CN115227636A - BSH-loaded soluble microneedle transdermal delivery system and preparation method and application thereof - Google Patents
BSH-loaded soluble microneedle transdermal delivery system and preparation method and application thereof Download PDFInfo
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- A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
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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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- 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
- A61M2037/0061—Methods for using microneedles
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Abstract
The invention relates to the technical field of tumor treatment, and provides a soluble microneedle transdermal delivery system loaded with BSH, and a preparation method and application thereof. The soluble microneedle transdermal drug delivery system loaded with BSH comprises a substrate made of hyaluronic acid and microneedles, wherein the boron drug BSH is loaded in the microneedles. The invention also provides a preparation method of the BSH-loaded soluble microneedle transdermal delivery system by using a vacuum drying method, which comprises the steps of firstly preparing a BSH solution and an HA solution, then filling the BSH solution into a cleaned microneedle mould, after vacuum drying and exhausting air in the microneedle mould, injecting an NA solution into the microneedle mould for ultrasonic mixing, drying the microneedle mould, demoulding, packaging and sterilizing to obtain the BSH-loaded soluble microneedle transdermal delivery system. The invention adopts the soluble microneedle loaded with BSH to be applied to BNCT, improves the concentration of boron medicine enriched in tumor, reduces the dosage of boron medicine and toxic and side effects on normal tissues, and effectively improves the curative effect of boron neutron capture treatment.
Description
Technical Field
The invention relates to the technical field of tumor treatment, in particular to a soluble microneedle transdermal delivery system loaded with BSH (B-schwann) and a preparation method and application thereof.
Background
Radiation tumor is used as a conventional technical means for treating malignant tumor, and damages normal tissues while treating tumor, resulting in serious toxic and side effects. Clinical tension is often limited by the dose tolerated by normal tissues such that adequate radiation doses cannot be administered to tumors, resulting in failure of tumor therapy. Boron Neutron Capture Therapy (BNCT) is used as a binary, cell-scale and strong-targeting accurate radiotherapy mode, has remarkable advantages compared with the traditional radiotherapy, has excellent killing effect on malignant tumors such as melanoma, glioma and recurrent head and neck cancer, and is beneficial to solving the targeted radiotherapy of tumors.
The killing of cells by Boron Neutron Capture Therapy (BNCT) relies on non-radioactive isotopes 10 B, after capturing thermal neutrons, generating alpha particles and back flushing 7 Li nuclei, all of which have high linear mass transfer and a certain penetration ability, but have a limited penetration ability (5 to 9 μm, about one cell diameter), so that they can kill only tumor cells without damaging cells of normal tissues. Boron neutron capture therapy as a binary therapy is divided into two treatment processes: boron drug delivery and neutron irradiation; firstly, the boron drug delivery process is carried out, and the boron carrying agent is injected to ensure that each tumor cell is internally provided with the boron carrier 10 The number of B atoms is not less than 10 9 Second, neutron irradiation process, which causes the tumor cells to be irradiated with neutrons 10 The B atom absorbs neutrons producing cytocidal power. At present, benefiting from linear accelerator neutronsThe development of sources and neutron irradiation technology have been effectively solved, so the limitation of boron neutron capture therapy at present is mainly focused on the boron drug delivery process. Therefore, in order to ensure the therapeutic effect of boron neutron capture therapy, efforts are made to deliver boron drugs for BNCT therapy.
To ensure optimal therapeutic efficacy of BNCT, boron carriers need to meet the following requirements: (1) In tumor cells 10 The content of B is not less than 20 μ g/g, i.e. each tumor cell contains at least 10 9 An 10 A B atom; (2) The ratio of the boron concentration in the tumor tissue to the boron concentration in the normal tissue (T/N) and the ratio of the boron concentration in the tumor tissue to the boron concentration in the blood (T/B) are all more than 3; (3) Can be retained in tumor cells for a long time, and can be cleared from blood and normal tissues at a higher speed; (4) Has low intrinsic toxicity and is used to increase the maximum tolerated dose for boron carriers.
Currently, boron carriers have been developed to the second generation. The first generation of boron carriers are borax, boric acid and derivatives thereof, which lack tumor specificity, resulting in poor therapeutic effect and susceptibility to serious side effects when applied to BNCT therapy. The second generation boron carrier adopts 4-dihydroxyborol-L-phenylalanine (BPA) and sodium undecylmercapto dodecaboride (BSH), BPA and BSH are used as the only medicines clinically applied to the BNCT process at present, but BPA and BSH still have certain defects, BPA can be selectively accumulated in tumors through amino acid transporters rich in LAT1 and other tumors, but the BPA is easily discharged by tumor cells under the influence of a reverse transport mechanism, the retention time is short, and BPA also has the problems of poor water solubility and low boron content. BSH has a problem of poor tumor specificity. Therefore, in order to solve the problems of applying BPA and BSH to BNCT, researchers are working on developing a third generation boron carrier including boron-containing small molecules (amino acid derivatives, porphyrin derivatives, etc.), boron-containing biological macromolecules (specific ligands, monoclonal antibodies, etc.), and boron-containing nano-drugs (liposomes, boron carbide nano-materials, boron nitride nano-materials, etc.).
The clinical BSH adopts an intravenous injection mode when being applied to boron neutron capture treatment, because the boron dosage required by the boron neutron capture treatment is higher and the BSH dosage required by the clinical application to BNCT is 100mg/kg, the neutron irradiation is required to be carried out while dripping in the BNCT process, which is very inconvenient, and the medicament is distributed on the whole body after intravenous dripping, so that the toxic and side effects on normal tissues can be increased, and the mode of transdermal administration for replacing the intravenous injection can be adopted.
Transdermal drug delivery can avoid the first pass effect because of its unique mode of administration, has the characteristics of preventing gastrointestinal tract side effect, improving patient compliance, but traditional transdermal drug delivery adopts the paster preparation to administer, because the skin stratum corneum has the barrier effect, the transdermal rate is low and the infiltration capacity is low when the medicine is absorbed transdermally. Therefore, in order to deliver a sufficient amount of boron drug into tumor cells during BNCT, it is highly desirable to improve transdermal delivery to increase the enrichment of BSH in tumor cells, improve the effect of boron neutron capture therapy, and promote the development of boron neutron capture therapy.
Disclosure of Invention
The invention aims to solve the problem of delivering sufficient BSH into tumor cells, and provides a BSH-loaded soluble microneedle transdermal drug delivery system, a preparation method and application thereof.
The invention specifically adopts the following technical scheme:
a soluble microneedle transdermal delivery system loaded with BSH comprises a substrate and microneedles distributed on the substrate in an array mode, wherein the microneedles and the substrate are made of hyaluronic acid, the microneedles are arranged to be of a conical structure, and BSH is loaded in the microneedles.
Preferably, the diameter of the bottom surface of the microneedle is not less than 300 μm, and the length of the microneedle is 500-1000 μm.
The preparation method of the soluble microneedle transdermal delivery system loaded with the BSH based on the vacuum drying method comprises the following steps:
step 1, dissolving sodium undecylmercapto dodecaboride powder in water to prepare a BSH solution, and dissolving hyaluronic acid powder in water to prepare an HA solution;
step 3, taking the microneedle mould out of the vacuum drying box, removing deionized water in the microneedle mould, pouring HA solution into the microneedle mould, ultrasonically mixing, placing the microneedle mould in the air drying box again, drying in a vacuum environment, taking out the microneedle mould, stripping and demoulding to obtain the soluble microneedle transdermal drug delivery system loaded with BSH;
and 4, packaging and irradiating the BSH-loaded soluble microneedle transdermal delivery system for sterilization.
Preferably, in the step 1, the concentration of the BSH solution is 3 to 50mg/mL, and the mass fraction of the HA solution is 20%.
Preferably, in the step 3, the temperature of the air drying oven is set to be 42 ℃ during the drying treatment, and the drying time is set to be 12h.
The application of the BSH-loaded soluble microneedle transdermal drug delivery system in boron neutron capture treatment is provided.
Preferably, after the soluble microneedle transdermal delivery system loaded with the BSH is used for delivering, the BSH is enriched in the tumor tissue, and the boron concentration in the tumor tissue is not lower than 20ppm.
Preferably, after the BSH-loaded soluble microneedle transdermal delivery system is used for delivery, the ratio of the boron concentration in the tumor tissue to that in the normal tissue is not lower than 3.
The invention has the following beneficial effects:
the invention takes hyaluronic acid as a substrate material to prepare the boron drug BSH-loaded soluble microneedle transdermal delivery system, and the soluble microneedle is used for replacing intravenous drip infusion to inject the boron drug in the BNCT process, thereby avoiding the inconvenience of neutron irradiation while dripping the boron drug in the BNCT treatment process. Meanwhile, the microneedles in the soluble microneedle transdermal delivery system can be dissolved in the skin and release drugs, even if the microneedles break in the skin, the human body cannot be damaged, the residues are less, the biological pollution risk is low, compared with the coated microneedles and the hollow microneedles, the drug-loading rate is higher and safer, and the soluble microneedle transdermal delivery system can be quickly dissolved in tissue fluid and is sister in vivo by adopting hyaluronic acid as a substrate material, so that the soluble microneedle transdermal delivery system has more excellent biocompatibility, high viscoelasticity, plasticity and permeability.
The invention adopts the soluble micro-needle to load the BSH, has stronger tumor specificity, avoids toxic and side effects of the medicine on normal tissues when the medicine is spread all over the body, reduces the pain of patients in the treatment process, and improves the compliance of the patients in the treatment process.
The invention adopts the soluble micro-needle to load BSH, improves the concentration of boron medicine enriched in tumor, effectively solves the problem of insufficient delivery of boron element in tumor cells, concentrates the boron medicine in tumor tissues for a long time, prolongs the action time of the boron medicine, reduces the dosage and toxic and side effects of the boron medicine, effectively improves the curative effect of boron neutron capture treatment, particularly has unique advantages in superficial tumor treatment, and provides a new administration mode for BNCT treatment.
Drawings
Fig. 1 is an SEM image of a dissolvable microneedle transdermal delivery system.
Fig. 2 is a graph of displacement-stress analysis of microneedles.
Fig. 3 is a graph of the linear relationship between boron loading and BSH concentration in soluble microneedles.
FIG. 4 is a statistical graph of boron concentration in each part of the mice after 2.5h transdermal drug delivery.
FIG. 5 is a tumor suppression curve of mice.
Detailed Description
The invention provides a BSH-loaded soluble microneedle transdermal delivery system and a preparation method and application thereof, and in order to make the purpose, technical scheme and effect of the invention clearer and clearer, the invention is further described in detail with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
The embodiment provides a soluble microneedle transdermal drug delivery system loaded with BSH, which comprises a substrate and microneedles distributed on the substrate in an array mode, wherein the microneedles and the substrate are both made of hyaluronic acid, the microneedles are arranged in a conical structure, and the BSH is loaded inside the microneedles. The microneedles in this example were set to a bottom diameter of 357 μm and a length of 787 μm.
Example 2
The present embodiment provides a method for preparing a transdermal delivery system with soluble microneedles in example 1, and the method for preparing a transdermal delivery system with BSH loaded on a soluble microneedle based on a vacuum drying method specifically includes the following steps:
step 1, dissolving sodium undecylmercaptododecaboride powder in water to prepare a BSH solution with the concentration of 23mg/mL, and dissolving hyaluronic acid powder in water to prepare an HA solution with the mass fraction of 20%.
And 3, taking the microneedle mould out of the vacuum drying box, removing deionized water in the microneedle mould, pouring the HA solution into the microneedle mould, ultrasonically mixing for 5min, putting the microneedle mould into the air drying box again, setting the temperature of the air drying box to be 42 ℃, drying the microneedle mould in a vacuum environment for 12h, taking out the microneedle mould, stripping and demoulding to obtain the BSH-loaded soluble microneedle.
And 4, after packaging and irradiation sterilization are carried out on the soluble microneedle transdermal delivery system loaded with the BSH, observing the soluble microneedle transdermal delivery system loaded with the BSH by using a scanning electron microscope, and characterizing the prepared soluble microneedle transdermal delivery system as shown in figure 1.
Example 3
In this example, a microneedle mechanical strength test was performed on the BSH-loaded dissolvable microneedle transdermal delivery system prepared in example 2 using a mouse as a study subject.
Because the microneedles in the soluble microneedle transdermal delivery system prepared in the embodiment 2 are distributed in an array and have uniformity and integrity, the microneedles can be dissolved in interstitial fluid of a mouse after penetrating through the skin of the mouse, in order to detect the mechanical strength of the microneedles in the soluble microneedle transdermal delivery system, the stress values borne by the microneedles at different penetration depths are detected by using inductively coupled plasma mass spectrometry (ICP-MS), and the relationship between the penetration depth of the microneedles into the skin and the stress borne by the microneedles is obtained, as shown in fig. 2, the relationship can be obtained from fig. 2, and the stress borne by each microneedle in the soluble microneedle transdermal delivery system exceeds 0.03N, and can penetrate through the skin of the mouse. For better penetrability of the hanging-poor microneedle to the skin of the mouse, after the skin of the back of the mouse is subjected to transdermal treatment by using the microneedle, trypan blue is adopted to dye cells in the skin of the back of the mouse for observation, and the microneedle in the soluble microneedle transdermal drug delivery system loaded with the BSH is further verified to be capable of effectively penetrating the skin of the mouse, so that the microneedle has good penetrability in the embodiment.
Example 4
In this example, a mouse is used as a study object, and the degree of BSH enrichment in tumors after transdermal administration using the prepared soluble microneedle transdermal delivery system in example 2 is studied.
Fluorescent dye Cy5.5 is used as a mode drug instead of BSH solution, the preparation method in the embodiment 2 is adopted to load the fluorescent dye Cy5.5 into the microneedle of the soluble microneedle transdermal delivery system, the soluble microneedle transdermal delivery system is inverted after the loading is finished, and the fluorescent dye Cy5.5 is determined to be loaded in the microneedle by fluorescence observation.
The tumor part of a mouse is treated by transdermal administration of the soluble microneedle transdermal administration system prepared in the embodiment 2, optical imaging of the mouse is obtained at different time points, and the fluorescence intensity of the tumor part of the mouse is obviously higher than that of other parts after observation, so that the soluble microneedle transdermal administration system prepared by the invention can enrich drugs in the tumor part after transdermal administration and can be applied to tumor treatment.
Example 5
In order to verify the relationship between the boron loading amount in the soluble microneedle transdermal delivery system loaded with BSH and the concentration of the BSH solution adopted in the preparation process. In this embodiment, the preparation method in embodiment 2 is adopted to prepare a BSH-loaded soluble microneedle transdermal drug delivery system, BSH solutions with different concentrations are prepared according to concentration gradients, the BSH solutions with different concentrations are sequentially loaded in the soluble microneedles and dissolved in deionized water to form a mixed solution, and the content of boron element in the mixed solution is respectively detected by ICP-MS to obtain a relationship between the boron loading amount in the soluble microneedles and the BSH concentration, as shown in fig. 3, and as can be seen from fig. 3, the boron loading amount of the soluble microneedles prepared by the present invention has a definite linear relationship with the BSH solution.
The preparation method in the embodiment 2 is utilized, the BSH solution with the concentration of 23mg/mL is adopted to prepare the BSH-loaded soluble microneedle transdermal drug delivery system, namely the concentration of boron in the soluble microneedle is 13.6mg/mL, a plurality of mice are selected as research objects, in the embodiment, three mice are selected as samples, the soluble microneedle scalp drug delivery system is adopted to carry out transdermal drug delivery treatment on each mouse, after the microneedle acts on the skin of the mouse, a needle body penetrates through the horny layer on the surface of the skin to puncture to form a plurality of small pore channels, the existence of the pore channels provides possibility for macromolecular substances and water-soluble substances to enter the skin, and the boron drug reaches the dermis along the pore channels and reaches a lesion part along with blood circulation to carry out treatment. After transdermal administration treatment for 2.5h, the mice are sacrificed and the tumors, muscles, blood and main organs of the mice are taken out, and the ICP-MS is utilized to detect the boron content in the tumors, muscles, blood and main organs of the mice respectively, as shown in figure 4, the result shows that the boron concentration in the tumors of the mice reaches more than 20ppm, but the boron concentration in the main organs is very low, and meanwhile, the ratio of the boron concentration in the tumor tissues and normal tissues of the mice and the ratio of the boron concentration in the tumor tissues and blood are more than 3, so that the soluble microneedle scalp administration system loaded with the boron medicament BSH, prepared by the invention, is suitable for boron neutron capture treatment.
Example 6
In order to verify the application effect of the BSH-loaded soluble microneedle transdermal delivery system in BNCT treatment, a mouse is used as an experimental object, the preparation method in example 2 is utilized, BSH solution with a concentration of 23mg/mL is used to prepare the BSH-loaded soluble microneedle transdermal delivery system, and the transdermal delivery treatment is performed on the mouse, that is, the concentration of boron in the soluble microneedle is 13.6mg/mL, after the transdermal delivery treatment is performed for 2.5h, the mouse is subjected to neutron irradiation for 1h, and the radiation intensity is 2.57 × 10 8 cm-2·s -1 Monitoring the growth condition of the tumor of the mouse within 20 days, measuring the long diameter and the short diameter of the tumor of the mouse every day, calculating the tumor volume of the mouse, obtaining the change curve of the tumor volume of the mouse along with time, drawing the tumor inhibition curve of the mouse, and comparing the change curve with the control group of the mouse which is not subjected to transdermal drug delivery treatment, as shown in figure 5, the soluble microneedle transdermal drug delivery system loaded with BSH can effectively inhibit the growth of the tumor in the BNCT process through comparison, and effectively prolongs the survival time of the mouse.
It is to be understood that the above description is not intended to limit the present invention, and the present invention is not limited to the above examples, and those skilled in the art may make modifications, alterations, additions or substitutions within the spirit and scope of the present invention.
Claims (8)
1. The soluble microneedle transdermal delivery system loaded with BSH is characterized by comprising a substrate and microneedles distributed on the substrate in an array manner, wherein the microneedles and the substrate are made of hyaluronic acid, the microneedles are arranged in a conical structure, and BSH is loaded in the microneedles.
2. The transdermal drug delivery system with soluble microneedles carrying the BSH of claim 1, wherein the diameter of the bottom surface of the microneedles is not less than 300 μm, and the length of the microneedles is 500-1000 μm.
3. The method for preparing the BSH-loaded dissolvable microneedle transdermal delivery system according to any one of claims 1-2, wherein the method for preparing the BSH-loaded dissolvable microneedle transdermal delivery system based on a vacuum drying method comprises the following steps:
step 1, dissolving sodium undecylmercapto dodecaboride powder in water to prepare a BSH solution, and dissolving hyaluronic acid powder in water to prepare an HA solution;
step 2, preparing a microneedle mould, injecting BSH solution into the microneedle mould after ultrasonically cleaning the microneedle mould to ensure that the microneedle mould is filled with the BSH solution, placing the microneedle mould in a vacuum drying box, vacuumizing to remove bubbles in the microneedle mould, and exhausting air in the microneedle mould;
step 3, taking the microneedle mould out of the vacuum drying box, removing deionized water in the microneedle mould, pouring the HA solution into the microneedle mould, ultrasonically mixing, placing the microneedle mould in the air drying box again, drying in a vacuum environment, taking out the microneedle mould, stripping and demoulding to obtain the BSH-loaded soluble microneedle transdermal delivery system;
and 4, packaging and irradiating the BSH-loaded soluble microneedle transdermal delivery system for sterilization.
4. The method for preparing a soluble microneedle transdermal delivery system loaded with BSH according to claim 3, wherein in the step 1, the concentration of BSH solution is 3-50 mg/mL, and the mass fraction of HA solution is 20%.
5. The method for preparing a soluble microneedle transdermal delivery system loaded with BSH according to claim 3, wherein in step 3, the temperature of an air drying oven is set to 42 ℃ during the drying process, and the drying time is set to 12h.
6. Use of a BSH-loaded dissolvable microneedle transdermal delivery system according to any one of claims 1-2 in boron neutron capture therapy.
7. The application of the soluble microneedle transdermal delivery system loaded with BSH in boron neutron capture therapy according to claim 6, wherein after the soluble microneedle transdermal delivery system loaded with BSH is used for delivery, BSH is enriched in tumor tissues, and the boron concentration in the tumor tissues is not lower than 20ppm.
8. The application of the soluble microneedle transdermal delivery system for supporting BSH in boron neutron capture therapy according to claim 6, wherein after the soluble microneedle transdermal delivery system for supporting BSH is used for delivery, the ratio of boron concentration in tumor tissue to that in normal tissue is not lower than 3.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116327936A (en) * | 2023-04-19 | 2023-06-27 | 东莞市人民医院 | Soluble microneedle applied to boron neutron capture treatment, preparation method and application thereof |
| CN116407488A (en) * | 2023-04-19 | 2023-07-11 | 东莞市人民医院 | Skin patch for boron neutron capture treatment, preparation method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116327936A (en) * | 2023-04-19 | 2023-06-27 | 东莞市人民医院 | Soluble microneedle applied to boron neutron capture treatment, preparation method and application thereof |
| CN116407488A (en) * | 2023-04-19 | 2023-07-11 | 东莞市人民医院 | Skin patch for boron neutron capture treatment, preparation method and application thereof |
| CN116407488B (en) * | 2023-04-19 | 2024-03-08 | 东莞市人民医院 | Skin patch for boron neutron capture treatment, preparation method and application thereof |
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