CN115645380A - Anti-synovitis microneedle patch and preparation method thereof - Google Patents

Anti-synovitis microneedle patch and preparation method thereof Download PDF

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Publication number
CN115645380A
CN115645380A CN202211402942.3A CN202211402942A CN115645380A CN 115645380 A CN115645380 A CN 115645380A CN 202211402942 A CN202211402942 A CN 202211402942A CN 115645380 A CN115645380 A CN 115645380A
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solution
microneedle
camphor
microneedle patch
borneol
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李长杰
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Henan Lijitang Pharmaceutical Technology Co ltd
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Henan Lijitang Pharmaceutical Technology Co ltd
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Abstract

The invention discloses a microneedle patch for resisting synovitis and a preparation method thereof, which comprises the steps of preparing an inclusion compound aqueous solution of mint, camphor and borneol; mixing the clathrate compound aqueous solution with glucosamine, chondroitin sulfate, traditional Chinese medicine extract and a thermal inductance agent to form a mixture A; the mixture A takes a pullulan solution as a substrate to form a needlepoint solution; adding the needle point solution into a PDMS mold, and drying after removing bubbles in vacuum; and pouring a back lining layer solution, and demolding after vacuum drying again to obtain the compound microneedle patch. The camphor and the borneol have the effects of dissipating heat and relieving pain, the mint can play the roles of dispelling wind and removing dampness, and dissipating heat and relieving pain, and the chondroitin sulfate can reduce the joint swelling, accelerate the recovery of hydrops and promote the regeneration of cartilage; the glucosamine can repair cartilage, resist inflammation and reduce swelling; the heat-sensitive agent can generate heat and promote blood circulation. The medicine can effectively reduce the inflammation of immune cells related to synovitis and the swelling degree of joints of arthritis.

Description

Anti-synovitis microneedle patch and preparation method thereof
Technical Field
The invention relates to a microneedle patch and a preparation method thereof, in particular to an anti-synovitis microneedle patch and a preparation method thereof, and belongs to the technical field of synovitis treatment medicaments.
Background
The synovium is the connective tissue that wraps the joint cavity and is an important tissue that makes up the joint capsule. Synovitis refers to inflammation and hyperplasia of the synovial membrane of joints, which causes pain and swelling of joints and is liable to induce osteoarthritis and cartilage/bone erosion.
The common treatment method of synovitis comprises hormone drugs, antibiotic drugs, plaster and the like, and the common administration modes comprise oral administration, joint cavity injection and transdermal administration; the micro-needle is a novel transdermal administration technology, and compared with oral administration and injection administration, the transdermal administration has the following advantages:
1. the use is convenient, the interruption can be carried out at any time, and the safety is high;
2. the first pass effect of the liver is avoided, and the bioavailability is high;
3. does not stimulate the gastrointestinal tract, avoids uncomfortable feeling and infection risk of repeated injection and has small side effect, thereby being a drug delivery mode with great potential.
However, a large barrier of transdermal drug delivery is skin tissue, the special physicochemical properties of the skin tissue greatly reduce the transdermal absorption efficiency of drugs, and how to deliver a plurality of drugs transdermally with high efficiency is a big problem.
Disclosure of Invention
The present invention is directed to solving at least one of the above problems and to providing an anti-synovitis microneedle patch and a method for manufacturing the same.
The invention achieves the above purpose through the following technical scheme: a method of preparing a microneedle patch for anti-synovitis, the method comprising:
step one, preparing an inclusion compound aqueous solution of mint, camphor and borneol;
step two, mixing the clathrate compound aqueous solution with glucosamine, chondroitin sulfate, traditional Chinese medicine extract and a thermal inductance agent to form a mixture A;
step three, forming a needle tip solution by taking a pullulan solution as a substrate in the mixture A;
adding the needle point solution into a PDMS mold, and drying after removing bubbles in vacuum;
and step five, pouring a back lining layer solution, performing vacuum drying again, and demolding to obtain the compound microneedle patch.
As a still further scheme of the invention: in the first step, peppermint, camphor and borneol are prepared into inclusion compound aqueous solution by using hydroxypropyl-beta-cyclodextrin.
As a still further scheme of the invention: in the first step, the concentration ranges of the mint, the camphor and the borneol are 0.5-1.5%, 1-3% and 0.5-1.5% in sequence.
As a still further scheme of the invention: in the second step, the concentration ranges of the glucosamine, the chondroitin sulfate, the extract and the thermal inductance agent are 4-8%, 2-6%, 3-7% and 1-3% in sequence.
As a still further scheme of the invention: in the third step, the concentration of the pullulan polysaccharide solution is 15-30% (w/w).
As a still further scheme of the invention: in the fourth step, the PDMS mold is 7cm × 7cm in size and contains 87 × 87 microneedle bodies with a length of 500 μm.
As a still further scheme of the invention: in the fifth step, the backing layer solution is an ethyl cellulose ethanol solution, and the concentration of the ethyl cellulose ethanol solution is 5-20% (w/w).
The microneedle patch comprises a backing layer and microneedle bodies, wherein the backing layer and the microneedle bodies are respectively cast and integrally connected;
wherein the back lining layer is ethyl cellulose, and the micro needle body is uniformly dispersed with glucosamine, chondroitin, mint, camphor, borneol, a water-based heat-sensitive agent and pullulan polysaccharide gel of traditional Chinese medicine extract.
The invention has the beneficial effects that: the camphor and the borneol have the effects of dissipating heat and relieving pain, the mint can play the roles of dispelling wind and removing dampness, and dissipating heat and relieving pain, and the chondroitin sulfate can reduce the joint swelling, accelerate the recovery of hydrops and promote the regeneration of cartilage; the glucosamine can repair cartilage, resist inflammation and reduce swelling; the heat-sensitive agent can generate heat and promote blood circulation. The compound microneedle patch can effectively reduce the inflammation of immune cells related to synovitis and the joint swelling degree and inflammation level of arthritis mice, is expected to efficiently treat the synovitis, realizes the common delivery of fat-soluble drugs and water-soluble drugs by a drug inclusion technology, has larger area and total drug loading amount compared with other microneedle patches, and can better meet the treatment requirement.
Drawings
FIG. 1 is a schematic diagram of the preparation process of the present invention;
FIG. 2 is an infrared spectrum of mint prepared according to the present invention, and inclusion compounds and mixtures thereof of mint and HP-beta-CD;
FIG. 3 is an infrared spectrum of the clathrate and the mixture of borneol and HP-beta-CD prepared by the present invention;
FIG. 4 is an infrared spectrum of camphor, and inclusion compounds and mixtures of camphor and HP-beta-CD prepared according to the present invention;
fig. 5 is a picture of the overall morphology of a microneedle patch prepared in accordance with the present invention and a toughness test thereof;
fig. 6 is an enlarged partial view of a microneedle patch of the present invention;
fig. 7 is a schematic diagram showing cytotoxicity of the microneedle patch of the present invention to macrophage RAW264.7 and vascular endothelial cell HUVEC;
fig. 8 is an in vitro anti-inflammatory effect of the microneedle patch of the present invention on inflammatory macrophage RAW264.7 and inflammatory vascular endothelial cell HUVEC;
fig. 9 is a therapeutic effect of the microneedle patch of the present invention on adjuvant-induced joint swelling and inflammation in arthritic mice.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Examples
A method of preparing an anti-synovitis microneedle patch, the method comprising:
firstly, the method comprises the following steps: preparing an inclusion compound aqueous solution of mint, camphor and borneol, wherein the mint, the camphor and the borneol are prepared into the inclusion compound aqueous solution by using hydroxypropyl-beta-cyclodextrin, and the concentration ranges of the mint, the camphor and the borneol are 0.5-1.5%, 1-3% and 0.5-1.5% in sequence.
Dissolving mint, camphor and borneol in absolute ethyl alcohol to obtain a solution A, dissolving hydroxypropyl-beta-cyclodextrin in water to obtain a solution B, and dropwise adding A into the solution B under the stirring state to obtain an inclusion compound aqueous solution.
Secondly, the method comprises the following steps: mixing the clathrate compound aqueous solution with glucosamine, chondroitin sulfate, traditional Chinese medicine extract and a thermal inductance agent to form a mixture A; the concentration ranges of the glucosamine, the chondroitin sulfate, the extract and the thermal inductance agent are 4-8%, 2-6%, 3-7% and 1-3% in sequence.
Thirdly, the method comprises the following steps: the mixture A takes a pullulan solution as a substrate to form a needlepoint solution; the concentration of the pullulan solution is 15-30% (w/w).
Mixing glucosamine, chondroitin sulfate and pullulan, adding water, stirring, mixing with the clathrate aqueous solution, adding the Chinese medicinal extract and water-soluble heat-sensitive agent, and stirring to obtain needle tip solution.
Fourthly: adding the needle point solution into a PDMS mold, and drying after removing bubbles in vacuum; the PDMS mold was 7cm × 7cm in size and contained 87 × 87 microneedle bodies with a needle length of 500 μm.
Fifth, the method comprises the following steps: pouring a back lining layer solution, and demolding after vacuum drying again to obtain the compound microneedle patch; the back lining layer solution is ethyl cellulose ethanol solution, and the concentration of the ethyl cellulose ethanol solution is 5-20% (w/w).
And adding the needle point solution into a PDMS mold, leveling to cover the whole PDMS mold, placing the PDMS mold in a vacuum drying oven, vacuumizing, scraping off redundant needle point solution, repeating the steps for three times to ensure that the needle point solution fully enters the cavity of the PDMS mold, and drying the needle body. Pouring a backing layer solution into the PDMS mould after drying, then vacuumizing, removing air in gaps between the backing layer solution and the needle tip body due to the shrinkage of the needle tip solution after drying, adding the backing layer solution again, scraping off excessive solution on the surface, slowly adding the backing layer solution after repeating the operation, and drying.
The microneedle patch comprises a backing layer and microneedle bodies, wherein the backing layer and the microneedle bodies are respectively cast and formed and integrally connected.
Wherein the back lining layer is ethyl cellulose, and the micro needle body is uniformly dispersed with glucosamine, chondroitin, mint, camphor, borneol, a water-based heat-sensitive agent and pullulan polysaccharide gel of traditional Chinese medicine extract. The mint, camphor and borneol are water-insoluble substances, and are included by hydroxypropyl-beta cyclodextrin, so that good water-solubility characteristics can be obtained.
Example two
As shown in fig. 1 to 9, the present embodiment provides a microneedle patch for resisting synovitis, which comprises a backing layer and a microneedle body, wherein all drugs are located in the microneedle body by respectively casting and integrally connecting the backing layer and the microneedle body, and after application, the microneedle body is dissolved in the skin and releases the drugs, and the backing layer is removed.
Specifically, the microneedle body is made of pullulan as a matrix, the back lining layer is made of ethyl cellulose, glucosamine, chondroitin sulfate, a traditional Chinese medicine extract and a water-based heat-sensitive agent are directly loaded into the microneedle body, and the mint, the camphor and the borneol need to be made into inclusion compounds to improve the solubility and then are dissolved in the microneedle body, and the inclusion compounds are quickly released along with the dissolution of the microneedle body after application to relieve the symptoms of synovitis (as shown in figure 1).
The preparation method comprises the following steps:
(1) Preparation and characterization of aqueous solution of inclusion compound of mint, camphor and borneol
Firstly, mixing mint, borneol and camphor in a ratio of 1:1:2 in absolute ethyl alcohol to obtain a solution A, then dissolving hydroxypropyl-beta-cyclodextrin in water to obtain a solution B, and dropwise adding the solution A into the solution B under the stirring state to obtain an inclusion compound solution of mint, borneol and camphor.
Dropwise adding the traditional Chinese medicine extract into the clathrate under stirring to form a uniform brown solution, adding 1% of thermal sensation agent twice each time, and dropwise adding the rest thermal sensation agent after the thermal sensation agent is uniformly mixed.
The infrared spectra of mint, camphor, borneol, mint, HP-beta-CD, camphor and HP-beta-CD, borneol and HP-beta-CD, mint HP-beta-CD inclusion compound, borneol HP-beta-CD inclusion compound and camphor HP-beta-CD inclusion compound are respectively measured, and the characteristic absorption peaks of O-H of the three substances exist in the chart, and the peak shapes of the three substances are widened after the three substances are mixed or form the inclusion compound, so that the HP-beta-CD and the three substances exist mutual acting force. At 1160cm-1 to 900cm-1, the peak of clathrate absorption for the three substances was significantly reduced, probably due to the fact that the groups forming the absorption peak in this region were encapsulated by HP- β -CD after clathrate formation, and the absorption peak was masked by the absorption peak of HP- β -CD (FIG. 2 to FIG. 4). Camphor, however, has its characteristic absorption peak of carbonyl group at 1741cm-1, and HP- β -CD mixture, which is attenuated by interference of other peaks, but the absorption peak becomes evident after clathrate formation, probably because carbonyl group is exposed alone after clathrate formation (FIG. 4), and finally, the absorption peaks of clathrates of three substances show similar characteristics, indicating the formation of clathrates.
(2) Preparation of anti-synovitis compound microneedle patch
Microneedle patches were prepared using a mold method using a 7cm side PDMS mold containing 87 x 87 needles 500 μm long.
The microneedle is prepared by adopting a two-step pouring method, the microneedle tip solution is firstly coated on a mold and then placed in a vacuum drying oven, the temperature is set to be 20 ℃, after 20min of vacuum, the redundant liquid is scraped off, after three times of repeated operation, the temperature is set to be 35 ℃, after 12h of drying, a back lining layer is poured and coated, the back lining layer is placed in the vacuum drying oven, the vacuum pumping is carried out for 20min, the redundant solution is removed, then the back lining layer is continuously poured, and after 24h of drying, the microneedle is obtained by demolding.
(3) Anti-synovitis compound microneedle patch performance evaluation
The obtained microneedle is concave under the condition of no external force, can be well matched with knee joint, has good toughness through bending, and is easy to store (as shown in figure 5). The tip is shown in a magnified view in the form of a quadrangular pyramid (see FIG. 6).
(4) Detection of cytotoxicity of microneedle
The microneedle patch, human umbilical vein epithelial cells HUVEC and mouse macrophage RAW264.7 are co-cultured for 24 hours, and the cell survival rate of the two cells after co-incubation with the microneedle patch is respectively determined by adopting a CCK-8 method. The results show that the drug-loaded microneedle patch has very slight cytotoxicity, and the cytotoxicity slightly increases with increasing drug-loading concentration (as in fig. 7).
(5) In vitro anti-inflammatory Activity evaluation of microneedles
Respectively stimulating HUVEC (human umbilical vein epithelial cells) and RAW (mouse macrophage) for 264.7 hours by using 1 mu g/mL bacterial Lipopolysaccharide (LPS), and establishing an inflammatory cell model. After stimulation of LPS, both HUVEC (human umbilical vein epithelial cells) and RAW264.7 of mouse macrophages highly express inflammatory cytokines IL-6 and TNF-alpha, microneedle patches with different drug loading rates are respectively cultured with the HUVEC and RAW264.7 of the inflammatory mouse macrophages for 24 hours, cell supernatant is collected and centrifuged at the rotating speed of 300g for 10min to remove impurities, and the content of the inflammatory cytokines IL-6 and TNF-alpha in the cell supernatant is detected by adopting an ELISA kit. The results show that the drug-loaded microneedle patch can reduce the secretion of IL-6 and TNF-alpha by inflammatory cells, and the inhibition rate of inflammatory factors of the microneedle patch is increased along with the increase of the drug-loaded concentration (as shown in figure 7).
(6) Evaluation of efficacy of microneedle against synovitis in vivo
As shown in fig. 8 and 9, a arthritis model was established using male kunming mice, and after acclimatization, the toe of the mice was sterilized, and then complete freund's adjuvant was injected subcutaneously into the toe (day 1), and a booster dose was injected again one week later, to establish an adjuvant-induced arthritis model. The toe swelling degree and physiological state of the mice are observed every other day in the molding process. On day 14, the joints of the mice showed significant swelling and stiffness, and the success of molding was judged. Mice successfully modelled were randomly divided into 5 groups, respectively: a normal saline treatment group, a dexamethasone treatment group, a low dose treatment group, a medium dose treatment group, and a high dose treatment group, and a healthy control group was also established. The dosage of Dex group is 0.02 mg/mouse, the healthy control group and the model control group are injected with physiological saline with the same volume, and the normal saline is administrated every other day, 200 mu L of each time, and the normal saline is administrated for 5 times (respectively administrated on days 15, 17, 19, 21 and 23), the toe swelling degree of the mice is observed and measured every other day, the experiment is ended on day 24, the serum of the mice is collected, and the contents of two inflammatory cytokines of IL-6 and TNF-alpha in the serum of the mice of different treatment groups are evaluated. In the treatment process, both the Dex and each microneedle treatment group can reduce the toe swelling degree of an arthritic mouse, and the efficiency of the microneedles for reducing the swelling degree of the arthritic mouse tends to be enhanced along with the increase of the drug loading amount. After the treatment is finished, the toe swelling degree of the mice in the high-dose treatment group is lowest, and the concentration of IL-6 and TNF-alpha in the serum of the mice in the group is lowest, which indicates that the treatment effect is best and is equivalent to that of a powerful anti-inflammatory drug Dex.
The working principle is as follows: the compound microneedle patch is prepared by including mint, camphor and borneol by adopting hydroxypropyl-beta-cyclodextrin to improve the water solubility of the components and reduce the volatilization of the components, then loading the inclusion compound, water-soluble chondroitin sulfate, glucosamine, traditional Chinese medicine extract and a thermal sensing agent by using microneedles to obtain the compound microneedle patch, and the compound microneedle patch simultaneously loads and delivers a plurality of medicines and nutrients capable of treating and alleviating Jie Huamo inflammation, directly pierces the stratum corneum barrier of the skin, delivers the medicines to the dermis layer rich in capillary vessels, and remarkably improves the transdermal absorption efficiency of the medicines.
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. Any reference sign in a claim should not 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.

Claims (8)

1. A preparation method of an anti-synovitis microneedle patch is characterized by comprising the following steps:
step one, preparing an inclusion compound aqueous solution of mint, camphor and borneol;
step two, mixing the clathrate compound aqueous solution with glucosamine, chondroitin sulfate, traditional Chinese medicine extract and a thermal inductance agent to form a mixture A;
step three, forming a needle tip solution by taking a pullulan solution as a substrate in the mixture A;
adding the needle point solution into a PDMS mold, and drying after removing bubbles in vacuum;
and step five, pouring a back lining layer solution, performing vacuum drying again, and demolding to obtain the compound microneedle patch.
2. The method of claim 1, wherein: in the first step, peppermint, camphor and borneol are prepared into inclusion compound aqueous solution by using hydroxypropyl-beta-cyclodextrin.
3. The method of claim 1, wherein: in the first step, the concentration ranges of the mint, the camphor and the borneol are 0.5-1.5%, 1-3% and 0.5-1.5% in sequence.
4. The method of claim 1, wherein: in the second step, the concentration ranges of the glucosamine, the chondroitin sulfate, the extract and the thermal inductance agent are 4-8%, 2-6%, 3-7% and 1-3% in sequence.
5. The method of claim 1, wherein: in the third step, the concentration of the pullulan polysaccharide solution is 15-30% (w/w).
6. The method of claim 1, wherein: in the fourth step, the PDMS mold is 7cm × 7cm in size and contains 87 × 87 microneedle bodies with a length of 500 μm.
7. The method of claim 1, wherein: in the fifth step, the backing layer solution is an ethyl cellulose ethanol solution, and the concentration of the ethyl cellulose ethanol solution is 5-20% (w/w).
8. A microneedle patch based on the preparation method of the anti-synovitis microneedle patch according to claim 1, wherein the microneedle patch comprises a backing layer and microneedle bodies, and the backing layer and the microneedle bodies are respectively formed by casting and integrally connected;
wherein the back lining layer is ethyl cellulose, and the micro needle body is uniformly dispersed with glucosamine, chondroitin, mint, camphor, borneol, a water-based heat-sensitive agent and pullulan polysaccharide gel of traditional Chinese medicine extract.
CN202211402942.3A 2022-11-09 2022-11-09 Anti-synovitis microneedle patch and preparation method thereof Pending CN115645380A (en)

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