WO2023159702A1 - 一种司美格鲁肽可溶性微针组合物及其制备方法 - Google Patents

一种司美格鲁肽可溶性微针组合物及其制备方法 Download PDF

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WO2023159702A1
WO2023159702A1 PCT/CN2022/081495 CN2022081495W WO2023159702A1 WO 2023159702 A1 WO2023159702 A1 WO 2023159702A1 CN 2022081495 W CN2022081495 W CN 2022081495W WO 2023159702 A1 WO2023159702 A1 WO 2023159702A1
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semaglutide
soluble microneedle
solution
microneedle composition
hyaluronidase
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PCT/CN2022/081495
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English (en)
French (fr)
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吴传斌
陈航平
李峰
冯地桑
杨蓓蓓
赵志明
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广州新济药业科技有限公司
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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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0012—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
    • 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
    • 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
    • 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

Definitions

  • the invention relates to the field of biomedicine, in particular to a semaglutide soluble microneedle composition and a preparation method thereof.
  • GLP-1 receptor agonists As a new generation of hypoglycemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists are second only to insulin in hypoglycemic effect, with strong hypoglycemic effect, low risk of hypoglycemia, obvious weight loss effect and cardiovascular Benefits and other multiple clinical advantages. Diabetes is a progressive disease, and GLP-1 receptor agonists, as a transitional therapy between oral hypoglycemic agents and insulin therapy, have the biological effect of delaying disease progression. From the perspective of current clinical application trends, GLP-1 receptor agonists It is one of the hypoglycemic drugs with the most market potential in the world at present.
  • Semaglutide also known as semaglutide, is a glucagon-like peptide-1 (GLP-1) receptor agonist that stimulates insulin secretion and reduces glucagon secretion, thereby lowering blood sugar.
  • GLP-1 glucagon-like peptide-1
  • semaglutide injection is usually used and administered by subcutaneous injection, which has a long-term effect and can achieve a weekly dosing frequency, so as to better exert the curative effect of the drug, but subcutaneous injection is a This invasive way of administering drugs will cause problems such as pain and discomfort at the injection site, which will bring physical and psychological discomfort to the patient.
  • the injection pen used for drug administration cannot be reused, and the cost of the injection pen accounts for a large part of the cost of research and development, production and use of injections.
  • subcutaneous injection has problems such as complicated filling process.
  • Soluble microneedles have the advantages of painlessness, high efficiency, and convenient operation, and can deliver drugs into the skin by breaking the stratum corneum barrier, realizing the possibility of drug delivery through the skin.
  • the skin extracellular matrix is a complex macromolecular network, it plays an important role in regulating various cellular mechanisms, such as proliferation, adhesion, migration and other mechanisms.
  • Hyaluronic acid is an important component in the extracellular matrix of the skin.
  • the function of hyaluronic acid in the tissue matrix is to limit the diffusion of water and other extracellular substances, including the diffusion of drugs. This makes most of the macromolecular drugs stay on the superficial skin, unable to effectively diffuse into the skin, let alone enter the systemic circulation, which greatly reduces the bioavailability of the drugs.
  • one of the objects of the present invention is to provide a semaglutide-soluble microneedle composition, which combines semaglutide and hyaluronidase
  • a semaglutide-soluble microneedle composition which combines semaglutide and hyaluronidase
  • the effect of the soluble microneedle composition of the present invention on regulating blood sugar is nearly 40 times higher than that of the oral tablet of semaglutide, which greatly improves the bioavailability of the soluble microneedle composition of the present invention.
  • the second object of the present invention is to provide a preparation method of semaglutide soluble microneedle composition.
  • the first aspect of the present invention is to provide a semaglutide soluble microneedle composition
  • the soluble microneedle composition includes a needle material and a base material; the needle material includes semaglutide and transparent
  • a mass ratio of semaglutide to hyaluronidase is (0.05-172):1.
  • the mass ratio of semaglutide to hyaluronidase is (1-100):1; further preferably, the mass ratio of semaglutide to hyaluronidase is (1-100):1 50): 1; Still further preferably, the mass ratio of the semaglutide and hyaluronidase is (1-30): 1; more preferably, the semaglutide and hyaluronidase The mass ratio is (4-10):1.
  • the needle body material includes the following components in mass percentage: 2.5%-51.5% of semaglutide, 0.3%-45.5% of hyaluronidase, 32%-96% of polymer skeleton material, pH regulator 0.02% to 0.8%.
  • the pH regulator includes at least one of sodium hydroxide, potassium hydroxide, and sodium carbonate; more preferably, the pH regulator is sodium hydroxide.
  • the mass percentage of the semaglutide is 5% to 50%; further preferably, the mass percentage of the semaglutide is 20% to 45%; more preferably, the semaglutide
  • the mass percentage of glutide is 35%-45%.
  • the mass percentage of the hyaluronidase is 1% to 40%; more preferably, the mass percentage of the hyaluronidase is 1% to 25%; more preferably, the hyaluronidase The mass percentage is 5% to 15%.
  • the mass percentage of the polymer framework material is 40% to 80%; more preferably, the mass percentage of the polymer framework material is 40% to 60%; more preferably, the polymer framework material The mass percentage is 45% to 55%.
  • the mass percent of the pH regulator is 0.1% to 0.8%; more preferably, the mass percent of the pH regulator is 0.1% to 0.5%; more preferably, the mass percent of the pH regulator is 0.1% to 0.3%.
  • the polymer skeleton material includes at least one of polyvinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, and N-(2-hydroxypropyl) methacrylamide copolymer; further preferably, the The polymer skeleton material is polyvinylpyrrolidone/vinyl acetate copolymer.
  • Polyvinylpyrrolidone/vinyl acetate copolymer is PVP/VA.
  • PVP/VA is a linear copolymer of N-vinylpyrrolidone (NVP) and vinyl acetate (VA), which combines the properties of PVP and PVAC, retains the good water solubility, adhesion and film-forming properties of PVP, and Compared with PVP, it has relatively much lower water absorption, wider solubility, better plasticity and stronger surface activity, and is used as a microneedle framework material with excellent properties in the present invention.
  • NVP N-vinylpyrrolidone
  • VA vinyl acetate
  • the polyvinylpyrrolidone/vinyl acetate copolymer includes at least one of PVP/VA 64, PVP/VA 64W, PVP/VA 73W; further preferably, the polyvinylpyrrolidone/vinyl acetate copolymer 64 for PVP/VA.
  • the base material includes at least one of polyvinylpyrrolidone, polyvinyl alcohol, and sodium carboxymethylcellulose.
  • the alcohol liquid includes at least one of ethanol and propylene glycol.
  • the polyvinylpyrrolidone includes at least one of PVP K90, PVP K30, and PVP K60; further preferably, the polyvinylpyrrolidone is PVP K90.
  • the mass ratio of the needle material to the base material is (0.5-3.5):100; more preferably, the mass ratio of the needle material to the base material is (1-3):100; more preferably , the mass ratio of the needle body material to the base material is (1-2):100.
  • the second aspect of the present invention is to provide a method for preparing the semaglutide soluble microneedle composition provided in the first aspect of the present invention, comprising the following steps:
  • the step of preparing the base material solution is specifically mixing the alcohol liquid and polyvinylpyrrolidone evenly.
  • alcohol liquid and polyvinylpyrrolidone are mixed, polyvinylpyrrolidone will swell.
  • the mixing time is 6-24 hours; more preferably, in the preparation of the base material solution, the mixing time is 8-18 hours; more preferably, in the preparation of the base material solution, the mixing The time is 8-15 hours.
  • At least one of stirring, ultrasonic and vibration is used for mixing; further preferably, in the preparation of the base material solution, the mixing is in the form of stirring and mixing.
  • the stirring rate is 500-3000rpm; more preferably, in the preparation of the base material solution, the stirring rate is 1000-3000rpm; more preferably, in the preparation of the base material solution, the stirring The speed is 1500 ⁇ 2500rpm.
  • the centrifuging step specifically includes: centrifuging for 5-40 min at a centrifugation speed of 3800-4500 rpm.
  • the centrifugal speed is 4000-4500 rpm; further preferably, the centrifugal speed is 4000-4300 rpm.
  • the centrifugation time is 10-40 min; further preferably, the centrifugation time is 10-30 min.
  • the step of preparing the needle material solution specifically includes: mixing hyaluronidase with a solvent, and then mixing it with a polymer skeleton material to prepare an excipient solution; adjusting the pH of the excipient solution, and then mixing it with semaglutide Peptides were mixed to prepare the needle material solution.
  • the step of adjusting the pH of the excipient solution is to adjust the pH of the solution to 6.5-7.5.
  • the drying temperature is 20-40°C; further preferably, the drying temperature is 20-30°C; more preferably, the drying temperature is 25-30°C.
  • the drying time is 20-50 hours; more preferably, the drying time is 25-40 hours; more preferably, the drying time is 30-40 hours.
  • the drying step is performed in a dryer.
  • the step of preparing the base material solution specifically includes: mixing the base material with alcohol solution.
  • the mass ratio of the alcohol solution to the base material is (2-4.5):1; further preferably, the mass ratio of the alcohol solution to the base material is (2.5-4.5):1; more preferably, the The mass ratio of the alcohol solution to the base material is (3-4.5):1.
  • the present invention combines semaglutide and hyaluronidase to make a soluble microneedle composition, which can better promote the diffusion of semaglutide into the body circulation;
  • the effect of the soluble microneedle composition in the present invention on regulating blood sugar has been improved by nearly 40 times, the bioavailability of semaglutide has been greatly improved, and the dosage and cost of hypoglycemic drugs have been reduced.
  • the micro-needle technology is painless during use, reducing the discomfort of users.
  • the bioavailability of the soluble microneedle composition of the present invention is significantly increased, and there is a significant difference (p ⁇ 0.05), which better solves the problem
  • the conventional microneedle of semaglutide is difficult to penetrate into the blood due to the high molecular weight of semaglutide, and thus stays inside the epidermis.
  • FIG. 1 is a graph showing the results of pharmacokinetic experiments of Example 1, Comparative Example 1 and Comparative Example 2.
  • Fig. 2 is the graph of the pharmacokinetic experiment result of embodiment 2 and embodiment 3.
  • composition ratio of the semaglutide soluble microneedle composition in this example is shown in Table 1 below.
  • Table 1 Composition ratio of semaglutide soluble microneedle composition.
  • the semaglutide soluble microneedle composition in this example was prepared by the following preparation method.
  • composition ratio of the semaglutide soluble microneedle composition in this example is shown in Table 3 below.
  • Table 3 Composition ratio of semaglutide soluble microneedle composition.
  • the ratio of raw materials for the preparation of the semaglutide soluble microneedle composition in this example is shown in Table 4 below, and the preparation method of the soluble microneedle composition in Example 1 was used to prepare this
  • the composition ratio of the soluble microneedle composition in the example is shown in Table 3.
  • composition ratio of the semaglutide soluble microneedle composition in this example is shown in Table 5 below.
  • Table 5 Composition ratio of semaglutide soluble microneedle composition.
  • the ratio of raw materials for the preparation of the semaglutide soluble microneedle composition in this example is shown in Table 6 below, and the preparation method of the soluble microneedle composition in Example 1 was used to prepare this product according to the ratio of raw materials in Table 6.
  • the composition ratio of the semaglutide soluble microneedle composition in the example is shown in Table 5.
  • composition ratio of the dissolvable microneedle composition in this example is shown in Table 7 below:
  • Table 7 Composition ratio of the soluble microneedle composition.
  • the preparation method of the dissolvable microneedle composition in this example comprises the following steps:
  • Table 8 Raw material ratio of the soluble microneedle composition.
  • Example 1 group adopts the soluble microneedle composition in Example 1 for percutaneous dorsal administration
  • Comparative Example 1 group adopts the soluble microneedle composition in Comparative Example 1 for percutaneous dorsal administration
  • Comparative Example 2 uses Semaglutide tablets (trade name: Rybel sus, semaglutide, oral preparation, 3 mg/tablet) were administered by intragastric administration.
  • the administration method is as follows: the back of the rat is depilated in advance, the microneedle is fixed on the probe of the tension meter, and the microneedle is applied to the back of the rat with a force of 100 N and a speed of 500 mm/min, and the force is maintained for 5 minutes.
  • the microneedle was fixed on the back of the rat for 2 hours and then removed; in the comparative example 2 group, the semaglutide tablet was pulverized by a mortar, then transferred to a beaker and added a certain amount of water to prepare a suspension, and then Suspension content Rats were intragastrically administered, and the dosage of each group was 214ug/rat.
  • the soluble microneedle composition of the present invention has a high blood drug concentration after administration in the case of small dosage administration, and the blood drug concentration is relatively high compared with that in Comparative Example 1.
  • the microneedles containing hyaluronidase have been greatly improved, indicating that the penetration rate of sguanglutide in Example 1 of the present invention is significantly higher than that of Comparative Example 1 group, and the combination of soluble microneedles in Example 1 When drugs regulate blood sugar levels, the effect can be achieved more quickly.
  • the high blood drug concentration of the soluble microneedle composition in the present invention can be maintained for a long time after administration, which can be as long as 24 hours, indicating that when the soluble microneedle composition in Example 1 is used to regulate blood sugar levels, the interval can be longer Time to administer medicine, treatment dosage and treatment cost are also lower. It can be seen from Table 11 and Figure 1 that after the soluble microneedle composition in the present invention combines semaglutide with hyaluronidase, the bioavailability increases, and the introduction of hyaluronidase plays a role in promoting semaglutide in the skin. Role of Glutide Penetration.
  • Example 2 Group and Example 3 Group wherein, Example Group 2 used the soluble microneedle composition in Example 2 for transdermal dorsal administration; Example 3 group used the soluble microneedle composition in Example 3 for transdermal dorsal administration.
  • the administration method is as follows: the back of the rat is depilated in advance, the microneedle is fixed on the probe of the tension meter, and the microneedle is applied to the back of the rat with a force of 100 N and a speed of 500 mm/min, and the force is maintained for 5 minutes. The microneedles were fixed on the back of the rats for 2 hours and then removed. The dosage of each group was 214ug/rat. At 0, 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, and 48 hours after administration, 0.5 mL of blood was collected and placed in a centrifuge tube coated with sodium heparin, centrifuged at 5000 rpm for 10 min to separate the plasma, and then stored in in a refrigerator at -20°C.
  • Example 2 As can be seen from Table 9 to Table 14, the peak concentration and bioavailability of Example 2 (the proportion of hyaluronidase in the raw material is 0.1%) is close to that of Comparative Example 1 (without hyaluronidase), and Example 2 Compared with Comparative Example 1, it increased slightly. Moreover, comparing Figures 1 and 2, it can be seen that the blood concentration of Comparative Example 1 dropped to about 500 ng/mL after 12 hours of administration. The reason may be that semaglutide has a relatively large molecular weight, stays in the skin, and releases slowly through osmosis.
  • Example 3 the hyaluronidase accounts for 5% in the raw material
  • Example 1 the hyaluronidase accounts for 1% in the raw material
  • the blood concentration and bioavailability of the embodiment 3 do not increase with the hyaluronidase
  • the proportion of acidase increases and increases, but it is smaller than that of Example 1.

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Abstract

一种司美格鲁肽可溶性微针组合物及其制备方法，所述可溶性微针组合物包括针体材料和基底材料；所述针体材料包括司美格鲁肽和透明质酸酶，其中，所述司美格鲁肽和透明质酸酶的质量比为(0.05～172)：1。将司美格鲁肽与透明质酸酶结合制成可溶性微针组合物，能更好地促进司美格鲁肽扩散进入体循环；与司美格鲁肽口服片剂相比，可溶性微针组合物调节血糖方面的效果提高了近40倍，提升了司美格鲁肽的生物利用度，降低了降糖用药量和用药成本，同时采用可溶性微针技术，在使用时无痛感，降低了使用人群的不适感。

Description

一种司美格鲁肽可溶性微针组合物及其制备方法 技术领域
本发明涉及生物医药领域，具体涉及一种司美格鲁肽可溶性微针组合物及其制备方法。
背景技术
胰高血糖素样肽-1(GLP-1)受体激动剂作为新一代降糖药，其降糖效果仅次于胰岛素，具有降糖效果强、低血糖风险低、减肥效果明显和心血管获益等多重临床优势。糖尿病为进展性疾病，而GLP-1受体激动剂作为口服降糖药与胰岛素治疗之间的过渡疗法，具有延缓疾病进展的生物学作用，从当前临床应用趋势看，GLP-1受体激动剂是目前全球最具市场潜力的降糖药之一。
司美格鲁肽，又称为索马鲁肽，是胰高血糖素样肽-1(GLP-1)受体激动剂，以葡萄糖依赖的方式，刺激胰岛素的分泌，并降低胰高血糖素分泌，从而降低血糖。现有技术中通常采用司美格鲁肽注射剂，通过皮下注射的方式给药，具有长效的作用，可实现每周一次的给药频率，从而更好地发挥药物疗效，但皮下注射是一种有创的给药方式，会产生疼痛，注射部位不适等问题，从而会给患者带来生理及心理上的不适。同时，用于给药的注射笔不能重复利用，注射笔的成本占据了注射剂研发、生产和使用成本的一大部分。此外，皮下注射存在灌装工艺繁杂等问题。
继2017年索马鲁肽注射剂(商品名：Ozempic)上市后在降糖、减重、心血管系统等方面表现出优势，诺和诺德公司克服了肽类药物易受消化酶降解的技术限制，研发出的口服制剂索马鲁肽片(商品名：Rybelsus)于2019年9月被美国食品和药物管理局(FDA)正式批准上市，用于成人T2DM患者的血糖控制。N-(8-(2-羟基苯甲酰基)氨基)辛酸钠(SNAC)技术可防止胃里的司美格鲁肽被破坏，并通过胃膜促进细胞吸收，使司美格鲁肽能够完整达到体循环。口服司美格鲁肽虽然加强了患者的顺应性，但生物利用度远远低于皮下注射给药，仅有0.9～1.2％，且给药频率频繁，需每天给药一次。
可溶性微针具有无痛、高效、操作方便等优势，可通过打破角质层屏障将药物递送到皮内，实现了药物经皮给药的可能。然而，由于皮肤细胞外基质是一个复杂的大分子网络，在调控多种细胞机制，如增殖、粘附、迁移等机制中起着重要的作用。而透明质酸是皮肤细胞外基质中的重要成分，透明质酸在组织基质中的功能是限制水分及其它细胞外物质的扩散，其中包括药物的扩散。这使得大部分的大分子药物都滞留在皮肤浅表，无法有效地扩散进入皮肤，更无法有效的进入体循环，大大降低了药物的生物利用度。
发明内容
为了克服上述现有技术存在的问题，本发明的目的之一在于提供一种司美格鲁肽可溶性微针组合物，该可溶性微针组合物将司美格鲁肽和透明质酸酶结合在一起，令人惊讶地发现可以有效解决现有司美格鲁肽微针在使用时因司美格鲁肽分子量大而难以渗透入血液，从而滞留在表皮层内部的问题。此外，本发明中的可溶性微针组合物在调节血糖方面的效果比司美格鲁肽口服片剂提高了近40倍，极大地提升了本发明中的可溶性微针组合物的生物利用度。
本发明的目的之二在于提供一种司美格鲁肽可溶性微针组合物的制备方法。
为了实现上述目的，本发明所采取的技术方案是：
本发明的第一个方面在于提供一种司美格鲁肽可溶性微针组合物，所述可溶性微针组合物包括针体材料和基底材料；所述针体材料包括司美格鲁肽和透明质酸酶，其中，所述司美格鲁肽和透明质酸酶的质量比为(0.05～172)：1。
优选地，所述司美格鲁肽和透明质酸酶的质量比为(1～100)：1；进一步优选地，所述司美格鲁肽和透明质酸酶的质量比为(1～50)：1；再进一步优选地，所述司美格鲁肽和透明质酸酶的质量比为(1～30)：1；更优选地，所述司美格鲁肽和透明质酸酶的质量比为(4～10)：1。
优选地，所述针体材料包括以下质量百分比的组分：司美格鲁肽2.5％～51.5％，透明质酸酶0.3％～45.5％，聚合物骨架材料32％～96％，pH调节剂0.02％～0.8％。
优选地，所述pH调节剂包括氢氧化钠、氢氧化钾、碳酸钠中的至少一种；进一步优选地，所述pH调节剂为氢氧化钠。
优选地，所述司美格鲁肽的质量百分比为5％～50％；进一步优选地，所述司美格鲁肽的质量百分比为20％～45％；更优选地，所述司美格鲁肽的质量百分比为35％～45％。
优选地，所述透明质酸酶的质量百分数为1％～40％；进一步优选地，所述透明质酸酶的质量百分比为1％～25％；更优选地，所述透明质酸酶的质量百分比为5％～15％。
优选地，所述聚合物骨架材料的质量百分数为40％～80％；进一步优选地，所述聚合物骨架材料的质量百分比为40％～60％；更优选地，所述聚合物骨架材料的质量百分比为45％～55％。
优选地，所述pH调节剂的质量百分数为0.1％～0.8％；进一步优选地，所述pH调节剂的质量百分比为0.1％～0.5％；更优选地，所述pH调节剂的质量百分比为0.1％～0.3％。
优选地，所述聚合物骨架材料包括聚乙烯吡咯烷酮/乙酸乙烯酯共聚物、聚乙烯吡咯烷酮、N-(2-羟丙基)甲基丙烯酰胺共聚物中的至少一种；进一步优选地，所述聚合物骨架材料为聚乙烯吡咯烷酮/乙酸乙烯酯共聚物。聚乙烯吡咯烷酮/乙酸乙烯酯共聚物即为PVP/VA。PVP/VA是N-乙烯基吡咯烷酮(NVP)与醋酸乙烯酯(VA)的线性共聚物，兼具了PVP和PVAC的性质，保留了PVP良好的水溶性、粘结性和成膜性，又比PVP具有相对低得多的吸水性和更为宽广的溶解性能、更好的塑性和更强的表面活性，在本发明中作为一种性质优良的微针骨架材料。
优选地，所述聚乙烯吡咯烷酮/乙酸乙烯酯共聚物包括PVP/VA 64、PVP/VA 64W、PVP/VA 73W中的至少一种；进一步优选地，所述聚乙烯吡咯烷酮/乙酸乙烯酯共聚物为PVP/VA 64。
优选地，所述基底材料包括聚乙烯吡咯烷酮、聚乙烯醇、羧甲基纤维素钠中的至少一种。
优选地，所述醇液包括乙醇和丙二醇中的至少一种。
优选地，所述聚乙烯吡咯烷酮包括PVP K90、PVP K30、PVP K60中的至少一种；进一步优选地，所述聚乙烯吡咯烷酮为PVP K90。
优选地，所述针体材料与基底材料的质量比为(0.5～3.5)：100；进一步优选地， 所述针体材料与基底材料的质量比为(1～3)：100；更优选地，所述针体材料与基底材料的质量比为(1～2)：100。
本发明的第二个方面在于提供一种本发明的第一个方面提供的司美格鲁肽可溶性微针组合物的制备方法，包括以下步骤：
S1：配制针体材料溶液和基底材料溶液；
S2：将所述针体材料溶液加入微针阴模中，离心；
S3：加入基底材料溶液，离心，然后干燥、脱模，制得所述司美格鲁肽可溶性微针组合物。
优选地，所述配制基底材料溶液的步骤具体为将醇液和聚乙烯吡咯烷酮混合均匀。在醇液和聚乙烯吡咯烷酮混合时，聚乙烯吡咯烷酮发生溶胀现象。
优选地，所述配制基底材料溶液中，混合时间为6～24h；进一步优选地，所述配制基底材料溶液中，混合时间为8～18h；更优选地，所述配制基底材料溶液中，混合时间为8～15h。
优选地，所述配制基底材料溶液中，混合采用搅拌、超声、震荡中的至少一种；进一步优选地，所述配制基底材料溶液中，混合采用搅拌混合的方式。
优选地，所述配制基底材料溶液中，搅拌速率为500～3000rpm；进一步优选地，所述配制基底材料溶液中，搅拌速率为1000～3000rpm；更优选地，所述配制基底材料溶液中，搅拌速率为1500～2500rpm。
优选地，所述离心步骤具体为：在离心转速为3800～4500rpm的条件下离心5～40min。
优选地，所述离心转速为4000～4500rpm；进一步优选地，所述离心转速为4000～4300rpm。
优选地，所述离心时间为10～40min；进一步优选地，所述离心时间为10～30min。
优选地，所述配制针体材料溶液的步骤具体为：将透明质酸酶与溶剂混合，然后与聚合物骨架材料混合，制得辅料溶液；调节辅料溶液的pH，然后再与司美格鲁肽混合，制得所述针体材料溶液。
优选地，所述调节辅料溶液pH的步骤为将溶液的pH调节为6.5～7.5。
优选地，所述干燥步骤中，干燥温度为20～40℃；进一步优选地，所述干燥温度为20～30℃；更优选地，所述干燥温度为25～30℃。
优选地，所述干燥步骤中，干燥时间为20～50h；进一步优选地，所述干燥时间为25～40h；更优选地，所述干燥时间为30～40h。
优选地，所述干燥步骤是在干燥器中进行。
优选地，所述配制基底材料溶液的步骤具体为：将基底材料与醇液混合。
优选地，所述醇液和基底材料的质量比为(2～4.5)：1；进一步优选地，所述醇液和基底材料的质量比为(2.5～4.5)：1；更优选地，所述醇液和基底材料的质量比为(3～4.5)：1。
本发明的有益效果是：本发明将司美格鲁肽与透明质酸酶结合制成可溶性微针组合物，能更好地促进司美格鲁肽扩散进入体循环；与司美格鲁肽口服片剂相比，本发明中的可溶性微针组合物调节血糖方面的效果提高了近40倍，大大提升了司美格鲁肽的生物利用度，降低了降糖用药量和用药成本，同时采用可溶性微针技术，在使用时无痛感，降低了使用人群的不适感。
此外，相对于不含透明质酸酶的常规微针而言，本发明中的可溶性微针组合物的生物利用度明显增加，且具有显著性差异(p<0.05)，更好的解决了现有司美格鲁肽常规微针因司美格鲁肽分子量较大难以渗透入血，从而滞留在表皮层内部的问题。
附图说明
图1为实施例1、对比例1和对比例2的药动学实验结果图。
图2为实施例2和实施例3的药动学实验结果图。
具体实施方式
以下结合附图和实例对本发明的具体实施作进一步详细说明，但本发明的实施和保护不限于此。需要指出的是，以下若为有未特别详细说明之过程，均是本领域技术人员可参照现有技术实现或理解的。所用试剂或仪器未注明生产厂商者，视为可以通过市售 购买得到的常规产品。
实施例1：
本例中的司美格鲁肽可溶性微针组合物的组成配比如下表1所示。
表1司美格鲁肽可溶性微针组合物的组成配比。
Figure PCTCN2022081495-appb-000001
本例中的司美格鲁肽可溶性微针组合物采用以下制备方法制备。
(1)分别按照下表2中的原料及原料配比称取微针的制备原料。
表2司美格鲁肽可溶性微针组合物的原料配比。
Figure PCTCN2022081495-appb-000002
(2)针体材料溶液的配制
1)将配方量的透明质酸酶加到离心管中，加入配方量的超纯水，搅拌溶解，得到 透明质酸酶溶液；
2)在透明质酸酶溶液中加入配方量的PVP/VA，搅拌溶解，得到辅料溶液；
3)在辅料溶液中逐滴加入0.25mmol/L的NaOH溶液，调节溶液pH至7.0；
4)精密称取配方量的司美格鲁肽，加入到上述辅料溶液中，搅拌溶解，得到针体材料溶液。
(3)基底材料溶液的配制
称取配方量的PVP K90加入到50mL离心管中，加入配方量的无水乙醇，搅拌溶胀过夜，得到基底材料溶液。
(4)可溶性微针组合物的制备
1)吸取上述针体材料溶液200μL到微针阴模中，在0～10℃以4000rpm转速离心10min；
2)取出模具，刮去上层残余的针体材料溶液，回收利用，继续在0～10℃以4000rpm转速离心30min；
3)加入上述基底材料溶液到微针阴模中，在0～10℃以4000rpm转速离心5min；
4)置于干燥器中干燥36h，小心剥离模具，得到本例中的司美格鲁肽可溶性微针组合物。
实施例2：
本例中的司美格鲁肽可溶性微针组合物的组成配比如下表3所示。
表3司美格鲁肽可溶性微针组合物的组成配比。
Figure PCTCN2022081495-appb-000003
本例中的司美格鲁肽可溶性微针组合物的制备原料的配比如下表4所示，采用表4的原料配比参照实施例1中的可溶性微针组合物的制备方法制备出本例中的可溶性微针组合物，其组成配比如表3所示。
表4司美格鲁肽可溶性微针组合物的原料配比。
Figure PCTCN2022081495-appb-000004
实施例3：
本例中的司美格鲁肽可溶性微针组合物的组成配比如下表5所示。
表5司美格鲁肽可溶性微针组合物的组成配比。
Figure PCTCN2022081495-appb-000005
本例中的司美格鲁肽可溶性微针组合物的制备原料的配比如下表6所示，采用表6的原料配比参照实施例1中的可溶性微针组合物的制备方法制备出本例中的司美格鲁肽可溶性微针组合物，其组成配比如表5所示。
表6司美格鲁肽可溶性微针组合物的原料配比。
Figure PCTCN2022081495-appb-000006
对比例1：
本例中的可溶性微针组合物的组成配比如下表7所示：
表7可溶性微针组合物的组成配比。
Figure PCTCN2022081495-appb-000007
本例中的可溶性微针组合物的制备方法包括以下步骤：
(1)分别按照下表8中的原料及原料配比称取微针的制备原料；
表8可溶性微针组合物的原料配比。
Figure PCTCN2022081495-appb-000008
(2)针体材料溶液的配制：
1)精密称取配方量的PVP/VA，加入配方量的超纯水，搅拌溶解，得到辅料溶液；
2)在辅料溶液中逐滴加入0.25mmol/L的NaOH溶液，调节溶液pH到7.0；
3)精密称取配方量的司美格鲁肽，加入到上述辅料溶液中，搅拌溶解，得到针体材料溶液。
(3)基底材料溶液的配制：
称取10g的PVP K90加入到50mL离心管中，加入30mL无水乙醇，搅拌溶胀过夜，得到基底材料溶液。
(4)可溶性微针组合物的制备：
1)吸取上述针体材料溶液200μL到微针阴模中，在0～10℃以4000rpm转速离心10min；
2)离心结束后将模具180°翻转，继续在0～10℃以4000rpm转速离心10min；
3)取出模具，刮去上层残余的针体材料溶液，回收利用；
4)加入0.5mL基底材料溶液到微针阴模中，在0～10℃以4000rpm的转速离心5min；
5)置于干燥器中干燥36h，小心剥离模具，得到对比例1中的可溶性微针组合物。
性能测试
(1)药动学性能测试。
按照伦理学要求，选取体重在180-200g区间的雄性SD大鼠9只，检疫3天后按每组各3只随机分成3组，分别为实施例1组、对比例1组和对比例2组，其中，实施例1组采用实施例1中的可溶性微针组合物经皮背部给药；对比例1组采用对比例1中的可溶性微针组合物经皮背部给药；对比例2组采用司美格鲁肽片剂(商品名：Rybe l sus，司美格鲁肽，口服制剂，3mg/片)经灌胃给药。
给药方法如下：大鼠背部提前脱毛，将微针固定在拉力计的探头上，以100N的作用力，500mm/min的速度，将微针作用于大鼠背部，该作用力维持5min，给药后微针固定在大鼠背部2h后除去；其中对比例2组将司美格鲁肽片剂通过研钵粉碎后，转移到烧杯中加入一定量的水，配制成混悬液，再根据混悬液含量对大鼠进行灌胃给药，每组的给药剂量为214ug/只。在给药后的0、0.25、0.5、1、2、3、4、8、12、24、48h采血0.5mL置于内壁涂有肝素钠的离心管中，5000rpm离心10min分离血浆，后保存在-20℃的冰箱中。通过LC/MS检测司美格鲁肽的血药浓度，并将检测的司美格鲁肽的血药浓度记录在表9和表10中，根据表9和表10中的司美格鲁肽血药浓度绘制药-时曲线，计算药代动力学参数。其中，实施例1、对比例1和对比例2的药动学实验结果见图1所示；实施例1、对比例1和对比例2的药动学参数见表11所示。
表9实施例1、对比例1和对比例2的0～2h的司美格鲁肽的血药浓度。
Figure PCTCN2022081495-appb-000009
表10实施例1、对比例1和对比例2的3～48h的司美格鲁肽的血药浓度。
Figure PCTCN2022081495-appb-000010
表11药动学参数表。
组别 T max(h) C max(ng/mL) AUC 0-48h(h＊ng/mL) Frel(％)
实施例1 4 2407 54770 43.89
对比例1 3 1660 26305 21.08
对比例2 0.5 159.4 1208 0.97
。
由表9和表10可以看出，本发明中的可溶性微针组合物在小剂量给药的情况下，给药后的血药浓度仍然很高，血药浓度相对于对比例1中的不含透明质酸酶的微针有了很大的提升，表明本发明实施例1中的司关格鲁肽渗透皮肤的速率明显高于对比例1组，使用实施例1中的可溶性微针组合物调节血糖水平时，可以更快的起到疗效。此外，本发明中的可溶性微针组合物给药后的高血药浓度维持的时间长，可以长达24h，表明使用实施例1中的可溶性微针组合物调节血糖水平时，可以间隔更长的时间施药，治疗用 量和治疗成本也更低。由表11和图1可知，本发明中的可溶性微针组合物将司美格鲁肽与透明质酸酶结合后，生物利用度增大，透明质酸酶的引入在皮肤内起到了促进司美格鲁肽渗透的作用。
(2)不同透明质酸酶浓度微针的药动学性能测试。
按照伦理学要求，选取体重在180-200g区间的雄性SD大鼠6只，检疫3天后按每组各3只随机分成2组，分别为实施例2组、实施例3组，其中，实施例2组采用实施例2中的可溶性微针组合物经皮背部给药；实施例3组采用实施例3中的可溶性微针组合物经皮背部给药。
给药方法如下：大鼠背部提前脱毛，将微针固定在拉力计的探头上，以100N的作用力，500mm/min的速度，将微针作用于大鼠背部，该作用力维持5min，给药后微针固定在大鼠背部2h后除去，每组的给药剂量为214ug/只。在给药后的0、0.25、0.5、1、2、3、4、8、12、24、48h采血0.5mL置于内壁涂有肝素钠的离心管中，5000rpm离心10min分离血浆，后保存在-20℃的冰箱中。通过LC/MS检测司美格鲁肽的血药浓度，并将检测的司美格鲁肽的血药浓度记录在表12和表13中，根据表12和表13中的司美格鲁肽血药浓度绘制药-时曲线，计算药代动力学参数。其中，实施例2、实施例3的药动学实验结果见图2所示；实施例2、实施例3的药动学参数见表14所示。
表12实施例2、实施例3的0～2h司美格鲁肽的血药浓度。
Figure PCTCN2022081495-appb-000011
表13实施例2、实施例3的3～48h司关格鲁肽的血药浓度。
Figure PCTCN2022081495-appb-000012
表14药动学参数表。
组别 T max(h) C max(ng/mL) AUC 0-48h(h＊ng/mL) Frel(％)
实施例2 4 1338 28145 22.55
实施例3 4 1733 40652 32.58
。
由表9至表14可知，实施例2(原料中透明质酸酶占比0.1％)的达峰浓度和生物利用度与对比例1(不含透明质酸酶)的接近，且实施例2相对于对比例1小幅度增高。而且对比图1和图2可知，对比例1给药12h后的血药浓度即降到500ng/mL左右，原因可能是司美格鲁肽分子量较大，在皮肤中滞留，缓慢渗透释放。而实施例2给药后的血药浓度在快速达峰后也以近乎恒定的速率快速消除，说明在处方中添加透明质酸酶可以起到一定的促渗作用，减少司美格鲁肽的皮内滞留。对比实施例3(原料中透明质酸酶占比5％)与实施例1(原料中透明质酸酶占比1％)，实施例3的血药浓度和生物利用度并没有随着透明质酸酶的占比增加而增大，反而比实施例1的小，原因可能是透明质酸酶的占比越高，对微针针体的机械强度的影响越大，针体材料进入皮肤的数量和深度都减弱。但由于实施例3处方中含有的透明质酸酶占比较大，它的促渗作用还是比实施例2的强，再次证明了透明质酸酶的经皮促渗效果好。
上面对本发明实施例作了详细说明，但是本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下做出各种变化。此外，在不冲突的情况下，本发明的实施例及实施例中的特征可以相互组合。

Claims (10)

  1. 一种司美格鲁肽可溶性微针组合物，其特征在于：所述可溶性微针组合物包括针体材料和基底材料；所述针体材料包括司美格鲁肽和透明质酸酶，其中，所述司美格鲁肽和透明质酸酶的质量比为(0.05～172)：1。
  2. 根据权利要求1所述的司美格鲁肽可溶性微针组合物，其特征在于：所述针体材料包括以下质量百分比的组分：司美格鲁肽2.5％～51.5％，透明质酸酶0.3％～45.5％，聚合物骨架材料32％～96％，pH调节剂0.02％～0.8％。
  3. 根据权利要求2所述的司美格鲁肽可溶性微针组合物，其特征在于：所述聚合物骨架材料包括聚乙烯吡咯烷酮/乙酸乙烯酯共聚物、聚乙烯吡咯烷酮、N-(2-羟丙基)甲基丙烯酰胺共聚物中的至少一种。
  4. 根据权利要求1所述的司美格鲁肽可溶性微针组合物，其特征在于：所述基底材料包括聚乙烯吡咯烷酮、聚乙烯醇、羧甲基纤维素钠中的至少一种。
  5. 根据权利要求1所述的司美格鲁肽可溶性微针组合物，其特征在于：所述针体材料与基底材料的质量比为(0.5～3.5)：100。
  6. 权利要求1～5任一项所述司美格鲁肽可溶性微针组合物的制备方法，其特征在于：包括以下步骤：
    S1：配制针体材料溶液和基底材料溶液；
    S2：将所述针体材料溶液加入微针阴模中，离心；
    S3：加入基底材料溶液，离心，然后干燥、脱模，制得所述司美格鲁肽可溶性微针组合物。
  7. 根据权利要求6所述司美格鲁肽可溶性微针组合物的制备方法，其特征在于：所述离心步骤为：在离心转速为3800～4500rpm的条件下离心5～40min。
  8. 根据权利要求6所述司美格鲁肽可溶性微针组合物的制备方法，其特征在于：所述配制针体材料溶液的步骤为：将透明质酸酶与溶剂混合，然后与聚合物骨架材料混合，制得辅料溶液；调节辅料溶液的pH，然后再与司美格鲁肽混合，制得所述针体材料溶液。
  9. 根据权利要求8所述司美格鲁肽可溶性微针组合物的制备方法，其特征在于：所述调节辅料溶液pH的步骤为将溶液的pH调节为6.5～7.5。
  10. 根据权利要求6所述司美格鲁肽可溶性微针组合物的制备方法，其特征在于：所述配制基底材料溶液的步骤为：将基底材料与醇液混合；所述醇液和基底材料的质量比为(2～4.5)：1。
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