CN114146048A - Needle and medicine integrated hydrogel microneedle - Google Patents

Needle and medicine integrated hydrogel microneedle Download PDF

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Publication number
CN114146048A
CN114146048A CN202111466714.8A CN202111466714A CN114146048A CN 114146048 A CN114146048 A CN 114146048A CN 202111466714 A CN202111466714 A CN 202111466714A CN 114146048 A CN114146048 A CN 114146048A
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microneedle
needle
solution
drug
cinnamon oil
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CN114146048B (en
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张永太
冯年平
侯晓琳
王志
郭腾
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Shanghai University of Traditional Chinese Medicine
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Shanghai University of Traditional Chinese Medicine
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Priority to PCT/CN2022/114243 priority patent/WO2023098158A1/en
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Abstract

The invention relates to the technical field of medicines, and discloses a hydrogel microneedle integrating needles and medicines. The microneedle matrix is hydrogel formed by cross-linking product of gelatin and tannic acid, and the matrix contains medicine which is oleum Cinnamomi nanocapsule. The cinnamon oil nanocapsule hydrogel microneedle (HFMNs-CIO @ NCs) can better encapsulate cinnamon oil nanocapsules (CIO @ NCs) and deliver the CIO @ NCs to deep layers of skin in acupoint regions, so that the effect of warming spleen and stomach for dispelling cold is fully exerted, meanwhile, the microneedle absorbs water and swells, can stimulate tissues in the Shenque acupoint region, stimulate the acupoint region effect, and improve the symptom of congealing cold of blood stasis type dysmenorrheal model rats. The needle-drug integrated hydrogel microneedle can be used for various drug-containing drugs and preparations thereof, is further used for clinical treatment of acupuncture point therapy, and has clinical popularization and use values.

Description

Needle and medicine integrated hydrogel microneedle
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a hydrogel microneedle integrating needle and medicine.
Background
The traditional Chinese medicine theory considers that acupuncture points (acupoints) are special parts of viscera channels and collaterals in qi and blood infusion, and the acupuncture points are closely related to and communicated with deep tissues and organs. The acupuncture points of the human body are stimulated by modes of acupuncture, massage, drug administration and the like, so that the effects of dredging the channels and collaterals, regulating yin and yang, promoting qi and blood circulation and stimulating the effect of acupuncture points can be achieved, and the aims of strengthening body resistance, eliminating evil and preventing and treating diseases are fulfilled. Umbilical administration is one of the umbilical therapy methods commonly used in traditional Chinese medicine. The traditional Chinese medicine considers that after the drug is administrated at the umbilical region, the drug enters into the tissue of the acupoint region through the skin, and the acupoint region can be stimulated to stimulate the special regulation effect and play the treatment effect of the drug at the same time. In recent years, clinical reports of abdominal needles, press needles, umbilical needles and the like for treating dysmenorrhea are increasing day by day, and the effects of regulating viscera and meridians, promoting qi circulation, dissipating blood stasis and relieving pain are achieved by stimulating the Shenque acupoint area through fine needles and shallow thorns and combining moxibustion, medicine application and the like. In the current clinical application, acupuncture needs professional medical technicians, the main approaches of acupuncture point administration are acupuncture point injection and acupoint region application, the compliance of patients with acupuncture point injection is poor, and the acupoint region application is difficult to concentrate the medicine in the acupoint region tissues in the subcutaneous deep layer due to the barrier effect of the skin and the rapid transportation of intradermal blood.
Microneedles (MNs) are a novel transdermal drug delivery permeation promoting technology integrating injection and transdermal, and have the characteristics of no pain and minimal invasion. The micro-needle can be made of metal, ceramic, silicon or high molecular polymer materials, has the length of 100-1000 mu m, has a single micro-needle and a plurality of integrated micro-needle arrays, and can be made into different forms such as pens, rollers, patches and the like according to requirements. The treatment method combining the micro-needle and the medicine can be used for firstly carrying out acupuncture and then administering the medicine, and the medicine can also be attached to and wrapped on the needle body and then directly conveyed into the body. Because the drug delivery pore canal can be formed on the surface of the skin after the acupuncture, the percutaneous absorption of the drug can be effectively promoted, and the treatment effect is enhanced. The micro-needle has the characteristics of no pain and minimal invasion, and the compliance of patients is high.
The cinnamon oil has the effects of warming the middle-jiao and dispelling cold, and can fully exert the effect if being delivered to the deep layer of the skin of the acupuncture point in clinic of acupuncture point therapy, thereby achieving the purpose of treatment; especially in the umbilical region.
If the cinnamon oil is attached to the microneedle body for acupuncture treatment, the drug-loading rate may be insufficient; if carried on a needle, the release problem in vivo is not solved.
Therefore, there is a need to improve the prior art and develop a drug-loaded microneedle, which combines acupuncture and acupoint administration to realize integrated treatment of "needle" and "drug".
Hydrogel microneedles (HFMNs) consist of a swelling material and a drug reservoir. After the hydrogel microneedle penetrates into the skin, the swelling material and the drug storage in the microneedle array can absorb interstitial fluid so as to swell the needle body and release the drug. Therefore, the micro-needle is used for encapsulating the medicine, and the acupuncture in the umbilical region and the acupoint administration are combined, so that the integrated treatment of 'needle' and 'medicine' is realized.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, combines acupuncture and acupoint administration in the umbilical region, realizes an integrated acupoint treatment strategy of 'acupuncture' and 'medicine', is easy to operate, and enhances the treatment effect.
A hydrogel microneedle (HFMNs-CIO @ NCs) integrated with needle and medicine comprises a microneedle substrate and medicine contained in the microneedle substrate. The microneedle matrix is hydrogel formed by cross-linking products of gelatin and tannic acid.
Preferably, the drug contained in the microneedle matrix is a nanocapsule, and more preferably a cinnamon oil nanocapsule, namely, the needle-drug integrated hydrogel microneedle is a cinnamon oil nanocapsule hydrogel microneedle (HFMNs-CIO @ NCs).
The cinnamon oil nano capsules (CIO @ NCs) are prepared by loading cinnamon oil in a shell-core structure formed by chitosan and sodium alginate; the particle size of the cinnamon oil nano capsule is 50-500 nm, wherein the drug-loading rate of cinnamaldehyde is 26-36 wt%.
The mass ratio of the microneedle substrate to the cinnamon oil nanocapsules is 0.2-0.5:1, calculated by the usage amount of the gelatin and the cinnamon oil respectively.
The microneedle substrate is a gelatin and tannic acid crosslinking product (Gel-Tan), and is obtained by crosslinking reaction of amino and carboxyl in gelatin and hydroxyl in tannic acid, and the preparation method comprises the following steps:
(1) slowly dripping the tannic acid solution into the gelatin solution, adjusting the pH to 5-6, and reacting at 45-65 ℃ for 2-16 h;
(2) adding glycerol into the reaction solution and stirring uniformly.
The mass ratio of the tannic acid to the glycerol to the gelatin is 0.02-0.05:0.05-0.2:1, preferably 0.04:0.1: 1; the concentration of the gelatin solution is 100-200mg/mL, and the concentration of the tannic acid solution is 40-80 mg/mL.
Preferably, in the step (1), the pH is adjusted to 5.5, and the reaction is carried out for 2-16h at 50-60 ℃.
The cinnamon oil nanocapsule is prepared by using cation-induced controllable gelling effect of alginate, and the preparation method comprises the following steps:
(a) dissolving cinnamon oil and phospholipid in alcohol, adding the solution into a sodium alginate solution, and performing ultrasonic dispersion to obtain O/W emulsion;
(b) dropwise adding the calcium chloride solution into the O/W emulsion obtained in the step (a), and stirring for 15-60 min;
(c) dropwise adding a chitosan solution into the solution obtained in the step (b), continuously stirring after dropwise adding, and standing;
(d) separating to obtain precipitate, and obtaining the cinnamon oil nano capsule.
The phospholipid is yolk lecithin, soybean lecithin, hydrogenated soybean lecithin, distearoyl phosphatidylcholine, dimyristoyl phosphatidylcholine or dipalmitoyl phosphatidylcholine, and the purity of the phospholipid is more than 95%, more preferably more than 98%.
Preferably, the alcohol is ethanol.
The weight ratio of the cinnamon oil to the phospholipid, the calcium chloride and the chitosan is 4-6:1:0.4-0.6:0.2-0.4, the concentration of the sodium alginate solution in the step (a) is 0.3-1mg/mL, and the dosage ratio of the cinnamon oil to the alcohol is 30-60 mg/mL; the concentration of the calcium chloride solution in the step (b) is 0.3-1 mg/mL; the concentration of the chitosan solution in the step (c) is 0.3-1 mg/mL.
The Cinnamon Oil is prepared according to the specification of pharmacopeia, is the volatile Oil of Cinnamon, wherein the content of cinnamaldehyde meets the quality standard specification of Cinnamon Oil (CIO) in China pharmacopeia of 2020 edition.
Preferably, in the step (a), sodium alginate is stirred in pure water at 200-; in the step (a), the cinnamon oil and the alcohol solution of the phospholipid are added into the sodium alginate solution while ultrasonic treatment is carried out, after mixing, ultrasonic treatment is carried out for 10-20min, and then ultrasonic treatment is carried out for 10-20min by a probe under the ice bath condition.
In the step (b), calcium chloride is dripped into the O/W emulsion in the step (a) at the speed of 6-10mL/h, and stirring is continued at 500rpm of 200-.
In the step (c), the chitosan is dissolved by 0.5 to 2 percent acetic acid water solution, and the pH value is adjusted to 4.5 to 5.5, and the preferable pH value is 5; and adding the chitosan solution into the solution in the step (b) at the speed of 8-15mL/h while stirring, after the dropwise addition is finished, continuously stirring at 200-500rpm for 2-6h, and standing for 8-16 h.
In the step (d), 100000-.
The preparation method of the needle-drug integrated hydrogel microneedle comprises the following steps: and (3) uniformly mixing the drug solution and the microneedle matrix solution, forming and drying.
When the medicine is the cinnamon oil nanocapsule, the preparation method of the cinnamon oil nanocapsule hydrogel microneedle comprises the following steps: and (3) uniformly mixing the cinnamon oil nano capsule solution and the microneedle matrix solution, forming and drying. The method specifically comprises the following steps: mixing the cinnamon oil nano capsule solution and the microneedle matrix solution uniformly, casting the mixture in a microneedle mould, decompressing, putting the mixture into the mould, drying the mixture in vacuum, and demoulding to obtain the cinnamon oil nano capsule.
The microneedle substrate obtained by crosslinking gelatin and tannic acid is easy to form and demould, and has good mechanical strength and high swellability. Loading of the nanocapsules may enhance the strength of the microneedles.
The cinnamon oil nanocapsule hydrogel microneedle can be used for preparing a medicine for treating cold-congealing blood-stasis type dysmenorrhea. The microneedle can be used for realizing a needle-drug integrated treatment strategy. The micro-needle can deliver the cinnamon oil nanocapsule to the deep part of the acupoint region, and meanwhile, the hydrogel micro-needle absorbs water and swells, continuously stimulates tissues of the acupoint region, excites the acupoint region effect, and achieves the treatment effects of dredging channels and collaterals, promoting qi circulation, dissipating blood stasis, relieving pain and the like.
Nanocapsule (NCs) technology encapsulates a trace amount of drug molecules by using a polymer film, in which the encapsulated substance is called a core material and the polymer coating the core material is called a wall material. The particle size of the common nanocapsule is in a nanometer level, and the nanometer size effect of the nanocapsule enables the nanocapsule to have good biocompatibility, targeting property and slow release property. Chitson (CS) is an N-deacetylated product of chitin, a linear polysaccharide, linked by glucosamine and N-acetylglucosamine units via β - (1 → 4) glycosidic linkages. Chitosan can be dissolved in acidic media after deacetylation treatment, and is the only polysaccharide with high positive charge density due to protonation of the amino groups on its main chain. The chitosan also has the characteristics of no toxicity, biocompatibility, biodegradability and the like. Sodium Alginate (SA) is a natural polysaccharide extracted from brown algae and seaweed, and is a water-soluble linear polysaccharide, and carboxylic acid groups make Alginate negatively charged, and thus can electrostatically interact with positively charged molecules. In the invention, the cross-linked product of sodium alginate and calcium ions is used as the shell of the nano capsule, cinnamon oil is used as the core, the cinnamon oil nano capsule is prepared by an ion gel method, and chitosan is used for modification. The hydrogel microneedle matrix is prepared by uniformly mixing the cinnamon oil nanocapsules and the microneedle matrix and using a casting method, wherein a crosslinked product of gelatin and tannic acid is used as the hydrogel microneedle matrix, so that the cinnamon oil nanocapsules can be better encapsulated and used for umbilical region administration, and the cinnamon oil nanocapsules can be delivered to the deep part of a cave region to better exert the drug effect.
The invention provides a novel needle and drug integrated microneedle which can be used for acupuncture point treatment, takes the microneedle as a carrier, wraps and carries a traditional Chinese medicine extract and a preparation thereof, in particular to a nanocapsule of the traditional Chinese medicine extract, and simultaneously carries out acupuncture and drug delivery in acupuncture points, thereby playing the comprehensive effect of the acupuncture and the drug treatment.
The cinnamon oil nanocapsule hydrogel microneedle (HFMNs-CIO @ NCs) prepared by the invention is used for applying medicine to an umbilical region (Shenque acupoint) to treat cold-congealing and blood stasis type dysmenorrhea, the cinnamon oil nanocapsule can be delivered to the deep part of the acupoint region through the umbilical region (Shenque acupoint), and meanwhile, the hydrogel microneedle absorbs water to swell, continuously stimulates the tissues of the acupoint region, excites the acupoint region effect, and achieves the treatment effects of dredging channels and collaterals, promoting qi circulation, dissipating blood stasis, relieving pain and the like.
Compared with the prior art, the invention has the beneficial effects that:
the gelatin and tannic acid crosslinked product is used as the hydrogel microneedle substrate, so that the hydrogel microneedle substrate is easy to form and demould, good in mechanical strength and high in swellability. And the loading of the nanocapsules can strengthen the strength of the microneedles. When the cinnamon oil nano capsule is carried, the cinnamon oil is carried in a shell-core structure formed by chitosan and sodium alginate to form the cinnamon oil nano capsule; the cinnamon oil nanocapsule hydrogel microneedle prepared by taking a crosslinked product of gelatin and tannic acid as a microneedle substrate and encapsulating the cinnamon oil nanocapsules can deliver the cinnamon oil nanocapsules to the deep layer of skin in a cave region, so that the effect of warming the middle and dissipating cold of the cinnamon oil is fully exerted, and meanwhile, the microneedle absorbs water and swells, so that the cave region tissue can be stimulated, the cave region effect is stimulated, and the treatment purpose is achieved. The cinnamon oil nanocapsule hydrogel microneedle umbilical administration can improve the symptoms of congealing cold blood stasis type dysmenorrhea model rats, prolong the latency period of writhing, reduce the times of writhing and the score of writhing, obviously increase the PGE2 content of uterine tissues, reduce the PGF2 alpha content and the PGF2 alpha/PGE 2 ratio, and obviously increase the number of mast cells and the degranulation rate of the mast cells in the Shenque acupoint area, thereby obviously improving the treatment effect on congealing cold blood stasis type dysmenorrhea of rats.
The microneedle can realize a needle-drug integrated treatment strategy, is expected to carry free drugs and preparations thereof and contain various drugs and preparations thereof, is further used for clinical treatment of acupuncture point therapy, and is worthy of clinical popularization and use; in addition, the microneedle preparation method is simple, does not need special equipment and harsh conditions, is easy to realize large-scale production, and has extremely high practical value.
Drawings
FIG. 1 is a transmission electron microscope image of the cinnamon oil nano-capsules prepared in example 2 of the present invention;
fig. 2 is a scanning electron microscope image of the hydrogel microneedle of the cinnamon oil nanocapsule prepared in example 3 of the present invention, wherein: the magnification of A is 100 times, and the magnification of B is 350 times;
FIG. 3 shows mechanical strength test patterns of a hydrogel microneedle (GB-Tan-MNs-CIO @ NCs) carrying a cinnamon oil nanocapsule prepared in example 3 of the present invention and a control blank hydrogel microneedle (GB-Tan-MNs) carrying no drug;
FIG. 4 is swelling test patterns of hydrogel microneedles carrying cinnamon oil nanocapsules (GB-Tan-MNs-CIO @ NCs) prepared in example 3 of the present invention and control blank hydrogel microneedles carrying no drug (GB-Tan-MNs);
FIG. 5 is an optical photograph of rat excised skin penetrated by a blank microneedle patch labeled with rhodamine B prepared in example 3 of the present invention;
FIG. 6 is a toluidine blue-stained photomicrograph of rat shenque acupoint area mast cells obtained in example 4 of the present invention, in which: the (A, B) is blank group, C is model group, D is acupuncture group, E is blank micro needle group, and F is medicine carrying micro needle group.
Detailed Description
The technical solutions provided by the present invention will be described in detail below with reference to specific examples, and it should be understood that the following specific embodiments are only illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1 preparation of cinnamon oil nanocapsules
1.1 extraction of cinnamon oil
According to a cinnamon medicinal material specified in 'Chinese pharmacopoeia' of 2020 edition, 200.2g of the cinnamon medicinal material is weighed, the cinnamon medicinal material is crushed into 20 meshes of coarse powder, 8 times of water is added for soaking for 1h, the cinnamon volatile oil is extracted for 6h by a steam distillation method at 200 ℃, and 3mL of the cinnamon volatile oil is collected. HPLC detection shows that the cinnamic aldehyde content in the Cinnamon volatile Oil is 93.1 +/-4.45%, and meets the quality standard regulation of Cinnamon Oil (CIO) in the 'Chinese pharmacopoeia' of 2020 edition.
1.2 preparation of cinnamon oil nanocapsules
Weighing 60mg sodium alginate, adding purified water to 100mL to obtain a solution with a concentration of 0.6 mg/mL-1Heating at 60 deg.C, stirring at 300rpm for 30min to dissolve, and adding 1% acetic acid water solution to adjust pH to 5.5.
120mg of cinnamon oil and 24mg of soybean lecithin (purity 98.6%) are weighed, 2mL of ethanol is added, and the mixture is stirred uniformly. Adding the solution into the sodium alginate solution while performing ultrasonic dispersion, continuing performing ultrasonic treatment for 15min, and performing ultrasonic treatment for 15min (ice bath) by using a probe to obtain the blue opalescent O/W emulsion.
Weighing 12mg of calcium chloride, adding 20mL of purified water to prepare 0.6 mg/mL-1The solution of (1). Adding calcium chloride solution at a volume of 8.5 ml.h-1While stirring at (1000rpm), the mixture was dropped into the O/W emulsion, and after the dropping, stirring was continued at 300rpm for 30 minutes.
6mg of chitosan was dissolved in 10mL of 1% acetic acid aqueous solution to prepare a solution with a concentration of 0.6 mg/mL-1The pH of the solution of (1) was adjusted to 5.0 with a 4% NaOH solution. Then the chitosan solution is added at a rate of 10 mL.h-1Dropping the solution into the sodium alginate solution while stirring at the speed of 1000rpm, continuing stirring at 300rpm for 3h after dropping, standing overnight, centrifuging at 140,000 Xg for 60min, removing supernatant, adding 20mL of purified water into precipitate, and storing at 4 ℃ for later use.
Example 2 preparation of hydrogel microneedle carrying cinnamon oil nanocapsules
1.3 preparation of hydrogel microneedle carrying cinnamon oil nanocapsule
4g of gelatin was weighed, 15mL of purified water was added, heated at 55 ℃ and stirred (300rpm) for 1h to complete dissolution. 160mg of tannic acid was weighed, 5mL of purified water was added, and dissolved with stirring at 300 rpm. Slowly dripping tannic acid solution into gelatin solution, adjusting pH to 5.5 with 1% sodium hydroxide solution, and heating at 55 deg.C for 4 hr. Adding 400mg of glycerol into the gelatin-tannic acid solution, and uniformly stirring to obtain the hydrogel microneedle matrix.
And (3) uniformly stirring 20mL of cinnamon oil nanocapsule solution and 2mL of hydrogel microneedle matrix, casting 1mL of cinnamon oil nanocapsule solution in a clean microneedle mould, standing for 15min under a vacuum environment of-0.08 mPa, scraping an upper layer of matrix which is not in the mould, and simultaneously supplementing a new matrix solution. Drying completely in a drying oven at 30 deg.C, and demolding to obtain hydrogel microneedle (HFMNs-CIO @ NCs) carrying oleum Cinnamomi nanocapsule
Example 3 evaluation and characterization of hydrogel microneedles carrying cinnamon oil nanocapsules (HFMNs-CIO @ NCs)
3.1 morphological characterization of HFMNs-CIO @ NCs
And (3) uniformly spraying gold powder on the surface of the dried HFMNs-CIO @ NCs, and carrying out morphological observation on the gold powder under a scanning electron microscope under a vacuum condition.
Fig. 2 is a scanning electron microscope image of a hydrogel microneedle of the cinnamon oil-loaded nanocapsule prepared in example 3 of the present invention, wherein a magnification is 100 times, and B magnification is 350 times. As can be seen from FIG. 2, the demolding rate of HFMNs-CIO @ NCs reaches 100%, the needle tip is intact and has no damage after demolding, the needle body is pyramid-shaped and consists of four-side pyramid-shaped needle bodies, the thickness of the substrate is uniform, and the array is arranged orderly. The microneedle patch was square with a side length of 1.4cm, with a 10 x 10 microneedle array, a microneedle substrate of about 600 μm in length and 600 μm in width, and microneedles of about 1450 μm in height. The microneedle substrate spacing was 600 μm and the tip spacing was 900 μm.
3.2 mechanical Strength of HFMNs-CIO @ NCs
And (3) respectively taking the dried HFMNs-CIO @ NCs to ensure that the needle body is complete in shape and the substrate is flat and uniform. The needle was placed upward on a test plate of a texture analyzer, and a cylindrical probe having a diameter of 5mm was set to compress the microneedles at a speed of 30mm/min until the amount of compression set was 40%. The initial trigger force was 0.05N and the force-displacement curve of the microneedles was plotted.
Fig. 3 is a mechanical strength test pattern of a hydrogel microneedle of the cinnamon oil-loaded nanocapsule prepared in example 3 of the present invention, and as can be seen from fig. 3, the mechanical strength of the BSP composite microneedle before and after drug loading can both reach more than 18N. Since the microneedle molds were 11 × 11 arrays, the mechanical strengths of HFMNs and HFMNs-CIO @ NCs were calculated as 0.15N/needle, 0.18N/needle, respectively, i.e., loading of nanocapsules slightly increased the microneedle strength.
3.3 swellability of HFMNs-CIO @ NCs
Taking blank microneedle patches (HFMNs) and drug-loaded microneedle patches (HFMNs-CIO @ NCs), and recording initial mass WL. Sequentially wrapping the micro-needle sheets with different prescriptions with polytetrafluoroethylene film and tinfoil paper to expose the needle tip. PBS 0.7mL was added to each well of the 24-well plate, and the wrapped microneedle patch was inverted into the well so that the exposed needle tip was immersed in water. Taking out the microneedle patch from the 24-well plate at 5min, 15min, 30min, 60min and 90min, wiping off excessive water on the surface, weighing, and recording the mass at 0 as W0And t is denoted as WtTo (W)t-W0)/WLThe swelling ratio of the microneedle patch at t is shown, and the above test was repeated 3 times for each set of samples. And (3) respectively drawing by taking t as an abscissa and the swelling ratio as an ordinate, and investigating the influence of the drug loading on the swelling ratio of the microneedle.
Fig. 4 is a swelling test pattern of a hydrogel microneedle of the cinnamon oil-loaded nanocapsule prepared in example 3 of the present invention, and as can be seen from fig. 4, the swelling rate of the blank microneedle reaches 350% in 30min, and then the swelling speed gradually decreases and becomes gentle, and the swelling rate is about 430% in 90 min. The swelling rate of the microneedle after drug loading is slightly increased, the swelling rate reaches 390% in 30min and reaches 470% in 90min, and the swelling degree and the swelling speed are both superior to those of the blank microneedle.
3.4 microneedle skin penetration
Taking SD rat, anesthetizing with 10% chloral hydrate, depilating with razor, scrubbing with normal saline, peeling abdominal skin with scalpel, removing subcutaneous tissue and fat, cleaning with normal saline, storing in refrigerator at-4 deg.C, and using within one week.
A water-soluble dye rhodamine B is adopted to mark a blank microneedle substrate, and the rhodamine-marked microneedle is prepared. Pressing the surface of the isolated skin of the rat by hand, maintaining for 5min, taking down the microneedle patch, and observing the capability of the microneedle penetrating into the skin.
Fig. 5 is an optical photograph of rat excised skin penetrated by a blank microneedle patch labeled with rhodamine B prepared in example 3 of the present invention, and as can be seen from fig. 5, microneedles can successfully penetrate rat excised skin.
Example 4 study of analgesic Effect of cinnamon oil nanocapsule-loaded hydrogel microneedles (HFMNs-CIO @ NCs) on cold-congealing blood-stasis type dysmenorrhea model rats
4.1 animal groups
The female SD rats have the body mass of 180-220 g and are four groups as follows: (1) a blank control group, (2) a model group, (3) an umbilical acupuncture group, (4) a blank microneedle umbilical region treatment group, and (5) a cinnamon oil-loaded nanocapsule microneedle umbilical region acupuncture treatment group. Except for the blank control group, the model group and each treatment group were grouped after the model was successfully created.
4.2 preparation of model of dysmenorrhea with congealing cold and blood stasis
A rat model with cold accumulation and blood stasis type dysmenorrhea was established according to a literature method (Chinese medical society, preparation standard of dysmenorrhea animal models (draft) [ J ]. China experimental prescriptions, 2018). Continuously administering estradiol benzoate to the animal to improve uterine sensitivity; oxytocin is injected again to generate similar dysmenorrhea reaction. The ice-water bath can cause the animal to experience a reduction in body temperature.
Injecting estradiol benzoate into rats in the model group and the treatment group subcutaneously 1 time a day for 10 days continuously; the dosage of the extract on day 1 and 10 is 2.5 mg/kg-1The dosage of the composition for the rest of time is 1 mg/kg-1(ii) a Meanwhile, the rats are placed in ice-water bath for 10min every day, and in order to promote the formation of a blood stasis model, the rats can be injected with adrenaline hydrochloride (8 microgram kg) for 2 times subcutaneously on the 11 th day-1) At 2h intervals, after the 2 nd injection of epinephrine hydrochloride, the animals were placed in ice water for 5min, and after 5min the rats were taken out and returned to their cages for feeding. On day 12, the rats were injected with estradiol benzoate subcutaneously for 1h, and then immediately injected with oxytocin intraperitoneally (dose 10U. kg)-1) The model of the iced water bath rat dysmenorrheal combining estrogen and oxytocin is prepared. And observing the writhing reaction behavior of the rat, and judging that the model is successfully made.
The blank control group is fed normally, water is freely drunk, no treatment is carried out, and the physiological saline is injected subcutaneously into the thigh every day on 1-10 days of molding, 0.25 mL/body on 1 day, 0.1 mL/body on 2-9 days, 0.25 mL/body on 10 days, and subcutaneously for 2 times on 11 days, 0.1 mL/body each time, and the interval is 2 hours. Injecting normal saline 0.25 mL/injection subcutaneously on day 12, and immediately injecting oxytocin (dosage 10 U.k) intraperitoneally after 1hg-1) And observing the writhing response behavior of the rat.
4.3 Point selection method
The method comprises the following steps of selecting a Shenque acupoint of a rat according to a literature method (Jifeng, an adult female rat Shenque acupoint positioning method, exploring [ C ]. seventeenth acupuncture on a regulation mechanism of body functions and an acupuncture clinical unique experience workshop conference proceedings 2014) by adopting a 'comparative dissection acupoint selection method': in the naturally relaxed and partially stretched condition of the lower limbs, the rat "Shenque" point is located approximately 1/3 above the line connecting the midpoints of the 4 th and 5 th nipples. In the case of full extension of the lower limb, the "Shenque" point is substantially parallel to the 4 th pair of teats.
4.4 methods of treatment
The rats are administered with isoflurane inhalation for anesthesia on the 5 th day of molding, coarse hairs around the Shenque point of the rats are removed by an electric shaver after the rats are anesthetized, and fine hairs around the Shenque point are removed by depilatory cream. Rats were given treatment 1 time daily for a total of 7 times on day 6 of molding.
4.4.1 intradermal methods
After the rat is fixed on the back, the Shenque acupoint is regarded as a dial, an intradermal needle is adopted, 6 points are taken, transverse puncturing is carried out on the corresponding acupoint area, the fixing is carried out by a medical adhesive plaster, the needle is left for 30 minutes, and the needle insertion depth is 4-5 mm.
4.4.2 microneedle method
Fixing the rat in supine position, placing the blank or drug-loaded microneedle in the Shenque acupoint region of the rat, pressing with hand for 1min to make the microneedle penetrate into the Shenque acupoint of the rat, fixing with medical adhesive plaster, and retaining the needle for 30 min.
The blank group and the model group are synchronously grabbed and fixed with the groups without treatment.
4.5 index detection
4.5.1 rat State Change
Rat diet, body weight, rat hair color, behavior, mental state were recorded.
In the molding process, the weight of a model group is maintained to be stable or gradually reduced, curling and moving appear in the later stage, the model group is easy to be tangled and piled up, and is occasionally wary, hazy and sleepy, unserviceable in two eyes, slow in reaction, fluffy, upright and lusterless by hair, the skin colors of the ear, the four limbs, the tail and other parts are pink red, the stool is moist, and the feces are soft. According to Yanjiamin (evaluation and selection of the preparation method of the animal model with the syndrome of congealing cold and blood stasis [ J ]. Chinese medicine science report, 2014), the cold symptom characterization score of the model-making rat is moderate. The state of the rat in the early molding process of each treatment group is the same as that of the model group, the symptoms are improved in the later treatment process, the weight is maintained stably or gradually increased, the spirit is improved, the hair is bright, the skin colors of the ear, the limbs, the tail and other parts are pink, the stool is slightly moist, and the feces are slightly soft.
4.5.2 writhing reaction
And observing the incubation period, writhing times and writhing score of writhing response of rats in 20min after intraperitoneal injection of oxytocin in the blank group and the model group. After the acupuncture group, the blank microneedle umbilical region treatment group and the cinnamon oil-carrying nanocapsule microneedle umbilical region treatment group are treated for the last time, oxytocin is injected into the abdominal cavity, and the incubation period, the body twisting times and the body twisting score of the body twisting reaction of each group of rats within 20min are observed.
The twist behavior is classified into four levels of 0 to 3 according to the behavioral scoring criteria set forth In Schmauss (In vivo students on specific ideal receiver systems formatting a differential evaluation of mu, delta and kappa receivers with visual chemical and cosmetic properties In the rate [ J ]. J pharmacological Exp Ther, l 984). Level 0: normal posture (paw lying on bottom of box or normal probing behavior); level 1: the body inclines to one side; and 2, stage: hind limb extension, dorsiflexion of hind paw, body extension with frequent pelvic lateral rotation; and 3, level: the abdominal muscles contract and the hind limbs extend. The writhing latency period is the time from the injection of oxytocin to the occurrence of writhing reaction; the twist score is 0 (times) × 0 +1 (times) × 1 +2 (times) × 2 +3 (times) × 3. The results are shown in Table 1.
Compared with the blank group, the model group rat writhing reaction latency is obviously shortened, and the writhing times and writhing score are obviously increased, which indicates that the model of the cold coagulation blood stasis type rat dysmenorrhea is successfully modeled. Compared with a model group, the number of times of twisting the body of the umbilical acupuncture treatment group is remarkably reduced (P <0.05), the number of times of twisting the body of a blank microneedle umbilical treatment group and the score of the twisting body are remarkably reduced (P <0.05), the latency period of the twisting body of the microneedle umbilical treatment group carrying the cinnamon oil nanocapsule is remarkably prolonged (P <0.05), the number of times of twisting the body and the score of the twisting body are remarkably reduced (P <0.01), and the fact that each treatment group has a certain treatment effect on a cold coagulation blood stasis type dysmenorrheal model rat is shown, wherein the treatment effect of the microneedle umbilical treatment group carrying the cinnamon oil nanocapsule is most remarkable.
TABLE 1 comparison of writhing response in rats in each group: (
Figure BDA0003391860280000111
n＝6)
Figure BDA0003391860280000112
Note: in comparison with the blank set, the results,#P<0.05，##P<0.01; compared with model group, P <0.05, and P < 0.01.
4.5.3 measurement of prostaglandin E2(PGE2) and prostaglandin F2 alpha (PGF2 alpha) contents in rat uterine tissue by ELISA method
After injecting oxytocin for 1h, rats were anesthetized by intraperitoneal injection of 1.0mL (150mg/kg) of 3% sodium pentobarbital, the uterus was rapidly taken off from an ice tray of a sterile workbench, weighed, and the sample was stored in a refrigerator at-80 ℃ for later use.
Uterine samples were removed immediately before use and thawed at room temperature. Taking a proper amount of sample, adding physiological saline to prepare 10% of uterine tissue homogenate, centrifuging at the low temperature of 3000r/min for 15min, taking supernatant, and determining the contents of PGE2 and PGF2 alpha according to the method of an ELISA kit specification. The results are shown in Table 2.
Compared with the blank group, the content of PGF2 alpha in the model group is remarkably increased (P <0.01), the ratio of PGF2 alpha/PGE 2 is remarkably increased (P <0.05), and the success of model building of the cold coagulation blood stasis type rat dysmenorrheal model is shown. Compared with the model group, the umbilical acupuncture treatment group has extremely reduced content of PGF2 alpha (P <0.01), the PGF2 alpha/PGE 2 ratio is reduced significantly (P <0.05), the content of PGE2 in the cinnamon oil nanocapsule-loaded microneedle umbilical treatment group is increased significantly (P <0.01), the content of PGF2 alpha and the PGF2 alpha/PGE 2 ratio are reduced significantly (P <0.05), and the fact that each treatment group has a certain treatment effect on the low cold coagulation and blood stasis type dysmenorrheal model rats is shown, wherein the treatment effect of the cinnamon oil nanocapsule-loaded microneedle umbilical treatment group is most significant.
TABLE 2 comparison of the rat uterus PGE2, PGF2 alpha content and PGF2 alpha/PGE 2 ratio in each group ((S))
Figure BDA0003391860280000121
n＝6)
Figure BDA0003391860280000122
Note: compared with the control group, the compound of the formula,#P<0.05，##P<0.01; compared with model group, P <0.05, and P < 0.01.
4.5.4 number of mastocyte in acupoint area and degranulation rate
After injecting oxytocin for 1h, the rat was anesthetized by intraperitoneal injection of 1.0mL (150mg/kg) of 3% pentobarbital sodium, the skin of the rat shenque acupoint area together with subcutaneous muscle tissue (3mm × 3mm × 3mm) was rapidly taken on an ice tray of a sterile workbench, washed with normal saline, fixed with 4% paraformaldehyde for toluidine blue staining, and a photograph was taken under a 10 × 40 microscope, with the results shown in fig. 6. 3 tissue sections were taken from each rat's acupoint area, 3 fields were randomly selected, 1 field for muscle layer and 2 fields for fascia layer, and the mast cell morphology of the sections was observed under 10X 20 microscope and counted (both intact and degranulated), the counting result is expressed as "number/high power field (one/HPF)", and the results are shown in Table 3.
TABLE 3 comparison of mast cell count and degranulation in the Shenque acupoint area in rats (
Figure BDA0003391860280000131
n＝6)
Figure BDA0003391860280000132
Note: compared with the control group, the compound of the formula,#P<0.05，##P<0.01; compared with model group, P <0.05, and P < 0.01.
FIG. 6 is a toluidine blue stained photomicrograph of rat shenque acupoint area mast cell obtained in example 4 of the present invention, in which: A. b, blank group C, model group, D, acupuncture group E, blank microneedle group and F, drug-loaded microneedle group; as shown in FIG. 6 and Table 3, the number of mast cells in the Shenque acupoint area and the degranulation rate of mast cells were significantly increased compared with those in the blank group, and the statistical difference was observed (P < 0.05). Compared with the model group, the number of the mast cells in the Shenque acupoint area and the degranulation rate of the mast cells are increased remarkably in each treatment group (P < 0.01).
According to the needle and drug integrated treatment strategy provided by the invention, the drug can be delivered to the deep layer of the skin of the acupoint region to play the treatment effect of the drug in the acupoint region, and meanwhile, the microneedle body absorbs water and swells, so that the acupoint region tissue can be stimulated, the acupoint region effect is stimulated, and the treatment purpose is achieved. The cinnamon oil nanocapsule hydrogel microneedle umbilical administration can improve symptoms of cold-coagulation blood-stasis type dysmenorrheal model rats, prolong the latency period of wriggling, reduce the times of wriggling and wriggling scores, obviously increase the PGE2 content of uterine tissues, reduce the PGF2 alpha content and the PGF2 alpha/PGE 2 ratio, and obviously increase the mast cell number and mast cell degranulation rate in the Shenque acupoint region, so that the cinnamon oil nanocapsule hydrogel microneedle umbilical administration can play a meridian acupoint acupuncture effect and has an important effect on improving symptoms of cold-coagulation blood-stasis type dysmenorrheal. The integrated needle and drug treatment strategy is expected to utilize the microneedle to entrap the free drug and the preparation thereof, is further used for clinical treatment of acupuncture point therapy, and is worthy of clinical popularization and application.

Claims (10)

1. The needle-drug integrated hydrogel microneedle is characterized in that a microneedle substrate is hydrogel formed by a cross-linking product of gelatin and tannic acid, and drugs are loaded in the microneedle substrate.
2. The needle-drug integrated hydrogel microneedle according to claim 1, wherein the drug is a cinnamon oil nanocapsule, the particle size is 50-500 nm, and the drug-loading rate of cinnamaldehyde is 26-36 wt%.
3. The needle-drug integrated hydrogel microneedle according to claim 1, wherein the mass ratio of the microneedle substrate to the cinnamon oil nanocapsules is 0.2-0.5:1 in terms of the amounts of gelatin and cinnamon oil, respectively.
4. The needle-drug integrated hydrogel microneedle according to claim 1, wherein the preparation method of the microneedle substrate comprises the following steps:
(1) slowly dripping the tannic acid solution into the gelatin solution, adjusting the pH to 5-6, and reacting at 45-65 ℃ for 2-16 h;
(2) adding glycerol into the reaction solution and stirring uniformly.
5. The needle-drug integrated hydrogel microneedle according to claim 4, wherein the mass ratio of tannic acid, glycerol and gelatin is 0.02-0.05:0.05-0.2: 1; the concentration of the gelatin solution is 100-200mg/mL, and the concentration of the tannic acid solution is 40-80 mg/mL.
6. The needle-drug integrated hydrogel microneedle according to claim 1 or 2, wherein the preparation method of the cinnamon oil nanocapsule comprises the steps of:
(a) dissolving cinnamon oil and phospholipid in alcohol, adding the solution into a sodium alginate solution, and performing ultrasonic dispersion to obtain O/W emulsion;
(b) dropwise adding the calcium chloride solution into the O/W emulsion obtained in the step (a), and stirring for 15-60 min;
(c) dropwise adding a chitosan solution into the solution obtained in the step (b), continuously stirring after dropwise adding, and standing;
(d) separating to obtain precipitate, and obtaining the cinnamon oil nano capsule.
7. The needle-drug integrated hydrogel microneedle according to claim 6, wherein the phospholipid is egg yolk lecithin, soybean lecithin, hydrogenated soybean lecithin, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine or dipalmitoylphosphatidylcholine.
8. The needle-drug integrated hydrogel microneedle according to claim 6, wherein the weight ratio of cinnamon oil to phospholipids, calcium chloride and chitosan is 4-6:1:0.4-0.6:0.2-0.4, the concentration of the sodium alginate solution in the step (a) is 0.4-0.8mg/mL, and the dosage ratio of cinnamon oil to alcohol is 40-100 mg/mL; the concentration of the calcium chloride solution in the step (b) is 0.4-1 mg/mL; the concentration of the chitosan solution in the step (c) is 0.4-1 mg/mL.
9. A method for preparing a hydrogel microneedle integrated with a needle and a drug according to any one of claims 1 to 8,
the method comprises the following steps: and (3) uniformly mixing the drug solution and the microneedle matrix solution, forming and drying.
10. Use of the needle-drug integrated hydrogel microneedle according to any one of claims 2 to 8 for preparing a medicament for treating cold-coagulation blood-stasis type dysmenorrhea.
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