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CN113288883A - Long-acting depression relieving microneedle patch and preparation method thereof - Google Patents

Long-acting depression relieving microneedle patch and preparation method thereof Download PDF

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Publication number
CN113288883A
CN113288883A CN202110566463.4A CN202110566463A CN113288883A CN 113288883 A CN113288883 A CN 113288883A CN 202110566463 A CN202110566463 A CN 202110566463A CN 113288883 A CN113288883 A CN 113288883A
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microneedle
drug
layer
parts
pdms
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李景华
张建波
高京丕
陈美君
李光大
杨宪园
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Henan University of Science and Technology
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Henan University of Science and Technology
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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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
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Abstract

本发明涉及一种用于长效缓解抑郁症状的微针贴片其制备方法，属于透皮或经皮给药制剂技术领域。所述长效缓解抑郁症状的微针贴片是由四层有效成分组成，包含用于贴合皮肤的水凝胶贴合层，用于刺穿皮肤的可降解微针层，用作装载抗抑郁药物成分药物贮池的PDMS载药层，以及最外层的防水无纺布层。本发明用含有碳酸钙的生物可降解高分子材料制作微针，有效增强微针强度，提高微针穿刺性能，使之能有效穿透皮肤角质层。利用含双亲性十四烷醇作为药物贮池的缓释门阀，一方面其双亲性能够同时包裹亲疏水性不同的药物，另一方面其具有较好的缓释性能，使微针贴片能够长时效达到药物持续释放的功效。制造工艺简单，成本低廉、安全性高。

Figure 202110566463

The invention relates to a preparation method of a microneedle patch for long-acting relief of depression symptoms, and belongs to the technical field of transdermal or transdermal drug delivery preparations. The long-acting microneedle patch for relieving depressive symptoms is composed of four layers of active ingredients, including a hydrogel adhesive layer for fitting the skin, a degradable microneedle layer for piercing the skin, and a layer for loading anti- The PDMS drug-loading layer of the depressive drug ingredient drug reservoir, and the outermost waterproof non-woven layer. The invention uses the biodegradable polymer material containing calcium carbonate to make the microneedle, which effectively enhances the strength of the microneedle, improves the puncture performance of the microneedle, and enables it to effectively penetrate the stratum corneum of the skin. Using the slow-release gate valve containing amphiphilic tetradecanol as the drug reservoir, on the one hand, its amphiphilicity can encapsulate drugs with different hydrophilic and hydrophobic properties at the same time; Aging achieves the effect of sustained drug release. The manufacturing process is simple, the cost is low, and the safety is high.

Figure 202110566463

Description

Long-acting depression relieving microneedle patch and preparation method thereof
Technical Field
The invention belongs to the technical field of transdermal or percutaneous administration preparations, and particularly relates to a long-acting depression relieving microneedle patch and a preparation method thereof.
Background
Depression (depression) is a typical symptom of slow thinking, low emotion, slow movement, speech loss, etc. caused by various physiological, organic or environmental causes. The life and work of patients are seriously puzzled by depression, about 15 percent of depression patients die from suicide eventually, heavy burden is brought to families and society, and the study of the world health organization shows that the depression becomes a major disease of Chinese disease burden.
Modern society is in fierce competition and has high survival pressure, and the incidence rate of depression is increased year by year. At present, the psychoses are mainly treated by medicines, and common medicines comprise tricyclic and tetracyclic antidepressants, monoamine oxidase, 5-hydroxytryptamine medicines and the like. Because the clinical medication of the depressive psychosis needs to consider toxic and side effects, large adverse reactions and price factors, and consider the interference of individual mental conditions of patients on autonomous regular medication, the depressive psychosis is often difficult to autonomously and continuously adhere to regular quantitative medication following medical advice, and the treatment effect is influenced.
The transdermal administration or percutaneous administration technology refers to a kind of external preparation, patch or patch which is applied by percutaneous application, the medicine penetrates the skin through the skin patch or is absorbed by the skin and finally enters the systemic blood circulation so as to achieve the effective therapeutic blood concentration and realize the disease prevention and treatment. The technology is characterized by avoiding the reduction or loss of the drug activity of the drug in the first-pass effect of the liver and the extreme pH environment of the gastrointestinal tract, reducing the difference of individuals in oral administration, avoiding the peak-valley condition of the blood concentration caused by an oral administration mode, maintaining more accurate long-acting/effective blood concentration and simultaneously greatly reducing the toxic and side effect and the adverse reaction brought by the drug. The medicine can improve the treatment time efficiency and dose effect while reducing the administration times, and is convenient to use and easier to accept by patients.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a long-acting depression-relieving microneedle patch, and an object of the present invention is to provide a method for preparing the long-acting depression-relieving microneedle patch.
The invention combines the advantages of the latest transdermal drug delivery and microneedle patch, overcomes the disadvantages of the existing oral antidepressant such as toxic and side effects, large adverse reaction, easy inactivation in the stomach and intestine, and disturbance of the individual mental status of the patient to the autonomous administration, realizes one-time application treatment, realizes stable blood concentration and treatment effect for a long time, can be automatically operated by the patient, is convenient to use, and is more acceptable by the patient. Microneedle technology has recently received much attention from the biomedical field, and as one of the physical permeation-promoting means for transdermal drug delivery, painless precise drug delivery can be realized. However, the use of the micro-needle is still limited by the physical and chemical properties of the micro-needle, and the traditional micro-needle made of silicon-based or metal-based materials has the risk of falling in vivo and causing the risk of injury to human bodies. The organic polymer micro-needle with high biosecurity and good degradability has the problems of insufficient puncture performance and incapability of effectively penetrating the stratum corneum of skin due to the problem of strength.
The microneedle patch based on the organic microneedle containing the calcium carbonate and capable of relieving depression symptoms for a long time and the preparation method thereof have the advantages of good skin puncture performance, small skin irritation, long drug release and drug effect time, good biological safety, simple preparation and contribution to industrial mass production.
In order to achieve the purpose, the invention adopts the specific scheme that:
a long-acting depression relieving microneedle patch sequentially comprises a hydrogel attaching layer for attaching to skin, a degradable microneedle layer for piercing the skin, a PDMS drug-carrying layer for loading a drug storage tank for antidepressant drug ingredients and a waterproof non-woven fabric layer on the outermost layer from inside to outside;
the hydrogel adhesive layer is prepared by taking 20-50 parts of catechol, 20-50 parts of sorbate, 20-100 parts of gelatin, 50-100 parts of dioctyl maleate, 10-20 parts of polyquaternary ammonium, 200-500 parts of glycerol and 500-1000 parts of distilled water as raw materials, taking potassium persulfate as an initiator and taking methylene bisacrylamide as a cross-linking agent;
the degradable microneedle layer is prepared by adding microneedle injection molding liquid into a microneedle mould; the microneedle injection molding liquid contains calcium carbonate and a degradable organic high molecular polymer; the size of a needle point of the microneedle mould is 10-100 mu m, the size of a needle point base is 200-1000 mu m, and the distance between the needle bases is 500-1000 mu m;
a slow-release drug storage tank is arranged on the PDMS drug-carrying layer; the storage tank is shaped like a square groove, the width of the groove is 200-1000 mu m, and the depth of the groove is 50-300 mu m; the antidepressant drug filled in the groove comprises the following components: 100-500 parts of amphiphilic short-chain alkanol tetradecanol, 5-100 parts of SSRI antidepressant drugs and 5-100 parts of drug extracts, wherein the drug extracts are at least one of 10-100 parts of saffron extract, 10-100 parts of rhodiola rosea extract, 10-100 parts of honeysuckle extract and 10-100 parts of mint extract;
the waterproof non-woven fabric layer is one of medical SMS, SMMS and SSMMS.
Further, the organic high molecular polymer in the microneedle injection molding liquid is polyvinylpyrrolidone, polylactic acid-glycolic acid-polyvinyl alcohol copolymer, polylactide-glycolide copolymer or polylactic acid-gamma-hydroxybutyric acid copolymer or PLGA.
Further, the body of the microneedle is shaped as a cone, a triangular pyramid, a rectangular pyramid, a pentagonal pyramid, a hexagonal pyramid, a seven pyramid, or an eight pyramid.
Further, the SSRI antidepressant is a 5-hydroxytryptamine reuptake inhibitor, namely one or more of fluoxetine, paroxetine, sertraline, flufenacet and citalopram.
The invention also provides a preparation method of the long-acting depression relieving microneedle patch, which comprises the following steps:
step one, preparing a hydrogel laminating layer:
placing catechol, sorbate, gelatin, dioctyl maleate, polyquaternary ammonium, glycerol and distilled water in a polytetrafluoroethylene beaker according to a proportion, mixing and dissolving, placing the mixture in a constant-temperature water bath kettle at 40-80 ℃ for heating for 20-60 minutes, adding an initiator potassium persulfate and a cross-linking agent methylene bisacrylamide when the temperature of the beaker is constant, stirring and heating the mixture in a constant-temperature heating magnetic stirrer to 60-80 ℃, keeping the temperature range for reaction for 0.5-1 hour, stopping heating when the mixed solution of the system is thickened, wherein a colorless and transparent colloidal substance in the beaker is hydrogel, placing the prepared hydrogel in distilled water for fully purifying for 2-3 days, and fully drying the hydrogel in a constant-temperature drying box at 50-60 ℃ to constant weight to obtain a hydrogel adhesive layer;
step two, preparing the degradable microneedle layer:
mixing a degradable organic high molecular polymer containing calcium carbonate with an organic solvent to obtain microneedle injection molding liquid; heating microneedle injection molding liquid and injecting the microneedle injection molding liquid into a 304 stainless steel or PDMS microneedle mould with a needle point size of 10-100 mu m, a needle point base size of 200-1000 mu m and a needle base spacing of 500-1000 mu m, heating for 1-3 h under the water bath condition of 50-80 ℃, preparing a needle body and a base, removing an organic solvent, cooling, drying and demoulding to obtain a degradable microneedle layer;
step three, preparing a PDMS drug-loaded layer:
firstly, preparing a PDMS drug storage tank with a square groove structure by using a PDMS stamp technology, then dissolving SSRI antidepressant drugs and drug extracts in 45 ℃ amphiphilic short-chain alkanol tetradecanol according to a proportion, cooling to room temperature, solidifying the tetradecanol, and solidifying drug components in the square groove of the PDMS drug storage tank to obtain a PDMS drug-loaded layer;
and step four, bonding and curing the hydrogel laminating layer, the degradable microneedle layer, the PDMS drug-carrying layer and the waterproof non-woven fabric layer together by using a medical adhesive to obtain the long-acting depression relieving microneedle patch.
Further, the medicine extract in the third step is obtained by adopting an alcohol extraction and water precipitation process, an organic solvent extraction process, an alcohol extraction and organic solvent extraction process or a supercritical fluid extraction process. Further, the extract is obtained by the following method: one or more of saffron, rhodiola rosea, honeysuckle and mint in a certain proportion are taken, fully dried, pulverized into powder by a pulverizer, extracted by refluxing with 60-90% ethanol for 2-5 times at a flow rate of 2-5 ml for min-1, decocted for 100-200 minutes by 6-10 times of water, filtered and combined with filtrate, filtered after a rotary evaporation method, and dried, and repeated for 3-5 times in the way, and precipitates are combined for later use.
The invention also claims application of the long-acting depression relieving microneedle patch in preparation of a depression psychosis treatment drug.
Has the advantages that: the invention provides a slow-release drug storage tank which takes an organic high molecular polymer containing calcium carbonate as a puncture microneedle and a PDMS drug-loaded layer, and the long-acting depression relieving microneedle patch can be released continuously for 24-168 hours. The microneedle patch for relieving depression for a long time is characterized in that microneedles are made of a biodegradable high polymer material containing calcium carbonate, so that the strength of the microneedles is effectively enhanced, the puncture performance of the microneedles is improved, and the microneedles can effectively penetrate through the stratum corneum of the skin. And the amphiphilic tetradecanol is used as a slow release gate valve of the drug reservoir, so that on one hand, the amphipathy of the slow release gate valve can wrap drugs with different hydrophilicity and hydrophobicity at the same time, and on the other hand, the slow release gate valve has better slow release performance, so that the microneedle patch can achieve the effect of drug sustained release for a long time, and can relieve depression symptoms for a long time.
Drawings
Fig. 1 is a schematic illustration of a microneedle patch construction and use;
fig. 2 is a photograph under a stereomicroscope of a microneedle patch;
fig. 3 is a graph of the rate of degradation of the microneedles;
FIG. 4 is a graph of the results of a sustained release profile of fluoxetine;
FIG. 5 is a view of the puncture situation of the microneedle patch applied to the pigskin;
figure 6 is a graph of the results for the sustained release profile of paroxetine.
Detailed Description
The foregoing and other objects of the invention are further illustrated by the following examples of specific embodiments, which are intended to be illustrative only and are not intended to limit the scope of the invention in any way. Various alterations and modifications made by those skilled in the art and conventional means without departing from the technical spirit of the invention are within the scope of the invention.
Example 1 preparation of a fluoxetine-containing microneedle patch for long-acting depression relief
Weighing 50 parts of catechol, 50 parts of sorbate, 50 parts of gelatin, 50 parts of dioctyl maleate, 20 parts of polyquaternary ammonium, 200 parts of glycerol and 1000 parts of distilled water, placing the mixture in a constant-temperature water bath kettle at 40 ℃ for heating for 30 minutes, adding 10 parts of a hair agent potassium persulfate and 25 parts of a cross-linking agent methylene bisacrylamide after complete dissolution, heating the mixture to 60 ℃ while stirring in a constant-temperature heating magnetic stirrer, keeping the cross-linking reaction for 1 hour to obtain colorless transparent colloidal hydrogel, placing the hydrogel into a 5000mL distilled large beaker for purification for 2 days, taking out the hydrogel, and placing the hydrogel in a 50 ℃ constant-temperature drying oven for fully drying to constant weight to obtain the hydrogel adhesive layer.
30 parts of calcium carbonate, 50 parts of N-methylpyrrolidone, 20 parts of PLGA with the molecular weight of 10.0kDa and 100 parts of gelatin are weighed and dissolved in 20mL of distilled water together to prepare the microneedle injection molding liquid.
Adding the microneedle injection molding liquid into a stainless steel microneedle mould, wherein the specific shape and size of the mould are as follows: the shape is conical, the size of the needle point is 50 mu m, the size of the needle point base is 500 mu m, the distance between the needle bases is 500 mu m, the microneedle injection molding liquid enters the needle hole of the selected microneedle mould by a vacuumizing method, the microneedle injection molding liquid is heated for 1 hour under the water bath condition of 60 ℃, and the microneedle injection molding liquid is taken out and cooled to the room temperature of 25 ℃. Respectively washing with distilled water and alcohol for 5 times, washing for 2h each time, drying the microneedle mould at 25 deg.C and 35% humidity for 4 hr, and demoulding to obtain degradable microneedle layer. The scanning electron micrograph of the microneedle is shown in fig. 2.
PDMS stamp technology was used to prepare PDMS reservoirs with a serpentine-shaped trench structure (500 μm width and 200 μm depth).
Extracting the medicine: taking 10 parts of dry powder of stigma croci Sativi and herba Menthae, drying, pulverizing into powder, extracting with 90% ethanol under reflux for 5 times with flow rate controlled at 5ml for min～1Then decocting with 10 times of water for 120 min, filtering and combining the filtrates, collecting the filtrate after rotary evaporation, drying, repeating for 3 times, and combining the precipitates for later use.
Weighing 100 parts of tetradecanol, melting at 50 ℃, weighing 5 parts of SSRI antidepressant fluoxetine and 5 parts of drug extract, adding the components into the melted tetradecanol, sucking the solution by a microsyringe in a 50 ℃ thermostat, injecting the solution into a clip-shaped groove of a PDMS stamp, enabling the liquid level to be parallel to the groove, and cooling to 25 ℃ to room temperature to obtain the PDMS drug-loaded layer.
Cutting the four layers of components (the hydrogel attaching layer, the degradable microneedle layer, the PDMS drug-loaded layer and the waterproof non-woven fabric layer in sequence) into the same size by using a cutting machine, and bonding and curing the four layers of components (the hydrogel attaching layer, the degradable microneedle layer, the fluoxetine-containing PDMS drug-loaded layer and the waterproof non-woven fabric layer in sequence) together by using medical adhesive cyanoacrylate to obtain the fluoxetine-containing long-acting depression-relieving microneedle patch.
Evaluating the extradermal degradable dissolution speed of the degradable microneedle layer: adding 2mg of methylene blue into microneedle injection molding liquid, preparing the degradable microneedles containing the methylene blue according to the preparation method of the degradable microneedle layer in the embodiment 1, respectively putting 10 degradable microneedles containing the methylene blue into 250mL clean beakers containing 100mL of distilled water, releasing the contained methylene blue along with degradation and melting of the microneedles, sampling 10 mu L once every 0.5h, and detecting the light absorption condition of the solution at 664nm by using a Nano drop micro ultraviolet visible spectrophotometer. As shown in fig. 3, as the microneedles degrade, the ultraviolet absorbance of the methylene blue solution in each beaker gradually increases, and finally reaches the plateau phase, and the time required for reaching the plateau phase can represent the degradation speed of the microneedles.
Evaluation of slow release effect of fluoxetine in PDMS drug-loaded layer: 10 PDMS drug-loaded layers of the antidepressant drug fluoxetine prepared in example 1 were placed in a 250mL clean beaker containing 100mL distilled water, 10. mu.L of the solution was taken every 1 day, and the extract (V) was addedAcetonitrile：VN-hexane= 4: 1) 2.0 mL, mixed for 1min, 12000 r.min-1Centrifuging for 10 min under the condition, collecting supernatant, evaporating organic phase to dryness, adding methanol 100 μ L for redissolving, and analyzing by sample injection. The detection conditions are as follows: chromatographic column Agilent ZORBAX SB-C18(100 mm. times.4.6 mm, 5 μm, Agilent Technologies, USA), mobile phase (V)Water (W)：VMethanol= 80: 20) flow rate of 1.0 mL/min-1And the detection wavelength is 226 nm. The results of the slow release profile of fluoxetine are shown in figure 4: and (3) gradually increasing the dissolution rate of the fluoxetine in each beaker along with the increase of the time, finally reaching a plateau stage, and representing the slow release condition of the fluoxetine by the time required for reaching the plateau stage.
Skin puncture test of the fluoxetine-containing long-acting depression relieving microneedle patch: the microneedle patch prepared in example 1 was applied to fresh pig skin, pressed with a finger for 1min, stained with 1% trypan blue for 20min, and excess trypan blue was wiped off with a cotton swab, and then the skin was observed for the presence of a pinhole, and as shown in fig. 5, a photograph of trypan blue-stained pig skin was obtained, a microneedle pinhole was clearly seen.
Seven performance indexes of formability, initial adhesion, peeling force, toughness and elasticity, skin irritation, preparation stability and patient compliance of the fluoxetine-containing long-acting depression relieving microneedle patch are investigated, and the results are shown in the following table 1. The definition criteria are as follows.
Formability: the patch is placed in a constant temperature incubator at the temperature of 20 ℃ to 37 ℃, and the overall appearance and the loose degree of the structure of the microneedle patch are observed.
Initial adhesion: the microneedle patch under the condition of 20-37 ℃ is measured and compared according to the measuring method of the initial adhesive force of the patch in the XJ patch adhesion force measuring method in the second appendix of the Chinese pharmacopoeia (2005).
Peeling force: the microneedle patch is measured and compared under the condition of 20-37 ℃ according to the measuring method of the peel strength in the XJ patch adhesion measuring method in the second appendix of the Chinese pharmacopoeia (2005).
Toughness and elasticity: placing a glass sheet with the same shape and size on the microneedle patch at the temperature of-20-37 ℃, placing a weight of 20g in the center of the glass sheet, relieving the pressure, and observing the shape recovery condition of the microneedle patch.
Skin irritation: the animals were observed for local irritation response to single and multiple contact of the gel with intact skin. The microneedle patch is stored for one month for later use at the temperature of 20-37 ℃. Healthy white guinea pigs (300 g +/-20 g) are selected, and the male and female guinea pigs are divided into 8 groups, and each group comprises 5-6 animals. Unhairing the two sides of the vertebral column of the guinea pigs 24h before applying the microneedle patch, checking whether the unhaired skin has a wound, respectively applying the microneedle patch on the left side of each guinea pig, not applying the microneedle patch on the right side, and comparing and observing the conditions of erythema and edema of the skin after removing the microneedle patch lh, 24h, 48h and 72h after single application. Applying for more than one week, stopping, observing for one week, and observing to record red swelling condition of rat skin and whether pigmentation and hemorrhage exist at the applied part.
Stability: the microneedle patch is placed for 1 month at the temperature of 20-37 ℃, and the change condition of the properties of the microneedle patch is observed.
Patient compliance: selecting a plurality of healthy adults, placing the hydrogel adhesive layer at the temperature of between 20 and 37 ℃ for 1 month, attaching the hydrogel adhesive layer on the inner side of the upper arm, and inspecting and recording the conditions of skin feeling, use convenience and the like.
Table 1: the performance index result of the long-acting depression relieving microneedle patch containing fluoxetine.
Figure DEST_PATH_IMAGE002
Note: preferably, + + +; , + is middle; + is a difference
Example 2 preparation of Long-acting Depression-relieving microneedle Patch containing paroxetine
Weighing 50 parts of catechol, 40 parts of sorbate, 60 parts of gelatin, 50 parts of dioctyl maleate, 10 parts of polyquaternary ammonium, 200 parts of glycerol and 1000 parts of distilled water, placing the mixture in a constant-temperature water bath kettle at 50 ℃ for heating for 30 minutes, adding 10 parts of a hair agent potassium persulfate and 25 parts of a cross-linking agent methylene bisacrylamide after complete dissolution, heating the mixture to 60 ℃ while stirring in a constant-temperature heating magnetic stirrer, keeping the cross-linking reaction for 1 hour to obtain colorless transparent colloidal hydrogel, placing the hydrogel into a 5000mL distilled large beaker for purification for 2 days, taking out the hydrogel, and placing the hydrogel in a constant-temperature drying oven at 50 ℃ for fully drying to constant weight to obtain the hydrogel adhesive layer.
45 parts of calcium carbonate, 60 parts of N-methylpyrrolidone, 20 parts of PLGA with the molecular weight of 10.0kDa and 120 parts of gelatin are weighed and dissolved in 20mL of distilled water together to prepare the microneedle injection molding liquid.
Adding the microneedle injection molding liquid into a stainless steel microneedle mould, wherein the specific shape and size of the mould are as follows: the shape is conical, the size of the needle point is 50 mu m, the size of the needle point base is 500 mu m, the distance between the needle bases is 500 mu m, the microneedle injection molding liquid enters the needle hole of the selected microneedle mould by a vacuumizing method, the microneedle injection molding liquid is heated for 1 hour under the water bath condition of 60 ℃, and the microneedle injection molding liquid is taken out and cooled to the room temperature of 25 ℃. Respectively washing with distilled water and alcohol for 5 times, washing for 2h each time, drying the microneedle mould at 25 deg.C and 35% humidity for 4 hr, and demoulding to obtain degradable microneedle layer.
PDMS stamp technology was used to prepare PDMS reservoirs with a serpentine-shaped trench structure (500 μm width and 200 μm depth).
Extracting the medicine: taking 10 parts of each of saffron crocus, rhodiola rosea and mint dry powder, fully drying, pulverizing into powder by a pulverizer, extracting for 5 times by refluxing with 90% ethanol at a flow rate of 5ml for min-1, then decocting for 60 minutes by 10 times of water, filtering and combining filtrates, collecting filtrate after a rotary evaporation method, drying, repeating for 5 times, and combining precipitates for later use.
Weighing 100 parts of tetradecanol, melting at 50 ℃, weighing 5 parts of SSRI antidepressant paroxetine and 5 parts of drug extract, adding the weighed materials into the melted tetradecanol, sucking the solution by a microsyringe in a 50 ℃ thermostat, injecting the solution into a clip-shaped groove of a PDMS stamp, enabling the liquid level to be parallel to the groove, and cooling to 25 ℃ to room temperature to obtain the PDMS drug-loaded layer.
Cutting the four layers of components (the hydrogel attaching layer, the degradable microneedle layer, the PDMS drug-loaded layer and the waterproof non-woven fabric layer in sequence) into the same size by using a cutting machine, and bonding and curing the four layers of components (the hydrogel attaching layer, the degradable microneedle layer, the PDMS drug-loaded layer containing paroxetine and the waterproof non-woven fabric layer in sequence) together by using medical adhesive cyanoacrylate to obtain the long-acting depression relieving microneedle patch containing paroxetine.
Evaluation of slow release effect of paroxetine in PDMS drug-loaded layer: 10 PDMS drug-loaded layers of the antidepressant drug paroxetine prepared in example 1 were placed in a 250mL clean beaker containing 100mL distilled water, 10. mu.L of the solution was taken every 1 day (d), and the extract (V) was addedToluene：VN-hexane= 1: 4) 2.0 mL, mixing for 1min, centrifuging for 10 min at 12000 r min-1, collecting supernatant, evaporating to dryness, adding methanol 100 μ L, redissolving, and analyzing by sample injection. The detection conditions are as follows: shimadzu VP-DOS (100 mm. times.4.6 mm, 5 μm, Shimadzu, Japan), mobile phase (methanol: water: chloroform: isopropanol: tetramethylethylenediamine: glacial acetic acid: 280: 142: 2: 1: 0.8), flow rate 1.0 mL min-1, detection wavelength 295 nm. The results of the sustained release profile of paroxetine are shown in figure 6:the dissolution rate of the paroxetine in each beaker is gradually increased along with the increase of the time, the plateau period is finally reached, and the time required for reaching the plateau period can represent the slow release condition of the paroxetine.
Seven performance indexes of formability, initial adhesion, peeling force, tough elasticity, skin irritation, preparation stability and patient compliance of the paroxetine-containing microneedle patch for relieving depression for a long time are examined, and the results are shown in the following table 2. The definition criteria are as follows.
Formability: the patch is placed in a constant temperature incubator at the temperature of 20 ℃ to 37 ℃, and the overall appearance and the loose degree of the structure of the microneedle patch are observed.
Initial adhesion: the microneedle patch under the condition of 20-37 ℃ is measured and compared according to the measuring method of the initial adhesive force of the patch in the XJ patch adhesion force measuring method in the second appendix of the Chinese pharmacopoeia (2005).
Peeling force: the microneedle patch is measured and compared under the condition of 20-37 ℃ according to the measuring method of the peel strength in the XJ patch adhesion measuring method in the second appendix of the Chinese pharmacopoeia (2005).
Toughness and elasticity: placing a glass sheet with the same shape and size on the microneedle patch at the temperature of-20-37 ℃, placing a weight of 20g in the center of the glass sheet, relieving the pressure, and observing the shape recovery condition of the microneedle patch.
Skin irritation: the animals were observed for local irritation response to single and multiple contact of the gel with intact skin. The microneedle patch is stored for one month for later use at the temperature of 20-37 ℃. Healthy white guinea pigs (300 g +/-20 g) are selected, and the male and female guinea pigs are divided into 8 groups, and each group comprises 5-6 animals. Unhairing the two sides of the vertebral column of the guinea pigs 24h before applying the microneedle patch, checking whether the unhaired skin has a wound, respectively applying the microneedle patch on the left side of each guinea pig, not applying the microneedle patch on the right side, and comparing and observing the conditions of erythema and edema of the skin after removing the microneedle patch lh, 24h, 48h and 72h after single application. Applying for more than one week, stopping, observing for one week, and observing to record red swelling condition of rat skin and whether pigmentation and hemorrhage exist at the applied part.
Stability: the microneedle patch is placed for 1 month at the temperature of 20-37 ℃, and the change condition of the properties of the microneedle patch is observed.
Patient compliance: selecting a plurality of healthy adults, placing the hydrogel adhesive layer at the temperature of between 20 and 37 ℃ for 1 month, attaching the hydrogel adhesive layer on the inner side of the upper arm, and inspecting and recording the conditions of skin feeling, use convenience and the like.
Table 2: the performance index result of the long-acting depression relieving microneedle patch containing paroxetine is shown.
～20℃ 0℃ 20℃ 37℃
Formability + ++ +++ +++
Initial adhesion + ++ +++ +++
Peeling force + + +++ +++
Toughness and elasticity ++ ++ +++ +++
Irritation to skin ++ ++ +++ +++
Stability of ++ ++ +++ +++
Patient compliance ++ ++ +++ +++
Note: preferably, + + +; , + is middle; + is a difference
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 belonging to the technical solutions of the present invention are within the scope of the present invention.

Claims (8)

1. A long-acting depression-relieving microneedle patch, which is characterized in that: the anti-depression drug-loaded medical device sequentially comprises a hydrogel attaching layer for attaching to the skin, a degradable microneedle layer for puncturing the skin, a PDMS drug-loaded layer for loading an anti-depression drug component drug storage tank and a waterproof non-woven fabric layer on the outermost layer from inside to outside;
the hydrogel adhesive layer is prepared by taking 20-50 parts of catechol, 20-50 parts of sorbate, 20-100 parts of gelatin, 50-100 parts of dioctyl maleate, 10-20 parts of polyquaternary ammonium, 200-500 parts of glycerol and 500-1000 parts of distilled water as raw materials, taking potassium persulfate as an initiator and taking methylene bisacrylamide as a cross-linking agent;
the degradable microneedle layer is prepared by adding microneedle injection molding liquid into a microneedle mould; the microneedle injection molding liquid contains calcium carbonate and a degradable organic high molecular polymer; the size of a needle point of the microneedle mould is 10-100 mu m, the size of a needle point base is 200-1000 mu m, and the distance between the needle bases is 500-1000 mu m;
a slow-release drug storage tank is arranged on the PDMS drug-carrying layer; the storage tank is shaped like a square groove, the width of the groove is 200-1000 mu m, and the depth of the groove is 50-300 mu m; the antidepressant drug filled in the groove comprises the following components: 100-500 parts of amphiphilic short-chain alkanol tetradecanol, 5-100 parts of SSRI antidepressant drugs and 5-100 parts of drug extracts, wherein the drug extracts are at least one of 10-100 parts of saffron extract, 10-100 parts of rhodiola rosea extract, 10-100 parts of honeysuckle extract and 10-100 parts of mint extract;
the waterproof non-woven fabric layer is one of medical SMS, SMMS and SSMMS.
2. The long-acting depression-relieving microneedle patch according to claim 1, wherein: the organic high molecular polymer in the microneedle injection molding liquid is polyvinylpyrrolidone, polylactic acid-glycolic acid-polyvinyl alcohol copolymer, polylactide-glycolide copolymer, polylactic acid-gamma-hydroxybutyric acid copolymer or PLGA.
3. The long-acting depression-relieving microneedle patch according to claim 1, wherein: the shape of the needle body of the microneedle is a cone, a triangular pyramid, a rectangular pyramid, a pentagonal pyramid, a hexagonal pyramid, a seven pyramid or an eight pyramid.
4. The long-acting depression-relieving microneedle patch according to claim 1, wherein: the SSRI antidepressant drug is a 5-hydroxytryptamine reuptake inhibitor, namely one or more of fluoxetine, paroxetine, sertraline, flufenacet and citalopram.
5. The preparation method of the long-acting depression-relieving microneedle patch as claimed in claim 1, wherein: the method comprises the following steps:
step one, preparing a hydrogel laminating layer:
placing catechol, sorbate, gelatin, dioctyl maleate, polyquaternary ammonium, glycerol and distilled water in a polytetrafluoroethylene beaker according to a proportion, mixing and dissolving, placing the mixture in a constant-temperature water bath kettle at 40-80 ℃ for heating for 20-60 minutes, adding an initiator potassium persulfate and a cross-linking agent methylene bisacrylamide when the temperature of the beaker is constant, stirring and heating the mixture in a constant-temperature heating magnetic stirrer to 60-80 ℃, keeping the temperature range for reaction for 0.5-1 hour, stopping heating when the mixed solution of the system is thickened, wherein a colorless and transparent colloidal substance in the beaker is hydrogel, placing the prepared hydrogel in distilled water for fully purifying for 2-3 days, and fully drying the hydrogel in a constant-temperature drying box at 50-60 ℃ to constant weight to obtain a hydrogel adhesive layer;
step two, preparing the degradable microneedle layer:
mixing a degradable organic high molecular polymer containing calcium carbonate with an organic solvent to obtain microneedle injection molding liquid; heating microneedle injection molding liquid and injecting the microneedle injection molding liquid into a 304 stainless steel or PDMS microneedle mould with a needle point size of 10-100 mu m, a needle point base size of 200-1000 mu m and a needle base spacing of 500-1000 mu m, heating for 1-3 h under the water bath condition of 50-80 ℃, preparing a needle body and a base, removing an organic solvent, cooling, drying and demoulding to obtain a degradable microneedle layer;
step three, preparing a PDMS drug-loaded layer:
firstly, preparing a PDMS drug storage tank with a square groove structure by using a PDMS stamp technology, then dissolving SSRI antidepressant drugs and drug extracts in 45 ℃ amphiphilic short-chain alkanol tetradecanol according to a proportion, cooling to room temperature, solidifying the tetradecanol, and solidifying drug components in the square groove of the PDMS drug storage tank to obtain a PDMS drug-loaded layer;
and step four, bonding and curing the hydrogel laminating layer, the degradable microneedle layer, the PDMS drug-carrying layer and the waterproof non-woven fabric layer together by using a medical adhesive to obtain the long-acting depression relieving microneedle patch.
6. The method of claim 5, wherein: and step three, the medicine extract is obtained by adopting an alcohol extraction and water precipitation process, an organic solvent extraction method, an alcohol extraction and organic solvent extraction method or a supercritical fluid extraction process.
7. The method of claim 6, wherein: the medicine extract is obtained by extracting according to the following method: one or more of saffron, rhodiola rosea, honeysuckle and mint in a certain proportion are taken, fully dried, pulverized into powder by a pulverizer, extracted by refluxing with 60-90% ethanol for 2-5 times at a flow rate of 2-5 ml for min-1, decocted for 100-200 minutes by 6-10 times of water, filtered and combined with filtrate, filtered after a rotary evaporation method, and dried, and repeated for 3-5 times in the way, and precipitates are combined for later use.
8. The long-acting depression-relieving microneedle patch as claimed in claim 1, for use in the preparation of a medicament for treating depressive psychosis.
CN202110566463.4A 2021-05-24 2021-05-24 Long-acting depression relieving microneedle patch and preparation method thereof Pending CN113288883A (en)

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WO2023178818A1 (en) * 2022-03-23 2023-09-28 深圳大学 Self-heating microneedle drug-loaded patch and preparation method therefor
US11773063B1 (en) 2022-08-19 2023-10-03 Beckley Psytech Limited Pharmaceutically acceptable salts and compositions thereof
US12264131B2 (en) 2022-08-19 2025-04-01 Beckley Psytech Limited Pharmaceutically acceptable salts and compositions thereof
US12246005B2 (en) 2023-06-13 2025-03-11 Beckley Psytech Limited 5-methoxy-n,n-dimethyltryptamine (5-MeO-DMT) formulations

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