CN114146048B - Needle and medicine integrated hydrogel microneedle - Google Patents
Needle and medicine integrated hydrogel microneedle Download PDFInfo
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- CN114146048B CN114146048B CN202111466714.8A CN202111466714A CN114146048B CN 114146048 B CN114146048 B CN 114146048B CN 202111466714 A CN202111466714 A CN 202111466714A CN 114146048 B CN114146048 B CN 114146048B
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- microneedle
- cinnamon oil
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- needle
- hydrogel
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Abstract
The invention relates to the technical field of medicines, and discloses a hydrogel microneedle integrating needles and medicines. The micro-needle matrix is hydrogel formed by cross-linking products of gelatin and tannic acid, and the matrix is loaded with medicine which is cinnamon oil nanocapsules. The cinnamon oil nanocapsule hydrogel microneedle (HFMNs-CIO @ NCs) can better wrap 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 of cinnamon oil is fully exerted, meanwhile, the microneedle absorbs water and swells, can stimulate tissues in the Shenque acupoint regions, excite the acupoint effect, and improve the symptoms of congealing cold and blood stasis of cold congealing type dysmenorrheal model rats. The needle-drug integrated hydrogel microneedle can be used for various drug-encapsulated drugs and preparations thereof, is further used for clinical treatment of acupoint therapy, and has clinical popularization and use values.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a hydrogel microneedle integrating needles and medicines.
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 current clinical application, acupuncture needs professional medical technicians, main approaches of acupuncture point administration are acupuncture point injection and acupoint application, but compliance of patients with acupuncture point injection is poor, and acupoint application is difficult to concentrate medicine in acupoint tissues in subcutaneous deep layer due to barrier effect of skin and rapid transfer 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 material, has the length of 100-1000 μm, has a single micro-needle and a plurality of integrated micro-needle arrays, and can be made into different forms such as pen type, roller, patch and the like according to the requirements. The treatment method combining the micro-needle and the medicament can be used for firstly carrying out acupuncture and then administering the medicament, and can also be used for directly conveying the medicament into a human body after the medicament is attached to and wrapped on the needle 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 the umbilical acupoint 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 matrix and medicine contained in the microneedle matrix. The microneedle matrix is hydrogel formed by cross-linking products of gelatin and tannic acid.
Preferably, the drug encapsulated 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 grain diameter of the cinnamon oil nano capsule is 50-500 nm, wherein the drug-loading rate of the cinnamaldehyde is 26-36 wt%.
The mass ratio of the microneedle substrate to the cinnamon oil nanocapsules is 0.2-0.5 according to 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 2-16h;
(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, preferably 0.04; the concentration of the gelatin solution is 100-200mg/mL, and the concentration of the tannic acid solution is 40-80mg/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 gelation 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 a calcium chloride solution into the O/W emulsion in the step (a), and stirring for 15-60min;
(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); the concentration of the calcium chloride solution in the step (b) is 0.3-1mg/mL; the concentration of the chitosan solution in the step (c) is 0.3-1mg/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 200-600rmp until dissolved, so as to prepare a sodium alginate solution; in the step (a), adding cinnamon oil and phospholipid alcoholic solution into sodium alginate solution while performing ultrasonic treatment, mixing, continuing to perform ultrasonic treatment for 10-20min, and performing ultrasonic treatment for 10-20min by using a probe under an 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 200-500rpm for 20-40min after the dripping is finished.
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, continuing stirring at 200-500rpm for 2-6h after the dropwise addition is finished, and standing for 8-16h.
In the step (d), 100000-150000 Xg is centrifuged for 45-120min, and the precipitate is taken out.
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: the cinnamon oil nano capsule solution and the microneedle matrix solution are uniformly mixed, then cast in a microneedle mould, and are subjected to decompression, mould filling, vacuum drying and demoulding to prepare the cinnamon oil nano capsule.
The microneedle matrix obtained by crosslinking gelatin and tannic acid is easy to form and demould, and has good mechanical strength and high swelling property. 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 small 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 backbone. The chitosan also has the characteristics of no toxicity, biocompatibility, biodegradability and the like. Sodium Alginate (SA), a natural polysaccharide extracted from brown algae and seaweeds, is a water-soluble linear polysaccharide, and the carboxylic acid group makes 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 medicine 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 gives acupuncture and administration to an acupuncture point region, thereby exerting the comprehensive effect of the acupuncture and the medicine treatment.
The cinnamon oil nanocapsule hydrogel microneedle (HFMNs-CIO @ NCs) prepared by the invention is used for applying medicine to the umbilical region (Shenque acupoint) to treat cold-congealing 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 and swells, continuously stimulates the tissues of the acupoint region, excites the acupoint region effect, and achieves the treatment effects of acupuncture dredging channels and collaterals, promoting qi circulation, dissipating 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 and 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 and 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 preparation method of the microneedle is simple, special equipment and harsh conditions are not needed, large-scale production is easy to realize, and the microneedle 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 is a mechanical strength test pattern of a hydrogel microneedle (GB-Tan-MNs-CIO @ NCs) carrying the 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 (GB-Tan-MNs-CIO @ NCs) carrying the cinnamon oil nanocapsules prepared in example 3 of the present invention and control blank hydrogel microneedles (GB-Tan-MNs) carrying no drug;
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 a blank group, the C is a model group, the D is an acupuncture group, the E is a blank micro-needle group, and the F is a drug-loading 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, the coarse powder is soaked for 1h, the extraction is carried out for 6h by a steam distillation method at 200 ℃, and the volatile oil is collected to obtain 3mL of the cinnamon volatile oil. 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 -1 Heating 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 -1 The solution of (1). The calcium chloride solution was diluted to 8 deg.f.5ml·h -1 While stirring at (1000 rpm), the mixture was dropped into the O/W emulsion, and after the dropping, stirring was continued at 300rpm for 30 minutes.
Weighing 6mg of chitosan, dissolving in 10mL of 1% acetic acid aqueous solution, and preparing to obtain a solution with a concentration of 0.6 mg/mL -1 The pH of the solution was adjusted to 5.0 by 4% NaOH solution. Then the chitosan solution is added at a rate of 10 mL.h -1 Dropping into the sodium alginate solution while stirring at 1000rpm, stirring at 300rpm for 3 hr, standing overnight, centrifuging at 140,000 Xg for 60min, removing supernatant, adding 20mL purified water into precipitate, and storing at 4 deg.C.
Example 2 preparation of hydrogel microneedle carrying cinnamon oil nanocapsules
1.3 preparation of hydrogel microneedle carrying cinnamon oil nanocapsules
4g of gelatin was weighed, 15mL of purified water was added, heated at 55 ℃ and stirred (300 rpm) 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 into a clean microneedle mould, standing for 15min under a vacuum environment of-0.08 mPa, scraping the upper layer of matrix which is not filled into 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 hydrogel micro-needles of the cinnamon oil-loaded nanocapsules 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 undamaged 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 neatly. 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 distance between the microneedle substrates is 600 μm, and the distance between the needle tips is 900 μm.
3.2 Mechanical Strength of HFMNs-CIO @ NCs
Taking the dried HFMNs-CIO @ NCs respectively to ensure the needle body to be in a complete shape and the substrate to be flat and uniform. The needle body was placed upward on a test board 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 variation of the compression deformation 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 11X 11 arrays, the mechanical strength of HFMNs and HFMNs-CIO @ NCs were calculated to be 0.15N/needle, 0.18N/needle, respectively, i.e., loading of the nanocapsules resulted in a slight increase in microneedle strength.
3.3 Swellability of HFMNs-CIO @ NCs
Taking blank microneedle patches (HFMNs) and drug-loaded microneedle patches (HFMNs-CIO @ NCs), recording initial mass W L . 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 W 0 And t is denoted as W t To (W) t -W 0 )/W L The swelling ratio of the microneedle patch at t is expressed, 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% at 30min, and then the swelling speed gradually decreases and becomes gentle, and the swelling rate is about 430% at 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 in vitro 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 in vitro skin.
Example 4 study of analgesic Effect of cinnamon oil nanocapsule-loaded hydrogel microneedle (HFMNs-CIO @ NCs) on congealing cold blood stasis type dysmenorrhea model rat
4.1 animal groups
Female SD rats, with a body mass of 180-220 g, are four groups: the system comprises (1) a blank control group, (2) a model group, (3) an umbilical acupuncture group, (4) a blank micro-needle umbilical part treatment group, and (5) a micro-needle umbilical part acupuncture treatment group carrying cinnamon oil nanocapsules. 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 cold coagulation blood stasis type dysmenorrheal rat model is established according to a literature method (Chinese medicine society, dysmenorrheal animal model preparation standard (draft) [ J ]. China experiment formulary journal, 2018). Continuously administering estradiol benzoate to animals to improve uterine sensitivity; oxytocin was injected again, producing a dysmenorrhoea-like response. 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 1 st and 10 th days is 2.5 mg/kg -1 The dosage of the composition for the rest of time is 1 mg/kg -1 (ii) a Simultaneously placing the rat in ice water bath for 10min every day, and injecting epinephrine hydrochloride (8 μ g. Kg) for 2 times subcutaneously on day 11 -1 ) At intervals of 2h, 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 the 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.kg) intraperitoneally after 1h -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': under the natural relaxation and partial stretching of the lower limbs, the rat "Shenque" acupoint is located at about 1/3 of 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 4-5mm.
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 30min.
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
The rats were recorded on diet and body weight, and observed for hair color, behavioral behavior, and mental status.
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 Yangmai (evaluation and selection of the preparation method of the animal model with the syndrome of congealing cold and blood stasis [ J ]. Chinese medicine report 2014), the characteristic score of the cold syndrome 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 micro-needle umbilical region treatment group and the cinnamon oil-carrying nanocapsule micro-needle umbilical region treatment group are treated for the last time, oxytocin is injected into the abdominal cavity, and the incubation period, the twisting frequency and the twisting score of the rats in each group are observed within 20min.
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 and cosmetic properties In the rate [ J ]. J Pharmacol Exp Ther, l 984). Stage 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, stage: 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; twist score =0 grade (times) × 0min +1 grade (times) × 1min +2 grade (times) × 2 min +3 grade (times) × 3 min. 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: (
n＝6)
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 ELISA method for determining prostaglandin E2 (PGE 2) and prostaglandin F2 alpha (PGF 2 alpha) contents in rat uterine tissues
After injecting oxytocin for 1h, rats were anesthetized by intraperitoneal injection of 1.0mL (150 mg/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 a low temperature of 3000r/min for 15min, taking supernate, 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 a 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 and the blank microneedle umbilical treatment group have the advantages that the content of PGF2 alpha is reduced extremely remarkably (P < 0.01), the ratio of PGF2 alpha/PGE 2 is reduced remarkably (P < 0.05), the content of PGE2 in the microneedle umbilical treatment group of the cinnamon oil-carrying nanocapsule is increased extremely remarkably (P < 0.01), the content of PGF2 alpha and the ratio of PGF2 alpha/PGE 2 are reduced remarkably (P < 0.05), and the fact that each treatment group has a certain treatment effect on the low cold coagulation blood stasis type dysmenorrheal model rat is shown, wherein the treatment effect of the microneedle umbilical treatment group of the cinnamon oil-carrying nanocapsule is most remarkable.
TABLE 2 comparison of the PGE2, PGF 2. Alpha. Content and PGF 2. Alpha./PGE 2 ratio in the uterus of rats in each group: (
n＝6)
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 the number of mast cells in the crypt area and degranulation Rate
After injecting oxytocin for 1h, the rats were anesthetized by intraperitoneal injection of 1.0mL (150 mg/kg) of 3% pentobarbital sodium, the skin of the shenque acupoint area of the rats together with subcutaneous muscle tissue (3 mm × 3mm × 3 mm) were rapidly taken on an ice tray of a sterile workbench, washed with normal saline, fixed with 4% paraformaldehyde for toluidine blue staining, and photographs were taken under a 10 × 40 microscope, with the results shown in fig. 6. 3 tissue sections were taken from each rat cave area, 3 fields were randomly selected, 1 field was selected for muscular layer, and 2 fields were selected for fascia layer, mast cell morphology of the sections was observed under 10X 20 fold optical microscope and counted (both intact and degranulated), and the counting result was 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 (
n＝6)
Note: compared with the control group, the compound is added, # 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, a blank group C, a model group, D, an acupuncture group E, a blank micro-needle group F, a medicine-carrying micro-needle 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 medicine integrated treatment strategy provided by the invention, the medicine can be delivered to the deep layer of the skin of the acupoint region to play the treatment effect of the medicine in the acupoint region, and meanwhile, the micro-needle body absorbs water and swells, so that the tissue of the acupoint region can be stimulated, the acupoint effect is stimulated, and the treatment purpose is achieved. The cinnamon oil nanocapsule hydrogel microneedle umbilical administration can improve symptoms of congealing cold and blood stasis type dysmenorrhea model rats, prolong the body twisting latency, reduce body twisting times and body twisting scores, obviously increase the PGE2 content of uterine tissues, reduce the PGF2 alpha content and the PGF2 alpha/PGE 2 ratio, obviously increase the number of mast cells and the degranulation rate of the mast cells in the Shenque acupoint area, and show that the cinnamon oil nanocapsule hydrogel microneedle umbilical administration can play a meridian acupoint acupuncture effect, and has an important role in improving symptoms of congealing cold and blood stasis type dysmenorrhea. The integrated treatment strategy of the needle and the medicine is expected to utilize the microneedle to package the free medicine and the preparation thereof, is further used for clinical treatment of the acupuncture point therapy, and is worthy of clinical popularization and application.
Claims (4)
1. A needle and medicine integrated hydrogel microneedle for treating cold-congealing blood stasis type dysmenorrhea is characterized in that a microneedle substrate is hydrogel formed by a gelatin and tannin cross-linked product, a medicine is loaded in the substrate, the medicine is a cinnamon oil nanocapsule, the particle size is 50-500 nm, the medicine loading capacity of cinnamaldehyde is 26-36 wt%, and the mass ratio of the microneedle substrate to the cinnamon oil nanocapsule is 0.2-0.5;
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 2-16h;
(2) Adding glycerol into the reaction solution and uniformly stirring;
the mass ratio of the tannic acid to the glycerol to the gelatin is 0.02-0.05; the concentration of the gelatin solution is 100-200mg/mL, and the concentration of the tannic acid solution is 40-80mg/mL;
the preparation method of the cinnamon oil nano capsule comprises the following steps:
(a) Dissolving cinnamon oil and phospholipid in alcohol, adding the dissolved cinnamon oil and phospholipid into a sodium alginate solution, and performing ultrasonic dispersion to obtain an O/W emulsion, wherein the weight ratio of the cinnamon oil to the phospholipid to the calcium chloride to the chitosan is (4-6);
(b) Dropwise adding a calcium chloride solution into the O/W emulsion obtained in the step (a), and stirring for 15-60min, wherein the concentration of the calcium chloride solution is 0.4-1mg/mL;
(c) Dropwise adding a chitosan solution into the solution obtained in the step (b), continuously stirring after dropwise adding, and standing, wherein the concentration of the chitosan solution is 0.4-1mg/mL;
(d) Separating to obtain precipitate, and obtaining the cinnamon oil nanocapsule.
2. The needle-drug integrated hydrogel microneedle according to claim 1, wherein the phospholipid is egg yolk lecithin, soybean lecithin, hydrogenated soybean lecithin, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine, or dipalmitoylphosphatidylcholine.
3. A method for preparing a needle-drug integrated hydrogel microneedle according to claim 1 or 2, comprising the steps of: and (3) uniformly mixing the cinnamon oil nano capsule solution and the microneedle matrix solution, forming and drying.
4. Use of the needle-drug integrated hydrogel microneedle according to claim 1 or 2 for preparing a medicament for treating cold-coagulation blood-stasis type dysmenorrhea.
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