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US20200253865A1 - Supraparticles - Google Patents

Supraparticles Download PDF

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Publication number
US20200253865A1
US20200253865A1 US16/648,858 US201816648858A US2020253865A1 US 20200253865 A1 US20200253865 A1 US 20200253865A1 US 201816648858 A US201816648858 A US 201816648858A US 2020253865 A1 US2020253865 A1 US 2020253865A1
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United States
Prior art keywords
supraparticles
payload
another example
composition
sps
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US16/648,858
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English (en)
Inventor
Andrew Wise
Frank Caruso
Mattias Bjornmalm
Yutian Ma
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Melbourne
Bionics Institute
Original Assignee
University of Melbourne
Bionics Institute of Australia
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Priority claimed from AU2017903828A external-priority patent/AU2017903828A0/en
Application filed by University of Melbourne, Bionics Institute of Australia filed Critical University of Melbourne
Publication of US20200253865A1 publication Critical patent/US20200253865A1/en
Assigned to THE UNIVERSITY OF MELBOURNE reassignment THE UNIVERSITY OF MELBOURNE ASSIGNMENT DEED SIGNED BY EMPLOYEE Assignors: CARUSO, FRANK, BJORNMALM, Mattias
Assigned to THE BIONICS INSTITUTE OF AUSTRALIA reassignment THE BIONICS INSTITUTE OF AUSTRALIA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MA, Yutian, WISE, ANDREW
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
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    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
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    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present disclosure relates to improved supraparticles loaded with high levels of payload and methods for their production. Such supraparticles may be used in a range of therapeutic applications.
  • Mesoporous silica's are porous materials with extremely high surface areas which have been widely used to encapsulate various compounds and for the template synthesis of diverse nanostructured materials. While, porous materials of this type are of interest in a diverse range of applications such as drug delivery, various issues such as efficient loading and sustained drug delivery remain unresolved.
  • the present disclosure is based on the unexpected production of supraparticles that can be loaded with high levels of payload.
  • the present inventors have also identified that supraparticles of the present disclosure appear to have unique pore sizes which may account for the increased levels of loading. Accordingly, in a first example, the present disclosure relates to a composition comprising a supraparticle, wherein the supraparticle comprises at least 1.5 ⁇ g of payload. In another example, the present disclosure relates to a composition comprising a supraparticle, wherein the supraparticle comprises at least 5 ⁇ g of payload. In another example, the present disclosure relates to a composition comprising a supraparticle, wherein the supraparticle comprises at least 8 ⁇ g of payload.
  • the present disclosure relates to a composition comprising a supraparticle, wherein the supraparticle comprises at least 10 ⁇ g of payload. In another example, the present disclosure relates to a composition comprising a supraparticle, wherein the supraparticle comprises 1.5 ⁇ g to 10 ⁇ g of payload.
  • the supraparticle comprises pores having a diameter of at least 60 nm. In another example, the supraparticle comprises pores having a diameter of at least 100 nm. In another example, the supraparticle comprises pores having a diameter of at least 60-200 nm. In another example, the supraparticle comprises pores having a diameter of at least 50-100 nm.
  • the supraparticles have a disordered pore structure.
  • the supraparticle is comprised of nanoparticles having a bimodal pore structure.
  • the nanoparticles bimodal pore structure has a large pore diameter greater than 30 nm.
  • the payload is a small molecule, a peptide or a protein.
  • the payload may be an antibody.
  • the payload is a stem cell, virus, nucleic acid, neurotrophic factor, anti-cancer agent, neuroprotectant or combination thereof.
  • the payload is a neurotrophic factor.
  • the payload is a neurotrophin.
  • the neurotrophic factor has an isoelectric point between 9 and 10.
  • the payload is neurotrophin-3.
  • the payload is BDNF or neurotrophin-3.
  • the supraparticle comprises at least 2, at least 3, at least 4, at least 5 different payloads. In another example, the supraparticle comprises at least two payloads, one payload being a neurotrophic factor. In another example, the supraparticle comprises at least two payloads, one payload being a neurotrophin.
  • composition disclosed herein comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10 supraparticles.
  • the supraparticles may comprise different payloads.
  • supraparticles may be produced by electrospraying a composition comprising nanoparticles into a di-cationic aqueous solution.
  • the composition comprising nanoparticles also comprises an Alginic acid or a polysaccharide derivative thereof.
  • supraparticles may be produced by electrospraying a composition comprising nanoparticles and Alginic acid or a polysaccharide derivative thereof into a di-cationic aqueous solution.
  • Supraparticles produced in these examples may be loaded with 1.5 ⁇ g to 15 ⁇ g of a payload such as a neurotrophin.
  • supraparticles may also be subject to calcination to remove alginic acid before being loaded with payload.
  • calcination is performed at around 650° C. In an example, the calcination is performed for about 6 to about 30 hours.
  • the Alginic acid is Alginic acid sodium salt.
  • the present disclosure encompasses compositions comprising supraparticles disclosed herein, wherein the supraparticles are manufactured by electrospraying a composition comprising nanoparticles and alginic acid or a polysaccharide derivative thereof into a di-cationic aqueous solution.
  • the supraparticles may be subjected to calcination to remove alginic acid.
  • the calcination is performed at around 650° C. In an example, the calcination is performed for about 6 to about 30 hours.
  • supraparticles disclosed herein can, in some aspects release payload over a relatively long period of time.
  • supraparticles disclosed herein can, in some aspects be provided in various formulations to manipulate release of payload.
  • the present inventors have identified in certain examples, that supraparticles according to the present disclosure can release their respective payload over a prolonged duration. They have also identified that supraparticles disclosed herein can, in some aspects be provided in various formulations to accelerate or slow the release of payload.
  • a supraparticle or composition disclosed herein may be provided as a slow release formulation.
  • the slow release formulation is a foam or a gel.
  • a composition disclosed herein comprised a glycogen hydrogel.
  • a composition disclosed herein comprises Alginic acid [(C 6 H 8 O 6 ) n ] or a polysaccharide derivative thereof. In another example, a composition disclosed herein comprises Alginic acid sodium salt [Na(C 6 H 8 O 6 ) n ] or a polysaccharide derivative thereof.
  • a composition disclosed herein is provided as an accelerated release formulation.
  • the accelerated release formulation is a foam or a gel.
  • the gel or foam is thermoreversible.
  • the accelerated formulation may comprise a supraparticle disclosed herein and a PF127 based hydrogel.
  • the present disclosure encompasses use of a composition defined herein in the manufacture of a medicament for treating a disease or disorder.
  • the disease or disorder is hearing loss.
  • the hearing loss is characterised as sensorineural hearing loss (SNHL), presbycusis or noise induced.
  • the present disclosure encompasses a method for promoting survival of spiral ganglion neurons in an ear of a subject, the method comprising administering a composition defined herein to a subject.
  • the composition can be administered to a subject's ear.
  • the present disclosure encompasses a method for treating a condition in which sustained delivery of a therapeutic payload is desirable in a subject, the method comprising administering a composition defined herein to a subject.
  • the composition is administered to an ear of a subject.
  • the composition is administered intraperitoneally.
  • the composition is administered to the central nervous system.
  • the composition is administered via ventricular administration.
  • the composition is administered in a scaffold which retains the supraparticles.
  • the present disclosure encompasses a kit comprising a composition defined herein when used for treating a disease or disorder.
  • the disorder is hearing loss.
  • the kit further comprises a cochlear implant.
  • the present inventors have also identified that electrospraying a composition comprising nanoparticles and Alginic acid can produce supraparticles that can be loaded with high levels of payload. Accordingly, in an example, the present disclosure also encompasses a composition comprising nanoparticles and Alginic acid when used for manufacturing supraparticles defined herein.
  • the Alginic acid is Alginic acid sodium salt.
  • the present disclosure encompasses a method of manufacturing supraparticles comprising electrospraying a composition comprising nanoparticles and alginic acid or a polysaccharide derivative thereof into a di-cationic aqueous solution.
  • the method further comprises subjecting the supraparticles to calcination to remove alginic acid.
  • calcination is performed at around 650° C. In an example, the calcination is performed for about 6 to about 30 hours.
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.
  • FIG. 1 Procedure of making MS-SPs.
  • FIG. 2 Zeta potential of MS-SPs as a function of different pH values. Zeta potential measurements were carried out in 10 mM sodium acetate buffer (pH 4), 10 mM phosphate buffer (pH 6), 10 mM HEPES buffer (pH 8) and 10 mM sodium bicarbonate buffer (pH 10).
  • FIG. 3 Confocal microscopy images of MS-SPs loaded with FITC-lysozyme (green). a, b) MS-SPs at different magnifications. c) Inside of a fragmented MS-SP loaded with FITC-lysozyme.
  • FIG. 4 Drug loading after 3 days (72 h) incubation time using different FITC-lysozyme loading concentration.
  • FIG. 5 FITC-lysozyme loading and release behaviour from MS-SPs with different diameters. a) FITC-lysozyme loading amount, b) In-vitro FITC-lysozyme release profile, c) the value of FITC-lysozyme released at each individual time point, d) In-vitro FITC-lysozyme release standard curve from MS-SPs with the diameter of 200, 550, 650, 1000 ⁇ m.
  • FIG. 6 Cell viability of human brain glioblastoma cells (U87MG cell line) incubated with different numbers of MS-SPs for 48 h. Ethanol added to cells with inserts was prepared as negative (cytotoxic) control and untreated cells represent 100% viability. Data presented is average of four samples, and error bars represent standard deviation.
  • FIG. 7 In-vitro cumulative drug release profile.
  • BDNF ELISA Abcam was used for the measurement of BDNF concentration.
  • FIG. 8 The value of FITC-lysozyme released in each individual time point for MS-SPs alg and MS-SPs (loading conditions: 100 ⁇ L of 0.2 mg mL ⁇ 1 of FITC-lysozyme loaded, 3 days loading time). Data presented is average of three replicates, each using ten supraparticles, and error bars represent standard deviation.
  • FIG. 9 The value of FITC-lysozyme released in each individual time point for MS-SPs (loading conditions: 100 ⁇ L of 1.0 mg mL ⁇ 1 of FITC-lysozyme loaded over 3 days). Drug loading was 6.49 ⁇ 0.48 ⁇ g per supraparticle. Data presented is average of three replicates, each using ten MS-SPs, and error bars represent standard deviation.
  • FIG. 10 The absolute value in each individual time points for in-vitro BDNF drug studies (loading conditions: 1.0 mg mL ⁇ 1 BDNF loaded over 3 days). Data presented is average of three replicates, each using one MS-SP, and error bars represent standard deviation.
  • FIG. 11 a) MicroBCA assay for the measurement of BDNF from MS-SPs. b) The value of BDNF released at each individual time point of using MS-SPs. Drug loading is 6.82 ⁇ g per supraparticle. Data presented is average of three replicates, and error bars represent standard deviation.
  • FIG. 12 a) In-vitro FITC-lysozyme release profile of MS-SPs (red circle), and MS-SPs alg (black square) in PF127 hydrogel system. b) The value of FITC-lysozyme released at each individual time point for figure (a) (100 ⁇ L of 0.2 mg mL ⁇ 1 FITC-lysozyme loaded). Drug loading is 1.89 ⁇ 0.08 ⁇ g per supraparticle and 1.93 ⁇ 0.03 ⁇ g per supraparticle in MS-SPs and MS-SPs alg respectively. Data presented is average of three replicates, each using ten supraparticles, and error bars represent standard deviation.
  • FIG. 13 In vitro release profile when 50% loaded (3.65 ⁇ g/SP)
  • FIG. 14 Degradation of MS-SPs after 150 days of in-vitro drug release studies. a) SEM image of MS-SPs after 150 days of incubation in PBS (pH 7.4) at 37° C. b, c) SEM images of the surface structure of MS-SPs after 150 days of incubation in PBS (pH 7.4) at 37° C.
  • FIG. 15 Amount of neurotrophin-3 (% of loaded) and the total in ⁇ g is shown. After 1 week of implantation each SP contained 2 ug of neurotrophin-3 ( ⁇ 40%) of initial loaded amount.
  • treatment refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology.
  • exemplary desirable effects of treatment include reduction in symptoms associated with a disorder being treated.
  • desirable effects of treatment include decreasing the rate of hearing loss and ameliorating or palliating hearing loss.
  • An individual is successfully “treated”, for example, if one or more symptoms associated with the disorder are mitigated or eliminated.
  • a “therapeutically effective amount” refers to at least the minimum amount required to effect a measurable improvement of a particular disorder.
  • a therapeutically effective amount can also include at least the minimum amount required to effect a measurable improvement in a subjects disorder.
  • a therapeutically effective amount can be provided in one or more administrations. The therapeutically effective amount may vary according to the severity of the disorder being treated and also according to the weight, age, racial background, sex, health and/or physical condition of a subject being treated. Typically, the effective amount will fall within a relatively broad range (e.g. a “dosage” range) that can be determined through routine trial and experimentation by a medical practitioner.
  • the therapeutically effective amount can be administered in a single dose or in a dose repeated once or several times over a treatment period.
  • Supraparticles can comprise various payloads.
  • the “payload” can be any agent useful for treating a disorder.
  • agents include biological products such as polynucleotides, antibodies, monoclonal antibodies, antibody fragments, antibody drug conjugates, proteins, biologically active proteins, fusion proteins, recombinant proteins, peptides, polypeptides, synthesized polypeptides, vaccines, therapeutic serums, viruses, polynucleotides, cells such as stem cells or parts thereof as well as small molecules.
  • Exemplary viral payloads can comprise appropriately modified retrovirus, Adenovirus (AdV), Adeno-associated virus (AAV) or a recombinant form such as recombinant adeno-associated virus (rAAV) and derivatives thereof such as self-complementary AAV (scAAV) and non-integrating AV.
  • Other exemplary viral therapeutic payloads can comprise herpes simplex virus (HSV), lentivirus, vaccina and vesicular stomatitis virus (VSV).
  • HSV herpes simplex virus
  • VSV vesicular stomatitis virus
  • the viral therapeutic payload can comprise AAV.
  • Various AAV serotypes are known and may be suitable viral payloads.
  • the AAV is serotype 2.
  • the AAV is serotype 1.
  • the AAV is serotype 3, 4, 7, 8, 9, 10, 11, 12 or 13.
  • the small molecule is a neurotransmitter.
  • neurotransmitter is used in the context of the present disclosure to refer to a substance that transmits signal(s) across a chemical synapse from one cell to another.
  • a neurotransmitter transmits signal(s) across a chemical synapse from one neuron to a target cell such as another neuron, muscle cell or gland cell.
  • the small molecule is a receptor agonist.
  • agonist is used in the context of the present disclosure to refer to a substance which initiates a physiological response when combined with a receptor.
  • the small molecule is a receptor antagonist.
  • antagonist is used in the context of the present disclosure to refer to a substance which interferes with or inhibits the physiological action of a receptor.
  • Exemplary polynucleotides include antisense polynucleotides, double stranded DNA (dsDNA) or double stranded RNA (dsRNA).
  • dsDNA or dsRNA is an aptamer.
  • the dsRNA is a siRNA, miRNA or shRNA.
  • Exemplary antibodies and fragments thereof include human antibodies, humanized antibodies, chimeric antibodies, single chain antibodies, diabodies, triabodies, tetrabodies or single domain antibodies.
  • the antibody can be bi-specific, an antibody-drug conjugate or a biosimilar antibody.
  • Other exemplary polypeptides include cytokines, chemokines, hormones and blood coagulation factors.
  • the polypeptide is an enzyme.
  • Exemplary enzymes include proteases, lipases, asparaginases, liprotamases, tissue plasminogen activators, collagenases, glutaminases, hyaluronidases, streptokinases, uricases, urokinases or nucleases, such as a programmable nuclease.
  • the enzyme can be a DNA methyltransferase.
  • the enzyme can be a programmable nuclease targeted to introduce a genetic modification into a gene or a regulator region thereof.
  • the programmable nuclease can be a RNA-guided engineered nuclease (RGEN).
  • the RGEN is from an archaeal genome or may be a recombinant version thereof. In another example, the RGEN may be from a bacterial genome or is a recombinant version thereof. In another example, the RGEN is from a Type I (CRISPR)-cas (CRISPR-associated) system. In another example, the RGEN is from a Type II (CRISPR)-cas (CRISPR-associated) system. In another example, the RGEN is from a Type III (CRISPR)-cas (CRISPR-associated) system. In an example, the nuclease is from a class I RGEN or a class II RGEN.
  • the therapeutic payload is a DNA methylation inhibitor, a histone acetyl transferase inhibitor or a histone deacetylase inhibitor.
  • the therapeutic payload may be an antigen which stimulates an immune response in a subject.
  • antigens include proteins, peptides, polysaccharides or oligosaccharides (free or conjugated to a protein carrier) or mixtures thereof.
  • Other exemplary antigens include cells or parts thereof or a viral particle or a part thereof.
  • the therapeutic payload is an antineoplastic agent.
  • therapeutic payloads include agonists or antagonists to membrane receptors in the inner ear. Such therapeutic payloads may modulate neurotransmission.
  • the therapeutic payload is a neurological agent useful for treating one or more neurological disorders, such as Alzheimer's disease, Parkinson's disease, Epilepsy or multiple sclerosis.
  • the payload is a “neurotrophic factor”.
  • neurotrophic factor is used in the context of the present disclosure to refer to molecules that enhance the growth or survival potential of any cells including those from the auditory system.
  • neurotrophic factors encompassed by the present disclosure can enhance growth or survival of cells from the auditory system or their synaptic connections located in the inner ear, middle ear or vestibular system.
  • Exemplary cells include spiral ganglion neurons (SGNs), hair cells, including inner and outer ear hair cells, cochlear glial cells and Schwann cells.
  • SGNs spiral ganglion neurons
  • hair cells including inner and outer ear hair cells
  • exemplary synaptic connections include connections between hair cells, hair cells and SGNs or other neurons discussed above.
  • Other examples include neuronal cell bodies in Rosenthal's canal or their synaptic connections, neurons or synaptic connections in the upper middle cochlear regions and/or nerve fibres in the osseous spiral la
  • Exemplary neurotrophic factors can include agents discussed above with known therapeutic efficacy for directly or indirectly enhancing survival of cells from the auditory system and/or their synaptic connections.
  • the neurotrophic factor is a neurotrophic peptide.
  • exemplary neurotrophic peptides include, brain derived neuroptrophic factor (BDNF), nerve growth factor, neurotrophin-3, neurotrophin-4, members of the ciliary neurotrophic factor (CNTF) family such as CNTF, Leukemia inhibitory factor (LIF), Interleukin-6 (IL-6), Glia maturation factor (GMF), insulin growth factor-1 (IGF-1), Neuregulin 1, Neuregulin 2, Neuregulin 3 and Neuregulin 4, vascular endothelial growth factor (VEGF), members of the Glial Cell Derived Neurotrophic Factor (GDNF) family such as GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN), ephrins such as A1, A2, A3, A4, A5, B1, B2 and B3, insulin growth factor-1 (IGF-1) and interleukins such as IL-11.
  • BDNF brain derived
  • the neurotrophic factor is selected from the group consisting of brain derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, neurotrophin-4, ciliary neurotrophic factor (CNTF), Glial Cell Derived Neurotrophic Factor (GDNF) and IL-11.
  • BDNF brain derived neurotrophic factor
  • nerve growth factor neurotrophin-3
  • neurotrophin-4 neurotrophin-4
  • CNTF ciliary neurotrophic factor
  • GDNF Glial Cell Derived Neurotrophic Factor
  • IL-11 IL-11.
  • the neurotrophic factor is a neurotrophin.
  • the term “neurotrophin” is used in the context of the present disclosure to refer to proteins that induce the survival, development and/or function of neurons and/or their synaptic connections. Exemplary neurotrophins are discussed above and include BDNF, nerve growth factor, neurotrophin-3 and neurotrophin-4. Accordingly, in an example, the supraparticle comprises BDNF. In another example, the supraparticle comprises nerve growth factor. In another example, the supraparticle comprises neurotrophin-3. In another example, the supraparticle comprises neurotrophin-4. In an example, supraparticles can comprise at least two different neurotrophins. In other examples, supraparticles can comprise at least three or four different neurotrophins.
  • supraparticles comprising multiple different therapeutic payloads.
  • supraparticles can comprise at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10 different therapeutic payloads.
  • supraparticles can comprise at least two different neurotrophic factors.
  • supraparticles can comprise at least three, at least four, at least five different neurotrophic factors.
  • various combinations of neurotrophic factors such as neurotrophins are contemplated.
  • neurotrophic factors include BDNF and nerve growth factor, BDNF and neurotrophin-3, BDNF and neurotrophin-4, BDNF and CNTF, BDNF and GDNF, BDNF and IL-11, neurotrophin-3 and neurotrophin-4, neurotrophin-3 and CNTF, neurotrophin-3 and CNTF, neurotrophin-3 and GDNF, neurotrophin-3 and IL-11, neurotrophin-4 and CNTF, neurotrophin-4 and GDNF, neurotrophin-4 and IL-11, CNTF and GDNF, CNTF and IL-11, GDNF and IL-11, BDNF, neurotrophin-3 and neurotrophin-4, BDNF, neurotrophin-3 and CNTF, BDNF, neurotrophin-3 and GDNF, BDNF, BDNF, CNTF and GDNF, BDNF, CNTF and IL-11, neurotrophin-3, neurotrophin-4 and CNTF, neurotrophin-3 and GDNF, BDNF, BDNF, CNTF
  • neurotrophic factors assist in tissue repair, reducing inflammation and/or reducing infection.
  • additional exemplary neurotrophic factors include steroids or antioxidants.
  • Other exemplary neurotrophic factors include antibodies or other binding proteins such as anti-Tropomyosin receptor kinase (TrK) B, anti-TrK C or binding proteins that interact with p75 neurotrophin receptor. For example, p75 neurotrophin receptor antagonists.
  • neurotrophic factors include nucleic acids.
  • the neurotrophic factor can comprise a gene therapy, silencing RNA such as a siRNA or miRNA, expression constructs such as DNA plasmids comprising a nucleic acid of interest.
  • the neurotrophic factor is an expression construct comprising a nucleic acid encoding an opsin(s).
  • a supraparticle can comprise a steroid such as dexamethasone or prednisolone and any one or more of BDNF, nerve growth factor, neurotrophin-3, neurotrophin-4 and GDNF.
  • a supraparticle can comprise an expression vector comprising an opsin and any one or more of BDNF, nerve growth factor, neurotrophin-3, neurotrophin-4 and GDNF.
  • a supraparticle can comprise an antibody such as anti-Tropomyosin receptor kinase (TrK) B or anti-TrK C and any one or more of BDNF, nerve growth factor, neurotrophin-3, neurotrophin-4, GDNF and IL-11.
  • TrK anti-Tropomyosin receptor kinase
  • supraparticles can comprise at least two, at least three, at least four, at least five different therapeutic payloads wherein at least one therapeutic payload is a neurotrophic factor.
  • supraparticles can comprise at least three different therapeutic payloads wherein two therapeutic payloads are neurotrophic factors.
  • supraparticles can comprise at least four different therapeutic payloads wherein three therapeutic payloads are neurotrophic factors.
  • the therapeutic payload need not enhance the growth or survival potential of cells from the auditory system but rather can provide another therapeutic benefit.
  • the therapeutic payload may suppress a subject's immune system following administration of supraparticles.
  • supraparticles may comprise a payload that reduces survival of cells from the auditory system or their synaptic connections and a neurotropic factor(s).
  • the neurotrophic factor may alleviate the reduction in survival of cells from the auditory system or their synaptic connections caused by the therapeutic payload.
  • supraparticles comprise antineoplastic agents including cisplatinum or related compounds, antibiotics including aminoglycosides such as tobrahmycin or related compounds, loop diuretics such as furosemide, antimetabolites such as methotrexate, salicylates such as aspirin or a radioactive moiety and a neurotrophic factor(s).
  • a supraparticle can comprise an antibiotic and any one or more of BDNF, nerve growth factor, neurotrophin-3, neurotrophin-4, GDNF and IL-11.
  • supraparticles may comprise a molecule(s) that assist diffusion of the payload across the round and oval windows to the inner ear and/or vestibular system.
  • the payload has an isoelectric point greater than 7. In another example, the payload has an isoelectric point greater than 8. In another example, the payload has an isoelectric point greater than 9. In another example, the payload has an isoelectric point greater than 10. In another example, the payload has an isoelectric point between 7 and 10. In another example, the payload has an isoelectric point between 7 and 9. In another example, the payload has an isoelectric point between 8 and 10. In another example, the payload has an isoelectric point between 9 and 10.
  • Supraparticles comprising a payload may be referred to as loaded supraparticles in the context of the present disclosure.
  • Methods of producing loaded supraparticles are not particularly limited so long as the resulting supraparticle can be loaded with at least 1.5 ⁇ g of payload.
  • the resulting supraparticle can deliver the payload to an ear of a subject.
  • Exemplary methods of loading are reviewed in Wang et al. (2009) J. Mater. Chem. 19, 6451 and include payload encapsulation and entrapment.
  • supraparticles may be loaded by contacting the supraparticle with an aqueous solution of the payload followed by a period of incubation.
  • the payload solution can contain an excess of the amount of payload to be loaded onto the supraparticle and incubation can occur at room temperature. Agitation of the solution containing the supraparticle and the payload may be used to enhance loading of the payload.
  • SAP agglomerated particles comprising a network of pores.
  • the network of pores provides supraparticles with a large pore volume and surface area for carrying a payload.
  • a large pore volume and surface area is advantageous as it can enhance the amount of payload that can be carried by supraparticles.
  • supraparticles according to the present disclosure are agglomerated nanoparticles.
  • supraparticles according to the present disclosure comprise at least 1.5 ⁇ g of payload. In another example, supraparticles comprise at least 2.0 ⁇ g of payload.
  • supraparticles according to the present disclosure comprise at least 2.5 ⁇ g of payload. In another example, supraparticles comprise at least 2.6 ⁇ g of payload. In another example, supraparticles comprise at least 2.7 ⁇ g of payload. In another example, supraparticles comprise at least 2.7 ⁇ g of payload. In another example, supraparticles comprise at least 2.8 ⁇ g of payload. In another example, supraparticles comprise at least 2.9 ⁇ g of payload. In another example, supraparticles comprise at least 3.0 ⁇ g of payload. In another example, supraparticles comprise at least 3.1 ⁇ g of payload. In another example, supraparticles comprise at least 3.2 ⁇ g of payload.
  • supraparticles comprise at least 3.3 ⁇ g of payload. In another example, supraparticles comprise at least 3.4 ⁇ g of payload. In another example, supraparticles comprise at least 3.5 ⁇ g of payload. In another example, supraparticles comprise at least 3.6 ⁇ g of payload. In another example, supraparticles comprise at least 3.7 ⁇ g of payload. In another example, supraparticles comprise at least 3.8 ⁇ g of payload. In another example, supraparticles comprise at least 3.9 ⁇ g of payload. In another example, supraparticles comprise at least 4.0 ⁇ g of payload. In another example, supraparticles comprise at least 4.5 ⁇ g of payload.
  • supraparticles comprise at least 5.0 ⁇ g of payload. In another example, supraparticles comprise at least 5.5 ⁇ g of payload. In another example, supraparticles comprise at least 6.0 ⁇ g of payload. In another example, supraparticles comprise at least 6.5 ⁇ g of payload. In another example, supraparticles comprise at least 7.0 ⁇ g of payload. In another example, supraparticles comprise at least 7.5 ⁇ g of payload. In another example, supraparticles comprise at least 8.0 ⁇ g of payload. In another example, supraparticles comprise at least 8.5 ⁇ g of payload. In another example, supraparticles comprise at least 9.0 ⁇ g of payload.
  • supraparticles comprise at least 9.5 ⁇ g of payload. In another example, supraparticles comprise at least 10 ⁇ g of payload. In another example, supraparticles comprise at least 10.5 ⁇ g of payload. In another example, supraparticles comprise at least 11 ⁇ g of payload. In another example, supraparticles comprise at least 11.5 ⁇ g of payload. In another example, supraparticles comprise at least 12 ⁇ g of payload. In another example, supraparticles comprise at least 15 ⁇ g of payload. In another example, supraparticles comprise at least 20 ⁇ g of payload.
  • supraparticles can comprise at least 6 ⁇ g of payload. In another example, supraparticles can comprise between about 2.5 and 10 ⁇ g of payload. In another example, supraparticles can comprise between about 3 and 10 ⁇ g of payload. In another example, supraparticles can comprise between about 4 and 10 ⁇ g of payload. In another example, supraparticles can comprise between about 5 and 10 ⁇ g of payload. In another example, supraparticles can comprise between about 6 and 10 ⁇ g of payload. In another example, supraparticles can comprise between about 5 and 15 ⁇ g of payload. In another example, supraparticles can comprise between about 5 and 20 ⁇ g of payload. In another example, supraparticles can comprise between about 8 and 20 ⁇ g of payload. In another example, supraparticles can comprise between about 8 and 15 ⁇ g of payload.
  • supraparticles can comprise between about 6 and 8 ⁇ g of payload.
  • supraparticles according to the present disclosure comprise at least 1.5 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 2.0 ⁇ g of neurotrophic factor.
  • supraparticles comprise at least 2.5 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 3.0 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 3.5 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 4.0 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 5.0 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 6.0 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 7.0 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 8.0 ⁇ g of neurotrophic factor.
  • supraparticles comprise at least 9.0 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 10 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 10.5 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 11 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 11.5 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 12 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 15 ⁇ g of neurotrophic factor. In another example, supraparticles comprise at least 20 ⁇ g of neurotrophic factor.
  • supraparticles can comprise at least 6 ⁇ g of neurotrophic factor. In another example, supraparticles can comprise between about 2.5 and 10 ⁇ g of neurotrophic factor. In another example, supraparticles can comprise between about 5 and 10 ⁇ g of neurotrophic factor. In another example, supraparticles can comprise between about 6 and 10 ⁇ g of neurotrophic factor. For example, supraparticles can comprise between about 6 and 8 ⁇ g of neurotrophic factor. In another example, supraparticles can comprise between about 5 and 15 ⁇ g of neurotrophic factor. In another example, supraparticles can comprise between about 5 and 20 ⁇ g of neurotrophic factor. In another example, supraparticles can comprise between about 8 and 20 ⁇ g of neurotrophic factor. In another example, supraparticles can comprise between about 8 and 15 ⁇ g of neurotrophic factor.
  • supraparticles according to the present disclosure comprise at least 1.5 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 2.0 ⁇ g of neurotrophin.
  • supraparticles comprise at least 2.5 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 3.0 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 3.5 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 4.0 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 5.0 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 6.0 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 7.0 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 8.0 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 9.0 ⁇ g of neurotrophin.
  • supraparticles comprise at least 10 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 10.5 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 11 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 11.5 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 12 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 15 ⁇ g of neurotrophin. In another example, supraparticles comprise at least 20 ⁇ g of neurotrophin.
  • supraparticles can comprise at least 6 ⁇ g of neurotrophin. In another example, supraparticles can comprise between about 2.5 and 10 ⁇ g of neurotrophin. In another example, supraparticles can comprise between about 5 and 10 ⁇ g of neurotrophin. In another example, supraparticles can comprise between about 6 and 10 ⁇ g of neurotrophin. For example, supraparticles can comprise between about 6 and 8 ⁇ g of neurotrophin. In another example, supraparticles can comprise between about 5 and 15 ⁇ g of neurotrophin. In another example, supraparticles can comprise between about 5 and 20 ⁇ g of neurotrophin. In another example, supraparticles can comprise between about 8 and 20 ⁇ g of neurotrophin. In another example, supraparticles can comprise between about 8 and 15 ⁇ g of neurotrophin.
  • supraparticles according to the present disclosure comprise at least 1.5 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 2.0 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10.
  • supraparticles comprise at least 2.5 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 3.0 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 3.5 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 4.0 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 5.0 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10.
  • supraparticles comprise at least 6.0 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 7.0 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 8.0 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 9.0 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 10 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10.
  • supraparticles comprise at least 10.5 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 11 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 11.5 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 12 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 15 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles comprise at least 20 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10.
  • supraparticles can comprise at least 6 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10.
  • supraparticles can comprise between about 2.5 and 10 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles can comprise between about 5 and 10 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles can comprise between about 6 and 10 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. For example, supraparticles can comprise between about 6 and 8 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles can comprise between about 5 and 20 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10.
  • supraparticles can comprise between about 5 and 15 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles can comprise between about 8 and 20 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10. In another example, supraparticles can comprise between about 8 and 15 ⁇ g of payload, wherein the payload has an isoelectric point between 9 and 10.
  • the payload can be a neurotrophin which has an isoelectric point between 9 and 10.
  • supraparticles having an above referenced payload can be provided in an alginate hydrogel.
  • supraparticles of the present disclosure can be loaded with an above exemplified payload and can have a pore size selected from the examples discussed below.
  • supraparticles are microporous.
  • the term “microporous” is used in the context of the present disclosure to refer to particles having a pore size of less than about 2 nm.
  • microporous supraparticles can have a pore size of about 0.5 nm to about 2 nm.
  • microporous supraparticles have a pore size of about 1 nm to about 2 nm, about 1.5 nm to about 2 nm.
  • supraparticles are mesoporous.
  • mesoporous is used in the context of the present disclosure to refer to particles having pores with diameters between about 2 nm and about 50 nm.
  • mesoporous supraparticles can have a pore size of about 2 nm to about 50 nm.
  • mesoporous supraparticles have a pore size of about 2 nm to about 40 nm, about 2 nm to about 30 nm.
  • supraparticles are macroporous.
  • macroporous is used in the context of the present disclosure to refer to particles having a pore size of greater than about 50 nm.
  • macroporous supraparticles can have a pore size of about 50 nm to about 500 nm. In other examples, macroporous supraparticles have a pore size of about 50 nm to about 250 nm, about 50 nm to about 150 nm, about 50 nm to about 100 nm.
  • supraparticles are comprised of microporous nanoparticles.
  • supraparticles are comprised of nanoparticles having a pore size of about 0.5 nm to about 2 nm.
  • supraparticles are comprised of nanoparticles having a pore size of about 1 nm to about 2 nm, about 1.5 nm to about 2 nm.
  • supraparticles are comprised of mesoporous nanoparticles.
  • supraparticles are comprised of nanoparticles having a pore size of about 2 nm to about 50 nm.
  • supraparticles are comprised of nanoparticles having a pore size of about 2 nm to about 40 nm, about 2 nm to about 30 nm.
  • supraparticles are comprised of macroporous nanoparticles.
  • supraparticles are comprised of nanoparticles having a pore size of about 50 nm to about 95 nm.
  • supraparticles are comprised of nanoparticles having a pore size of about 50 nm to about 85 nm, about 50 nm to about 75 nm, about 50 nm to about 65 nm.
  • supraparticles are comprised of nanoparticles having a bimodal pore structure.
  • the term “bimodal” is used in the context of the present disclosure to refer to particles comprising multiple pore sizes, generally a smaller pore size and a larger pore size.
  • supraparticles can comprise nanoparticles having mesopores and macropores.
  • such supraparticles are comprised of nanoparticles having pores ranging from 2 nm to 95 nm.
  • supraparticles are comprised of bimodal nanoparticles having pores ranging from 10 nm to 95 nm.
  • supraparticles are comprised of bimodal nanoparticles having pores ranging from 15 nm to 95 nm.
  • supraparticles can comprise pore sizes ranging from 1 nm to 200 nm.
  • supraparticles are comprised of bimodal nanoparticles having smaller pore sizes of about 1 nm to about 5 nm and larger pore sizes of about 10 nm to about 50 nm.
  • supraparticles are comprised of bimodal nanoparticles having smaller pore sizes of about 2 nm to about 4 nm and larger pore sizes of about 15 nm to about 40 nm.
  • supraparticles are comprised of bimodal nanoparticles having smaller pore sizes of about 2 nm to about 3 nm and larger pore sizes of about 4 nm to about 40 nm.
  • supraparticles are comprised of bimodal nanoparticles having smaller pore sizes of about 10 nm to about 50 nm and larger pore sizes of about 70 nm to about 95 nm. In another example, supraparticles are comprised of bimodal nanoparticles having smaller pore sizes of about 15 nm to about 40 nm and larger pore sizes of about 80 nm to about 95 nm.
  • supraparticles are comprised of microparticles. In another example, supraparticles are comprised of microporous microparticles. In an example, supraparticles are comprised of microparticles having a pore size of about 0.5 nm to about 2 nm. In other examples, supraparticles are comprised of microparticles having a pore size of about 1 nm to about 2 nm, about 1.5 nm to about 2 nm. In another example, supraparticles are comprised of mesoporous microparticles. In an example, supraparticles are comprised of microparticles having a pore size of about 2 nm to about 50 nm.
  • supraparticles are comprised of microparticles having a pore size of about 2 nm to about 40 nm, about 2 nm to about 30 nm.
  • supraparticles are comprised of macroporous microparticles.
  • supraparticles are comprised of microparticles having a pore size of about 50 nm to about 500 nm.
  • supraparticles are comprised of microparticles having a pore size of about 50 nm to about 250 nm, about 50 nm to about 150 nm, about 50 nm to about 100 nm.
  • supraparticles are comprised of microparticles having a bimodal pore structure.
  • supraparticles can comprise microparticles having mesopores and macropores.
  • such supraparticles are comprised of microparticles having pores ranging from 2 nm to 500 nm.
  • supraparticles are comprised of bimodal microparticles having pores ranging from 10 nm to 250 nm.
  • supraparticles are comprised of bimodal microparticles having pores ranging from 15 nm to 150 nm.
  • supraparticles are comprised of bimodal microparticles having smaller pore sizes of about 1 nm to about 5 nm and larger pore sizes of about 10 nm to about 50 nm.
  • supraparticles are comprised of bimodal microparticles having smaller pore sizes of about 2 nm to about 4 nm and larger pore sizes of about 15 nm to about 70 nm.
  • supraparticles are comprised of bimodal microparticles having smaller pore sizes of about 2 nm to about 3 nm and larger pore sizes of about 15 nm to about 65 nm.
  • supraparticles are comprised of bimodal microparticles having smaller pore sizes of about 10 nm to about 30 nm and larger pore sizes of about 15 nm to about 200 nm.
  • supraparticles are comprised of bimodal microparticles having smaller pore sizes of about 15 nm to about 40 nm and larger pore sizes of about 15 nm to about 150 nm.
  • supraparticles are comprised of bimodal microparticles having smaller pore sizes of about 20 nm to about 30 nm and larger pore sizes of about 100 nm to about 120 nm.
  • supraparticles are loaded with at least 3 ⁇ g of an above referenced payload and are comprised of bimodal nanoparticles having smaller pore sizes of about 2 nm to about 4 nm and larger pore sizes of about 15 nm to about 40 nm.
  • supraparticles are loaded with at least 5 ⁇ g of an above referenced payload and are comprised of bimodal nanoparticles having smaller pore sizes of about 2 nm to about 4 nm and larger pore sizes of about 15 nm to about 40 nm.
  • supraparticles are loaded with at least 8 ⁇ g of an above referenced payload and are comprised of bimodal nanoparticles having smaller pore sizes of about 2 nm to about 4 nm and larger pore sizes of about 15 nm to about 40 nm.
  • supraparticles are loaded with at least 10 ⁇ g of an above referenced payload and are comprised of bimodal nanoparticles having smaller pore sizes of about 2 nm to about 4 nm and larger pore sizes of about 15 nm to about 40 nm.
  • the supraparticles can be provided in an alginate hydrogel.
  • supraparticles are comprised of microparticles and nanoparticles.
  • microparticles and nanoparticles can have an above referenced pore size(s).
  • supraparticles can be comprised of microparticles and nanoparticles having a bimodal pore structure.
  • supraparticles can have a substantially uniform pore size.
  • supraparticles comprise variable pore sizes.
  • pore size may be variable but fall within a particular size range.
  • supraparticles can be predominantly mesoporous.
  • supraparticles can be predominantly macroporous.
  • supraparticles are comprised of nanoparticles having a substantially uniform pore size.
  • supraparticles are comprised of bimodal nanoparticles having substantially uniform small and large pore sizes.
  • supraparticles are comprised of microparticles having a substantially uniform pore size.
  • supraparticles are comprised of bimodal microparticles having substantially uniform small and large pore sizes.
  • above referenced supraparticles can have an ordered pore structure. These supraparticles have pores with a regular, three-dimensional spacing. In another example, above referenced supraparticles can have a disordered pore structure. These supraparticles have pores with an irregular, three-dimensional spacing. In another example, supraparticles have a combination of both ordered and disordered pore structures.
  • supraparticle pore size can be measured by, for example, transmission electron microscopy (TEM), scanning electron microscopy (SEM) and X-Ray computed tomography.
  • TEM transmission electron microscopy
  • SEM scanning electron microscopy
  • X-Ray computed tomography One of skill in the art can identify supraparticles having the above exemplified pore sizes by measuring the width across the widest point of their three dimensional structure. In an example, the widest point or a pore may be at the surface of the supraparticle.
  • Supraparticles of the present disclosure may be characterised by the distance between their particles.
  • the average distance between particles can range from about 80 nm to about 400 nm.
  • the average distance between colloidal particles ranges from about 90 nm to about 300 nm, about 100 nm to
  • supraparticle pores are connected.
  • supraparticles can comprise a series of interconnected pores.
  • supraparticle pores are not connected.
  • supraparticles have a combination of both connected and unconnected pores.
  • supraparticles of the present disclosure may be characterised by the volume of their pores.
  • supraparticle pore volume ranges from about 0.5 mLg ⁇ 1 to about 10 mLg ⁇ 1 .
  • supraparticles have a pore volume of about 0.8 mLg ⁇ 1 to about 5 mLg ⁇ 1 , about 1 mLg ⁇ 1 to about 2.5 mLg ⁇ 1 , about 1.5 mLg ⁇ 1 to about 2 mLg ⁇ 1 .
  • Supraparticles of the present disclosure may have a hollow core or a toroidal core.
  • the internal volume of the supraparticle core is at least about 45%, at least about 55%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95% of the total volume of the supraparticle.
  • Exemplary methods of producing hollow core supraparticles include acid core processes such as those described in U.S. Pat. No. 4,468,498 and ester core process such as those described in U.S. Pat. Nos. 5,157,084 and 5,521,253.
  • Supraparticles of the present disclosure may be characterised by the surface area of their structure.
  • the surface area of supraparticles range from about 500 m 2 g ⁇ 1 to about 1500 m 2 g ⁇ 1 .
  • supraparticles have a surface area of between about 5500 m 2 g ⁇ 1 and about 1250 m 2 g ⁇ 1 , about 600 m 2 g ⁇ 1 and 1000 m 2 g ⁇ 1 , about 600 m 2 g ⁇ 1 and 700 m 2 g ⁇ 1 .
  • the surface area of supraparticles is about 600 m 2 g ⁇ 1 .
  • the surface area of supraparticles is about 620 m 2 g ⁇ 1 .
  • Supraparticles according to the present disclosure may be characterised by a particular in-vitro release profile.
  • supraparticles release payload for at least 50 days.
  • supraparticles release payload for at least 100 days.
  • supraparticles release payload for at least 150 days.
  • supraparticles release an initial burst of payload followed by sustained release of payload.
  • supraparticles release a high level of payload for around 3 to 10 days followed by sustained release profile for 30 days or more.
  • supraparticles release a high level of payload for around 8 to 10 days followed by sustained release profile for 50 days or more.
  • the initial burst of payload is 1.2 ⁇ g/day for at least 2 days. In another example, the initial burst of payload is 1.3 ⁇ g/day for at least 3 days. In another example, the initial burst of payload is 1.4 ⁇ g/day for 2 to 4 days.
  • An example of a sustained release profile is at least 0.04 ⁇ g/day. Another example of a sustained release profile is at least 0.06 ⁇ g/day. Other examples of sustained release profiles are at least 0.07 ⁇ g/day and at least 0.1 ⁇ g/day.
  • supraparticles release at least 2 ⁇ g of payload for at least 20 days. In another example, supraparticles release at least 2 ⁇ g of payload for at least 30 days. In another example, supraparticles release at least 2 ⁇ g of payload for at least 40 days. In another example, supraparticles release at least 4 ⁇ g of payload for at least 20 days. In another example, supraparticles release at least 4 ⁇ g of payload for at least 30 days. In another example, supraparticles release at least 4 ⁇ g of payload for at least 40 days.
  • supraparticles release at least 2 ⁇ g of neurotrophic factor for at least 20 days. In another example, supraparticles release at least 2 ⁇ g of neurotrophic factor for at least 30 days. In another example, supraparticles release at least 2 ⁇ g of neurotrophic factor for at least 40 days. In another example, supraparticles release at least 4 ⁇ g of neurotrophic factor for at least 20 days. In another example, supraparticles release at least 4 ⁇ g of neurotrophic factor for at least 30 days. In another example, supraparticles release at least 4 ⁇ g of neurotrophic factor for at least 40 days. For example, supraparticles release at least 2 ⁇ g of BDNF for at least 20 days.
  • supraparticles can release at least 2 ⁇ g of BDNF for at least 40 days. In another example, supraparticles can release at least 4 ⁇ g of BDNF for at least 20 days. In another example, supraparticles can release at least 4 ⁇ g of BDNF for at least 40 days.
  • supraparticles disclosed herein can be loaded with a labelled payload such as FITC-lysozyme before being incubated in solution such as PBS. Intermittent measurements of fluorescence can be used to determine the level of payload (e.g. ⁇ g) released over time.
  • a labelled payload such as FITC-lysozyme
  • supraparticles of the present disclosure are produced from nanoparticles having a diameter of between about 1 nm and 100 nm. In another example, supraparticles are produced from microparticles having a diameter of between about 0.1 ⁇ m and 100 ⁇ m. In another example, supraparticles are produced from nanoparticles and microparticles.
  • Exemplary particles forming the supraparticles of the present disclosure include organic particles, inorganic particles, metal particles or a combination thereof.
  • Exemplary organic particles include polymeric particles such as polyglycolic acid (PGA), polylactic acid (PLA), poly(methacryclic acid), poly(ethacrylic acid), polyacrylic acid (PAA), poly(N-isopropylacrylamide), poly(N,N-dimethyl acrylamide), polyamides, poly-2-hydroxy butyrate (PHB), gelatines, polycaprolactone (PCL), and poly (lactic-co-glycolic acid) (PLGA).
  • Exemplary inorganic particles include mineral fillers such as heavy fillers or high density fillers, pigments, clays and other synthetic particles.
  • exemplary inorganic particles include dense minerals such as barite, hematite, magnesium oxide, inorganic oxides including titanium dioxide, calcium oxide, zinc oxide, magnesium oxide, cerium oxide, zirconium dioxide, and silicon dioxide.
  • the material is silicon dioxide (i.e. silica).
  • the supraparticles can be referred to as silica supraparticles.
  • Exemplary metal particles include gold, silver, and copper.
  • supraparticles may comprise the same particles.
  • supraparticles can substantially consist of silica particles.
  • supraparticles may comprise different particles; for example silica and clay particles.
  • supraparticles can comprise at least three, at least four, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10 different particles.
  • supraparticles comprise polyelectrolytes or polyelectrolyte material. Examples of such supraparticles are disclosed in WO 2006/037160.
  • the polyelectrolyte may be a positively charged polyelectrolyte (or have the ability to be positively charged) or a negatively charged polyelectrolyte (or have the ability to be negatively charged) or have a zero net charge.
  • supraparticles of the present disclosure can have various shapes.
  • supraparticles can have a spherical shape.
  • Exemplary spherical shapes include spheres and ovoids.
  • supraparticles have a non-spherical shape.
  • Exemplary non-spherical shapes include dumbbell, hemisphere, disc, tetrahedron, fibre, spherocylinder and irregular shapes.
  • supraparticles can have an ordered structure.
  • supraparticles may comprise an ordered array.
  • Spherical supraparticles of the present disclosure may be characterised by their diameter.
  • supraparticles of the present disclosure have a diameter greater than 100 ⁇ m.
  • supraparticles of the present disclosure can have a diameter of at least about 150 ⁇ m, about 200 ⁇ m, about 250 ⁇ m, about 300 ⁇ m, about 350 ⁇ m, about 400 ⁇ m, about 450 ⁇ m, about 500 ⁇ m, about 550 ⁇ m, about 600 ⁇ m, about 650 ⁇ m, about 700 ⁇ m, about 750 ⁇ m, about 800 ⁇ m, about 850 ⁇ m, about 900 ⁇ m, about 950 ⁇ m, about 1000 ⁇ m.
  • supraparticles can have a diameter of about 550 ⁇ m. This diameter of supraparticle is advantageous as it allows for high drug loading while facilitating inner ear delivery via cannula.
  • supraparticles can have a diameter of between about 150 ⁇ m and about 1000 ⁇ m, about 200 ⁇ m and about 900 ⁇ m, about 300 ⁇ m and about 800 ⁇ m.
  • supraparticles can have a diameter of between about 400 ⁇ m and about 600 ⁇ m.
  • supraparticles can have a diameter of between about 450 ⁇ m and about 550 ⁇ m.
  • supraparticles can have a diameter of between about 520 ⁇ m and about 580 ⁇ m.
  • supraparticles can have a diameter of between about 460 ⁇ m and about 540 ⁇ m. In another example, supraparticles can have a diameter of between about 470 ⁇ m and about 530 ⁇ m. In another example, supraparticles can have a diameter of between about 480 ⁇ m and about 520 ⁇ m. In another example, supraparticles can have a diameter of between about 490 ⁇ m and about 510 ⁇ m. In other examples, supraparticles can be characterised by the width across the widest point of their three dimensional structure. For example, supraparticles can have a width consistent with the above exemplified diameters.
  • the supraparticle surface is modified by the addition of functional moieties to enhance the loading of a payload.
  • Any number of functional moieties may be added to the surface of a supraparticle, with the choice of functional moiety being chosen to compliment the payload being loaded.
  • a moiety such as 3-aminopropyltriethoxysilane (APTS), is grafted onto the surface of silica supraparticle. This introduces an amine functionality that can interact with any carboxyl groups present on a payload.
  • the supraparticle is modified to bear an overall net charge that enhances loading of the payload (Tan et al. Adv. Mater. (2012) 24, 3362-3366).
  • the surface of the supraparticle can be modified to bear an overall net positive charge, such that loading of a payload bearing an overall net negative charge is enhanced.
  • the surface of the supraparticle is modified to bear an overall net negative charge, such that loading of a payload bearing an overall net positive charge is enhanced.
  • the supraparticles of the present disclosure may also comprise cross linked functional moieties.
  • functional moieties may be crosslinked through a chemical reaction.
  • polyglycolic acid (PGA) molecules are crosslinked by a chemical reaction of the PGA molecules with cystamine (Tan et al. Adv. Mater. (2012) 24, 3362-3366).
  • Supraparticles may be formulated as a pharmaceutical composition suitable for administration to a subject.
  • exemplary pharmaceutical compositions may provide supraparticles alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient. In these compositions supraparticles are provided in an amount sufficient to deliver a therapeutically effective amount of payload to a subject.
  • a variety of acceptable carriers known in the art may be used, as for example described in Remington's Pharmaceutical Sciences (Mack Publishing Co. N.J. USA, 1991).
  • Exemplary pharmaceutical compositions may also comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents or antibacterial and antifungal agents.
  • supraparticles can be incorporated into slow release or targeted delivery systems.
  • the present inventors have identified that providing supraparticles disclosed herein with an alginate hydrogel slows the release of payload from the supraparticles.
  • Such slow release systems can include foams, gels, drops and sprays for topical administration or a depot for injection or injection cannula.
  • Exemplary slow release systems include polymer matrices, liposomes, and microspheres.
  • Polymer matrices include reservoir based systems where supraparticles are enclosed in porous polymer coatings (Yang and Pierstorff (2012) JALA. 17, 50-58) and monolithic matrix systems where supraparticles are embedded in polymer matrices (Langer R (1990) Science.
  • Liposomes may be biodegradable and amphiphilic drug delivery systems, which may be formulated using phospholipids and cholesterol.
  • Microspheres may be formulated using biodegradable and biocompatible polymers.
  • the slow release system can be polysaccharide based.
  • a supraparticle formulation can comprise an anionic polysaccharide.
  • the polysaccharide can be alginic acid or a derivative thereof.
  • the supraparticle can comprise an alginate hydrogel.
  • alginic acid derivatives are known in the art. Examples include sodium alginate, potassium alginate and calcium alginate. Other examples include barium alginate and strontium alginate.
  • the alginic acid is sodium alginate. Accordingly, in an example, the present disclosure encompasses a formulation comprising an above referenced supraparticle and sodium alginate.
  • Alginate can be obtained from various sources (e.g. Sigma, FMC Health and Nutrition).
  • the polysaccharide is an unbranched polysaccharide such as a glycosaminoglycan.
  • the polysaccharide can be hyaluronic acid.
  • supraparticles are provided in a formulation that accelerates release of a payload.
  • supraparticles can be provided with Pluronic F127 based (PF127) hydrogel or an analogue thereof
  • supraparticles can be provided with PF127 based hydrogel.
  • supraparticles are provided in a formulation that enhances diffusion across a membrane within the subjects ear such as the tympanic membrane, oval or round windows.
  • supraparticle formulations may comprise artificial perilymph.
  • supraparticles are incorporated or embedded within scaffolds that are subject-compatible and which degrade into products that are not harmful to a subject. These scaffolds house the supraparticles that are to be transplanted into a subject.
  • scaffolds include, but are not limited to biological, degradable scaffolds.
  • Natural biodegradable scaffolds include collagen, fibronectin, and laminin scaffolds.
  • Suitable scaffolds include polyglycolic acid scaffolds or synthetic polymers such as polyanhydrides, polyorthoesters, and polylactic acid.
  • compositions comprising supraparticles according to the present disclosure are administered to a subject in an amount effective to treat a disease or disorder in the subject.
  • the disease or disorder is hearing loss.
  • hearing loss is used in the context of the present disclosure to refer to any reduction in a subject's ability to detect or process sound.
  • reference to hearing loss encompasses a partial hearing deficit or total inability to hear.
  • the hearing loss is characterised as sensorineural hearing loss (SNHL).
  • SNHL is used in the context of the present disclosure to refer to hearing loss resulting from damage to the delicate sensory hair cells within the cochlea, or loss of their synaptic connections with spiral ganglion neurons (SGNs) or dysfunction of the cochlear Schwann cells.
  • the hearing loss is characterised as presbycusis.
  • the hearing loss is noise induced.
  • the hearing loss is disease induced or genetic.
  • the hearing loss is induced by exposure to ototoxins, for example aminoglycosides.
  • the subject is a mammal.
  • the subject is a human.
  • the human subject can be an adult.
  • the human subject is a child.
  • Other exemplary mammalian subjects include companion animals such as dogs or cats, or livestock animals such as horses or cows.
  • Terms such as “subject”, “patient” or “individual” are terms that can, in context, be used interchangeably in the present disclosure.
  • supraparticles according to the present disclosure are administered intraperitoneally.
  • the present disclosure also encompasses methods of delivering a payload to a cell, tissue or organ in a subject via the ear, the method comprising administering to the ear of a subject a supraparticle according to the present disclosure.
  • the method may deliver a payload to a cell from a subjects inner ear, middle ear and/or vestibular system.
  • the method delivers a therapeutic payload to a neural cell, neural tissue or the brain of a subject.
  • compositions are administered onto the tympanic membrane.
  • compositions may be formulated for topical administration (e.g. drops, gels, foams, sprays).
  • compositions are administered to the “middle ear” cavity.
  • the term “middle ear” in the context of the present disclosure is used to refer to the space between the tympanic membrane and the inner ear.
  • the middle ear is external to all inner ear tissue.
  • compositions can be administered to the middle ear via injection through the tympanic membrane.
  • supraparticles may be administered as a depot injection.
  • an opening in the tympanic membrane can be produced by a treating clinician to facilitate access of compositions to the middle ear.
  • compositions can be administered onto the round and/or oval window.
  • supraparticles are administered into the inner ear.
  • supraparticles can be administered to the cochlea.
  • supraparticles can be administered to the basal turn of the cochlea.
  • Surgical techniques to gain access to the cochlea or other structures of the inner ear are known in the art. Exemplary techniques for surgically accessing the human cochlea are described in, for example, Clark GM, et al., “Surgery for an improved multiple-channel cochlear implant”, Ann Otol Rhinol Laryngol 93:204-7, 1984, and in Clark G M, et al., “Surgical and safety considerations of multichannel cochlear implants in children”, Ear and Hearing Suppl. 12:15S-24S, 1991.
  • otic intervention may occur simultaneously with administration of supraparticles.
  • a cochlear device can be implanted simultaneously with supraparticles.
  • increased survival of spiral ganglion neurons can improve the utility of a cochlear implant.
  • a cochlear device can be implanted about one month, about two months, about three months, about six months after the supraparticles have been administered.
  • additional supraparticles can be administered with the cochlear device.
  • a first dose of supraparticles are administered to the subjects cochlea and at least a second dose of supraparticles are administered onto the subjects round and/or oval window(s).
  • a therapeutically effective amount is administered to an ear of the subject.
  • multiple supraparticles are administered to an ear of the subject.
  • at least two, at least three, at least four, at least 5, at least 10, at least 20 supraparticles can be administered to an ear of the subject.
  • about one to 10 supraparticles are administered.
  • about two to 9, about three to 8, about four to 7, about 5 to 6 supraparticles are administered to an ear of the subject.
  • supraparticles can comprise the same payload.
  • supraparticles are loaded with different payloads.
  • a supraparticle loaded with a neurotrophic factor and a supraparticle loaded with a steroid may be administered.
  • a supraparticle loaded with a neurotrophic factor and a supraparticle loaded with an antibiotic may be administered.
  • a supraparticle loaded with a neurotrophic factor can be administered with an antibiotic.
  • compositions disclosed herein may be packaged in a suitable container with written instructions for treating an inner ear disorder.
  • compositions may be provided in a single dose container such as an ear dropper or pre-filled syringe.
  • the kit comprises a supraparticle according to the present disclosure for use in methods of treating an inner ear disorder.
  • the kit comprises a supraparticle according to the present disclosure for use in methods of treating hearing loss.
  • the hearing loss is SNHL.
  • the hearing loss is noise induced hearing loss.
  • a kit according to the present disclosure further comprises a hearing aid or an implant. Accordingly, in an example, the kit can comprise a supraparticle and a cochlear implant.
  • the present disclosure encompasses a method of manufacturing supraparticles that can be loaded with high levels of payload.
  • the supraparticles can be manufactured from a composition comprising nanoparticles and alginic acid or a polysaccharide derivative thereof.
  • Various examples of nanoparticles are provided above.
  • the nanoparticles have a bimodal pore structure. Nanoparticles can be produced using various methods. One such method is described in Cui et al. 2015, ACS Nano, 9, 1571-1580.
  • supraparticles according to the present disclosure are produced by electrospraying.
  • electrospraying are reviewed in Ja wornk A., 2007 Powder Technology 1, 18-35.
  • An example of electrospraying is also exemplified below.
  • the present disclosure encompasses a method of manufacturing supraparticles, the method comprising electrospraying a composition comprising nanoparticles and alginic acid or a polysaccharide derivative thereof into a di-cationic aqueous solution.
  • electrospray parameters can be optimized based on the type of the solution used for electro spraying.
  • voltage and flow rates can be optimised to provide supraparticles of a desired size.
  • the flow rate is about 6-10 mL h ⁇ 1 .
  • the flow rate is about 7-9 mL h ⁇ 1 .
  • the flow rate is about 8 mL h ⁇ 1 .
  • the voltage is between about 10 and 25 KV.
  • the voltage is between about 11 and 20 KV.
  • the voltage is between about 12 and 14 KV.
  • the voltage is about 13 KV.
  • supraparticles are produced by electrospraying a nanoparticle solution.
  • the concentration of nanoparticles in solution is about 20 mg/ml.
  • the concentration of nanoparticles in solution is about 30 mg/ml.
  • the concentration of nanoparticles in solution is about 40 mg/ml.
  • the concentration of nanoparticles in solution is about 50 mg/ml.
  • the concentration of nanoparticles in solution is about 60 mg/ml.
  • supraparticles are produced by electrospraying a nanoparticle solution comprising alginic acid or a derivative thereof
  • the nanoparticle solution is prepared from 5 mg mL ⁇ 1 alginic acid solution.
  • the nanoparticle solution is prepared from 10 mg mL ⁇ 1 alginic acid solution.
  • the nanoparticle solution is prepared from 20 mg mL ⁇ 1 alginic acid solution.
  • the nanoparticle solution is prepared from 30 mg mL ⁇ 1 alginic acid solution.
  • the nanoparticle solution is prepared from 5 mg mL ⁇ 1 to 30 mg mL ⁇ 1 alginic acid solution.
  • the nanoparticle solution is prepared from 10 mg mL ⁇ 1 to 30 mg mL ⁇ 1 alginic acid solution. In another example, the nanoparticle solution is prepared from 20 mg mL ⁇ 1 to 30 mg mL ⁇ 1 alginic acid solution.
  • the nanoparticle solution is prepared from 5 mg mL ⁇ 1 alginic acid in water. In an example, the nanoparticle solution is prepared from 10 mg mL ⁇ 1 alginic acid in water. In an example, the nanoparticle solution is prepared from 20 mg mL ⁇ 1 alginic acid in water. In an example, the nanoparticle solution is prepared from 30 mg mL ⁇ 1 alginic acid in water. In another example, the nanoparticle solution is prepared from 5 mg mL ⁇ 1 to 30 mg mL ⁇ 1 alginic acid in water. In another example, the nanoparticle solution is prepared from 10 mg mL ⁇ 1 to 30 mg mL ⁇ 1 alginic acid in water. In another example, the nanoparticle solution is prepared from 20 mg mL ⁇ 1 to 30 mg mL ⁇ 1 alginic acid in water.
  • supraparticles are produced by electrospraying a nanoparticle solution comprising alginic acid.
  • Alginic acid derivatives are not particularly limited so long as they form a gel at a defined temperature.
  • the alginic acid derivative is a polysaccharide derivative.
  • Alginic acid derivatives include various alginic acid salt forms. Examples include sodium alginate, potassium alginate and calcium alginate. Other examples include barium alginate and strontium alginate.
  • the alginic acid is sodium alginate.
  • supraparticles are produced by electrospraying a nanoparticle solution comprising alginic acid.
  • Alginates of various viscosities may be used to produce supraparticles according to the present disclosure depending on the desired size and shape of supraparticle.
  • alginate having a viscosity of about 20 to 300 mPa*s can be used.
  • the alginate has a viscosity of about 20 to 200 mPa*s.
  • the alginate has a viscosity of 20 mPa*s.
  • the alginate has a viscosity of 100 mPa*s.
  • the alginate has a viscosity of 200 mPa*s.
  • supraparticles are produced by electrospraying a composition comprising nanoparticles into an aqueous solution.
  • this is a di-cationic aqueous solution.
  • Exemplary di-cationic components include Ca 2+ and Ba 2+ .
  • the aqueous solution can comprise calcium chloride.
  • the aqueous solution comprises barium chloride.
  • supraparticles are produced by electrospraying a composition wherein the concentration of alginate in the composition is 5 mg mL ⁇ 1 to 30 mg mL ⁇ 1 , the concentration of nanoparticles in the composition is 20 mg mL ⁇ 1 to 50 mg mL ⁇ 1 and the voltage is 10 kV to 25 kV.
  • supraparticles are produced by electrospraying a composition wherein the concentration of alginate in the composition is 10 mg mL ⁇ 1 to 30 mg mL ⁇ 1 , the concentration of nanoparticles in the composition is 30 mg mL ⁇ 1 to 50 mg mL ⁇ 1 and the voltage is 11 kV to 21 kV.
  • supraparticles are produced by electrospraying a composition wherein the concentration of alginate in the composition is 20 mg mL ⁇ 1 to 30 mg mL ⁇ 1 , the concentration of nanoparticles in the composition is 35 mg mL ⁇ 1 to 45 mg mL ⁇ 1 and the voltage is 12 kV to 14 kV.
  • the flow rate can be 8 mL h ⁇ 1 .
  • supraparticles are produced by electrospraying a composition wherein the concentration of alginate in the composition is 30 mg mL ⁇ 1 , the concentration of nanoparticles in the composition is 40 mg mL ⁇ 1 , the voltage is 13 kV, and the flow rate is 8 mL h ⁇ 1 .
  • supraparticles manufactured using methods defined herein are subjected to calcination to remove alginic acid or a derivative thereof.
  • calcination is performed at around 500° C.
  • calcination is performed at around 550° C.
  • calcination is performed at around 600° C.
  • calcination is performed at around 650° C.
  • calcination is performed at around 700° C.
  • calcination is performed for about 6 to about 30 hours.
  • calcination is performed for about 10 hours.
  • calcination is performed for about 20 hours.
  • calcination is performed for about 30 hours.
  • MS-NP Mesoporous silica nanoparticles
  • TEOS Tetraethyl orthosilicate
  • the as-synthesized MS-NP were washed with ethanol once, water twice and ethanol twice and finally dried at 90° C.
  • the organic templates were removed by calcination at 550° C. for 30 h.
  • MS nanoparticles were prepared according to Wang et al. (2010) Chem Mater. 22, 3829-3831.
  • MS nanoparticles were dispersed in Milli-Q water with a particle concentration of 5 wt % and briefly sonicated to form a stable colloidal suspension.
  • a 0.5 to 2.0 ⁇ L aliquot of the MS nanoparticle dispersion was then applied to a flat surface, which was pre-covered with a paraffin film.
  • the droplets were dried under air flow to drive assembly of the MS nanoparticles into mesoporous silica supraparticles (capillary force MS-SPs) via capillary force action.
  • the size of the capillary force MS-SPs was controlled by the volume of the nanoparticle dispersion applied in the droplet.
  • the MS colloids Under capillary force, the MS colloids self-assembled into a compact structure to form MS-SPs.
  • the capillary force MS-SPs were then removed from the paraffin film and transferred into a ceramic container, and annealed at 923 K to enhance mechanical stability of the capillary force MS-SPs.
  • Capillary force MS-SPs were then loaded with payload. About 1.33 ⁇ g protein was loaded per particle.
  • the capillary force MS-SPs were shown to have a bimodal pore structure (2-3 nm and 15-30 nm) and the macropores within the capillary force MS-SP, the space between the densely packed nanoparticles, was 100-200 nm.
  • MS-NPs powder 80 mg was added into 2 ml of alginic acid sodium salt solution (30 mg mL ⁇ 1 in water). The resulting solution was sonicated for 1 hour until the MS-NPs distributed uniformly in alginic acid sodium salt solution.
  • L MS-SPs large pore MS-SPs
  • the sonicated solution was added into a 3 mL plastic syringe and positioned in a syringe pump, with liquid being electrosprayed into a bath of calcium chloride solution (1 wt % prepared in water) using flow rates around 8 mL h ⁇ 1 (electrospray setup shown in FIG. 1 ).
  • Droplet size was controlled by applying an electric field between the end of the tubing and the calcium chloride solution.
  • the alginate beads MS-SPs L MS-SPs alg
  • Significantly enhanced drug-loading loading performance was observed for these particles ( L MS-SPs) compared to those produced by process A: about 7.8 ⁇ g protein per particle, with improved mechanical stability.
  • MS-SPs ( L MS-SP alg ) were produced using the method described in Example 3. Alginic acid sodium salt was removed by calcination at 650° C. for 30 h. This step removed all organic components and left behind only the mesoporous silica nanoparticles (MS-SP) and trace amounts of calcium and sodium chloride. MS-SPs were then loaded with payload. Significantly enhanced drug-loading performance was observed for these particles compared to those produced by process A: about 7.8 ⁇ g protein per particle.
  • Supraparticles were also made from nanoparticles without pores (non porous N MS-SPs alg ; N MS-SPs alg ) and nanoparticles having pore sizes ⁇ 2 nm (small pore MS- S SPs alg ; S MS-SPs alg ). When alginate was removed from these supraparticles drug-loading performance was significantly reduced (Table 1).
  • FITC-lysozyme-loaded SPs were prepared for in vitro release studies by incubating sterilized SPs with 100 ⁇ L of FITC-lysozyme solution (0.2 mg mL ⁇ 1 in Milli-Q water).
  • FIG. 4 parts a) and b) and FIG. 7 part a In vitro release profile of lysozyme loaded MS-SPs are shown in FIG. 4 parts a) and b) and FIG. 7 part a). Release profiles of MS-SP produced by process A and C are similar. Although MS-SP produced by process C are loaded with significantly higher levels of labelled lysozyme. Payload release is significantly reduced for MS-SP produced by process B compared to MS-SP produced by processes A and C.
  • MS-SPs were then loaded with fluorescein-labelled lysozyme (FITC-lysozyme).
  • FITC-lysozyme fluorescein-labelled lysozyme
  • FIG. 2 MS-SPs exhibited negative zeta potentials ranging from ⁇ 7.6 mV to ⁇ 33.9 mV as the pH value increased from 4 to 10. Positively charged lysozyme and BDNF can therefore be loaded into MS-SPs with the help of electrostatic driving forces.
  • Confocal microscopy images FIG. 3 a, b ) showed FITC-lysozyme loaded onto the surface of MS-SPs.
  • the loading capacity for different types of SPs was then investigated using FITC-lysozyme at different loading concentrations with 3 days incubation time ( FIG. 4 ).
  • concentration of FITC-lysozyme increased, the amount of drug loading increased.
  • the results show that the alginate-containing N MS-SPs alg , S MS-SPs alg and L MS-SPs alg had higher loading capacities than the alginate-removed N MS-SPs, S MS-SPs and L MS-SPs (at comparable concentrations). This may be due to increased electrostatic interactions between positively charged FITC-lysozyme and negatively charged alginate around neutral pH value.
  • L MS-SPs alg had a similar drug loading capacity as non porous MS-SPs alg and S MS-SPs alg , but when the concentration was higher (>0.4 mg mL ⁇ 1 ), more FITC-lysozyme could be loaded into L MS-SPs alg compared to N MS-SPs alg and S MS-SPs alg .
  • concentration >0.4 mg mL ⁇ 1
  • L MS-SPs could load more FITC-lysozyme than N MS-SPs and S MS-SPs.
  • the experimentally determined maximum loading amount of FITC-lysozyme into N MS-SPs and S MS-SPs alg were about 3 ⁇ g per SP and 2 ⁇ g per SP respectively, which were significantly lower than L MS-SPs with approximately 15 ⁇ g per SP (FITC-lysozyme concentration was 1.5 mg mL ⁇ 1 , and loading time was 3 days).
  • the experimentally determined maximum loading amount of FITC-lysozyme into N MS-SPs and S MS-SPs were about 2 ⁇ g per SP and 1 ⁇ g per SP respectively, which were also dramatically less than L MS-SPs with approximately 10 ⁇ g per SP (FITC-lysozyme concentration was 5.0 mg mL ⁇ 1 , and loading time was 3 days).
  • FIGS. 4 c and 4 d The drug loading efficiency of six different SPs is shown in FIGS. 4 c and 4 d . As the loading concentration of FITC-lysozyme increased, more FITC-lysozyme could be loaded into SPs.
  • MS-SPs were sterilized by soaking them in 100 ⁇ l of ethanol (80 vol/vol %) for 4 hours prior to rinsing with 100 ⁇ l of Milli-Q water six times. MS-SPs were then washed once in 0.1 M phosphate buffered saline (PBS). MS-SPs were loaded by placing them in an Eppendorf tube containing 15 ⁇ l of BDNF (Geneway, BDNF Human Protein, Cat. #10-663-45078) solution (1 mg/ml of BDNF) and incubating them at ambient room temperature for three days with occasional hand shaking. Remarkably, loading of about 10 ⁇ g BDNF was achieved.
  • BDNF Geneway, BDNF Human Protein, Cat. #10-663-45078
  • MS-SPs could be applied as biocompatible drug carriers.
  • Human brain glioblastoma cells U87MG cell line
  • cell viability was assessed by an Alamar Blue assay.
  • MS-SPs were non-toxic even when the number of MS-SPs was increased to ten per well (1 ⁇ 10 4 cells per well).
  • Typical in vivo treatment scenarios of similar particle systems suggest the administration of 1-8 SPs per inner ear.
  • release studies for FITC-lysozyme were performed by incubating ten L MS-SPs and ten MS-SPs alg in PBS (pH 7.4) at 37° C.
  • FITC-lysozyme-loaded SPs for in vitro release studies were prepared by sterilizing the SPs, followed by incubation of either ten MS-SPs or ten MS-SPs alg with 100 ⁇ L of low concentration' FITC-lysozyme solution (0.2 mg mL ⁇ 1 in Milli-Q water). After three days, the supernatant was removed and 100 ⁇ L of phosphate buffered saline (PBS, pH 7.4) was added into each tube and incubated at 37° C. At defined time intervals (over 150 days), 90 ⁇ L of solution was collected and replaced with fresh PBS. The fluorescence of the collected samples was measured with an Infinite M200 microplate reader and using a standard curve, the concentration of FITC-lysozyme in the supernatant could then be determined.
  • PBS phosphate buffered saline
  • the FITC-lysozyme loading following loading in the low concentration solution were 1.89 ⁇ 0.02 ⁇ g and 1.93 ⁇ 0.01 ⁇ g per SP for L MS-SPs and L MS-SPs alg , respectively.
  • > 1 ⁇ g of FITC-lysozyme per MS-SP was released over more than 150 days, while a lower amount of FITC-lysozyme ( ⁇ 0.4 ⁇ g per SP) was released from MS-SPs alg over this time.
  • FITC-lysozyme loaded amount ⁇ amount released during burst release
  • the individual values of FITC-lysozyme released at each time point was tens to hundreds of nanograms per SP ( FIG. 9 ).
  • the in vitro BDNF release profile was similar to that for FITC-lysozyme, with a burst release observed in the first three days followed by a more sustained release for over 40 days.
  • the cumulative released value of the SPs after 40 days was ⁇ 4.68 ⁇ g of drug, and the weight of each SP was ⁇ 0.05 mg.
  • the observed cumulative release was about 93.6 ⁇ g mg ⁇ 1 .
  • the individual values of BDNF released at each time point ranged from tens to hundreds of nanograms per SP ( FIG. 10 ).
  • the amount of BDNF released was also measured by a MicroBCA assay ( FIG. 11 ), with similar results.
  • PF127 hydrogels form as viscous liquids at cold temperatures (e.g. 4° C.) and gel at body temperature (37° C.).
  • most of the FITC-lysozyme was observed to be released from both MS-SPs and MS-SPs alg (both in PF127 hydrogels) by approximately day 14 ( FIG. 12 ) indicating accelerated release kinetics. Therefore, the supraparticle—PF127 system is suitable when shorter term drug release is desired ( ⁇ 1 week), while SPs without the PF127 hydrogel is more suitable for longer term (several months) drug release.
  • Porous silica particles that can be degraded in biological environments e.g. into silicic acid, which can be excreted through urine
  • MS-SPs were incubated for 150 days (PBS, pH 7.4, 37° C.) ( FIG. 14 ).
  • a 55% decrease in diameter of the MS-SPs was observed, and the shape/morphology of the MS-SPs also changed substantially.
  • the silica primary particles on the surface of the MS-SPs changed in both morphology and size.

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EP3941442A4 (fr) * 2019-03-19 2022-12-21 The Bionics Institute of Australia Formulations de supraparticules
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US20230047254A1 (en) * 2019-12-29 2023-02-16 Gloriana Therapeutics Mammalian Cells Secreting GDNF and Their Therapeutic Use
WO2022269540A1 (fr) * 2021-06-24 2022-12-29 Cochlear Limited Procédés et formulations pharmaceutiques pour moduler les propriétés de la barrière hémato-labyrinthique
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