WO2024061310A1 - 一种glp-1和gip双受体激动剂药物组合物及其用途 - Google Patents

一种glp-1和gip双受体激动剂药物组合物及其用途 Download PDF

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WO2024061310A1
WO2024061310A1 PCT/CN2023/120363 CN2023120363W WO2024061310A1 WO 2024061310 A1 WO2024061310 A1 WO 2024061310A1 CN 2023120363 W CN2023120363 W CN 2023120363W WO 2024061310 A1 WO2024061310 A1 WO 2024061310A1
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pharmaceutical composition
glp
concentration
value
stabilizer
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PCT/CN2023/120363
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English (en)
French (fr)
Inventor
李会芳
冯欣
张波
郑芳芳
李佳晗
省盼盼
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博瑞生物医药（苏州）股份有限公司
博瑞制药(苏州)有限公司
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Publication of WO2024061310A1 publication Critical patent/WO2024061310A1/zh

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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons

Definitions

  • the present disclosure belongs to the field of medicine, and specifically relates to a GLP-1 and GIP dual receptor agonist pharmaceutical composition and its use.
  • Glucose-dependent insulinotropic peptide is a 42-amino acid gastrointestinal regulatory peptide that plays a role in glucose homeostasis by stimulating insulin secretion from pancreatic ⁇ -cells in the presence of glucose and protecting pancreatic ⁇ -cells. exert physiological effects.
  • Glucagon-like peptide-1 (GLP-1) is a 37-amino acid peptide that stimulates insulin secretion, protects pancreatic beta cells, and inhibits glucagon secretion, gastric emptying, and food Ingestion, leading to weight loss.
  • GIP and GLP-1 are secreted by K cells and L cells of the small intestinal endothelium, respectively, and are known as incretins. Incretin receptor signaling plays a key physiologically relevant role in glucose homeostasis.
  • GIP and GLP-1 produce corresponding physiological effects by binding to their specific receptors, which bind to the GIP (GIPR) receptor and the GLP-1 receptor (GLP-1R) respectively.
  • GIP GIP
  • GLP-1R GLP-1 receptor
  • co-agonizing GLP-1R/GIPR can exert a synergistic hypoglycemic effect, and dual receptor agonists of GIP and GLP-1 may produce more excellent hypoglycemic effects and stimulate insulin secretion. Therefore, the development of GLP-1 and GIP dual receptor agonists and pharmaceutical compositions with novel structures and good efficacy has always been one of the research hotspots in the field of treatment of metabolic diseases such as diabetes or obesity.
  • peptide drugs are mostly stored and used in the form of liquid preparations.
  • the active ingredients of peptides are easily affected by the external environment, resulting in chemical changes such as hydrolysis and oxidation.
  • the resulting impurities can seriously affect the effectiveness and safety of the drugs.
  • GLP-1 and GIP dual receptor agonists are generally linear peptides, and since the pH of the preparation needs to be close to the physiological pH of the human body, the pH value of the preparation is generally controlled at around 7 to 8. Polypeptide drugs are easily destroyed under this pH condition. Microbial degradation, generally consider adding bacteriostatic agents (such as phenol) to the prescription to improve product stability. For example, 8.25 mg of phenol is added as a bacteriostatic agent to the commercially available antidiabetic drug preparation semaglutide (OZEMPIC); 2.64 mg m-cresol is added to exenatide as a bacteriostatic agent, and 2.64 mg of m-cresol is added to exenatide (VICTOZA).
  • bacteriostatic agents such as phenol
  • lixisenatide contains 8.1 mg m-cresol as a bacteriostatic agent.
  • injections directly enter the human body circulation, and the use of bacteriostatic agents will increase drug safety risks.
  • national regulatory agencies have issued multiple documents stating that the use of preservatives should be minimized when screening insulin product prescriptions. Therefore, the development of antibacterial-free prescriptions for polypeptide antidiabetic drugs is also a technical problem in this field.
  • the development of preservative/bacteriostatic-free GLP-1 and GIP dual receptor agonist preparations will have good prospects. Application prospects.
  • peptide drugs are connected to each other by multiple amino acids forming amide bonds through condensation reactions. Since peptide drugs have many electron-rich and electron-withdrawing groups, they are very prone to mutual attraction between molecules when they are prepared into pharmaceutical preparations. Causes polymerization of drug molecules. Once peptide drugs polymerize, they will not be able to exert their efficacy. In addition, drug aggregation may also cause quality problems such as turbidity or discoloration of injections. Therefore, solving the problem of drug polymerization when polypeptide drugs are prepared into preparations has always been a technical difficulty in this field.
  • GLP-1 and GIP dual receptor agonist In order to develop a GLP-1 and GIP dual receptor agonist that has a novel structure and can effectively treat obesity, diabetes and its complications, the applicant of this application has filed an application with the application number 202210294984.3 and the invention name is "GIP and GLP-1 dual receptor agonist".
  • the patent application "Agonists, Pharmaceutical Compositions and Uses” provides a GLP-1 and GIP dual receptor agonist.
  • the dual receptor agonist is a glucose-dependent incretin polypeptide GLP-1 and GIP dual receptor agonist independently developed by the applicant of the present application.
  • the intended clinical indication is type 2 diabetes.
  • the drug is a linear peptide containing 40 amino acids and has GLP-1R and GIPR agonistic effects.
  • this dual-receptor agonist has a strong agonistic effect on both GLP-1 and GIP receptors, and its activity is 2 to 3 times stronger than Tirzepatide; the side chain is composed of a fatty acid chain and a double AEEEA chain. The main function of the chain is to combine with albumin in the blood (albumin has basic residues) to extend the half-life and achieve long-term effect.
  • Preclinical pharmacokinetic study results show that the binding rate of this dual receptor agonist to various plasma proteins exceeds 99.4%, and its half-life in rats and cynomolgus monkeys is approximately 14h and 40h respectively.
  • the present disclosure intends to provide a GLP-1 and GIP dual receptor agonist pharmaceutical composition and its use.
  • the GLP-1 and GIP dual receptor agonist can be prepared in a liquid preparation. It remains stable and effectively prevents physical and chemical degradation.
  • the first aspect of the present disclosure provides a pharmaceutical composition, which includes a GLP-1 and GIP dual receptor agonist, a stabilizer and a buffer salt; the GLP-1 and GIP dual receptor agonist is as shown in Formula I A compound or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotopic label or prodrug thereof:
  • the pharmaceutical composition is a liquid preparation; preferably, the pharmaceutical composition is an injection.
  • the concentration of the GLP-1 and GIP dual receptor agonist in the pharmaceutical composition is 2 to 36 mg/mL, preferably 5 to 30 mg/mL.
  • the stabilizer is polyols; preferably, the stabilizer is propylene glycol, mannitol or glycerol; more preferably, the stabilizer is propylene glycol.
  • the concentration of the stabilizer in the pharmaceutical composition is 10-20 mg/mL.
  • the buffer salt is selected from hydrogen phosphate, hydrogen phosphate hydrate, citrate or citrate hydrate; preferably, the buffer salt is dihydrogen phosphate. Sodium dodecahydrate or sodium citrate dihydrate; more preferably, the buffer salt is sodium hydrogen phosphate dodecahydrate.
  • the concentration of buffer salt in the pharmaceutical composition is 7-23mM.
  • the pH value of the pharmaceutical composition is 6.5 to 8.5; preferably, the pH value of the pharmaceutical composition is 7.0 to 8.4; preferably, the pH value of the pharmaceutical composition is 7.2 to 8.2; more preferably, the pH value of the pharmaceutical composition is 7.2 to 7.6.
  • the pharmaceutical composition also contains a pH adjuster and water;
  • the pH adjuster is hydrochloric acid and/or sodium hydroxide; the pH value of the pharmaceutical composition is adjusted by the pH adjuster;
  • Water is preferably purified water and/or water for injection.
  • the pharmaceutical composition does not contain bacteriostatic agents.
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises a GLP-1 and GIP dual receptor agonist as shown in formula I, a stabilizer and a buffer salt, wherein the stabilizer is propylene glycol, the buffer salt is disodium hydrogen phosphate dodecahydrate, and the pH value of the pharmaceutical composition is 7.0 to 8.4; and in the pharmaceutical composition, the GLP-1 and GIP dual receptor agonist as shown in formula I
  • the concentration of the receptor agonist is 5 to 30 mg/mL
  • the concentration of the propylene glycol is 10 to 20 mg/mL
  • the concentration of the disodium hydrogen phosphate dodecahydrate is 7 to 23 mM;
  • the pharmaceutical composition is an injection.
  • the pH value of the pharmaceutical composition is 7.2-8.2, and the concentration of disodium hydrogen phosphate dodecahydrate in the pharmaceutical composition is 10-20mM.
  • the pH value of the pharmaceutical composition is 7.2 to 7.6; in the pharmaceutical composition, the concentration of the GLP-1 and GIP dual receptor agonist represented by Formula I is 5 to 25 mg/mL, The concentration of propylene glycol is 14 mg/mL, and the concentration of disodium hydrogen phosphate dodecahydrate is 10 mM.
  • the pharmaceutical composition also contains a pH adjuster and water; preferably, the pH adjuster is hydrochloric acid and/or sodium hydroxide; preferably, the water is purified water and/or water for injection.
  • the pH adjuster is hydrochloric acid and/or sodium hydroxide; preferably, the water is purified water and/or water for injection.
  • the third aspect of the present disclosure provides a preparation method of the pharmaceutical composition described in the first or second aspect, which includes the following steps: formulating a stabilizer, a buffer salt and a GLP-1 and GIP dual receptor agonist into a solution, Adjust the pH value of the solution to the target value.
  • the preparation method includes the following steps: dissolve the stabilizer and buffer salt in the solvent, add GLP-1 and GIP dual receptor agonists to prepare a solution, and add a pH regulator to make GLP-1 and GIP dual receptor agonists.
  • the body agonist is completely dissolved, and then a pH adjuster is used to adjust the pH value of the solution to the target value.
  • the fourth aspect of the present disclosure provides the use of the pharmaceutical composition described in the first or second aspect in the preparation of medicaments for preventing and/or treating diseases related to metabolic disorders; preferably, the disease related to metabolic disorders is diabetes. , diabetes complications, obesity or obesity complications.
  • the present invention provides a pharmaceutical composition in which excipients such as stabilizers and buffer salts are added to maintain good stability of GLP-1 and GIP dual receptor agonists as active pharmaceutical ingredients in a liquid preparation, while avoiding quality problems such as drug failure caused by polymerization between GLP-1 and GIP dual receptor agonists as polypeptide drugs, thereby ultimately achieving drug efficacy.
  • excipients such as stabilizers and buffer salts are added to maintain good stability of GLP-1 and GIP dual receptor agonists as active pharmaceutical ingredients in a liquid preparation, while avoiding quality problems such as drug failure caused by polymerization between GLP-1 and GIP dual receptor agonists as polypeptide drugs, thereby ultimately achieving drug efficacy.
  • the long-term preservation of the biocomposition shows important application prospects in the prevention and treatment of metabolic disorder-related diseases such as diabetes or diabetic complications, obesity or obesity complications.
  • the present invention utilizes a pH regulator to control the pH value of the pharmaceutical composition within a specific range, and is more conducive to the complete dissolution of the GLP-1 and GIP dual receptor agonists during the preparation of the pharmaceutical composition, and ensures the stability of the GLP-1 and GIP dual receptor agonists as active pharmaceutical ingredients during storage of the composition to avoid degradation.
  • the present disclosure greatly improves the solubility of GLP-1 and GIP dual receptor agonists (such as compounds of formula I) by selecting specific stabilizers, while allowing them to have complete structure and biological activity during storage.
  • the present invention can ensure the stability of the pH value of the pharmaceutical composition during storage by selecting a specific buffer salt, without affecting the quality and stability of the active ingredients of the medicine.
  • the preparation method of the pharmaceutical composition provided by the present disclosure is simple to operate, has low production cost, is conducive to large-scale production, and provides assistance for the wide range of applications of pharmaceutical preparations.
  • the pharmaceutical composition provided by the present disclosure can effectively prevent and/or treat metabolic disorder-related diseases such as diabetes, diabetic complications, obesity or obesity complications, and the method of use is convenient.
  • Figure 1 shows the specificity diagram for verifying the multimer detection method.
  • Figure 2 is the detection spectrum of multimer injection of compound of formula I.
  • the words “comprises,” “having,” “including,” or “containing” mean inclusive or open-ended and do not exclude additional, unrecited elements or methods. step. Meanwhile, “comprises,” “having,” “includes” or “containing” can also mean closed terms, excluding additional, unrecited elements or method steps.
  • the term "about” means that a value includes the standard deviation of the error of the device or method used to determine the value.
  • the term "agonist” refers to a substance (ligand) that activates signaling through the targeted receptor type.
  • the agonist has GLP-1 receptor activating activity, for example It is a GLP-1 polypeptide or an analog thereof.
  • treatment refers to contacting (eg, administering) a pharmaceutical composition of the present disclosure to a subject after suffering from a disease, thereby reducing the symptoms of the disease compared with the absence of exposure. This means that the symptoms of the disease must be completely suppressed. Suffering from a disease means that the body has symptoms of the disease.
  • prevention refers to contacting (e.g., administering) a pharmaceutical composition of the present disclosure to a subject before suffering from the disease, thereby alleviating the symptoms after suffering from the disease compared with the absence of exposure, and It does not mean that the disease must be completely suppressed.
  • mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., , mice and rats).
  • domestic animals e.g., cattle, sheep, cats, dogs, and horses
  • primates e.g., humans and non-human primates such as monkeys
  • rabbits e.g., mice and rats.
  • the term "therapeutically effective amount” refers to an amount effective to achieve the desired therapeutic result, at the required dose and for the required period of time.
  • the therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure can vary depending on a variety of factors such as the disease state, the age, sex and weight of the individual and the ability of the immune adjuvant or pharmaceutical composition to elicit the desired response in the individual.
  • the term "pharmaceutically acceptable salt” refers to a salt prepared from a compound in this disclosure and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the free form with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine salts or similar salts.
  • acid addition salts can be obtained by contacting the free form with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (e.g., hydrochlorides, hydrobromides, hydroiodates, nitrates, carbonates, bicarbonates, phosphates , monohydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, hydrogen sulfate, etc.), organic acid salts (such as acetate, propionate, isobutyrate, malonate, succinate , suberate, maleate, fumarate, citrate, tartrate, lactate, mandelate, benzoate, phthalate, methanesulfonate, benzene sulfonate acid salt, p-toluenesul
  • inorganic acid salts e.g., hydrochlorides, hydrobromides, hydroio
  • the term "metabolic disorder” may refer to glucose metabolism disorders such as diabetes, diabetic complications, obesity, and obesity complications. Since the association between obesity, diabetes, and glucose metabolism is well known, these conditions may but do not have to be separate or mutually exclusive.
  • diabetes or diabetic complications include insulin resistance, glucose intolerance, elevated fasting glucose, prediabetes, type I diabetes, type II diabetes, gestational diabetic hypertension, dyslipidemia, or combinations thereof.
  • obesity complications include obesity-associated inflammation, obesity-associated gallbladder disease, or obesity-induced sleep apnea, or may be selected from the group consisting of: atherogenic dyslipidemia, dyslipidemia, elevated blood pressure Hypertension, prothrombotic state, and proinflammatory state or combinations thereof.
  • the pharmaceutical composition of the present disclosure has excellent dual agonist activity of GIPR and GLP-1R, can effectively reduce blood sugar, control the weight gain of type 2 diabetes model mice, and can be used to prevent and/or treat metabolic disorders. It has good Clinical applications and medicinal uses.
  • GLP-1 and GIP dual receptor agonists refer to substances that target GLP-1 receptor and GIP receptor and have activating activity on both GLP-1R and GIPR.
  • the GLP-1 and GIP dual receptor agonists of the present disclosure are compounds represented by Formula I or pharmaceutically acceptable salts, esters, solvates, and optical isomers thereof , tautomers, isotopic labels or prodrugs:
  • the present disclosure does not specifically limit the content of active pharmaceutical ingredients in the pharmaceutical composition, which can be determined by those skilled in the art according to actual needs.
  • the concentration of GLP-1 and GIP dual receptor agonists of the present disclosure is 2 to 36 mg/mL; for example, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL , 7mg/mL, 8mg/mL, 9mg/mL, 10mg/mL, 11mg/mL, 12mg/mL, 13mg/mL, 14mg/mL, 15mg/mL, 16mg/mL, 17mg/mL, 18mg/mL, 19mg /mL, 20mg/mL, 21mg/mL, 22mg/mL, 23mg/mL, 24mg/mL, 25mg/mL, 26mg/mL, 27mg/mL, 28mg/mL, 29mg/mL, 30mg/mL, 31mg/mL , 32 mg/mL, 33 mg/mL,
  • stabilizers refer to substances used to stabilize the structure and biological activity of polypeptide substances in solution.
  • screening suitable stabilizers is the main means to prevent physical and chemical degradation of peptide drug molecules in liquid preparations. Selecting the appropriate stabilizer can improve the stability of the peptide molecule by binding to the hydrophobic part of the peptide molecule, increasing the viscosity of the solution, and affecting the folding state of the peptide molecule.
  • the stabilizer described in the present disclosure is selected from polyols.
  • the stabilizer of the present disclosure is propylene glycol, mannitol, or glycerin.
  • the present disclosure prefers propylene glycol as the stabilizer, which can effectively maintain the structure and biological activity of the main drug, and can also stabilize the pH value of the pharmaceutical composition during storage.
  • the amount of the above stabilizer is not particularly limited in this disclosure and can be determined by those skilled in the art according to actual needs.
  • the stabilizer concentration disclosed herein is 10-20 mg/mL; for example, 10 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, etc.; preferably 14 mg/mL.
  • sodium chloride is considered to maintain electrolyte balance and stabilize the polypeptide structure. It exists as a stabilizer in a variety of existing polypeptide preparations.
  • sodium chloride instead of propylene glycol (for example, 2 mL of a pharmaceutical composition containing 40.0 mg of the compound of formula I, 3.58 mg of disodium hydrogen phosphate dodecahydrate, and 16.4 mg of sodium chloride
  • a pH adjuster is used After adjusting the pH value to 7, use water for injection to make up the balance).
  • the solubility of the compound of formula I is only 0.15mg/mL, which is far from meeting the requirements.
  • propylene glycol is used as a stabilizer (for example, 1 mL of a pharmaceutical composition contains 20.0 mg of the compound of formula I, 3.58 mg of disodium hydrogen phosphate dodecahydrate, and 14 mg of propylene glycol), use a pH adjuster to adjust the pH to 7 and then use water for injection to make up the remainder. amount), the solubility of the compound of formula I can reach more than 30 mg/mL, meeting the solubility requirements of the main drug. Therefore, in some preferred embodiments of the present disclosure, sodium chloride is not included in the pharmaceutical composition.
  • the pH value has a great influence on the stability of the polypeptide drug GLP-1 and GIP dual receptor agonists. At the same time, it also affects the dissolution of the main drug during the preparation process of the pharmaceutical composition.
  • An acidic environment is not conducive to the provision of the present disclosure.
  • the pH value of the pharmaceutical composition of the present disclosure is 6.5-8.5; for example, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, etc.; preferably 7.0-8.4; more preferably 7.2-8.2; further preferably 7.2-7.6.
  • a reasonable pH value range not only ensures the purity and stability of the pharmaceutical composition of the present disclosure during storage, but also takes into account pH fluctuations during drug storage, thereby ensuring the stability of the pharmaceutical composition throughout the process from production to use. .
  • the present disclosure utilizes a pH adjusting agent to adjust the pH of a pharmaceutical composition.
  • the pH adjusting agent described in the present disclosure is hydrochloric acid and/or sodium hydroxide.
  • Hydrochloric acid is a transparent, colorless, fuming hydrochloric acid solution with a pungent odor, and is commonly used as an acidulant in pharmaceutical preparations.
  • Sodium hydroxide is a molten white dry granule, block, rod or flake, which is generally considered to be non-toxic at low concentrations and is widely used in pharmaceutical preparations to adjust the pH value of the solution.
  • the pH adjusting agent described in the present disclosure can be a certain concentration of hydrochloric acid and/or a certain concentration of sodium hydroxide solution.
  • the present disclosure does not limit the concentration of the above-mentioned pH regulator, and those skilled in the art can adjust it according to actual production needs.
  • a lower concentration of pH regulator can be selected, such as a pH regulator with a concentration lower than 3M, or a higher concentration of pH regulator can be selected, such as a pH regulator with a concentration higher than 3M, both of which have no adverse effects on the active ingredients of the drug.
  • the present disclosure preferably uses 0.1M hydrochloric acid and/or 0.1M sodium hydroxide solution.
  • buffer salts refer to substances used to stabilize the pH of a solution.
  • selecting a suitable buffer salt system is an important means to prevent physical and chemical degradation of peptide drug molecules in liquid preparations. Choosing an appropriate buffer salt system can improve the stability of the peptide by maintaining a stable pH value of the peptide solution and affecting electrostatic interactions.
  • buffer salts of the present disclosure are selected from hydrogen phosphate salts, hydrogen phosphate hydrates, citrate salts, or citrate hydrates.
  • the buffer salt of the present disclosure is sodium phosphate disodium dodecahydrate or sodium citrate dihydrate.
  • the buffer salt of the present disclosure is sodium phosphate disodium phosphate dodecahydrate. It not only helps to stabilize the pH value of the pharmaceutical composition of the present disclosure during storage, but also helps to stabilize the pharmaceutical composition during storage. In-process purity.
  • this disclosure gives priority to disodium hydrogen phosphate dodecahydrate as the buffer salt. Its chemical properties are stable, it does not affect the quality and stability of the main drug, and it maintains a stable pH value of the preparation. Works well.
  • the amount of the above buffer salt is not particularly limited in this disclosure and can be determined by those skilled in the art according to actual needs.
  • the buffer salt concentration described in the present disclosure is 7-23mM; for example, 7mM, 8mM, 9mM, 10mM, 11mM, 12mM, 13mM, 14mM, 15mM, 16mM, 17mM, 18mM, 19mM, 20mM, 21mM, 22mM, 23mM, etc.; preferably 7-20mM; more preferably 7-15mM.
  • the present disclosure gives priority to selecting a low concentration buffer salt, such as a concentration of 10mM.
  • the GLP-1 and GIP dual receptor agonist described in this disclosure is a linear peptide containing 40 amino acids, and the pH value of the preparation is initially set between 7.2 and 8.2. It is easily degraded by microorganisms and will generally be considered in the prescription. Bacteriostatic agents (such as phenol) are added to improve product stability.
  • bacteriostatic agents to peptide anti-diabetic drugs is a common technical method in this field.
  • 8.25 is added to the commercially available anti-diabetic drug product semaglutide (OZEMPIC). mg phenol as a bacteriostatic agent; 2.64 mg m-cresol is added to exenatide as a bacteriostatic agent, 16.5 mg phenol is added to liraglutide (VICTOZA) as a bacteriostatic agent, and lixisenatide (ADLYXIN) is added to 8.1 mg of m-cresol was added as a bacteriostatic agent.
  • OZEMPIC anti-diabetic drug product semaglutide
  • the inventors of the present disclosure have found that the safety of clinical medication can be ensured without adding bacteriostatic agents, and the risk factors during the application process of the pharmaceutical composition can also be further reduced.
  • the composition does not contain a bacteriostatic agent, it is more conducive to controlling or reducing the risks of the clinical use of the pharmaceutical preparation, and to a certain extent, the production cost of the pharmaceutical composition is reduced, and it is more conducive to the large-scale production of the drug. and applications.
  • compositions of the present disclosure include GLP-1 and GIP dual receptor agonists, stabilizers and buffer salts.
  • a pH adjuster and a solvent are further included in the pharmaceutical compositions of the present disclosure.
  • compositions of the present disclosure consist of a GLP-1 and GIP dual receptor agonist, a stabilizer, a buffer salt, a pH adjuster, and a solvent.
  • composition exhibits good activating effects on GLP-1R and GIPR in vivo.
  • drugs The description of each ingredient in the composition is as previously described.
  • compositions of the present disclosure are liquid formulations.
  • the pharmaceutical compositions of the present disclosure are injectables.
  • the solvent used for the pharmaceutical composition of the present disclosure as a liquid preparation is water, preferably purified water or water for injection.
  • the present disclosure also provides a preparation method of the pharmaceutical composition, which includes the following steps: formulating a stabilizer, a buffer salt and a GLP-1 and GIP dual receptor agonist into a solution, and adjusting the pH value of the solution to a target value, That’s it.
  • the preparation method of the pharmaceutical composition includes the following steps: dissolving a stabilizer and a buffer salt in a solvent, adding a GLP-1 and GIP dual receptor agonist, and adding a pH adjuster to make the GLP The -1 and GIP dual receptor agonists are completely dissolved, and then a pH adjuster is used to adjust the pH value of the solution to the target value.
  • the preparation method of the pharmaceutical composition includes the following steps: dissolving a prescription amount of disodium hydrogen phosphate dodecahydrate and propylene glycol in purified water or water for injection, and adding a prescription amount of GLP- 1 and GIP dual receptor agonists, and add sodium hydroxide to completely dissolve the GLP-1 and GIP dual receptor agonists, then use hydrochloric acid and/or sodium hydroxide to adjust the pH value of the solution to 6.5 ⁇ 8.5, and use purification Dilute water or water for injection to volume.
  • the purpose of adding sodium hydroxide is to appropriately increase the pH value of the solution, which is more conducive to the dissolution of the GLP-1 and GIP dual receptor agonists.
  • the route of administration can be varied or adjusted in any applicable manner to meet the requirements of the properties of the drug, the convenience of the patient and the medical staff, and other relevant factors.
  • the pharmaceutical composition of the present disclosure can be used to prevent and/or treat diseases related to metabolic disorders; preferably, the diseases related to metabolic disorders are diabetes, complications of diabetes, obesity or complications of obesity.
  • the pharmaceutical composition of the present disclosure can be further used to prepare drugs for preventing and/or treating diseases related to metabolic disorders; preferably, the diseases related to metabolic disorders are diabetes, complications of diabetes, obesity or complications of obesity.
  • the present disclosure also provides a method for preventing and/or treating diseases related to metabolic disorders, which includes administering to a subject a preventive and/or therapeutically effective amount of a pharmaceutical composition according to the present disclosure; preferably, the The diseases related to metabolic disorders are diabetes, complications of diabetes, obesity or complications of obesity.
  • reagents or instruments used in the examples are all conventional products that are commercially available. If no specific conditions are specified, general conditions or conditions recommended by the manufacturer shall be followed.
  • Stabilizers can improve the stability of peptide preparations by binding to the hydrophobic part of the peptide molecule, increasing the viscosity of the solution, and affecting the folding state of the peptide molecule.
  • propylene glycol, mannitol, and glycerol were used to prepare formulations, and the prepared samples were placed at 40°C and 2-8°C for high-temperature and long-term stability investigation. Samples were taken at different time points to detect properties, pH value and purity, and the impact of different stabilizers on the quality of the medicinal solution was examined. Prescription information is shown in Table 1, and results are shown in Table 2.
  • the samples using stabilizers are relatively stable at 2 to 8°C. After being left for 1 month, the properties, pH value, purity, There was no significant change in the maximum single hybridity. When placed at a high temperature of 40°C for 10 days, the purity of the sample decreased, and the properties and maximum impurity did not change significantly. However, it was surprisingly found that the stabilizer was propylene glycol. Under the conditions of high-temperature accelerated stabilization experiments, , the pH change is less than 3%, and the pH can be kept stable, indicating that the prescription using propylene glycol as the stabilizer has achieved unexpected technical effects in maintaining pH stability.
  • pH value is an important quality attribute of peptide pharmaceutical preparations. It directly affects the solubility, stability and aggregation of peptide molecules. This disclosure is conducted in the pH range of 5.0 to 8.4, focusing on the dissolution of the API and the stability of the product. Prescription information is shown in Table 3, and results are shown in Table 4.
  • buffer system is also critical to improving formulation stability.
  • sodium citrate dihydrate and disodium hydrogen phosphate dodecahydrate were used to prepare preparations, and the prepared samples were placed at 40°C and 2-8°C for high temperature and long-term testing. Investigation of relevant indicators. The specific prescription information is shown in Table 7, and the results are shown in Table 8.
  • the concentration of active pharmaceutical ingredients can also be 5 mg/mL, 10 mg/mL, 15 mg/mL, 25 mg/mL, or 30 mg/mL, and the concentrations of other excipients remain unchanged. It is understood that those skilled in the art can also adjust the API concentration according to the specific conditions of the patient, which is within the scope of the present disclosure.
  • the purified water in the above-mentioned prescriptions 1-16 can be replaced with water for injection, and the experimental result data obtained for the water for injection prescription obtained after the replacement is not significantly different from the experimental result data of the above-mentioned purified water prescription.
  • Example 2 Preparation of a GLP-1 and GIP dual receptor agonist pharmaceutical composition
  • the rest of the recipes refer to this preparation method.
  • Test solution Get the GLP-1 and GIP dual receptor agonist pharmaceutical composition (compound formula I injection).
  • the compound of formula I is a chemically synthesized polypeptide drug, and its preparation may aggregate to form polymers during production and storage.
  • the polymers are detected by SEC method.
  • composition of this product is stable under appropriate storage conditions, and the polymer content is within limits.

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Abstract

本发明提供一种GLP-1和GIP双受体激动剂药物组合物，包含GLP-1和GIP双受体激动剂、稳定剂和缓冲盐。本发明还提供所述药物组合物在制备用于预防和/或治疗代谢紊乱相关疾病的药物中的用途。

Description

一种GLP-1和GIP双受体激动剂药物组合物及其用途
本公开要求如下专利申请的优先权：于2022年09月23日提交中国专利局、申请号为202211167785.2的中国专利申请；上述专利申请的全部内容通过引用结合在本公开中。
技术领域
本公开属于医药领域，具体涉及一种GLP-1和GIP双受体激动剂药物组合物及其用途。
背景技术
葡萄糖依赖性促胰岛素肽(glucose-dependent insulinotropic peptide，GIP)是42个氨基酸的胃肠调节肽，其通过在葡萄糖存在下刺激从胰腺β细胞分泌胰岛素以及保护胰腺β细胞，在葡萄糖内稳态中发挥生理作用。胰高血糖素样肽-1(Glucagon-like peptide-1，GLP-1)是37个氨基酸的肽，其刺激胰岛素分泌、保护胰腺β细胞、并抑制胰高血糖素分泌、胃排空和食物摄入，导致体重减轻。GIP和GLP-1分别由小肠内皮的K细胞和L细胞分泌，被称为肠促胰岛素，肠促胰岛素受体信号传导对葡萄糖内稳态发挥关键的生理相关作用。
GIP和GLP-1都是通过与其特异性受体结合来产生相应的生理作用，其分别与GIP(GIPR)受体和GLP-1受体(GLP-1R)结合。有研究表明，共同激动GLP-1R/GIPR可以发挥协同降血糖作用，GIP和GLP-1的双受体激动剂可能产生更加优异的降低血糖作用以及胰岛素分泌刺激。因此，开发结构新颖且具有良好疗效的GLP-1和GIP双受体激动剂及其药物组合物一直是糖尿病或肥胖等代谢疾病治疗领域的研究热点之一。
目前，多肽类药物多以液体制剂的形式保存和使用，而多肽活性成分容易受到外界环境的影响，从而发生水解、氧化等化学变化，所产生的杂质会严重影响药物的有效性和安全性。
GLP-1和GIP双受体激动剂一般是线性肽，且由于制剂的pH需要接近人体生理pH一般会将制剂的pH值控制在7～8左右，多肽类药物在该pH条件下极易被微生物降解，一般情况下会考虑在处方中加入抑菌剂(例如苯酚)来提高产品的稳定性。如市售降糖药制剂索马鲁肽(OZEMPIC)中添加了8.25mg苯酚作为抑菌剂；艾塞那肽中添加了2.64mg间甲酚作为抑菌剂，利拉鲁肽(VICTOZA)中添加了16.5mg苯酚作为抑菌剂，利西那肽 (ADLYXIN)中添加了8.1mg间甲酚作为抑菌剂。然而，注射剂直接进入人体内循环，使用抑菌剂会增加药品安全风险，目前国家监管机构也多次发文，在胰岛素类产品处方筛选时，应尽可能减少防腐剂的使用。因此，在多肽类降糖药中开发不含抑菌剂的处方也是本领域的技术难题，开发不含防腐剂/抑菌剂的GLP-1和GIP双受体激动剂制剂将具有很好的应用前景。
此外，多肽类药物是由多个氨基酸通过缩合反应形成酰胺键而彼此连接的，多肽类药物因富电子和吸电子基团较多，在制备成药物制剂时非常容易发生分子间相互吸引，从而引起药物分子聚合。多肽类药物一旦发生聚合，则无法发挥药效。并且，药物聚合也可能会使注射剂产生浑浊或变色的质量问题。因此，解决多肽类药物在制备成制剂时的药物聚合的问题也一直是本领域的技术难点。
综上，开发适于长期保存且药效稳定的GLP-1和GIP双受体激动剂药物组合物配方是本领域亟待解决的问题。
发明内容
发明要解决的问题
为了开发结构新颖且能够有效治疗肥胖、糖尿病及其并发症的GLP-1和GIP双受体激动剂，本申请的申请人在申请号为202210294984.3、发明名称为“GIP和GLP-1的双受体激动剂、药物组合物及用途”的专利申请中提供了一种GLP-1和GIP双受体激动剂。该双受体激动剂为本申请的申请人自主开发的葡萄糖依赖性的肠促胰岛素多肽GLP-1和GIP双受体激动剂，临床拟用适应症为2型糖尿病。该药物是含有40个氨基酸的线性肽，具有激动GLP-1R和GIPR作用。临床前研究表明该双受体激动剂对GLP-1和GIP受体都有较强激动作用，活性相比于Tirzepatide强2～3倍；侧链由一个脂肪酸链和双AEEEA链连接组成，侧链主要功能是可以与血液中白蛋白(白蛋白有碱性残基)结合，延长半衰期，实现长效化。临床前药代动力学研究结果表明该双受体激动剂与各种属血浆蛋白结合率均超过99.4％，在大鼠和食蟹猴体内半衰期分别约为14h和40h。
而针对上述GLP-1和GIP双受体激动剂，目前尚未出现适于其长期保存且保证药效稳定的药物制剂。对此，本公开拟提供一种GLP-1和GIP双受体激动剂药物组合物及其用途，通过添加稳定剂、缓冲盐等辅料，使得GLP-1和GIP双受体激动剂在液体制剂中保持稳定，有效防止其发生物理和化学降解。
用于解决问题的方案
本公开第一方面提供了一种药物组合物，其包含GLP-1和GIP双受体激动剂、稳定剂和缓冲盐；所述GLP-1和GIP双受体激动剂为如式I所示的化合物或其药学上可接受的盐、酯、溶剂合物、光学异构体、互变异构体、同位素标记物或前药：
进一步的，所述药物组合物为液体制剂；优选的，所述药物组合物为注射剂。
进一步的，所述药物组合物中所述GLP-1和GIP双受体激动剂的浓度为2～36mg/mL，优选5～30mg/mL。
进一步的，在所述药物组合物中，所述稳定剂为多元醇类；优选的，所述稳定剂为丙二醇、甘露醇或甘油；更优选的，所述稳定剂为丙二醇。
更进一步的，所述药物组合物中稳定剂的浓度为10～20mg/mL。
进一步的，在所述药物组合物中，所述缓冲盐选自磷酸氢盐、磷酸氢盐水合物、枸橼酸盐或枸橼酸盐水合物；优选的，所述缓冲盐为磷酸氢二钠十二水合物或枸橼酸钠二水合物；更优选的，所述缓冲盐为磷酸氢二钠十二水合物。
更进一步的，所述药物组合物中缓冲盐的浓度为7～23mM。
进一步的，所述药物组合物的pH值为6.5～8.5；优选的，所述药物组合物的pH值为7.0～8.4；优选的，所述药物组合物的pH值为7.2～8.2；更优选的，所述药物组合物的pH值为7.2～7.6。
更进一步的，所述药物组合物中还含有pH调节剂和水；所述pH调节剂为盐酸和/或氢氧化钠；所述药物组合物的pH值由所述pH调节剂调节；所述水优选为纯化水和/或注射用水。
进一步的，所述药物组合物不含有抑菌剂。
本发明第二方面提供了一种药物组合物，其包含式I所示的GLP-1和GIP双受体激动剂、稳定剂和缓冲盐，所述稳定剂为丙二醇，所述缓冲盐为磷酸氢二钠十二水合物，所述药物组合物的pH值为7.0～8.4；并且，在所述药物组合物中，所述式I所示的GLP-1和GIP双 受体激动剂的浓度为5～30mg/mL，所述丙二醇的浓度为10～20mg/mL，所述磷酸氢二钠十二水合物的浓度为7～23mM；
所述药物组合物为注射剂。
进一步的，所述药物组合物的pH值为7.2～8.2，所述药物组合物中磷酸氢二钠十二水合物的浓度为10～20mM。
进一步的，所述药物组合物的pH值为7.2～7.6；在所述药物组合物中，所述式I所示的GLP-1和GIP双受体激动剂的浓度为5～25mg/mL，所述丙二醇的浓度为14mg/mL，所述磷酸氢二钠十二水合物的浓度为10mM。
进一步的，所述药物组合物中还包含pH调节剂和水；优选的，所述pH调节剂为盐酸和/或氢氧化钠；优选的，所述水为纯化水和/或注射用水。
本公开第三方面提供了第一方面或第二方面所述的药物组合物的制备方法，其包括如下步骤：将稳定剂、缓冲盐和GLP-1和GIP双受体激动剂配制为溶液，将溶液的pH值调节至目标值，即得。
进一步的，所述制备方法包括如下步骤：将稳定剂和缓冲盐溶解于溶剂中，加入GLP-1和GIP双受体激动剂配制为溶液，并加入pH调节剂使GLP-1和GIP双受体激动剂完全溶解，再利用pH调节剂将溶液的pH值调节至目标值，即得。
本公开第四方面提供了第一方面或第二方面所述的药物组合物在制备用于预防和/或治疗代谢紊乱相关疾病的药物中的用途；优选的，所述代谢紊乱相关疾病为糖尿病、糖尿病并发症、肥胖症或肥胖并发症。
发明的效果
本公开在提供的药物组合物中通过添加稳定剂、缓冲盐等辅料，使作为药物活性成分的GLP-1和GIP双受体激动剂在液体制剂中保持良好的稳定性，同时避免了作为多肽类药物的GLP-1和GIP双受体激动剂之间发生聚合而导致药物失效等质量问题，最终实现药 物组合物的长久保存，在预防、治疗糖尿病或糖尿病并发症，以及肥胖症或肥胖并发症等代谢紊乱相关疾病中表现出重要的应用前景。
本公开利用pH调节剂控制药物组合物的pH值在特定范围内，并且更有利于药物组合物在制备过程中GLP-1和GIP双受体激动剂的完全溶解，并保证了组合物在储存过程中作为药物活性成分的GLP-1和GIP双受体激动剂的稳定性，避免其发生降解。
本公开通过选择特定的稳定剂，极大的提高了GLP-1和GIP双受体激动剂(如式I化合物)的溶解度，同时使其在储存过程中具有完整的结构和生物活性。
本公开通过选择特定的缓冲盐，能够保证药物组合物在储存过程中的pH值稳定，且不影响药物活性成分的质量和稳定性。
本公开提供的药物组合物的制备方法操作简便，生产成本低，有利于规模化生产，为药物制剂的大范围应用提供帮助。
本公开提供的药物组合物可以有效预防和/或治疗糖尿病、糖尿病并发症、肥胖症或肥胖并发症等代谢紊乱相关疾病，且使用方法便捷。
附图说明
图1为多聚体检测方法验证专属性图谱。
图2为式I化合物注射剂多聚体检测图谱。
具体实施方式
<定义>
除非有相反陈述，否则在本公开中所使用的术语具有下述含义。
在本发明的权利要求和/或说明书中，词语“一(a)”或“一(an)”或“一(the)”可以指“一个”，但也可以指“一个或多个”、“至少一个”以及“一个或多于一个”。
如在权利要求和说明书中所使用的，词语“包含”、“具有”、“包括”或“含有”是指包括在内的或开放式的，并不排除额外的、未引述的元件或方法步骤。与此同时，“包含”、“具有”、“包括”或“含有”也可以表示封闭式的，排除额外的、未引述的元件或方法步骤。
在本公开中，术语“约”表示：一个值包括测定该值所使用的装置或方法的误差的标准偏差。
在本公开中，术语“激动剂”是指通过所针对的目标受体类型活化信号传号的物质(配体)。示例性的，以GLP-1受体为目标受体，则激动剂具有GLP-1受体的激活活性，例如 为GLP-1多肽或其类似物。
在本公开中，术语“治疗”是指：在罹患疾病之后，使受试者接触(例如给药)本公开的药物组合物，从而与不接触时相比使该疾病的症状减轻，并不意味着必需完全抑制疾病的症状。罹患疾病是指：身体出现了疾病症状。
在本公开中，术语“预防”是指：在罹患疾病之前，通过使受试者接触(例如给药)本公开的药物组合物，从而与不接触时相比减轻罹患疾病后的症状，并不意味着必需完全抑制患病。
在本公开中，术语“个体”、“患者”或“受试者”包括哺乳动物。哺乳动物包括但不限于，家养动物(例如，牛，羊，猫，狗和马)，灵长类动物(例如，人和非人灵长类动物如猴)，兔，以及啮齿类动物(例如，小鼠和大鼠)。
在本公开中，术语“治疗有效量”指以需要的剂量并持续需要的时间段，有效实现所需治疗结果的量。本公开的化合物或药物组合物的治疗有效量可以根据多种因素如疾病状态、个体的年龄、性别和重量和免疫佐剂或药物组合物在个体中激发所需反应的能力而变动。
在本公开中，术语“药学上可接受的盐”是指由本公开中的化合物与相对无毒的酸或碱制备得到的盐。当本公开中的化合物含有相对偏酸性的官能团(例如羧基或磺酸基)时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与其游离形式接触的方式获得碱加成盐。药学上可接受的碱加成盐的非限制性实例包括但不限于钠盐、钾盐、铵盐、钙盐、镁盐、有机胺盐或类似的盐。当本公开中的化合物含有相对偏碱性的官能团(例如氨基或胍基)时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与其游离形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的非限制性实例包括但不限于无机酸盐(例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸盐、碳酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、亚磷酸盐、硫酸盐、硫酸氢盐等)、有机酸盐(例如乙酸盐、丙酸盐、异丁酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、马来酸盐、富马酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、苯甲酸盐、邻苯二甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、葡糖醛酸等)以及氨基酸盐(例如精氨酸盐等)。药学上可接受的盐的具体形式还可参见Berge et al.,“Pharmaceutical Salts”,Journal of Pharmaceutical Science,1977,66:1-19)。
在本公开中，术语“代谢紊乱”可以是糖尿病、糖尿病并发症、肥胖、肥胖并发症等糖代谢紊乱疾病。由于肥胖、糖尿病与血糖代谢之间的关联是公知的，因此这些病症可 以但并不必须是分开的或相互排斥的。在一些实施方案中，糖尿病或糖尿病并发症包括胰岛素抵抗、葡萄糖耐受不良、空腹血糖升高、前驱糖尿病、I型糖尿病、II型糖尿病、妊娠期糖尿病高血压、血脂异常或其组合。在一些实施方案中，肥胖并发症包括肥胖关联的炎症、肥胖关联的胆囊疾病或肥胖诱发的睡眠呼吸暂停，或可选自以下相关病症：致动脉粥样硬化性血脂异常、血脂紊乱、血压升高、高血压、血栓前状态和促炎状态或其组合。
本公开的药物组合物具有优良的GIPR和GLP-1R的双激动剂活性，能够有效降低血糖、控制二型糖尿病模型小鼠的体重增长，用于预防和/或治疗代谢紊乱疾病，具有良好的临床应用和医药用途。
<GLP-1和GIP双受体激动剂>
在本公开中，GLP-1和GIP双受体激动剂是指以GLP-1受体和GIP受体为目标受体，对GLP-1R和GIPR同时具有激活活性的物质。
在一些具体的实施方案中，本公开所述的GLP-1和GIP双受体激动剂为如式I所示的化合物或其药学上可接受的盐、酯、溶剂合物、光学异构体、互变异构体、同位素标记物或前药：
本公开对药物组合物中药物活性成分的含量不作特别限定，可由所属领域技术人员根据实际需要而确定。
在一些实施方案中，本公开所述的GLP-1和GIP双受体激动剂的浓度为2～36mg/mL；例如2mg/mL、3mg/mL、4mg/mL、5mg/mL、6mg/mL、7mg/mL、8mg/mL、9mg/mL、10mg/mL、11mg/mL、12mg/mL、13mg/mL、14mg/mL、15mg/mL、16mg/mL、17mg/mL、18mg/mL、19mg/mL、20mg/mL、21mg/mL、22mg/mL、23mg/mL、24mg/mL、25mg/mL、26mg/mL、27mg/mL、28mg/mL、29mg/mL、30mg/mL、31mg/mL、32mg/mL、33mg/mL、34mg/mL、35mg/mL、36mg/mL等；优选为5～30mg/mL。
<稳定剂>
在本公开中，稳定剂是指用来稳定溶液中多肽类物质的结构及生物活性的物质。特别是对于多肽类制剂而言，筛选合适的稳定剂是防止液体制剂中的多肽类药物分子发生物理和化学降解的主要手段。选择合适的稳定剂可以通过结合多肽分子的疏水部分、增加溶液的粘稠度以及影响多肽分子折叠状态来提高多肽分子的稳定性。
本公开对于稳定剂的具体种类不作特别限定，可由所属领域技术人员根据实际需要而确定。
在一些实施方案中，本公开所述的稳定剂选自多元醇类。
在一些具体的实施方案中，本公开所述的稳定剂为丙二醇、甘露醇或甘油。
基于处方筛选试验的结果，结合稳定性试验结果，本公开优先选择丙二醇作为稳定剂，其能够有效维持主药的结构和生物活性，同时还能够稳定药物组合物在储存过程中的pH值。
对于上述稳定剂的用量，本公开不作特别限定，可由所属领域技术人员根据实际需要而确定。
在一些实施方案中，本公开所述的稳定剂浓度为10～20mg/mL；例如10mg/mL、11mg/mL、12mg/mL、13mg/mL、14mg/mL、15mg/mL、16mg/mL、17mg/mL、18mg/mL、19mg/mL、20mg/mL等；优选为14mg/mL。
值得一提的是，在多肽类制剂中，氯化钠被认为有维持电解质平衡，稳定多肽结构的作用，其作为稳定剂存在于现有的多种多肽类制剂中。然而，当本公开的发明人在使用氯化钠替代丙二醇时(例如2mL药物组合物中含有40.0mg式I化合物、3.58mg十二水合磷酸氢二钠、16.4mg氯化钠，利用pH调节剂调节pH值至7后用注射用水补足余量)，式I化合物的溶解度仅有0.15mg/mL，远不满足要求。而当使用丙二醇作为稳定剂时(例如1mL药物组合物中含有20.0mg式I化合物、3.58mg十二水合磷酸氢二钠、14mg丙二醇，利用pH调节剂调节pH值至7后用注射用水补足余量)，式I化合物的溶解度可达30mg/mL以上，满足主药溶解度要求。因此，在本公开一些优选的实施方案中，所述药物组合物中不含有氯化钠。
<pH值及pH调节剂>
pH值对于多肽类药物GLP-1和GIP双受体激动剂的稳定性具有较大影响，同时其还影响着药物组合物配置过程中主药的溶解情况，偏酸性的环境不利于本公开提供的GLP-1和GIP双受体激动剂的溶解，而随着pH的升高，在产品储存过程中，纯度降低的越快， 说明偏碱性的条件不利于产品的稳定。
在一些实施方案中，本公开的药物组合物的pH值为为6.5～8.5；例如6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9、8.0、8.1、8.2、8.3、8.4、8.5等；优选为7.0～8.4；更优选为7.2～8.2；进一步优选为7.2～7.6。
合理的pH值范围，不仅保证了本公开的药物组合物在储存过程中的纯度和稳定性，还可以兼顾药物储存期间的pH波动，从而保证了药物组合物从生产到使用整个过程中的稳定。
在一些实施方案中，本公开利用pH调节剂调节药物组合物的pH值。
在一些具体的实施方案中，本公开所述的pH调节剂为盐酸和/或氢氧化钠。盐酸是一种透明无色、并带有刺激臭的发烟的氢氯酸溶液，在药物制剂中，常用作酸化剂。氢氧化钠为熔制的白色干燥颗粒、块、棒或薄片，一般认为在低浓度时无毒，广泛应用于药物制剂中用以调节溶液的pH值。在一些更具体的实施方案中，本公开所述的pH调节剂可以为一定浓度的盐酸和/或一定浓度的氢氧化钠溶液。
本公开对上述pH调节剂的浓度不做限定，本领域的技术人员可以根据实际生产需要进行调整。例如，可以选择较低浓度的pH调节剂，例如浓度低于3M的pH调节剂，也可以选择较高浓度的pH调节剂，例如浓度高于3M的pH调节剂，其均对药物活性成分无不良影响。本公开优选使用0.1M盐酸和/或0.1M氢氧化钠溶液。
<缓冲盐>
在本公开中，缓冲盐是指用来稳定溶液酸碱度的物质。特别是对于多肽类制剂而言，筛选合适的缓冲盐体系是防止液体制剂中的多肽类药物分子发生物理和化学降解的重要手段。选择合适的缓冲盐体系可以通过保持多肽溶液的pH值稳定，影响静电作用来提高多肽的稳定性。
本公开对于缓冲盐的具体种类不作特别限定，可由所属领域技术人员根据实际需要而确定。
在一些实施方案中，本公开所述的缓冲盐选自磷酸氢盐、磷酸氢盐水合物、枸橼酸盐或枸橼酸盐水合物。
在一些具体的实施方案中，本公开所述的缓冲盐为磷酸氢二钠十二水合物或枸橼酸钠二水合物。
在一些优选的实施方案中，本公开所述的缓冲盐为磷酸氢二钠十二水合物。其不仅有助于稳定本公开的药物组合物在储存过程中的pH值，也有助于稳定药物组合物在储存 过程中纯度。
基于处方筛选试验的结果，结合稳定性试验数据，本公开优先选择磷酸氢二钠十二水合物作为缓冲盐，其化学性质稳定，不影响主药的质量和稳定性，维持制剂pH值稳定的作用良好。
对于上述缓冲盐的用量，本公开不作特别限定，可由所属领域技术人员根据实际需要而确定。
在一些实施方案中，本公开所述的缓冲盐浓度为7～23mM；例如7mM、8mM、9mM、10mM、11mM、12mM、13mM、14mM、15mM、16mM、17mM、18mM、19mM、20mM、21mM、22mM、23mM等；优选为7～20mM；更优选为7～15mM。
基于处方筛选试验的结果，综合考虑药物组合物作为注射制剂等在后续临床应用过程中的风险程度，本公开优先选择低浓度缓冲盐，例如10mM浓度。
<抑菌剂>
本公开所述的GLP-1和GIP双受体激动剂是含有40个氨基酸的线性肽，且制剂pH值初定在7.2～8.2之间，极易被微生物降解，一般情况下会考虑在处方中加入抑菌剂(例如苯酚)来提高产品的稳定性。
并且，由于多肽类药物极易被微生物降解，在多肽类降糖药物中添加抑菌剂是本领域的惯用技术手段，例如，市售降糖药产品索马鲁肽(OZEMPIC)中添加了8.25mg苯酚作为抑菌剂；艾塞那肽中添加了2.64mg间甲酚作为抑菌剂，利拉鲁肽(VICTOZA)中添加了16.5mg苯酚作为抑菌剂，利西那肽(ADLYXIN)中添加了8.1mg间甲酚作为抑菌剂。
然而，本公开发明人经过长期的探索研究发现，不添加抑菌剂也可以保证临床用药的安全性，也进一步减少药物组合物在应用过程中的风险因素。
在组合物中不含有抑菌剂的情况下，更有利于控制或降低药物制剂在临床使用中的风险，并在一定程度上降低了药物组合物的生产成本，更有利于药物的大规模生产和应用。
<药物组合物>
本公开的药物组合物包含GLP-1和GIP双受体激动剂、稳定剂和缓冲盐。
在一些实施方案中，本公开所述的药物组合物中还包含pH调节剂和溶剂。
在一些具体的实施方案中，本公开所述的药物组合物由GLP-1和GIP双受体激动剂、稳定剂、缓冲盐、pH调节剂和溶剂组成。
本公开提供的药物组合物在体内表现出对GLP-1R和GIPR的良好激活效果。对于药物 组合物中各成分的说明如前所述。
在一些实施方案中，本公开的药物组合物为液体制剂。
在一些具体的实施方案中，本公开所述的药物组合物为注射剂。
在一些更具体的实施方案中，本公开的药物组合物作为液体制剂所使用的溶剂为水，优选纯化水或注射用水。
本公开还提供了所述药物组合物的制备方法，其包括如下步骤：将稳定剂、缓冲盐和GLP-1和GIP双受体激动剂配制为溶液，将溶液的pH值调节至目标值，即得。
在一些具体地实施方案中，所述药物组合物的制备方法包括如下步骤：将稳定剂和缓冲盐溶解于溶剂中，加入GLP-1和GIP双受体激动剂，并加入pH调节剂使GLP-1和GIP双受体激动剂完全溶解，再利用pH调节剂将溶液的pH值调节至目标值，即得。
在一些更具体的实施方案中，所述药物组合物的制备方法包括如下步骤：将处方量的磷酸氢二钠十二水合物和丙二醇溶解于纯化水或注射用水中，加入处方量的GLP-1和GIP双受体激动剂，并加入氢氧化钠使GLP-1和GIP双受体激动剂完全溶解，再利用盐酸和/或氢氧化钠将溶液的pH值调节至6.5～8.5，使用纯化水或注射用水定容，即得。其中，加入氢氧化钠的目的在于适当升高溶液的pH值，更有利于GLP-1和GIP双受体激动剂的溶解。
在本公开中，施用途经能够以任何适用的方式进行变化或调整，以满足药物的性质、患者和医务人员的便利以及其它相关因素的需求。
<药物组合物的医药用途>
本公开的药物组合物可以用于预防和/或治疗代谢紊乱相关疾病；优选的，所述代谢紊乱相关疾病为糖尿病、糖尿病并发症、肥胖症或肥胖并发症。
本公开的药物组合物可以进一步制备用于预防和/或治疗代谢紊乱相关疾病的药物；优选的，所述代谢紊乱相关疾病为糖尿病、糖尿病并发症、肥胖症或肥胖并发症。
本公开还提供了一种用于预防和/或治疗代谢紊乱相关疾病的方法，其包括向受试者施用预防和/或治疗有效量的根据本公开所述的药物组合物；优选的，所述代谢紊乱相关疾病为糖尿病、糖尿病并发症、肥胖症或肥胖并发症。
实施例
为了使本公开的目的和技术方案更加清楚，以下结合实施例对本公开的实施方案进行详细描述。但是本领域技术人员将会理解，下列实施例仅用于说明本公开，而不应视为限定本公开的范围。
实施例中所使用的试剂或仪器均为可以通过市购获得的常规产品。未注明具体条件者，均按照常规条件或制造商建议的条件进行。
实施例1：处方筛选
结合本品为注射剂的剂型特点，现对处方中缓冲盐的浓度及种类，稳定剂的种类，药液pH值范围进行筛选。处方研究中所使用的式I化合物为申请人自制，其余所用的物料均为市售获得。
(1)稳定剂种类筛选
稳定剂可以通过结合多肽分子的疏水部分、增加溶液粘稠度以及影响多肽分子的折叠状态来提高多肽制剂的稳定性。为筛选合适的稳定剂，分别采用丙二醇、甘露醇、甘油进行制剂制备，并将制备的样品分别置于40℃和2～8℃条件下进行高温和长期的稳定性考察。在不同时间点取样检测性状、pH值和纯度，考察不同稳定剂对药液质量的影响。处方信息见表1，结果见表2。
表1处方信息

注：“NA”表示未添加。
表2稳定剂种类筛选结果
使用稳定剂的样品在2～8℃条件下均比较稳定，放置1个月后，性状、pH值、纯度、 最大单杂均无明显变化。在高温40℃条件下放置10天时，样品的纯度均有所下降，性状及最大单杂均无明显变化；但是，令人意外的发现，稳定剂为丙二醇的处方，在高温加速稳定实验条件下，pH变化小于3％，能够保持pH稳定，说明稳定剂为丙二醇的处方在保持pH稳定性方面，取得了预料不到的技术效果。而稳定剂为甘露醇及甘油的处方样品，在高温加速稳定实验条件下pH值变化较大，pH值下降了0.7-0.8，有明显下降的趋势，故本品稳定剂优选丙二醇。
(2)pH值范围筛选
pH值是多肽类药物制剂的重要质量属性，它直接影响多肽分子的溶解度，稳定性以及多肽分子的聚集情况。本公开以5.0～8.4的pH范围进行考察，重点关注原料药的溶解情况及产品的稳定性。处方信息见表3，结果见表4。
表3处方信息
表4制剂pH范围初步确认结果
结果显示，pH值在5.0～6.0时，原料药的溶解度无法满足本品成药的需求，pH值越高，越有利于原料药的溶解。在目标pH值7.4～8.4范围内，样品在高温和加速条件下，pH值越高纯度下降越多，即偏碱性的条件不利于产品的稳定，但从降解程度来看，目标pH值8.4的条件下，产品纯度的减少依然可接受；其他考察项目(性状、pH值)各样品均无明显变化。
(3)缓冲盐浓度筛选
一般来说，pH值和离子强度对多肽的稳定性及溶解度都有很大的影响，而在保证多肽类药物的溶解度的情况下提高其稳定性和安全性一直是多肽药物制剂需要解决的技术问题，适当的缓冲盐浓度有利于解决这一技术问题。因此，为筛选合适的缓冲盐浓度，分别采用浓度为10mM、15mM、20mM的枸橼酸钠二水合物进行制剂配制，并将制备的样品分别置于40℃和25℃条件下进行高温和长期的相关指标考察。具体处方信息见表5，结果见表6。
表5处方信息
表6缓冲盐浓度筛选结果
结果显示，不同缓冲盐浓度下配制的注射剂样品只有在25℃条件下放置1个月时，10mM缓冲盐浓度处方的纯度略优于15mM和20mM缓冲盐浓度处方的纯度，其他各考察项目无明显差异，10mM～20mM的缓冲盐浓度均能满足要求。但考虑到注射剂中辅料用量越大，将导致制剂临床应用风险越大，故选择最低浓度10mM作为本公开注射剂的缓冲盐浓度，更大程度保证了制剂使用的安全性。
(4)缓冲盐体系筛选
缓冲液体系的选择对提高制剂稳定性也是至关重要的。为筛选合适的缓冲盐，分别采用枸橼酸钠二水合物、磷酸氢二钠十二水合物进行制剂配制，并将制备的样品分别置于40℃和2～8℃条件下进行高温和长期的相关指标考察。具体处方信息见表7，结果见表8。
表7处方信息

注：“NA”表示未添加。
表8缓冲盐体系筛选结果
结果显示，磷酸氢二钠十二水合物和枸橼酸钠均可以作为本公开注射剂的缓冲盐，在高温40℃条件下放置10天时，磷酸盐处方的纯度略优于枸橼酸盐处方的纯度，可以优选磷酸氢二钠十二水合物作为缓冲盐。
(5)pH范围进一步确认
根据pH范围初步确认结果可知，pH值中性条件下有利于产品的稳定，且针对本品皮下注射的给药途径，越接近生理pH刺激性越小，因此，现设计试验利用磷酸氢二钠十二水合物作为缓冲盐围绕pH 7.4进行更窄范围的考察，以进一步确认本品的最佳pH值。处方信息见表9，结果见表10。
表9处方信息
表10制剂pH范围进一步确认结果
结果显示，pH值在7.2～7.6时，样品在高温40℃下放置10天，总杂质和多聚体略有增加，性状、pH值、最大单杂和RRT 1.04均无明显变化；样品在长期条件下1个月，各考察项目均无明显变化；不同pH值样品之间无显著差异。并且，本公开的处方中未添加抑菌剂，仍能将杂质控制在无明显变化范围内，取得了预料不到的技术效果。
在本公开其他实施例中，药物活性成分(Active pharmaceutical ingredient，API)浓度还可以是5mg/mL、10mg/mL、15mg/mL、25mg/mL、30mg/mL，其他辅料浓度不变。可以理解的本领域的技术人员还可以根据患者的具体情况来调整API浓度，都在本公开保护范围之内。
在本公开中，上述处方1-16中的纯化水均可以替换为注射用水，替换后获得的注射用水处方所取得的各实验结果数据与上述纯化水处方的各项实验结果数据没有明显差别。
实施例2：GLP-1和GIP双受体激动剂药物组合物的制备
以处方15为例制备组合物。将71.6mg磷酸氢二钠十二水合物(缓冲盐)及280mg丙二醇(供注射用)(稳定剂)溶解于纯化水中，加入400mg式I化合物，同步加入0.1M氢氧化钠溶液(pH调节剂)并搅拌至原料溶解，用0.1M盐酸或0.1M氢氧化钠溶液调节pH至目标pH值7.4，最后以纯化水定容至20mL。其余处方参照此制备方法。
实施例3：GLP-1和GIP双受体激动剂药物组合物中多聚体杂质检测
1.多聚体检测方法
研究内容：空白溶液和空白辅料对多聚体检测的干扰情况。
预期要求：空白溶液和空白辅料应不干扰多聚体的检测。
试验过程：
(1)空白溶液：溶剂。
(2)空白辅料溶液：取空白辅料，即得。
(3)系统适用性溶液：取式I化合物对照品约10mg，精密称定，置西林瓶中，加5ml溶剂超声溶解。将溶液在60℃条件下放置4小时。
(4)供试品溶液：取GLP-1和GIP双受体激动剂药物组合物(式I化合物注射剂)，即得。
精密量取系统适用性溶液20μL和空白溶液、空白辅料溶液、供试品溶液2μL注入液相色谱仪中，记录色谱图。
试验结果：
空白溶液和空白辅料不干扰多聚体的检测，系统适用性溶液色谱图中，多聚体与式I化合物依次出峰。具体结果见表11与图1。
表11多聚体与本品分离情况表
2.GLP-1和GIP双受体激动剂药物组合物中多聚体杂质检测
式I化合物为化学合成的多肽药物，其制剂在生产和储存过程中可能聚集形成多聚体。通过SEC法对多聚体进行检测。
对处方15进行多聚体检测，考察处方在高温、光照条件下多聚体含量情况，多聚体的限度暂定为2.0％，具体数据见表12及图2。
表12式I化合物注射剂多聚体检测结果
令人惊讶的发现，该处方样品在在拟定的储藏条件(2～8℃)下放置1个月，多聚体含量无变化，2-8℃是本药物处方预计上市后说明书上体现的储藏条件，说明本公开设计的处方，解决了多肽药物容易发生多聚的技术难题，在后期药物上市后，能够保证产品稳定。不仅如此，即使在更苛刻的储藏条件下，在25℃和30℃条件下分别储存30天，多聚体略有增加但含量仍在限度范围内；2～8℃放置时，在总照度不低于1.2×106lux·hr、近紫外灯能量不低于200W·hr/m2的光照下，无包装的样品多聚体含量增加但仍在限度范围内，而有包装的样品多聚体含量无显著变化。
综上所述，本品在合适的储存条件下成分稳定，多聚体含量均在限度范围内。

Claims (15)

  1. 一种药物组合物，其包含GLP-1和GIP双受体激动剂、稳定剂和缓冲盐；所述GLP-1和GIP双受体激动剂为如式I所示的化合物或其药学上可接受的盐、酯、溶剂合物、光学异构体、互变异构体、同位素标记物或前药：
  2. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物为液体制剂；
    优选的，所述药物组合物为注射剂。
  3. 根据权利要求2所述药物组合物，其特征在于，所述GLP-1和GIP双受体激动剂的浓度为2～36mg/mL。
  4. 根据权利要求1～3中任一项所述的药物组合物，其特征在于，所述稳定剂为多元醇类；
    优选的，所述稳定剂为丙二醇、甘露醇或甘油；
    更优选的，所述稳定剂为丙二醇。
  5. 根据权利要求2～4中任一项所述的药物组合物，其特征在于，所述药物组合物中稳定剂的浓度为10～20mg/mL。
  6. 根据权利要求1～5中任一项所述的药物组合物，其特征在于，所述缓冲盐选自磷酸氢盐、磷酸氢盐水合物、枸橼酸盐或枸橼酸盐水合物；
    优选的，所述缓冲盐为磷酸氢二钠十二水合物或枸橼酸钠二水合物；
    更优选的，所述缓冲盐为磷酸氢二钠十二水合物。
  7. 根据权利要求2～6中任一项所述的药物组合物，其特征在于，所述药物组合物中缓冲盐的浓度为7～23mM。
  8. 根据权利要求1～7中任一项所述的药物组合物，其特征在于，所述药物组合物的pH值为6.5～8.5；
    优选的，所述药物组合物的pH值为7.0～8.4；
    更优选的，所述药物组合物的pH值为7.2～8.2；
    进一步优选的，所述药物组合物的pH值为7.2～7.6。
  9. 根据权利要求1～8中任一项所述的药物组合物，其特征在于，所述药物组合物不含有抑菌剂。
  10. 一种药物组合物，其包含式I所示的GLP-1和GIP双受体激动剂、稳定剂和缓冲盐，所述稳定剂为丙二醇，所述缓冲盐为磷酸氢二钠十二水合物，所述药物组合物的pH值为7.0～8.4；并且，在所述药物组合物中，所述式I所示的GLP-1和GIP双受体激动剂的浓度为5～30mg/mL，所述丙二醇的浓度为10～20mg/mL，所述磷酸氢二钠十二水合物的浓度为7～23mM；
    所述药物组合物为注射剂。
  11. 根据权利要求10所述的药物组合物，其特征在于，所述药物组合物的pH值为7.2～8.2，所述药物组合物中磷酸氢二钠十二水合物的浓度为10～20mM。
  12. 根据权利要求10或11所述的药物组合物，其特征在于，所述药物组合物的pH值为7.2～7.6；在所述药物组合物中，所述式I所示的GLP-1和GIP双受体激动剂的浓度为5～25mg/mL，所述丙二醇的浓度为14mg/mL，所述磷酸氢二钠十二水合物的浓度为10mM。
  13. 根据权利要求10～12中任一项所述的药物组合物，其特征在于，所述药物组合物还包含pH调节剂和水；所述pH调节剂为盐酸和/或氢氧化钠。
  14. 根据权利要求1～13中任一项所述的药物组合物的制备方法，其包括如下步骤：将稳定剂、缓冲盐和GLP-1和GIP双受体激动剂配制为溶液，将溶液的pH值调节至目标值，即得。
  15. 根据权利要求1～13中任一项所述的药物组合物在制备用于预防和/或治疗代谢紊乱相关疾病的药物中的用途；
    优选的，所述代谢紊乱相关疾病为糖尿病、糖尿病并发症、肥胖症或肥胖并发症。
PCT/CN2023/120363 2022-09-23 2023-09-21 一种glp-1和gip双受体激动剂药物组合物及其用途 WO2024061310A1 (zh)

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Publication number Priority date Publication date Assignee Title
CN106554403A (zh) * 2015-09-25 2017-04-05 博瑞生物医药（苏州）股份有限公司 艾塞那肽修饰物及其用途
CN107207576A (zh) * 2015-01-09 2017-09-26 伊莱利利公司 Gip和glp‑1共激动剂化合物
CN112312926A (zh) * 2018-06-22 2021-02-02 伊莱利利公司 Gip/glp1激动剂组合物
CN112351994A (zh) * 2019-04-11 2021-02-09 江苏豪森药业集团有限公司 一种多受体激动剂及其医药用途
CN115124602A (zh) * 2021-03-25 2022-09-30 博瑞生物医药（苏州）股份有限公司 Gip和glp-1的双受体激动剂、药物组合物及用途

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CN107207576A (zh) * 2015-01-09 2017-09-26 伊莱利利公司 Gip和glp‑1共激动剂化合物
CN106554403A (zh) * 2015-09-25 2017-04-05 博瑞生物医药（苏州）股份有限公司 艾塞那肽修饰物及其用途
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