parkinson's disease in an animal.
Technical effects achieved by the invention
The invention realizes the aim of the invention through each technical scheme, namely the invention fully utilizes the advantages of the micro-needle patch and the advantages of photoinduced administration, and provides a micro-needle patch product for treating the Parkinson disease by the light-operated administration. After near-infrared irradiation, azo molecules in the mesoporous silica absorb ultraviolet visible light emitted by the upconversion micrometer rod, reversible photoisomerization is immediately carried out, and the azo molecules continuously rotate and reversely move. Oscillation of the azo molecule results in controlled release of L-DOPA from the microneedles. The microneedle patch product can realize high-efficiency transdermal absorption of drugs after being applied to the skin, has higher blood drug concentration and brain drug concentration under the same administration condition, has sensitive light-operated drug release characteristics, can control the drug concentration in a proper range, and overcomes the defects of more side effects, poor absorption and the like of the traditional administration mode. Importantly, treatment with the new microneedle system significantly restored motor function in the treatment of the parkinson mouse model, and further mechanistic studies showed that it reduced neuroinflammation and dopaminergic neuronal death in the substantia nigra. In addition, the released levodopa directly enters blood, so that the side effect on gastrointestinal tracts is reduced, and the utilization rate of the medicine is improved. In addition, the obtained microneedle patch delivery system also shows good biocompatibility, showing good potential in the field of transformation medicine.
In particular, the advantages of the invention are:
(1) the L-DOPA released by the light-operated microneedle patch product is a common medicament for treating the Parkinson's disease, and the microneedle patch mode can avoid nausea, vomiting, abdominal distension and inappetence caused by the intestinal side effect of the medicament when the medicament is orally taken, and can also avoid the damage of gastric acid, gastric juice, intestinal juice and intestinal microorganisms to the medicament.
(2) The light-operated drug-loaded microneedle patch product can puncture the stratum corneum which limits drug absorption, and can penetrate the stratum corneum and epidermis without pain and infection to deliver drugs in a minimally invasive way, thereby greatly improving the drug absorption efficiency.
(3) The light-operated drug-loaded microneedle patch product can stimulate the release of drugs by using near infrared light, thereby achieving the control of the drug concentration, effectively improving the utilization rate and the treatment effect of the drugs and reducing the toxic and side effects.
(4) The light-operated drug-loaded microneedle patch product utilizes infrared light to excite the up-conversion material to release ultraviolet light and visible light, so that azo is isomerized in cis. The damage of direct ultraviolet light to biological tissues such as skin and the oxidation and damage of high-energy ultraviolet light to drug molecules are eliminated.
(5) The method for preparing the microneedle array by using the microneedle template reverse mould is simple, convenient to operate, low in price, reusable, free of high technical requirements, easy to control the basic appearance of the microneedle array, high in safety and suitable for popularization.
Drawings
In order to more clearly illustrate the present invention, the following description and drawings of the present invention will be described and illustrated.
It should be apparent that the drawings in the following description illustrate only certain aspects of some exemplary embodiments of the invention, and that other drawings may be derived therefrom by those skilled in the art without the exercise of inventive faculty. It should be noted that the drawings of the present specification are only schematic, and the sizes and the size ratios of the components depicted therein do not represent actual sizes and ratios of products, but are only for schematically representing the positional relationships or the connection relationships between the components. Dimensions of components may be scaled differently for ease of drawing and understanding. Further, the same or similar reference numerals denote the same or similar members.
Fig. 1 is a side view schematically illustrating a portion of a light-medicated microneedle patch article of the present invention.
Fig. 2 is a side view schematically illustrating a portion of a microneedle mold used to make a light-loaded microneedle patch article of the present invention.
FIG. 3 is a schematic diagram of an experimental apparatus of a modified Franz diffusion cell and a schematic diagram of the disassembled transdermal device.
Description of the reference numerals
100 light-operated microneedle patch made of 110 microneedle 120 backing
200 micro-needle mould 201 forming hole 202 upper surface
Detailed Description
Hereinafter, the present invention will be described in detail with reference to the accompanying drawings.
In a first aspect, the present disclosure is directed to a light-controlled drug-loaded microneedle patch article 100. As shown in fig. 1 of the specification, the drug-loaded microneedle patch product 100 of the present invention includes a backing 120 and a drug-loaded microneedle array attached to one side of the backing 120, where the drug-loaded microneedle array includes a plurality of microneedles 110, each microneedle 110 includes a substrate and an up-conversion nanorod drug delivery system loaded in the substrate, and the up-conversion nanorod drug delivery system can emit blue light and ultraviolet light under the excitation of near infrared light, so that azo compounds therein are subjected to trans-cis isomer conversion, and the purpose of exciting and releasing drugs by infrared light is achieved.
In the photo controlled drug-loaded microneedle patch product 100 of the present invention as described above, the drug L-DOPA, which is one of the main drugs for treating parkinson's disease, can pass through the blood brain barrier and thus enter the central nervous system, be converted into dopamine, activate dopamine receptors, thereby improving the function of the motor control center in the brain, and alleviating and treating parkinson's disease.
In the light-controlled drug-loaded microneedle patch product 100 of the present invention, the up-conversion nanorod drug delivery system needs to achieve a light-controlled drug delivery effect, so that photosensitive molecules are selected to achieve the light-controlled drug delivery effect. Among a plurality of photosensitive molecules, azobenzene as a cis-trans isomer can be very quickly switched between cis-trans structures, and has an outstanding effect in controlled release of drugs. However, azo cis-isomerization often requires UV light and mayThe excitation of light can only occur, and the direct ultraviolet irradiation can cause certain damage to biological tissues such as skin, and in addition, the high-energy ultraviolet light can also cause the oxidation or structural damage of drug molecules containing unsaturated double bonds. And contains Tm3+、Yb3+The upconverter material of (a) has the property of converting biocompatible near infrared light into localized ultraviolet and visible light. The up-conversion material uses lanthanide substituted NaYF4Tm, Yb UCMRs. The mesoporous silicon dioxide is successfully modified by utilizing tetraethoxysilane and hexadecyl trimethyl ammonium bromide, and azobenzene can be successfully modified in the mesopores. Preparing the materials into UCMRs @ mSiO2-azo。
The upconversion nanorod delivery system is formed by preparing UCMRs @ mSiO in the microneedle 1102-azo and therapeutic drug (L-DOPA) were stirred at room temperature for 24h, thus obtaining UCMRs @ mSiO2azo-L-DOPA, this being the upconversion microrod delivery system described above.
In addition, in the photo-controlled drug-loaded microneedle patch product 100 of the present invention as described above, the content of the therapeutic drug (L-DOPA) in the microneedles 110 is not particularly limited as long as it can release a sufficient concentration during a treatment period, and the content can be adjusted for different degrees of progression and symptoms of parkinson's disease.
In the light-controlled drug-loaded microneedle patch product 100 of the present invention as described above, the base material in which the matrix is formed is not particularly limited as long as the base material commonly used in the art for preparing microneedle products can be used in the present invention.
However, considering that the microneedles 110 formed in the case of the present invention need to have a certain mechanical strength and that the microneedles 110 after curing also preferably need to have a certain porosity, the matrix is preferably formed by crosslinking and/or drying an aqueous solution containing one or more of the following: polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinylpyrrolidone and polyvinyl alcohol, preferably methacrylate gelatin and/or hyaluronic acid, more preferably methacrylate gelatin.
Here, the matrix is preferably selected from methacrylate gelatin and/or hyaluronic acid. Methacrylate Gelatin is prepared from Methacrylic Anhydride (MA) and Gelatin (Gelatin), wherein they are crosslinked by ultraviolet irradiation under the mediation of a photosensitizer to form a porous structure with certain intensity. Methacrylate gelatin has excellent biocompatibility. Hyaluronic acid is a mucopolysaccharide, has skin protecting effect, and can be used for accelerating wound healing.
In the light-controlled drug-loaded microneedle patch article 100 of the present invention as described above, the backing material in which the backing 120 is formed is not particularly limited as long as a backing material commonly used in the art for preparing microneedles can be used in the present invention.
However, in the present invention, in view of the need for the formed backing 120 to have a certain mechanical strength and flexibility, the backing 120 is preferably formed by crosslinking and/or drying an aqueous solution containing one or more of the following: polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinylpyrrolidone and polyvinyl alcohol, preferably polyvinyl alcohol.
Here, the thickness of the formed backing 120 is not limited, but in view of a certain strength and flexibility of the backing 120, the thickness of the backing 120 is preferably about 0.1 to about 15mm, more preferably 1 to 10mm, and most preferably 2 to 3 mm.
In addition, it is preferred that in some cases, in the light-controlled drug-loaded microneedle patch article 100 of the present invention, the material forming the matrix and the backing 120 is the same. In these cases, the microneedle 110 and backing 120 are more firmly bonded, and in the method of manufacturing the light control drug-loaded microneedle patch microneedle article 100 as described below, the microneedle array and the backing 120 may be integrally formed, simplifying the manufacturing process.
Alternatively, in other cases, the material of the matrix and the backing 120 are preferably different, for example, the matrix material is methacrylate gelatin and the backing material is polyvinyl alcohol. In this case, the microneedles 110 have a certain strength and a porous structure and excellent biocompatibility, and the backing 120 has a better protective effect on the skin, reducing the possibility of skin infection and inflammation.
It is to be noted that it is well within the ability of the person skilled in the art to make a suitable choice of the base material and the backing material depending on the desired application.
In addition, in the light control drug-loaded microneedle patch product 100 of the present invention, the size and shape of the microneedles 110 are not particularly limited and may be varied within a wide range according to the site to which the light control drug-loaded microneedle patch product 100 of the present invention is applied.
For example, as shown in fig. 1 of the specification, in the light control drug-loaded microneedle patch product 100 of the present invention, each microneedle 110 has a tip end and a base end, the tip end is far away from the backing 120, the microneedle 110 is attached to the backing 120 via the base end, and the height h from the tip end to the base end is not particularly limited, but is preferably 200 μm to 1 mm. The height h is preferably not less than 200 μm, otherwise the microneedles 110 are not easily penetrated through the stratum corneum of the skin of some animal bodies, preferably some parts of the human body. However, said height h is also preferably not higher than 1mm, otherwise it may penetrate the stratum corneum of the skin of some animal bodies, preferably of some parts of the human body, to reach the nerve layer, causing pain.
In addition, as shown in fig. 1 of the specification, in the light control drug-loaded microneedle patch product 100 of the present invention, the base end of the microneedle 110 preferably has a base end diameter w of 100 μm to 500 μm. The base diameter w is preferably not less than 100 μm, otherwise the microneedles 110 may have insufficient mechanical strength and may be easily broken. In addition, the base end diameter w is also preferably no greater than 500 μm, which would otherwise leave a large hole in the skin after the light-controlled drug-loaded microneedle patch product 100 of the present invention is applied to some portion of an animal body, preferably a human body, resulting in problems with skin aesthetics and healing.
In addition, in the light control drug-loaded microneedle patch article 100 of the present invention, the stereoscopic shape of the microneedles 110 is not particularly limited, and may be a cylinder, a cone, a truncated cone, or the like, or a combination thereof, preferably a regular or irregular cone, a cone-like, a triangular pyramid, a rectangular pyramid, or a higher pyramid, and these cones, cone-like, triangular pyramids, rectangular pyramids, or higher pyramids may be regular pyramids or oblique pyramids.
In addition, as shown in fig. 1, in the light-controlled drug-loaded microneedle patch product 100 of the present invention, the distance d between the tips of the neighboring microneedles 110 is preferably 300 μm to 800 μm. Within this range, the light-controlled drug-loaded microneedle patch product 100 of the present invention can achieve optimal penetration depth into stratum corneum and drug delivery efficiency.
It should be noted that it is within the ability of those skilled in the art to select the shape, size, etc. of the microneedles 110 of the light-controlled drug-loaded microneedle patch product 100 according to the practical application.
In addition, in practical applications, the microneedles 110 in the photo-controlled drug-loaded microneedle patch product 100 of the present invention may be the same or different from each other in size, shape, and composition. Here, the differences between the plurality of microneedles 110 may be various, including but not limited to shape, height h, bottom surface diameter w, tip distance d, included matrix material, upconversion microrod drug delivery system, and the like. For example, in the light control drug-loaded microneedle patch article 100 of the present invention, a portion of the microneedles 110 may have a higher content of L-DOPA, and another portion of the microneedles 110 may have a lower content of L-DOPA. Alternatively, the microneedles 110 may have regularly periodically varying volumes at intervals. In these cases, the applicability of the light-loaded microneedle patch article 100 of the present invention to mitigate and/or treat various degrees of progression of parkinson's disease can be broadened.
In addition, as will be readily understood by those skilled in the art, in the microneedle 110 and/or the backing 120 in the light control drug-loaded microneedle patch article 100 of the present invention, other auxiliary agents known in the art, including but not limited to, a forming agent, a preservative, a photoinitiator (photosensitizing mediator), and the like, such as 2, 4-dihydroxybenzophenone, diphenylethanone, and the like, may be included as needed, in addition to the ingredients explicitly described above. The amount of the other adjuvant preferably does not exceed about 10 wt%, more preferably about 5 wt%, and most preferably does not exceed about 1 wt% of the weight of the matrix of the microneedles 110 and/or the backing 120.
In a second aspect of the invention, the invention also relates to a method of making a light-controlled drug-loaded microneedle patch article 100 according to the invention as described above, comprising the following steps 1-7.
Step 1: preparation of upconversion micrometer rod drug delivery system, synthesis of lanthanide substituted NaYF4Preparing UCMRs @ mSiO by using Tm and Yb UCMRs and azo and mesoporous silica2-azo. The prepared UCMRs @ mSiO2-azo and therapeutic drug (L-DOPA) were stirred at room temperature for 24h to give UCMRs @ mSiO2–azo-L-DOPA。
In the above step 1, the azo compound may be one in which cis-trans isomer interconversion can be performed by light control, which is well known in the art. It is within the ability of one skilled in the art to conveniently determine the type of upconversion nanorod delivery system based on the azo compound selected.
In the solution containing the upconversion nanorod delivery system, the content of the therapeutic drug (L-DOPA) is not particularly limited as long as it is matched with the amount of the base material used in the following step 2 such that its content in the final microneedle article 100 meets the range defined above.
In addition, as described above with respect to the portion of the light-controlled drug-loaded microneedle patch product 100 of the present invention, the therapeutic drug L-DOPA is one of the major drugs for treating parkinson's disease, which can pass through the blood-brain barrier to enter the central nervous system, be converted into dopamine, activate dopamine receptors, thereby improving the function of the motor control center in the brain, and alleviating and treating parkinson's disease.
Step 2: adding a base material capable of forming the matrix and a photoinitiator to the upconversion nanorod administration system obtained in the step 1 to form a mixed solution.
In the above step 2, the concentration of the matrix material in the mixed solution is not particularly limited as long as the amount thereof can ensure the formation of the microneedles 110 in the final microneedle article 100 of the present invention. Preferably, however, the matrix material is present in the solution in an amount of about 20 wt.% to about 40 wt.%, preferably about 25 wt.% to about 35 wt.%, more preferably about 30 wt.%. Within this range, the microneedles 110 formed of the base material have both sufficient mechanical strength and a certain porosity, thereby enabling optimal drug release efficiency.
In addition, as described above with respect to the portion of the light loaded microneedle patch article 100 of the present invention, the matrix material is preferably selected from polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinylpyrrolidone, polyvinyl alcohol, or a mixture of two or more thereof, more preferably methacrylate gelatin and/or hyaluronic acid, most preferably methacrylate gelatin.
And step 3: providing a microneedle mould 200, as shown in fig. 2 of the specification, wherein the microneedle mould 200 comprises an upper surface 202 and a moulding hole 201 extending downwards from the upper surface 202, wherein the moulding hole 201 has a tip end and a bottom end, the tip end is far away from the upper surface 202, and the plane of the bottom end is flush with the upper surface 202.
In the above step 3, in the microneedle mold 200, the three-dimensional shape of the molding hole 201 is matched with the shape of the microneedle 110 desired to be formed. As mentioned above, it may be cylindrical, conical, truncated cone, etc. or a combination thereof, preferably regular or irregular conical, cone-like, triangular pyramid, rectangular pyramid or higher pyramid, etc., and these cones, cone-like, triangular pyramid, rectangular pyramid or higher pyramids may be regular pyramids or oblique pyramids.
The molding holes 201 should have a height h, a bottom width w, and a tip interval d of the molding holes 201 corresponding to the height h, the bottom width w, and the tip interval d of the microneedles 110. However, in some cases, the molding hole 201 may also have a height h and a bottom surface width w of the molding hole 201 greater than the height h and the bottom surface width w of the microneedle 110. In the latter case, the microneedles 110 are formed not to fill the molding holes 201.
Optionally, the upper surface 202 of the microneedle mould 200 (which comprises the inner surface of the molding aperture 201) may be coated with an anti-adhesive layer.
In the present invention, the microneedle mould 200 is commercially available, for example it may be a custom PDMS mould commercially available from taizhou mini-core pharmaceutical technology corporation, the mould parameters being customizable as required by the needle body dimensions as described above. Specifically, in the microneedle mold 200 used in the embodiment of the present invention, the height h of all the molding holes 201 is about 600 μm, the bottom surface width w is about 320 μm, and the tip pitch d is about 500 μm, and the microneedle mold 200 has an overall length × width of about 15mm × about 15 mm.
And 4, step 4: placing the mixed solution obtained from step 2 in the molding hole 201 and filling at least a part of the volume of the molding hole 201.
In the above step 4, the volume amount of the mixed solution filling the molding holes 201 is not particularly limited, but it is preferable to fill at least about 1/4, at least about 1/3, at least about 1/2, at least about 2/3, at least about 3/4, and most preferably to fill the molding holes 201, of the volume amount of the molding holes 201. Without filling the molding holes 201, the portions of the molding holes 201 volume not filled by the microneedles 110 should be filled with the backing material solution in the following step 6.
And 5: and (2) crosslinking and/or drying and curing the mixed solution containing the matrix material and the up-conversion micron rod drug delivery system in the molding hole 201, so that the microneedles 110 are formed in the molding hole 201, and the plurality of microneedles 110 form the light-controlled drug-loaded microneedle array.
In the step 5, the crosslinking can be achieved by various means such as ultraviolet, heat, electron beam, radiation, and the like. The drying and curing can be achieved, for example, by natural drying or drying in an oven at a certain temperature. For example, one skilled in the art can determine that the crosslinking can be achieved by uv crosslinking in the presence of photosensitizing mediators well known in the art. The time for the uv crosslinking is preferably less than about 20 seconds, preferably from about 5 seconds to about 15 seconds, more preferably about 10 seconds; the oven drying is preferably at a temperature of less than about 50 ℃ for less than about 4 hours, preferably from about 1 hour to about 3 hours.
Step 6: a solution comprising a backing material is applied over the bottom end surface of the microneedles 110 and the upper surface 202 of the microneedle mould 200 not covered by the microneedles 110 to form a backing solution layer, whereby the light controlled drug loaded microneedle array is attached to the backing solution layer.
In step 6 above, the backing material is preferably selected from polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinylpyrrolidone, polyvinyl alcohol, or a mixture of two or more thereof, preferably polyvinyl alcohol, as described above with respect to the portion of the light-loaded microneedle patch article 100 of the present invention.
In step 6 above, the backing material is optionally crosslinked to form a continuous backing layer, such that the drug-loaded microneedle array is attached to the backing layer. Here, the crosslinking may be achieved by various means such as ultraviolet, heat, electron beam, radiation, and the like. For example, one skilled in the art can determine that the crosslinking can be achieved by uv crosslinking in the presence of photosensitizing mediators well known in the art. The time for the uv crosslinking is preferably less than about 20 seconds, preferably from about 5 seconds to about 15 seconds, more preferably about 12 seconds.
And 7: the light control drug loaded microneedle patch article 100 is formed by drying and curing the backing solution layer obtained from step 6 and optionally simultaneously drying and curing the microneedle array attached to the backing solution layer.
In step 7 above, the drying can be achieved, for example, by natural drying or, preferably, drying in an oven at a certain temperature. The oven drying is preferably at a temperature of less than about 50 ℃, for example at about 37 ℃ for less than about 4 hours, preferably from about 1 hour to about 3 hours. Exceeding the upper limit may cause degradation of the drug and decrease the drug efficacy.
In steps 6 and 7, as described above, the drying step preferably results in a water content in the microneedles 110 and the backing 120 of less than about 20 wt.%, preferably less than about 10 wt.%, and most preferably less than about 5 wt.%.
In the method of making the drug-loaded microneedle patch article 100 of the present invention as described above, the technical features described in the aspect of the drug-loaded microneedle patch article 100 of the present invention as described above and the preferred ranges thereof are still applicable here.
In a third aspect of the invention, the invention relates to the use of a light-medicated microneedle patch article 100 as described in the first aspect above or a light-medicated microneedle patch article 100 prepared according to the method of preparing the light-medicated microneedle patch article 100 as described in the second aspect above for alleviating and/or treating parkinson's disease in an animal body.
In a fourth aspect of the invention, the invention relates to the use of a light-medicated microneedle patch article 100 as described in the first aspect above or a light-medicated microneedle patch article 100 prepared according to the method of preparing the light-medicated microneedle patch article 100 as described in the second aspect above for the preparation of a medical device for the alleviation and/or treatment of parkinson's disease of an animal body.
In the above third and fourth aspects, the animal body is preferably a human body. The disease is Parkinson's disease.
Also in the third and fourth aspects described above, the technical features described in the light-operated drug-loaded microneedle patch article 100 of the present invention and the method for manufacturing the same, as described above, and the preferred ranges thereof, are still applicable here.
The materials and instruments used were as follows:
yttrium (III) chloride hexahydrate (YCl)3·6H2O), ytterbium chloride hexahydrate (YbCl)3·6H2O) and thulium (III) chloride hexahydrate (TmCl)3·6H2O): purchased from Shandong Jining Tianyi GmbH;
oleic acid (90%, technical grade), cetyltrimethylammonium bromide (CTAB), Tetraethylorthosilicate (TEOS), 4-benzoyl chloride and polyvinyl alcohol (PVA): purchased from Shanghai Aladdin Biotechnology Ltd;
ammonium fluoride (NH)4F, 99.99%) and Methacrylic Anhydride (MA) were purchased from michelin biochemical technologies, inc;
ethanol and acetic acid were purchased from Tianjin Yunli chemical Co., Ltd;
sodium hydroxide (NaOH) was purchased from tianjin jiang chemicals science and technology ltd;
3, 4 dihydroxy-L-phenylalanine (L-DOPA) was purchased from Michelle chemical technology, Inc., Shanghai;
dimethyl sulfoxide (DMSO), rhodamine B, MTT cell proliferation and cytotoxicity detection kits and anti-fluorescence quenching solid-sealed liquid (including DAPI) were purchased from Beijing Solebao technologies, Inc.;
the one-step TUNEL apoptosis detection kit and the dopaminergic neuron immunohistochemical kit are purchased from Shanghai Biyuntian biotechnology limited company;
gelatin (Gel): purchased from shanghai yan chemical technology, ltd;
methacrylate gelatin (methacrylate gelatin): self-made by crosslinking 94% methacrylate commercially available from Shanghai Merland Biotech Co., Ltd and gelatin having a gel strength of 250g commercially available from Shanghai Chamaecyparis pisifera Biotech Co., Ltd according to a conventional method in the art;
microneedle mould: length × width 15 × 15mm, height h of the right circular cone shaped hole: 600 μm, bottom width w: 320 μm, tip spacing d: 500 μm, commercially available from Taizhou micro core pharmaceutical science and technology;
HMPP (photosensitizing mediator): commercially available from Tianjin Xiansi Oppon technology, Inc.;
an ultraviolet curing instrument: commercially available from Shanghai Luyang instruments, Inc.;
ultraviolet spectrophotometer: evolution 220, commercially available from Thermo Scientific.
Preparation examples 1 to 6: the light-controlled drug-loaded microneedle patch preparations 1 to 6 of the present invention were prepared in the following general preparation procedure. The general preparation method comprises the following steps: (1) preparing an up-conversion micron rod drug delivery system; (2) adding a matrix material (methacrylate gelatin or HA) in an amount as shown in table 1 to the solution containing the upconversion nanorod delivery system obtained in step (1) to form a mixed solution: (3) providing the microneedle mould; (4) placing the mixed solution obtained in the step (2) into a molding hole of the microneedle mould and filling the molding hole with the mixed solution; (5) crosslinking the mixed solution containing the base material and the upconverting microrod drug delivery system solution in the molding hole under the conditions as shown in table 1, thereby forming the microneedles in the molding hole; (6) applying a solution comprising a backing material as shown in table 1 on the bottom end surface of the microneedles and the upper surface of the microneedle mould not covered by the microneedles to form a backing solution layer, and heat curing the backing material to form a continuous backing, thereby attaching the light control drug loaded microneedle array; (7) simultaneously heat-drying the backing obtained from step (6) and the microneedle array attached to one side of the backing under the conditions as shown in table 1 to a water content of less than 5 wt% to form the drug-loaded microneedle patch article. Preparation of control sample: the control sample was prepared using the same general procedure as described above.
Table 1: control sample and preparation of preparation examples 1 to 6
Evaluation of transdermal drug delivery efficiency examples
Control samples and samples of microneedle articles of preparation examples 1 to 6 were taken and sampled at 0.5, 1, 2,4, 8 and 12 hours, respectively, using excised pig skin as a permeation barrier. The test group was irradiated with near infrared light for 30s after each sampling, and the released content of L-DOPA was determined by high performance liquid chromatography. The schematic diagram of the experimental apparatus and the schematic diagram of the disassembled transdermal device of the modified Franz diffusion cell are shown in the attached picture 3 of the specification.
The specific operation steps are as follows: the pigskin is fixed in a Franz diffusion cell, the cuticle of the epidermis faces upwards, and the lower surface is in contact with the liquid surface of the diffusion cell. Putting 0.9% sodium chloride solution at 37 + -0.1 deg.C into a receiving tank, heating in water bath, stirring at constant speed of 300 + -5 r/min, and balancing for 1 hr. Groups used microneedle patches on pig skin. Thereafter, 1.0mL of the receiving solution was aspirated within 0.5, 1, 2,4, 8, and 12 hours, and 1.0mL of the stock receiving solution was replenished. The taken-out receiving solution is filtered by a 0.22 mu m microporous membrane, the content is measured, and the accumulated drug permeation amount and time regression at each time point are calculated. The slope obtained is the skin permeability and the measurements are shown in table 2.
Table 2: transdermal regression equation, skin penetration rate and percent increase for control samples and samples of microneedle articles of preparation examples 1 to 6
As can be seen from the data in table 2, the microneedle article of the present preparation example 6 has the best cumulative drug permeability. After 12h of the experiment, the preparation example 6 had higher drug permeability and lower drug retention than the other groups.
Examples of therapeutic effects
Establishing a mouse Parkinson model, applying the control sample and the microneedle product prepared in the embodiment 1 to 6 to a Parkinson mouse, and evaluating the effectiveness of the microneedle in relieving or treating the Parkinson symptom through animal behavior experiments, dopaminergic neuron vitality level, inflammatory factor level in brain tissues and the like.
Specific procedures can be found in the prior art documents Lishuai Feng et al, neutral-like Cell-Membrane-Coated Nanozyme Therapy for Ischemic Brain data and Long-Term Neurological Functional recovery. ACS NANO, 1 month 2021, DOI: 10.1021/acsano.0c07973.
The test results are shown in table 3.
Table 3: data on the effects of control samples and samples of microneedle articles of preparation examples 1 to 6 on the treatment of parkinsonian mice
As can be seen from the data in table 3, the hydrogen-producing biological microneedle preparations of the preparation examples 1 to 6 of the present invention all had excellent treatment and improvement effects on the parkinson's disease of mice. Wherein the hydrogen-producing biological microneedle preparation of example 6 was prepared with the best effect.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein, and any reference signs in the claims are not intended to be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art. These other embodiments are also covered by the scope of the present invention.
It should be understood that the above-mentioned embodiments are only for explaining the present invention, and the protection scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical scope of the present invention and the equivalent replacement or change of the technical solution and the inventive concept thereof in the technical scope of the present invention.
The use of the word "comprising" or "comprises" and the like in the present invention means that the element preceding the word covers the element listed after the word and does not exclude the possibility of also covering other elements. The terms "inner", "outer", "upper", "lower", and the like indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the referred devices or elements must have a specific orientation, be constructed and operated in a specific orientation, and thus are not to be construed as limiting the present invention, and when the absolute position of the described object is changed, the relative positional relationships may be changed accordingly. In the present invention, unless otherwise expressly stated or limited, the terms "attached" and the like are to be construed broadly, e.g., as meaning a fixed connection, a removable connection, or an integral part; either directly or indirectly through intervening media, either internally or in any other relationship. The specific meanings of the above terms in the present invention can be understood by those skilled in the art according to specific situations. The term "about" as used herein has the meaning well known to those skilled in the art, and preferably means that the term modifies a value within the range of ± 50%, ± 40%, ± 30%, ± 20%, ± 10%, ± 5% or ± 1% thereof.
All terms (including technical or scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs unless specifically defined otherwise. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate.
The disclosures of the prior art documents cited in the present description are incorporated by reference in their entirety and are therefore part of the present disclosure.
Claims (7)
1. The Parkinson disease microneedle patch based on the L-DOPA spatio-temporal controllable drug delivery strategy comprises a backing (120) and a light-operated drug-loaded microneedle array attached to one side of the backing (120), wherein the light-operated drug-loaded microneedle array comprises a plurality of microneedles (110), and is characterized in that each microneedle (110) comprises a matrix and a photoinitiator HMPP, each microneedle comprises a large number of mesoporous silica coating upconversion micrometer rods, L-DOPA is loaded in a mesoporous hole, azo is used as a hole sealing agent, each microneedle comprises a large number of mesoporous silica coating upconversion micrometer rods, L-DOPA is loaded in the mesoporous hole, and azo is used as the hole sealing agent;
the photo-responsive azo molecules in the mesoporous silica can undergo reversible photo-isomerization under the condition of absorbing photons, so that azo is continuously rotated and reversely moved, and the controlled release of L-DOPA from the micro-needle is triggered.
2. The Parkinson's disease microneedle patch based on the L-DOPA spatio-temporal controllable drug delivery strategy as claimed in claim 1, wherein the upper conversion micrometer rod can emit blue light and ultraviolet light under the excitation of near infrared, and due to the impeller type rotation process of azo, the drug is loaded on the upper conversion micrometer rod, so that the drug release can be excited by infrared light, and the purpose of spatio-temporal control of drug release is achieved.
3. The parkinson's disease microneedle patch based on an L-DOPA spatio-temporal controllable drug delivery strategy according to claim 1, wherein the matrix is formed by crosslinking and/or drying and curing an aqueous solution comprising one or more of: polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinylpyrrolidone and polyvinyl alcohol;
preferably methacrylate gelatin and/or hyaluronic acid, more preferably methacrylate gelatin.
4. The parkinson's disease microneedle patch based on the L-DOPA spatio-temporally controllable drug delivery strategy according to claim 1, wherein the backing (120) is formed by crosslinking and/or drying and curing an aqueous solution comprising one or more of: polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinylpyrrolidone and polyvinyl alcohol, preferably polyvinyl alcohol.
5. The parkinson's disease microneedle patch based on an L-DOPA spatio-temporally controllable drug delivery strategy according to claim 1, wherein each microneedle (110) has a tip end and a base end, the tip end being distant from the backing (120), the microneedle (110) being attached to the backing (120) via the base end, the tip end-to-base end distance being 200 μm to 1mm, the base end having a base end diameter of 100 μm to 500 μm, a pitch between tip ends of adjacent microneedles (110) being 300 μm to 800 μm.
6. Method for preparing parkinson's disease microneedle patches based on L-DOPA spatio-temporally controllable dosing strategy according to any of claims 1 to 5, characterized in that it comprises the steps of:
1) preparing the upconversion micron rods: the up-conversion micron rod can emit blue light and ultraviolet light under infrared excitation to synthesize lanthanide-substituted NaYF4: tm, YbUCMRs, utilizes tetraethoxysilane and hexadecyl trimethyl ammonium bromide to modify mesoporous silicon dioxide, azobenzene (azo) is successfully modified in mesopores, and the material is prepared into UCMRs @ mSiO2-azo；
The prepared UCMRs @ mSiO2-azo and therapeutic drug (L-DOPA) were stirred well at room temperature to obtain UCMRs @ mSiO2-azo-L-DOPA；
Under ultraviolet light and visible light, trans-and cis-isomers of azo compounds can be reversibly converted into each other;
2) preparing main materials of a matrix: preparing methacrylate gelatin and mixing the methacrylate gelatin with a photoinitiator HMPP to be used as a main material of a matrix, wherein in a tip material of the microneedle patch, the content of the methacrylate gelatin has an important influence on the mechanical strength and permeability of the microneedle patch;
testing the mechanical strength of microneedle patches containing 10%, 15%, 20%, 25% and 30% methacrylate gelatin, preferably microneedle patches containing 30% methacrylate gelatin;
addition of UCMRs @ mSiO2-azo-L-DOPA had little effect on the mechanical strength of the microneedle patch, and UCMRs @ mSiO prepared in 1)2-azo-L-DOPA and methacrylate gelatin and mixing them with a photoinitiator HMPP;
3) providing a microneedle mould (200): the microneedle mould (200) comprises an upper surface (202) and a shaped hole (201) extending downwards from the upper surface (202), wherein the shaped hole (201) preferably has a tip end and a base end, the tip end is far away from the upper surface (202), the base end plane is flush with the upper surface (202), the distance from the tip end to the base end is preferably 200 μm to 1mm, the base end preferably has a base end diameter of 100 μm to 500 μm, and the distance between adjacent tip ends is preferably 300 μm to 800 μm;
4) placing the mixed solution obtained from step 2) in the molding hole (201) and filling at least a portion of the volume of the molding hole (201), preferably filling the molding hole (201);
5) causing said near-infrared triggered anti-Parkinsonian drug release system UCMRs @ mSiO comprising said matrix material in said molding well (201)2-azo-L-DOPA, and curing under an ultraviolet lamp after removing excessive materials, thereby forming the micro-needles (110) in the molding holes (201), wherein a plurality of micro-needles (110) form the light-operated drug-loaded micro-needle array, each micro-needle (110) has a tip end and a bottom end, and the tip end of the micro-needle (110) is far away from the upper surface (202) relative to the bottom end of the micro-needle (110);
6) applying a solution comprising a backing material, preferably selected from the group consisting of polyethylene glycol diacrylate, silk fibroin, methacrylate gelatin, carboxymethyl cellulose, trehalose, hyaluronic acid, polylactic acid-glycolic acid copolymer, polylactic acid, galactose, polyvinyl pyrrolidone, polyvinyl alcohol or a mixture of two or more thereof, preferably polyvinyl alcohol, on the bottom end surface of the microneedles (110) and the upper surface (202) of the microneedle mould (200) not covered by the microneedles (110) to form a backing solution layer, and optionally cross-linking the backing material to form a continuous backing layer, thereby attaching the light control drug loaded microneedle patch to the backing solution layer or the backing layer;
7) covering the microneedle patch with the backing solution layer or the backing layer obtained from step 6) as a backing material, drying at 50 ℃, and finally demolding to obtain the complete microneedle patch (100).
7. The method of claim 6, for use in alleviating and/or treating symptoms of parkinson's disease in an animal.
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| CN114272374A (en) * | 2021-12-29 | 2022-04-05 | 广州纳丽生物科技有限公司 | Photosensitive controlled-release microneedle and preparation method thereof |
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| WO2020092229A1 (en) * | 2018-10-31 | 2020-05-07 | The Regents Of The University Of California | Biodegradable microneedles for transdermal therapeutic agent delivery |
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| WO2020092229A1 (en) * | 2018-10-31 | 2020-05-07 | The Regents Of The University Of California | Biodegradable microneedles for transdermal therapeutic agent delivery |
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| CN114272374A (en) * | 2021-12-29 | 2022-04-05 | 广州纳丽生物科技有限公司 | Photosensitive controlled-release microneedle and preparation method thereof |
| CN114272374B (en) * | 2021-12-29 | 2022-08-02 | 广州纳丽生物科技有限公司 | Photosensitive controlled-release microneedle and preparation method thereof |
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Application publication date: 20211224 |