WO2019143293A1 - Micro-réservoirs de médicament auto-implantables pour une administration de médicament oculaire localisée et contrôlée - Google Patents

Micro-réservoirs de médicament auto-implantables pour une administration de médicament oculaire localisée et contrôlée Download PDF

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Publication number
WO2019143293A1
WO2019143293A1 PCT/SG2019/050025 SG2019050025W WO2019143293A1 WO 2019143293 A1 WO2019143293 A1 WO 2019143293A1 SG 2019050025 W SG2019050025 W SG 2019050025W WO 2019143293 A1 WO2019143293 A1 WO 2019143293A1
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Prior art keywords
biocompatible material
drug delivery
delivery device
drug
microneedles
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PCT/SG2019/050025
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English (en)
Inventor
Peng Chen
Xiao Meng WANG
Chenjie Xu
Aung THAN
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Nanyang Technological University
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Publication of WO2019143293A1 publication Critical patent/WO2019143293A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration

Definitions

  • the present disclosure relates to a drug delivery device and a method of fabricating such drug delivery device.
  • intraocular injection e.g. intracameral and intravitreal injections
  • conventional hypodermic needles to penetrate the surface barriers (cornea and sclera)
  • injecting drugs into ocular surface tissues e.g. comeal intrastromal layer, sclera
  • ocular surface tissues e.g. comeal intrastromal layer, sclera
  • both conventional topical administration and local injection tend to produce burst release of drug that has a short effective duration, and this is not ideal for treating chronic progressive eye diseases, such as glaucoma.
  • contact lens-like hydrogels have been developed for improved topical delivery, such as providing for prolonged dmg residence time with minimal burst effect, their bioavailability remains poor.
  • the solution of the present disclosure relates to a device for overcoming one or more of the issues mentioned above.
  • the solution also relates to a method of forming such a device.
  • a drug delivery device comprising a substrate having a surface comprising one or more microneedles, wherein each of the one or more microneedles comprises:
  • each of the one or more microneedles is defined by a shell portion formed around a core portion, wherein the shell portion comprises a first biocompatible material and the core portion comprises a second biocompatible material which is different from the first biocompatible material.
  • a drug delivery device as described in the above aspect for use in the treatment and/or prevention of a disease comprising an ocular disease, obesity, a metabolic disease, and/or a skin disease.
  • a drug delivery device as described in the above aspect in the manufacture of a drug delivery patch for the treatment and/or prevention of a disease comprising an ocular disease, obesity, a metabolic disease, and/or a skin disease.
  • a disease comprising an ocular disease, obesity, a metabolic disease, and/or a skin disease, the method comprising:
  • a shell portion comprised of a first biocompatible material for each of one or more microneedles in a mold which configures each of the one or more microneedles to have an apex shaped to penetrate a tissue layer;
  • a core portion comprised of a second biocompatible material on the shell portion of each of the one or more microneedles in the mold, wherein the second biomaterial is different from the first biocompatible material;
  • FIG. 1A is a schematic of the synthesis of methacarylated hyaluronic acid (MeHA) and the crosslinking through photo-activation.
  • MeHA methacarylated hyaluronic acid
  • N,N-dimethyl- formamide (133.3 mL) and methacrylic anhydride (4.7 mL) were added dropwise to HA solution (4.0 g of about 300 kDa HA in 200 mL deionized (DI) water), and adjusted to pH 8-9 with sodium hydroxide (NaOH). After continuous stirring for 1 day (4°C), the reaction solution was supplemented with sodium chloride (NaCl, 9.88 g) to precipitate MeHA in ethanol.
  • MeHA precipitates were washed again with ethanol for 3 times, dissolved in DI water and dialyzed for 7 days. After lyophilisation, the purified MeHA was characterized by 'H NMR spectroscopy (Bruker Avance II 300MHz NMR). The degree of modification was determined by digital integration of the anomeric protons signals or methyl protons signals of HA and of the methacrylate proton signals at about 6.1, about 5.7, and about 1.9 ppm.
  • FIG. 1B shows a representative 'H NMR spectrum of HA.
  • FIG. 1C shows a representative 'H NMR spectrum of MeHA. The degree of methacrylation was about 70% according to the 1 H NMR map.
  • FIG. 1D is an illustration of ocular drug delivery using an eye-contact patch equipped with self-implantable micro-drug-reservoirs.
  • FIG. 2A is a schematic of the fabrication process of polymeric patch with an array of needle-shaped and double-layered micro-reservoirs.
  • FIG. 2B shows a bright-field image of stainless steel microneedles (MN) master-mold.
  • the scale bar denotes 400 pm.
  • FIG. 2C shows a bright-field image of the corresponding double-layered MN obtained from the mold of FIG. 2B.
  • the scale bar denotes 400 pm.
  • FIG. 2D shows a scanning electron microscopy (SEM) image of the stainless steel MN master-mold.
  • the scale bar denotes 100 pm.
  • FIG. 2E shows a SEM image of the corresponding double-layered MN obtained from the mold of FIG. 2D.
  • the scale bar denotes 100 pm.
  • FIG. 2F shows a SEM image of a stainless steel MN of the master-mold of
  • FIG. 2B The scale bar denotes 10 pm.
  • FIG. 2G shows a SEM image of a corresponding double-layered MN obtained from the mold of FIG. 2D.
  • the scale bar denotes 10 pm.
  • FIG. 2H shows the results of mechanical compression test (average from 4 measurements) of un-loaded and IgG(680)-loaded DL-MN (2 pg in 9 MNs).
  • FIG. 21 shows the bright-field images of DL-MN before (top) and after (below) compression.
  • FIG. 3A shows the characterization of double-layered MNs. Specifically, FIG. 3A shows a schematic of a polymeric patch with an array of DL-MN (the outer layer made of crosslinked MeHA and inner core made of HA).
  • FIG. 3B shows a SEM image of a polymeric patch with an array of DL-MN (the outer layer made of crosslinked MeHA and inner core made of HA).
  • the scale bar denotes 100 pm.
  • FIG. 3C shows a representative confocal image of DL-MN loaded with IgG(680) in outer layer and IgG(488) in inner core.
  • the scale bar denotes 100 pm.
  • FIG. 3D shows a representative confocal image of DL-MN with IgG(680) in outer layer only. The scale bar denotes 100 pm.
  • FIG. 3E shows a representative confocal image of DL-MN with IgG(488) in inner core only. The scale bar denotes 100 pm.
  • FIG. 31 shows the quantification of anti-VEGFR2 IgGs loaded in 3 x 3 array of DL-MN using an Easy-Titer IgG assay kit (ThermoFisher Scientific). 1 pg of IgG equally divided into the inner core and outer shell of MN.
  • FIG. 3J shows the protein staining on 12% polyacrylamide gel loaded with anti-VEGFR2 IgGs.
  • Lane 1 freshly-prepared IgG.
  • Lane 2 IgG collected from HA- MN.
  • Lane 3 IgG collected from MeHA-MN.
  • Lane M molecular weight markers. Protein bands were stained with InstantBlue solution (Expedeon), and detected in a G:BOX Chemi XT4 imaging system (Syngene).
  • FIG. 3K shows the representative confocal images of immunostained VEGFR2 in primary human endothelial cells (HUVECs), using the freshly-prepared anti-VEGFR2 IgG, or anti-VEGFR2 IgG released from HA-MN / MeHA-MNs (being stored for 5 days) over 24 hrs.
  • Hoechst 33342 NucBlue Live ReadyProbes Reagent, Life Technologies was used to stain the nuclei.
  • the red fluorescence indicates the staining of VEGFR2 (Alexa Fluor 680).
  • the scale bar denotes 10 pm.
  • FIG. 4A shows the in vitro anti-angiogenic activity of anti-VEGFR2 IgG in primary human endothelial cells (HUEVCs) (tube formation assay).
  • HUEVCs human endothelial cells
  • FIG. 4A shows anti-VEGFR2 IgG released from DL-MNs (being stored for 5 days) over 6 hrs (5 pg/ml), 24 hrs (10 pg/ml) or 120 hrs (50 pg/ml), which were used to treat the cells for about 18 hrs (with 10 ng VEGF). Freshly prepared IgG at different concentrations were also tested for comparison. Representative bright-field images (on the left) of tube formation in Matrigel and the statistics (rightmost bar graph) of tube length (% control) are shown.
  • FIG. 4C shows the biphasic release profile of double-layered microneedles. Specifically, FIG. 4C shows the schematic release profile of DL-MN in agarose hydrogel.
  • FIG. 4D shows the merge of optical and fluorescence images of DL-MNs with the supporting patch (before insertion) and visualization of real-time release of IgG(680) and IgG(488) from DL-MN in agarose hydrogel (3 mins to 6 hrs).
  • the scale bar denotes 200 pm.
  • FIG. 5B shows the representative time-lapse confocal images and corresponding bright-field images of DL-MN in agarose hydrogel, showing the slow- release of IgG(680) from the outer layer of DL-MN.
  • DL-MN becomes clear and transparent after 2 mins.
  • the scale bar denotes 200 pm.
  • FIG. 5C shows the application of a polymeric patch containing 3 x 3 DL-MN array on the central region of porcine eye (about 30 seconds). Specifically, FIG. 5C shows a bright-field image before MN insertion.
  • FIG. 5D shows the application of a polymeric patch containing 3 x 3 DL-MN array on the central region of porcine eye (about 30 seconds). Specifically, FIG. 5D shows a bright-field image after MN insertion.
  • FIG. 5E shows a bright-field image of the cornea (cross-sectional view) upon MN insertion.
  • FIG. 5F shows a bright-field image of the cornea (cross-sectional view) after removal of the supporting patch.
  • FIG. 5G shows the hematoxylin and eosin stained section of the cornea showing the cavity caused by DL-MN penetration.
  • the scale bar denotes 100 pm.
  • FIG. 51 shows a confocal image of embedded DL-MNs in cornea.
  • FIG. 5K shows the confocal visualization of real-time release of IgG(680) and IgG(488) from DL-MN into the cornea.
  • FIG. 6A shows the in vivo studies of self-implantable double-layered microneedles. Specifically, FIG. 6A shows a polymeric patch containing 3 x 3 DL- MNs applied on the central region of a mouse eye (about 30 seconds application duration).
  • FIG. 6B shows two bright-field images of the patch, before (left) and after (right) insertion into the mouse eye.
  • FIG. 6C shows the in vivo imaging of the mouse eyes, applied without (left) or with IgG(680)-loaded MN patch (right).
  • FIG. 6D shows two bright-field images of the eye treated with a IgG(680)- loaded MN patch, at day 0 (immediately after insertion) and at day 3.
  • FIG. 6E shows the red fluorescence spots in the cornea marking the penetration sites.
  • FIG. 6F shows the representative histological changes of mouse cornea, at day
  • FIG. 6J shows the in vivo distribution of IgG in mice, treated without (control) or with systemic injection (intraperitoneal, I.P), eye drop (ED) (one-side only) or MN patch application (one side only) of IgG(680).
  • I.P systemic injection
  • ED eye drop
  • MN patch application one side only
  • FIG. 7 A shows images of the DL-MN patch improving therapeutic efficacy of anti-VEGF therapy.
  • Mouse eyes were treated differently 2 days after being inflicted with alkali-bum, and examined at day 7.
  • FIG. 7A shows the representative images of differently treated eyes.
  • the dotted lines indicate the extent of neovascular outgrowth from the limbus.
  • FIG. 8A demonstrates the DL-MN patch for ocular delivery of DC 101 and diclofenac (Diclo) for synergistic therapeutic effect on comeal NV.
  • Mouse eyes were treated differently 2 days after being inflicted with alkali-bum, and examined at day 7.
  • FIG. 8A illustrates dmg loadings in DL-MN and the representative images of differently treated eyes.
  • the dotted lines indicate the extent of neovascular outgrowth from the limbus.
  • FIG. 8D demonstrates the DL-MN patch for ocular drug delivery.
  • FIG. 8D demonstrates diclofenac (diclo) (0, 1, 2 or 5 pg in inner core of HA) loaded in DL-MN.
  • the mouse eyes were then treated differently 2 days after being inflicted with alkali-burn, and examined at day 7.
  • the dotted lines indicate the extent of neovascular outgrowth from the limbus.
  • FIG. 9A shows the inflammation assessment of combinational therapy using double-layered microneedles. Mouse eyes were treated differently 2 days after being inflicted with alkali-burn, and examined at day 7. Specifically, FIG. 9 A shows the immunohistochemical staining of cornea with a specific macrophage marker - F4/80 surface antigen.
  • FIG. 9B shows the quantifications of macrophage accumulation (% of positive staining of F4/80; ED: eye drop).
  • FIG. 9C shows cytokine concentrations in collected tear film of differently treated eyes. Tear films were collected with MeHA-based MN-free eye patches (patches were put on the eyes for 1 min to absorb tear film).
  • FIG. 9D shows a SEM image of the patch soaked with PBS, and a confocal image of the patch with cy5-conjugated albumin absorbed from agarose hydrogel.
  • FIG. 10A shows the representative confocal image of triple-layered MN, with the outer layer made of crosslinked MeHA containing IgG(488), middle layer made of HA (about 50 kDa) containing IgG(680), and inner core made of HA (less than 10 kDa) containing IgG(405).
  • the scale bar denotes 200 pm.
  • FIG. 10B shows the time-lapse confocal images of real-time release from triple-layered MN in agarose hydrogel, showing rapid release of IgG(405), followed by slower release of IgG(680), and slowest release of IgG(488).
  • the scale bar denotes 200 pm.
  • FIG. 11A shows the prolonged release of HA-IgG conjugates loaded in microneedles. Specifically, FIG. 11A shows a schematic of HA and IgG conjugation, and loading into MeHA-MN.
  • FIG. 11B shows the UV-Vis spectra of HA, IgG(680) and HA-IgG(680) conjugate confirming the success of conjugation.
  • FIG. 11C shows the size distribution of HA, IgG(680) and HA-IgG(680) determined by dynamic light scattering (DLS) analysis, indicating that HA-IgG(680) forms larger nanoparticles.
  • DLS dynamic light scattering
  • FIG. 11D shows a representative confocal image of MeHA-MN loaded with HA-IgG(680) conjugates.
  • the scale bar denotes 200 pm.
  • FIG. 11E shows the in vitro release profiles of HA-IgG(680) from MeHA-MN in PBS (0 /2 of about 1 week).
  • FIG. 12A shows layered microneedles for transdermal drug delivery.
  • FIG. 12A shows a bright-field image of the polymeric-patch equipped with an array of double-layered microneedles (DL-MN) (10x10 DL-MNs).
  • the scale bar denotes 400 pm.
  • FIG. 12A to FIG. 12C demonstrate DL-MNs can be well-pierced into the skin, creating about 300 pm deep cavities into the dermal layer at the insertion sites.
  • FIG. 12B shows representative confocal images of DL-MNs loaded with immunoglobulin G conjugated with Alexa Fluor: IgG(488) (green colour) in outer layer and IgG(680) (red colour) in inner core.
  • the scale bar denotes 200 pm.
  • FIG. 12A to FIG. 12C demonstrate DL-MNs can be well-pierced into the skin, creating about 300 pm deep cavities into the dermal layer at the insertion sites.
  • FIG. 12C shows hematoxylin and eosin stained section of the porcine skin showing the cavity caused by DL-MN penetration.
  • the scale bar denotes 100 pm.
  • FIG. 12A to FIG. 12C demonstrate DL-MNs can be well-pierced into the skin, creating about 300 pm deep cavities into the dermal layer at the insertion sites.
  • the present disclosure provides for a drug delivery device and its uses.
  • the present disclosure also provides for a method of fabricating the drug delivery device.
  • the present drug delivery device may comprise a flexible base with one or more structures each designed to release drugs at different rates.
  • Each of the one or more structures may have a shell portion and a core portion, wherein the shell portion and/or the portion may include at least one drug, and the shell portion and the core portion are configured to release the drug at different rates.
  • the structures may be referred to as microneedles in the present disclosure, as each of the structures has an apex designed to penetrate a biological layer, e.g. a tissue layer or a biological membrane. This means that the apex may comprise a sharp end shaped to allow the one or more structures for penetrating the biological layer.
  • a biological layer e.g. a tissue layer or a biological membrane.
  • the term“flexible” as used herein refers to a material that can be bent without getting damage, and reverts to its original form even after bending.
  • a drug delivery device comprising a substrate having a surface comprising one or more microneedles.
  • Each of the one or more microneedles may comprise an apex shaped to penetrate a tissue layer, and each of the one or more microneedles may be defined by a shell portion formed around a core portion, wherein the shell portion may comprise a first biocompatible material and the core portion may comprise a second biocompatible material which is different from the first biocompatible material.
  • biocompatible refers to a material or substance capable of being in contact with living tissues or organisms without causing harm to the living tissue or the organism.
  • a biocompatible material or substance in the context of the present disclosure, encompasses a biodegradable material or substance that may be readily decomposed by biological means.
  • biological means may include, without being limited to, dissolution by a biological fluid such as tissue fluid, or the degradability may be brought about by a living organism, such as microorganisms.
  • the apex allows for each of the one or more microneedles to easily penetrate a biological layer, such as a tissue layer or membrane layer, by simply pressing the drug delivery device onto the tissue layer.
  • a biological layer such as a tissue layer or membrane layer
  • the apex is designed to be a sharp end that can penetrate the biological layer without exerting a significant amount of force.
  • a human finger can be used to press the drug delivery device against the tissue layer, and the one or more microneedles remain implanted in the tissue layer even after the finger is removed. This allows for the drug to be delivered from the one or more microneedles to a diseased tissue layer or affected area.
  • the present drug delivery is patient-friendly in the sense that no surgical procedures nor supervision from a medical practitioner is required for the drug to be administered, and due to the ease of penetration, pain is minimized or eliminated.
  • the term“apex” refers to a point or vertex where all the lateral surfaces or all the lateral edges meet, and such a point or vertex is positioned opposite to the base of a microneedle.
  • a cone is shaped to have a circular base at one end and a sharp end apex disposed opposite to the circular base.
  • a square -based pyramid is shaped to have a square base at one end and a sharp end apex disposed opposite to the square base.
  • each of the one or more microneedles may have one end that forms the base and an opposing end (i.e. opposite to the base) that forms the apex.
  • each of the one or more microneedles may have a pyramidal or conical shape.
  • Each of the one or more microneedles may also have a tubular shape having a flat base at one end and an apex with a sharp tip positioned at the opposing end (i.e. opposite to the flat base).
  • each of the one or more microneedles may be structurally designed for improved mechanical strength to withstand the opposing force from a biological layer when the drug delivery device is inserted into the biological layer.
  • each of the one or more microneedles may have an aspect ratio of 1:1 to 10:1, 1:1 to 3:1, etc., according to various embodiments.
  • the aspect ratio refers to a ratio of the height to a dimension of the base.
  • the dimension of the base refers to the diameter of the conical base.
  • each of the one or more microneedles has an aspect ratio of 2:1.
  • the microneedle is of a pyramidal shape with a rectangular or square base
  • the dimension of the base may refer to the width of the rectangular or square base.
  • the present drug delivery device is also advantageous as it provides for release of drugs at different rates.
  • Each of the one or more microneedles may be defined by a shell portion formed around a core portion, and the shell portion may have a slower drug release rate compared to the core portion.
  • the microneedles are formed of two different portions, they may be referred to as dual-layered or bi-lay ered microneedles.
  • the shell and core portions may be made of different biocompatible materials.
  • the shell portion may be formed of a first biocompatible material that dissolves slower in a body fluid than the second biocompatible material for the core portion.
  • the use of such a first biocompatible material also results in a shell portion that can maintain the shape of each of the one or more microneedles, especially the structural integrity of the sharp end apex, such that the drug delivery device has the ease of penetration as described above.
  • a first biocompatible material need not be of a stiffness that is higher than the second biocompatible material forming the core portion.
  • the first biocompatible material may have a slower drug release rate compared to the second biocompatible material.
  • the second biocompatible material forming the core portion may be a substance that dissolves faster in a body fluid compared to the first biocompatible material forming the shell portion.
  • the core portion is formed of such a second biocompatible material, it can even provide for burst release of the drug that is encapsulated in the core portion, hence providing a different drug release rate from the shell portion.
  • the second biocompatible material which may be faster-dissolving, is designed specifically for forming the core portion, as it may not be able to maintain the structural integrity of the sharp-pointed apex if such a second biocompatible material is solely used to form the entire one or more microneedles.
  • different biocompatible materials can be utilized to improve the structural integrity of the microneedles for ease of penetration and yet provide for different drug release profiles.
  • the shell portion may be formed of a first biocompatible material that dissolves faster in a body fluid than the second biocompatible material for the core portion.
  • the first biocompatible material may have a faster drug release rate compared to the second biocompatible material.
  • the present device is therefore versatile in that the shell portion and the core portion may be configured to provide different drug release rates. Said differently, the first biocompatible material and the second biocompatible material may be configured to have different drug release rates, according to various embodiments.
  • each of the first biocompatible material and the second biocompatible material may comprise hyaluronic acid, poly(lactic-co-glycolic acid), a polysaccharide, polyvinyl alcohol, or a crosslinked derivative thereof.
  • a crosslinked derivative may be used for the first biocompatible material or the second biocompatible material, depending on whether the shell or core portion requires a slower drug release rate.
  • One example of a crosslinked derivative may be methacrylated hyaluronic acid.
  • Other crosslinked derivatives may include biocompatible crosslinked polymers as an example.
  • the crosslinked derivative may also be a crosslinked derivative of poly(lactic-co-glycolic acid), a polysaccharide, or polyvinyl alcohol.
  • Crosslinked derivatives tend to dissolve slower in a body fluid compared to their non-crosslinked counterparts.
  • Non-limiting examples of polysaccharide may include chitosan, pullulan, etc.
  • the first biocompatible material may comprise or consist of methacrylated hyaluronic acid while the second biocompatible material may comprise or consist of hyaluronic acid.
  • the second biocompatible material may comprise or consist of methacrylated hyaluronic acid while the first biocompatible material may comprise or consist of hyaluronic acid.
  • the first biocompatible material or the second biocompatible material may comprise methacrylated hyaluronic acid.
  • the core portion is formed from hyaluronic acid, which is considered a fast-dissolving substance in body fluids.
  • hyaluronic dissolves at a fast rate in body fluids, it may not be suitable for prolonged release of drugs.
  • the structural integrity of the one or more microneedles cannot be suitably maintained.
  • the shell portion may be formed of methacrylated hyaluronic acid, which forms a biocompatible crosslinked polymer that has a slower dissolution rate in body fluid, and this in turn helps to preserve the structural integrity of the one or more microneedles, such that when the microneedles contact the body fluid, the microneedles do not start dissolving but maintain its structural integrity for ease of penetration.
  • a drug that is encapsulated in the shell portion takes a longer time to be released or diffused out, thereby providing a different (i.e. slower) drug release profile from the core portion.
  • the present drug delivery device provides for different drug release profiles without sacrificing the ease of penetration.
  • each of the one or more microneedles may further comprise a middle layer disposed adjacent to the shell portion and the core portion.
  • the middle layer is sandwiched between the shell portion and the core portion.
  • the middle layer may be configured to have a different drug release rate from the first biocompatible material and the second biocompatible material.
  • the middle layer may comprise hyaluronic acid, poly(lactic-co-glycolic acid), a polysaccharide, polyvinyl alcohol, or a crosslinked derivative thereof.
  • the crosslinked derivative may be a crosslinked derivative of poly(lactic-co-glycolic acid), a polysaccharide, or polyvinyl alcohol.
  • the middle layer may comprise methacrylated hyaluronic acid. The presence of a middle layer helps to encapsulate a drug that may not be compatible for encapsulation in the shell portion and core portion, or may not be compatible for encapsulation with another drug in the shell portion and core portion.
  • each of the one or more microneedles may have a base.
  • the base of each of the one or more microneedles may be formed directly on the surface of the substrate according to various embodiments. This means there is no intervening layer or material between the base of a microneedle and the substrate.
  • the core portion may not be entirely surrounded by the shell portion. That is to say, after detaching the one or more microneedles from the substrate to be embedded in a tissue, the base of the core portion of each microneedle becomes exposed, and this allows for a drug to be released from the core portion through the exposed portion of the base.
  • the microneedles may be detached from the substrate by peeling off the substrate from the tissue layer after the microneedles are embedded in the tissue.
  • the substrate may comprise a biomaterial which has a lower molecular weight compared to the first biocompatible material and the second biocompatible material.
  • biomaterial refers to a biological or synthetic material which can be introduced to a body tissue as part of an implanted device without causing any adverse effects on the body tissue.
  • the biomaterial being smaller in molecular weight can dissolve faster when contacted with a body fluid.
  • a non limiting example of such biomaterial may be hyaluronic acid having a molecular weight of 3 kDa.
  • the body fluid may be tears from the eye or any other tissue fluid.
  • the shell portion, the core portion, and/or the middle layer may comprise at least one drug.
  • the drug may comprise an immunoglobulin, an anti-vascular endothelial growth factor, a nonsteroidal anti-inflammatory drug, a peptide, or a nucleic acid.
  • the peptide may be a protein.
  • the drug may also comprise an antibody or may be a small molecule drug.
  • Other therapeutic drugs may be used.
  • the drug may be conjugated to the first biocompatible material forming the shell portion, the second biocompatible material forming the core portion, and/or the material forming the middle layer, for slower release of drug, which in turn provides for different drug release profile.
  • the one or more microneedles may be referred to as“drug-reservoirs” in the present disclosure.
  • the present disclosure also provides for a drug delivery device as described above for use in therapy.
  • the present disclosure also provides for a drug delivery device as described above for use in the treatment and/or prevention of a disease comprising an ocular disease, obesity, a metabolic disease, and/or a skin disease.
  • the present disclosure also provides for use of a drug delivery device as described above in the manufacture of a drug delivery patch for the treatment and/or prevention of a disease comprising an ocular disease, obesity, a metabolic disease, and/or a skin disease.
  • the drug delivery patch may be an eye patch or a skin patch.
  • the present disclosure also provides for a method of treating and/or preventing a disease comprising an ocular disease, obesity, a metabolic disease, and/or a skin disease, the method comprising applying a drug delivery device as described above to a tissue layer, and removing the substrate of the drug delivery device from the one or more microneedles of the drug delivery device.
  • a disease comprising an ocular disease, obesity, a metabolic disease, and/or a skin disease
  • the method comprising applying a drug delivery device as described above to a tissue layer, and removing the substrate of the drug delivery device from the one or more microneedles of the drug delivery device.
  • the present disclosure further provides for a method of fabricating a drug delivery device as described above.
  • the method may comprise forming a shell portion comprised of a first biocompatible material for each of one or more microneedles in a mold which configures each of the one or more microneedles to have an apex shaped to penetrate a tissue layer, forming a core portion comprised of a second biocompatible material on the shell portion of each of the one or more microneedles in the mold, wherein the second biocompatible material is different from the first biocompatible material, removing the one or more microneedles from the mold, and attaching the one or more microneedles to a substrate to form the drug delivery device.
  • the present method involves forming a shell portion for each of the one or more microneedles.
  • the shell and core portions may be made of different biocompatible materials.
  • the shell portion may be formed of a first biocompatible material that, when crosslinked, dissolves slower in a body fluid than the second biocompatible material for the core portion.
  • the use of such a first biocompatible material also results in a shell portion that can maintain the shape of each of the one or more microneedles, especially the structural integrity of the sharp end apex, such that the drug delivery device has the ease of penetration as described above.
  • Such a first biocompatible material need not be of a stiffness that is higher than the second biocompatible material forming the core portion.
  • the shell portion may comprise a first biocompatible material as already described above.
  • forming the shell portion may comprise adding the first biocompatible material to the mold.
  • the first biocompatible material may be allowed to set in the mold and dried to form the shell portion.
  • forming the shell portion may comprise drying the first biocompatible material in the mold. The drying can be carried out by any suitable means as long as the shell portion can be formed in the mold.
  • the present method may further comprise subjecting the shell portion to a crosslinking agent after removing the one or more microneedles from the mold to form crosslinkages in the first biocompatible material.
  • the crosslinking agent may comprise ultraviolet light. Forming crosslinkages allows for the shell portion to dissolve slower, thereby providing slower drug release compared to a biocompatible material that is not crosslinked.
  • the second biocompatible material for forming the core portion may be added on top of the shell portion in the mold.
  • the second biocompatible material forming the core portion may be a substance that dissolves faster in a body fluid compared to the first biocompatible material forming the shell portion.
  • the core portion is formed of such a second biocompatible material, it can even provide for burst release of the drug that is encapsulated in the core portion, hence providing a different drug release rate from the shell portion.
  • the core portion is formed of a faster-dissolving biocompatible material, it may not be able to maintain the structural integrity of the sharp-pointed apex if such a second biocompatible material is solely used to form the one or more microneedles.
  • forming the core portion may comprise adding an aqueous solution to the mold, wherein the aqueous solution may comprise the second biocompatible material.
  • forming the core portion may comprise drying the aqueous solution in the mold.
  • the shell portion may be configured to provide for a faster drug release rate compared to the core portion, and this has already been mentioned above.
  • the first biocompatible material may have a faster drug release rate compared to the second biocompatible material.
  • the present device is therefore versatile in that the shell portion and the core portion may be configured to provide different drug release rates. Said differently, the first biocompatible material and the second biocompatible material may be configured to have different drug release rates, according to various embodiments.
  • each of the first biocompatible material and the second biocompatible material may comprise hyaluronic acid, poly(lactic-co-glycolic acid), a polysaccharide, polyvinyl alcohol, or a crosslinked derivative thereof.
  • Forming crosslinkages to obtain the crosslinked derivatives for use as the first biocompatible material or the second biocompatible material depends on whether the shell or core portion requires a slower drug release rate.
  • One example of a crosslinked derivative may be methacrylated hyaluronic acid.
  • the crosslinked derivative may also be a crosslinked derivative of poly(lactic-co-glycolic acid), a polysaccharide, or polyvinyl alcohol.
  • Other crosslinked derivatives may include biocompatible crosslinked polymers as an example.
  • Forming crosslinkages to form crosslinked derivatives tend to cause slower dissolution of a biocompatible material in a body fluid compared to their non-crosslinked counterparts.
  • Non-limiting examples of polysaccharide may include chitosan, pullulan, etc.
  • the first biocompatible material may comprise or consist of methacrylated hyaluronic acid while the second biocompatible material may comprise or consist of hyaluronic acid.
  • the second biocompatible material may comprise or consist of methacrylated hyaluronic acid while the first biocompatible material may comprise or consist of hyaluronic acid.
  • the first biocompatible material or the second biocompatible material may comprise methacrylated hyaluronic acid.
  • Forming the shell portion and the core portion may take place in the mold.
  • the mold may be one designed to have cavities that are shaped for each of the one or more microneedles to be formed with an apex.
  • the advantage of forming the one or more microneedles through such a mold provides for ease of penetration of the drug delivery device due to formation of the apex. Advantages of the apex have already been described above.
  • the apex allows for each of the one or more microneedles to easily penetrate a biological layer, such as a tissue layer or membrane layer, by simply pressing the drug delivery device onto the tissue layer.
  • a biological layer such as a tissue layer or membrane layer
  • the apex is formed to be a sharp end that can penetrate the biological layer without exerting a significant amount of force.
  • a human finger can be used to press the drug delivery device against the tissue layer, and the one or more microneedles remain implanted in the tissue layer even after the finger is removed.
  • the present drug delivery is patient-friendly in the sense that no surgical procedures nor supervision from a medical practitioner is required for the drug to be administered, and due to the ease of penetration, pain is minimized or eliminated.
  • the present method may further comprise forming a middle layer on the shell portion before forming the core portion on the middle layer.
  • forming a middle layer helps to create another portion for encapsulating a drug that may not be compatible for encapsulation in the shell portion and core portion, or may not be compatible for encapsulation with another drug in the shell portion and core portion.
  • the middle layer may also provide for a different drug release rate from the shell portion and/or the core portion.
  • the middle layer may be of the same biocompatible material as the core portion.
  • the middle layer may be of a different biocompatible material from the first biocompatible material and the second biocompatible material so as to have the middle layer configured to have a different drug release rate from the shell portion (i.e. first biocompatible material) and the core portion (i.e. second biocompatible material).
  • the middle layer may comprise hyaluronic acid, poly(lactic-co-glycolic acid), a polysaccharide, polyvinyl alcohol, or a crosslinked derivative thereof, according to various embodiments.
  • the crosslinked derivative may be a crosslinked derivative of poly(lactic-co-glycolic acid), a polysaccharide, or polyvinyl alcohol.
  • the middle layer may comprise methacrylated hyaluronic acid.
  • the substrate may be formed of a biomaterial comprising a lower molecular weight compared to the first biocompatible material and the second biocompatbile material, thereby allowing for easier detachment of the one or more microneedles from the substrate as the lower molecular weight biomaterial dissolves faster. This helps to avoid using an amount of force that may entirely remove the penetrated microneedles from the tissue layer.
  • the body fluid may be tears from the eye or any other tissue fluid.
  • forming the shell portion may further comprise adding at least one drug to be encapsulated in the shell portion.
  • forming the core portion may further comprise adding at least one drug to be encapsulated in the core portion.
  • forming the middle layer may further comprise adding at least one drug to be encapsulated in the middle layer. Embodiments regarding the drug have already been described above.
  • the word“substantially” does not exclude“completely” e.g. a composition which is“substantially free” from Y may be completely free from Y. Where necessary, the word“substantially” may be omitted from the definition of the invention.
  • the articles“a”,“an” and“the” as used with regard to a feature or element include a reference to one or more of the features or elements.
  • the term“about” or“approximately” as applied to a numeric value encompasses the exact value and a reasonable variance.
  • the present disclosure provides for a strategy that utilizes an array of detachable microneedles.
  • the microneedles may be disposed on an eye patch. This strategy can fulfill the clinical need for safe and effective ocular drug delivery for treatment of eye diseases and injuries, which can be challenging for conventional solutions due to presence of ocular barriers.
  • the microneedles can penetrate the ocular surface tissue and serve as implanted micro-reservoirs for controlled drug delivery.
  • the biphasic drug release kinetics i.e. both fast and sustained releases
  • a neutralizing antibody to vascular endothelial growth factor receptor type 2 (DC101) via an eye patch comprising the microneedles produces about 90% reduction of the comeal neovascular area.
  • an anti-inflammatory compound (diclofenac) followed by a sustained release of DC 101 provides synergistic therapeutic outcome.
  • a swellable eye patch without microneedles is also compared to assess the treatment effectiveness.
  • the flexible polymeric eye patch may be equipped with an array of biodegradable and detachable microneedles for localized, highly efficient, and controlled ocular drug delivery.
  • Microneedles can penetrate the ocular barriers (epithelial and stromal layers of cornea) with minimal invasiveness and be self- implanted as drug reservoirs for controlled drug release.
  • the microneedles may have double-layer microneedles for biphasic release kinetics and packaging of multiple drugs for synergistic therapy.
  • NV corneal neovascularization
  • a swellable eye patch without microneedles is also used to collect eye fluid for monitoring the therapeutic effectiveness based on biomarker detection.
  • the present drug delivery device could be paradigm- shifting for long term home- based treatment and management of various eye diseases. [00139] Details of the present drug delivery device, its uses, and method of fabricating such a drug delivery device, are discussed, by way of non-limiting examples, as set forth below.
  • Sodium hyaluronate with different molecular weights (MW) (less than 10 kDa, about 50 kDa, about 300 KDa) were purchased from Freda Biochem Co., Ltd. (China).
  • Vascular endothelial growth factor receptor 2 antibody (VEGFR2; GTX14094; GTX10972) was obtained from GeneTex (USA). All reagents were of analytical grade and used without further purification.
  • MeHA was synthesized by the following steps. Briefly, hyaluronic acid (HA) aqueous solution (4.0 g of HA, MW about 300 kDa, dissolved in 200 mL deionized water (DI)) was continuously stirred overnight (at 4°C), before 133.3 mL DMF and 4.76 mL MA were added dropwise to the HA solution. The reaction solution was then regulated to pH 8-9 with 1 M NaOH, followed by continuous stirring for another 18 hrs (at 4°C). Subsequently, the reaction solution was supplemented with 9.88 g NaCl to reach a 0.5 M NaCl concentration.
  • HA hyaluronic acid
  • DI deionized water
  • the MeHA precipitates were washed again with ethanol for 3 times before being dissolved in DI water, and dialyzed for 7 days. After lyophilisation, the purified MeHA was characterized by 'H NMR spectroscopy (Bruker Avance II 300MHz NMR). The degree of modification was determined by digital integration of the anomeric protons signals or methyl protons signals of HA and of the methacrylate proton signals at about 6.1, about 5.7, and about 1.9 ppm.
  • Microneedles (MN) patches were prepared via a micromolding method. Briefly, polydimethyl-siloxane (PDMS, Sylgard 184, Dow Coming USA) micromolds were created by pouring PDMS solution into the custom-designed stainless steel master-molds (Micropoint Technologies, Singapore), which was followed by degassing (10 mins in vacuum oven) and curing (70°C for 2 hrs).
  • PDMS polydimethyl-siloxane
  • Sylgard 184 Dow Coming USA
  • MeHA aqueous solution 50 mg/mL MeHA together with 0.5 mg/mL Irgacure 2959 in DI water
  • MeHA aqueous solution 50 mg/mL MeHA together with 0.5 mg/mL Irgacure 2959 in DI water
  • un-modified HA solution about 50 kDa, 200 mg/mL
  • centrifuged 805 g, 5 mins
  • HA solution less than 10 kDa, 500 mg/mL
  • MN patches were gently peeled off from the micromolds, and exposed to low-intensity ultraviolet light for 3 minutes (360 nm, about 2 mW/cm 2 ).
  • MN patches were examined using a field-emission scanning electron microscope (FESEM) (JSM-6700, JEOL), and digital microscope (Leica DVM6). MN patches loaded with different IgGs, such as IgG(405), IgG(488) and IgG(680), were visualized with a confocal laser scanning microscope (LSM800, Carl Zeiss). The mechanical property of MNs was tested using an Instron 5543 Tensile Tester (Instron). A vertical force was applied to the MNs using a flat-headed stainless steel cylindrical probe (at a constant speed of 0.5 mm/min). The force was continuously recorded until a displacement of 450 pm was reached. Microneedle insertion test was performed.
  • FESEM field-emission scanning electron microscope
  • LSM800 Carl Zeiss
  • MNs (3 x 3 MN patch, loaded with or without 2 pg IgG) were mounted onto the cylindrical probe, and pressed perpendicular to the isolated porcine cornea at a rate of 5 mm/min until a pre-set maximum load of 4 N was reached. Force exerted on the cornea by the MN as a function of its displacement into cornea was recorded. The insertion force was estimated when the force against the cornea showed discontinuity followed by a steep slope.
  • the transmittance of the MNs (loaded with or without 2 pg IgG), isolated porcine cornea and aqueous humor (in PBS) was measured in a spectrophotometer (Shimadzu UV-1800).
  • the cells After being blocked with 1% BSA in PBST (PBS with 0.1% tween20) (1 hr), the cells were incubated overnight in PBST containing 1% BSA and anti-VEGFR2 IgG (free IgG or IgG released from MNs). After washing with PBS, the cells were then incubated with the secondary antibody tagged with Alexa Fluor 680 (2 hrs), and after washing again, the cells were imaged using a confocal microscope.
  • PBST PBS with 0.1% tween20
  • HUVECs exposed to 10 ng/mL VEGF were treated with different doses of anti-VEGFR2 IgG (free IgG or IgG released from MNs) for about 18 hrs.
  • Tube formation of HUVECs grown on the Geltrex matrix were then recorded using an inverted microscope, and tube lengths were measured using the ImageJ (NIH.gov).
  • MN patches (3 x 3 MN array) were applied briefly to the porcine cornea (about 30 seconds), before the supporting base was removed. The corneas were then excised, washed with PBS, and analysed for the presence of fluorescence spots produced from IgG(680) loaded in MNs using confocal microscopy.
  • the corneal tissues were fixed with 4% formaldehyde solution (24 hrs), and cryoprotected with 30% sucrose solution (24 hrs), before embedding in FSC22 Frozen Section Media (Leica Microsystem) for cryo sectioning (5 mhi thick) (CM 1950 cryostat, Leica Microsystems), and haematoxylin and eosin staining (Sigma- Aldrich).
  • Example 5 Evaluation of In Vitro and In Vivo Drug Release Profiles
  • MNs were immersed in 0.5 mL of simulated tear fluid (NaCl 0.68 g, NaHCOs 0.22 g, KC1 0.14 g, CaCl 2 -2H 2 0 0.008 g, in 100 mL DI water, pH 7.4), gelatin hydrogel (15% w/v gelatin type b from Sigma- Aldrich, in DI water, pH 7.4) or PBS (pH 7.4), and placed in an incubator shaker (50 rpm, 37°C). IgG molecules (conjugated with Alexa Fluor dyes) released from MNs were measured using a fluorescence spectrometer (SpectraMax M5, Molecular Devices). The real-time visualization of IgG releases from double-layered MNs (DL- MNs) in agarose hydrogel (1.4% w/v, in DI water, pH 7.4) or porcine cornea were analysed using a confocal microscopy.
  • simulated tear fluid NaCl 0.68 g, NaHCOs 0.
  • mice C57BL/6J, 7-8 weeks old male. Specifically, under anesthetized condition, a MN patch with 3 x 3 array of IgG(680)-loaded double-layered MNs was gently applied on one cornea (one eye only) for 30 seconds. The mice were then imaged immediately (day 0) or at day 3 using an in vivo imaging system (IVIS Spectrum, Perkin Elmer). In some experiments, MN treated mice were euthanized before collecting their eye balls and incising the cornea to identify the presence of fluorescence spots produced by MNs using confocal microscopy.
  • mice were divided into 4 groups, with treatment of 10 pg IgG(680) through intraperitoneal injection, topical eye-drop instillation or intra-corneal delivery using MN patch, or without treatment as control. After 2 hrs of treatment, the mice were euthanized and their eyes and major organs (liver, heart, kidney and lung) were dissected and visualized by IVIS imaging system.
  • mice were housed in light and temperature controlled facility (l2-hr light/ l2-hr dark cycle, 2l°C), and allowed free access to water and normal diet.
  • Double-layered MN patches (3 x 3 MN array) were applied onto the central cornea area of anesthetized mice for 30 seconds. After removing the supporting base, corneas were imaged by a bright-field microscope. After receiving MN insertion, mice were immediately returned to their cages, allowing recovery from anaesthesia.
  • mice were euthanized immediately after MN insertion or later (at day 1, 3 and 7), and corneas were collected to examine histological changes.
  • Example 7 Ocular Bum Mouse Model for Ocular Delivery of MN Patches
  • mice were anesthetized first before a sterilized Whatman filter paper (2 mm) soaked with 1 M NaOH solution was placed on the mice eyes for 30 seconds (at day 0). Eyes were then extensively flushed with sterilized PBS solution (about 10 mL) using a syringe. At day 2, corneal neovascular outgrowths were imaged by a microscope.
  • mice were then randomly divided into 6 groups, treated only once with eye-drop instillation of either non-specific control IgG or anti-VEGFR2-IgG (DC 101) (10 pg in 20 pL PBS), application of HA-only MN loaded with either control IgG or DC101 (1 pg), or application of DL-MN loaded with either control IgG or DC101 (1 pg, about 0.5 pg each in both layers).
  • DC 101 non-specific control IgG or anti-VEGFR2-IgG
  • mice were randomly divided into different groups, treated only once with DClOl-loaded DL-MN (0.5 pg in MeHA layer), diclofenac-loaded DL-MN (1 pg in HA core), 2-drug-loaded DL- MN (DC101 in MeHA and diclofenac in HA core), or eye-drop instillation of both drugs.
  • DClOl-loaded DL-MN 0.5 pg in MeHA layer
  • diclofenac-loaded DL-MN (1 pg in HA core
  • 2-drug-loaded DL- MN DC101 in MeHA and diclofenac in HA core
  • VL vessel lengths
  • CH clock hours
  • VA vessel area
  • VA 0.2p x VL x CH.
  • mice were euthanized and corneas were collected for immunohistochemistry analyses of macrophage infiltration in corneal stromal layer. F4/80 as a major macrophage marker was stained with a specific antibody (R&D systems). Tear films from differently treated mice were collected by simply placing MeHA patch without MNs on their ocular surface for 1 min, before centrifugation of the patch at 16,000 g for 5 mins. Subsequently, interleukin-6 (IL6) and VEGF concentrations were determined by IL6 and VEGF ELISA kits (Invitrogen), respectively.
  • IL6 interleukin-6
  • VEGF VEGF ELISA kits
  • Example 9 Results - Fabrication of Eye Patch with Double-Layered Microneedles
  • Hyaluronic acid is a non-sulphated glycosaminoglycan that is distributed abundantly throughout the human body in the connective tissues as well as vitreous eye fluid.
  • HA has been widely used in ophthalmology, particularly in artificial tear solution as a lubricant for dry eyes.
  • HA-MNs cannot maintain its sharp-pointed structural integrity and mechanical strength during penetration into a wet surface like cornea.
  • HA-MN can only afford burst release of drugs.
  • MeHA crosslinked methacrylated HA
  • FOG. 1A crosslinked methacrylated HA
  • FIG. 1D an eye-contact patch equipped with double-layered MNs (DL-MN) for controlled ocular drug delivery is presently developed (FIG. 1D), using a simple micromolding method (FIG. 2A).
  • the MNs have a HA inner core and a MeHA outer layer. Because the highly dissolvable HA is covered by MeHA, the MNs are able to penetrate the wet cornea surface. Briefly, a small amount of MeHA aqueous solution, with or without therapeutic compounds, was centrifuged into the reverse MN structures in the female polydimethylsiloxane (PDMS) mold.
  • PDMS polydimethylsiloxane
  • the fabricated patch consists of an array of pyramidal- shaped MNs with tip diameter of about 10 pm, height of about 500 pm, base width of about 250 pm, and inter-needle spacing of about 400 pm.
  • the final MN dimensions are smaller than the stainless steel templates (300 pm bases with 600 pm height), due to the shrinkage of PDMS and HA/MeHA during the fabrication process.
  • the MN design is based on the findings that pyramidal-pointed tips (compared to conical one) with the aspect ratio of 2:1 (height to base diameter) have better tissue penetration.
  • the eye patches (about 2 x 2 mm) with a 3 x 3 MN array were used for mice whose cornea size is about 3 mm in diameter (FIG. 2B to 2G).
  • Immunoglobulins (IgG) labelled with Alexa Fluor 680 or Alexa Fluor 488 as the model therapeutic compounds were separately loaded in the different layers of MNs (FIG. 3A and 3B).
  • the confocal fluorescence imaging confirms that red IgG (680) and green IgG (488) can be separately encapsulated in the outer and inner layers of MN, respectively, while the substrate is free of IgG molecules (FIG. 3C to 3E).
  • the tissue fluid is drawn into the MNs and quickly dissolves the interfacial HA layer between the MNs and substrate, thereby causing detachment of MNs (FIG. 1D).
  • the embedded DL-MNs serve as the micro-reservoirs for localized and sustained drug release.
  • the inner HA core being exposed to the tissue fluid undergoes quick dissolution and discharge of the drugs, whereas the outer MeHA layer dissolves slowly letting the drug molecules slowly seep through the cosslinked polymer matrix.
  • IgG recovered from 3 x 3 DL-MNs dissolved in phosphate buffer saline (PBS) was 0.92 ⁇ 0.21 pg, correlating well with the nominal loading amount (1 pg) (FIG. 31).
  • PBS phosphate buffer saline
  • IgGs were tested by evaluating their molecular weight on polyacrylamide gel electrophoresis after storage of MN patch at 4°C for 1 week.
  • Majority of IgGs (82.11 ⁇ 11.2%) released from either HA or crosslinked MeHA matrix was intact as evidenced by the expected band at about 150 kDa (FIG. 3J).
  • Example 10 Characterization of Double-Layered Micro-Drug-Reservoirs
  • IgG(488) loaded in the fast dissolving inner HA layer can be quickly released in both artificial tear fluid (which mimics tear) and gelatin hydrogel (which mimics comeal stromal tissue). Specifically, more than 80% was released within 5 mins in the former and 30 mins in the latter.
  • prolonged release profile was observed for IgG(680) loaded in the crosslinked MeHA outer layer (ti /2 of about 2 days in tear fluid and about 3 days in gelatin hydrogel) because IgG molecules can only slowly diffuse through the interwoven meshwork of MeHA.
  • the biphasic release profile was realized when a single drug molecule, IgG(680), was loaded in both compartments of DL-MNs (FIG. 3G).
  • DL-MNs were embedded within the agarose hydrogel (which mimics corneal tissue in which water content is about 80%) and were continuously monitored under confocal microscope (FIG. 4C).
  • DL-MNs were quickly detached from the supporting substrate (less than 60 seconds) into the hydrogel because fluid was quickly drawn into MN- substrate junction.
  • the supporting substrate is made of highly-dissolvable low molecular weight HA (3-10 kDa)
  • HA molecules at the MN-substrate junction dissolve rapidly as the fluid inside and at the surface are quickly drawn into the hydrophilic HA matrix.
  • the patches were then removed allowing MNs embedded into the hydrogel.
  • the mechanic perturbation caused by the penetration and substrate removal process also facilitates MN detachment.
  • the fast-dissolving HA inner-core released the loaded green IgG(488) within 10 mins, while the crosslinked MeHA outer-shell gradually swelled and slowly discharged the encapsulated red IgG(680) into the hydrogel (FIG. 4D, FIG. 5A).
  • the real-time release profile of double-layered micro-implants in hydrogel was captured by fluorescence microscopy as shown in FIG. 4D.
  • the data demonstrated the biphasic release kinetics of DL- MNs, i.e. a burst phase followed by a slow discharge over several days.
  • MNs in hydrogel were barely visible under bright-field imaging (FIG. 5B), suggesting that they are essentially transparent and hence suitable for use in corneal tissue.
  • MNs The mechanical strength of MNs was assessed by compression test. Consistent with other studies, the mechanical strength of HA-MNs (about 0.4 N per needle) is strong enough for skin penetration (FIG. 3H). In contrast, the mechanical strength of crosslinked MeHA-MNs (about 0.15 N per needle) is much weaker. Because MeHA is highly viscose, only a lower polymer concentration can be used to fabricate MNs (50 mg/mL for MeHA-MNs vs. 200 mg/mL for HA-MNs). This compromises the mechanical strength of MeHA.
  • the mechanical strength of DL-MNs is similar to that of HA-MNs (about 0.4 N per needle), indicating that the mechanical property of DL-MN is dictated by the inner HA core.
  • drug loading into DL-MNs (2 pg) does not compromise the mechanical properties of DL-MNs (FIG. 2H).
  • the force required to penetrate human cornea may be about 0.5 N per needle.
  • the sharp tip of a MN about 10 pm
  • the force needed to penetrate the cornea can be much lower, thereby greatly lowering the amount of pain associated with administration of the MN.
  • HA inner- core quickly discharged its cargo IgG(488) while the crosslinked MeHA outer-shell slowly released IgG(680) into the comeal tissue.
  • the transmittance in the visible range of fully hydrated DL-MN is about 73-86%, which is comparable to that of cornea and aqueous humour (FIG. 5L).
  • FIG. 6D shows a representative bright-field image of mouse eye immediately after MN insertion (day 0).
  • the MN applied corneas were further analysed under confocal microscope. It was found that IgG(680)-loaded MNs were embedded within the cornea (about 90% success rate), as evidenced by visual inspection of the removed substrate (FIG. 6B) and the fluorescence marks left behind (FIG. 6E). Subsequent histological examination revealed the small penetration cavities (about 100 pm) inside the comeal stromal layer, similar to the observation in porcine cornea (FIG. 5G).
  • FIG. 6G and 6H There were no significant differences of body weight and food intake between the control and test groups (FIG. 6G and 6H). There were no visible indications of corneal opacity, inflammation or haemorrhage in any MN-treated eyes (FIG. 6D). No signs of pain in the test group were observed based on the grimace scale pain assessment (FIG. 61). All these observations indicate that MN insertion and implantation into cornea is minimally invasive without causing obvious adverse effects on the eyes, general health state and behaviour.
  • Example 12 Double-Layered Micro-Drug-Reservoirs Improving Efficacy of Anti-VEGF Therapy
  • Eye trauma including chemical injury and infection, can trigger corneal neovascularization (NV), and may cause comeal opacity, visual impairment and even blindness.
  • VEGF vascular endothelial growth factor
  • VEGF promotes blood vessel formation mainly via VEGF receptor type 2 (VEGFR2).
  • anti- VEGF therapies e.g. ranibizumab
  • ocular barrier e.g. comeal epithelium
  • adverse effects e.g. subconjunctival haemorrhage
  • DC 101 was used because of its proven effectiveness against angiogenesis in murine models. Similar to the untreated eyes, eyes treated with control IgG eye-drop showed substantial comeal NV (1.48 ⁇ 0.45 mm 2 vs. 1.50 ⁇ 0.24 mm 2 ) (day 7).
  • Example 13 Combinational Therapy Using Double-Layered Micro-Drug- Reservoirs for Synergistic Effect
  • Ocular delivery of multiple drugs at different stages of the disease progression can offer a more effective treatment outcome due to their synergistic effects.
  • the initial inflammatory response is a factor that triggers ocular neovascularization (e.g. corneal NV, uveitis-related ocular NV).
  • ocular neovascularization e.g. corneal NV, uveitis-related ocular NV.
  • inflammatory cells e.g. macrophages
  • pro-inflammatory cytokines e.g. interleukin 6, IL6
  • VEGF angiogenic growth factors
  • DL-MNs were loaded with two drugs, nonsteroidal anti-inflammatory drug (1 pg diclofenac) in its fast-dissolving HA core and anti-VEGFR2 drug (0.5 pg DC101) in slow-dissolving crosslinked MeHA shell.
  • nonsteroidal anti-inflammatory drug (1 pg diclofenac)
  • anti-VEGFR2 drug 0.5 pg DC101
  • ocular delivery of either only DC 101 in MeHA layer or only diclofenac in HA core using DL-MN patch exerted inhibition on neovascular area (0.52 ⁇ 0.20 mm 2 and 0.63+ 0.25 mm 2 , respectively).
  • the therapy combining both drugs was much more effective (0.16+ 0.24 mm 2 ). It is further shown in FIG.
  • FIG. 9A and 9B The corneal inflammation was further analysed by immunofluorescence staining (FIG. 9A and 9B), and demonstrated that the cornea treated with diclofenac alone in HA core showed significantly fewer infiltrating F4/80+ macrophages as compared to the untreated cornea.
  • DC 101 alone loaded in MeHA shell
  • DL-MNs-loaded with both diclofenac and DC 101 showed most significant suppression on the number of infiltrating macrophages.
  • Tear fluid can accurately reflect the dynamic changes of ocular surface tissue (e.g. cornea, sclera).
  • MeHA based patch As MeHA based patch is highly swellable, it was used to collect mouse tear film for analysis of the concentration of inflammatory and angiogenic cytokines (e.g. IL6, VEGF) in tear film after treatment (FIG. 9C).
  • IL6, VEGF inflammatory and angiogenic cytokines
  • FIG. 9D the pore size of the fully swelled MeHA-patch was 2-5 pm, suggesting that large proteins can be easily absorbed.
  • the absorption of Cy5-conjugated albumin from agarose hydrogel confirmed the suitability of the patch to collect biomarkers in tear film.
  • Example 14 Summarized Discussion of the above Examples
  • the present eye patch with micro-drug-reservoirs self implantable into the ocular surface tissue for controlled drug release is advantageous for overcoming such a challenge.
  • the flexible patch can be readily applied by gentle and brief thumb pressing on the ocular surface, which is as easy as wearing a disposable contact lens without causing discomfort or requiring high skills.
  • the micro-drug-reservoirs may be comprised of multiple compartments, they allow the release of the same drug with biphasic kinetics or sequential release of different drugs for synergistic therapy.
  • the demonstrated eye patches offer a unique opportunity for patients to conveniently and effectively manage their eye disorders at home.
  • NV comeal neovascularization
  • DC 101 a monoclonal antibody that blocks VEGFR2
  • micro-implants can achieve about 90% reduction of neovascular area with a single treatment of 1 pg dosage.
  • eye drop application of DC 101 even at a much higher dosage (10 pg) failed to show significant therapeutic effect.
  • Systemic intraperitoneal injection of 1 mg DC 101 (every second day for 1 week) only led to marginal effect (about 20% reduction of neovascular area).
  • ranibizumab eye drop about 0.2 mg, 4 times daily for 3 weeks
  • bevacizumab eye drop about 0.1 mg, 5 times daily for about 3 months
  • single treatment with about 20 mg should be effective for human comeal NV based on the present approach.
  • a larger patch e.g. 10 x 10 MN array
  • longer MNs e.g. 800 pm
  • the present microneedle approach can realize low effective dosage and application frequency. This is needed to relieve the patient’s burden and enhance patient compliance.
  • PLGA has been used in conventional intraocular implants for sustained ocular drug delivery (e.g. ozurdex, a dexamethasone-loaded PLGA-based intravitreal implant).
  • sustained ocular drug delivery e.g. ozurdex, a dexamethasone-loaded PLGA-based intravitreal implant.
  • the present microneedle approach can be applied for other eye diseases as well, for example, delivery of b-adrenergic receptor blockers or prostaglandin analogues for glaucoma, corticosteroids (e.g., prednisolone) for anterior uveitis, fluconazole for fungal keratitis. It may also be used for intra-comeal delivery of riboflavin to patients with keratoconus without the need of comeal epithelial scraping and debridement, thereby avoiding post-operative pain, infection and permanent damage usually associated with the traditional surgical methods.
  • corticosteroids e.g., prednisolone
  • fluconazole for fungal keratitis.
  • the microneedle eye patch demonstrated herein comprises implantable micro-drug- reservoirs for localized, controlled, and efficient ocular dmg delivery in a convenient, safe and painless manner, and provides a cost-effective home-based solution for many ocular diseases.
  • Example 15 Commercial and Potential Applications
  • the present device provides for a minimally-invasive self-implantable micro- drug-reservoirs that enable controlled release of therapeutic molecules, and is also suitable for transdermal drug delivery system.
  • the device has been developed for prevention and treatment of various diseases, apart from ocular diseases.
  • Non-limiting examples of such other diseases include obesity, diabetic mellitus and other metabolic diseases, skin infection and other skin diseases.
  • the trans-dermally delivered drugs could be any drugs or compounds that can be used in obesity, diabetic mellitus and other metabolic diseases, skin infection and other skin diseases, etc.
  • the layered microneedle may also include other biocompatible and biodegradable polymers, and non-limting examples include poly(lactic-co-glycolic acid) and its derivatives, chitosan and its derivatives, etc.
  • a self-implantable, biodegradable, and multi-layered (multi- compartmented) micro-drug-reservoirs for controlled ocular delivery of anti- angiogenic agents (or other drugs) have been developed herein.
  • the sharp-pointed pyramidal- shaped (or otherwise shaped) microneedle arrays are tethered on a rapidly dissolvable and flexible polymeric patch, which can be easily and comfortably applied on the ocular surface daily or regularly by the patient at home without pain and need of skills (“patient- friendly”). After thumb-pressing for a short period of time (e.g.
  • the micro-drug-reservoirs may be detached from the patch substrate and be embedded in the ocular tissue serving as the reservoir-based drug delivery (“short administration time”). As the entire patch does not need to remain attach, eye discomfort and irritation are minimized (“comfort and convenient”). No surgical method is needed to implant the microneedles.
  • the biocompatible biopolymer e.g. naturally occurring hyaluronic acids (HA)
  • HA hyaluronic acids
  • the fabrication process is also simple and inexpensive, only loading and low speed centrifugation are involved without any destructive processes (pressurization, heating, etc.).
  • Unmodified HA is used to make fast-dissolving layer of microneedles for quick delivery of anti-angiogenic agents (within minutes) while crosslinked MeHA is used for slow and sustained release of drugs over a few days.
  • the drug release kinetics can be tailored by engineering the polymeric microneedles, e.g. crosslinking degree, loading the larger drug-polymer conjugates.
  • the achieved controlled drug release which comprises a fast-release from un-modified HA and a sustained-release from outer crosslinked MeHA, is found to be superior to fast-releasing drug delivery platform, in terms of treatment efficacy and efficiency.
  • the present drug delivery device allows for lowering the therapeutic dose, which not only produces lesser side effects but reduces the cost as well.
  • the flexible patches as disclosed herein are equipped with micro-drug-reservoirs amenable for effective, patient-friendly, and convenient home -based treatment and management. Such a technology platform could be paradigm- shifting to combat not only angiogenic eye diseases but also other eye diseases.

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Abstract

La présente invention concerne un dispositif d'administration de médicament comprenant un substrat ayant une surface comprenant une ou plusieurs micro-aiguilles, chacune de la ou des micro-aiguilles comprenant un sommet façonné pour pénétrer dans une couche de tissu, et chacune de la ou des micro-aiguilles étant définie par une partie enveloppe formée autour d'une partie noyau, la partie enveloppe comprenant un premier matériau biocompatible et la partie noyau comprenant un second matériau biocompatible qui est différent du premier matériau biocompatible. Dans un mode de réalisation préféré, le premier matériau biocompatible comprend de l'acide hyaluronique méthacrylé et le second matériau biocompatible comprend de l'acide hyaluronique non modifié. La présente invention concerne également des utilisations du dispositif d'administration de médicament, de préférence pour une administration de médicament oculaire. La présente invention concerne en outre un procédé de fabrication d'un dispositif d'administration de médicament tel que décrit ci-dessus.
PCT/SG2019/050025 2018-01-16 2019-01-15 Micro-réservoirs de médicament auto-implantables pour une administration de médicament oculaire localisée et contrôlée WO2019143293A1 (fr)

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CN113332589A (zh) * 2021-05-26 2021-09-03 四川大学 用于口腔黏膜给药的装载双重药物的聚合物微针及其制备方法
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CN115414381A (zh) * 2022-11-07 2022-12-02 西南民族大学 一种具有瘢痕抑制和/或促伤口愈合作用的组合物及其制备方法和用途
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11666239B2 (en) 2017-03-14 2023-06-06 University Of Connecticut Biodegradable pressure sensor
US11426570B2 (en) * 2018-03-05 2022-08-30 University Of Connecticut Core-shell microneedle platform for transdermal and pulsatile drug/vaccine delivery and method of manufacturing the same
US11678989B2 (en) 2019-03-01 2023-06-20 University Of Connecticut Biodegradable piezoelectric nanofiber scaffold for bone or tissue regeneration
US11826495B2 (en) 2019-03-01 2023-11-28 University Of Connecticut Biodegradable piezoelectric ultrasonic transducer system
CN110812688A (zh) * 2019-11-20 2020-02-21 广州中医药大学(广州中医药研究院) 一种透皮给药的微针及其制备方法
US11745001B2 (en) 2020-03-10 2023-09-05 University Of Connecticut Therapeutic bandage
CN113332589A (zh) * 2021-05-26 2021-09-03 四川大学 用于口腔黏膜给药的装载双重药物的聚合物微针及其制备方法
CN113332589B (zh) * 2021-05-26 2023-05-09 四川大学 用于口腔黏膜给药的装载双重药物的聚合物微针及其制备方法
CN115414381A (zh) * 2022-11-07 2022-12-02 西南民族大学 一种具有瘢痕抑制和/或促伤口愈合作用的组合物及其制备方法和用途
CN115414381B (zh) * 2022-11-07 2023-03-28 西南民族大学 一种具有瘢痕抑制和/或促伤口愈合作用的组合物及其制备方法和用途

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