WO2022002008A1 - Composé d'insuline à action rapide et son utilisation médicale - Google Patents

Composé d'insuline à action rapide et son utilisation médicale Download PDF

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WO2022002008A1
WO2022002008A1 PCT/CN2021/102939 CN2021102939W WO2022002008A1 WO 2022002008 A1 WO2022002008 A1 WO 2022002008A1 CN 2021102939 W CN2021102939 W CN 2021102939W WO 2022002008 A1 WO2022002008 A1 WO 2022002008A1
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pharmaceutical composition
arginine
insulin aspart
iloprost
insulin
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PCT/CN2021/102939
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English (en)
Chinese (zh)
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李金宇
孙琼
杨晓容
陈昊
王琪
卢韵
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江苏恒瑞医药股份有限公司
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Priority to CN202180040994.8A priority Critical patent/CN115697379A/zh
Publication of WO2022002008A1 publication Critical patent/WO2022002008A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
    • 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
    • A61K38/28—Insulins
    • 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 disclosure belongs to the field of biomedicine, and relates to a pharmaceutical formulation comprising 1) insulin aspart, and 2) at least one of iloprost and tafluprost.
  • Diabetes Mellitus is a common chronic non-communicable disease, a clinical syndrome caused by the interaction of genetic and environmental factors, and a metabolic and lifelong disease characterized by elevated blood sugar.
  • IDF insulin-deficiency inosia
  • the number of people with diabetes in China in 2019 was about 116 million, and China has become the country with the largest number of people with diabetes in the world; at the same time, the number of diabetic patients continues to grow rapidly. IDF predicts that the number of people with diabetes in China will reach 151 million in 2040. The growth rate of my country's insulin market has also exceeded the global average growth rate.
  • diabetic patients need to implement multiple long-term injection therapy; insulin is divided into rapid-acting insulin, intermediate-acting insulin, and long-acting insulin according to the duration of action.
  • insulin is divided into rapid-acting insulin, intermediate-acting insulin, and long-acting insulin according to the duration of action.
  • their blood sugar rises rapidly due to food absorption after a meal. If the onset of insulin is too slow or the release of insulin is insufficient at this time, it will lead to postprandial hyperglycemia.
  • insulin preparation products have been developed to reduce the injection-onset interval, and the mechanism of action includes changing the sequence of the amino acid chain in human insulin and thereby changing the onset time of insulin (such as insulin lispro, API; Insulin Aspart, APIDRA) and change the existing state of insulin aggregates to accelerate the onset of insulin (such as insulin glulisine APIDRA, lack of Zn and reduce the existence of hexamers).
  • insulin lispro, API; Insulin Aspart, APIDRA change the existing state of insulin aggregates to accelerate the onset of insulin
  • insulin glulisine APIDRA lack of Zn and reduce the existence of hexamers.
  • composition comprising:
  • At least one of iloprost and tafluprost At least one of iloprost and tafluprost.
  • insulin aspart refers to human insulin in which amino acid 28 of the B chain is mutated to aspartic acid, CAS number 116094-23-6, and molecular weight 5826.
  • the pharmaceutical composition further comprises arginine.
  • the pharmaceutical composition further comprises:
  • metal ions such as zinc ions
  • isotonic agents such as glycerol and/or sodium chloride
  • the buffer is selected from the group consisting of phosphate buffer, acetate buffer, and citrate buffer.
  • the buffer is a phosphate buffer, such as disodium hydrogen phosphate.
  • the preservative is selected from the group consisting of phenol, m-cresol, and benzyl alcohol.
  • the preservatives are phenol and m-cresol.
  • the concentration of insulin aspart in the pharmaceutical composition is 0.3 mM-2.4 mM, 0.4 mM-2 mM, 0.5 mM-1.5 mM, 0.5 mM-1 mM, or 0.5 mM-0.8 mM, eg, about 0.5 mM, about 0.51 mM, about 0.52 mM, about 0.53 mM, about 0.54 mM, about 0.55 mM, about 0.56 mM, about 0.57 mM, about 0.58 mM, about 0.59 mM, about 0.6 mM, about 0.61 mM, about 0.62 mM, about 0.63 mM, about 0.64 mM, about 0.65 mM, about 0.66 mM, about 0.67 mM, about 0.68 mM, about 0.69 mM, or about 0.7 mM.
  • the concentration of iloprost in the pharmaceutical composition is 0.01 ⁇ M-60 ⁇ M, eg, the concentration of iloprost is 0.05 ⁇ M-60 ⁇ M, 0.05 ⁇ M-55 ⁇ M, 0.05 ⁇ M-50 ⁇ M, 0.05 ⁇ M-45 ⁇ M, 0.05 ⁇ M-40 ⁇ M, 0.05 ⁇ M-35 ⁇ M, 0.05 ⁇ M-30 ⁇ M, 0.05 ⁇ M-25 ⁇ M, 0.05 ⁇ M-20 ⁇ M, 0.1 ⁇ M-18 ⁇ M, 0.5 ⁇ M-15 ⁇ M, 0.5 ⁇ M-10 ⁇ M, 1 ⁇ M-5 ⁇ M, or 2 ⁇ M-4 ⁇ M, specific about 0.05 ⁇ M, about 0.1 ⁇ M, about 0.5 ⁇ M, about 1 ⁇ M, about 1.5 ⁇ M, about 2 ⁇ M, about 2.5 ⁇ M, about 2.6 ⁇ M, about 2.7 ⁇ M, about 2.8 ⁇ M, about 2.9 ⁇ M, about 3.0 ⁇ M, about 5.0 ⁇ M , about 6.0
  • the concentration of tafluprost in the pharmaceutical composition is 0.005 ⁇ M-10 ⁇ M, eg, the concentration of tafluprost is 0.01 ⁇ M-10 ⁇ M, 1 ⁇ M-10 ⁇ M, or 5 ⁇ M-10 ⁇ M, specifically, about 6 ⁇ M, about 7 ⁇ M, about 8 ⁇ M, about 8.1 ⁇ M, about 8.2 ⁇ M, about 8.3 ⁇ M, about 8.4 ⁇ M, about 8.5 ⁇ M, about 9 ⁇ M, or about 10 ⁇ M.
  • the concentration of arginine in the pharmaceutical composition is 10mM-100mM, such as 20mM-80mM, 20mM-40mM, 40mM-60mM, or 60mM-80mM, specifically, about 10mM, about 15mM, about 20mM, About 25 mM, about 30 mM, about 50 mM, about 70 mM, about 90 mM, or about 100 mM.
  • the zinc ions are present in the pharmaceutical composition in a ratio of about 2-4 zinc ions per 6 insulin molecules. In some embodiments, the zinc ions are present in the pharmaceutical composition in a ratio of about 2.5-3.5 zinc ions per 6 insulin molecules. In some embodiments, the concentration of zinc ions in the pharmaceutical composition is 0.1 mM-0.5 mM, such as 0.2 mM-0.4 mM, such as 0.3 mM.
  • the pharmaceutical composition comprises:
  • 0.3mM-2.4mM insulin aspart such as 0.5mM-1.5mM insulin aspart or 0.5mM-1mM insulin aspart;
  • ⁇ M-65 ⁇ M iloprost such as 0.05 ⁇ M-65 ⁇ M iloprost, 0.05 ⁇ M-50 ⁇ M iloprost, 0.1 ⁇ M-15 ⁇ M iloprost, or 1 ⁇ M-10 ⁇ M iloprost;
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • 0.3mM-2.4mM insulin aspart for example 0.5mM-1.5mM or 0.5mM-1mM insulin aspart;
  • 0.005 ⁇ M-10 ⁇ M tafluprost such as 0.01 ⁇ M-10 ⁇ M tafluprost or 1 ⁇ M-10 ⁇ M tafluprost;
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the concentration of insulin aspart in the pharmaceutical composition is 1.75 mg/mL-14 mg/mL, 2.33 mg/mL-11.65 mg/mL, 2.91 mg/mL-8.74 mg/mL, 2.91 mg/mL- 5.83 mg/mL, or 2.91 mg/mL-4.67 mg/mL; in some embodiments, the concentration of insulin aspart in the pharmaceutical composition is 1.75 mg/mL-14 mg/mL, such as 3.5 mg/mL-7 mg/mL ; In some embodiments, the concentration of insulin aspart in the pharmaceutical composition is about 3.5 mg/mL.
  • the concentration of iloprost in the pharmaceutical composition is 0.0036 ⁇ g/mL-21.6 ⁇ g/mL, eg, the concentration of iloprost is 0.018 ⁇ g/mL-21.6 ⁇ g/mL, 0.018 ⁇ g/mL- 19.8 ⁇ g/mL, 0.018 ⁇ g/mL-18 ⁇ g/mL, 0.018 ⁇ g/mL-16.2 ⁇ g/mL, 0.018 ⁇ g/mL-14.4 ⁇ g/mL, 0.018 ⁇ g/mL-12.6 ⁇ g/mL, 0.018 ⁇ g/mL-10.8 ⁇ g/mL, 0.018 ⁇ g/mL-9 ⁇ g/mL, 0.018 ⁇ g/mL-7.2 ⁇ g/mL, 0.036 ⁇ g/mL-6.48 ⁇ g/mL, 0.18 ⁇ g/mL-5.4 ⁇ g/mL, 0.18 ⁇ g/mL-3.6 ⁇ g /mL, 0.36 ⁇ g/mL-1.8
  • the concentration of tafluprost is 0.00225 ⁇ g/mL-4.5 ⁇ g/mL, eg, the concentration of tafluprost is 0.0045 ⁇ g/mL-4.5 ⁇ g/mL, 0.45 ⁇ g/mL-4.5 ⁇ g/mL , or 2.25 ⁇ g/mL-4.5 ⁇ g/mL; in some embodiments, the concentration of tafluprost is about 3.75 ⁇ g/mL.
  • the concentration of arginine is from 10 mM to 100 mM, eg, 20 mM to 80 mM, eg, about 20 mM.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition is in the form of a solution or a lyophilized formulation. In some embodiments, the pharmaceutical composition is an injectable solution. In some embodiments, the pharmaceutical composition is formulated into a prefilled needle.
  • Routes of use of the pharmaceutical compositions of the present disclosure include, but are not limited to, subcutaneous injection by self-administration, such as by use of a syringe or pen device, or by continuous subcutaneous insulin infusion therapy with an insulin pump device, intravenous, intradermal or intraperitoneal route.
  • the pharmaceutical composition is stable at 25 ⁇ 2°C for at least 3 months, at least 6 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the pharmaceutical composition is stable at 40 ⁇ 2°C for at least 5 days, at least 7 days, at least 14 days, or at least 28 days, and after low temperature cycling, freeze-thaw cycling and good stability.
  • the pharmaceutical composition is placed at 25°C ⁇ 2°C for 3 months, 6 months, 9 months, 12 months or 18 months, and the high molecular protein content is not more than 1%, and can be 0.9% , 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less.
  • the pharmaceutical composition is placed at 40 ⁇ 2°C for 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months or 6 months, and the high molecular protein content is not greater than 1%, for example, can be 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less.
  • the pharmaceutical composition is placed at 25°C ⁇ 2°C for 3 months, 6 months, 9 months, 12 months or 18 months, and the known impurity content is not greater than 1.75%, for example, it can be 1.7 %, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1% or less.
  • the pharmaceutical composition is placed at 40 ⁇ 2°C for 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months or 6 months, and the known impurity content is not greater than 1.75%, for example, can be 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1% or less.
  • the pharmaceutical composition is placed at 25°C ⁇ 2°C for 3 months, 6 months, 9 months, 12 months or 18 months, and the other total impurity content is not more than 0.75%, for example, it can be 0.74 %, 0.73%, 0.72%, 0.71%, 0.7%, 0.69%, 0.68%, 0.67%, 0.66%, 0.65%, 0.64%, 0.63%, 0.62%, 0.61%, 0.6% or less.
  • the pharmaceutical composition is placed at 40 ⁇ 2°C for 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months or 6 months, and other total impurities are not greater than 0.75%, can be 0.74%, 0.73%, 0.72%, 0.71%, 0.7%, 0.69%, 0.68%, 0.67%, 0.66%, 0.65%, 0.64%, 0.63%, 0.62%, 0.61%, 0.6% or lower.
  • the pharmaceutical composition is placed at 25°C ⁇ 2°C for 3 months, 6 months, 9 months, 12 months or 18 months, and the purity of the main peak is not less than 97%, which can be 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98% or higher.
  • the pharmaceutical composition is placed at 40 ⁇ 2°C for 5 days, 7 days, 14 days, 28 days, 1 month, 2 months, 3 months or 6 months, and the purity of the main peak is not less than 97 %, which can be 97.1%, 97.2%, 97.3%, 97.4%, 97.5%, 97.6%, 97.7%, 97.8%, 97.9%, 98% or higher.
  • the chemical stability of protein formulations can be assessed by measuring the amount of chemical degradation products at various time points after exposure to different environmental conditions (often by accelerating the formation of degradation products, for example, by increasing temperature).
  • the amount of each individual degradation product is often determined by separating the degradation products according to molecular size and/or charge using various chromatographic techniques (eg, SEC-HPLC and/or RP-HPLC), such as are typical of the stability of pharmaceutical compositions in the present disclosure.
  • the accepted criterion is that generally no more than about 10%, preferably no more than about 5%, of the active ingredient is degraded as measured by HPLC.
  • the pharmaceutical compositions of the present disclosure are non-irritating to the injection site and surrounding tissues. According to the skin irritation part of the technical guidelines for drug irritation, allergy and hemolysis research, the skin irritation intensity score of 0-0.49 is regarded as non-irritating.
  • the irritation score of the pharmaceutical composition of the present disclosure to the injection site and surrounding tissues is lower than 0.49, lower than 0.45, lower than 0.4, lower than 0.35, lower than 0.34, lower than 0.33, below 0.32, Below 0.31, below 0.3, Below 0.29, Below 0.28, Below 0.27, Below 0.26, Below 0.25, Below 0.24, Below 0.23, Below 0.22, Below 0.21, Below 0.2, below 0.19, below 0.18, below 0.17, below 0.16, below 0.15, below 0.14, below 0.13, below 0.12, below 0.11, below 0.1 or 0.
  • the pharmaceutical composition of the present disclosure has a rapid onset of action after injection, and the onset time of subcutaneous injection is 3-30 minutes, 5-25 minutes, 5-20 minutes, 5-15 minutes, or 5-10 minutes minutes, or subcutaneous injection within 30 minutes, within 25 minutes, within 20 minutes, within 18 minutes, within 15 minutes, within 12 minutes, within 10 minutes, within 8 minutes, within 5 minutes, or within 3 minutes; Peak times were 20 minutes-2 hours, 30 minutes-2 hours, or 30 minutes-1 hour; durations were 1-6 hours, 2-6 hours, 3-6 hours, or 4-6 hours.
  • the present disclosure also provides a method of preparing the aforementioned pharmaceutical composition, comprising the step of mixing insulin aspart with at least one of iloprost and tafluprost; in an optional embodiment, the method further Include a step for adding arginine.
  • the present disclosure provides the use of a pharmaceutical composition in the manufacture of a medicament for the treatment and/or prevention of hyperglycemia.
  • the present disclosure provides a method of treating hyperglycemia comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions.
  • the present disclosure also relates to the aforementioned pharmaceutical compositions for use in the treatment of hyperglycemia.
  • the hyperglycemia is selected from the group consisting of type I diabetes, type II diabetes, gestational diabetes, and other diseases that cause hyperglycemia.
  • the present disclosure relates to pharmaceutical composition formulations comprising 1) insulin aspart, and 2) at least one of iloprost and tafluprost, for rapidly lowering blood glucose levels at mealtime or after meals, preventing possible occurrence of Glucagon.
  • the pharmaceutical compositions provided by the present disclosure have equivalent or better physical and/or chemical stability, lower irritation, and faster pharmacokinetics compared to commercially available formulations of existing insulin analog products.
  • Figure 1 shows the whole blood glucose test results, where: A is the listed reference substance insulin aspart C is insulin aspart + iloprost + arginine; H is insulin aspart + tafluprost + arginine.
  • Figure 2 shows the results of serum blood glucose testing, where: A is the listed reference substance insulin aspart C is insulin aspart + iloprost + arginine; H is insulin aspart + tafluprost + arginine.
  • Figure 3 shows the detection results of serum blood glucose, wherein: a is the detection result of serum blood glucose at 0 min, b is the detection result of serum blood glucose at 15 min, and c is the detection result of serum blood glucose at 18 min.
  • Sample A is the listed reference substance insulin aspart
  • Sample C is insulin aspart + iloprost + arginine
  • sample H is insulin aspart + tafluprost + arginine.
  • Figures 4A-4C show the results of hypoglycemic effect after administration of the pharmaceutical formulations R, S, and T of the present disclosure, respectively, in the LYD pig model;
  • Figures 4D-4F show the administration of the pharmaceutical formulations of the present disclosure in the LYD pig model, respectively Changes in plasma insulin concentration after R, S, and T.
  • Figures 5A-5B show the percent change in blood glucose after administration of Formulation R or S in the LYD pig model;
  • Figure 5C shows the results of the change in plasma insulin concentration after administration of Formulation S.
  • Figure 6 shows the results of the hypoglycemic effect of Formulation S in human subjects.
  • a “pharmaceutical composition” of the present disclosure means a mixture comprising insulin aspart in combination with at least one of iloprost and tafluprost described herein, and other chemical components, such as physiological/ Pharmaceutically acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to maintain the stability of insulin aspart and iloprost and/or tafluprost, promote administration to the organism, facilitate the absorption of active ingredients and exert biological activity.
  • pharmaceutical composition and “preparation” are not mutually exclusive and are sometimes used interchangeably.
  • “Chemical stability” of a composition is used herein to refer to changes in covalent protein structure that result in the formation of chemical degradation products that have potentially less biological potential and/or potentially increased potential compared to the native protein structure. Immunogenic properties. Various chemical degradation products can be formed, depending on the type and properties of the native protein and the environment to which the protein is exposed. Increased amounts of chemical degradation products are often seen during storage and use of protein formulations. Most proteins are susceptible to deamidation, which is the hydrolysis of side chain amide groups in glutamyl or asparagine residues to form free carboxylic acids or the hydrolysis of asparagine residues to form IsoAsp (isoaspartic acid) derivatives the process of.
  • HMWP high molecular weight protein
  • type I diabetes also known as insulin-dependent diabetes mellitus (IDDM) and juvenile-onset diabetes
  • IDDM insulin-dependent diabetes mellitus
  • type II diabetes also known as non-insulin-dependent diabetes mellitus (NIDDM) and adult-onset diabetes
  • NIDDM non-insulin-dependent diabetes mellitus
  • adult-onset diabetes is primarily associated with insulin resistance and thus relative insulin deficiency and/or insulin secretion deficiency predominately accompanied by insulin resistance.
  • onset time refers to the time from administration (eg, subcutaneous administration) of a pharmaceutical composition of the present disclosure to the first detection of insulin aspart in the blood.
  • absorption rate refers to the slope of the PK curve.
  • arginine or "Arg” includes arginine and/or salts thereof.
  • the pharmaceutical excipients or reagents involved in the present disclosure can all come from commercial sources.
  • the present disclosure is further described below in conjunction with the examples, but these examples do not limit the scope of the present disclosure.
  • the experimental methods that do not specify specific conditions in the embodiments of the present disclosure are generally carried out in accordance with conventional conditions; or in accordance with conditions suggested by raw material or commodity manufacturers.
  • the reagents without specific sources are the conventional reagents purchased in the market.
  • preparations of insulin aspart according to the preparation composition of Table 1, the preparations are prepared as a mixture containing active ingredients and zinc ions (for example, zinc acetate or zinc chloride can be added), buffer salts, preservatives, isotonic agents aqueous solution.
  • zinc ions for example, zinc acetate or zinc chloride can be added
  • buffer salts for example, buffer salts
  • preservatives for example, isotonic agents aqueous solution.
  • Known impurities the impurities whose chemical structure has been clarified, this product mainly refers to B 28 isoAsp insulin aspart, A 21 Asp insulin aspart, B 3 Asp insulin aspart, B 3 isoAsp insulin aspart; 2 ⁇ Other total impurities: that is, the sum of impurities other than known impurities; 3.
  • High molecular protein also called high molecular polymer, mainly refers to the polymer formed by the polymerization of two or more units of main components or impurities .
  • Tables 6 and 7 are the skin irritation part in the technical guidelines for drug irritation, allergy and hemolysis, and the irritation of the preparations in this study was scored with reference to this standard.
  • Table 8 shows the irritation score results.
  • formulation C and formulation H could be regarded as non-irritant, and formulation H containing iloprost had a better irritation score than formulation C containing tafluprost.
  • blood glucose monitoring and fasting blood glucose monitoring were performed at any time.
  • the fasting blood glucose was measured in each round of the test (fasting and water overnight), subcutaneous injection, and the test sample was not diluted.
  • the control group was given the preparation A
  • the experimental group was given the preparation C or H
  • the dosage a single subcutaneous injection of 1 nmol/kg using a micro-syringe.
  • Blood glucose was measured again 12 times within 1 hour after administration (before administration and 3, 6, 9, 12, 15, 18, 24, 30, 36, 48, 60 min after administration).
  • Blood collection method Take a long rope as thick as chopsticks, make one end of the rope into a looper, put it into the back of the upper canine teeth of the pig's mouth, and then tighten the rope and lift it up. At this time, the pig's attention is focused on the nose.
  • the upper part is mostly in a backward posture, so as to maintain a stable standing state. Sterilize the lowest part of the right chest cavity with an alcohol cotton ball and insert the needle. If there is a negative pressure and there is blood returning, it means that the anterior vena cava has been pierced, and the inner core of the syringe is gently pulled to collect blood. After the blood was collected, the needle was pulled out and the bleeding was stopped by pressing with a cotton ball.
  • Blood glucose meter detects blood glucose in real time: after blood collection, drop a drop of whole blood on a clean surface and use a blood glucose meter for real-time measurement.
  • Determination of serum blood glucose by biochemical method The collected whole blood was injected into a coagulation tube, and after blood coagulation, centrifuged at 2500 ⁇ g for 10 min at 4°C, and serum was collected, and blood glucose was measured with a biochemical analyzer.
  • Figures 1 and 2 show the results of the whole blood glucose test and serum blood glucose test results at 12 time points, respectively, and Figure 3 shows the results before administration (0min, a) and 15min (b) and 30min (c) after administration ), it can be seen that preparations C and H show a faster hypoglycemic effect than control group A, and preparation H containing iloprost lowers blood sugar faster than preparation C containing tafluprost.
  • Formulations R, S, T and U were prepared according to the formulation composition of Table 9. Pharmacokinetic/pharmacodynamic studies and plasma/serum assays were performed in LYD pig model (around 50 kg, single sex) according to the method of Example 4.
  • Formulation U was comparable to Formulation S.
  • the 12 male subjects were equally divided into 2 groups, with 6 people in each group, and a double-crossover test within each group was performed (see Table 10 for the protocol).
  • the subjects entered the Phase I clinical trial ward on the day before the trial, and were provided with standard meals and drinking water on time. Before administration, the research doctor and research nurse double check the random code of the subjects and the drug code, and the administration can only be done after confirmation.
  • a standard breakfast was eaten at 7:00 in the morning on the day of administration, and administered two hours later (9:00 in the morning), with no food or water within 4 hours after administration.
  • the administered dose is: 0.2 U/kg (0.002 mL/kg), wherein 1 ml of insulin solution contains 100 U of insulin aspart (equivalent to 3.5 mg).
  • the onset time of insulin aspart was 19min and 29min respectively, and the corresponding plasma concentration of insulin aspart was about 250pM; the average plasma concentration of preparation S at 15min was about 380pM, which had exceeded the onset concentration of insulin aspart (or called the effective concentration; see Figure 6);

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Abstract

Sont divulguées une composition d'insuline à action rapide et son utilisation médicale, la composition contenant : 1) De l'insuline asparte, et 2) de l'iloprost et/ou du tafluprost. La composition présente une pharmacocinétique plus rapide, une meilleure stabilité, et provoque moins d'irritation au niveau d'un site d'injection que des préparations commerciales de produits analogues d'insuline existants.
PCT/CN2021/102939 2020-06-30 2021-06-29 Composé d'insuline à action rapide et son utilisation médicale WO2022002008A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015171484A1 (fr) * 2014-05-08 2015-11-12 Eli Lilly And Company Compositions d'insuline à action rapide
WO2017015760A1 (fr) * 2015-07-28 2017-02-02 Societe De Commercialisation Des Produits De La Recherche Appliquee Socpra Sciences Sante Et Humaines, S.E.C. Préparation pharmaceutique pour améliorer l'absorption et l'action hypoglycémique postprandiale de l'insuline
WO2017034956A1 (fr) * 2015-08-27 2017-03-02 Eli Lilly And Company Compositions d'insuline à action rapide
WO2020069138A1 (fr) * 2018-09-28 2020-04-02 Axsome Therapeutics, Inc. Formes posologiques comprenant des principes pharmaceutiques actifs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015171484A1 (fr) * 2014-05-08 2015-11-12 Eli Lilly And Company Compositions d'insuline à action rapide
WO2017015760A1 (fr) * 2015-07-28 2017-02-02 Societe De Commercialisation Des Produits De La Recherche Appliquee Socpra Sciences Sante Et Humaines, S.E.C. Préparation pharmaceutique pour améliorer l'absorption et l'action hypoglycémique postprandiale de l'insuline
WO2017034956A1 (fr) * 2015-08-27 2017-03-02 Eli Lilly And Company Compositions d'insuline à action rapide
WO2020069138A1 (fr) * 2018-09-28 2020-04-02 Axsome Therapeutics, Inc. Formes posologiques comprenant des principes pharmaceutiques actifs

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