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WO2024137003A1 - Procédé évolutif et continu pour préparer des nanoparticules de médicament solide pour une thérapie de maladie oculaire - Google Patents

Procédé évolutif et continu pour préparer des nanoparticules de médicament solide pour une thérapie de maladie oculaire Download PDF

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Publication number
WO2024137003A1
WO2024137003A1 PCT/US2023/066302 US2023066302W WO2024137003A1 WO 2024137003 A1 WO2024137003 A1 WO 2024137003A1 US 2023066302 W US2023066302 W US 2023066302W WO 2024137003 A1 WO2024137003 A1 WO 2024137003A1
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WIPO (PCT)
Prior art keywords
nanoparticles
drug molecule
drug
solvent
mixing
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Application number
PCT/US2023/066302
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English (en)
Inventor
Hu Yang
Da HUANG
Original Assignee
The Curators Of The University Of Missouri
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Publication of WO2024137003A1 publication Critical patent/WO2024137003A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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

Definitions

  • the present disclosure relates to methods of preparing solid drug nanoparticles, such as those for treatment of ocular diseases.
  • nanoparticles are prepared via a nanoprecipitation method in the fomi of the dropwise addition of a drug solution in a water-miscible organic solvent to water or aqueous solution.
  • nanoparticles formed by nanoprecipitation often have a broad and inconsistent size range.
  • scaling up prior art nanoprecipitation processes in batch mode often leads to high variability between different batches.
  • the poor batch to batch consistency has been the main bottleneck problem that limits the industrialized production and clinical translation of nanoparticle formulations.
  • the present disclosure relates to a method comprising mixing a drug molecule and a solvent system in a multi-inlet vortex mixer until nanoparticles of the drug molecule are formed.
  • the disclosure is directed towards nanoparticles that have an average PDI of less than about 0.5 and comprise agglomerated drug molecules and less than about 2% by weight of polymeric micelles, liposomes, nanogels, microcapsules, vesicles, dendrimers, inorganic nanoparticles, and/or excipients.
  • Figure (Fig.) 1 is a schematic representation (not to scale) of a continuous, solid drug nanoparticle generation platform
  • Fig. 4 is a graph of the size distributions of the brimonidine solid drug nanoparticles formed as described in Example 1;
  • Fig. 5 is a photograph showing the brimonidine solid drug nanoparticle solutions of Example 1 before and after freeze-drying and redispersal with trehalose as a cryoprotectant;
  • Fig. 13 is a graph showing the cytotoxicity against HCE-2 cells of brimonidine/betaxolol solid drug nanoparticles with or without trehalose (Example 5);
  • the present invention is broadly concerned with solid drug nanoparticles and methods of preparing those nanoparticles.
  • the embodiments described herein provide a versatile platform for preparation of various eyedrop formulations based on these solid drug nanoparticles by using different drugs or combinations of drugs. Additionally, the continuous and reproducible preparation enables production of uniform, solid drug nanoparticles in a large scale, overcoming the bottleneck of industrialized production of nanoparticle fonnulations for ocular drug delivery.
  • Platform 10 comprises a micromixer 12 and syringe pumps 14, 16 operably connected to the micromixer 12.
  • syringe pumps 14, 16 comprises respective pairs of syringes 18, 20, and 22, 24.
  • syringes 18, 20, 22, 24 is operatively connected to respective tubing 26, 28, 30, 32.
  • Upper surface 36 comprises inlets 38a-d, inlet channels 40a-d, and mixing chamber 42 formed therein.
  • inlets 38a-d is operably connected to respective tubing 26, 28, 30, 32 via respective inlet ports (not shown). Additionally, each inlet 38a-d is in (fluidic) communication with a respective inlet channel 40a-d.
  • the inlet channels 40a-d are in (fluidic) communication with, and oriented tangentially to, mixing chamber 42.
  • Mixing chamber 42 is generally circular in cross section and is operably connected to a reaction product outlet (not shown).
  • Drug stream 44 comprises drug molecules dissolved or dispersed in a solvent for the drug and is typically introduced into inlet 38a (and subsequently passed through inlet channel 40a).
  • the drug molecules comprise an ocular drug.
  • the drug molecules are hydrophobic or amphiphilic.
  • hydrophobic refers to low solubility, i.e., solubility of less than about 1 mg/mL after 2 hours in water having a temperature of about 22°C
  • drug stream 44 consists essentially of, or consists of, the drug molecules and solvent in which the drug molecules were dissolved or dispersed prior to introduction into drug stream 44.
  • the confined impinging and/or turbulent, circular mixing of the streams 44, 46, 48, and 50 effect the mixing of the drug molecules and solvent(s) in a continuous and reproducible manner so as to cause a quantity of said drug molecules to nanoprecipitate (i.e., agglomerate and form the nanoparticles).
  • nanoprecipitate i.e., agglomerate and form the nanoparticles.
  • no chemical reactions take place during mixing.
  • the solid drug nanoparticles can have an average hydrodynamic size (determined as described in Example 1) of about 10 nm to about 1,000 nm, preferably about 25 nm to about 750 nm, and more preferably about 50 nm to about 500 nm.
  • some embodiments result in solid drug nanoparticles having an average size distribution of about 10 nm to about 1,000 nm, preferably about 25 nm to about 750 nm, and more preferably about 50 nm to about 500 nm.
  • the size distribution is measured using a Zetasizer Lab (Malvern Panalytical, UK) instrument and graphed using Graphpad Prism 8.0 software.
  • the solid drug nanoparticles have a poly dispersity index (PDI, determined as described in Example 1) of less than about 0.5, preferably less than about 0.4, more preferably less than about 0.3, and most preferably less than about 0.2.
  • PDI poly dispersity index
  • the solid drug nanoparticles will have two or three of the abovedescribed average hydrodynamic sizes, average size distributions, and/or PDIs.
  • hydrophobic or amphiphilic drug molecules formed into solid drug nanoparticles as described herein will pass through the cornea in an amount that is at least about 2 times, preferably at least about 2.5 times, and more preferably at least about 3 times more than that of its hydrophilic counterpart after about 4 hours.
  • a further advantage is superior intraocular pressure (IOP) reduction in solid drug nanoparticles formed herein that are intended for glaucoma treatment. That is, in some embodiments, a single dose of a formulation comprising hydrophobic or amphiphilic drug molecules formed into solid drug nanoparticles as described herein will preferably have an IOP reduction that is at least about 1.5 times, more preferably at least about 2 times, and even more preferably at least about 3 times the size of the IOP reduction achieved by its hydrophilic counterpart at about 14, 30, and/or 72 hours after administering that single dose, as described in Example 7 and Fig. 16.
  • IOP intraocular pressure
  • the phrase "and/or," when used in a list of two or more items, means that any one of the listed items can be employed by itself or any combination of two or more of the listed items can be employed.
  • the composition can contain or exclude A alone; B alone; C alone; A and B in combination; A and C in combination; B and C in combination; or A, B, and C in combination.
  • BM Brimonidine
  • the Transmission Electron Microscopy (TEM) image of the BM SDNs indicated that they were spherical particles with a size of about 100-180 nm.
  • the average hydrodynamic size of the SDNs was determined by dynamic light scattering (DLS) using a Zetasizer Lab (Malvern Panalytical, UK) instrument, and the poly dispersity index of the SDNs was determined using a Zetasizer Lab (Malvern Panalytical, UK) instrument.
  • the average hydrodynamic size was about 180 nm (Fig. 4), and the size distribution was narrow with a low poly dispersity index (PDI), indicating good uniformity of the BM SDNs.
  • PDI poly dispersity index
  • BX was dissolved in methanol with a concentration of 2 mg/mL.
  • the drug solution was introduced into one inlet of MIVM, and water was introduced into the remaining three inlets.
  • the four streams were then mixed in the MIVM with a flow rate of 40 mL/min.
  • the BX SDNs were obtained.
  • trehalose was added to the solution, and the solution was freeze-dried.
  • the yielded pale powder was stored at room temperature, and PBS was added to reconstitute it before use.
  • the TEM image of the BX SDNs indicated that they were spherical particles with a size of about 50-100 nm.
  • the average hydrodynamic size determined by DLS was about 90 nm (Fig. 7), and the size distribution was narrow with a low PDI, indicating good uniformity of the BX SDNs.
  • the size distribution of SDNs from three independent batches showed negligible variation, indicating excellent batch-to-batch consistency.
  • Fig. 8 showed that the reconstituted BX SDNs solution was homogeneous and nearly transparent, showing no difference with the BX SDNs solution before lyophilization. These results indicated that no aggregations were formed during the lyophilization, and that the reconstituted BX SDNs solution is suitable for use as eye drops.
  • BM and BX were dissolved in methanol with a concentration of 0.4 mg/mL and 1 mg/mL, respectively.
  • the drug solution was introduced into one inlet of MIVM, and water was introduced into the remaining three inlets.
  • the four streams were then mixed in the MIVM with a flow rate of 40 mL/min.
  • the BM/BX SDNs were obtained.
  • trehalose was added to the solution, and the solution was freeze-dried. The yielded paleyellow powder was stored at room temperature, and PBS was added to reconstitute it before use.
  • the TEM image of the BM/BX SDNs indicated that they were spherical particles with a size of about 60-110 nm.
  • the average hydrodynamic size determined by DLS was about 100 nm (Fig. 10), and the size distribution was narrow with a low PDI (about 0. 1 to about 0.3 over three batches), indicating the good uniformity of the BM/BX SDNs.
  • the size distribution of SDNs from three independent batches showed negligible variation, indicating excellent batch-to-batch consistency.
  • Fig. 11 showed that the reconstituted BM/BX SDNs solution was homogeneous and nearly transparent, showing no difference with the BM/BX SDNs solution before lyophilization. The results indicated that no aggregations were formed during the lyophilization, and that the reconstituted BM/BX SDNs solution is suitable for use as eye drops.
  • PBS release medium
  • BM and BX in the samples were analyzed using liquid chromatography-mass spectrometry' (LC-MS), and the cumulative release ratios of BT and BH from the BT/BH solution, as well as BM and BX from the BM/BX SDNs, were calculated. These experiments were carried out in triplicate.
  • LC-MS liquid chromatography-mass spectrometry'
  • BM/BX SDNs are composed of hydrophobic drugs, the release was expected to slow' down in comparison to their hydrophilic counterparts BT and BH.
  • in vitro drug release experiments of BM/BX SDNs and BT/BH were carried out at 37°C in phosphate buffer with a pH of 7.4 at sink condition. As shown in Fig. 12, more than 60% of BT and 70% of BH were released wdthin 4h, while less than 40% of BM and 55% of BX were released from the BM/BX SDNs after 4h.
  • HCE-2 cells were cultured at 37°C in ATCC medium supplemented with Comeal Epithelial Cell Growth Kit components (apo-transferrin, epinephrine, extract P, hydrocortisone hemisuccinate, L-glutamine, rh insulin, and CE growth factor) in a 5% CO2 incubator. After the cells reached a confluence of 70-80%, they were detached by trypsin to make a cell suspension. Subsequently, the cells were seeded into a 96-well plate with a density of 2*104/well and cultured overnight. Trehalose, BM/BX SDNs with or without trehalose with various concentrations were then added to the medium.
  • Comeal Epithelial Cell Growth Kit components apo-transferrin, epinephrine, extract P, hydrocortisone hemisuccinate, L-glutamine, rh insulin, and CE growth factor
  • BT and BH eyedrops have a BT concentration of 2 mg/mL and a BH concentration of 5 mg/mL. Given that most of the administered drugs are washed away by tears and that the absorbed drugs will be further diluted by aqueous humor, only the cytotoxicity of formulations with BM concentrations of about 0.02-0.1 mg/mL and BX concentrations of about 0.05-0.25 mg/mL were evaluated. In the tested range, the freshly prepared BM/BX SDNs showed concentration-dependent toxicity to the cells, with less than 40% viability at the highest concentration. The viabilities of cells treated with reconstituted BM/BX SDNs were higher than 85% (Fig. 13), which maybe be due to the improved cytocompatibility by trehalose.
  • FITC-labeled Dextran was tested to confirm the intactness of the cornea, and the permeation of the FITC-labeled Dextran was quantified by measuring the fluorescence intensity of FITC (Emission: 525 nm, Excitation: 490 nm) using a microplate reader.
  • BM/BX SDNs To investigate whether the BM/BX SDNs would show better cornea permeation, ex vivo cornea permeation was performed using a Franz Cell, and freshly excised rabbit cornea was placed between the donor chamber and receptor chamber (Fig. 14). As summarized in Fig 15, the BM/BX SDNs brought more drugs across the cornea. Within 4h, the BM/BX SDNs enabled more than 30% of BM and BX to pass through the cornea, w hile only less than 10% of the hydrophilic counterparts BT and BH penetrated across the cornea.
  • IOP intraocular pressure
  • the respective lOPs of the rats were measured at 9 am for 3 successive days using an ICare TONOLAB tonometer to obtain the baseline.
  • the right and left eyes of the rats were topically treated with BM/BX SDNs (2*5 pL, 0.2% w/v BM and 0.5% w/v BX) and BT/BH solutions (2*5 pL, equal to 0.2% w/v BM and 0.5% w/v BX), respectively, at 9 am.
  • the IOP of each eye was measured at 6, 24, 30, 48, 72, 96, 120 h post treatment.
  • the IOP of the rats was measured at 9 am for 3 successive days to obtain the baseline.
  • the right and left eyes of the rats were topically treated with BM/BX SDNs (2*5 pL, 0.2% w/v BM and 0.5% w/v BX) and BT/BH solutions (2*5 pL, equal to 0.2% w/v BM and 0.5% w/v BX), respectively, at 9 am.
  • BM/BX SDNs 2*5 pL, 0.2% w/v BM and 0.5% w/v BX
  • BT/BH solutions 2*5 pL, equal to 0.2% w/v BM and 0.5% w/v BX
  • the average IOP reduction caused by the BM/BX SDNs was 2.91 mmHg, which is 3.3-fold stronger than IOP reduction resulted from the BT/BH (0.88 mmHg) (P ⁇ 0.005). Additionally, at 24, 30, and 48 h post-treatment, the IOP reduction of BM/BX SDNs was significantly different from that of the BT/BH-treated eyes. Therefore, one dose of BM/BX SDNs maintained an effective IOP reduction for at least 48h.

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Abstract

La présente divulgation traite les problèmes liés à la faible biodisponibilité de formulations de gouttes oculaires actuelles et à la difficulté de préparer à grande échelle des nouvelles formulations de gouttes oculaires sur la base de nanoparticules de médicament solides en fournissant un procédé évolutif et continu pour produire ces nanoparticules de médicament solides à l'aide d'un mélangeur à vortex à entrées multiples (MIVM). Les nanoparticules de médicament solide sont préparées par nanoprécipitation, qui comprend généralement les étapes suivantes consistant à : 1) dissoudre des médicaments hydrophobes ou amphiphiles dans un solvant organique qui peut être mélangé avec de l'eau ; 2) ajouter la solution de médicament à une solution aqueuse avec agitation ou tourbillonnement, les particules se formant pendant le mélange ; et 3) éliminer le solvant organique par évaporation ou dialyse.
PCT/US2023/066302 2022-12-20 2023-04-27 Procédé évolutif et continu pour préparer des nanoparticules de médicament solide pour une thérapie de maladie oculaire WO2024137003A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011127255A1 (fr) * 2010-04-08 2011-10-13 Merck Sharp & Dohme Corp. Préparation de nanoparticules de lipide
WO2021163455A1 (fr) * 2020-02-14 2021-08-19 The Trustees Of Columbia University In The City Of New York Technologie de revêtement de membrane cellulaire évolutive et facile à la fois pour des particules chargées positivement et négativement
CN113908287A (zh) * 2021-10-11 2022-01-11 华东理工大学 一种载药型植物蛋白纳米粒子的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011127255A1 (fr) * 2010-04-08 2011-10-13 Merck Sharp & Dohme Corp. Préparation de nanoparticules de lipide
WO2021163455A1 (fr) * 2020-02-14 2021-08-19 The Trustees Of Columbia University In The City Of New York Technologie de revêtement de membrane cellulaire évolutive et facile à la fois pour des particules chargées positivement et négativement
CN113908287A (zh) * 2021-10-11 2022-01-11 华东理工大学 一种载药型植物蛋白纳米粒子的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ZENG ZHIPENG, ZHAO PENGFEI, LIU LIXIN, GAO XIAOHU, MAO HAI-QUAN, CHEN YONGMING: "Lipid Stabilized Solid Drug Nanoparticles for Targeted Chemotherapy", APPLIED MATERIALS & INTERFACES, AMERICAN CHEMICAL SOCIETY, US, vol. 10, no. 30, 1 August 2018 (2018-08-01), US , pages 24969 - 24974, XP093186693, ISSN: 1944-8244, DOI: 10.1021/acsami.8b07024 *
ZHENG HUANGLIANG, TAO HAI, WAN JINZHAO, LEE KEI YAN, ZHENG ZHANYING, LEUNG SHARON SHUI YEE: "Preparation of Drug-Loaded Liposomes with Multi-Inlet Vortex Mixers", PHARMACEUTICS, MDPI AG, SWITZERLAND, vol. 14, no. 6, Switzerland, pages 1223, XP093186695, ISSN: 1999-4923, DOI: 10.3390/pharmaceutics14061223 *

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