WO2024008059A1 - Composition pour administration orale de médicaments polypeptidiques - Google Patents

Composition pour administration orale de médicaments polypeptidiques Download PDF

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WO2024008059A1
WO2024008059A1 PCT/CN2023/105660 CN2023105660W WO2024008059A1 WO 2024008059 A1 WO2024008059 A1 WO 2024008059A1 CN 2023105660 W CN2023105660 W CN 2023105660W WO 2024008059 A1 WO2024008059 A1 WO 2024008059A1
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type
glp
particles
snac
solid composition
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PCT/CN2023/105660
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English (en)
Chinese (zh)
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曹海燕
林兆生
曹丙洲
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北京惠之衡生物科技有限公司
惠升生物制药股份有限公司
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Publication of WO2024008059A1 publication Critical patent/WO2024008059A1/fr

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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to the technical field of polypeptides and their oral delivery, and in particular to a polypeptide drug oral delivery composition, particularly a composition suitable for GLP-1 receptor agonists and GLP-1 receptor-related multi-target co-agonists. Pharmaceutical compositions are delivered orally.
  • Diabetes In modern social life, diabetes and its complications have gradually become another chronic non-communicable disease with serious harm after cardiovascular and cerebrovascular diseases and cancer. Diabetes is mainly divided into type 1 diabetes, type 2 diabetes and other special types of diabetes. The inability of the insulin secreted by patients to effectively function is the cause of type 2 diabetes, and type 2 diabetes accounts for the highest proportion of the disease, reaching more than 90%.
  • the drugs used clinically to treat type II diabetes mainly include biguanides, sulfonylureas, thiazolidinediones, DPP-4 receptor inhibitors, SGLT-2 receptor inhibitors and long-acting glucagon-like drugs.
  • Peptide-1 derivatives (GLP-1 derivatives).
  • GLP-1 derivatives are gradually becoming the main treatment drugs and research hotspots for type II diabetes because they have similar hypoglycemic effects as insulin, and at the same time almost no risk of hypoglycemia, as well as weight loss effects and cardiovascular protective functions. .
  • Semaglutide is a long-acting GLP-1 derivative developed by Novo Nordisk. The drug only requires once-weekly subcutaneous injection and has been approved for marketing in many countries. From a structural point of view, semaglutide connects Lys at position 26 on the GLP-1 (7-37) chain to AEEA, glutamic acid and octadecane fatty acid side chains, and uses amino acid at position 8.
  • the unnatural amino acid aminoisobutyric acid (Aib) replaces the original Ala, and Lys at position 34 is replaced by Arg.
  • Semaglutide Compared with liraglutide, semaglutide has longer aliphatic chains and increased hydrophobicity, but Semaglutide has been modified with short-chain AEEA, which greatly enhances its hydrophilicity. After modification, AEEA can not only bind tightly to albumin, mask the hydrolysis site of DPP-4 enzyme, but also reduce renal excretion, extend biological half-life, and achieve long circulation. Semaglutide has been proven in multiple clinical trials that combined with different oral hypoglycemic drugs can effectively control blood sugar and enable patients to lose weight, reduce systolic blood pressure and improve pancreatic beta cell function.
  • semaglutide replaces Ala at position 8 with Aib on the GLP-1 (7-37) chain, Lys at position 34 with Arg, and Lys at position 26 is connected to an octadecanoic acid fatty chain. , that is, there is a longer fatty chain in the structure of semaglutide, which increases the hydrophobicity and makes it difficult to ensure the dissolution behavior of oral administration.
  • CN201611150925 For sulfonylureas, biguanides or thiazolidinediones hypoglycemic drugs, the active ingredients of the drug are wrapped into sustained-release carrier materials to prepare sustained-release microspheres, which are then mixed with pharmaceutically acceptable excipients and pressed into a certain shape. tablets for oral use, providing long-acting sustained release.
  • the disadvantage is that semaglutide is easily decomposed prematurely during subsequent administration, and its stability is difficult to guarantee, which can easily lead to waste of semaglutide.
  • Semaglutide has low oral bioavailability and can only be detected in minimal or even undetectable amounts in the blood after oral administration. Therefore, an optimized pharmaceutical composition for oral administration is needed to make semaglutide Lutide has excellent oral bioavailability.
  • the present invention provides a polypeptide drug oral delivery composition.
  • the oral delivery composition provided by the present invention has excellent oral bioavailability and broad application prospects.
  • GLP-1 receptor agonist can be defined as a GLP-1 receptor agonist that binds to the receptor and induces Compounds that respond typically to natural ligands.
  • a full agonist may be defined as an agonist that elicits a response of the same magnitude as the native ligand (see, e.g., "Principles of Biochemistry", AL Lehninger, DL Nelson, MMCox, 2nd ed., Worth Publishers, 1993, p. 763 Page).
  • a "GLP-1 receptor agonist” may be defined as a compound capable of binding to the GLP-1 receptor and capable of activating it.
  • SNAC refers to sodium N-[8-(2-hydroxybenzoyl)amino]caprylate, which is a low-toxicity oral penetration enhancer .
  • the term "semaglutide” refers to N- ⁇ 26 -[2-(2- ⁇ 2-[2-(2- ⁇ 2-[(S)-4-carboxy-4-(17 -Carboxyheptadecanoylamino)butyrylamino]ethoxy ⁇ ethoxy)acetylamino]ethoxy ⁇ ethoxy)acetyl][Aib 8 Arg 34 ]GLP-1 (7-37).
  • the term "derivative" related to a peptide means a peptide or its analogue that has been chemically modified (such as covalent modification, etc.). Typical modifications are amides, sugars, alkyl groups, acyl groups, esters, etc.
  • GLP-1(7-37) derivatives are N- ⁇ 26 -((4S)-4-(hexadecanoyl amino)-carboxy-butyryl)[Arg 34 Lys 26 ]GLP-1-(7 -37).
  • excipient broadly refers to any component other than the active therapeutic ingredient (also known in the art as a drug substance or active pharmaceutical ingredient). Excipients may be inert substances in the sense that they do not essentially have any therapeutic and/or prophylactic effect per se.
  • Excipients can serve many different purposes, for example, as enhancers, absorption enhancers, vehicles, fillers (also known as diluents), binders, lubricants, glidants, disintegrants, crystallization retarders Agents, acidifiers, alkalizers, preservatives, antioxidants, buffers, chelating agents, complexing agents, surfactants, emulsifiers and/or solubilizers, sweeteners, wetting agents, stabilizers, colorants , flavoring agents, and/or improve administration and/or absorption of active substances.
  • lubricant refers to stearic acid, magnesium stearate, calcium stearate or other stearate metal salts, talc, wax, glyceryl esters, light mineral oil, glyceryl behenate , hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycol, alkyl sulfate or sodium benzoate.
  • lactose for example, spray-dried lactose, ⁇ - Lactose, beta-lactose, various grades
  • microcrystalline cellulose variants
  • other cellulose derivatives sucrose, sorbitol, mannitol, dex
  • Methocel A Methocel A4C, Methocel A15C, Methocel A4M
  • hydroxyethylcellulose ethylcellulose, sodium carboxymethylcellulose, other cellulose derivatives, sucrose, dextrin, maltodextrin, starch or modified starch (including potato starch, corn starch and rice starch), calcium lactate, calcium carbonate, gum arabic, sodium alginate, agar, carrageenan, gelatin, guar gum, pectin, PEG or povidone.
  • bioavailability refers to the proportion of the administered dose of the raw material drug (such as GLP-1 peptide or its derivative) that reaches the systemic circulation and remains unchanged.
  • the raw material drug such as GLP-1 peptide or its derivative
  • bioavailability is 100%.
  • the drug substance is administered by other routes (e.g., orally)
  • its bioavailability is reduced (due to degradation and/or incomplete absorption and first-pass metabolism).
  • Knowledge of bioavailability is important when calculating doses for non-intravenous routes of administration of drug substances.
  • Plasma concentration versus time was plotted after oral and intravenous administration. Absolute bioavailability is (AUC - oral divided by dose) divided by (AUC - intravenous divided by dose).
  • the present invention provides a solid composition for oral administration of a GLP-1 receptor agonist.
  • the components of the solid composition include first type particles and second type particles.
  • the The composition also includes the above-mentioned pharmaceutically acceptable excipients added outside the granules.
  • the excipients are preferably magnesium stearate, wherein the granules can be:
  • the first type of granules contains 280-300 mg of SNAC and 5-20% of GLP-1 receptor Body agonist
  • the second type of particles contains 80-95% GLP-1 receptor agonist and 5-20 mg SNAC
  • the total amount of the GLP-1 receptor agonist is 2-25 mg, preferably 2 -20mg, 3-20mg, 3-15mg, 2mg, 3mg, 5mg, 7mg, 9mg, 12mg, 14mg, 15mg, 20mg.
  • the GLP-1 receptor agonist in the first type of particles accounts for 5-20%, 5-15% or 10-15% of the total amount of polypeptide; the GLP-1 receptor agonist in the second type of particles The agent accounts for 80-95%, 85-95% or 85-90% of the total amount.
  • the GLP-1 receptor agonist in the first type of particles accounts for 5-15% of the total amount of the polypeptide, and the GLP-1 receptor agonist in the second type of particles accounts for 85-95% of the total amount; or
  • the GLP-1 receptor agonist in the first type of particles accounts for 10-15% of the total amount of the polypeptide, and the GLP-1 receptor agonist in the second type of particles accounts for 85-90% of the total amount.
  • the content of SNAC in the first type of particles is 290 mg or 300 mg; the content of SNAC in the second type of particles is 10 mg or 20 mg.
  • the content of SNAC in the first type of particles is 290 mg; the content of SNAC in the second type of particles is 10 mg.
  • the content of SNAC in the first type of particles is 300 mg; the content of SNAC in the second type of particles is 20 mg.
  • the content of SNAC in the first type of granules is 290 mg, and the content of GLP-1 agonist is 0.5 mg; the content of SNAC in the second type of granules is 10 mg, and the content of GLP-1 agonist is 2.5 mg.
  • the content of SNAC in the first type of particles is 290 mg and the content of GLP-1 agonist is 1 mg; the content of SNAC in the second type of particles is 10 mg and the content of GLP-1 agonist is 6 mg.
  • the content of SNAC in the first type of granules is 290 mg and the content of GLP-1 agonist is 2 mg; the content of SNAC in the second type of granules is 10 mg and the content of GLP-1 agonist is 12 mg.
  • the first type of particles further comprises a lubricant, such as magnesium stearate; and/or a filler, such as microcrystalline cellulose.
  • the second type of particles further comprises fillers, such as microcrystalline cellulose; and/or binders, such as povidone.
  • the composition also contains magnesium stearate added outside the particles.
  • the first type of particles further comprises magnesium stearate and microcrystalline cellulose; the second type of particles further comprises microcrystalline cellulose and povidone.
  • the microcrystalline cellulose is microcrystalline cellulose PH101, and the povidone is povidone K90.
  • the content of microcrystalline cellulose PH101 in the first type of particles is 20-60 mg, The content of magnesium stearate is 5-10 mg; the content of microcrystalline cellulose PH101 in the second type of particles is 5-30 mg, and the content of povidone K90 is 5-10 mg; the outer surface of the particles is hard
  • the amount of magnesium fatty acid is 1-5mg.
  • the content of microcrystalline cellulose PH101 in the first type of particles is 57 mg, and the content of magnesium stearate is 7.7 mg; the content of microcrystalline cellulose PH101 in the second type of particles is 23 mg,
  • the content of povidone K90 is 8 mg; the amount of extragranular magnesium stearate is 2 mg.
  • the content of microcrystalline cellulose PH101 in the first type of particles is 37 mg, and the content of magnesium stearate is 7.7 mg; the content of microcrystalline cellulose PH101 in the second type of particles is 13mg, the povidone K90 content is 8mg; the extragranular magnesium stearate content is 2mg.
  • the present invention provides a method for preparing the solid composition for oral administration according to the first aspect, the preparation method comprising:
  • the step (1) is: magnesium stearate and SNAC are mixed using an equal amount increasing method to obtain a first mixture; semaglutide is mixed with microcrystalline cellulose and then sieved, and equal volumes with microcrystalline cellulose After mixing the first mixture, the mixture is mixed with the remaining amount of the first mixture and granulated to obtain the first type of granules.
  • the step (2) is: semaglutide and povidone are sieved respectively, and then semaglutide, povidone, SNAC and microcrystalline cellulose are mixed, tableted, pulverized, and sieved, The second type of particles is obtained.
  • the step (3) is: mixing the granules obtained in steps (1) and (2) and then mixing them with magnesium stearate and compressing them into tablets to obtain the solid composition for oral administration.
  • the oral delivery pharmaceutical composition of the present invention can more effectively deliver GLP-1 derivatives or GLP-1 related multi-target agonists, has excellent oral bioavailability, and is suitable for The future is bright.
  • Preparation of granules 1 Weigh the materials according to the prescription, mix magnesium stearate and an equal volume of SNAC in the weighing ship for 60 seconds, then take an equal volume of SNAC and mix it in the weighing ship for 60 seconds, and mix the mixture with the remaining SNAC for 6 minutes; take it out and mix it with microcrystalline fiber equal volumes of mixture of cellulose and microcrystalline cellulose Mix on the weighing boat for 60 seconds, mix the above mixture with the remaining mixture of SNAC and magnesium stearate for 3 minutes, and then control the dry granulator for granulation.
  • the parameters of the dry granulator are shown in Table 2:
  • Preparation of granule 2 Pass semaglutide through a 80-mesh sieve and weigh it; pass povidone through a 50-mesh sieve and weigh it; mix semaglutide, microcrystalline cellulose and povidone in a weighing boat for 3 minutes and pass through a 50-mesh sieve. Sieve twice, mix for 4 minutes, use a tablet press to compress tablets with granule 2, crush with a mortar, and pass through a 24-mesh sieve.
  • Total mixing and tableting Weigh Granule 1, Granule 2 and magnesium stearate according to the prescription conversion; after mixing Granule 1 and Granule 2 for 5 minutes, mix the mixture with magnesium stearate for 2 minutes; prepare the mixture into tablets.
  • Preparation of granule 2 pass semaglutide through an 80-mesh sieve and weigh it; pass povidone through a 50-mesh sieve and weigh it; mix semaglutide, microcrystalline cellulose, povidone, and SNAC in a weighing boat for 3 minutes. Pass through a 50 mesh sieve twice and mix for 4 minutes; use a tablet press to press granule 2 tablets, crush with a mortar, and pass through a 24 mesh sieve.
  • This embodiment provides a method for preparing polypeptide oral tablets.
  • the GLP-1 receptor agonist used is HS-G3, which is a GLP-1 analogue constructed earlier in our laboratory. Its structure is: N- ⁇ 34 -[2-(2-[2- (2-[2-(2-[4-(17-Carboxyheptadecanoyl)-4(S)-carboxybutyrylamino]ethoxy)ethoxy]acetamido)ethoxy]ethoxy [Ile 8 Glu 22 Arg 26 Lys 34 Arg 35 Gly 36 ] GLP-1 (7-37), see CN202210113945.9 for details.
  • Example 3 Referring to the same method as in Example 3, conduct a bioavailability experiment on the formulation 3 prepared in Example 4, and use the formulation 1 as a control.
  • the bioavailability of the polypeptide oral tablet of prescription 3 provided by the present invention was significantly higher than the bioavailability of prescription 1 for 7 days, and even reached nearly three times that of prescription 1 at one time.
  • the oral delivery pharmaceutical composition disclosed in the present invention can more effectively deliver GLP-1 derivatives or GLP-1 related multi-target agonists orally, has excellent oral bioavailability, and has broad application prospects.

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Abstract

La présente invention concerne une composition pharmaceutique pour l'administration orale de médicaments polypeptidiques. La composition pharmaceutique comprend une première particule et une seconde particule. La première particule comprend 280 à 300 mg de SNAC et 5 à 20 % d'un agoniste du récepteur GLP-1, et la seconde particule comprend 5 à 20 mg de SNAC et 80 à 95 % de l'agoniste du récepteur GLP-1. La composition pharmaceutique pour administration orale selon la présente invention peut administrer de manière plus efficace des dérivés de GLP-1 ou des agonistes multi-cibles associés au GLP-1 par voie orale et présente une excellente biodisponibilité orale et de vastes perspectives d'application.
PCT/CN2023/105660 2022-07-04 2023-07-04 Composition pour administration orale de médicaments polypeptidiques WO2024008059A1 (fr)

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CN114984191B (zh) * 2022-07-04 2022-10-25 北京惠之衡生物科技有限公司 一种多肽类药物口服递送组合物

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CN111494323A (zh) * 2012-03-22 2020-08-07 诺和诺德股份有限公司 包含递送剂的组合物及其制备
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