WO2024077705A1 - 载胰高血糖素微针贴片 - Google Patents

载胰高血糖素微针贴片 Download PDF

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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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glucagon
microneedle
microneedles
microneedle patch
loaded
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French (fr)
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郑超
于翔
谷卫
常皓
张亦凯
徐健晨
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Zhejiang University
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Zhejiang University
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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

一种载胰高血糖素微针贴片，包括多个微针组成的阵列和基底，各个微针包括针尖、针体和基底面，微针贴片由聚合物和促溶剂制成，并含有载胰高血糖素。当微针的长度与相邻微针的针尖间距的比值为1.2-1.7，则微针长度越长，使得胰高血糖素透皮速率越快。载胰高血糖素微针贴片的针体和基底均载有胰高血糖素，实施经皮给药，具有先爆释后缓释的特征，起效快，作用时间长，可用于低血糖病危症的抢救治疗。

Description

载胰高血糖素微针贴片 技术领域
本发明涉及医药发明领域，具体涉及一种在蛋白药物可溶性微针，作为输送载体，实现蛋白药物的体内快速输送。
背景技术
随着生活模式的改变以及人口老龄化的增长，糖尿病患者的数量正在逐年增加。目前，治疗糖尿病的关键措施是严格控制血糖水平。然而，严格的强化降糖治疗会增加低血糖事件的发生率。低血糖情况严重且没有得到及时救治时会对身体造成不可逆的伤害，若救治不及时，持续性的严重低血糖会引起意识丧失,造成永久性的神经损伤,甚至死亡。据报道I型糖尿病患者中每年要花费近2000美元用于控制低血糖，但仍有4％的患者死于低血糖。针对于低血糖的抢救，国内主要是通过口服含单糖类的食物或者静注50％的葡萄糖液。但该方法往往会超过临床推荐的碳水化物数量，导致血糖控制不佳。国外主要通过静注或者皮下注射胰高血糖素救治低血糖患者。
胰高血糖素于1922年首次发现具有升血糖作用，并在1955年引入糖尿病护理治疗。胰高血糖素在水中容易重构、聚合，起初的胰高血糖素注射液保存时间仅仅为24h。为了解决该问题，美国Eli Lilly、Novo Nordisk和Fresenius Kabi等公司相继开发出胰高血糖素冻干粉注射剂。虽然保质期的障碍被克服，但该制剂存在“给药过程复杂问题”。首先要监测血糖水平，根据血糖值，设计成年人和儿童的给药剂量。之后，胰岛素冻干粉要与专用的稀释剂混溶后，装入特定的注射器中进行给药。该过程步骤较多，不利于低血糖抢救。另外，胰高血糖素半衰期(仅为5min)远小于胰岛素的半衰期(为2h)，治疗低血糖症时，往往会发生血糖回升后又再次降低的现象，通常需要二次治疗。在胰岛素冻干粉注射剂的使用调研研究中，64％的受访者声称胰高血糖素冻干粉针注射剂，使用复杂，当人经历严重的低血糖症经常无法自行管理。目前上市的另外一种剂型就是胰岛素冻干粉鼻喷剂，该制剂存在两个弊端：(1)容易受温度影响，环境温度较低时，胰高血糖素不易被鼻黏膜吸收，影响药效发挥；(2)患者往往会因为低血糖失去知觉，很难主动吸入药物。
随着制剂学的发展，胰高血糖素在低血糖抢救方面的应用逐步拓展，但目前仍需要结合现代制剂技术优化低血糖的治疗，提高胰高血糖素的适用性。
微针是以多个微小针体集合的阵列，针体直径一般小于300μm，针体长度一般范围为 200μm至2000μm。与传统的经皮给药制剂相比，微针的优势在于可以快速递送胃肠道不易吸收的生物大分子药物，如：蛋白质、多肽、抗体、疫苗、RNA和DNA等。微针按照制备工艺和材料性质可以分为四类，即：实体微针、涂层微针、可溶性微针和空心微针。其中，可溶性微针是目前研究最广，也是微针给药系统热点。可溶性微针以水溶性或者可生物降解性聚合物为基质的微针，能够很好的维持多肽、蛋白、干细胞以及载药囊泡的活性，并且可通过皮肤角质层微创实现药物的便捷、高效递送。可溶性微针用于胰岛素和胰高血糖素递送的研究已有报道。但上述制剂的药物透皮速率达不到临床急救的时间要求，无法实现低血糖症的抢救治疗。因此，其只能作为低血糖的预防制剂使用。基于微针给药的突出优势和目前研究状态，微针用于控糖药物递送的发展空间很大，但至今没有关于用于救治低血糖的微针给药系统的报道。
发明内容
针对现有技术的不足，本发明提供了一种载胰高血糖素微针贴片，系可溶性微针，用于低血糖救治。
本发明的载胰高血糖素微针贴片，由聚合物和促溶剂制成，包括多个微针组成的阵列和基底，各个微针包括针尖、针体和基底面。适合的聚合物如：但不限于聚乙烯醇、聚乳酸、丝素蛋白、羧甲基纤维素钠、壳聚糖、海藻酸盐、透明质酸盐和聚乙烯吡咯烷酮等，这些聚合物单独或组合应用于本发明。其中，更倾向于使用聚乙烯吡咯烷酮，以避免胰高血糖素与聚合物发生因凝聚而沉淀。促溶剂如：但不限于海藻糖、麦芽糖、蔗糖、甘露糖、木糖醇、乳糖、半乳糖和葡萄糖等，这些化合物单独或组合应用于本发明。其中，更倾向于使用海藻糖，以加快微针的溶解时间，并显著增加微针的机械强度。
微针的形态如：但不限于圆锥形、钉子形和棱形。其中，更倾向于使用圆锥形，以利于微针扎入皮肤。各个微针包括针尖、针体和基底面，基底面即为针体与贴片的基材相接触的面。
一种载胰高血糖素微针贴片的实施方式，微针的针尖至基底面的长度范围为1500μm～3000μm，较佳的为1800μm～2500μm。
另一种载胰高血糖素微针贴片的实施方式，微针为圆锥形，基底面直径为500μm～1000μm，较佳的为500μm～850μm。
载胰高血糖素微针贴片可以顺利地插入皮肤，递送胰高血糖素，实现血糖的快速回升。贴片的基底中的药物扩散到皮下，延长药物的控糖时间，避免因胰高血糖素半衰期过短，而引起的血糖回升后又再次降低的现象。
载胰高血糖素微针贴片由多个载胰高血糖素微针按一定规律排列组成。一般来说，每个微针之间的距离相等。将胰高血糖素制备成不同长度的微针，当微针的长度与相邻微针的针尖间距的比值为1.2～1.7，则微针长度越长，胰高血糖素透皮速率越快。以此实施经皮给药，可以快速逆转病患的低血糖情形，获得低血糖症的抢救效果。
另一种载胰高血糖素微针贴片的实施方式，在长度1mm范围内，设置1～3个微针，优先选择1～2个微针。
另一种载胰高血糖素微针贴片的实施方式，在面积为1cm 2的范围内，设置10～100个微针，优先选择50～100个微针。
目前制造微针贴片的常见工艺即可制得本发明的载胰高血糖素微针贴片。为便于本领域技术人员了解制取的方法，本发明示例性的，而非限制地列明如下制取工艺：
先制取乙醇的碱溶液，如：将乙醇和PBS水溶液(pH为9.0)混合得到；
再将前述促溶剂与聚合物加入乙醇碱溶液中溶解，得到制取微针贴片的材料溶液；
接着，将胰高血糖素加入上述材料溶液中，混合均匀，得到制取胰高血糖素微针贴片的工作溶液；
之后，将工作溶液加入预制的微针贴片模具中，置于减压条件下，使工作溶液完全进入微针模具孔中，室温下干燥即得载胰高血糖素微针贴片。
工作溶液中所含的胰高血糖素的质量浓度为5wt％～30wt％，尤其是15wt％～20wt％(超过20wt％，会形成粘稠的胶体，不利于抽真空制备微针，低于15wt％会使得微针发生空心化倾向)，比如：5wt％、6wt％、7wt％、8wt％、9wt％、10wt％、11wt％、12wt％、13wt％、14wt％、15wt％、16wt％、17wt％、18wt％、19wt％和20wt％。
工作溶液中所含的聚合物的质量浓度为10wt％～40wt％，尤其是10wt％～30wt％(超过30wt％的聚合物会与胰高血糖素聚沉反应，低于10wt％微针的强度下降)，比如：10wt％、11wt％、12wt％、13wt％、14wt％、15wt％、16wt％、17wt％、18wt％、19wt％和20wt％。
工作溶液中所含的促溶剂的质量浓度为5wt％～20wt％。当采用海藻糖时，浓度大于10wt％会使微针易于吸收空气中的水分，影响微针的强度，以及增加了插入皮肤的难度，为此优先选择5wt％～10wt％，比如：5wt％、6wt％、7wt％、8wt％、9wt％和10wt％。
本发明技术方案实现的有益效果如下：
1、可以快捷、安全的递送胰高血糖素，使得病患的血糖得以快速回升，并满足对于低血糖症的抢救时间的临床要求。
2、可以延长胰岛血糖素的控糖时间，避免因胰高血糖素半衰期过短，病患血糖回收后再次降低而进行二次给药。
附图说明
图1显示了胰高血糖素可溶性微针贴片的制备路线。
图2为各种规格载胰高血糖素微针的外观形貌图；其中A为大尺寸胰高血糖素微针扫描电镜图，B为中尺寸胰高血糖素微针扫描电镜图，C为小尺寸胰高血糖素微针的扫描电镜图，D为大尺寸胰高血糖素微针体式镜图，E为中尺寸胰高血糖素体式镜图，F为小尺寸胰高血糖素微针体式镜图，图中标尺为200μm；
图3为载胰高血糖素微针的位移与承载力曲线图；
图4为各个规格载胰高血糖素微针的皮肤病理穿刺图；其中，A为大尺寸胰高血糖素微针皮肤病理穿刺图，B为中尺寸胰高血糖素微针皮肤病理穿刺图，C为小尺寸胰高血糖素微针皮肤病理穿刺图，图中标尺为100μm；
图5为各种载胰高血糖素微针的胰高血糖素体外释放曲线；
图6为各种载胰高血糖素微针的体外透皮释放曲线；
图7为胰高血糖素可溶性微针贴片的安全性评价结果图；其中，A为大尺寸胰高血糖素微针从皮肤中剥离0小时的微针印迹照片、B为大尺寸胰高血糖素微针从皮肤中剥离3小时的微针印迹照片，C为为大尺寸胰高血糖素微针从皮肤中剥离24小时后的微针印迹照片；D为插入微针部位的皮肤，在微针剥离后第24小时的皮肤病理图；
图8为载胰高血糖素可溶性微针对正常大鼠低血糖模型的血糖恢复曲线；图中箭头代表微针给药时间。
具体实施方式
以下详细描述本发明的具体实施方式，但是根据本发明的载胰高血糖素可溶性微针实施例的制备过程、所用物质、所用物质的用量不限于文字表述，凡含有本发明提供的药物组合物，均属于本发明的保护范围。
图1显示了胰高血糖素可溶性微针贴片的制备路线，具体为以聚乙烯吡咯烷酮为聚合物，以海藻糖为促溶剂制取载胰高血糖素微针贴片过程，包括在材料溶液中加入胰高血糖素形成工作溶液滴入微针模具中，再经真空干燥后，将微针贴片从模具中剥离，获得载胰高血糖素可溶性微针。
实施例1胰高血糖素可溶性聚乙烯吡咯烷酮微针贴片
量取70ml的乙醇和30ml的PBS水溶液(pH为9.0)进行混合，得到乙醇水溶液；分别称取10g的海藻糖和15g的聚乙烯吡咯烷酮K90混合均匀，加入100g上述乙醇水溶液，得 到材料溶液。
称取100mg胰高血糖素，加入2g上述材料溶液，得到工作溶液。
将0.3g含药基质材料溶液滴入有225个圆锥形孔(1mm范围内，有2个针，1cm 2的范围内，有100个针)并且孔深800μm、孔最大直径300μm，针尖距离为500μm的微针模具中，置于减压条件下，溶液完全进入微针模具孔中，室温下干燥得到胰高血糖素可溶性聚乙烯吡咯烷酮微针贴片，在下文中称为：小尺寸载药微针，或小尺寸胰高血糖素微针，小微针或小针。
实施例2胰高血糖素可溶性聚乙烯吡咯烷酮微针贴片
量取70ml的乙醇和30ml的PBS水溶液(pH为9.0)进行混合，得到乙醇水溶液；分别称取10g的海藻糖和15g的聚乙烯吡咯烷酮K90混合均匀，加入100g上述乙醇水溶液，得到材料溶液。
称取100mg胰高血糖素，加入2g上述材料溶液，得到工作溶液。
将0.3g含药基质材料溶液滴入有100个圆锥形孔(1mm范围内，有1个针，1cm 2的范围内，有44个针)并且孔深1400μm、孔最大直径500μm，针尖距离为1000μm的微针模具中，置于减压条件下，溶液完全进入微针模具孔中，室温下干燥得到胰高血糖素可溶性聚乙烯吡咯烷酮微针贴片。在下文中称为：中尺寸载药微针，或中尺寸胰高血糖素微针，中微针或中针。
实施例3胰高血糖素可溶性聚乙烯吡咯烷酮微针贴片
量取70ml的乙醇和30ml的PBS水溶液(pH为9.0)进行混合，得到乙醇水溶液；分别称取10g的海藻糖和15g的聚乙烯吡咯烷酮K90混合均匀，加入100g上述乙醇水溶液，得到材料溶液。
称取100mg胰高血糖素，加入2g上述材料溶液，得到工作溶液。
将0.3g含药基质材料溶液滴入有144个圆锥形孔(1mm范围内，有1个针，1cm 2的范围内，有36个针)并且孔深2000μm，孔最大直径800μm，针尖距离为1500μm的微针模具中，置于减压条件下，溶液完全进入微针模具孔中，室温下干燥得到胰高血糖素可溶性聚乙烯吡咯烷酮微针贴片。在下文中称为：大尺寸载药微针，或大尺寸胰高血糖素微针，大微针或大针。
实验例4微针贴片的外观形貌
样品：将实施例1、实施例2和实施例3制取的小、中、大尺寸的胰高血糖素微针。
实验方法：
1、扫描电镜
用导电胶带分别将小、中、大尺寸的胰高血糖素微针固定，在5kV电压下，用扫描电子显微镜(SEM，JSM-6330F，日本)分别观测上述三种微针的形貌，得到图2A、图2B以及图2C。
2、体视镜
通过体视镜(S6D，Leica，Germany)对大、中、小尺寸的胰高血糖素微针进行观察，得到图2D、图2E和图2F，并测量针尖与针高的尺寸。
图2展示了三种微针的形貌特点。三种微针都有尖锐的针尖，但微针长度、底座半径以及针尖距离都有显著性差异(图2A、图2B和图2C)。体视镜下，三种微针的针体未见空心或者起泡等特征，大尺寸载药微针的长度约为2003μm，底座半径约为810μm，针尖距离约为1500μm，微针的长度与相邻微针的针尖间距的比值为1.33(图2D)，微针的长度与相邻微针的针尖间距的比值为1.44；中尺寸载药微针的长度约为1410μm，底座半径约为535μm，针尖距离约为984μm(图2E)，微针的长度与相邻微针的针尖间距的比值为1.43；小尺寸载药微针的长度约为807μm，底座半径约为307μm，针尖距离约为501μm(图2F)，微针的长度与相邻微针的针尖间距的比值为1.61。
实验例5微针贴片的机械性能
样品：按照实施例1、实施例2和实施例3分别制备小、中、大尺寸的胰高血糖素微针。
实验方法：
分别用双面胶贴于小、中、大尺寸的胰高血糖素微针贴片的背衬层面，将其固定于压力-拉力探测器的金属台上，微针针尖面向仪器的探针，探头向微针下压，记录位移和力的曲线。
大尺寸的胰高血糖素微针在0.78N下发生0.4mm的形变位移(图3)；中尺寸的微针达到0.4mm的形变位移需要0.2N，而小尺寸的微针在0.16N的施压下就会产生相同的形变位移。此结果证明，随着尺寸的增加，微针的机械强度也会增大。
实验例6微针贴片的皮肤插入性能
样品：按照实施例1、实施例2和实施例3分别制备小、中、大尺寸的胰高血糖素微针。
实验方法：
以Sprague Dawley大鼠为动物模型，使用剃须刀剃除Sprague Dawley大鼠的毛发，用乙 醇清洗暴露的皮肤表面。分别将小、中、大尺寸的胰高血糖素可溶性微针垂直插入大鼠的背部皮肤，保持5分钟后分别剥离。脱颈处死大鼠，剥离皮肤，将微针插入部位切包埋，并冷冻在液氮中。切片至5μm厚度，置于硅烷涂层玻片上。在倒置显微镜下观察皮肤切片(IX-71，奥林巴斯，东京，日本)。
微针的皮肤插入深度是影响药物递送和治疗效果的关键。图4显示3种微针均能有效插破皮肤角质层。大尺寸的载药微针透皮深度约为557μm(图4A)小微针透皮深度约为201μm(图4B)，中尺寸的微针透皮深度约为407μm(图4C)，尺寸的胰高血糖素可溶性。此结果说明当微针长度与针尖距离相同时，微针长度越长，皮肤插入性能越好。因此，大尺寸载药微针非常利于药物的传递。
实验例7微针贴片体外释放实验
样品：按照实施例1、实施例2和实施例3分别制备小、中、大尺寸的胰高血糖素微针。
实验方法：
分别将0.03g的小、中、大尺寸的胰高血糖素可溶性微针置于盛有10ml生理盐水的Franz接收池上，使微针完全浸没在32℃生理盐水中，以300rpm进行磁力搅拌。在预定的时间点，取出样品溶液(1ml)，过0.22μm的滤器，补充等量等温新鲜生理盐水，采用液质联用色谱法测定滤液中胰高血糖素的量。
色谱条件：选用Agilent C18色谱柱(100mm×2.1mm，1.7μm)，柱温设为40℃，流动相为0.1％的甲酸水溶液和乙腈(80∶20)，流速设定为0.3ml/min，m/z 871.3-217.4，进样量设定为5μl。
药物从制剂中释放的速率是经皮给药系统的药物透皮透速率的关键，图5显示在溶解5min后，三种规格的微针所释放的胰高血糖素均超过了50％，说明所制备的胰高血糖素微针具有快速溶解释放药物的特性，有利于胰高血糖素快速经皮渗透。
此外，30分内三种微针所释放的胰高血糖素均达到了80％且无显著性差异，说明微针的规格不会影响药物从制剂中释放的速率。
实验例8微针贴片体外透皮实验
样品：按照实施例1、实施例2和实施例3分别制备小、中、大尺寸的胰高血糖素微针。
实验方法：
将Sprague Dawley大鼠处死，取出背部皮肤，分别将小、中、大尺寸的胰高血糖素可溶性微针(三种微针的质量均为0.033g)插入背部皮肤，将皮肤固定在Franz供体池和接收池 之间，角质层面向供体池，小心夹紧两个扩散池。扩散池的有效扩散面积为1.2cm 2。在接收池中加入10ml的32℃生理盐水，300rpm搅拌。取出样品溶液(1ml)，过0.22μm的滤器，补充等量等温新鲜生理盐水，采用液质联用色谱法测定滤液中胰高血糖素的量，计算累积药物透过量。
图6显示在三种微针载药量相同的情况下，大尺寸微针在15min内可以进行爆释给药，药物渗透累积量(117μg)要远远大于中尺寸微针的药物渗透累积量(28μg)和小尺寸微针的药物渗透累积量(12μg)。另外，大尺寸微针在15min后仍有药物缓慢透过皮肤，截止到3小时，药物渗透累积量(225μg)，而中尺寸和小尺寸的微针在3小时药物渗透累积量仅仅为46μg和23μg。可见，大尺寸微针可以通过优秀的皮肤插入性能将针尖部位的药物快速递送到皮下。之后，从基底层扩散出的胰高血糖素，凭借微针造成的较大的皮肤孔道扩散到皮肤以下，实现药物的缓释渗透。而中尺寸和小尺寸的微针因为微针皮肤插入性能以及造成的皮肤孔道较小等原因，达不到想要的预期结果。
实验例9微针贴片的安全性评价
样品：按照实施例1、实施例2和实施例3分别制备小、中、大尺寸的胰高血糖素微针。
实验方法：
以Sprague Dawley大鼠为动物模型，使用剃须刀剃除Sprague Dawley大鼠的毛发。将大尺寸的胰高血糖素可溶性微针垂直插入大鼠的背部皮肤，保持3小时后分别剥离，分别在0h，3h和24h观察微针印迹，并在24h时间脱颈处死大鼠，通过H&E技术观察皮肤是否有炎症现象发生。
剥离大尺寸的胰高血糖素可溶性微针后发现大鼠皮肤只会留下微针阵列的印迹，而不会有红肿和血液的渗出(图7A)；3h后，微针阵列的痕迹会明显减少(图7B)；24h后，大鼠皮肤上的痕迹完全消失(图7C)。皮肤H&E图显示扎入微针的皮肤部位24h后无炎症细胞浸润(图7D)。胰高血糖素微针贴片具有很好的安全性。
实验例7.胰高血糖素可溶性聚乙烯吡咯烷酮微针贴片的药效学研究
样品：按照实施例1、实施例2和实施例3分别制备小、中、大尺寸的胰高血糖素可溶性微针。
实验方法：
选用SD大鼠(200±10g)为模型动物，共30只，分为模型组、大尺寸空白微针组、小尺寸的胰高血糖素可溶性微针组、中尺寸的胰高血糖素可溶性微针组以及大尺寸的胰高血糖 素可溶性微针组(每组各6只)。使用剃须刀剃除大鼠的背部毛发，各组大鼠测定初始血糖后均给与2IU胰岛素，模型组不加治疗，在预定的时间点内测定大鼠的血糖变化，给药阈值设置为2.8mmol。当血糖值低于阈值时，微针组大鼠均背部微针贴给药，在一定时间点测量血糖变化。
如图8显示模型组在给与胰岛素60分钟后血糖值降到2.5±1.1mmol，在不经治疗地情况下，血糖一直持续在低血糖水平。同样地，大尺寸空白微针组在给予胰岛素60分钟后血糖值降到2.6±0.7mmol。微针给药后，血糖值与模型组一致，无显著性差异。可见，微针中的基质材料(聚合物和促溶剂)不会影响大鼠的血糖水平。大尺寸微针给药5分钟后，血糖回升到3.5±0.8mmol。此后，血糖持续回升，180分钟时血糖值为5.45±1.1mmol。而中尺寸微针组血糖回升缓慢，在微针给药后的15min，血糖值仅达到3.2±0.7mmol。在整个过程中，小尺寸微针组血糖变化与模型组一致。该结果说明大尺寸微针可以实现低血糖的抢救治疗。
以上详细描述了本发明的较佳具体实施例。应当理解，本领域的普通技术人员无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此，凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案，皆应在由权利要求书所确定的保护范围内。

Claims (10)

  1. 一种载胰高血糖素微针贴片，包括多个微针组成的阵列和基底，各个微针包括针尖、针体和基底面，其特征在于所述的微针贴片由聚合物和促溶剂制成，并含有载胰高血糖素；
    当微针的长度与相邻微针的针尖间距的比值为1.2～1.7，则微针长度越长，使得胰高血糖素透皮速率越快；
    所述的聚合物选自于聚乙烯醇、聚乳酸、丝素蛋白、羧甲基纤维素钠、壳聚糖、海藻酸盐、透明质酸盐和聚乙烯吡咯烷酮之一种或几种；
    所述的促溶剂选自于海藻糖、麦芽糖、蔗糖、甘露糖、木糖醇、乳糖、半乳糖和葡萄糖之一种或几种。
  2. 根据权利要求1所述的胰高血糖素微针贴片，其特征在于长度1mm范围内，设置1～3个微针。
  3. 根据权利要求1所述的胰高血糖素微针贴片，其特征在于在面积为1cm 2的范围内，设置10～100个微针。
  4. 根据权利要求1所述的胰高血糖素微针贴片，其特征在于自所述的针尖至所述的基底面的长度为1500μm～3000μm。
  5. 根据权利要求1所述的胰高血糖素微针贴片，其特征在于微针的形态为圆锥形。
  6. 根据权利要求5所述的胰高血糖素微针贴片，其特征在于所述的基底面直径为500μm～1000μm。
  7. 根据权利要求1所述的胰高血糖素微针贴片，其特征在于按如下方法制取：
    先制取乙醇的碱溶液；
    再将所述促溶剂与所述的聚合物加入乙醇碱溶液中溶解，得到制取微针贴片的材料溶液；
    接着，将胰高血糖素加入所述材料溶液中，混合均匀，得到制取胰高血糖素微针贴片的工作溶液；
    之后，将所述工作溶液加入预制的微针贴片模具中，置于减压条件下，使所述工作溶液完全进入微针模具孔中，室温下干燥即得载胰高血糖素微针贴片。
  8. 根据权利要求7所述的胰高血糖素微针贴片，其特征在于所述的工作溶液中所含的胰高血糖素的质量浓度为5wt％～30wt％。
  9. 根据权利要求7所述的胰高血糖素微针贴片，其特征在于所述的工作溶液中所含的所述聚合物的质量浓度为10wt％～30wt％。
  10. 根据权利要求7所述的胰高血糖素微针贴片，其特征在于所述的工作溶液中所含的促溶剂的质量浓度为5wt％～20wt％。
PCT/CN2022/131856 2022-10-09 2022-11-15 载胰高血糖素微针贴片 Ceased WO2024077705A1 (zh)

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