Classifications

• • 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
• • 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
  • A61K47/02—Inorganic compounds
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
• • 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
  • A61K9/08—Solutions
• • 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
  • A61P3/04—Anorexiants; Antiobesity agents
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

• the invention relates to the field of pharmaceutical preparations. Specifically, the present invention relates to a stable GLP-1/GIP receptor agonist pharmaceutical composition, preparation method and application thereof.
• Type 2 diabetes Type 2 Diabetes Mellitus, T2DM
• T2DM Type 2 Diabetes Mellitus
• T2DM drug therapy is mainly divided into three categories, oral hypoglycemic agents, GLP-1 receptor agonists (GLP-1RAs) and insulin/insulin analogues.
• Oral hypoglycemic agents mainly include insulin secretagogues (sulfonylureas, non-sulfonylureas), insulin sensitizers (metformin, thiazolidinediones), etc.
• Metformin is the first choice for clinical treatment, which has a strong hypoglycemic effect, less risk of hypoglycemia, and has the advantage of weight loss.
• DPP-4 dipeptidyl peptidase-4
• GLP-1RAs etc.
• metabolic surgery can be performed to alleviate or even reverse diabetes while significantly reducing body weight.
• intestinal hormones change significantly, and metabolic effects such as weight loss and hypoglycemia are achieved through the enhancement of incretin secretion.
• Incretin secretion effect is one of the main reasons for the increase of insulin secretion in healthy people after eating, and the two intestinal hormones that play an important role are GLP-1 and GIP respectively.
• GLP-1 secretion decreases in T2DM patients after eating, but its insulin secretion-stimulating effect after binding to the receptor is similar to that of healthy people.
• GLP-1 in the human body can be rapidly degraded by DPP-4, so its half-life is very short.
• the human endogenous GLP-1 is structurally modified to have a longer half-life in the human body and play a role.
• the research and development of GLP-1RAs drugs has progressed rapidly. In addition to its significant hypoglycemic effect, it also has an obvious advantage in weight loss. Compared with the placebo group, it can also significantly reduce the risk of major cardiovascular events and all-cause mortality.
• dulaglutide and semaglutide are more effective.
• dulaglutide has been launched in China in 2019, and its hypoglycemic and weight loss effects are significantly better than liraglutide.
• semaglutide is better than dulaglutide in hypoglycemic and weight loss effects, and its safety is similar to dulaglutide.
• GLP-1RAs treatment can maintain good hypoglycemic and weight loss effects, but severe gastrointestinal side effects such as nausea and vomiting limit the use of the maximum dose of GLP-1RAs and fail to achieve its potential maximum efficacy Therefore, there is still a big gap in the efficacy of GLP-1RAs for T2DM compared with gastrointestinal metabolic surgery.
• a multi-target drug development strategy based on the mechanism of GLP-1RAs is proposed, and another GIP with incretin effect is an important research target.
• the hypoglycemic effect of GIP is severely impaired, but its insulin secretion-stimulating effect can be quickly restored when the blood glucose concentration returns to normal levels.
• GIP can regulate abnormal fat metabolism, reduce abnormal fat accumulation among various tissues and improve insulin sensitivity, and at the same time, it can cooperate with GLP-1 to reduce food intake in the central nervous system. GIP can also significantly reduce gastrointestinal reactions such as nausea and vomiting caused by the antineoplastic drug cisplatin, and may further improve the curative effect by increasing the tolerance of GLP-1RAs.
• the active ingredient of the present invention is a new generation of GIP/GLP-1 dual-receptor agonist developed by our company.
• the agonistic activity is intended for the treatment of type 2 diabetes (T2DM).
• T2DM type 2 diabetes
• the results of animal pharmacodynamic experiments show that the present invention can significantly reduce random blood sugar in db/db diabetic mice after a single administration, promote insulin secretion, reduce food intake, and have a certain effect of reducing body weight.
• the effect of the composition is better than that of semaglutide.
• the active ingredient in the present invention is a polypeptide, which is a compound formed by connecting multiple amino acids with peptide bonds.
• the results of the destruction test of the raw material drug show that it will be significantly degraded under the conditions of acid, alkali, oxidation and high temperature; the experimental results of the influencing factors of the raw material drug show that the polymer of the raw material drug grows under the conditions of high temperature and light. Due to the particularity of the active ingredient, the stability of the active ingredient is poor. In this case, a stable, high-quality pharmaceutical composition of a GLP-1/GIP receptor agonist capable of industrial production is obtained. , remains a huge challenge for researchers.
• the purpose of the present invention is to provide a stable GIP/GLP-1 double receptor agonist pharmaceutical composition.
• the pharmaceutical composition of the present invention comprises an active ingredient, a buffer, an osmotic pressure regulator and a pH regulator, and the structure of the active ingredient of the present invention is:
• amino acid sequence of the structure is as follows:
• the GIP/GLP-1 dual receptor agonist pharmaceutical composition is an injection, and the concentration of the active ingredient is selected from 0.5 mg/mL to 40 mg/mL, preferably 1 mg/mL to 30 mg/mL, more preferably 1 mg/mL mL, 2mg/mL, 5mg/mL, 10mg/mL, 15mg/mL, 20mg/mL, 25mg/mL, or 30mg/mL.
• the injection contains 0.05%-4.0% (W/V) active ingredient, preferably 0.1%-4.0% (W/V), more preferably 0.1%-3.0% (W/V).
• the unit of W/V is g/mL.
• the buffer is selected from phosphate buffer, acetate buffer, citrate buffer, carbonate buffer, tartrate buffer, Tris buffer, histidine salt, preferably citric acid Salt buffer or phosphate buffer, more preferably disodium hydrogen phosphate.
• the injection contains 0.05%-3.0% (W/V) buffer, preferably 0.05%-2.0% (W/V), more preferably 0.05%-1.0% (W/V).
• the osmotic pressure regulator is selected from one or more of mannitol, lactose, sucrose, propylene glycol, glycerin, preferably propylene glycol or mannitol.
• the injection contains 0.05% to 5.0% (W/V) of an osmotic pressure regulator, preferably 1.0% to 3.0% (W/V), more preferably 1.0% to 2.0% (W/V) .
• W/V osmotic pressure regulator
• the pH regulator is selected from one or more of hydrochloric acid and sodium hydroxide.
• the injection contains 0.1% to 3.0% (W/V) of the active ingredient, 0.05% to 3.0% (W/V) of the buffer, and 0.5% to 5.0% (W/V) of the osmotic Pressure regulator, appropriate amount of pH regulator.
• the injection contains 0.1% to 3.0% (W/V) of the active ingredient, 0.05% to 2.0% (W/V) of the buffer, and 1.0% to 3.0% (W/V) of the osmotic pressure regulator agent, an appropriate amount of pH regulator.
• the injection contains 0.1% to 3.0% (W/V) of active ingredients, 0.05% to 1.0% (W/V) of buffer, 1.0% to 2.0% (W/V) of osmotic pressure adjustment agent, an appropriate amount of pH regulator.
• the injection contains 0.1% to 3.0% (W/V) of active ingredients, 0.05% to 0.1% (W/V) of buffer, 1.0% to 2.0% (W/V) of osmotic pressure regulator agent, an appropriate amount of pH regulator.
• the injection comprises 0.1% to 3.0% (W/V) of active ingredients, 0.05% to 1.0% (W/V) of disodium hydrogen phosphate and/or sodium hydroxide, 1.0% to 2.0% ( W/V) propylene glycol, an appropriate amount of pH regulator.
• the injection also contains a preservative selected from the group consisting of m-cresol, phenol, benzyl alcohol, phenethyl alcohol, paraben, paraben, benzyl alcohol, chloroprene Alcohol, phenoxyethanol, methylparaben, etc., preferably m-cresol, phenol or chlorobutanol.
• a preservative selected from the group consisting of m-cresol, phenol, benzyl alcohol, phenethyl alcohol, paraben, paraben, benzyl alcohol, chloroprene Alcohol, phenoxyethanol, methylparaben, etc., preferably m-cresol, phenol or chlorobutanol.
• the injection contains 0.01% to 3% (W/V) of preservatives, preferably 0.05% to 1.5% (W/V) of preservatives, more preferably 0.1% to 1% ( W/V) of preservatives, more preferably 0.1% to 0.5% (W/V) of preservatives.
• the injection comprises 0.1% to 3.0% (W/V) of active ingredients, 0.05% to 1.0% (W/V) of disodium hydrogen phosphate and/or sodium hydroxide, 1.0% to 2.0% ( W/V) propylene glycol, 0.05% to 1.5% (W/V) preservative, and an appropriate amount of pH regulator.
• the injection comprises 0.1% to 3.0% (W/V) of active ingredients, 0.05% to 1.0% (W/V) of disodium hydrogen phosphate and/or sodium hydroxide, 1.0% to 2.0% ( W/V) of propylene glycol, 0.1% to 1% (W/V) of preservatives, and an appropriate amount of pH regulator.
• the injection comprises 0.1% to 3.0% (W/V) of active ingredients, 0.05% to 1.0% (W/V) of disodium hydrogen phosphate and/or sodium hydroxide, 1.0% to 2.0% ( W/V) of propylene glycol, 0.1% to 0.5% (W/V) of preservatives, and an appropriate amount of pH regulator.
• the weight ratio of the active ingredient to the buffer is 1:0.01-10, preferably 1:0.02-1, more preferably 1:0.02-0.5.
• the weight ratio of the active ingredient to the osmotic pressure regulator is 1:0.1-20, preferably 1:0.4-10.
• the total ratio of disodium hydrogen phosphate to sodium hydroxide in the buffer solution is 1:0-3.0, preferably 1:0.10-2.5, more preferably 1:0.13-1.5, further preferably 1:0.13-1.2.
• the weight ratio of the buffer solution to the osmotic pressure regulator is 1:5-80, preferably 1:5-60, more preferably 1:15-40, further preferably 1:15-25.
• the pH in the pharmaceutical composition ranges from 6.5 to 9.0, preferably from 7.0 to 8.5, more preferably from 7.0 to 8.0.
• the dosage volume of the pharmaceutical composition is 0.5ml-1ml.
• Another object of the present invention is to provide a method for preparing the pharmaceutical composition. Dissolve the buffer solution and the osmotic pressure regulator in water for injection, dissolve the active ingredient into the above-mentioned medicinal solution, stir to dissolve, add the pH regulator, constant volume, Filter and pack.
• the water for injection is cooled to ⁇ 25°C.
• the prepared pharmaceutical composition is sterile filtered, subpackaged and packaged.
• the filling process is completed under nitrogen protection.
• the pharmaceutical composition is subpackaged in prefilled syringes.
• the pharmaceutical composition is packaged in cartridges.
• the pharmaceutical composition is packaged in vials.
• Another object of the present invention is to provide a pharmaceutical composition used in the preparation of drugs for the treatment of non-insulin-dependent diabetes, insulin-dependent diabetes, obesity, insulin resistance or dyslipidemia, preferably, the non-insulin-dependent Insulin dependent diabetes is type 2 diabetes.
• the pharmaceutical composition of the present invention can be used simultaneously, separately or sequentially in combination with one or more agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase inhibitors and sodium glucose transporter .
• Drugs are different from other chemical products. Even a very small amount of impurity components may bring risks to the safety, effectiveness, and quality controllability of clinical drugs.
• the present invention controls the components and the ratio of each component in the prescription, without adding other auxiliary materials, can obtain a pharmaceutical composition with good stability, effectively controls the content of related substances, significantly reduces the content of specific impurities, and greatly reduces The toxicity of the drug is reduced, and the content of specific impurities increases slowly after the drug is placed for a long time, which improves the safety of the drug. Further, the stability of the preparation is improved by filling with nitrogen protection.
• Element Dosage active ingredient 0.2g, 1.0g, 2.0g, 3.0g, 4.0g Disodium hydrogen phosphate 1 0.071g Propylene Glycol 1.5g NaOH 2 0.01g sodium hydroxide Appropriate amount hydrochloric acid Appropriate amount Water for Injection Add to 100ml
• Need testing product the injection (active component 2.0g) that embodiment 1 prepares;
• test product Add different volumes (0.5-0.1mL) of the test product and different volumes (2.0-2.4mL) of sodium chloride injection into glass test tubes with 2.5mL 2% rabbit erythrocyte suspension, and simultaneously Sodium chloride injection and sterilized water for injection were used as negative control substance and positive control substance respectively.
• the total volume of each test tube was 5.0mL, and they were incubated in an electric thermostat (set temperature at 37°C) for 3 hours, and the erythrocytes were observed. dissolution and aggregation.
• red blood cells can be seen to settle at the bottom of the tube, and the upper layer solution is colorless and clear.
• the red blood cells at the bottom of the tube are evenly dispersed without hemolysis or aggregation; positive control of sterile water for injection It can be seen that some red blood cells have settled at the bottom of the tube, and the upper layer solution is clear red. After shaking, the red blood cells at the bottom of the tube are evenly dispersed, and some hemolysis occurs without aggregation.
• the pharmaceutical composition injection of the present invention with a marked concentration of 20 mg/mL has no hemolysis of rabbit erythrocytes in the test system of 0.1-0.5 mL, and does not cause erythrocyte aggregation.
• Test example 2 subcutaneous irritation research
• Need testing product the injection (active component 2.0g) that embodiment 1 prepares;
• the test selects New Zealand rabbits, adopts the self-control method of the left and right sides of the same body, and gives New Zealand rabbits a total of 4 subcutaneous injections to give New Zealand rabbits. During the test period, no pharmaceutical composition injection of the present invention was found in local observations of all animals administered. related exception.
• Test Example 3 Research on the therapeutic effect of the pharmaceutical composition of the application after a single subcutaneous injection of type 2 diabetes db/db mice
• Need testing product the injection (active component 2.0g) that embodiment 1 prepares;
• the maintenance time of the hypoglycemic effect of the pharmaceutical composition after a single subcutaneous injection is related to the dose, the random blood glucose reducing effect of 1nmol/kg can be maintained for 1 day, and the effect of 3nmol/kg and 10nmol/kg can be maintained for 2-3 days.
• Mouse Insulin ELISA Kit was used to measure serum insulin levels in db/db mice in each group 2 hours after administration. The results showed that after a single subcutaneous injection of 1, 3, and 10nmol/kg of the pharmaceutical composition in db/db mice, compared with the vehicle group, the serum insulin levels of mice in each dose group were significantly increased, and showed a good There is a dose-effect relationship; at the same time, the increase of serum insulin is also positively correlated with the decrease of blood sugar.
• Serum insulin between groups was analyzed using Fisher's LSD test in One-way ANOVA. Compared with vehicle group, *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001
• Test Example 4 Research on the therapeutic effect of type 2 diabetes db/db mice after long-term subcutaneous injection of the pharmaceutical composition of the application
• Need testing product the injection (active component 2.0g) that embodiment 1 prepares;
• Type 2 diabetes db/db mice were administered continuously for 9 times every 3 days. After the test (d26), the liver weights of db/db mice in 1, 3, and 10nmol/kg groups were 2.313 ⁇ 0.113g, 2.267 ⁇ 0.108g and 1.993 ⁇ 0.104g, both were significantly lower compared with the Vehicle group (p ⁇ 0.05, p ⁇ 0.05, p ⁇ 0.001); the pancreas weight had no statistical difference compared with the Vehicle group (p>0.05).
• the pharmaceutical composition can be dose-dependently reduced body weight and liver weight in type 2 diabetic db/db mice once every 3 days for a long period of time; The blood sugar effect is more obvious.
• Test Example 5 Pharmacokinetic study of a single subcutaneous or intravenous injection of the pharmaceutical composition of the application in cynomolgus monkeys
• Intravenous group subcutaneous injection low-dose, middle-dose and high-dose group 4 groups, the doses of each group were 0.1, 0.03, 0.1, 0.3 mg/kg, all were single administration.
• the elimination half-life t1/2 of the drug of the present invention in cynomolgus monkeys is between 50.7 ⁇ 51.5h, and the elimination is slow; the clearance rate CL is between 0.89 ⁇ 0.93mL/h/kg, which is low clearance; table The apparent volume of distribution Vd is between 66.0-68.1mL/kg, mainly distributed in plasma; after a single subcutaneous injection, the plasma concentration peak time Tmax of the drug of the present invention in cynomolgus monkeys is 13.3-18.0h; The elimination half-life T1/2 is between 48.9 and 65.4h, and the elimination is slow; the exposure (AUClast) of the drug of the present invention in animals of different sexes has no statistical difference (P>0.05). Within the dose range of 0.02-0.2 mg/kg, the exposure (AUC last ) of the pharmaceutical composition in animal plasma increases with the increase of the dose, and the increase ratio of the exposure is close to the increase ratio of the dose.

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• 2023
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