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WO2024077705A1 - Timbre à micro-aiguilles chargé de glucagon - Google Patents

Timbre à micro-aiguilles chargé de glucagon Download PDF

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Publication number
WO2024077705A1
WO2024077705A1 PCT/CN2022/131856 CN2022131856W WO2024077705A1 WO 2024077705 A1 WO2024077705 A1 WO 2024077705A1 CN 2022131856 W CN2022131856 W CN 2022131856W WO 2024077705 A1 WO2024077705 A1 WO 2024077705A1
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Prior art keywords
glucagon
microneedle
microneedles
microneedle patch
loaded
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PCT/CN2022/131856
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English (en)
Chinese (zh)
Inventor
郑超
于翔
谷卫
常皓
张亦凯
徐健晨
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Zhejiang University ZJU
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Zhejiang University ZJU
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Priority claimed from CN202211231468.2A external-priority patent/CN116440058B/zh
Application filed by Zhejiang University ZJU filed Critical Zhejiang University ZJU
Publication of WO2024077705A1 publication Critical patent/WO2024077705A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to the field of medical inventions, and in particular to a protein drug soluble microneedle used as a delivery carrier to achieve rapid in vivo delivery of the protein drug.
  • hypoglycemia With the change of lifestyle and the growth of aging population, the number of patients with diabetes is increasing year by year. At present, the key measure for treating diabetes is to strictly control blood sugar levels. However, strict intensive hypoglycemic treatment will increase the incidence of hypoglycemia. If hypoglycemia is severe and not treated in time, it will cause irreversible damage to the body. If it is not treated in time, persistent severe hypoglycemia will cause loss of consciousness, permanent nerve damage, and even death. It is reported that nearly $2,000 is spent on controlling hypoglycemia in patients with type 1 diabetes each year, but 4% of patients still die from hypoglycemia. For the rescue of hypoglycemia, China mainly adopts oral monosaccharide-containing foods or intravenous injection of 50% glucose solution. However, this method often exceeds the clinically recommended amount of carbohydrates, resulting in poor blood sugar control. Foreign countries mainly treat hypoglycemia patients by intravenous or subcutaneous injection of glucagon.
  • Glucagon was first discovered to have a blood sugar-raising effect in 1922 and was introduced into diabetes care and treatment in 1955. Glucagon is easily reconstituted and polymerized in water, and the initial glucagon injection solution can only be stored for 24 hours. In order to solve this problem, American companies such as Eli Lilly, Novo Nordisk and Fresenius Kabi have successively developed glucagon lyophilized powder injection. Although the obstacle of shelf life has been overcome, the preparation has a "complex administration process problem". First, blood sugar levels must be monitored, and the dosage for adults and children should be designed based on the blood sugar value. After that, the insulin lyophilized powder must be mixed with a special diluent and loaded into a specific syringe for administration.
  • Microneedles are arrays of multiple tiny needles, with a diameter of less than 300 ⁇ m and a length of 200 ⁇ m to 2000 ⁇ m.
  • the advantage of microneedles is that they can quickly deliver biomacromolecule drugs that are not easily absorbed by the gastrointestinal tract, such as proteins, peptides, antibodies, vaccines, RNA and DNA.
  • Microneedles can be divided into four categories according to the preparation process and material properties, namely: solid microneedles, coated microneedles, soluble microneedles and hollow microneedles. Among them, soluble microneedles are the most widely studied and the hot spot of microneedle drug delivery systems.
  • Soluble microneedles are microneedles with water-soluble or biodegradable polymers as the matrix, which can well maintain the activity of peptides, proteins, stem cells and drug-loaded vesicles, and can achieve convenient and efficient drug delivery through minimally invasive stratum corneum of the skin.
  • Research on soluble microneedles for insulin and glucagon delivery has been reported.
  • the drug transdermal rate of the above preparations does not meet the time requirements of clinical emergency treatment, and cannot achieve rescue treatment of hypoglycemia. Therefore, it can only be used as a preventive preparation for hypoglycemia.
  • Based on the outstanding advantages of microneedle drug delivery and the current research status there is great room for the development of microneedle drug delivery for glucose-control drugs, but there have been no reports on microneedle drug delivery systems for the treatment of hypoglycemia.
  • the present invention provides a glucagon-loaded microneedle patch, which is a soluble microneedle and is used for the treatment of hypoglycemia.
  • the glucagon-loaded microneedle patch of the present invention is made of a polymer and a solubilizing agent, and includes an array and a substrate composed of a plurality of microneedles, and each microneedle includes a needle tip, a needle body and a substrate surface.
  • Suitable polymers include, but are not limited to, polyvinyl alcohol, polylactic acid, silk fibroin, sodium carboxymethyl cellulose, chitosan, alginate, hyaluronate and polyvinyl pyrrolidone, etc., which are applied to the present invention alone or in combination. Among them, polyvinyl pyrrolidone is more preferred to be used to avoid precipitation of glucagon and polymer due to coagulation.
  • Solubilizing agents include, but are not limited to, trehalose, maltose, sucrose, mannose, xylitol, lactose, galactose and glucose, etc., which are applied to the present invention alone or in combination.
  • trehalose is more preferred to be used to accelerate the dissolution time of the microneedles and significantly increase the mechanical strength of the microneedles.
  • the shape of the microneedle is, but not limited to, a cone, a nail, and a prism. Among them, a cone is preferred to facilitate the microneedle to penetrate the skin.
  • Each microneedle includes a needle tip, a needle body, and a base surface, and the base surface is the surface where the needle body contacts the substrate of the patch.
  • An embodiment of a glucagon-carrying microneedle patch wherein the length from the tip of the microneedle to the base surface ranges from 1500 ⁇ m to 3000 ⁇ m, preferably from 1800 ⁇ m to 2500 ⁇ m.
  • the microneedles are conical, and the base diameter is 500 ⁇ m to 1000 ⁇ m, preferably 500 ⁇ m to 850 ⁇ m.
  • the glucagon-loaded microneedle patch can be smoothly inserted into the skin to deliver glucagon and achieve a rapid recovery of blood sugar.
  • the drug in the base of the patch diffuses into the subcutaneous tissue, prolonging the drug's blood sugar control time and avoiding the phenomenon of blood sugar rising and then falling again due to the short half-life of glucagon.
  • the glucagon-loaded microneedle patch is composed of multiple glucagon-loaded microneedles arranged in a certain pattern. Generally speaking, the distance between each microneedle is equal. Glucagon is prepared into microneedles of different lengths. When the ratio of the length of the microneedle to the distance between the needle tips of adjacent microneedles is 1.2 to 1.7, the longer the microneedle length, the faster the glucagon transdermal rate. In this way, transdermal administration can quickly reverse the patient's hypoglycemia and achieve a rescue effect for hypoglycemia.
  • Another implementation of the glucagon-loaded microneedle patch is to provide 1 to 3 microneedles within a length range of 1 mm, preferably 1 to 2 microneedles.
  • Another embodiment of the glucagon-loaded microneedle patch is to arrange 10 to 100 microneedles within an area of 1 cm 2 , preferably 50 to 100 microneedles.
  • the glucagon-loaded microneedle patch of the present invention can be prepared by the common process for manufacturing microneedle patches at present.
  • the present invention lists the following preparation process by way of example, but not limitation:
  • an ethanol alkaline solution such as mixing ethanol and PBS aqueous solution (pH 9.0);
  • the aforementioned dissolution agent and polymer are added into an ethanol alkaline solution to dissolve, thereby obtaining a material solution for preparing a microneedle patch;
  • glucagon is added to the above material solution and mixed evenly to obtain a working solution for preparing a glucagon microneedle patch;
  • the working solution is added into the prefabricated microneedle patch mold, which is placed under reduced pressure to allow the working solution to completely enter the microneedle mold holes, and then dried at room temperature to obtain the glucagon-loaded microneedle patch.
  • the mass concentration of glucagon contained in the working solution is 5wt% to 30wt%, especially 15wt% to 20wt% (more than 20wt%, a viscous colloid will be formed, which is not conducive to vacuum preparation of microneedles, and less than 15wt% will cause the microneedles to tend to hollow), for example: 5wt%, 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%, 16wt%, 17wt%, 18wt%, 19wt% and 20wt%.
  • the mass concentration of the polymer contained in the working solution is 10wt% to 40wt%, especially 10wt% to 30wt% (more than 30wt% of the polymer will react with glucagon for coagulation, and less than 10wt% will reduce the strength of the microneedle), for example: 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%, 16wt%, 17wt%, 18wt%, 19wt% and 20wt%.
  • the mass concentration of the solubilizing agent contained in the working solution is 5wt% to 20wt%.
  • a concentration greater than 10wt% will make the microneedles easily absorb moisture in the air, affecting the strength of the microneedles and increasing the difficulty of inserting into the skin.
  • 5wt% to 10wt% is preferably selected, such as: 5wt%, 6wt%, 7wt%, 8wt%, 9wt% and 10wt%.
  • Figure 1 shows the preparation route of the glucagon soluble microneedle patch.
  • FIG2 is a morphological diagram of the appearance of glucagon-loaded microneedles of various specifications;
  • A is a scanning electron micrograph of a large-sized glucagon microneedle
  • B is a scanning electron micrograph of a medium-sized glucagon microneedle
  • C is a scanning electron micrograph of a small-sized glucagon microneedle
  • D is a body micrograph of a large-sized glucagon microneedle
  • E is a body micrograph of a medium-sized glucagon microneedle
  • F is a body micrograph of a small-sized glucagon microneedle.
  • the scale in the figure is 200 ⁇ m.
  • FIG3 is a graph showing the displacement and load-bearing capacity of glucagon-loaded microneedles
  • FIG4 is a skin pathology puncture image of glucagon-loaded microneedles of various specifications; wherein A is a skin pathology puncture image of a large-sized glucagon microneedle, B is a skin pathology puncture image of a medium-sized glucagon microneedle, and C is a skin pathology puncture image of a small-sized glucagon microneedle, and the scale in the figure is 100 ⁇ m;
  • FIG5 is an in vitro release curve of glucagon from various glucagon-loaded microneedles
  • FIG6 is an in vitro transdermal release curve of various glucagon-loaded microneedles
  • FIG7 is a diagram showing the safety evaluation results of the glucagon soluble microneedle patch; wherein A is a microneedle imprint photograph of a large-sized glucagon microneedle peeled from the skin at 0 hours, B is a microneedle imprint photograph of a large-sized glucagon microneedle peeled from the skin at 3 hours, and C is a microneedle imprint photograph of a large-sized glucagon microneedle peeled from the skin 24 hours later; D is a skin pathology image of the skin at the microneedle insertion site 24 hours after microneedle peeling;
  • FIG8 is a blood glucose recovery curve of the hypoglycemia model of normal rats treated with soluble glucagon-loaded microneedles; the arrows in the figure represent the microneedle administration time.
  • Figure 1 shows the preparation route of the glucagon soluble microneedle patch, specifically the process of preparing the glucagon-loaded microneedle patch using polyvinyl pyrrolidone as the polymer and trehalose as the solubilizing agent, including adding glucagon to the material solution to form a working solution, dripping it into the microneedle mold, and then after vacuum drying, peeling the microneedle patch from the mold to obtain the glucagon-loaded soluble microneedles.
  • 0.3 g of drug-containing matrix material solution was dropped into a microneedle mold with 225 conical holes (2 needles within 1 mm, 100 needles within 1 cm2), a hole depth of 800 ⁇ m, a maximum hole diameter of 300 ⁇ m, and a needle tip distance of 500 ⁇ m.
  • the solution was placed under reduced pressure to completely enter the holes of the microneedle mold and dried at room temperature to obtain a glucagon soluble polyvinyl pyrrolidone microneedle patch, hereinafter referred to as: small-sized drug-loaded microneedles, or small-sized glucagon microneedles, small microneedles or small needles.
  • 0.3g of drug-containing matrix material solution was dripped into a microneedle mold with 100 conical holes (1 needle within 1mm, 44 needles within 1cm2 ), a hole depth of 1400 ⁇ m, a maximum hole diameter of 500 ⁇ m, and a needle tip distance of 1000 ⁇ m.
  • the solution was completely introduced into the microneedle mold holes under reduced pressure and dried at room temperature to obtain a glucagon soluble polyvinyl pyrrolidone microneedle patch. It is hereinafter referred to as: medium-sized drug-loaded microneedles, or medium-sized glucagon microneedles, medium microneedles or medium needles.
  • 0.3g of drug-containing matrix material solution was dripped into a microneedle mold with 144 conical holes (1 needle within 1mm, 36 needles within 1cm2 ), a hole depth of 2000 ⁇ m, a maximum hole diameter of 800 ⁇ m, and a needle tip distance of 1500 ⁇ m.
  • the solution was completely placed in the microneedle mold hole under reduced pressure, and dried at room temperature to obtain a glucagon soluble polyvinyl pyrrolidone microneedle patch. It is hereinafter referred to as: large-size drug-loaded microneedles, or large-size glucagon microneedles, large microneedles or large needles.
  • the glucagon microneedles of large, medium and small sizes were observed by stereoscope (S6D, Leica, Germany) to obtain Figures 2D, 2E and 2F, and the sizes of the needle tip and needle height were measured.
  • Figure 2 shows the morphological characteristics of the three microneedles. All three microneedles have sharp tips, but the microneedle length, base radius, and tip distance are significantly different (Figure 2A, Figure 2B, and Figure 2C). Under the stereomicroscope, the needle bodies of the three types of microneedles did not show features such as hollowness or blistering.
  • the length of the large-sized drug-loaded microneedle was about 2003 ⁇ m, the base radius was about 810 ⁇ m, the needle tip distance was about 1500 ⁇ m, the ratio of the microneedle length to the needle tip distance of adjacent microneedles was 1.33 ( Figure 2D), and the ratio of the microneedle length to the needle tip distance of adjacent microneedles was 1.44;
  • the length of the medium-sized drug-loaded microneedle was about 1410 ⁇ m, the base radius was about 535 ⁇ m, the needle tip distance was about 984 ⁇ m (Figure 2E), and the ratio of the microneedle length to the needle tip distance of adjacent microneedles was 1.43;
  • the length of the small-sized drug-loaded microneedle was about 807 ⁇ m, the base radius was about 307 ⁇ m, the needle tip distance was about 501 ⁇ m ( Figure 2F), and the ratio of the microneedle length to the needle tip distance of adjacent microneedles was 1.61.
  • Double-sided tape was used to stick to the backing layers of small, medium and large-sized glucagon microneedle patches, and they were fixed on the metal stage of the pressure-tension detector.
  • the microneedle tip faced the probe of the instrument, and the probe was pressed down on the microneedle to record the displacement and force curves.
  • Sprague Dawley rats were used as animal models. The hair of Sprague Dawley rats was shaved with a razor, and the exposed skin surface was cleaned with ethanol. Small, medium, and large-sized glucagon-soluble microneedles were vertically inserted into the dorsal skin of the rats, respectively, and kept for 5 minutes before being peeled off. The rats were killed by cervical dislocation, the skin was peeled off, the microneedle insertion site was cut and embedded, and frozen in liquid nitrogen. The sections were sliced to 5 ⁇ m thickness and placed on silane-coated slides. The skin sections were observed under an inverted microscope (IX-71, Olympus, Tokyo, Japan).
  • the skin insertion depth of microneedles is the key to drug delivery and therapeutic effects.
  • Figure 4 shows that all three types of microneedles can effectively penetrate the stratum corneum of the skin.
  • the large-sized drug-loaded microneedles have a transdermal depth of about 557 ⁇ m ( Figure 4A), the small microneedles have a transdermal depth of about 201 ⁇ m ( Figure 4B), and the medium-sized microneedles have a transdermal depth of about 407 ⁇ m ( Figure 4C).
  • This result shows that when the microneedle length is the same as the needle tip distance, the longer the microneedle length, the better the skin insertion performance. Therefore, large-sized drug-loaded microneedles are very conducive to drug delivery.
  • glucagon soluble microneedles 0.03g of small, medium and large glucagon soluble microneedles were placed on a Franz receiving cell containing 10ml of saline, and the microneedles were completely immersed in 32°C saline and magnetically stirred at 300rpm. At a predetermined time point, the sample solution (1ml) was taken out, filtered through a 0.22 ⁇ m filter, and supplemented with an equal amount of isothermal fresh saline, and the amount of glucagon in the filtrate was determined by liquid chromatography-mass spectrometry.
  • the rate of drug release from the preparation is the key to the drug permeation rate of the transdermal drug delivery system.
  • Figure 5 shows that after 5 minutes of dissolution, the glucagon released by the microneedles of the three specifications exceeded 50%, indicating that the prepared glucagon microneedles have the characteristics of rapid dissolution and drug release, which is conducive to the rapid permeation of glucagon through the skin.
  • the glucagon released by the three types of microneedles reached 80% within 30 minutes with no significant difference, indicating that the specifications of the microneedles will not affect the rate of drug release from the preparation.
  • Sprague Dawley rats were killed, and the back skin was taken out.
  • Small, medium and large glucagon soluble microneedles (the mass of the three microneedles was 0.033g) were inserted into the back skin respectively.
  • the skin was fixed between the Franz donor pool and the receiving pool, with the stratum corneum facing the donor pool, and the two diffusion pools were carefully clamped.
  • the effective diffusion area of the diffusion pool was 1.2cm2 .
  • 10ml of 32°C saline was added to the receiving pool and stirred at 300rpm.
  • the sample solution (1ml) was taken out and filtered through a 0.22 ⁇ m filter. An equal amount of isothermal fresh saline was added.
  • the amount of glucagon in the filtrate was determined by liquid chromatography-mass spectrometry, and the cumulative drug permeation was calculated.
  • Figure 6 shows that when the drug loading of the three microneedles is the same, the large-sized microneedle can be used for burst release within 15 minutes, and the cumulative amount of drug penetration (117 ⁇ g) is much larger than the cumulative amount of drug penetration of the medium-sized microneedle (28 ⁇ g) and the small-sized microneedle (12 ⁇ g). In addition, the large-sized microneedle still has drugs slowly penetrating the skin after 15 minutes. By 3 hours, the cumulative amount of drug penetration (225 ⁇ g), while the cumulative amount of drug penetration of the medium-sized and small-sized microneedles in 3 hours is only 46 ⁇ g and 23 ⁇ g.
  • the large-sized microneedle can quickly deliver the drug at the needle tip to the subcutaneous tissue through excellent skin insertion performance. Afterwards, the glucagon diffused from the basal layer diffuses to the skin below the skin by virtue of the larger skin pores created by the microneedles, realizing the sustained release of the drug.
  • the medium-sized and small-sized microneedles cannot achieve the desired expected results due to the microneedle skin insertion performance and the small skin pores caused.
  • Sprague Dawley rats were used as animal models, and their hair was shaved with a razor. Large-sized glucagon soluble microneedles were vertically inserted into the dorsal skin of the rats, and then peeled off after 3 hours. The microneedle imprints were observed at 0h, 3h and 24h, and the rats were killed by dislocation of the neck at 24h. H&E technology was used to observe whether there was any inflammation in the skin.
  • Example 1 Sample: According to Example 1, Example 2 and Example 3, small, medium and large sized glucagon soluble microneedles were prepared respectively.
  • SD rats (200 ⁇ 10g) were selected as model animals, with a total of 30 rats, divided into a model group, a large-size blank microneedle group, a small-size glucagon soluble microneedle group, a medium-size glucagon soluble microneedle group, and a large-size glucagon soluble microneedle group (6 rats in each group).
  • the back hair of the rats was shaved with a razor.
  • 2IU insulin was given to the rats in each group.
  • the model group was not treated.
  • the blood sugar changes of the rats were measured at a predetermined time point, and the administration threshold was set to 2.8mmol. When the blood sugar value was lower than the threshold, the rats in the microneedle group were all given microneedle patches on their backs, and the blood sugar changes were measured at a certain time point.
  • the blood glucose level of the model group dropped to 2.5 ⁇ 1.1mmol 60 minutes after insulin administration. Without treatment, blood glucose remained at a low blood glucose level. Similarly, the blood glucose level of the large-size blank microneedle group dropped to 2.6 ⁇ 0.7mmol 60 minutes after insulin administration. After microneedle administration, the blood glucose level was consistent with that of the model group, with no significant difference. It can be seen that the matrix material (polymer and solubilizer) in the microneedle does not affect the blood glucose level of the rat. Five minutes after the large-size microneedle administration, blood glucose returned to 3.5 ⁇ 0.8mmol. Thereafter, blood glucose continued to rise, and the blood glucose level was 5.45 ⁇ 1.1mmol at 180 minutes.
  • the blood glucose level of the medium-size microneedle group recovered slowly, and the blood glucose level only reached 3.2 ⁇ 0.7mmol 15min after microneedle administration. Throughout the process, the blood glucose changes in the small-size microneedle group were consistent with those in the model group. This result shows that large-size microneedles can achieve rescue treatment for hypoglycemia.

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Abstract

La présente invention concerne un timbre à micro-aiguilles chargé de glucagon, comprenant un réseau composé d'une pluralité de micro-aiguilles et d'un substrat, chaque micro-aiguille comprenant une pointe d'aiguille, un corps d'aiguille et une surface de substrat. Le timbre à micro-aiguilles est constitué d'un polymère et d'un solubilisant et du glucagon est chargé sur celui-ci. Lorsque le rapport de la longueur des micro-aiguilles à la distance entre les pointes de micro-aiguilles adjacentes est de 1,2 à 1,7, plus la longueur des micro-aiguilles est importante, plus le taux transdermique de glucagon est rapide. Les corps d'aiguille et le substrat du timbre à micro-aiguilles chargé de glucagon sont tous chargés avec du glucagon, ce qui permet de réaliser une administration transdermique de médicament, et le timbre à micro-aiguilles chargé de glucagon présente les caractéristiques d'une libération rapide dans un premier temps, puis d'une libération prolongée, fait effet rapidement, a un temps d'action long, et peut être utilisé comme traitement de secours d'une hypoglycémie critique.
PCT/CN2022/131856 2022-10-09 2022-11-15 Timbre à micro-aiguilles chargé de glucagon Ceased WO2024077705A1 (fr)

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CN202211231468.2A CN116440058B (zh) 2022-10-09 载胰高血糖素微针贴片
CN202211231468.2 2022-10-09

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140371713A1 (en) * 2012-02-17 2014-12-18 Cosmed Pharmaceutical Co., Ltd. Short-time soluble microneedle
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US20210128738A1 (en) * 2017-03-07 2021-05-06 North Carolina State University Insulin-responsive glucagon delivery patch
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