CN115475325A - Novel tranexamic acid hyaluronic acid microneedle for treating chloasma and preparation method thereof - Google Patents
Novel tranexamic acid hyaluronic acid microneedle for treating chloasma and preparation method thereof Download PDFInfo
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- CN115475325A CN115475325A CN202211106981.9A CN202211106981A CN115475325A CN 115475325 A CN115475325 A CN 115475325A CN 202211106981 A CN202211106981 A CN 202211106981A CN 115475325 A CN115475325 A CN 115475325A
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- hyaluronic acid
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 78
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- 229960000401 tranexamic acid Drugs 0.000 title claims abstract description 56
- 206010008570 Chloasma Diseases 0.000 title claims abstract description 11
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- Animal Behavior & Ethology (AREA)
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- Inorganic Chemistry (AREA)
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Abstract
The invention provides a preparation method of a novel tranexamic acid hyaluronic acid microneedle for treating chloasma. The microneedle is prepared by a casting method by utilizing the dissolvability of hyaluronic acid. Finally forming the micro-needle patch which has certain mechanical strength and biocompatibility and is connected with the base by a plurality of micro-sized fine needle points in an array mode. The microneedle formed by the invention can penetrate through the surface layer of the skin, can transmit the tranexamic acid to the basal layer of the skin through simple one-time operation, and then the tranexamic acid is competitively combined with the tyrosinase to inhibit the activity of the tyrosinase, thereby reducing the formation of melanin and playing a role in treating chloasma.
Description
Technical Field
The invention relates to the technical field of microneedle drug delivery development, in particular to a preparation method of tranexamic acid-loaded hyaluronic acid.
Background
Tranexamic acid is a protease inhibitor that, on the one hand, inhibits melanin formation by inhibiting the interaction of the plasminogen-fibrinolytic system interfering melanocytes and keratinocytes, reducing tyrosinase activity; on the other hand, tranexamic acid and tyrosine have similar chemical structures, can be competitively combined with tyrosinase to inhibit the activity of the tyrosinase, thereby reducing the formation of melanin and finally playing a role in treating chloasma. Microneedles are an emerging transdermal technology that is widely used in the medical field, such as drug delivery, wound healing promotion, vaccination, interstitial fluid extraction and biomarker detection, cosmetic, and the like. Hyaluronic acid is one of the main components of skin, has excellent biocompatibility and in-vivo degradability, and is one of natural polymer materials for preparing soluble microneedles. The microneedle prepared by using the hyaluronic acid has high mechanical strength and can penetrate through the surface layer of the skin. At present, the chloasma is usually treated by combining a microneedle technology with externally applied tranexamic acid clinically, but the operation steps are relatively complicated, so that a novel tranexamic acid hyaluronic acid microneedle for treating the chloasma is designed and prepared, is simple and convenient to operate and has a very high practical value.
Disclosure of Invention
The invention aims to design and prepare a tranexamic acid-loaded hyaluronic acid microneedle based on good biological safety and strong mechanical property of hyaluronic acid and the effect of reducing melanin formation of tranexamic acid aiming at the problem of complicated operation of clinically adopting a microneedle technology and externally applying the tranexamic acid to treat chloasma.
According to an aspect of the present invention, there is provided a hyaluronic acid microneedle for treating chloasma, the hyaluronic acid microneedle including tranexamic acid.
In the hyaluronic acid microneedle provided by the invention, the mass ratio of tranexamic acid to hyaluronic acid to ultrapure water is 1.
According to another aspect of the present invention, there is also provided a method for preparing tranexamic acid-loaded hyaluronic acid microneedles, the method comprising the steps of:
s1, respectively dissolving separate hyaluronic acid powder and powder mixed with tranexamic acid and hyaluronic acid in ultrapure water, and fully dissolving the mixed solution by using a vortex oscillator and ultrasound;
s2, adding the solution mixed with the tranexamic acid and the hyaluronic acid obtained in the step S1 into a PDMS mold, fully centrifuging, removing redundant solution, then adding a solution only containing the hyaluronic acid into a base layer of the PDMS mold, and centrifuging again;
and S3, placing the PDMS mold filled with the solution after the secondary centrifugation at room temperature for overnight drying, and finally demolding to obtain the hyaluronic acid microneedle with certain mechanical strength.
In the preparation method provided by the present invention, in step S1, the concentration of the hyaluronic acid solution alone is 300mg/ml, and in the solution in which tranexamic acid and hyaluronic acid are mixed, the concentration of hyaluronic acid is 300mg/ml and the concentration of tranexamic acid is 50mg/ml.
In the preparation method provided by the invention, in the step S2, the rotating speed of the two times of centrifugation is 4200rpm/min, and the time is 20 minutes.
According to still another aspect of the present invention, the bio-safety of tranexamic acid-loaded hyaluronic acid microneedles as described above was also verified.
The preparation method of the tranexamic acid-loaded hyaluronic acid microneedle has the following beneficial effects: compared with the traditional administration method of locally injecting tranexamic acid, the hyaluronic acid micro-needle has simpler operation and does not need to be operated by professional personnel; compared with a method that the microneedle technology is combined with external application of tranexamic acid and two-step operation is needed, the tranexamic acid can directly reach the skin basal layer along with the hyaluronic acid microneedle, the operation steps are simplified, and the tranexamic acid can be rapidly diffused and play a role. Therefore, compared with a treatment method combining local injection of tranexamic acid or microneedle technology with external tranexamic acid, the tranexamic acid-loaded hyaluronic acid microneedle not only saves the administration time of external drugs, improves the drug concentration, but also simplifies the operation steps, reduces the operation difficulty, improves the compliance of patients, and can be well used for treating chloasma.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art descriptions will be briefly described below, it is obvious that the drawings in the following description are only examples of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts:
fig. 1 is a process for preparing tranexamic acid-loaded hyaluronic acid microneedles according to the present invention;
FIG. 2 is a scanning electron microscope image of tranexamic acid-loaded hyaluronic acid microneedles of the present invention;
fig. 3 is a mechanical property test result of the hyaluronic acid microneedle of the present invention;
FIG. 4 is a graph showing the in vitro penetration rate detection of tranexamic acid microneedle-loaded hyaluronic acid;
FIG. 5 is a laser confocal observation of the situation of simulating tranexamic acid transdermal absorption after a hyaluronic acid microneedle loaded with rhodamine 6G penetrates into pigskin;
FIG. 6 is a picture of HE staining after a microneedle prepared according to the present invention has penetrated into a pigskin;
fig. 7 is a graph showing the effect of tranexamic acid-loaded hyaluronic acid microneedles on cell viability after coculture with HDF cells.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Exemplary embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The method for preparing tranexamic acid-loaded hyaluronic acid microneedles according to the present invention will be further described with reference to the accompanying drawings and examples:
a preparation method of tranexamic acid-loaded hyaluronic acid microneedles comprises the following steps:
s1, respectively dissolving separate hyaluronic acid powder and powder mixed with tranexamic acid and hyaluronic acid in ultrapure water, and fully dissolving the mixed solution by using a vortex oscillator and ultrasound;
specifically, in step S1, the concentration of the separate hyaluronic acid solution is 300mg/ml, and in the solution in which tranexamic acid and hyaluronic acid are mixed, the concentration of hyaluronic acid is 300mg/ml and the concentration of tranexamic acid is 50mg/ml.
S2, adding the solution mixed with tranexamic acid and hyaluronic acid obtained in the step S1 into a PDMS mold, fully centrifuging, removing redundant solution, adding a solution only containing hyaluronic acid into the basal layer of the PDMS mold, and centrifuging again;
specifically, in step S2, the rotation speed of the two centrifugations is 4200rpm/min, and the time is 20 minutes.
And S3, drying the PDMS mold filled with the solution after the secondary centrifugation at room temperature overnight, and finally demolding to obtain the hyaluronic acid microneedle with certain mechanical strength.
The following examples are intended to illustrate the invention in more detail. The embodiments of the present invention are not limited to the following specific embodiments. The present invention can be modified and implemented as appropriate within the scope of the main claim.
Example 1
The embodiment relates to a tranexamic acid-loaded hyaluronic acid microneedle, which is prepared by the following steps: 300mg of hyaluronic acid powder alone, 50mg of tranexamic acid mixed with the hyaluronic acid powder, and 300mg of hyaluronic acid powder were dissolved in 1ml of ultrapure water, respectively, and the mixed solution was sufficiently dissolved by a vortex shaker and ultrasonic waves. According to the process of FIG. 1, 90ul of the mixed solution containing tranexamic acid and hyaluronic acid was injected into a PDMS mold, and centrifuged in a centrifuge at 4200rpm/min for 20 minutes. After centrifugation, excess solution was removed, and then 90ul of a solution containing only hyaluronic acid was added to the base layer of the PDMS mold, which was centrifuged again at 4200rpm/min for 20 minutes. Then, the PDMS mold filled with the solution after the secondary centrifugation was dried overnight at room temperature, and finally demolded to obtain 10 tranexamic acid-loaded hyaluronic acid microneedles.
Example 2
The embodiment relates to a rhodamine 6G-loaded hyaluronic acid microneedle, and the preparation method comprises the following steps: preparing a mixed solution containing rhodamine 6G and hyaluronic acid, wherein the concentration of the rhodamine 6G is 4mg/ml, the concentration of the hyaluronic acid is 300mg/ml, and the solvent is ultrapure water, and fully dissolving the mixed solution by using a vortex oscillator and ultrasound. 180ul of the mixed solution was injected into a PDMS mold, and placed in a centrifuge for centrifugation at 4200rpm/min for 20 minutes. And after centrifugation, placing the PDMS mold at room temperature overnight for drying, and finally demolding to obtain the rhodamine 6G loaded hyaluronic acid microneedle.
Example 3
Fresh pigskin purchased from a local farmer market is cut into the size of about 2cm multiplied by 2cm, one of the pigskin is flatly laid on a laboratory table, hyaluronic acid micro-needles loaded with rhodamine 6G are vertically penetrated into the pigskin, and the micro-needles are removed after 3 minutes. And calculating the ratio of the number of red spots on the pigskin to the number of the microneedle bodies to finally obtain the in-vitro penetration rate of the hyaluronic acid microneedle with the concentration of 300 mg/ml. The results showed that 300mg/ml hyaluronic acid microneedles had a penetration rate of 100% in vitro.
Example 4
Fresh pigskin purchased from a local farmer market is cut into the size of about 2cm multiplied by 2cm, one of the pigskin is flatly laid on a laboratory table, hyaluronic acid micro-needles loaded with rhodamine 6G are vertically penetrated into the pigskin, and the micro-needles are removed after 3 minutes. And wiping off redundant red rhodamine 6G on the surface of the pigskin by using a wet cotton ball, and then placing the pigskin under a confocal microscope. Finding the point with the brightest fluorescence intensity under the condition that the exciting light is 532 nm; then, adjusting the microscope on the same Z axis to find the critical point with the weakest fluorescence intensity; then, fluorescence images are taken every 10um between the two points, so that a series of images simulating the depth that the medicine rhodamine 6G can reach the skin are obtained. The results show that the rhodamine 6G loaded hyaluronic acid microneedle can reach the depth of 210um at least and can penetrate the surface layer of the skin.
Example 5
Fresh pigskin purchased from a local farmer market is cut into about 2cm × 2cm, one of the pieces is flatly laid on a laboratory table, hyaluronic acid microneedles loaded with tranexamic acid are vertically inserted into the pigskin, and then the microneedles are immediately pulled out and put into a 15ml centrifuge tube filled with 4% paraformaldehyde for fixation. Then HE staining of the tissue section was performed, and the change of the epidermal tissue of the pig skin after the microneedle was inserted was observed. The result shows that the tranexamic acid-loaded hyaluronic acid microneedle can penetrate into the surface layer of the pigskin and has good mechanical strength.
Example 6
Human skin fibroblasts HDF-a were seeded in 96-well plates at 105 cells per well and after attachment, washed once with PBS. 5 groups are set, fresh culture mediums are added respectively, the culture mediums of the simple hyaluronic acid micro needles for 1 hour and 16 hours are dissolved, and the culture mediums of the hyaluronic acid micro needles loaded with tranexamic acid for 1 hour and 16 hours are dissolved for 100ul. After 24 hours, 10ul of CCK8 solution was added to each well. After one and a half hour of incubation, cell viability was measured with a microplate reader at a wavelength of 450 nm. Wherein 1 hour and 16 hours represent short-term and long-term contact with the skin. The wells with medium alone added are control and the viability of the remaining cells is calculated using normalization. The results show that the hyaluronic acid microneedle which is pure and loaded with tranexamic acid does not influence the cell activity of human skin fibroblasts, and the in vitro biological safety of the tranexamic acid-loaded hyaluronic acid microneedle is proved.
While the present invention has been described with reference to the embodiments shown in the drawings, the present invention is not limited to the embodiments, which are illustrative and not restrictive, and it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (6)
1. A microneedle for treating chloasma, which comprises hyaluronic acid and tranexamic acid.
2. The hyaluronic acid microneedle according to claim 1, wherein the mass ratio of tranexamic acid, hyaluronic acid and ultrapure water is 1.
3. A preparation method of a novel tranexamic acid hyaluronic acid microneedle is characterized by comprising the following steps:
s1, respectively dissolving separate hyaluronic acid powder and powder mixed with tranexamic acid and hyaluronic acid in ultrapure water, and fully dissolving the solution by using a vortex oscillator and ultrasound;
s2, adding the solution mixed with tranexamic acid and hyaluronic acid obtained in the step S1 into a PDMS mold, fully centrifuging, removing redundant solution, adding a solution only containing hyaluronic acid into the basal layer of the PDMS mold, and centrifuging again;
and S3, placing the PDMS mold filled with the solution after the secondary centrifugation at room temperature for overnight drying, and finally demolding to obtain the hyaluronic acid microneedle with certain mechanical strength.
4. The method according to claim 3, wherein the hyaluronic acid solution alone has a concentration of 300mg/ml, and the solution containing tranexamic acid and hyaluronic acid has a concentration of 300mg/ml and 50mg/ml, respectively, in step S1.
5. The method according to claim 3, wherein in step S2, the rotation speed of the two centrifugations is 4200rpm/min, and the time is 20 minutes.
6. The biosafety of the novel tranexamic acid hyaluronic acid microneedle of claim 1 or 2.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211106981.9A CN115475325A (en) | 2022-09-09 | 2022-09-09 | Novel tranexamic acid hyaluronic acid microneedle for treating chloasma and preparation method thereof |
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| CN202211106981.9A CN115475325A (en) | 2022-09-09 | 2022-09-09 | Novel tranexamic acid hyaluronic acid microneedle for treating chloasma and preparation method thereof |
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| CN107375008A (en) * | 2017-07-19 | 2017-11-24 | 广州新济药业科技有限公司 | Soluble microneedle patch for whitening and preparation method thereof |
| CN111184942A (en) * | 2020-03-18 | 2020-05-22 | 四川大学华西医院 | Soluble microneedle for treating chloasma |
| CN113679692A (en) * | 2020-05-15 | 2021-11-23 | 华中科技大学 | Microneedle array patch capable of generating gas and quickly taking effect and preparation and application thereof |
| CN114432232A (en) * | 2022-04-07 | 2022-05-06 | 广州纳丽生物科技有限公司 | Preparation method of sustained-release microneedle for removing chloasma |
| CN114939080A (en) * | 2022-06-14 | 2022-08-26 | 广州贝奥吉因生物科技股份有限公司 | Microneedle for removing black and whitening skin and preparation method and application thereof |
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| CN107375008A (en) * | 2017-07-19 | 2017-11-24 | 广州新济药业科技有限公司 | Soluble microneedle patch for whitening and preparation method thereof |
| CN111184942A (en) * | 2020-03-18 | 2020-05-22 | 四川大学华西医院 | Soluble microneedle for treating chloasma |
| CN113679692A (en) * | 2020-05-15 | 2021-11-23 | 华中科技大学 | Microneedle array patch capable of generating gas and quickly taking effect and preparation and application thereof |
| CN114432232A (en) * | 2022-04-07 | 2022-05-06 | 广州纳丽生物科技有限公司 | Preparation method of sustained-release microneedle for removing chloasma |
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