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WO2024138829A1 - Nanoparticules de composé et procédé de préparation à grande échelle associé - Google Patents

Nanoparticules de composé et procédé de préparation à grande échelle associé Download PDF

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Publication number
WO2024138829A1
WO2024138829A1 PCT/CN2023/074737 CN2023074737W WO2024138829A1 WO 2024138829 A1 WO2024138829 A1 WO 2024138829A1 CN 2023074737 W CN2023074737 W CN 2023074737W WO 2024138829 A1 WO2024138829 A1 WO 2024138829A1
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WO
WIPO (PCT)
Prior art keywords
polylactic acid
preparation
albumin
serum albumin
human serum
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/074737
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English (en)
Chinese (zh)
Inventor
沈松
黄晓仪
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GBA National Institute for Nanotechnology Innovation
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GBA National Institute for Nanotechnology Innovation
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Publication date
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Publication of WO2024138829A1 publication Critical patent/WO2024138829A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating

Definitions

  • the present invention relates to the field of medical technology, and in particular to human serum albumin/polylactic acid composite nanoparticles and a large-scale preparation method thereof.
  • a Chinese invention patent (CN 114516921 A) has been applied for.
  • the development of production processes for this technology platform is particularly important.
  • the laboratory ultrasonic emulsification-solvent evaporation method can achieve the simple preparation of single/bi/multi-specific nano antibodies, its preparation process has certain defects, such as poor repeatability, poor emulsification effect, poor particle uniformity, and the inability to achieve large-scale preparation.
  • the first aspect of the present invention provides a process for preparing human serum albumin/polylactic acid complex nanoparticles.
  • the second object of the present invention is to provide serum albumin/polylactic acid complex nanoparticles obtained by the above preparation method.
  • the third object of the present invention is to provide the use of the prepared complex nanoparticles in the preparation of specific antibody drugs.
  • the present invention optimizes the preparation process, especially controls the dosage ratio of human serum albumin/polylactic acid and the volume ratio during preparation, so as to obtain human serum albumin/polylactic acid composite nanoparticles with small and uniform particle size, high protein loading capacity and stability, and solves the problems of poor repeatability, poor emulsification effect, poor particle uniformity, and inability to achieve large-scale preparation in laboratory ultrasonic preparation methods.
  • FIG1 is a graph showing the effects of different protein to polylactic acid mass ratios, oil-water volume ratios, and albumin concentrations on the protein assembly rate and protein loading of human serum albumin/polylactic acid complex nanoparticles investigated in Examples 7-9.
  • FIG. 2 is a graph showing the effects of different protein concentrations, protein to polylactic acid mass ratios, and oil-water volume ratios on the particle size and distribution of human serum albumin/polylactic acid complex nanoparticles investigated in Examples 7-9.
  • FIG3 is a graph showing the effects of the rotation speeds of batch and pipeline online dispersers on the protein assembly rate and protein loading of human serum albumin/polylactic acid complex nanoparticles after homogenization.
  • FIG4 is a graph showing the effect of the rotation speed of batch and pipeline online dispersers on the particle size and distribution of human serum albumin/polylactic acid composite nanoparticles after homogenization.
  • FIG5 is a graph showing the effects of microfluidic high-pressure homogenization pressure and homogenization cycle number on the protein assembly rate and protein loading capacity of human serum albumin/polylactic acid complex nanoparticles.
  • FIG6 is a graph showing the effect of microfluidic high-pressure homogenization pressure and homogenization cycle number on the particle size and distribution of human serum albumin/polylactic acid composite nanoparticles.
  • FIG. 7 shows the particle size distribution and electron microscope image of the microparticles and nanoparticles prepared in Example 2.
  • the linear speed of the pipeline-type online disperser for mixing is 5m/s-40m/s, preferably 10m/s-40m/s, further preferably 20m/s-40m/s, and more preferably 20m/s-30m/s.
  • the homogenization pressure of the microfluidic high-pressure homogenization is 6000-25000 psi, preferably 10000-22000 psi, further preferably 10000-18000 psi, and more preferably 10000-15000 psi.
  • the microfluidic high-pressure homogenization is performed 1-9 times, preferably 3-7 times.
  • HSA Human serum albumin
  • Example 4 Take sample A in Example 4, perform Kjeldahl nitrogen determination to determine the protein content in the particles as M1, and take a corresponding amount of sample for freeze drying, weigh and obtain the total mass of the particles as M2, then the protein loading in the particles is
  • the albumin loading results of nanoparticles prepared by assembling polylactic acid with different molecular weights and structures and human serum albumin are shown in Table 1.
  • Example 8 Effect of human serum albumin and polylactic acid concentration on nanoparticle performance
  • Example 9 Effect of batch disperser speed on colostrum particle size
  • the homogenized emulsion was immediately transferred to a parallel evaporator, and the vacuum degree was maintained at 400, 300, 200, 100, 50, 30, 20, 10 mbar at room temperature for 5 minutes in sequence to fully remove chloroform and obtain a human serum albumin/polylactic acid complex nanoparticle solution. Purification was performed according to the tangential flow ultrafiltration method in Example 4.
  • the uniformly mixed colostrum was obtained, it was immediately transferred to a NanoGenizer 30K microfluidizer for high-pressure homogenization, the homogenization pressure was set to 10000 psi, and the number of homogenization cycles was 1-9 times; after the homogenization was completed, the homogenized emulsion was immediately transferred to a parallel evaporator, and the vacuum degree was kept at 400, 300, 200, 100, 50, 30, 20, 10 mbar for 5 minutes at room temperature to fully remove chloroform and obtain a human serum albumin/polylactic acid complex nanoparticle solution. Purification was carried out according to the tangential flow ultrafiltration method in Example 4. The protein encapsulation efficiency LE and protein loading LC were measured by the methods in Examples 3 and 5, respectively.
  • human serum albumin/polylactic acid complex microparticles and human serum albumin/polylactic acid complex nanoparticles were prepared. After the particles were purified according to the method of Example 4, the concentration of the microparticles and nanoparticles was diluted to 0.1 mg/ml HSA, 10 ⁇ L was added dropwise to a silicon wafer, and the microparticles were naturally dried at room temperature and observed under a scanning electron microscope.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Nanotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Dispersion Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un procédé de préparation à grande échelle de nanoparticules de composé. Les nanoparticules de composé sont préparées à partir d'albumine sérique humaine et d'acide polylactique au moyen d'un procédé d'émulsion-évaporation de solvant. La méthode de préparation consiste en : (1) le cisaillement et le mélange à grande vitesse ; (2) l'homogénéisation à haute pression ; (3) l'élimination d'un solvant organique sous pression réduite ; (4) la purification par écoulement tangentiel ; et (5) la filtration sur membrane et la stérilisation. Le rapport en masse de l'albumine sérique humaine à l'acide polylactique est (1-12):1. L'acide polylactique est choisi parmi l'acide poly-L-lactique à terminaison ester, l'acide poly-L-lactique à terminaison carboxyle et l'acide poly-D, L-lactique à terminaison ester. La taille de particule des nanoparticules de composé obtenues au moyen du procédé de préparation est inférieure à 130 nm et présente une bonne uniformité, de sorte que les nanoparticules de composé présentent une capacité de charge de protéine et une stabilité relativement élevées, ce qui permet de résoudre les problèmes que peuvent présenter un procédé de préparation ultrasonore de laboratoire tels qu'une faible répétabilité, un mauvais effet d'émulsification, une incapacité d'obtenir une préparation à grande échelle, et similaire.
PCT/CN2023/074737 2022-12-27 2023-02-07 Nanoparticules de composé et procédé de préparation à grande échelle associé Ceased WO2024138829A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211688877.5 2022-12-27
CN202211688877.5A CN118252817A (zh) 2022-12-27 2022-12-27 一种复合物纳米粒及其规模化制备方法

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WO2024138829A1 true WO2024138829A1 (fr) 2024-07-04

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2765222A1 (fr) * 1997-06-27 1999-01-07 Abraxis Bioscience, Llc Nouvelles formulations d'agents pharmacologiques, leurs procedes de preparation et d'utilisation
US20090263491A1 (en) * 2006-03-24 2009-10-22 Lts Lohmann Therapie-Systeme Ag Polylactide Nanoparticles
CN102068701A (zh) * 2011-01-18 2011-05-25 沈阳药科大学 可断裂peg脂质衍生物在制剂中的应用
CN110051653A (zh) * 2019-06-03 2019-07-26 辽宁大学 一种制备荜茇酰胺白蛋白纳米粒及冻干粉的方法
WO2022166720A1 (fr) * 2021-02-05 2022-08-11 华南理工大学 Protéine de fusion à base d'albumine sérique, et nano-ensemble, son procédé de préparation et son application

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2765222A1 (fr) * 1997-06-27 1999-01-07 Abraxis Bioscience, Llc Nouvelles formulations d'agents pharmacologiques, leurs procedes de preparation et d'utilisation
US20090263491A1 (en) * 2006-03-24 2009-10-22 Lts Lohmann Therapie-Systeme Ag Polylactide Nanoparticles
CN102068701A (zh) * 2011-01-18 2011-05-25 沈阳药科大学 可断裂peg脂质衍生物在制剂中的应用
CN110051653A (zh) * 2019-06-03 2019-07-26 辽宁大学 一种制备荜茇酰胺白蛋白纳米粒及冻干粉的方法
WO2022166720A1 (fr) * 2021-02-05 2022-08-11 华南理工大学 Protéine de fusion à base d'albumine sérique, et nano-ensemble, son procédé de préparation et son application

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