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WO2023098158A1 - Micro-aiguille d'hydrogel intégrant un médicament dans l'aiguille - Google Patents

Micro-aiguille d'hydrogel intégrant un médicament dans l'aiguille Download PDF

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Publication number
WO2023098158A1
WO2023098158A1 PCT/CN2022/114243 CN2022114243W WO2023098158A1 WO 2023098158 A1 WO2023098158 A1 WO 2023098158A1 CN 2022114243 W CN2022114243 W CN 2022114243W WO 2023098158 A1 WO2023098158 A1 WO 2023098158A1
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Prior art keywords
microneedle
cinnamon oil
acupuncture
solution
medicine
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Chinese (zh)
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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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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H39/00—Devices for locating or stimulating specific reflex points of the body for physical therapy, e.g. acupuncture
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H2201/00—Characteristics of apparatus not provided for in the preceding codes
    • A61H2201/10—Characteristics of apparatus not provided for in the preceding codes with further special therapeutic means, e.g. electrotherapy, magneto therapy or radiation therapy, chromo therapy, infrared or ultraviolet therapy
    • A61H2201/105—Characteristics of apparatus not provided for in the preceding codes with further special therapeutic means, e.g. electrotherapy, magneto therapy or radiation therapy, chromo therapy, infrared or ultraviolet therapy with means for delivering media, e.g. drugs or cosmetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a hydrogel microneedle integrating acupuncture and medicine.
  • acupoints are special parts where Qi and blood flow into and out of the viscera and meridians, and acupoints are closely connected with deep tissues and organs and communicate with each other. Stimulating the acupoints of the human body through acupuncture, massage, drug administration, etc. can dredge the meridians, reconcile yin and yang, promote qi and blood circulation, stimulate the effect of acupoints, and achieve the purpose of strengthening the body, eliminating pathogens, and preventing and curing diseases.
  • Umbilical drug administration is one of the commonly used umbilical therapy methods in traditional Chinese medicine.
  • acupoint administration is acupoint injection and acupoint application, but the compliance of patients with acupoint injection is poor. Due to the barrier effect of the skin and intradermal microblood Rapid transport, it is difficult to concentrate the drug in the subcutaneous deep acupoint tissue.
  • Microneedles is a new transdermal drug penetration enhancing technology integrating injection and transdermal, which is painless and minimally invasive.
  • Microneedles can be made of metal, ceramics, silicon or polymer materials, with a length of 100-1000 ⁇ m.
  • the treatment method combining microneedle and drug can be given by acupuncture first, or the drug can be attached and loaded in the needle body and then directly transported into the body. Since acupuncture can form drug delivery channels on the skin surface, it can effectively promote the percutaneous absorption of drugs and enhance the therapeutic effect.
  • Microneedling is painless and minimally invasive, and patients are highly compliant.
  • Cinnamon oil has the effect of warming the middle and dispelling cold.
  • acupoint therapy if it can be delivered to the deep layer of the skin at the acupoints, it can fully exert its efficacy and achieve the purpose of treatment; especially the administration of umbilical acupoints.
  • cinnamon oil is attached to the needle body of the microneedle for acupuncture treatment, the drug loading may be insufficient; if it is entrapped in the needle body, the release problem in the body has not been solved.
  • the present invention aims to overcome the defects of the prior art, combines acupuncture in the umbilical area with acupoint administration, develops a microneedle loaded with medicine, and realizes an integrated acupoint treatment strategy of "needle” and "medicine", which is easy to operate, and enhance the therapeutic effect.
  • the invention provides a hydrogel microneedle with integrated acupuncture and medicine (HFMNs-CIO@NCs), which comprises a microneedle matrix and a drug entrapped in the microneedle matrix, and the microneedle matrix is gelatin and tannic acid Hydrogels formed by co-products.
  • HFMNs-CIO@NCs integrated acupuncture and medicine
  • the medicine contained in the microneedle matrix is a nanocapsule, more preferably a cinnamon oil nanocapsule, that is, the described acupuncture-medicine integrated hydrogel microneedle is a cinnamon oil nanocapsule hydrogel microneedle (HFMNs- CIO@NCs).
  • cinnamon oil nanocapsules are cinnamon oil encapsulated in the shell-core structure formed by chitosan and sodium alginate; the particle diameter of the cinnamon oil nanocapsules is 50-500nm, and the The drug loading amount of cinnamon aldehyde in the cinnamon oil nanocapsules is 26wt%-36wt%.
  • the mass ratio of the microneedle matrix to the cinnamon oil nanocapsules is 0.2-0.5:1.
  • the microneedle matrix is gelatin and tannic acid cross-linked product (Gel-Tan), which is obtained by the cross-linking reaction between the amino group and carboxyl group in gelatin and the hydroxyl group in tannic acid.
  • the preparation method of needle matrix comprises the following steps:
  • the mass ratio of the tannic acid, glycerin and 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, the tannic acid The solution concentration is 40-80 mg/mL.
  • step (1) the pH is adjusted to 5.5, and the reaction is carried out at 50-60° C. for 2-16 hours.
  • the cinnamon oil nanocapsules are prepared by the controllable gelation of alginate induced by cations, and the preparation method of the cinnamon oil nanocapsules comprises the following steps:
  • step (b) Add the calcium chloride solution dropwise to the O/W emulsion in step (a), and stir for 15 to 60 minutes;
  • step (c) Add chitosan solution dropwise in the solution of step (b), continue to stir after dropping, leave standstill;
  • the phospholipid is egg yolk lecithin, soybean lecithin, hydrogenated soybean lecithin, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine or dipalmitoylphosphatidylcholine;
  • the phospholipids have a purity greater than 95%, more preferably greater than 98%.
  • the alcohol is ethanol.
  • the weight ratio of described cinnamon oil to phospholipid, calcium chloride and chitosan is 4 ⁇ 6:1:0.4 ⁇ 0.6:0.2 ⁇ 0.4
  • the sodium alginate solution concentration described in step (a) 0.3 ⁇ 1mg/mL
  • the consumption ratio of cinnamon oil and alcohol is 30 ⁇ 60mg/mL
  • the calcium chloride solution concentration described in step (b) is 0.3 ⁇ 1mg/mL
  • the chitosan described in step (c) The solution concentration is 0.3-1mg/mL.
  • the cinnamon oil is prepared according to the provisions of the Pharmacopoeia, and is the volatile oil of cinnamon, wherein the content of cinnamon aldehyde complies with the quality standards for cinnamon oil (Cinnamon Oil, CIO) in the 2020 edition of "Chinese Pharmacopoeia”.
  • step (a) sodium alginate is stirred in pure water at 200-600rmp until dissolved to obtain a sodium alginate solution; in step (a), the alcohol solution of cinnamon oil and phospholipids is added to the seaweed while ultrasonically After mixing, continue to sonicate for 10 to 20 minutes, and then sonicate the probe for 10 to 20 minutes in an ice bath.
  • step (b) calcium chloride is added dropwise to the O/W emulsion in step (a) at a rate of 6-10 mL/h, and after the dropwise addition is completed, stirring is continued at 200-500 rpm for 20-40 min.
  • step (c) chitosan is dissolved with 0.5% ⁇ 2% acetic acid aqueous solution, and adjusts pH to 4.5-5.5, preferred pH value is 5; And chitosan solution is stirred while stirring at the speed of 8 ⁇ 15mL/h Add to the solution in step (b), after the dropwise addition, continue stirring at 200-500 rpm for 2-6 hours, and let stand for 8-16 hours.
  • step (d) centrifuge at 100,000 to 150,000 ⁇ g for 45 to 120 min, and take the precipitate.
  • the invention provides a method for preparing the hydrogel microneedle integrating acupuncture and medicine.
  • the steps include: mixing the drug solution and the microneedle matrix solution, forming and drying.
  • the preparation method of cinnamon oil nanocapsule hydrogel microneedles comprises: mixing the cinnamon oil nanocapsule solution and the microneedle matrix solution, forming and drying. Specifically, the cinnamon oil nanocapsule solution and the microneedle matrix solution are evenly mixed, and then cast in a microneedle mold, put into the mold under reduced pressure, and then vacuum-dried, and then demoulded.
  • the invention adopts the microneedle matrix obtained by cross-linking gelatin and tannic acid, which is easy to form and demould, has good mechanical strength and high swelling property.
  • the loading of nanocapsules can enhance the strength of microneedles.
  • the above-mentioned cinnamon oil nanocapsule hydrogel microneedle can be used to prepare a medicine for treating dysmenorrhea of cold coagulation and blood stasis type. Using this kind of microneedle can realize the integrated treatment strategy of acupuncture and medicine.
  • the microneedle of the present invention can deliver the cinnamon oil nanocapsules to the deep part of the acupoint area.
  • the hydrogel microneedle absorbs water and swells, continuously stimulates the tissue of the acupoint area, stimulates the effect of the acupoint area, and achieves acupuncture to dredge the meridian, promote qi and dissipate blood stasis, Therapeutic effects such as pain relief.
  • Nanocapsules (Nanocapsules, NCs) technology uses polymer films to embed and encapsulate trace amounts of drug molecules.
  • the embedded substance is called the core material, and the polymer covering the core material is called the wall material.
  • the particle size of nanocapsules is at the nanometer level, and its nanosize effect makes it have good biocompatibility, targeting and sustained release.
  • Chitosan Choitson, CS
  • the N-deacetylation product of chitin is a linear polysaccharide composed of glucosamine and N-acetylglucosamine units linked by ⁇ -(1 ⁇ 4) glycosidic bonds.
  • Chitosan can be dissolved in acidic medium after deacetylation treatment, and becomes the only polysaccharide with high positive charge density due to the protonation of amino groups on its main chain. Chitosan also has characteristics such as non-toxicity, biocompatibility and biodegradability.
  • Sodium Alginate Sodium Alginate, SA
  • SA sodium Alginate
  • the sodium alginate and calcium ion cross-linked product is used as the shell of the nanocapsule
  • the cinnamon oil is used as the core
  • the cinnamon oil nanocapsule is prepared by an ion gel method and modified with chitosan.
  • the gelatin and tannic acid cross-linked product was used as the hydrogel microneedle matrix, and the cinnamon oil nanocapsules were mixed evenly with the microneedle matrix, and the hydrogel microneedles were prepared by casting method, which could better encapsulate cinnamon oil and be used for umbilical cord.
  • the cinnamon oil nanocapsules can be delivered to the deep part of the acupoint area for better drug efficacy.
  • Hydrogel forming microneedles consist of swelling materials and drug depots. After the hydrogel microneedles are pierced into the skin, the swelling material and the drug reservoir in the microneedle array can absorb the interstitial fluid so that the needle body swells and releases the drug. Therefore, by using microneedles to carry drugs, it is possible to combine acupuncture in the umbilicus region with acupoint administration, and realize the integrated treatment of "needle” and "medicine”.
  • the invention provides a new type of integrated acupuncture-medicine microneedle, which can be used for acupoint therapy.
  • the microneedle is used as a carrier, and the extract of traditional Chinese medicine and its preparation, especially the nanocapsule of the extract of traditional Chinese medicine, are used for acupuncture and drug delivery at the acupoints at the same time. Medicine, exerting the comprehensive effect of acupuncture and drug therapy.
  • the cinnamon oil nanocapsule hydrogel microneedle (HFMNs-CIO@NCs) prepared by the present invention is used for administration in the umbilical area (Shenque point) to treat dysmenorrhea of cold coagulation and blood stasis type.
  • the cinnamon oil nanocapsules are delivered to the deep part of the acupoint area.
  • the hydrogel microneedle absorbs water and swells, continuously stimulating the acupoint area tissue, stimulating the acupoint area effect, and achieving the therapeutic effects of acupuncture to dredge the meridians, promote qi and dissipate blood stasis, and relieve pain.
  • the invention uses the cross-linked product of gelatin and tannic acid as the hydrogel microneedle matrix, which is easy to form and demould, has good mechanical strength and high swelling property. And the loading of nanocapsules can enhance the strength of microneedles.
  • the shell-core structure formed by chitosan and sodium alginate is used to entrap cinnamon oil to form cinnamon oil nanocapsules; the cross-linked product of gelatin and tannic acid is used as the microneedle matrix to encapsulate cinnamon oil.
  • the prepared cinnamon oil nanocapsule hydrogel microneedles can not only deliver cinnamon oil nanocapsules to the deep layer of the skin in the acupoint area, but also give full play to the effect of cinnamon oil in warming and dispelling cold, and at the same time, the microneedle itself absorbs water and swells, which can stimulate the acupoints Area tissue, stimulating the effect of point area, to achieve the purpose of treatment.
  • Administration of cinnamon oil nanocapsules, hydrogel, and microneedles to the umbilicus can improve the symptoms of cold coagulation syndrome in rats with dysmenorrhea of cold coagulation and blood stasis type, prolong the writhing latency period, reduce the number of writhing times and writhing scores, and significantly increase the PGE2 of uterine tissue content, reduce PGF2 ⁇ content and PGF2 ⁇ /PGE2 ratio, significantly increase the number of mast cells and mast cell degranulation rate in Shenque acupoint area, thereby significantly improving the therapeutic effect on rats with cold coagulation and blood stasis type dysmenorrhea.
  • microneedle of the present invention can realize the integrated treatment strategy of acupuncture and medicine, and it is expected that the microneedle can be used to carry free medicine and its preparation, and to carry a variety of medicines and their preparations, which can be further used in the clinical treatment of acupoint therapy, which is worthy of clinical promotion Use;
  • the microneedle preparation method of the present invention is simple, does not require special equipment and harsh conditions, is easy to realize large-scale production, and has strong practical value.
  • Fig. 1 is the transmission electron micrograph of the cinnamon oil nanocapsule prepared by the embodiment of the present invention 2;
  • Fig. 2 is the scanning electron micrograph of the cinnamon oil nanocapsule hydrogel microneedle 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 the hydrogel microneedle (GB-Tan-MNs-CIO@NCs) loaded with cinnamon oil nanocapsules prepared in Example 3 of the present invention and the blank hydrogel microneedle (GB-Tan- MNs) mechanical strength test pattern;
  • FIG. 4 shows the hydrogel microneedles (GB-Tan-MNs-CIO@NCs) loaded with cinnamon oil nanocapsules prepared in Example 3 of the present invention and the blank hydrogel microneedles (GB-Tan- MNs) swelling test collection;
  • Fig. 5 is the optical photo of the rhodamine B-labeled blank microneedle patch pierced into rat isolated skin prepared in Example 3 of the present invention
  • Fig. 6 is the toluidine blue stained light microscope photo of mast cells in rat Shenque acupoint area obtained in Example 4 of the present invention, wherein: (A, B) is a blank group, C is a model group, D is an acupuncture group, and E is a blank Microneedle group, F is drug-loaded microneedle group.
  • Embodiment 1 Preparation of cinnamon oil nanocapsules
  • cinnamon medicinal material stipulated in the 2020 edition of "Chinese Pharmacopoeia”
  • weigh 200.2g of cinnamon medicinal material crush it into a 20-mesh coarse powder, add 8 times the amount of water, soak for 1h, extract by steam distillation at 200°C for 6h, and collect volatile oil to obtain 3mL Cinnamon essential oil.
  • the cinnamon aldehyde content in cinnamon volatile oil is 93.1 ⁇ 4.45%, which meets the quality standards for cinnamon oil (Cinnamon Oil, CIO) in the 2020 edition of "Chinese Pharmacopoeia”.
  • the chitosan solution was dripped into the above-mentioned sodium alginate solution while stirring (1000rpm) at a speed of 10mL ⁇ h -1 , continued to stir at 300rpm for 3h after the dropwise addition, left to stand overnight, centrifuged at 140,000 ⁇ g for 60min, and removed the above Then add 20 mL of purified water to the precipitate to disperse to obtain cinnamon oil nanocapsules (CIO@NCs), which are stored at 4°C for later use.
  • CIO@NCs cinnamon oil nanocapsules
  • the dried HFMNs-CIO@NCs were taken, and the surface was evenly sprayed with gold powder, and placed under a scanning electron microscope under vacuum conditions for morphological observation.
  • Fig. 2 is a scanning electron micrograph of the hydrogel microneedle of the cinnamon oil-loaded 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. It can be seen from Figure 2 that the demolding rate of HFMNs-CIO@NCs is 100%. After demoulding, the needle tip is intact and undamaged.
  • the needle body is pyramid-shaped and consists of four-sided cone-shaped needle bodies. The base thickness is uniform and the array is arranged neatly.
  • the microneedle patch is a square with a side length of 1.4 cm. The microneedle array is 10 ⁇ 10.
  • the length of the microneedle base is about 600 ⁇ m, the width is about 600 ⁇ m, and the height of the microneedles is about 1450 ⁇ m.
  • the distance between the base of the microneedles is 600 ⁇ m, and the distance between the needle tips is 900 ⁇ m.
  • the needle body is placed upwards on the test plate of the texture analyzer, and a cylindrical probe with a diameter of 5 mm is set to compress the microneedle at a speed of 30 mm/min until the extrusion deformation is 40%.
  • the initial trigger force was 0.05N, and the force-displacement curve of the microneedle was drawn.
  • Fig. 3 is the hydrogel microneedle mechanical strength test spectrum of the cinnamon oil nanocapsules prepared in Example 3 of the present invention, as can be seen from Fig. 3, the mechanical strength of the BSP composite microneedle before and after drug loading can reach more than 18N. Since the microneedle mold is an array of 11 ⁇ 11, the calculated mechanical strengths of HFMNs and HFMNs-CIO@NCs are 0.15 N/needle and 0.18 N/needle, respectively, that is, the loading of nanocapsules slightly increases the strength of microneedles.
  • microneedle patches Take blank microneedle patches (HFMNs) and drug-loaded microneedle patches (HFMNs-CIO@NCs), and record the initial mass W L .
  • the microneedle sheets with different prescriptions were wrapped with polytetrafluoroethylene film and tin foil in turn, so that the needle tip was exposed.
  • Add 0.7 mL of PBS to each well of the 24-well plate place the wrapped microneedle patch upside down in the well, and immerse the exposed needle tip in water. At 5, 15, 30, 60, and 90 minutes, the microneedle patch was taken out from the 24-well plate, and the excess water on the surface was wiped off, and then weighed.
  • the mass at 0 was recorded as W 0
  • the mass at t was recorded as W t
  • (W t -W 0 )/W L represents the swelling rate of the microneedle patch at time t
  • the above test was repeated 3 times for each group of samples. Take t as the abscissa and the swelling rate as the ordinate respectively to investigate the effect of drug loading on the swelling rate of microneedles.
  • Fig. 4 is the hydrogel microneedle swelling property test spectrum of the loaded cinnamon oil nanocapsule prepared by the embodiment of the present invention 3, as seen from Fig. 4, the swelling rate of blank microneedle reaches 350% in 30min, after that, the swelling rate gradually decreases, It tends to be gentle, and the swelling rate is about 430% at 90 minutes. However, the swelling rate of the microneedles increased slightly after loading the drug, reaching 390% at 30 minutes, and 470% at 90 minutes. The swelling degree and swelling speed were better than those of blank microneedles.
  • Rhodamine-labeled microneedles were prepared by labeling blank microneedle matrix with water-soluble dye rhodamine B. Press the surface of the isolated skin of the rat with your hands for 5 minutes, remove the microneedle patch, and observe the ability of the microneedle to penetrate the skin.
  • Fig. 5 is an optical photograph of the rhodamine B-labeled blank microneedle patch prepared in Example 3 of the present invention piercing the isolated rat skin. It can be seen from Fig. 5 that the microneedle can successfully penetrate the isolated rat skin.
  • Example 4 Study on the analgesic effect of hydrogel microneedles loaded with cinnamon oil nanocapsules (HFMNs-CIO@NCs) on model rats with cold coagulation and blood stasis type dysmenorrhea
  • Female SD rats with a body weight of 180-220 g, were divided into the following four groups: (1) blank control group, (2) model group, (3) umbilicus acupuncture group, (4) blank microneedle umbilicus treatment group, (5 ) containing cinnamon oil nanocapsule microneedle umbilical acupuncture treatment group. Except for the blank control group, the model group and each treatment group were divided into groups after successful modeling.
  • Rats in model group and treatment group were subcutaneously injected with estradiol benzoate, once a day, for 10 consecutive days; the dose was 2.5 mg ⁇ kg -1 on the first and 10th day, and 1 mg ⁇ kg -1 in the rest of the time; Put the rats in an ice-water bath for 10 minutes.
  • epinephrine the animals were placed in ice water for 5 minutes, and after 5 minutes, the rats were taken out and put back into the cages for feeding.
  • estradiol benzoate On the 12th day, 1 hour after the subcutaneous injection of estradiol benzoate, the rats were immediately intraperitoneally injected with oxytocin (dose 10U ⁇ kg -1 ) to prepare a rat model of dysmenorrhea in combination with estrogen and oxytocin in ice water bath. Observe the writhing reaction behavior of rats to judge the success of modeling.
  • the blank control group was given normal diet, free drinking water, and no treatment.
  • subcutaneous injection of normal saline was given to the thigh every day. , 0.25mL/monkey on the 10th day, subcutaneous injection twice on the 11th day, 0.1mL/bird each time, with an interval of 2h.
  • 0.25 mL of normal saline was injected subcutaneously, and 1 hour later, oxytocin (dose 10 U ⁇ kg -1 ) was injected intraperitoneally immediately, and the writhing response behavior of the rats was observed.
  • Rats were anesthetized by inhalation of isoflurane. After the rats were anesthetized, the coarse hairs around the Shenque acupoint were removed with an electric shaver, and then the fine hairs around the Shenque acupoint were removed with a depilatory cream. Rats were given treatment on the 6th day after modeling, once a day for a total of 7 treatments.
  • the Shenque acupoint was regarded as the dial, and the intradermal needle was used to take the 6 o’clock position and stab horizontally towards the corresponding acupoint area.
  • the needle was fixed with medical adhesive tape, and the needle was retained for 30 minutes at a depth of 4-5 mm.
  • the rats were fixed in a supine position, and the blank or drug-loaded microneedles were placed in the Shenque acupoint area of the rats, and pressed with hands for 1 min, so that the microneedles penetrated into the Shenque acupoints of the rats, fixed with medical adhesive tape, and the needles were left for 30 min.
  • the blank group and the model group were grasped and fixed synchronously with the above-mentioned groups, and no treatment was given.
  • the symptoms improved, the weight remained stable or gradually increased, the spirit improved, the hair became brighter, and the skin color of the ears, limbs, tail and other parts appeared pink.
  • the stool is slightly moist, and the fecal matter is slightly soft.
  • Table 1 The results are shown in Table 1.
  • the writhing reaction latency of rats in the model group was significantly shortened, and the number of writhing times and writhing scores were significantly increased, indicating that the model of dysmenorrhea rats with cold coagulation and blood stasis was successfully established.
  • the number of writhing times in the umbilical acupuncture treatment group was significantly reduced (P ⁇ 0.05), and the number of writhing times and writhing scores in the blank microneedle umbilicus treatment group were significantly reduced (P ⁇ 0.05).
  • the writhing latency period of the microneedle umbilicus treatment group was significantly prolonged (P ⁇ 0.05), and the number of writhing times and writhing ratings were significantly reduced (P ⁇ 0.01), indicating that each treatment group had a certain effect on the dysmenorrhea model rats of cold coagulation and blood stasis type. Among them, the treatment effect of the microneedle umbilicus treatment group loaded with cinnamon oil nanocapsules was the most significant.
  • the rat was anesthetized by intraperitoneal injection of 3% pentobarbital sodium 1.0mL (150mg/kg), and the uterus was quickly removed on the ice tray of the sterile workbench, weighed, and the sample was placed in a -80°C refrigerator Save for later use.
  • the content of PGF2 ⁇ in the model group was significantly increased (P ⁇ 0.01), and the ratio of PGF2 ⁇ /PGE2 was significantly increased (P ⁇ 0.05), indicating that the model of dysmenorrhea rats with cold coagulation and blood stasis was successfully established.
  • the PGF2 ⁇ content in the umbilical acupuncture treatment group and the blank microneedle umbilicus treatment group significantly decreased (P ⁇ 0.01), and the ratio of PGF2 ⁇ /PGE2 decreased significantly (P ⁇ 0.05).
  • the content of PGE2 in the microneedling umbilicus treatment group was significantly increased (P ⁇ 0.01), and the content of PGF2 ⁇ and the ratio of PGF2 ⁇ /PGE2 were significantly reduced (P ⁇ 0.05), indicating that each treatment group had a significant effect on the treatment of dysmenorrhea model rats with low cold blood stasis type. All have a certain therapeutic effect, and the treatment effect of the microneedle umbilicus treatment group loaded with cinnamon oil nanocapsules is the most significant.
  • the rats were anesthetized by intraperitoneal injection of 1.0 mL (150 mg/kg) of 3% pentobarbital sodium, and the skin of the Shenque acupoint area of the rat and the subcutaneous muscle tissue (3mm ⁇ 3mm ⁇ 3mm), washed with normal saline, fixed with 4% paraformaldehyde, used for toluidine blue staining, and photographed under a 10 ⁇ 40 light microscope, the results are shown in Figure 6.
  • Figure 6 is a light microscope photograph of mast cells stained with toluidine blue in the rat Shenque acupoint area obtained in Example 4 of the present invention, wherein: A, B. Blank group C. Model group, D. Acupuncture group E. Blank microneedle group F. Drug-loaded microneedle group; as can be seen from Figure 6 and Table 3, compared with the blank group, the number of mast cells and the mast cell degranulation rate in the Shenque acupoint area of the rats in the model group were significantly increased, with a statistical difference (P ⁇ 0.05) . Compared with the model group, the number of mast cells and the degranulation rate of mast cells in the Shenque acupoint area in each treatment group were significantly increased (P ⁇ 0.01).
  • the acupuncture-medicine integrated treatment strategy provided by the present invention can deliver the drug to the deep layer of the skin in the acupoint area, exert its therapeutic effect in the acupoint area, and at the same time, the microneedle body absorbs water and swells, which can stimulate the tissue in the acupoint area and stimulate Acupoint effect to achieve the purpose of treatment.
  • Administration of cinnamon oil nanocapsules, hydrogel, and microneedles to the umbilicus can improve the symptoms of dysmenorrhea model rats of cold coagulation and blood stasis type, prolong the writhing latency period, reduce the number of writhing times and writhing scores, significantly increase the content of PGE2 in uterine tissue, and reduce PGF2 ⁇
  • the content and the ratio of PGF2 ⁇ /PGE2 significantly increased the number of mast cells and the degranulation rate of mast cells in the Shenque acupoint area, indicating that the administration of cinnamon oil nanocapsules hydrogel microneedles to the umbilical region can exert the effect of acupuncture at acupoints and improve the effect of cold coagulation.
  • the symptoms of blood stasis type dysmenorrhea play an important role.
  • the integrated treatment strategy of acupuncture and medicine is expected to use microneedles to carry free medicine and its preparations, which can be further used in the clinical treatment of acupoint therapy, and it is worthy of clinical promotion and use.

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Abstract

La présente invention relève du domaine technique des médicaments. Est divulguée une micro-aiguille d'hydrogel intégrant un médicament dans l'aiguille. Une matrice de micro-aiguille est un hydrogel formé par un produit de réticulation entre de la gélatine et de l'acide tannique, un médicament est piégé dans la matrice, et le médicament correspond à des nanocapsules d'huile de cannelle (CIO@NC). La micro-aiguille d'hydrogel de nanocapsule d'huile de cannelle (HFMN-CIO@NC) peut mieux piéger les CIO@NC et administrer les CIO@NC dans la couche profonde de la peau dans une zone de point d'acupuncture pour exercer pleinement l'effet de réchauffement de la rate et de l'estomac pour dissiper le froid de l'huile de cannelle; et de plus, la micro-aiguille elle-même absorbe l'eau pour gonfler, et peut stimuler le tissu dans la zone du point d'acupuncture Shenque pour exciter un effet de la zone du point d'acupuncture, ce qui permet d'améliorer les symptômes de coagulation à froid d'un modèle de rat avec dysménorrhée de type coagulation à froid et stase sanguine. La micro-aiguille d'hydrogel intégrant un médicament dans l'aiguille peut être utilisée pour divers médicaments de piégeage et préparations associées, est aussi utilisée pour le traitement clinique de la thérapie par points d'acupuncture, et présente une valeur pour la popularisation et l'utilisation cliniques.
PCT/CN2022/114243 2021-12-03 2022-08-23 Micro-aiguille d'hydrogel intégrant un médicament dans l'aiguille Ceased WO2023098158A1 (fr)

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