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WO2024134032A1 - Micro-aiguille stratifiée pour la libération contrôlée d'agents thérapeutiques ou non thérapeutiques - Google Patents

Micro-aiguille stratifiée pour la libération contrôlée d'agents thérapeutiques ou non thérapeutiques Download PDF

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Publication number
WO2024134032A1
WO2024134032A1 PCT/FI2023/050720 FI2023050720W WO2024134032A1 WO 2024134032 A1 WO2024134032 A1 WO 2024134032A1 FI 2023050720 W FI2023050720 W FI 2023050720W WO 2024134032 A1 WO2024134032 A1 WO 2024134032A1
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WO
WIPO (PCT)
Prior art keywords
microneedle
polymer
polymer matrix
therapeutic
outer layer
Prior art date
Application number
PCT/FI2023/050720
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English (en)
Inventor
Hélder A. SANTOS
Flavia FONTANA
Antti RAHIKKALA
Nesma ELSAYED IBRAHIM
Mohammad-Ali SHAHBAZI
Carmine D'amico
Khalil ELBADRI
Original Assignee
Helsingin Yliopisto
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Helsingin Yliopisto filed Critical Helsingin Yliopisto
Publication of WO2024134032A1 publication Critical patent/WO2024134032A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles

Definitions

  • the present invention relates to the delivery of one or more therapeutic or non- therapeutic agents (hereinafter “agent” or “agents”) to a subject, and particularly to a layered microneedle for controlled release of the agents to the subject, and to a device comprising one or more of the layered microneedles.
  • agent therapeutic or non- therapeutic agents
  • the layered microneedle allows for the delivery of a loading dose and a maintenance dose in a single dosage form to the subject.
  • agents such as pharmaceuticals and other macromolecules.
  • agents such as pharmaceuticals and other macromolecules.
  • the most common delivery method for agents is oral delivery in the form of tablets, capsules, or as a liquid, e.g., in a suspension.
  • the oral delivery of many agents is limited since such agents must overcome several hurdles after swallowing before they reach target concentrations in a subject.
  • the enzymatic and pH barriers in the upper part of the gastrointestinal tract can degrade such agents.
  • the physicochemical properties of the agent such as poor water solubility, low dissolution rate, and low permeability, can reduce the fraction of the agent absorbed in the intestine.
  • every agent absorbed in the intestine must pass through the liver before being distributed systemically.
  • a fraction of the agent is metabolised before providing a therapeutic or other desired effect.
  • intra/inter-individual biological variability between subjects, e.g., humans or other mammals may cause differences in the absorption amount and absorption rate of the agent or on the fraction metabolised in the first pass through the liver.
  • patient compliance may be affected by a complicated therapeutic regimen with the requirement of ingesting multiple tablets or the like several times a day.
  • Transdermal patches constitute another type of device for delivery of agents via diffusion through the skin, with high user compliance.
  • this delivery method is limited to selected agents at low dosages and to agents with optimal physicochemical properties, particularly molecular size and hydrophobicity that allow the diffusion of the agents through the stratum comeum, i.e., the 15-20 pm outermost layer of the skin.
  • Permeation enhancers and external apparatus including iontophoresis and ultrasound transducers/transceivers, have been used to improve the delivery rate of such agents with agent-dependent results.
  • permeation enhancers and external apparatus often decrease user compliance because they are either cumbersome or too painful to use.
  • improved drug delivery systems are needed for the efficient delivery of therapeutic and/or non-therapeutic agents to a subject without the aforementioned issues.
  • a layered microneedle and a microneedle device comprising one or more of the microneedles for the delivery of one or more therapeutic or non-therapeutic agents (hereinafter “agent,” “agents,” or “agent(s)” for ease of reference) to a subject.
  • agent therapeutic or non-therapeutic agents
  • the term “subject” refers to any animal including, but not limited to, simians, humans, avians, felines, canines, equines, rodents, bovines, porcines, ovines, caprines, mammalian farm animals, mammalian sport animals, and mammalian pets.
  • the layered microneedle allows for the delivery of a loading dose and a maintenance dose in a single dosage form.
  • the layered microneedle comprises a body having an outer layer and an inner layer.
  • the outer layer and the inner layer are each formulated to release an amount of an agent therefrom at a controlled release rate.
  • the outer layer is formulated to release an agent therefrom at a faster release rate than the inner layer.
  • the outer layer may be formulated to administer a loading dose of an agent to a subject while the inner layer may be formulated to administer a maintenance dose of the agent to the subject.
  • the layered microneedles described herein instead or also allow for the administration of two or more different agents from the same layered microneedle or device.
  • a layered microneedle for the delivery of one or more therapeutic or non-therapeutic agents to a subject comprising: a body having an inner layer and an outer layer, wherein the outer layer at least partially covers the inner layer; wherein the outer layer comprises a first polymer matrix and the inner layer comprises a second polymer matrix, each of the first and second polymer matrices comprising one or more therapeutic or non-therapeutic agents therein; wherein the first polymer matrix of the outer layer is configured to deliver the one or more therapeutic and/or non-therapeutic agents therein at a first controlled release rate; wherein the second polymer matrix of the inner layer is configured to deliver the one or more therapeutic and/or non-therapeutic agents therein at a second controlled release rate; and wherein the first controlled release rate of the first polymer matrix of the outer layer is greater than the second controlled release rate of the second polymer matrix of the inner layer.
  • first and second polymer matrices comprise one or more polymers and at least one additional compound selected from the group consisting of a cross-linker, a plasticiser, a surfactant, and combinations thereof.
  • one or both of the first and second polymer matrices comprise a cross-linker.
  • the cross-linker may be selected from the group consisting of polyethylene glycol (PEG), poly(ethyleneglycol) diglycidyl ether (PEGDGE), polyvinyl alcohol (PVA), and mixtures thereof.
  • the one or more polymers of the first polymer matrix of the outer layer are not cross-linked or are cross-linked to a lesser degree than the one or more polymers of the second polymer matrix of the inner layer. In this way, the release rate may be greater in the outer layer vs. the inner layer.
  • the body of the layered microneedle extends between a base and a tip of the body, wherein the tip has a narrower width than the base.
  • the body may comprise a conical or pyramidal shape, for example.
  • the outer layer of the microneedle has a greater thickness than the inner layer. In further embodiments, the thicknesses of the inner and outer layer are the same. In still other embodiments, the inner layer has a greater thickness than the outer layer of the microneedle.
  • the first controlled release rate of the first polymer matrix of the outer layer is at least 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3, 4, 5, 10, 15, 25, 50, or 100 times greater (measured at, for example, ug/hr) than the second controlled release rate of the second polymer matrix of the inner layer.
  • the first controlled release rate of the first polymer matrix of the outer layer is from 2.5 to 10 times greater (measured at, for example, ug/hr) than the second controlled release rate of the second polymer matrix of the inner layer.
  • one or both of the first and second polymer matrices comprise at least one water-soluble polymer and/or at least one water-swellable polymer.
  • the polymer of the first polymer matrix of the outer layer and/or the polymer of the second polymer matrix of the inner layer comprises a member selected from the group consisting of poly(methylvinylether-a/t-maleic acid) (PMVE/MA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), carboxymethyl cellulose (CMC), hyaluronic acid (HA), poly(lactic-co-glycolic acid) (PLGA), silk-related hydrogels, copolymers thereof, and mixtures thereof.
  • PMVE/MA poly(methylvinylether-a/t-maleic acid)
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • CMC carboxymethyl cellulose
  • HA hyaluronic acid
  • PLGA silk-related hydrogels, copolymers thereof, and mixtures thereof.
  • each of the first and second polymer matrices comprises one or more therapeutic or non-therapeutic agents therein selected from the group consisting of a pharmaceutical compound, nanoparticle, microparticle, biomolecule, vaccine, diagnostic agent, vitamin, natural product, food supplement, herbal extract, cellular product, cell-derived product, cosmetic agent, imaging agent, and combinations thereof.
  • a microneedle for the delivery of a therapeutic agent, wherein the microneedle comprises a body extending between a base and a tip.
  • the body further includes an outer layer and an inner layer.
  • the outer layer which comprises a first polymer matrix comprising one or more polymers and one or more non-therapeutic and/or therapeutic agents, forms a shell that at least partially encloses the inner layer, which also comprises a second polymer matrix comprising one or more polymers and one or more non-therapeutic and/or therapeutic agents.
  • the first polymer matrix of the outer layer is adapted to deliver one or more non-therapeutic and/or therapeutic agents therefrom at a first controlled release rate
  • the second polymer matrix of the inner layer is adapted to deliver one or more therapeutic agents and/or non-therapeutic agents therefrom at a second controlled release rate, wherein the first controlled release rate is faster than the second controlled release rate
  • a microneedle device for delivery of one or more therapeutic agents and/or non-therapeutic agents therefrom.
  • the microneedle device comprises a backing layer and at least one layered microneedle, as described herein.
  • At least a portion of the backing layer is releasably secured to a base of the at least one microneedle for rapid removal of at least a portion of the backing layer.
  • at least a portion of the backing layer comprises a polymer selected from the group consisting of an ethylene-vinyl acetate copolymer, methylene vinyl acetate, polyvinylpyrrolidone, poly(methylvinylether-alt-maleic acid), cellulose and derivates thereof, alginates and derivates thereof, sucrose, and combinations thereof.
  • the backing layer comprises one or more disintegrating agents, such as a natural polymer (e.g., cellulose and derivates, alginates and derivates thereof, and/or sucrose) or a hydrophilic, fast-dissolving, synthetic polymer (e.g., poly vinyl pyrrolidone).
  • a natural polymer e.g., cellulose and derivates, alginates and derivates thereof, and/or sucrose
  • a hydrophilic, fast-dissolving, synthetic polymer e.g., poly vinyl pyrrolidone
  • Figure 1 illustrates a layered microneedle in accordance with embodiments of the present invention
  • Figure 2 illustrates a cross-section of the microneedle of Figure 1.
  • Figure 3 illustrates a top view of a microneedle in accordance with embodiments of the present invention.
  • Figure 4 illustrates a perspective view of a microneedle device in accordance with embodiments of the present invention.
  • Figures 5A-5D illustrate release properties from a microneedle device in accordance with embodiments of the present invention.
  • Dosage regimens of many modem prescription drugs require a high starting dose followed by frequent maintenance doses, which contain a smaller amount of the drug than the starting dose.
  • the starting dose also commonly known as the loading dose, increases the amount of drug to a therapeutic level in the body, and is administered as the first dosage when a therapy is assigned to a patient.
  • the body eliminates the drug at a certain rate, which means that a maintenance dose is needed to counter the drug elimination rate to keep the drug concentration at the therapeutic level.
  • the current state of the art suffers from the drawbacks set forth above, such as inefficient administration and poor patient compliance.
  • a layered microneedle and device comprising one or more of the layered microneedles, which advantageously provide a loading dose and a maintenance dose in the same dosage form.
  • the disclosed microneedles and devices incorporating the same may also or instead deliver more than one agent to a subject in a single dosage form.
  • Figure 1 shows an external side view of a layered microneedle 10 (also “microneedle 10”) in accordance with at least some embodiments of the present invention having a body 12 that extends between a base 14 to a tip 16 of the microneedle 10.
  • Figure 2 provides a cross-sectional view of the microneedle 10 of Figure 1.
  • the body 12 comprises at least an inner layer 18 that is at least partially encased (covered) by an outer layer 20.
  • the outer layer 20 comprises a first polymer matrix 22
  • the inner layer 18 comprises a second polymer matrix 24.
  • Each of the first and second polymer matrices 22, 24 comprises one or more polymers having one or more therapeutic or non-therapeutic agents (hereinafter again “agent,” “agent(s),” or “agents” for ease of reference) incorporated therein.
  • the agent is released from each of the first polymer matrix 22 and the second polymer matrix 24, respectively, at a controlled release rate.
  • the inner layer 18 and the outer layer 20 each have a maximum length from the base 14 to the tip 16 of the microneedle 10.
  • the inner layer 18 has a shorter maximum length than the outer layer 20, measured from the base 14 to the tip 16 of the microneedle.
  • the outer layer 20 has a maximum length equal to a maximum length of the inner layer 18 from the base 14 to tip 16. In such embodiments, the outer layer 20 may completely cover the inner layer 18 of the layered microneedle 10.
  • the layered microneedle 10 may have any overall three-dimensional (3D) shape having a tapered end at the tip 16.
  • 3D three-dimensional
  • a cross-sectional width of the body 12 is narrower at the tip 16 of the microneedle 10 than the base 14 so that the tip 16 more easily penetrates into a target substrate in use.
  • the target substrate may be skin, tissue, mucosa, or any other suitable body to which the microneedle(s) may be applied.
  • the layered microneedle 10 has a substantially conical shape.
  • the present invention is not so limited and that the layered microneedle 10 may comprise any other overall 3D shape with a tapered end at the tip 16, such as a pyramidal shape or the like.
  • the layered microneedle 10 may comprise a base (base 14) having a polygonal shaped-base and the body 12 may comprise four (4) or more triangular faces extending between the base 14 and the tip 16.
  • Figure 3 represents a top view looking down at the tip 16 of the layered microneedle 10, 1.e., the tip 16 of the microneedle coming out of the page showing a pyramidal-shaped tip with four faces.
  • the base 14 of the layered microneedle 10 may have a circular cross-sectional shape. In other embodiments, the base 14 of the layered microneedle 10 may have a polygonal, e.g., rectangular-shaped cross-sectional shape.
  • the inner layer 18 and the outer layer 20 may also have any suitable cross-sectional shape through the microneedle 10, for example, the cross-sectional shape shown in Figure
  • the inner layer 18 and outer layer 20 may individually have a conical or polygonal cross-sectional shape.
  • the inner layer 18 may have a polygonal, e.g., rectangular, cross-sectional shape while the outer layer 20 comprises a non-rectangular cross-sectional shape, such as a conical shape.
  • the tip 16 may be relatively sharp as shown in Figure 2 for penetration into a tissue surface, such as skin.
  • the sharpness of the tip 16, however, may be modified as needed for the degree of penetration desired or to account for the difficulty of penetrating the desired surface.
  • the layered microneedle 10 may comprise three (3) or more layers, each having a different release rate of an agent therefrom.
  • polymer, polymer(s), or polymers the difference in release rate between the first polymer matrix 22 of the outer layer 20 and the second polymer matrix 24 of the inner layer 18 (and any other polymer layers having an agent therein, if provided) may be accomplished by any suitable method, including but not limited to selection of the polymer in the matrices, controlling the degree of cross-linking, and/or by addition of one or more additives to the matrices.
  • the polymer of the first polymer matrix 22 and the second polymer matrix 24 may be the same, or alternatively the polymer in the first polymer matrix 22 may be different from the polymer in the second polymer matrix 24.
  • the polymer of the first polymer matrix 22 and the second polymer matrix 24 comprise one or more water-soluble and/or one or more water-swellable polymers.
  • the water-soluble and/or water-swellable polymers can be degradable and/or dissolvable.
  • the polymers of the first polymer matrix and/or second polymer matrix form a hydrogel.
  • the first polymer matrix of the outer layer comprises at least one water-soluble polymer and the second polymer matrix of the inner layer comprises at least one water-swellable polymer.
  • the second polymer matrix may further include a cross-linker with the at least one water- swellable polymer while the first polymer matrix does not include a cross-linker with the at least one water-soluble polymer.
  • the polymer of the first polymer matrix 22 of the outer layer 20 comprises a member selected from the group consisting of poly(methylvinylether-a/t-maleic acid) (PMVE/MA), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), carboxymethyl cellulose (CMC), hyaluronic acid (HA), poly(lactic-co-glycolic acid) (PLGA), silk-related hydrogels, copolymers thereof, and mixtures thereof.
  • PMVE/MA poly(methylvinylether-a/t-maleic acid)
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • CMC carboxymethyl cellulose
  • HA hyaluronic acid
  • PLGA poly(lactic-co-glycolic acid)
  • the polymer of the second polymer matrix 24 of the inner layer 18 may similarly comprise a member selected from the group consisting of PMVE/MA, PVP, PVA, CMC, HA, PLGA, silk-related hydrogels, copolymers thereof, and mixtures thereof.
  • each of the first and second polymer matrices consists only of one or more polymers and the one or more agents to be delivered by the respective microneedle 10.
  • the first polymer matrix of the outer layer comprises PVP while the second polymer matrix comprises PMVE/MA along with the agent(s) to be delivered.
  • the outer layer 20 may deliver the one or more agents at a greater release rate vs. the inner layer 18 without the need for cross-linking or other additives, e.g., surfactants.
  • the polymer in one or both of the first polymer matrix 22 and the second polymer matrix 24 are cross-linked.
  • the polymer in the first polymer matrix 22 and the second polymer matrix 24 are both cross-linked, but the polymer of the second polymer matrix 24 of the inner layer 18 is cross-linked to a greater degree than the first polymer matrix 22 of the outer layer 20. This may be accomplished by adding a greater amount of a cross-linker as described below or exposing the subject polymer to a greater (longer) curing time.
  • the second polymer matrix 24 of the inner layer 18 is cross-linked, but the first polymer layer 22 of the outer layer 20 is not crosslinked. In further embodiments, neither of the matrices 22, 24 are cross-linked.
  • the first polymer matrix 22 and the second polymer matrix 24 are formulated to release the agent(s) incorporated therein at a predetermined release rate or within a certain range of release rates.
  • the release rate(s) of an agent from the particular matrix 22 or 24 may be adjusted by one or more of polymer selection, controlling the curing process of the polymer matrices (e.g. , controlling degree of cross-linking), and/or by addition of one or more cross-linkers, plasticizers, and/or surfactants.
  • one or both of the polymer matrices 22, 24 comprise at least one additional compound selected from the group consisting of a cross-linker, a plasticiser, a surfactant, and combinations thereof.
  • cross-linker is added to the first polymer matrix and/or second polymer matrix.
  • the cross-linker may comprise any suitable material (e.g., compound) that increases a degree of cross-linking in one or more polymers of the first and/or second polymer matrix.
  • the cross-linker is selected from the group consisting of polyethylene glycol (PEG), poly(ethyleneglycol) diglycidyl ether (PEGDGE), polyvinyl alcohol (PVA), and mixtures thereof.
  • the cross/linker comprises PVA.
  • the polymer(s) of the first and/or second matrices are instead or additionally cross-linked by suitable thermal treatment of the selected polymer matrix.
  • the polymer in one or both of the first polymer matrix 22 and the second polymer matrix 24 may be cross-linked by subjecting the respective polymer to a temperature of from 40 to 400°C, such as 60°C to 150°C, for a duration of 15 minutes to 24 hours, such as from 30 minutes to 4 hours.
  • the amount of cross-linker added and degree of cross-linking can be used to control the rate of swelling/dissolution and/or degradation, which then translates to a modification of the release rate of an agent from the microneedle.
  • the addition of the cross-linker to the first and/or second polymer matrix 22, 24 is effective to decrease the release rate of an agent from the first and/or second polymer matrix.
  • the second polymer matrix 24 comprises a greater degree of cross-linking relative to the first polymer matrix 22. In this way, the first polymer matrix 22 of the outer layer 20 has a (first) controlled release rate greater than a (second) controlled release rate of the second polymer matrix 24 of the inner layer 18.
  • weight percentage refers solely to the weight percentages of the polymeric material(s) in the polymer matrix. Therefore, the weight(s) of one or more (therapeutic or non-therapeutic) agents are not considered in determining the weight percentage of polymeric material(s) in a selected polymer matrix.
  • 0.5% of PEGDGE denotes that the cross-linker PEGDGE comprises 0.5 weight-% of the weight of all polymers in a subject polymer matrix.
  • the polymer matrix further comprises one or more (therapeutic and/or non- therapeutic) agents.
  • a weight percentage of the cross-linker in either or both of the first polymer matrix 22 and second polymer matrix 24 is from 0.00001% to 30%, such as from 1 to 20.
  • the cross/linker comprises PVA in a weight percentage of from 0.00001% to 20%.
  • the ratio of the weight percentage of cross-linker to the polymer is from 0.00001% to 10%.
  • the ratio of the weight percentage of the cross-linker to the polymer is from 0.0001% to 0.12%.
  • one or both of the polymer matrices 22, 24 may comprise one or more surfactants (hereinafter “surfactant”) added therein.
  • the surfactant may be ionic (anionic or cationic) or non-ionic. While not wishing to be bound by theory, it is believed that the addition of one or more surfactants to the first and/or second polymer matrices 22, 24 may modify, e.g., increase, the release rate of an agent therefrom. For example, when administrating a hydrophobic drug, addition of a surfactant may accelerate the release and/or improve distribution of an agent from the layered microneedle 10 to the blood stream of a subject upon administration.
  • the surfactant comprises a non-ionic surfactant selected from the group consisting of poloxamers, Lutrol Fl 08, Pluronic F88, Tween 80, sorbitol esters, and mixtures thereof
  • the surfactant comprises an anionic surfactant, such as sodium lauryl sulphate.
  • the surfactant comprises a cationic surfactant, such as a quaternary salt, e.g., quaternary ammonium salts.
  • the added surfactants are effective to provide enhanced mechanical strength to the layered microneedle 10, to, for example, improve skin penetration and/or diffusion of the layered microneedle 10 into the dermis of a subject.
  • the surfactant may be utilized to further increase the loading of some agents, stabilize them in one or both of the matrices, and/or to provide pH-responsive release rates.
  • the first polymer matrix 22 and/or the second polymer matrix 24 may include one or more plasticizers therein (hereinafter “plasticizer”).
  • the plasticizer is expected to reduce the overall rigidity and brittleness of the respective polymer matrix upon drying. In this way, the plasticizer may, for example, allow for demolding of the microneedles 10 without fracturing the microneedle tips.
  • the plasticizer may be selected from the group consisting of phthalate esters, phosphate esters, fatty acid esters, glycol derivatives, and mixtures thereof.
  • the first polymer matrix 22 and the second polymer matrix 24 each comprise one or more non-therapeutic and/or therapeutic agents (herein again referred collectively referred to as “agent” or “agents” for ease of reference) to be released from the matrices 22, 24 of the outer layer 20 and the inner layer 18, respectively, when the microneedle 10 penetrates a target substrate, e.g. skin, mucosa, or tissue.
  • the agent(s) are homogeneously mixed into selected polymer(s) as the microneedle 10 is formed.
  • at least one agent is released when the microneedle 10 penetrates a surface, e.g., skin, mucosa, or tissue.
  • either or both of the inner layer 18 and the outer layer 20 comprise more than one agent therein.
  • the inner layer 18 and the outer layer 20 comprise the same agent.
  • one of the layers, e.g., inner layer 18 or outer layer 20 comprises at least one agent that is different from at least one agent in another layer, e.g., the other of inner layer 18 or outer layer 20.
  • more than one agent can be simultaneously released from a given layered microneedle 10.
  • the agent can be released from the matrix by any suitable mechanism, e.g. , due to diffusion of the agent, decomposition or degradation of the polymer matrices, or a combination thereof.
  • the one or more agents in the layered microneedle 10 comprise a member selected from the group consisting of a pharmaceutical compound, nanoparticle, microparticle, penetration or permeation enhancer, biomolecule, vaccine, diagnostic agent, vitamin, natural product, food supplement, herbal extract, cellular product, cell-derived product, cosmetic agent, imaging agent, or a combination of any of the above.
  • the selected agent(s) are loaded into any one or more of nanocrystals, nanoparticles, microparticles, extracellular vesicles, or nanovesicles (liposomes, niosomes, and ethosomes), which are then incorporated into the selected polymer matrix or matrices 22, 24.
  • the microneedle 10 is suitable for use in medicine, alternative therapies, as a provider of supplement(s), and in cosmetics.
  • the agent comprises a therapeutic agent approved for the prevention or treatment of a condition, disease, or a disorder, or symptom(s) thereof.
  • the therapeutic agent comprises a non-steroidal anti-inflammatory drug (NS AID).
  • the therapeutic agent comprises meloxicam.
  • NS AID non-steroidal anti-inflammatory drug
  • meloxicam is known to be a non-water soluble small drug difficult to formulate at therapeutic concentrations in dissolving and swelling microneedles.
  • the outer layer 20 Upon penetration of the microneedle 10 into a target substrate, e.g., skin, mucosa, or tissue, the outer layer 20 releases an agent therefrom.
  • the first polymer matrix 22 of the outer layer 20 is adapted to release an agent therefrom at a rate faster than the second polymer matrix 24 of the inner layer 18.
  • the release rate of an agent from the first polymer matrix 22 of the outer layer 20 is at least 1.1, 1.2, 1.3, 1.4, 1.5, 2, 3, 4, 5, 10, 15, 25, 50, or 100 times greater (faster) than a release rate of an agent from the second polymer matrix 24 of the inner layer 18.
  • the second polymer matrix 24 of the inner layer 18 is adapted to release an agent therefrom only after the release of all agents from the first polymer matrix 22 of the outer layer 20 has been completed. In other embodiments, the release of at least one agent from the first polymer matrix 22 of the outer layer 20 overlaps with the release of an agent from the second polymer matrix 24 of the inner layer 18.
  • a microneedle device 30 (also device 30) comprising one or more layered microneedles 10 as described herein for delivery of one or more agents as described herein to a subject.
  • the microneedle device 30 comprises a backing layer 32 and at least one layered microneedle 10 as described herein. Together, the one or more microneedles 10 and the backing layer 32 form the microneedle device 30.
  • the microneedle device 30 is in the form of a patch, which may be applied to a target substrate.
  • the microneedle device 30 may be any suitable size (area) and shape.
  • the backing layer 32 comprises a flexible material such that the microneedle device 30 can be flexibly secured on or about a non-planar or irregularly shaped surface.
  • the microneedle device 30 may be sized to provide the required dosage of the at least one therapeutic or non-therapeutic agent to the subject.
  • the thickness of the backing layer may be from 0.5 mm to 5.0 mm, such as from 0.6 mm to 3.0 mm.
  • the length of the one or more microneedles may be of any suitable size.
  • the microneedle(s) may have a longest dimension of from 0.1 mm to 5 mm, preferably from 0.2 mm to 2.0 mm, and more preferably from 0.5 mm to 0.8 mm.
  • the number of microneedles on the device can also vary depending on the intended purpose of the device 30, e.g., necessary dosage to be administered to a subject.
  • the microneedles 10 may further be organized on the backing layer in any suitable arrangement, such as an organized array of rows and columns, e.g. , a 10 x 10 array of the microneedles.
  • the microneedles 10 may be configured in an irregular pattern, such as when being administered to an irregular surface, to maximize contact with the target substrate.
  • the microneedle device 30 comprises a patch having a backing layer 32, the backing layer 32 having a first surface 34 and a second surface 36 opposite the first surface.
  • the first surface 34 of the backing layer 32 is attached to the base 14 of each microneedle 10 of the device 30.
  • the microneedle device 30 may be made by any suitable process.
  • the material for the microneedles 10 is cast onto a mold to make the microneedles having an inner layer and outer layer as described herein. Thereafter, the material of the backing layer is cast onto the mold, on top of the microneedles.
  • the backing layer 32 is prepared and the microneedles 10 are formed on top of the backing layer by 3D printing the inner layer 18 followed by the outer layer 20.
  • the backing layer 32 may be pulled away from the target substrate, e.g., tissue, thereby leaving the microneedles 10 intact in the target substrate to release the agent(s) therefrom.
  • the backing layer 32 may be completely removed from the target substrate, thereby leaving only the microneedles 10 intact on the target substrate, e.g., skin.
  • the microneedles 10 are formed from a water-soluble material such that after removal of the backing layer 32, there is no need for disposal of the device 30.
  • the backing layer 32 may be comprise more than one layer, e.g., a first backing layer and a second backing layer, such that, for example, the first backing layer may be removed from the device 30, leaving the second backing layer (which may be thinner, of a dissolvable water-soluble material, or of a less durable material) secured to the microneedle(s) 10.
  • the backing layer 32 may be coated with a release layer or coating as is known in the art where needed, e.g., on the surface 34 of the backing layer 32 adjacent the microneedles 10 or other layer, to facilitate removal of the backing layer 32 or portion thereof.
  • the backing layer 32 may be made of any suitable material.
  • the backing layer fully or partially comprises a material that at least provides the second surface 36 of the backing layer 32 with sufficient mechanical strength such that the microneedle device 30 may be pressed into a target substrate, e.g. , skin, tissue, or mucosa. When this occurs, the microneedles 10 described herein penetrate the target substrate.
  • the backing layer is a single layer of a suitable material.
  • the backing layer may comprise one or more layers, such as a surface layer providing additional mechanical strength.
  • the backing layer 32 comprises a water- soluble polymer that allows the backing layer 32 to be wholly or partially dissolved over time while in use, thereby eliminating or at least reducing the amount of material for disposal.
  • the backing layer 32 wholly or partially comprises a member selected from the group consisting of cellulose and derivates thereof, alginates and derivates thereof, sucrose, hydrophilic fast-dissolving polymers, poly vinyl pyrrolidone, ethylene vinyl acetate copolymer, methylene vinyl acetate, poly(methylvinylether-a/t-maleic acid) PMVE/MA, polylactic acid, polyglycolic acid, and mixtures thereof
  • the backing layer 32 comprises a polymer that dissolves at a physiological pH, such as a pH of 4.8 to 8.
  • the polymer of the backing layer 32 is thus one that may dissolve when contact with tissue, e.g., skin or mucosa, of a subject
  • Microneedle devices were made by solvent casting into polydimethylsiloxane (PDMS) molds. The dimensions of the molds are: height 800 pm, base 200 pm, and pitch 500 pm. Microneedles were provided in a 10 x 10 array, each having a pyramidal shape.
  • the outer layer was cast as a suspension of meloxicam (8.7 mg/mL) in polyvinylpyrrolidone (PVP) by centrifugation followed by vacuum.
  • PVP polyvinylpyrrolidone
  • the inner layer was added by casting a suspension of meloxicam (5.8 mg/mL) in PMVE/MA with 0.06 wt % PEGDGE by centrifugation followed by vacuum. Finally, PVP was added to the mold to form the backing layer.
  • the device was left to dry at room temperature before being demolded.
  • the crosslinking (CL) of the inner layer was achieved by placing the microneedles at +80°C for 0.5, 4, or 24 hours (h).
  • the results presented below are derived from at least three devices from the same batch.
  • Figure 5A shows the release of meloxicam from microneedle devices according to embodiments of the present invention cross-linked for 0, 0.5, 4, and 24 h.
  • the amount (pg) of Meloxicam released (y axis) is plotted against time (hr). The results are presented as mean ⁇ standard deviation.
  • Figure 5A shows the average release of meloxicam from the microneedle devices for 48 hours. The figure presents the effect of the cross-linking of the inner layer on the release rate of meloxicam.
  • the four different device sets evaluated in this figure include uncross-linked microneedles (0.06 wt % PEGDGE, 0 h at 80°C), and crosslinked microneedles (0.06 wt % PEGDGE, 80°C for 30 min, 4 h or 24 h) made according to Example 1.
  • FIG. 5 A illustrates different release rates of meloxicam from the microneedles with different degrees of cross-linking, particularly the difference in the release rates of meloxicam at 6 to 24 h between microneedles with inner layer un- or cross-linked.
  • Figure 5B shows the permeability of meloxicam from microneedle devices according to embodiments of the present invention cross-linked for 0, 4, and 24h.
  • the amount of meloxicam permeated through skin (pg) is plotted against time. The results are from three different samples and are presented as mean ⁇ standard deviation.
  • Figure 5B further presents the effect of the cross-linking of the inner layer on the permeability rate of meloxicam in porcine skin ex vivo.
  • the two different device sets evaluated in this figure include uncross-linked microneedles (0.06 wt % PEGDGE, 0 h at 80°C), and cross-linked microneedles (0.06 wt % PEGDGE, 4h, 24 h at 80°C) made according to Example 1.
  • Experimental setup of the permeability study was as follows. The permeability study was performed using Franz Diffusion Cells. Ex vivo pig skin was used as a model membrane. The skin was sandwiched between a donor and an acceptor compartment (chamber), leaving a diffusion area of 0.64 cm 2 . The media in the acceptor chamber was 12 mL of lx PBS (pH 7.4). The skin was kept at 37°C using a circulating water bath in the jacket of the Franz cells. A single microneedle device was inserted in the pig skin with a texture analyzer (30 s hold, 0.05 N trigger force, 30 N target force) to ensure an even penetration of the microneedles in the skin and an even force applied to all the microneedle devices.
  • a texture analyzer (30 s hold, 0.05 N trigger force, 30 N target force
  • the skin was then placed between the donor and the acceptor chamber.
  • the samples were collected at 0, 2, 6, and 24 h after insertion of the microneedles in the skin from the acceptor chamber.
  • skin was removed from the Franz cells, cleaned from the microneedle device left with adhesive tape, cut in small pieces, and added to 10 mL of methanol to extract the drug permeated in the viable skin for 24 h. All the samples were then analyzed by HPLC according to the method reported above for the release study.
  • the results in Figure 5B represent the sum of the amount of drug permeated in the acceptor compartment and the amount of drug permeated in the viable skin at each time point.
  • the results in Figure 5B are the mean of three different devices from the same batch.
  • Figure 5B illustrates the difference in the amount of drug permeated from the pig skin due to the degree of crosslinking.
  • Figure 5C shows meloxicam bioavailability (represented as % of the dose administered) for Metacam (oral suspension of meloxicam) compared to microneedle devices according to an embodiment of the present invention for 72 h (0, 2, 4, 6, 24, 48, and 72 hours).
  • the microneedle devices included cross-linked microneedles (0.06% wt % PEGDGE, 4 h at 80°C) made according to Example 1.
  • the figure compares the bioavailability of meloxicam after oral administration with a commercial formulation vs. a subcutaneous administration with microneedle devices according to an embodiment of the present invention. The results derive from three different rats at each time point and are presented as mean ⁇ standard deviation.
  • Each treatment group (Metacam oral administration mixed with Nutella, F4h-MNs) was composed of 7 animals - 4 males and 3 females.
  • All the animals were shaven with a razor followed by hair removal cream on the back and on the hind paws to allow for easier access to vena saphena during blood sampling.
  • the shaven areas were then cleaned with disinfectant containing glycerol to prevent skin inflammation.
  • each animal was anesthetized with isoflurane (2%).
  • the skin of the rats receiving the microneedle devices were slightly wetted with sterile PBS, the microneedle devices were then gently placed on the skin and pressed with a finger, followed by 5 rounds of microneedle device applicator (Micropoint Technologies Pte Ltd, Singapore). The device was then kept in place with two pieces of adhesive bandages. Each animal was then moved to a single cage for recovery. Once the animals woke from the anesthesia, the animals were offered Nutella or Nutella mixed with Metacam (0.5 mg/mL, oral formulation for cats, Boheringer Ingelheim) for the animals in the oral administration group.
  • Nutella or Nutella mixed with Metacam 0.5 mg/mL, oral formulation for cats, Boheringer Ingelheim
  • Blood samples 200 L/sample were collected from the vena saphena at the following time points 2, 4, 6, 24, 48, 72, 96 h in MiniCollect Tubes 0.25 mL/0.5 mL K2EDTA (Greiner Bio One, USA). At each time point, blood samples were collected from three animals for each group. After the first 6 h, the animals were placed back in the group cages for the rest of the study. Upon completion of the study, the animals were euthanized with CO2 followed by cervical dislocation.
  • FIG. 5D shows meloxicam plasma concentration (ug/mL vs. time) for Metacam (oral suspension of meloxicam) compared to microneedle devices according to an embodiment of the present invention for 72 h (0, 2, 4, 6, 24, 48, and 72 hours).
  • the microneedle devices included cross-linked microneedles (0.06% wt % PEGDGE, 4 h at 80°C) made according to Example 1.
  • the figure compares the plasma concentration of meloxicam after oral administration with a commercial formulation to a subcutaneous administration with the microneedle devices. The results derive from 3 different rats at each time point and are presented as mean ⁇ standard deviation.
  • the y axis is the plasma concentration (ug/mL) while the x axis represents time (h).
  • each animal was anesthetized with isoflurane (2%).
  • the skin of the rats receiving the microneedle devices were slightly wetted with sterile PBS, the microneedle devices were then gently placed on the skin and pressed with a finger, followed by 5 rounds of microneedle device applicator (Micropoint Technologies Pte Ltd, Singapore).
  • the microneedle devices were then kept in place with two pieces of adhesive bandages.
  • Each animal was then moved to a single cage for recovery. Once the animals woke from the anesthesia, the animals were offered Nutella or Nutella mixed with Metacam (0.5 mg/mL, oral formulation for cats, Boheringer Ingelheim) for the animals in the oral administration group.
  • Blood samples 200 pL/sample were then collected from the vena saphena at the following time points 2, 4, 6, 24, 48, 72, 96 h in MiniCollect Tubes 0.25 mL/0.5 mL K2EDTA (Greiner Bio One, USA). At each time point, blood samples were collected from three animals for each group. After the first 6 h, the animals were placed back in the group cages for the rest of the study. Upon completion of the study, the animals were euthanized with CO2 followed by cervical dislocation.
  • At least some embodiments of the present invention find industrial application in manufacturing of layered microneedles and devices including the same for the delivery of one or more therapeutic and non-therapeutic agents to a subject.

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Abstract

L'invention concerne une micro-aiguille stratifiée (10) comprenant une couche interne (18) et une couche externe (20) pour la libération contrôlée d'un ou de plusieurs agents thérapeutiques ou non thérapeutiques à partir de chacune des couches. L'invention concerne également un dispositif à micro-aiguilles (30) comprenant une couche de support (32) et une ou plusieurs micro-aiguilles stratifiées.
PCT/FI2023/050720 2022-12-20 2023-12-20 Micro-aiguille stratifiée pour la libération contrôlée d'agents thérapeutiques ou non thérapeutiques WO2024134032A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
CN103301563A (zh) * 2013-06-20 2013-09-18 吴传斌 可溶性同轴锥多层微针、微针阵列及其制备方法
US20130310665A1 (en) * 2010-11-18 2013-11-21 University College Cork Method
CN108245482A (zh) * 2018-02-06 2018-07-06 华中科技大学 一种可程序性释放药物的聚合物复合微针及其制备
US20200054869A1 (en) * 2018-08-15 2020-02-20 Allergan, Inc. Microneedle array with active ingredient
CN113952318A (zh) * 2021-09-08 2022-01-21 北京宝理泰科技有限公司 一种用于镇痛的多层微针贴片的制备方法

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US20130310665A1 (en) * 2010-11-18 2013-11-21 University College Cork Method
CN103301563A (zh) * 2013-06-20 2013-09-18 吴传斌 可溶性同轴锥多层微针、微针阵列及其制备方法
CN108245482A (zh) * 2018-02-06 2018-07-06 华中科技大学 一种可程序性释放药物的聚合物复合微针及其制备
US20200054869A1 (en) * 2018-08-15 2020-02-20 Allergan, Inc. Microneedle array with active ingredient
CN113952318A (zh) * 2021-09-08 2022-01-21 北京宝理泰科技有限公司 一种用于镇痛的多层微针贴片的制备方法

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THAN, A.LIU, C.CHANG, H. ET AL.: "Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug delivery.", NAT COMMUN, vol. 9, 2018, pages 4433, XP055628047, Retrieved from the Internet <URL:https://doi.org/10.1038/s41467-018-06981-w> DOI: 10.1038/s41467-018-06981-w
YANG, S.O'CEARBHAILL, E.SISK, G. ET AL.: "A bio-inspired swellable microneedle adhesive for mechanical interlocking with tissue.", NAT COMMUN, vol. 4, 2013, pages 1702, Retrieved from the Internet <URL:https://doi.org/10.1038/ncomms2715>

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