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WO2025096329A1 - Procédé de préparation de formulations de nanoparticules peptidiques stables - Google Patents

Procédé de préparation de formulations de nanoparticules peptidiques stables Download PDF

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Publication number
WO2025096329A1
WO2025096329A1 PCT/US2024/053194 US2024053194W WO2025096329A1 WO 2025096329 A1 WO2025096329 A1 WO 2025096329A1 US 2024053194 W US2024053194 W US 2024053194W WO 2025096329 A1 WO2025096329 A1 WO 2025096329A1
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peptide
nanosuspension
aqueous dispersion
nanosuspensions
formulations
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Dennis Hengho LEUNG
Chun-Wan YEN
Chloe Ying Xin HU
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Genentech Inc
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Genentech Inc
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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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/14—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
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient

Definitions

  • the present disclosure is directed to methods of preparing peptide nanoparticle formulations, and in particular, peptide nanosuspensions, using low shear milling. More specifically, the disclosure is directed to methods of preparing peptide nanosuspensions by applying low frequency acoustic energy to an admixture comprising a peptide, an aqueous dispersion medium comprising a surface-active polymer and optionally a surfactant, and milling media, until the peptide has been milled to nanoparticle size. Also described are stable peptide nanosuspensions prepared by the methods.
  • peptides are generally preferred to be formulated in aqueous solution (Nugrahadi, et al., “Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review,” Pharmaceutics 2023, 15, 935). Unlike larger proteins, peptides are smaller and often lack a strong secondary structure. As a result, hydrophobic residues can have a disproportionately large effect on solubility since the lack of a strong secondary structure results in their surface exposure. Additionally, peptides often exhibit sharp pH-dependent solubilities that are difficult to control effectively with buffers.
  • non-aqueous solvents such as the use of ethanol and Cremophor EL in formulating cyclosporine A, although their use remains relatively limited due to their potential for unfolding and denaturation as well as having limited pharmaceutical acceptability (Stevenson, C., “Characterization of Protein and Peptide Stability and Solubility in Non-Aqueous Solvents,” Curr. Pharm. Biotechnol. 2000, 1, 165-182).
  • suspensions for long-acting injectable depot formulations have been largely limited to lipid-based approaches or aqueous suspensions of small molecules (Sharma, et al., “Recent Advances in Lipid-Based Long-Acting Injectable Depot Formulations,” Adv. Drug Deliv. Rev. 2023, 199, 114901; Johnson, et al., “Retrospective Analysis of Preclinical and Clinical Pharmacokinetics from Administration of Long- Acting Aqueous Suspensions,” Pharmaceut Res 2023, 1-16).
  • Suspension formulation approaches may be able to overcome challenges with solubility limitations when formulating at higher concentrations.
  • the chemical stability of the peptide may be improved in the solid state.
  • Nanosuspensions have been demonstrated as an effective enabled formulation strategy for small molecules (Merisko-Liversidge, et al., “Drug Nanoparticles: Formulating Poorly Water-Soluble Compounds,” Toxicol Pathol 2008, 36, 43-48; Merisko- Liversidge, et al., “Nanosizing for Oral and Parenteral Drug Delivery: A Perspective on Formulating Poorly-Water Soluble Compounds Using Wet Media Milling Technology,” Adv Drug Deliver Rev 2011, 63, 427-440; Kesisoglou, et al., “Nanosizing — Oral Formulation Development and Biopharmaceutical Evaluation,” Adv Drug Deliver Rev 2007, 59, 631-644; Rabinow, B.E., “Nanosuspensions in Drug Delivery,” Nat Rev Drug Discov 2004, 3, 785-796; Muller, et al., “State of the Art of Nanocrystals - Special Features, Production, Nanotoxicology Aspect
  • Nanosuspensions often consist of nanoparticles of >75% drug load and can often be prepared at high overall drug concentration in aqueous suspension (i.e., >100 mg/mL). Due to their small particle size and large surface area, nanosuspension formulations exhibit dramatically increased dissolution rate and potentially saturation solubility (Patel, et al., “Nanosuspension: An Approach to Enhance Solubility of Drugs,” J Adv Pharm Technology Res 2011, 2, 81-87), enabling improved absorption in vivo when administered orally.
  • nanosuspensions can also be administered via parenteral delivery routes as well (Ma, et al., “Nanosuspensions Technology as a Master Key for Nature Products Drug Delivery and In Vivo Fate,” Eur J Pharm Sci 2023, 185, 106425; Marques, et al., “Factors Affecting the Preparation of Nanocrystals: Characterization, Surface Modifications and Toxicity Aspects,” Expert Opin Drug Del 2023, ahead-of-print, 1-24; Pinar, et al., “Formulation Strategies of Nanosuspensions for Various Administration Routes,” Pharm 2023, 15, 1520), including intravenous (IV) delivery (Chiang, et al., “Nanosuspension Delivery of Paclitaxel to Xenograft Mice Can Alter Drug Disposition and Anti-Tumor Activity,” Nanoscale Res Lett 2014, 9, 156; Gao, et al., “Preparation, Characterization, Pharmacokinetics,
  • the drug nanoparticles themselves are inherently high energy and unstable, presenting a risk of aggregation.
  • small amounts of polymer and/or surfactant excipients are added to stabilize the nanoparticles and prevent aggregation from occurring.
  • the present disclosure is directed to a method of preparing a peptide nanosuspension, the method comprising applying low frequency acoustic energy at a frequency of from about 10 to about 20,000 Hertz to an admixture comprising (i) a peptide; (ii) an aqueous dispersion medium comprising a surface-active polymer; and (iii) milling media.
  • the disclosure is directed to a method of screening aqueous dispersion media for use in a peptide nanosuspension, the method comprising: (a) admixing a peptide, milling media, and a plurality of aqueous dispersion media in one or more slurry containers to form a plurality of admixtures; and (b) applying low frequency acoustic energy at a frequency of from about 10 to about 20,000 Hertz to the admixtures.
  • the disclosure is directed to a kit for preparing a peptide nanosuspension comprising a slurry container, milling media, a peptide, and an aqueous dispersion media comprising a surface-active polymer.
  • a kit for preparing a peptide nanosuspension comprising a slurry container, milling media, a peptide, and an aqueous dispersion media comprising a surface-active polymer.
  • FIGs. 1 A-1C depict the structures of insulin (a large peptide hormone) (1A), GNE-A (a cystine-knot peptide) (IB), and cyclosporine A (CsA, a macrocyclic peptide) (1C).
  • FIG. 2 is a chart depicting the average particle size as measured by dynamic light scattering of insulin nanosuspension formulations prepared from 1) 25% PVP K29-32 and 1% SDS, or 2) 25% HPC-SL and 1% SDS (wt% to insulin). The formulations were prepared using resonant acoustic milling.
  • FIGs. 3 A and 3B are charts depicting the physical stability as measured by size exclusion chromatography of insulin nanosuspension formulations prepared from 1) 25% PVP K29-32 and 1% SDS (3 A), or 2) 25% HPC-SL and 1% SDS (3B) (wt% to insulin).
  • the formulations were prepared using resonant acoustic milling.
  • FIGs. 4A and 4B are charts depicting the chemical stability as measured by reverse phase chromatography of insulin nanosuspension formulations prepared from 1) 25% PVP K29-32 and 1% SDS (4A), or 2) 25% HPC-SL and 1% SDS (4B) (wt% to insulin).
  • the formulations were prepared using resonant acoustic milling.
  • FIG. 5 is a chart depicting the average particle size as measured by dynamic light scattering of GNE-A nanosuspension formulations prepared from 1) 25% Tween80, or 2) 25% Pluronic F127 (wt% to GNE-A). The formulations were prepared using resonant acoustic milling.
  • FIGs. 6A and 6B are charts depicting the physical stability as measured by size exclusion chromatography of GNE-A nanosuspension formulations prepared from 1) 25% Tween80 (6 A), or 2) 25% Pluronic Fl 27 (6B) (wt% to GNE-A). The formulations were prepared using resonant acoustic milling.
  • FIGs. 7A and 7B are charts depicting the chemical stability as measured by reverse phase chromatography of GNE-A nanosuspension formulations prepared from 1) 25% Tween80 (7 A), or 2) 25% Pluronic Fl 27 (7B) (wt% to GNE-A).
  • the formulations were prepared using resonant acoustic milling.
  • FIG. 8 is a graph comparing the 4-week stability as determined using size exclusion chromatography of a GNE-A nanosuspension formulation prepared with Pluronic Fl 27 using resonant acoustic milling and a GNE-A solution formulation at 100 mg/mL concentration at 37°C.
  • FIGs. 9A and 9B depict transmission electron microscopy (TEM) images of a cyclosporine A (CsA) nanosuspension formulation prepared with 25% HPC-SL and 1% SDS (wt% to CsA) using resonant acoustic milling.
  • CsA cyclosporine A
  • FIG. 10 is a chart depicting the average particle size as measured by dynamic light scattering of cyclosporine A (CsA) nanosuspension formulations prepared from 1) 25% HPC-SL and 1% SDS, or 2) 25% Tween80 (wt% to CsA). The formulations were prepared using resonant acoustic milling.
  • CsA cyclosporine A
  • FIG. 11 is a chart depicting the average particle size as measured by dynamic light scattering of cyclosporine A (CsA) nanosuspension formulations prepared with increasing ratios of SDS at a 10 mg/mL concentration. The formulations were prepared using resonant acoustic milling.
  • CsA cyclosporine A
  • FIG. 12 is a chart depicting the average particle size as measured by dynamic light scattering of cyclosporine A (CsA) nanosuspension formulations prepared with 25% SDS (wt% to CsA) over 28 days at a 10 mg/mL concentration.
  • the formulations were prepared using resonant acoustic milling.
  • FIG. 13 is a graph depicting the physical stability as measured by size exclusion chromatography of cyclosporine A (CsA) nanosuspension formulations with 25% SDS (wt% to CsA). The formulations were prepared using resonant acoustic milling.
  • CsA cyclosporine A
  • FIG. 14 is a graph depicting the chemical stability as measured by reverse phase chromatography of cyclosporine A (CsA) nanosuspension formulations with 25% SDS (wt% to CsA). The formulations were prepared using resonant acoustic milling.
  • FIG. 15 is a graph depicting the injection forces of the Sandimmune® lipid- based formulation as compared to an aqueous nanosuspension of cyclosporine A (CsA) prepared using resonant acoustic milling by using a BD 1-mL syringe attached with 25G needle.
  • the maximum injection forces of the Sandimmune® formulation and the CsA nanosuspension were 26.97 N and 4.33 N, respectively.
  • FIG. 16 is a graph depicting the PK profile of the commercial Sandimmune® formulation as compared to aqueous nanosuspension formulations prepared by resonant acoustic milling of cyclosporine A (CsA).
  • CsA cyclosporine A
  • FIG. 17 is a graph depicting the average particle sizes of various peptide formulations prepared using ultrasonication.
  • FIGs. 18A and 18B depict peptide formulations of insulin, cyclosporine A, and GNE-A milled using ultrasonication at formation (18A) and at day 3 (18B).
  • the formulation in the left vial was subjected to ultrasonicated for 5 minutes
  • the formulation in the right vial was subjected to ultrasonicated for 10 minutes.
  • the formulations exhibited settling behavior from the initial timepoint.
  • the present disclosure is directed to methods of preparing peptide nanoparticle formulations, and in particular, peptide nanosuspensions, using low shear milling.
  • the disclosure is directed to methods of preparing peptide nanosuspensions by applying low frequency acoustic energy to an admixture comprising a peptide, an aqueous dispersion medium comprising a surface-active polymer and optionally a surfactant, and milling media, until the peptide has been milled to nanoparticle size.
  • the nanosuspension formulations of the present disclosure are thus aqueous colloidal dispersions of peptide nanoparticles.
  • acoustic milling such as resonant acoustic milling
  • the methods of the present disclosure allow for formation of stable nanosuspensions, even at high concentrations (e.g., including 50-300 mg/mL) above the solubility limit, and without the need for harsh excipients. Because the peptides in the nanosuspensions remain in a solid state, the formulations have improved stability.
  • the method of the disclosure comprises admixing in a slurry-container an aqueous dispersion medium, a peptide, and milling media, and subjecting the admixture to acoustic energy of sufficient frequency and amplitude, and for a sufficiently sustained period, to provide a nanoparticle suspension (nanosuspension) of the peptide dispersed in the aqueous dispersion medium.
  • a nanoparticle suspension nanoparticle suspension
  • the nano-suspension is separated from the milling media.
  • the low frequency acoustic energy is applied to the admixture until the peptide has been milled to nanoparticle size.
  • the admixture is subjected to acoustic energy for from about 0.25 to about 24 hours, including from about 0.5 to about 10 hours, or from about 1 to about 5 hours, or from about 1 to about 2 hours. In one aspect, the admixture is subjected to acoustic energy for about 2 hours.
  • recovery of the nanosuspension can be accomplished by any known physical separation method, for example, where the media permits, separation can be accomplished by decantation, for example, as in the case of the Examples presented herein, a nanosuspension prepared using YTZ milling media can be recovered using a 18 gauge needle and syringe since the milling media is of sufficient density and size to permit such separation.
  • decantation is not possible, for example where the milling media is polyester prill
  • size exclusion separation can be employed, for example, by centrifuging through a properly sized sieve.
  • Milling media suitable for use in the method of the present disclosure include any particulate material compatible with acoustic mixing processes.
  • suitable milling media include glass beads, polyester prill; polystyrene milling beads, and yttria-stabilized zirconia milling beads (e g., YTZ grinding media from Tosoh).
  • acoustic energy is linear or spherical energy propagation through a tangible medium which is within the frequency range of 10 hertz to 20,000 hertz.
  • linear acoustic energy at a frequency of from about 10 hertz up to about 100 hertz, more preferably the acoustic energy is supplied at a frequency of about 60 hertz.
  • the exact frequency will be selected to provide a standing wave in the slurry from which a nanosuspension is being provided.
  • the frequency required to achieve a standing wave will vary according to known principles depending upon the nature of the slurry and the dimensions of the slurry to which acoustic energy is applied.
  • the acoustic energy is advantageously propagated uniformly throughout the slurry container.
  • the methods of the present disclosure utilize resonant acoustic mixing.
  • resonant acoustic mixing delivers energy to a sample at its resonant frequency, typically only between 58-62 Hz. This is an extremely efficient mechanism for mixing while, at the same time, the low frequencies used result in less stressful shear forces to the materials being mixed. As a result, resonant acoustic mixing results in more stable materials compared to earlier high shear techniques as well as an approach to mill sensitive compounds.
  • Acoustic energy can be supplied to an admixture using any known source, however, in general it is preferred to supply the energy by cyclic linear displacement of a container filled with the admixture.
  • the acoustic energy supplied by linear displacement exerts between about 10 times G-force (where “G” is the force of gravity) and about 100 times G-force. In one aspect, the acoustic energy supplied by linear displacement exerts about 50 times G-force.
  • acoustic mixer such as a ResodynTM acoustic mixer could be used to efficiently provide suspensions by mixing pre-formed nanoparticulate materials and an aqueous dispersion medium
  • acoustic mixing has not been previously employed to prepare peptide nanoparticles from bulk powdered solid materials (i.e., macro-particulate materials defined herein as having a D5O>1 micron).
  • macro-particulate materials defined herein as having a D5O>1 micron.
  • the methods of the present disclosure advantageously have been found to be highly general and have been demonstrated to be effective across a wide range of different peptide structures and molecular weights.
  • Peptide nanosuspensions produced by the methods of the present disclosure additionally exhibit improved chemical and physical stability compared to corresponding solution formulations, particularly at high concentrations.
  • certain nanosuspensions produced by the methods of the disclosure have been shown to exhibit similar exposures compared to current commercial formulations when dosed in vivo, with the additional benefit of not requiring high concentrations of lipids and surfactants.
  • a nanosuspension comprises sub-micron particles (i.e., particles yielding a D50 measurement of ⁇ 1 micron) of a peptide present as a colloidal dispersion in an aqueous dispersion medium.
  • the methods of the present disclosure produce nanosuspensions comprising peptide particles having a D50 measurement of less than 500 nm.
  • the term “macro-particulate” material is used herein to distinguish nano-particulated materials provided by the method of the present disclosure from powdered material provided by ordinary milling or precipitation techniques, for example, those which in general have a D50 value well in excess of 1 micron.
  • the methods of the present disclosure are generally applicable to structurally diverse peptides.
  • the term “peptide” refers to molecules comprising between 2 and 50 amino acids and having a molecular weight ranging from about 0.5 kDa to about 100 kDa, including from about 1 kDa to about 50 kDa, or from about 1.2 kDa to about 7.0 kDa.
  • the peptide present in a nanosuspension of the present disclosure may be any peptide including, but not limited to, macrocyclic peptides, cystine-knot peptides, and large peptide hormones.
  • the peptide is selected from the group consisting of insulin, cyclosporine A, and cystine-knot peptides.
  • the aqueous dispersion medium employed in nanosuspensions of the disclosure comprises primarily water (based on wt. %) and one or more water-miscible surface-active constituents.
  • the surface-active constituents are water-miscible polymers (also referred to herein as surfaceactive polymers), described in detail herein, and optionally, comprises also a surfactant.
  • the surfactant is an ionic surfactant, described in detail herein.
  • peptide nanosuspensions it will be appreciated that it is advantageous for peptide nanosuspensions to: (i) demonstrate physical and chemical stability; (ii) avoid the use of harsh excipients and organic solvents that may disrupt the peptide structure; (iii) demonstrate good absorption in vivo after subcutaneous injection; and (iv) retain high drug loading and good stability at high concentrations.
  • Two important metrics of a nanosuspension are: (i) the ratio of peptide to aqueous dispersion medium (i.e., “drug loading”) which can be employed in a slurry from which the nanosuspension is prepared; and (ii) the ratio of peptide to the surface-active constituents (water-miscible polymer and optional surfactant) employed in the slurry from which the nanosuspension is prepared to stabilize the nanoparticles formed.
  • drug loading i.e., “drug loading”
  • surface-active constituents water-miscible polymer and optional surfactant
  • the method of the present disclosure advantageously permits preparation of peptide nanosuspensions in which the slurry can employ a high weight percentage (wt. %) of the peptide relative to the aqueous dispersion medium (water and surface-active constituents described herein), while maintaining stability.
  • an aqueous dispersion medium utilized in a peptide nanosuspension of the present disclosure comprises water and one or more surface-active constituents which stabilize the particles present in a nanosuspension.
  • the ratio of aqueous dispersion medium and peptide will vary depending upon the nature of the peptide, in general the slurry from which a nanosuspension is prepared will comprise from about 0.1 wt% to about 50 wt% peptide relative to the weight of the aqueous dispersion medium employed (i.e., a peptide concentration of from about 1 mg/mL to about 500 mg/mL).
  • the slurry from which a nanosuspension is prepared will comprise from about 1 wt. % to about 40 wt. % peptide relative to the weight of aqueous dispersion medium employed (i.e., a peptide concentration of from about 10 mg/mL to about 400 mg/mL). In certain other aspects, the slurry from which a nanosuspension is prepared will comprise from about 1.3 wt% to about 10 wt% peptide relative to the weight of the aqueous dispersion medium employed (i.e., a peptide concentration of from about 13 mg/mL to about 100 mg/mL).
  • the slurry from which a nanosuspension is prepared will comprise from about 0.5 wt% to about 10 wt% peptide relative to the weight of the aqueous dispersion medium employed (i.e., a peptide concentration of from about 5 mg/mL to about 100 mg/mL).
  • the ratio will vary depending upon the nature of the peptide employed. In general, it is preferred to prepare a nanosuspension with the highest weight ratio of peptide relative to the weight of surface-active constituent which will provide a stable nanosuspension.
  • the nanosuspensions produced by the process of the disclosure comprise from about 25 wt. % to about 99 wt. % peptide relative to the weight of surface-active constituents present in the nanosuspension.
  • the nanosuspensions have in excess of at least about 40 wt. % peptide relative to the weight of surface-active constituents present in the nano-suspension. In some embodiments, the nanosuspensions have more than 90 wt. % peptide relative to the weight of surface-active constituents employed and in some embodiments more than 95 wt. % peptide relative to the amount of surface-active constituents employed. In some embodiments, as much as 98 wt. % peptide is present relative to the amount of surface-active constituents employed.
  • the methods of the disclosure produce nanosuspensions that comprise from about 1 wt% to about 500 wt%, including from about 1 wt% to about 200 wt% surface-active constituents relative to the weight of peptide present in the nanosuspension.
  • surface-active polymers suitable for use in the present disclosure are water miscible polymers, and in particular, include amphiphilic polymers.
  • the hydrophobic portion of the polymer adsorbs to the nanoparticle surface, while the hydrophilic portion of the polymer is exposed to water, thus stabilizing the nanoparticles.
  • suitable polymers include, but are not limited to: polymers based on hydroxypropylcellulose (HPC), for example, HPC-SL (Ashland Chemical); alkoxide block copolymers, for example an ethylene oxide/propylene oxide copolymer, for example, Plurionic F127 from BASF; polyethylenesorbitol polymers, for example Tween 80 (Sigma, article of commerce); polyvinylpyrrolidone (PVP) polymers, for example, Plasdone® K29-32 from Ashland Chemical; methyl Cellulose (article of commerce, for example, available from Sigma) and cellulose derivatives, for example, carboxycellulose derivatives, for example, hydroxypropylmethyl cellulose derivatives, for example, Methocel polymers from Dow Chemical, and polypropylene- and polyethylene glycol polymers and derivatives, for example, Carbowax® available from Dow Chemical. It will be appreciated that other surface-active polymers may be employed, dictated by the nature of the peptide being disper
  • the surface-active polymer is combined with a surfactant to help maintain dispersion.
  • a surfactant to help maintain dispersion.
  • surfactant suitable for use in nanosuspensions of the present disclosure include, but are not limited to, dioctyl sulfosuccinates (docusate sodium, DOSS, article of commerce), and sodium dodecyl sulfate (SDS), an ionic surfactant prepared from laurel alcohol, an article of commerce, both available, for example, from Fluka.
  • the method of the present disclosure can be applied to any volume of admixture, and thus is scalable.
  • the volume of admixture in the slurry container is at least 1 uL, including at least 10 uL, at least 100 uL, at least 1 mL, at least 10 mL, at least 100 mL, at least 1 L, at least 5 L, at least 10 L, at least 50 L, at least 100 L, or at least 200 L, or from about 1 uL to about 200 L, or from about 10 uL to about 100 L, or from about 100 mL to about 1 L, or from about 100 uL to about 100 mL.
  • a nanosuspension of the disclosure is prepared by applying acoustic energy to a slurry contained in a suitable slurry container.
  • a suitable slurry container for carrying out the process of the disclosure, any convenient, sealable container may be employed which can be fixed to the carriage of the acoustic mixing equipment utilized to prepare the slurry.
  • suitable containers are, but not limited to, sealable bottles (of any material, for example, glass, plastic or metal, preferably glass or plastic), a sealable plastic bag, and a sealable micro-titer well plate.
  • the present disclosure is a peptide nanosuspension prepared by the process of the disclosure.
  • peptide nanosuspensions prepared by the method of the disclosure exhibit good physical and chemical stability, even at higher concentrations.
  • the process of the present disclosure is readily adaptable to either a “batch” or “continuous process” mode for large-scale preparation of nanosuspensions for use in the preparation of medicaments.
  • the selection of surface-active polymer and optional surfactant may vary depending on the peptide included in the nanosuspension. It will be appreciated that the method of the present disclosure is amenable to the provision of multiple simultaneously prepared samples of a peptide nanosuspension using the same mixing conditions. This latter feature permits variations of a formulation to be prepared simultaneously, under the same conditions, for the purposes of comparing or optimizing formulations. It will be appreciated that the methods of the present disclosure provide for the screening and optimization of formulations while consuming only small amounts of peptide when a small sample size is prepared, for example, by the use of a sealable micro-titer well plate as a slurry container.
  • the disclosure is directed to a method of screening aqueous dispersion media for use in a peptide nanosuspension.
  • the method comprises (a) admixing a peptide, milling media, and a plurality of aqueous dispersion media in one or more slurry containers to form a plurality of admixtures; and (b) applying low frequency acoustic energy at a frequency of from about 10 to about 20,000 Hertz to the admixtures.
  • the slurry container is a multi-well plate, for example, a sealable microtiter well plate.
  • each of the plurality of admixtures is in a separate slurry container, or in a separate well of a single slurry container, such as a multi-well plate.
  • the low frequency acoustic energy may be applied to the admixtures simultaneously and/or sequentially.
  • the resulting nanosuspensions are analyzed for stability.
  • “stability” of the nanosuspensions may refer to physical and/or chemical stability.
  • physical stability of the nanosuspensions is evaluated using one or more of the following measures: 1) size of the peptide nanoparticles, 2) aggregation of the peptide nanoparticles, and/or peptide monomer content present in the nanosuspension over time.
  • chemical stability of the nanosuspensions is evaluated by determining the presence of peptide degradation products in the nanosuspension.
  • Stability may be analyzed using any known technique, such as those set forth in the examples.
  • stability is analyzed after storage of the admixtures for at least 14 days, or at least 28 days at room temperature, 4°C, and/or 37°C, as described in the Examples. It will be appreciated that following stability measurements of the nanosuspensions, the aqueous dispersion media producing a nanosuspension with the best stability may be selected for further development of peptide nanosuspension formulations.
  • a stable nanosuspension refers to a nanosuspension wherein the smallest particle size of the nanoparticles in the nanosuspension remain unchanged over the measured time period.
  • kits for preparing a peptide nanosuspension comprising a slurry container, milling media, a peptide, and an aqueous dispersion media comprising a surface-active polymer and optionally a surfactant.
  • the kit may comprise peptide, surface-active polymer, and/or surfactant in amounts suitable to prepare the nanosuspensions described herein.
  • Insulin (recombinant human) was obtained from Millipore Sigma Cat# 91077C-1G.
  • GNE-A is a disulfide constrained peptide and was obtained from Genentech Research Laboratories, South San Francisco, USA.
  • Cyclosporine A was obtained from Toronto Research Chemicals Cat# C988900 Lot# 15-XJZ-47-1.
  • Sandimmune® Injection (cyclosporine, USP) 50 mg/mL was obtained from McKesson Medical NDC #00078010901.
  • Formic acid was obtained from Alfa Aesar CAS #64-18-6.
  • Acetonitrile was obtained from VWR Cat# 099891.
  • Trifluoroacetic acid was obtained from J.T. Baker CAS #76-05-1.
  • Ammonium formate was obtained from Sigma-Aldrich CAS #540-69-2.
  • Sodium Dodecyl sulfate (SDS) was obtained from Spectrum Chemical CAS #151-21-3.
  • Plasdone (PVP) K29- 32 was obtained from Acros Organics CAS #2687-91-4.
  • Pluronic F127 was obtained from Sigma CAS #9003-11-6.
  • Tween 80 was obtained from Sigma CAS #9005-65-6.
  • Hydroxypropyl Cellulose (HPC)-SL was obtained from Alfa Aesar CAS #9004-64-2. Loadings and concentrations are reported as weight percent (wt%) unless otherwise noted.
  • Cyclosporin A was analyzed by using a BEH Cl 8 column (1.7mm, 2.1 x 150 mm). The injection volume was 5 pL and the column temperature was 45 °C. The detection wavelength was 214 nm and the flow rate was 0.5 mL per minute. 0.1% trifluoroacetic acid in water was used as mobile phase A and 0.1% trifluoroacetic acid in acetonitrile was used as mobile phase B.
  • GNE-A and insulin were analyzed by using a Halo Peptide ES-CN column (2.7 mm, 3.0 x 150 mm). The injection volume was 5 pL and the column temperature was 35 °C. The detection wavelength was 214 nm and the flow rate was 0.3 mL per minute. 0.1% formic acid in 10 mM ammonium formate (pH 3.2) was used as mobile phase A and 0.1% formic acid in 80/20 acetonitrile/lOmM ammonium formate was used as mobile phase B.
  • the viscosity was measured using a TA instruments HR-30 Discovery Hybrid Rheometer (Waters, New Castle, Delaware), equipped with a 20 mm stainless steel 1° angle cone. All samples were allowed to equilibrate at 25 °C prior to testing and a solvent trap was used to prevent solvent evaporation. The sample volume for each sample was 40 pL. The sample viscosity was measured every 15 s for 2.5 min at a constant shear rate of 1000/s. The viscosity (mPas or cP) was calculated by shear stress (Pa) divided by shear rate (1/s).
  • the injection force was measured using an Instron Materials Testing System (Model 5542; Norwood, MA) with an 100N load cell, a syringe holder fixture, a syringe plunger compression plate, and a glass vial to collect the expelled solution.
  • Model 5542 Norwood, MA
  • the samples (25 mg/mL) were prepared by attaching a 25G BD PrecisionGlide Needle (P/N 305122) to a BD 1 mL Luer-Lok syringe (P/N 309628) and extracting approximately 0.5 mL of nanosuspension or solution into the syringe.
  • the syringe and needle were primed to 0.3 mL, removing any air bubbles in the syringe.
  • the syringe was placed into the syringe holder and the Instron crosshead was lowered to contact the syringe plunger rod.
  • the program was initiated, displacing the instron crosshead 17.299 mm at 192 mm/min speed, while recording the associated injection force.
  • Example 1 Nanosuspension Screening Using Resonant Acoustic Milling
  • Resonant acoustic milling was evaluated as a technique for preparing stable nanoparticle suspensions using three structurally diverse peptides: cyclosporine A (CsA, a macrocyclic peptide), GNE-A (a cystine-knot peptide), and insulin (a large peptide hormone) (see FIGs. 1A-1C).
  • CsA cyclosporine A
  • GNE-A a cystine-knot peptide
  • insulin a large peptide hormone
  • Nanosuspension Screening Using Resonant Acoustic Milling A UV-Star clear, flat-bottom 96-well plate was used as a high throughput mixing container. Each well was charged with 500 pm YTZ grinding media from Tosoh (800 mg, 175 L by volume) (Tosoh USA, Inc., Grove City, OH, USA), 2 mg of peptide powder (1.3% drug loading), and 148 pL of an aqueous excipient solution. The concentrations of the polymer and/or surfactant excipients varied between 0.006% and 1.95% within each well. The plate was sealed with a Thermo Fisher Scientific ALPS 50 V Manual Heat Sealer (Thermo Fisher Scientific Inc., Waltham, MA, USA). The sealed plate was then placed on a Resodyn LabRAM II Resonant Acoustic mixer (Resodyn Acoustic Mixers, Butte, MT, USA) and milled at 50 G acceleration for 2 hours.
  • Tosoh 800 mg, 175 L by volume
  • Nanosuspension Scale-Up A 4-mL clear glass vial was used as a scale-up container. The vial was charged with 9.12 grams of 500 pm YTZ grinding media from Tosoh, 175 mg of peptide powder (10% drug loading), and 1.575 mL of an aqueous excipient solution. The vial was then placed on a Resodyn LabRAM II Resonant Acoustic mixer and milled at 50 G acceleration for 2 hours. The resulting nanosuspension was recovered by using a syringe equipped with an 18G needle.
  • Insulin is a large peptide hormone that regulates glucose metabolism in vivo. It consists of 51 amino acid residues in two linear peptide chains (21 peptide and 30 peptide chains) with an overall molecular weight of 5.8 kDa.
  • the insulin monomer is the physiologically active agent but is sensitive to instability (Brange, et al., “Stability and Characterization of Protein and Peptide Drugs, Case Histories,” Pharm. Biotechnol. 1993, 5, 315-350).
  • Insulin is particularly susceptible to aggregation, forming oligomers such as dimers, tetramers, and hexamers, as well as uncontrolled amyloid fibrils (Das, et al., “Molecular Aspects of Insulin Aggregation and Various Therapeutic Interventions,” ACS Bio Med Chem Au 2022, 2, 205-221).
  • insulin has been prepared as a zinc complex, which exists in a more stable hexamer form (Souto, et al., “Nanoparticle Delivery Systems in the Treatment of Diabetes Complications,” Molecules 2019, 24, 4209; Dunn, et al., “Zinc-Ligand Interactions Modulate Assembly and Stability of the Insulin Hexamer - A Review,” Biometals 2005, 18, 295-303).
  • most formulation work on insulin has been focused on mitigating aggregation in solution, particularly of the active monomeric form.
  • the samples were also analyzed by size exclusion chromatography (SEC).
  • SEC size exclusion chromatography
  • FIGs. 3A and 3B the insulin monomer concentration remains quantitative for both formulations even after 28 days for all of the samples with no presence of higher order oligomers such as dimers, trimers, or hexamers.
  • the chemical stability of the insulin nanosuspension was also investigated using reverse- phase (RP) chromatography (FIGs. 4A and 4B). Both of the formulations remained relatively chemically stable with only a small amount of degradation observed for the samples stored under the accelerated condition of 37 °C for 28 days.
  • GNE-A is a disulfide constrained peptide developed at Genentech. It is composed of a 30-residue linear peptide having three internal disulfide bonds with an overall molecular weight of 3.4 kDa. This peptide is highly prone to aggregation via multiple pathways, forming both amorphous non-covalent aggregates as well as oligomers formed from covalent disulfide scrambling (Chen, et al., “Discovery of a Dual Pathway Aggregation Mechanism for a Therapeutic Constrained Peptide,” J Pharm Sci 2021, 110, 2362-2371). As a result, the ability to overcome these risks and develop a stable high concentration formulation of GNE-A would be highly valuable.
  • nanosuspensions prepared with Tween80 and Pluronic Fl 27 retained their nanoparticle size after 28 days at room temperature and 4 °C conditions. However, a significant increase in the average particle size was observed for the Tween80 samples at the 37 °C conditions after 6 days. In contrast, the Pluronic F127 formulations remained relatively stable even after an extended period of time at 37 °C, with only a slight increase in average particle size with no excessive aggregation observed. In order to more closely quantitate the aggregation state and monomer content of GNE-A, the samples were also analyzed by SEC. As can be seen in FIGs. 6A and 6B, the GNE-A monomer concentration remains relatively stable under these conditions, although a reduction is seen for the samples stored at 37 °C.
  • GNE-A is also sensitive to chemical stability liabilities, particularly oxidation.
  • the nanosuspension samples were also analyzed by RP chromatography using a method to quantify the presence of the oxidative degradation product (FIGs. 7A and 7B).
  • the Tween80 formulations exhibited increasing amounts of oxidation degradation. This is likely due to the presence of small amounts of residual peroxide products in the Tween80 material (Ha, et al., Peroxide Formation in Polysorbate 80 and Protein Stability,” J. Pharm. Sci. 2002, 91, 2252-2264).
  • the Pluronic F127 formulation samples remained highly chemically stable with no significant oxidation degradation observed even after 28 days at 37 °C.
  • the nanosuspension formulations appeared to be highly chemically stable as well.
  • the stability benefits of the nanosuspension formulations of GNE-A are particularly striking when compared to a corresponding solution formulation prepared at the same concentration.
  • GNE-A can form a high concentration aqueous solution at pH levels >6.
  • a solution of GNE-A in 60 mM phosphate buffer at pH 7 was prepared at 100 mg/mL.
  • GNE-A rapidly begins to undergo aggregation and loss of monomer as determined by SEC (see FIG. 8).
  • the nanosuspension formulation also at 100 mg/mL concentration remains stable with 100% monomer over 28 days.
  • a nanoparticle suspension of GNE-A remains physically stable while reducing the tendency of the peptide to directly self-associate and undergo aggregation.
  • the active monomer form remains intact under these conditions.
  • Cyclosporine A is a macrocyclic peptide consisting of 11 amino acids and a molecular weight of 1.2 kDa. It has low solubility and low permeability, resulting in significant challenges in absorption (Pinar, et al., “Formulation Strategies of Nanosuspensions for Various Administration Routes,” Pharm 2023, 15, 1520). Due to aqueous solubility limitations, CsA is typically formulated by being dissolved in a mixture of lipids, surfactants, and cosolvents.
  • a current commercial oral formulation of CsA, Sandimmune® consists of an oral solution or liquid filled capsules with alcohol, com oil, glycerol, and Labrafil (Lemoine, et al., “Dose and Timing of Injections for Effective Cyclosporine A Pretreatment before Renal Ischemia Reperfusion in Mice,” Pios One 2017, 12, e0182358).
  • the corresponding injectable formulation consists of a large amount of Cremophor EL (a polyethoxylated castor oil) and alcohol to achieve the desired solubility.
  • the viscosities of the CsA nanosuspension formulation with 25% SDS was measured and compared to the commercial Sandimmune® solution to determine the feasibility of processing and injection at high concentrations.
  • the CsA nanosuspension was prepared at 100 mg/mL and diluted to 25 mg/mL and 5 mg/mL with water.
  • the commercial Sandimmune was purchased as a 50 mg/mL lipid-based formulation and was diluted to 25 mg/mL and 5 mg/mL with saline based on the package injection instructions. The two concentrations were chosen as the low and high doses for subcutaneous injection administration.
  • the CsA nanosuspension exhibits a low viscosity of 2.1 Pa*s even at a high concentration of 100 mg/mL, whereas the commercial Sandimmune® formulation only shows a similar viscosity at a much lower concentration of 5 mg/mL. Moreover, the Sandimmune® formulation shows significantly higher viscosities even at 25 mg/mL (Table 8). Interestingly, the viscosity at 25 mg/mL was observed to be higher than the viscosity at 50 mg/mL in the commercial Sandimmune formulation. The measurement was repeated twice with the same results. This may be due to the interaction of differing ratios of the lipid and aqueous phases at this shear range. Nevertheless, the viscosities of the CsA nanosuspension at all concentrations are dramatically lower and within the acceptable range with no injection concerns.
  • CsA cyclosporine A
  • SC single subcutaneous dose
  • the needle switching strategy was implemented on the high dose of Sandimmune® formulation due to its high injection force, whereas there was no injection concern for the aqueous nanosuspension formulations.
  • Male SD rats (6-9 weeks old) ranging from 237 to 251 g obtained from Charles River Laboratories (Hollister, CA) were used in the study with 4 rats per dose group. Animals were not fasted before subcutaneous dose administration. Blood samples (approximately 0.15 mL) were collected from each animal via jugular vein into tubes containing K2EDTA at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dose administration. Blood was centrifuged at 12,851 x g for 5 minutes to harvest plasma.
  • Compound concentration in each plasma sample was determined by a non-validated LC-MS/MS assay at Genentech, Inc.
  • the lower limit of quantitation (LLOQ) of CsA in plasma was 9.14 ng/mL or 0.00760 pM.
  • Mean CsA concentrations measured plasma were used to construct a semi logarithmic plasma concentration-time curve.
  • PK analysis was performed using nominal time, noncompartmental analysis, linear up log down calculation, and the extravascular input model (Model type: Plasma 200-202), PhoenixTM WinNonlin®, version 8.3 (Certara L.P.).
  • Table 9 Pharmacokinetic parameters of commercial Sandimmune® and nanosuspension formulations dosed via subcutaneous injection in rat at 10 and 50 mg/kg.
  • resonant acoustic milling can be used to prepare stable nanosuspension formulations of a wide variety of peptides with diverse sizes and structures. These peptide nanoparticles exhibit improved physical and chemical stability as well as benefits in formulation development and in vivo performance. In order to demonstrate that this is due to the unique nature of the resonant acoustic mixing effect, the same peptide materials were subjected to more traditional top-down nanomilling approaches as a comparison.
  • an ultrasonic probe supplies high intensity, high frequency waves (often above 20 kHz) to a sample in order to induce homogenization and reduce particle size (Sandhya, et al., “Ultrasonication an Intensifying Tool for Preparation of Stable Nanofluids and Study the Time Influence on Distinct Properties of Graphene Nanofluids - A Systematic Overview,” Ultrason. Sonochem. 2021, 73, 105479).

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Abstract

La présente invention concerne des procédés de préparation de formulations de nanoparticules peptidiques, et en particulier, des nanosuspensions peptidiques, à l'aide d'un broyage à faible cisaillement. Plus spécifiquement, l'invention concerne des procédés de préparation de nanosuspensions peptidiques par application d'énergie acoustique basse fréquence à un mélange comprenant un peptide, un milieu de dispersion aqueux comprenant un polymère tensioactif et éventuellement un tensioactif, et des milieux de broyage, jusqu'à ce que le peptide ait été broyé à la taille nanoparticulaire. L'invention concerne également des nanosuspensions peptidiques stables préparées selon les procédés.
PCT/US2024/053194 2023-10-31 2024-10-28 Procédé de préparation de formulations de nanoparticules peptidiques stables Pending WO2025096329A1 (fr)

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