WO2021066747A1 - Dispositif en forme de micro-lance polymère auto-administrable et implantable pour une administration contrôlée et ciblée - Google Patents

Dispositif en forme de micro-lance polymère auto-administrable et implantable pour une administration contrôlée et ciblée Download PDF

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WO2021066747A1
WO2021066747A1 PCT/SG2020/050552 SG2020050552W WO2021066747A1 WO 2021066747 A1 WO2021066747 A1 WO 2021066747A1 SG 2020050552 W SG2020050552 W SG 2020050552W WO 2021066747 A1 WO2021066747 A1 WO 2021066747A1
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core
peg
therapeutics
delivery device
plga
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PCT/SG2020/050552
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English (en)
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Peng Chen
Aung THAN
Phan Khanh DUONG
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Nanyang Technological University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—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
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/624—Nanocapsules
    • 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 disclosure relates to a therapeutics delivery device which is implantable and self-administrable.
  • the present disclosure also relates to a method of producing the therapeutics delivery device and applications of the therapeutics delivery device.
  • the therapeutics may include a drug, a cell, or a bioactive agent.
  • Implantable drug delivery (IDD) devices offer several advantages over conventional drug delivery forms (e.g. oral or parenteral).
  • implantable devices allow site- specific, localized drug administration where the drug is most needed. This may greatly enhance drug bioavailability and effects of the drug. It may also allow lower therapeutic dosage which not only minimizes potential side effects but also reduces the drug cost.
  • implantable devices allow for sustained (controlled) release of the bioactive agents. This may largely improve therapeutic efficacy as well as patient compliance, as the bioactive agents may be sustainably released for a longer period of time without the need of frequent and multiple applications.
  • IDD devices whether US-FDA approved ones, or the ones under consideration or testing in clinical trials, require a clinic visit, and one or more surgical or invasive procedures (e.g. surgical incision, large-bore needle insertion) to implant the system.
  • surgical or invasive procedures e.g. surgical incision, large-bore needle insertion
  • pain, infections, bleeding, bruise and reactions to the anesthetics if anesthesia is needed
  • Other potential side effects of conventional implants include, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, and/or warmth at the insertion site.
  • the device in one reported drug delivery device for subcutaneous implantation in animals, has a rod shaped polymeric inner matrix with an elongated body and two ends.
  • the device is a few millimeters in terms of its length and diameter in size with no sharp-pointed microneedle. More importantly, the device undesirably requires surgery to be implanted and is not self-administrable.
  • a medicament-dispensing medical implant was described.
  • the device was in the form of a stent, plug or a patch, fabricated from relatively non-inflammatory biogenic tissue or biopolymers, for implantation in the human body, for preventing restenosis following atherectomy.
  • the device was a few millimeters in length and diameter with no sharp-pointed microneedle. Similarly, the device undesirably requires surgery to be implanted and is not self-administrable.
  • an implantable drug delivery device that uses multiple reservoir elements covering with a shell and low-permeability barrier was reported. The shell may be breached by light irradiation to release drugs in the reservoir.
  • the device is a few millimeters in length and diameter with no sharp-pointed microneedle. Similarly, the device undesirably requires surgery to be implanted and is not self- administrable.
  • a drug delivery system that provides for mixing various drugs, for using flow controllers to guide multiple drugs into a single or into multiple catheters, for controlling a dispensing of a fluid drug to an internal target site of a patient, has been reported.
  • the system is apparently not for drug delivery implant.
  • the device was elongated in shape, contained two or more discrete reservoirs, was a few millimeters in length and diameter with no sharp-pointed microneedle.
  • the device undesirably needed the hollow bore of a needle, cannula, catheter, or trocar to inject the implantable medical device into a patient.
  • the device is cylindrically shaped, or in the form of multiple units, such as a plurality of beads. It needed surgery to implant the device and is not self-administrable.
  • a layered polymeric monofilament fiber that includes side-by- side layers was reported, wherein a portion of each of the layers is exposed to the environment, for implantation in a patient. It is a cylindrical-shaped elongated fiber, several millimetres in length along its longitudinal axis with no sharp-pointed microneedle. It needed surgery to implant the fibers and is not self-administrable.
  • a catheter and a stent were suggested for treating vascular conditions.
  • the stent includes tubing having a wall defining a central lumen and a plurality of holes. However, this is not designed for a drug delivery implant.
  • Another example describes a method for performing non-invasive neurostimulation therapy of the brain via a nasal cavity, which is clearly not a drug delivery implant.
  • FIG. 1 Another example describes a syringe needle-styled drug delivery system for implanting a drug-loaded rod into the vitreous of an eye. It includes a housing, with the first cannula that has an angulated end for facilitating penetration of tissue, and the second cannula to force the rod implant from the first cannula.
  • the intravitreal implant is in a rod-and-cylindrical shape with no sharp-pointed end. It has a sharp tip of the first cannula from the applicator (similar to the conventional hyponeedle) to penetrate the tissue (not implant itself) in order to force the rod-shaped implant into the vitreous cavity by the second cannula. Nevertheless, it is not self-administrable.
  • Another example reports a drug delivery system comprising a plurality of rod shaped segments, for implanting it into the ocular region of the patients, for treating ocular conditions.
  • the implant is a multi- segmented rod-shaped cylindrical shape. However, it needs surgery to implant the device and is not self-administrable.
  • Another example reports an implant into the suprachoroidal space for providing drugs to the eye.
  • the implant has no sharp-pointed microneedle, needs surgical incision in the cornea to implant the device, and is not self-administrable.
  • Another example describes an implant inside the sclera for providing drugs to the eye.
  • the implant has no sharp-pointed microneedle, needs surgical incision in the sclera to implant the device, and is not self-administrable.
  • Another implant was designed to be in the sclera for providing drugs to the eye.
  • the device is a few millimeters in size, with no sharp-pointed microneedle, needs surgery to implant the device, and needs an adhesive or a sealant in order to fix to the sclera, needs at least one electrode and an opposite electrode which are fixed to the sclera, to disrupt the material in order to create openings and release the loaded agents.
  • Another ocular implant device was contemplated for providing drugs to the vitreous cavity. The device is a few millimeters in size, with no sharp-pointed microneedle in shape, and needs surgery to implant the device.
  • the device is a few millimeters in size, with no sharp- pointed microneedle in shape, and needs surgery to implant the device.
  • a few examples describe a subconjunctival implant or an implant device for subconjunctival placement providing drugs to the eye.
  • the device is a few millimeters in size, with no sharp-pointed microneedle in shape, and needs surgery to implant the device.
  • FIG. 1 Another example describe an implant device for treating and/or preventing raised intraocular pressure, such as that associated with glaucoma or the use of corticosteroids, with carbonic anhydrase inhibitors.
  • the device is a few millimeters in size, with no sharp-pointed microneedle in shape, and needs surgery to implant the device.
  • Another example contemplates a continuous release drug delivery implant which, among other mentioned places, can be mounted either on the outer surface of the eye or within the eye.
  • the device is a few millimeters in size, with no sharp-pointed microneedle in shape, and needs surgery to implant the device.
  • FIG. 1 Another example reports on an ocular implant device for providing drugs to the vitreous cavity.
  • the device is a few millimeters in size, with no sharp-pointed microneedle in shape, and needs surgery to implant the device.
  • Another example relates to a bioadhesive ophthalmic inserts that are placed in the conjunctival sac.
  • the device is a few millimeters in size, with no sharp-pointed microneedle in shape, and needs surgery to implant the device.
  • a sustained-release implant for insertion into the vitreous of the eye.
  • the device is a few millimeters in size, with no sharp-pointed microneedle in shape, and needs surgery to implant the device.
  • Another example reports an ocular drug delivery device placed in the cul-de- sac between the sclera and lower eyelid for administering the drug and acting as a reservoir.
  • the device is a few millimeters in size, with no sharp-pointed microneedle in shape, and needs surgery to implant the device.
  • Another example contemplates a device for diagnosis of allergy.
  • the device involves microneedle loaded with allergy antigen.
  • ths device does not disclose its suitability for drug delivery.
  • a therapeutic agent i.e. therapeutics
  • the therapeutic agents may be delivered across the skin into the circulation to treat burn wound infection.
  • device, system or methods are not related to drug delivery implant, or the drugs are only coated on microneedles.
  • therapeutic agents are for delivery into the vagina mucosa, and thus used as an intravaginal device.
  • Another example reports a device to deliver insulin for diabetes patients using an integrated micro pump and microneedle array of closed-loop insulin delivery device.
  • Another application is to deliver vaccine across the skin into the circulation, to use as transcutaneous immunization or vaccination
  • microneedles in drug delivery.
  • hollow or solid metal microneedles were used to infuse drug solution or to dissolve coated-drug into the skin epidermis and dermis.
  • Those drug delivery systems tend to be similar to the conventional drug injection except in using micrometre scale size needles.
  • the “hollow or solid metal microneedles” are not implantable.
  • the drug release kinetics cannot be tailored using such hollow or solid metal microneedles, e.g. controlled release cannot be achieved.
  • MNs dissolving microneedles
  • these MNs tend to be insufficient for implanting directly into the deep tissue such as subcutaneous fat.
  • the skin penetration ability of those dissolving MNs tends to be significantly inefficient, wherein only about 60-70% of MN length (-400-500 pm) may be inserted into the skin.
  • those MNs embedded inside the skin may fail to perform as long-term drug depots because of the rapid turnover rate of epidermis and dermis (-28-40 days for human skin).
  • IDD systems may not be patient friendly nor suitable for long-term home-based usages.
  • the solution should at least provide for a safe, minimally- invasive, patient-friendly and self-administrable IDD strategy.
  • a therapeutics delivery device implantable in a biological tissue including: a core which is biodegradable, wherein the core includes a first polymer composition, wherein the core has a height of at least 1 mm, and wherein the core has one end shaped as a sharp tip sufficient to penetrate the biological tissue, wherein the sharp tip includes a single bevel-angled shape, a double bevel-angled shape, a chiseled edge, a bullet-shape, or a frustum- shape.
  • the therapeutics delivery device may further include a shell which is biodegradable, wherein the shell includes a second polymer composition, wherein the first polymer composition and the second polymer composition have different degradation rate. There can be more than one shell.
  • the core may be solid, hollow, or gutter-like.
  • an applicator operable to implant the therapeutics delivery device described in various embodiments of the first aspect, including: a housing including a lancing module and one or more holder tubes, wherein each of the one or more holder tubes is configured for loading the therapeutics delivery device therein, and wherein the lancing module is operable to drive the therapeutics delivery device out of the one or more holder tubes to implant the delivery device described in various embodiments of the first aspect into the biological tissue.
  • a method of producing the therapeutics delivery device described in various embodiments of the first aspect including: providing a mold to form the core, wherein the mold includes a depth of at least 1 mm and a closed end including a single bevel-angled shape, a double bevel-angled shape, a chiseled edge, a bullet-shape, or a frustum-shape; depositing a first polymer solution into the cavity, wherein the first polymer solution includes the first polymer composition; and drying the first polymer solution to form the core.
  • the method may further include coating a second polymer solution on the core to form the shell, wherein the second polymer solution includes the second polymer composition.
  • a method of treating a medical condition or delivering a therapeutics includes: operating the applicator described in various embodiments of the above aspect to implant the therapeutics delivery device described in various embodiments of the first aspect in the biological tissue.
  • FIG. 1A shows a bright field image of salt micro-particles used in the core- shelled micro-lances (ML) of the present disclosure. Scale bar denotes 50 pm.
  • FIG. IB shows a bright field image of a salt-mixed PLGA-ML (50% NaCl). Scale bar denotes 50 pm.
  • FIG. ID is a scanning electron microscopy (SEM) image of salt-mixed PLGA MLs (50% NaCl) changes over time in PBS at 37°C. Scale bar denotes 10 pm.
  • FIG. IE is a SEM image of salt-mixed PLGA MLs (50% NaCl) changes over time in PBS at 37 °C. Scale bar denotes 10 pm.
  • FIG. IF is a scanning electron microscopy (SEM) image of salt-mixed PLGA MLs (50% NaCl) changes over time in PBS at 37°C. Scale bar denotes 10 pm.
  • FIG. 1G is a scanning electron microscopy (SEM) image of salt-mixed PLGA MLs (50% NaCl) changes over time in PBS at 37°C. Scale bar denotes 10 pm.
  • FIG. 1H is a schematic illustration of the fabrication and application of polymeric core-shelled micro-lances of the present disclosure.
  • FIG. 2A shows bright field and confocal images of salt-mixed PLGA-MLs (50% NaCl) without CMC coating, or MLs coated with CMC (core-shelled ML).
  • the ML is loaded with red Cy5 dye (top), and the CMC shell is loaded with green FITC dye (bottom).
  • Scale bar denotes 250 pm.
  • FIG. 2B shows confocal images of real-time releases of Cy5 and FITC from core-shelled ML in 4% agarose hydrogel. Scale bars denotes 250 pm.
  • FIG. 2E shows the in vitro and release profiles of salt-mixed PLGA- MLs using bright field images of salt-free PLGA-ML and salt-mixed PLGA-MLs (50% salt) after 50 days of incubation in PBS at 37 °C. Scale bars dnotes 250 pm.
  • FIG. 2G shows bright field images of different salt-mixed PLGA-MLs incubated in PBS at 37 °C, at day 0, day 5, day 15 and day 30.
  • FIG. 3A is a bright field image of porcine tissue (skin epidermis, Epi; dermis, D and subcutaneous white adipose tissue, sWAT) after lancing ML. Scale bar denotes 2 mm.
  • FIG. 3B shows a representative histological section of porcine tissue depicting ML insertion track (arrow) and ML implanted inside sWAT. Scale bar denotes 250 pm. It is to be noted that ML appears transparent because of the thin slice.
  • FIG. 3C shows bright field images of mouse skin, immediately (day 0) or 1 day (day 1) or 2 days (day 2) after ML application. Scale bars denotes 1 mm.
  • FIG. 3G shows representative histological sections of mouse tissue showing ML penetration through the skin (left) and implantation inside sWAT (right). Scale bars denote 250 pm.
  • FIG. 3H depicts the in vivo imaging of the mice, at day 0, day 1 or day 7.
  • FIG. 31 depicts in vivo distribution of Cy5 delivered through intraperitoneal (IP) injection or ML application. It is noted that fluorescence intensity is highly concentrated at the ML implantation site. The representative fluorescence images of dissected organs, at day 0 (2 h post-treatment) or day 7, are shown.
  • FIG. 3J shows representative force-displacement curves of salt-free PLGA-ML and salt-mixed PLGA-ML (50% salt). Failure load is defined as the maximum load the ML can sustain without buckling or breaking (fracture).
  • FIG. 3K shows bright field images of MLs after pressing with their respective failure loads (-1.5N), showing a typical buckling of salt- free PLGA-ML in the left image and breakage of salt-mixed PLGA-ML (50% NaCl salt) in the right image.
  • FIG. 3L shows mechanical compression tests of different salt-mixed PLGA- MLs (0%, 10%, 50% and 75% NaCl salt).
  • FIG. 3N shows mechanical compression tests of the same salt-mixed PLGA- MLs (50% salt) without or with carboxymethyl cellulose (CMC) coating layer.
  • FIG. 3P shows the representative insertion force of salt-mixed PLGA-ML (50% salt) into porcine skin.
  • the insertion force for ML upon its penetration into the porcine skin is -0.1 N as indicated by a small dip in the force-displacement curve followed by a steeper slope.
  • FIG. 4A depicts effective anti-obesity treatment using diet-induced obese mice treated with MLs without drug (control), or with CL316,243 (CL, 1 mg/kg/week) via IP injection or ML application (CL316,243 loaded in both core and shell), once every 1 week (1 wk) or 2 weeks (2 wk) for 6 weeks.
  • FIG. 4A shows representative images of differently treated mice at week 6.
  • FIG. 4B shows the relative body weight increases at week 6. Each data point represents mean ⁇ SD from four to five mice in each group.
  • FIG. 4C shows the relative body weight increases over the course of treatment (C). Each data point represents mean ⁇ SD from four to five mice in each group.
  • FIG. 4E shows representative images of IgWAT, EpiWAT and interscapular BAT.
  • FIG. 4G shows infrared thermographic images of the representative mice at week 6.
  • FIG. 41 shows a prototype image of a lancing applicator of the present disclosure, which includes a stainless- steel spring house within a chamber, and a shaft connected with a stainless- steel rod which is fitted into a tube holder. The spring loading force is -1.5 kgf.
  • FIG. 4J shows time-lapse images of a salt-mixed PLGA-ML (50% salt) lancing from the applicator, recorded with 240 fps.
  • the lancing speed is determined to be ⁇ 1 m/s.
  • FIG. 4K shows a bright field image salt-mixed PLGA-MLs (50% salt) embedded within 4% agarose hydrogel, showing a typical ML’s trajectory path and insertion depth.
  • the trajectory angle is -22° deviated from the insertion line (white dash line), and the insertion depth is 2-3 mm between the gel surface and the blunted end of ML.
  • Scale bar denotes 2 mm.
  • FIG. 4L shows a bright field image of a salt-mixed PLGA-ML, showing its bevel angle ( ⁇ ) of ⁇ 75°. Scale bar denotes 250 pm.
  • FIG. 4M is an illustrative diagram of the proposed ML’s trajectory mechanism:
  • the asymmetry of the resistive forces from the agarose gel acting on ML’s tip causes a moment on ML’s tip, causing the whole ML to bend as it is advanced into the agarose gel.
  • the net resultant force (F) experienced by ML is proportional to the sine of the bevel angle (sin ⁇ ).
  • FIG. 4N is an illustrative diagram of the proposed ML’s trajectory mechanism: The asymmetry of the resistive forces from the agarose gel acting on ML’s tip causes a moment on ML’s tip, causing the whole ML to bend as it is advanced into the agarose gel.
  • FIG. 5A illustrates that present ML approach improves browning and metabolic effects of CL316,243 in obese mice. Diet-induced obese mice were treated with ML without drug (control), or with CL316,243 (CL, ⁇ 1 mg/kg/week) via IP injection or core-shelled ML application (loaded in both core and shell), once every 1 or 2 weeks for 6 weeks.
  • 5A shows representative hematoxylin and eosin staining images of IgWATs isolated from differently treated mice. Asterisks * indicate white adipocytes while the circle indicates a brown-like adipocyte. Scale bar denotes 50 pm.
  • FIG. 5B illustrates that present ML approach improves browning and metabolic effects of CL316,243 in obese mice. Diet-induced obese mice were treated with ML without drug (control), or with CL316,243 (CL, ⁇ 1 mg/kg/week) via IP injection or core-shelled ML application (loaded in both core and shell), once every 1 or 2 weeks for 6 weeks.
  • FIG. 5B shows representative immunoblots of UCP1, PRDM16, PGCla, aP2 and actin in IgWAT.
  • FIG. 5C illustrates that present ML approach improves browning and metabolic effects of CL316,243 in obese mice. Diet-induced obese mice were treated with ML without drug (control), or with CL316,243 (CL, ⁇ 1 mg/kg/week) via IP injection or core-shelled ML application (loaded in both core and shell), once every 1 or 2 weeks for 6 weeks.
  • FIG. 5D illustrates that present ML approach improves browning and metabolic effects of CL316,243 in obese mice. Diet-induced obese mice were treated with ML without drug (control), or with CL316,243 (CL, ⁇ 1 mg/kg/week) via IP injection or core-shelled ML application (loaded in both core and shell), once every 1 or 2 weeks for 6 weeks.
  • FIG. 5E illustrates that present ML approach improves browning and metabolic effects of CL316,243 in obese mice. Diet-induced obese mice were treated with ML without drug (control), or with CL316,243 (CL, ⁇ 1 mg/kg/week) via IP injection or core-shelled ML application (loaded in both core and shell), once every 1 or 2 weeks for 6 weeks.
  • FIG. 5F illustrates that present ML approach improves browning and metabolic effects of CL316,243 in obese mice. Diet-induced obese mice were treated with ML without drug (control), or with CL316,243 (CL, ⁇ 1 mg/kg/week) via IP injection or core-shelled ML application (loaded in both core and shell), once every 1 or 2 weeks for 6 weeks.
  • FIG. 5G illustrates that present ML approach improves browning and metabolic effects of CL316,243 in obese mice. Diet-induced obese mice were treated with ML without drug (control), or with CL316,243 (CL, ⁇ 1 mg/kg/week) via IP injection or core-shelled ML application (loaded in both core and shell), once every 1 or 2 weeks for 6 weeks.
  • FIG. 5H shows the in vitro biocompatibility of CMC-coated salt-mixed PLGA- MLs (50% salt) tested on human white adipocytes.
  • human pre-adipose cells Zen-Bio Inc., USA; SP-F-2
  • SP-F-2 human pre-adipose cells collected from subcutaneous WAT of non-diabetic human subjects (BMI 25 - 29.9) were grown till confluence in DMEM/ F-12 containing 10% FBS.
  • the cells (defined as day 0) were then treated for 7 days with serum-free differentiation medium (DMEM/F-12 containing 0.5 pg/ml insulin, 0.5 mM IBMX, 100 nM dexamethasone, 100 nM rosiglitazone, 33 mM biotin, 17 pM pantothenate, 10 pg/ml transferrin and 1 nM triiodothyronine).
  • the cells were then cultured for another 7 days with serum-free growth medium (DMEM/F-12 containing insulin and dexamethasone).
  • white adipocytes cultured in 96 wells were exposed to ML for 2 weeks. Representative bright field images of adipocytes with lipid droplets are shown. Oil Red O staining confirmed the formation of lipid droplets in white adipocytes (inset).
  • FIG. 5J shows i/7 vitro bioactivity of mirabegron released from salt-mixed PLGA-MLs.
  • Drug released from MLs or freshly prepared drug ( ⁇ 1 pM, lpg/2.5 ml) was used to treat white adipocytes for ⁇ 7 days before conducting the immunoblot experiment.
  • the representative immunoblot images of uncoupling protein 1 (UCP1) and actin are shown.
  • FIG. 6A shows the results of diet-induced obese mice were treated ML without drug (control), or with CL316,243 and rosiglitazone (combined dosage of 1 mg/kg/week) via subcutaneous (SC) injection or ML application, once every 2 weeks for 6 weeks.
  • MLs loaded with rosiglitazone in core (Ro-c) and CL316,243 in shell (CL s) or MLs loaded with rosiglitazone in shell (Ro-s) and CL316,243 in core (CL-c) were used in the experiments.
  • the relative body weight increases of differently treated mice. Data represents mean ⁇ SD (n 4 or 5).
  • FIG. 6C shows the representative images of IgWAT, EpiWAT and interscapular BAT.
  • FIG. 6D shows the representative hematoxylin and eosin staining images of IgWATs. Scale bar denotes 50 pm.
  • FIG. 6K shows a bright field image, and their corresponding histological and fluorescence images of mouse IgWATs collected after 1 week. Scale bar denotes 250 pm.
  • FIG. 6L shows a bright field image, and their corresponding histological and fluorescence images of mouse IgWATs collected after 1 week. Scale bar denotes 250 pm.
  • FIG. 6M shows a bright field image, and their corresponding histological and fluorescence images of mouse IgWATs collected after 1 week. Scale bar denotes 250 pm.
  • FIG. 6N shows a bright field image, and their corresponding histological and fluorescence images of mouse IgWATs collected after 6 weeks post-application of Cy5- loaded salt- mixed PLGA-MLs (50% salt). Scale bar denotes 250 pm.
  • FIG. 60 shows a bright field image, and their corresponding histological and fluorescence images of mouse IgWATs collected after 6 weeks post-application of Cy5- loaded salt- mixed PLGA-MLs (50% salt). Scale bar denotes 250 pm.
  • FIG. 6P shows a bright field image, and their corresponding histological and fluorescence images of mouse IgWATs collected after 6 weeks post-application of Cy5- loaded salt- mixed PLGA-MLs (50% salt). Scale bar denotes 250 pm.
  • FIG. 7B shows the average daily food intake of obese mice treated without (Control) or with CL316,243 +rosiglitazone (combined dosage of 1 mg/kg/week) via subcutaneous (SC) injection or ML application, once every 2 weeks for 6 weeks.
  • FIG. 8B demonstrates for the in vivo study of present core-shelled MLs for diet-induced obese mice that were treated without (Control) or with CL316,243
  • FIG. 8C demonstrates for the in vivo study of present core-shelled MLs for diet- induced obese mice that were treated without (Control) or with CL316,243
  • FIG. 8C shows representative hematoxylin and eosin staining images of IgWATs. Scale bar denotes 50 pm.
  • FIG. 8D demonstrates for the in vivo study of present core-shelled MLs for diet- induced obese mice that were treated without (Control) or with CL316,243
  • FIG. 8E demonstrates for the in vivo study of present core-shelled MLs for diet- induced obese mice that were treated without (Control) or with CL316,243
  • FIG. 8F demonstrates for the in vivo study of present core-shelled MLs for diet- induced obese mice that were treated without (Control) or with CL316,243
  • FIG. 8G demonstrates for the in vivo study of present core-shelled MLs for diet- induced obese mice that were treated without (Control) or with CL316,243
  • FIG. 9 depicts core-shelled ML coated with crosslinked methacrylated- hyaluronic acids (MeHA).
  • MeHA crosslinked methacrylated- hyaluronic acids
  • FIG. 10 shows, in the left image, a representative bright field image of hollow micro-lances (MLs) made of Poly (D, L-lactide-co-glycolide) (PLGA, 50:50, Mw 54,000-69,000, loaded with Cy5 fluorescence dye). Scale bar denotes 1 mm.
  • the right image is a plot of the mechanical compression test of a PLGA-based hollow micro- lance. As shown in the left image, the fabricated PLGA-based hollow MLs are long cylindrical in shape with the diameter of -250 pm and length of -4 mm.
  • the ML has a sharp-pointed tip at one end, with the diameter of -30 pm and a single bevel angle of -75°, and a flat-blunted one at the other end.
  • the central hollow channel has the diameter of -100 pm.
  • PLGA-based hollow MLs could attain the mechanical force of more than 1 N per needle (stiffness of -3.5 N/mm) without breaking or deformation (Supplementary Figurelb). It indicates that those hollow MLs are strong enough for skin penetration, as the force required to penetrate the human skin is -150 - 300 mN/needle for sharp-tipped microneedles (-40 pm tip diameter).
  • FIG. 11 demonstrates hyaluronic acids-based MLs for fast drug release kinetic.
  • Fast-dissolving low-molecular weight hyaluronic acids (HA) miniHA, 3 - 10 kDa molecular weight; 1000 mg/ml
  • HA-ML can be successfully fabricated (-250 pm diameter, -4 mm length, with a sharp-pointed tip of -30 pm).
  • Those HA-MLs are strong enough to penetrate porcine skin and provide very fast releasing kinetic (within minutes).
  • FIG. 12A demonstrates fast-dissolving polymeric MLs.
  • Bright field images of MLs, made of polyvinyl alcohol (PVA; 9 kDa) and propylene glycol (PG) by thermal pressing molding method are shown.
  • PVA/PG-MLs are strong enough to penetrate porcine skin (FIG. 12C) and provide fast releasing kinetic (within minutes).
  • FIG. 12B demonstrates fast-dissolving polymeric MLs.
  • Bright field images of MLs, made of polyvinylpyrrolidone (PVP), 10 kDa molecular weight by thermal pressing molding method are shown.
  • PVP-MLs are strong enough to penetrate porcine skin (FIG. 12D) and provide fast releasing kinetic (within minutes).
  • FIG. 12C is a bright field image of porcine tissue (skin - epidermis and dermis, and subcutaneous white adipose tissue, sWAT) immediately after lancing a ML made of polyvinyl alcohol (PVA) and propylene glycol (PG).
  • porcine tissue skin - epidermis and dermis, and subcutaneous white adipose tissue, sWAT
  • ML made of polyvinyl alcohol (PVA) and propylene glycol (PG).
  • PVA polyvinyl alcohol
  • PG propylene glycol
  • FIG. 12D is a bright field image of porcine tissue (skin and sWAT) immediately after lancing a ML made of polyvinylpyrrolidone (PVP).
  • FIG. 13 A shows PLGA-based gutter-like MLs acting as a cell delivery device. Specifically, FIG. 13A shows the bright field and corresponding image of the gutter like ML loaded with cells. FIG. 13 A shows the ML. Cells were stained with NucBlueTM Live ReadyProbesTM Reagent (Hoechst 33342, a nucleic acid stain) (ThermoFisher Scientific). PLGA-based gutter-like MLs were surface-modified with poly-L-lysine (PLL) coating before cell loading. Scale bar denotes 50 pm.
  • FIG. 13B shows PLGA-based gutter-like micro-lances acting as a cell delivery device. Specifically, FIG. 13B shows the bright field and corresponding image of the gutter-like ML loaded with cells. FIG. 13B shows the ML tip. Cells were stained with NucBlueTM Live ReadyProbesTM Reagent (Hoechst 33342, a nucleic acid stain) (ThermoFisher Scientific). PLGA-based gutter- like MLs were surface-modified with poly-L-lysine (PLL) coating before cell loading. Scale bar denotes 50 pm.
  • FIG. 13C shows PLGA-based gutter-like micro-lances acting as a cell delivery device. Specifically, FIG. 13C shows the bright field and corresponding image of cell- loaded gutter-like ML inserted in a 4% agarose hydrogel. FIG. 13C shows ML. Cells were stained with NucBlueTM Live ReadyProbesTM Reagent (Hoechst 33342)
  • PLGA-based gutter-like micro-lances were surface- modified with poly-L-lysine (PLL) coating before cell loading. Scale bar denotes 50 pm.
  • FIG. 13D shows PLGA-based gutter-like micro-lances acting as a cell delivery device. Specifically, FIG. 13D shows the bright field and corresponding image of cell- loaded gutter-like ML inserted in a 4% agarose hydrogel. FIG. 13D shows ML tip. Cells were stained with NucBlueTM Live ReadyProbesTM Reagent (Hoechst 33342)
  • PLGA-based gutter-like micro-lances were surface- modified with poly-L-lysine (PLL) coating before cell loading. Scale bar denotes 50 pm.
  • FIG. 14 illustrates different types of MLs, such as a solid ML (having a solid core), a hollow ML (having a hollow core), and a gutter-like ML (a gutter-like core).
  • MLs such as a solid ML (having a solid core), a hollow ML (having a hollow core), and a gutter-like ML (a gutter-like core).
  • the present disclosure relates to a self-administrable and implantable polymeric micro-implant for controlled and localized therapeutics delivery into the tissues safely and effectively.
  • the therapeutics may include or may be a drug, a cell, any bioactive agent, or a mixture thereof.
  • the micro-implant may be termed herein a therapeutics delivery device or micro-lance (ML), as the micro-implant is shaped like a lance having a sharp-pointed end for penetrating biological tissue.
  • ML therapeutics delivery device
  • the sharp-pointed lance-shaped micro-implant (micro-lance) can be easily and comfortably injected into the skin or other tissues weekly or regularly by the patient at home without pain and need of skills (“patient-friendly”).
  • the micro-lance can quickly be pierced into the skin or tissue (within a fraction of second) and embedded in the deep tissue (e.g. subcutaneous tissue, sclera) in a minimally-invasive and painless manner (i.e. comfort and convenient).
  • the embedded micro-lance is operable as long-acting micro reservoirs in tissues for “controlled and targeted therapeutics delivery”. As the micro lances are biodegradable, there is advantageously no need for them to be manually removed from the biological tissues or body.
  • the therapeutics delivery device may be configured as a polymeric micro lance having a core and optionally one or more shells forming an outer layer coating the core.
  • the therapeutics delivery device may be configured as a polymeric core-shell micro-lance, with the outer coating layer of fast-dissolving polymer and the inner core of slow-dissolving polymer, in order to achieve several advantages: (1) fast-dissolving polymer (e.g. CMC) is used to make the coating-layer of micro-lance (shell) for quick delivery of bioactive agents within minutes while the core of micro-lance made up of slow-dissolving polymer (e.g.
  • fast-dissolving polymer e.g. CMC
  • the core of micro-lance made up of slow-dissolving polymer e.g.
  • PLGA is for slow and sustained release of bioactive agents over several weeks to months (up to 3-6 months), (2) the sustained drug release kinetic (several weeks to months) engineered through the polymeric core, e.g. mixture of different concentration of porogens, combination or mixture of different polymers, etc., (3) a PLGA-based micro-lance core is a non limiting example that can provide a strong mechanical strength to pierce the skin and implant into the underlying subcutaneous tissue, (4) the micro-lance implanted into the subcutaneous fat or tissue can then serve as the long-acting micro-dmg-reservoir which slowly discharges its cargo.
  • the achieved controlled drug release including the fast- release from outer coating-shell and sustained-release from core is superior to delivery devices that has only fast or slow releasing drug delivery platform, and in terms of treatment efficacy and efficiency. Due to the continuously drug releasing capability of the present implanted micro-lances, low therapeutic dose and prolonged dosing interval can be realized. Lowering the therapeutic dose not only produces lesser side-effects but also reduces the cost. Lengthening the dosing interval greatly enhances the patient compliance.
  • the therapeutics delivery device wherein the therapeutics may contain a cell, may be configured as a polymeric hollow micro-lance, wherein a hollow channel lay inside the center of the core (hollow core).
  • the polymeric micro-lance may also have a gutter-like core wherein a central hollow channel is laterally open through the lateral wall of the core.
  • the present polymeric hollow micro-lance or gutter-like micro-lance for cell delivery or replacement therapy e.g.
  • the central cavity or channel of the micro-lance is designed to create local micro-environment of transplanted cells, and thus, cells can be largely insulated from the hostile host environment, and at the same time, easily accessible to the nutrient and gas exchange, (2) the lateral wall of the micro-lance can behave as a drug- containing material that can improve cell survival, and enhance cell function, (3) the lateral wall of the micro-lance can also be capable of releasing the immunosuppressant drug, and thus, through sustained local immunosuppression, the host may be considered as the foreign transplanted cells as self, achieving long term toleration of transplanted cells, (4) co-delivery of both therapeutic cells and bio-active agents is possible, with appropriate cells and drug ratio, to allow for synergistic therapeutic effect.
  • the lateral wall of the micro-lance can be porous (e.g. pores each having 0.5 - 5 pm diameter pore size) to allow better nutrient and gas exchange between inner transplanted cell environment and outer recipient tissue environment.
  • the micro-lance fabrication is simple, inexpensive, and suitable for mass production.
  • a biocompatible biopolymer for example PLGA
  • the polymeric carrier may include more than one polymer species or each species may have a range of molecular weights.
  • the present disclosure also provides for a lancing device or applicator operable to achieve several advantages: (1) a strong spring is included in the applicator to offer fast lancing speed and short lancing duration (millisecond range) for efficient and pain-free micro-lance injection into the tissue, (2) by inspiring the buckling prevention- strategy in nature, a rigid column (a stainless-steel tube) is included in the applicator to laterally support the micro-lance during injection into the tissue. The lateral support greatly enhances the critical buckling load of micro-lance, which in turn reduce or resist buckling or breaking during insertion.
  • the custom- made high-speed lancing device includes of a spring and a shaft connected with a stainless-steel rod which is well-fitted into a stainless- steel tube, into which a micro lance can be seamlessly loaded. Once the spring is relieved, the force transferred through the rod can quickly push the micro-lance towards the tissue.
  • other methods such as pneumatic pressure or pyro-drive produced by a high-pressure compressed air or gas can also be applied for lancing (i.e. driving) the micro-lance out of the applicator and into a biological tissue to be implanted.
  • a therapeutics delivery device implantable in a biological tissue.
  • the therapeutics delivery device may include a core which is biodegradable, wherein the core includes a first polymer composition, wherein the core has a height of at least 1 mm (e.g. 1 - 30 mm, 1 - 10 mm, etc.), and wherein the core has one end shaped as a sharp tip sufficient to penetrate the biological tissue, wherein the sharp tip includes a single bevel-angled shape, a double bevel-angled shape, a chiseled edge, a bullet-shape, or a frustum- shape.
  • the therapeutics delivery device herein exchangeably refers to a micro-lance described in the present disclosure.
  • micro-lances can be used and implanted simultaneously.
  • the micro-lance may be configured as an array having a plurality of such micro-lances.
  • the micro-lance may have a solid core (solid micro lance) or hollow core (hollow micro-lance).
  • the solid core and hollow core are capable of housing a therapeutics.
  • the core may be coated with one or more shells.
  • the therapeutics delivery device may further include a shell which is biodegradable, wherein the shell includes a second polymer composition, wherein the first polymer composition and the second polymer composition have different degradation rate. That is to say, there is provided a therapeutics delivery device implantable in a biological tissue.
  • the therapeutics delivery device may include a core and a shell both of which are biodegradable.
  • the core may include a first polymer composition and the shell may include a second polymer composition, wherein the first polymer composition and the second polymer composition have different degradation rate.
  • the core may be coated with one or more of such shells. Where multiple shells are present, each of the shells may have a different degradation rate.
  • the core may have a height of at least 1 mm (e.g. 1 - 30 mm, 1 - 10 mm, etc.), and the core may have one end shaped as a sharp tip sufficient to penetrate the biological tissue, wherein the sharp tip comprises a single bevel-angled shape, a double bevel-angled shape, a chiseled edge, a bullet-shape, or a frustum-shape.
  • a frustum shape refers to a shape that has one end broader than the other end, wherein the cross-section from one end tapers down (decreases in size) toward the other end.
  • Non limiting examples include fmsto-conical shape and a pyramidal frustum shape.
  • the core may be a solid core, a hollow core, or a gutter-like core.
  • the first polymer composition can contain one or more polymers.
  • the first polymer composition may include, without being limited to, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), polyanhydride, polyorthoester, polyetherester, polycaprolactone (PCL), polyesteramide, poly(butyric acid), poly(valeric acid), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), a block copolymer of PEG-PLA, PEG-PLA-PEG, PLA-PEG-PLA, PEG-PLGA, PEG-PLGA-PEG, PLGA-PEG-PLGA, PEG-PCL, PEG-PCL-PEG, PCL-PEG-PCL, a copolymer of ethylene glycol-propylene glycol-ethylene glycol (PEG-PPG-PEG
  • the polymers for the first polymer composition may have a variety of molecular weights.
  • the poly(lactic acid-co-glycolic acid) may include poly(D-lactic- co-glycolic acid), poly(L-lactic-co-glycolic acid), and/or poly(D,L-lactic-co-glycolic acid).
  • the first polymer composition may be formed from two monomers, wherein the two monomers may include lactic acid and glycolic acid, wherein the two monomers are present in a molar ratio of 1:100 to 100:1.
  • the therapeutic delivery device may have multiple layers of shell coating the core.
  • Each of the shell may include the second polymer composition.
  • the second polymer composition can contain one or more polymers.
  • the second polymer composition may include, without being limited to, hyaluronic acid and its derivatives, methacrylate hyaluronic acid, sodium alginate, collagen and its derivatives, polyurethane, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), polyanhydride, polyorthoester, polyetherester, polycaprolactone (PCL), polyesteramide, poly(butyric acid), poly(valeric acid), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycol (PEG), a block copolymer of PEG-PLA, PEG-PLA-PEG, PLA-PEG-PLA, P
  • the polymers for the second polymer composition may have a variety of molecular weights.
  • the poly(lactic acid- co-glycolic acid) may include poly(D-lactic-co-glycolic acid), poly(L-lactic-co- glycolic acid), and/or poly(D,L-lactic-co-glycolic acid).
  • the core and/or shell may further include a porogen.
  • porogen may include, without being limited to, sodium chloride (NaCl), polyethylene glycol, an ionic liquid, or a mixture thereof.
  • the ionic liquid may include a pyridinium salt or an imidazolium salt.
  • Non-limiting examples of an imidazolium salt may include or may be 1 -butyl-3 -methyl-pyridinium dicyanamide (Bmp-dca), 1-ethyl- 3-methyl-imidazolium dicyanamide (Emim-dca), 1 -ethyl-3 -methyl-imidazolium tetracyanoborate (Emim-tcb), 1-heptyl-pyridinium tetrafluoroborate, etc.
  • porogens e.g. salt microparticles
  • the core and/or shell may be made from one or more polymers.
  • both the core and the shell may be made by a mixture of different polymers tailored specially therefor. This is easily achieved by the method of producing the therapeutic delivery device described herein, such as simply using a polymer solution having a mixture of polymers to make the core and/or shell.
  • the porogen may be present in amount of less than 75 wt% of (i) the first polymer composition forming the core and/or (ii) the second polymer composition forming the shell.
  • this renders the core sufficiently flexible for penetration into the biological and not too brittle such that the core breaks when penetrating the biological tissue.
  • the core may have a cross-sectional diameter ranging from 200 mhi to 600 mhi, 300 mhi to 600 mhi, 400 mhi to 600 mhi, 500 mhi to 600 mhi, etc.
  • the core may further include a reservoir which houses one or more therapeutics, or the first polymer composition may house one or more therapeutics.
  • the shell may include one or more therapeutics.
  • the one or more therapeutics housed in the core and the shell may be same or different.
  • the core may be a solid core or a hollow core.
  • the solid core may house one or more therapeutics therein.
  • the first polymer composition used to form the solid core may house one or more therapeutics.
  • the core may have a hollow reservoir defined by a polymer matrix.
  • the first polymer composition used to form a polymer matrix defining the hollow core may house one or more therapeutics, or both the polymer matrix and the hollow core may house one or more therapeutics.
  • the core may further have a polymer matrix defining a hollow reservoir, wherein either or both the polymer matrix and hollow reservoir may each house one or more therapeutics.
  • the one or more therapeutics housed in the polymer matrix and the hollow core, and even the shell may be same or different.
  • the one or more therapeutics may include or may be a drug, a cell or a bioactive agent.
  • Non-exclusive examples of the therapeutics may include an adipose browning agent, a lipolytic agent, an anti-obesity agent, a blood sugar lowing agent, an insulin sensitizing agent, an anti cancer agent, an anti-psychotic agent, an anti-fungal agent, an anti-microbial agent, an anti-psychotic agent, an anesthetic agent, a pro-angiogenic agent, an anti- angiogenic agent, a hair-growth promoting agent, a hormonal agent, a protein or peptide, an amino acid, an antibody or antibody fragment, an oligonucleotide, a cell or cell fragment, an exosome or microvesicle, or a combination thereof.
  • the one or more therapeutics may be in the form of nanoparticles, nanospheres, nanocapsules, nanodots, nanorods, or a combination thereof.
  • the one or more therapeutics may be organic or inorganic.
  • Non exclusive examples of organic nanoparticles may includes indocyanine green, heptamethine cyanine, cryptocyanine, phthalocyanine, perylene diimide, porphyrin and its derivatives, polyaniline, poly(BIBDF-BT), polypyrrole and its derivatives, diketopyrrolopyrrole, dopamine, melanin, croconaine, squaraine, benzobisthiadiazole, or a combination thereof.
  • Non-exclusive examples of inorganic nanoparticles may contain gold, tungsten, copper, silicon, copper sulfide, molybdenum, iron oxide, manganese dioxide, silicon dioxide, carbon-based materials, or a combination thereof.
  • the present dislosure also provides for an applicator operable to implant the therapeutics delivery device as described herein in various embodiments of the first aspect.
  • the applicator may include a lancing module and one or more holder tube, wherein each of the one or more holder tubes is configured for loading the therapeutics device therein, and wherein the lancing module is operable to drive the therapeutics delivery device out of the one or more holder tubes to implant the therapeutics delivery device described according to various embodiments of the first aspect into the biological tissue.
  • the applicator may be used to implant the multiple micro-lances simultaneously.
  • the lancing module herein refers to any mechanism that can lance the therapeutics delivery device loaded in the applicator into a biological tissue.
  • the lancing module may include a spring coupled to one or more rods and the one or more holder tubes.
  • the applicator may include a housing that includes a spring coupled to one or more rods and one or more holder tubes, wherein each of the one or more holder tubes may be configured for loading the therapeutics delivery device therein, and wherein the spring is operable to have the one or more rods drive the one or more holder tubes to implant the therapeutics delivery device into the biological tissue.
  • each of the one or more rods may be a hard object of any shape which is operable to strike and propel the therapeutics delivery device out of the applicator and into the biological tissue.
  • the one or more rods may differ in shapes.
  • the lancing module may contain an air jet which lances or ejects the therapeutics delivery device into the biological tissue. Any other suitable mechanisms capable of lancing the therapeutics delivery device into the biological tissue may be adopted in the applicator.
  • Embodiments and advantages described for the present therapeutics delivery device of the first aspect can be analogously valid for the present applicator subsequently described herein, and vice versa. As the various embodiments and advantages have already been described above and examples demonstrated herein, they shall not be iterated for brevity.
  • the applicator can be designed to launch an array of the therapeutics delivery devices. By doing this, more therapeutics can be delivered and a larger administration area can be covered.
  • an example is to have the housing of the applicator configured to have multiple rod-tube combinations in order to load multiple therapeutics delivery devices.
  • the housing can alternatively have multiple holder tubes, wherein each of them is loaded with one therapeutics delivery device and all the therapeutics delivery device can be lanced or driven by one rod or a hard object with a different shape.
  • the housing, the lancing module, the rod, and/or the one or more holder tubes may be formed of stainless steel.
  • the stainless steel may be medical or food grade.
  • the present disclosure also provides for a method of producing the therapeutics delivery device described in various embodiments of the first aspect.
  • Embodiments and advantages described for the present therapeutics delivery device of the first aspect and the applicator can be analogously valid for the present method subsequently described herein, and vice versa.
  • the various embodiments and advantages have already been described above and examples demonstrated herein, they shall not be iterated for brevity.
  • the method may include providing a mold to form the core, wherein the mold includes a cavity having a depth of at least 1 mm and a closed end comprising a single bevel-angled shape, a double bevel-angled shape, a chiseled edge, a bullet-shape, or a frustum-shape, depositing a first polymer solution into the cavity, wherein the first polymer solution includes the first polymer composition, and drying the first polymer solution to form the core.
  • the method may further include coating a second polymer solution on the core to form the shell, wherein the second polymer solution includes the second polymer composition. That is to say, the present method may include providing a mold to form the core, wherein the mold includes a cavity having a depth of at least 1 mm (e.g.
  • first polymer solution includes the first polymer composition
  • second polymer solution includes the second polymer composition
  • the mold may be formed of a polymer material (e.g. polydimethylsiloxane, polyurethane), a ceramic material, or a metallic material (e.g. stainless steel, nickel, copper or gold).
  • a polymer material e.g. polydimethylsiloxane, polyurethane
  • a ceramic material e.g. aluminum, copper, copper or gold
  • a metallic material e.g. stainless steel, nickel, copper or gold.
  • the mold may be porous or/and contains porogens (e.g. polyethylene glycol) or superabsorbent polymers (e.g. a poly-acrylic acid sodium salt).
  • the mold, or portion of it, may be subjected to surface treatments to make it more hydrophilic or hydrophobic, which make it easier for filling polymeric solution into the mold, for example, by using radiofrequency or plasma treatment, or by coating with a surfactant such as polysorbate, docusate, sodium salt, benzethonium chloride, alkyltrimethylammonium bromide or hexadecyl trimethyl ammonium bromide (CTAB).
  • a surfactant such as polysorbate, docusate, sodium salt, benzethonium chloride, alkyltrimethylammonium bromide or hexadecyl trimethyl ammonium bromide (CTAB).
  • depositing the first polymer solution may include dissolving the first polymer composition in an organic solvent to form the first polymer solution, then introducing the first polymer solution into the mold, or may include heating a first polymer composite to a high temperature (e.g. 50 - 200°C), and applying a pressure on the first polymer solution or the first polymer composite to introduce it into the mold, wherein the pressure may be a hydraulic pressure ranging from 10 to 500 pounds per square inch (psi).
  • the polymer composite refers to a mixture of polymers that are not dissolved in an organic solvent.
  • Heating the first polymer composite may include melting the first polymer composite. Heating the polymers in the polymer composite above their glass transition temperature (Tg; e.g.
  • depositing the first polymer solution may include mixing the porogen and/or the one or more therapeutics in the first polymer solution.
  • the present method may further include heating the mold after depositing the first polymer solution and prior to drying the first polymer solution, wherein heating the mold may include heating the mold to a temperature ranging from 50 to 200°C without damaging the therapeutics and/or the mold.
  • the method may further include mixing the one or more therapeutics in the second polymer solution, removing the core from the mold prior to coating the second polymer solution, and immersing the core into the second polymer solution to form the shell.
  • the present disclosure may further provide for a method of treating a medical condition or delivering a therapeutics.
  • Embodiments and advantages described for the present therapeutics delivery device of the first aspect, the applicator and the method of producing the therapeutics delivery device can be analogously valid for the present method of of treating a medical condition or delivering a therapeutics subsequently described herein, and vice versa.
  • the various embodiments and advantages have already been described above and examples demonstrated herein, they shall not be iterated for brevity.
  • the present method may include operating the applicator to implant the therapeutics delivery device in the biological tissue.
  • the medical condition may include obesity, a metabolic disease, a cancer, an eye disease, a skin disease, alopecia, or schizophrenia.
  • a multi-modal controlled drug (and cell) delivery system which can be easily and comfortably self-administered at home, to directly implant into the deep subcutaneous fat or tissue, and thus patient friendly and well- suited for long-term home-based management of many diseases.
  • the present therapeutics delivery device is operable as a self-administrable and implantable drug delivery device for controlled and targeted delivery.
  • the therapeutics delivery device is operable with an applicator which allows for the therapeutics delivery device (i.e. micro-lance) to be released at high speed.
  • the applicator as described above, can include a spring and a shaft connected with a rod fitted into a housing, and a dissolvable lanced-shaped needle (ML) (solid, hollow or gutter-like) in the housing that has a porous core, a sharp tip, a shell coating layer that may be made of caboxymethylcellulose sodium (CMC) on the porous core and sharp tip, and therapeutics loaded in both the core and coating.
  • ML dissolvable lanced-shaped needle
  • CMC caboxymethylcellulose sodium
  • the fabricated MLs are long cylindrical in shape with the diameter of -250 pm and length of -4 mm.
  • the MLs has a sharp-pointed tip at one end, with a diameter of -30 pm and a single bevel angle of -75°, and a flat-blunted one at the other end.
  • the central hollow channel has the diameter of -100 pm.
  • the housing of the applicator helps resist buckling during skin insertion of the needle by providing a rigid column for supporting the needle.
  • the needle is released at a high speed to reduce pain.
  • the therapeutics delivery device allows the solid, hollow or gutter-like MLs to penetrate beyond the skin epidermis and dermis, and embedded deep into the underlying subcutaneous fat, with the tilted position, -2-6 mm from the skin’s stratum comeum.
  • the present disclosure relates to a self-administrable and implantable therapeutics delivery device into the biological tissues in a safe and minimally-invasive manner for controlled release of the therapeutics, and a method for preparing the same. Some features of the device and method are discussed below.
  • the therapeutics may include or may be a drug, a cell, or a bioactive agent.
  • the therapeutics delivery device is suitable for controlled release of therapeutics and may comprise a lance-shaped micro-implant (hereinafter, generically referred to as micro-lance) and operable with an applicator, wherein the micro-lance is made of a biocompatible and biodegradable polymer material, has a lance-shaped structure with a core and a sharp tip, is loaded with one or more biological active agent, is self-administrable and implantable into the biological tissues in a minimally-invasive manner, and the applicator is the spring-based applicator for lancing the micro-lance to pierce into the biological tissues.
  • a plurality of micro-lances i.e. therapeutics delivery device
  • the biocompatible and biodegradable polymer may for example be poly(D- lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid) and their derivatives (hereinafter, generically referred to as poly(lactic-co-glycolic acid or PLGA), with a molecular weight from 1,000 Da to 100,000 Da, and a molar ratio of lactic acid and glycolic acid from 1:100 to 100:1.
  • poly(lactic-co-glycolic acid or PLGA) poly(lactic-co-glycolic acid or PLGA)
  • polyethylene glyco) PEG
  • polyvinyl alcohol PVA
  • polyvinylpyrrolidone PVP
  • hyaluronic acid HA
  • the micro-lances can contain a different polymer, ceramic, drug, additive, or any combination or mixture thereof.
  • the micro-lance has a core, that can be either solid, hollow or gutter-like, and configured to have any cross-sectional shape (e.g. rounded, hexagonal, rectangular, etc.), with a diameter of 200-600 pm and the a height of 1 - 30 mm (e.g. 1 - 10 mm).
  • the central hollow cavity or channel with a diameter of 50-400 pm and a height of 1 - 30 mm (e.g. 1 - 10 mm), may contain different polymer, hydrogel, cryogel, nanoparticles, aqueous solution or any combination or mixture thereof, loading with different bioactive agents, proteins, peptides, oligonucleotides, cells or any combination or mixture thereof.
  • the polymeric micro-lance may include one or more porogen in the core for making porous micro-lance in the biological tissues, wherein the porogen, with a percentage of 1% up to 90 wt%, is any of the biocompatible fast-dissolving pore forming material or particles, preferably the inorganic compounds such as sodium chloride (NaCl), etc., polymeric material such as polyethylene glycol (PEG), and ionic liquids such as pyridinium or imidazolium salts.
  • the porogen with a percentage of 1% up to 90 wt%, is any of the biocompatible fast-dissolving pore forming material or particles, preferably the inorganic compounds such as sodium chloride (NaCl), etc., polymeric material such as polyethylene glycol (PEG), and ionic liquids such as pyridinium or imidazolium salts.
  • the polymeric micro-lance may include one or more coating layer (outer shell), wherein the coating layer is made of any of the biocompatible fast-dissolving viscosity-enhancing coating solution, preferably carboxymethylcellulose sodium (CMC), sucrose, HA, methacrylated HA (MeHA), sodium alginate, poly-vinyl- pyrrolidone (PVP), and one or more bioactive agent is loaded into the coating layers.
  • the coating layers can contain a different polymer, ceramic, drug, additive, or any combination or mixture thereof.
  • the micro-lance may have a sharp-pointed tip, preferably a single or double bevel-angled shape, or pyramidal or conical in shape, with a diameter of 5-50 pm.
  • the applicator may include one or more arrays of blunted or rounded hollow microchannel or tubes for loading and laterally- supporting the micro-lances, and the spring connected with one or arrays of rods perfectly fitted inside the microchannel or tubes for pushing, driving and directing the micro-lances toward the targeted tissues.
  • the implantation site is any of the biological tissues, preferably the skin, subcutaneous tissue, subcutaneous fat, tumor, sclera, vitreous cavity, joint cavity, etc.
  • the bioactive agents could be any drugs or compounds that can be used in obesity, metabolic diseases, tumor mass (malignant tumor such as melanoma, as well as benign tumor such as lipoma) and other diseases (e.g. skin diseases, alopecia).
  • diseases e.g. skin diseases, alopecia
  • bio-active agents may include adipose browning agents (e.g. b3 -adrenergic receptor agonist), lipolytic agents (e.g. deoxycholic acid), blood sugar lowing agents (e.g., PPAR agonist), anti-cancer agents (e.g. tamoxifen), anti-psychotic agents (e.g. risperidone), anti-fungal agents (e.g.
  • amphotericin anti- angiogenic agents
  • hair-growth promoting agents e.g. minoxidil
  • synthetic hormonal agents e.g. levonorgestrel
  • the present therapeutics delivery device is operable for treating, preventing, ameliorating, reducing or delaying the onset of obesity, metabolic diseases, cancers, eye diseases, and other diseases.
  • diseases may include obesity, metabolic diseases (e.g. type 2 diabetics, hypertriglyceridemia, and hypercholesterolemia), malignant tumor (e.g. breast cancer, prostate cancer and melanoma), benign tumor (e.g. lipoma), eye diseases (e.g. diabetes retinopathy, age- related macular degeneration), skin diseases (alopecia and deep skin infection, etc) and other diseases (e.g. schizophrenia).
  • the device is also suitable for use in other conditions such as hormone replacement therapy, contraception and family planning, therapeutic cell delivery, immunization, etc.
  • the micro-lance with hollow cavity or channel filling with hydrogel or cryogel is operable for cell delivery or replacement therapy (e.g. islet cells, stem cells, neurons, melanocytes), cell-based vaccination and immunotherapy (e.g. dendritic cells), etc., in order to treat, prevent, ameliorate, reduce or delay the onset of diabetes, metabolic diseases, cancers and other diseases, or to promote skin re -pigmentation, hair- follicle growth, nerve regeneration, re- vascularization, etc.
  • cell delivery or replacement therapy e.g. islet cells, stem cells, neurons, melanocytes
  • immunotherapy e.g. dendritic cells
  • the preparation method of polymeric micro-lance may be characterized as follows.
  • PLGA (20-50% w/v) (or other polymer) and bioactive agents are dissolved in a solvent (e.g., dimethylformamide, acetone, etc.) to obtain the polymer-drug solution.
  • a solvent e.g., dimethylformamide, acetone, etc.
  • the drug-embedded polymeric matrix or rubber is filled into the micro-lance shaped mold cavities made of polydimethylsiloxane (PDMS).
  • the mold cavities can be made of PDMS alone or PDMS mixed with sodium polyacrylate (20 wt.%).
  • the molding process can be done by directly pressing the matrix at 50- 200 °C, using a hydraulic pressure (10 - 500 pounds per square inch).
  • porogens e.g.
  • PDMS -mold cavity may contain central filament, threadlike object or fiber, and thus, the fabricated micro-lance could have hollow cavity or channel.
  • a filament, threadlike object or fiber can also be inserted into the polymeric matrix or rubber before the molding process, to make the hollow micro-lances.
  • micro-lances can be coated with the coating solution which may also contain bioactive agents.
  • the hydrogel or cryogel containing cells or other bioactive agents can be loaded into the hollow cavity of micro-lance by using a syringe or centrifugation.
  • the micro lances are then stored in the air-tight containers at the room temperature or 4 °C fridge.
  • Example 1A Materials Used
  • Poly (D, L-lactide-co-glycolide) (PLGA, 50:50 ratio, Mw 54,000-69,000), carboxymethylcellulose (CMC), poloxamer 188 (Pluronic F68), sodium chloride (NaCl), polydimethylsiloxane (PDMS, SYLGARD 184) and dimethylsulfoxide (DMSO) were purchased from Sigma- Aldrich.
  • CL316,243 (a selective p3-adrenergic receptor agonist), rosiglitazone (a selective PPARy agonist) and insulin (human recombinant) were obtained from Tocris Bioscience.
  • Cyanine5 (Cy5) and fluorescein were acquired from Lumiprobe.
  • DMEM/F12 fetal bovine serum
  • BSA bovine serum albumin
  • PBS phosphate buffered saline
  • penicillin- streptomycin trypsin- EDTA
  • AlamarBlue cell viability reagent obtained from ThermoFisher Scientific. All other reagents and solvents were also purchased from Sigma- Aldrich and used without further purification.
  • Example IB Fabrication of Polymeric Micro-Lances
  • MLs microlances
  • PLGA and drug or fluorescence molecules were dissolved in a dimethylformamide solution to obtain the polymer-drug solution. After complete evaporating the solvent, the drug-embedded PLGA matrix or rubber was thoroughly mixed with the salt microparticles ( ⁇ 30 pm).
  • the salt- mixed PLGA matrix was then casted into the PDMS micromolds, the reverse replica of the stainless- steel master- molds (33G Lancet, with the diameter of 0.25 mm and the height of 4 mm), by applying a ⁇ 50-pound per square inch load at 80°C for 30 min.
  • RT room temperature
  • polymeric MLs were peeled off from the micromolds.
  • the micro-lances were coated with the CMC-based coating solution, with or without containing the drug or fluorescent molecules.
  • the MLs were then stored in the air-tight containers at the RT.
  • the salt- mixed PLGA-based MLs (PLGA/NaCl ratio of 50:50) were used in all the experiments unless otherwise indicated.
  • MLs were prepared via a simple thermal pressing method. Firstly, NaCl micro-particles were obtained by grinding the powder and filtering through a fine mesh with a pore size of ⁇ 50 pm. The mixture of PLGA and salt micro particles was then prepared using the solvent casting method. Briefly, PLGA was dissolved in acetone before salt micro-particles were added. After thorough mixing and complete evaporation of the solvent at room temperature (e.g. 20 - 28 °C), a homogeneous solid mixture was obtained. Rosiglitazone or fluorescent dyes were added directly into the salt-polymer solution.
  • the deionized (DI) water solution of the drug was thoroughly mixed with acetone solution of PLGA. Then salt micro-particles were added, following by complete evaporation of solvent and water. The solid mixture was then placed on top of the PDMS mold, which is the reverse replica of a home-made stainless-steel master-mold having a vertical array of 32G ultrafine needle (diameter of 0.23 mm and height of 4 mm), before heating at ⁇ 90 °C for 10 mins and pressing with a compression force of ⁇ 20 kg for 2 hrs.
  • DI deionized
  • PDMS mold filled with dmg-salt-PLGA mixture, was then heated for another 15 mins without pressing to allow the PDMS mold to restore to its original shape. After cooling at room temperature (e.g. 20 - 28 °C) for 30 mins, polymeric MLs were individually taken out using forceps. Subsequently, MLs were gradually dipped into a 20 pi DI water solution containing 0.6 mg CMC and 0.2 mg Pluronic F68 and dried in air for 15 mins to form CMC-PLGA core-shelled MLs. The coating process was repeated for 3 times.
  • MLs The morphology of MLs was examined using a field-emission scanning electron microscope (FESEM; JSM-6700, JEOL) and a digital microscope (Leica DVM6). MLs loaded with different fluorescence dyes were visualized with a confocal laser scanning microscope (LSM800, Carl Zeiss). Drug loading amount in ML was determined using a UV-Vis spectroscopy (Shimadzu UV-1800). The mechanical property of MLs was tested using an Instron 5543 Tensile Tester. Briefly, a vertical force was applied onto a ML using a flat-headed stainless- steel cylindrical probe at a constant speed of 0.5 mm/min and the force exerted on the MN was continuously recorded.
  • ML insertion test was performed on the isolated porcine skin as previously described. Briefly, MLs were mounted onto the cylindrical probe, and pressed perpendicular to the isolated porcine skin at a rate of 5 mm/min until a pre-set maximum load of 4 N was reached. Force exerted on the skin by the ML as a function of its displacement into skin was recorded. The insertion force was estimated when the force against the skin showed discontinuity followed by a steep slope.
  • adipocytes differentiated from the primary human pre-adipose cells were exposed to MLs for 2 weeks, before analyzing cell morphology using an inverted microscope (1X71, Olympus, equipped with a digital camera OlympusE330) and cytotoxicity using an almarBlue cell viability assay.
  • these adipocytes were treated with free CL316,243 or CL316,243 released from MLs (1 pg/ml) for 7 days.
  • M-PER Mammalian Protein Extraction Reagent containing Halt protease and phosphatase inhibitor cocktail, ThermoFisher Scientific
  • UCP1 phosphatase inhibitor cocktail
  • MLs were administered vertically into the porcine skin and its underlying subcutaneous fat tissue using a home-made lancing applicator.
  • the applicator contains a spring and a shaft connected with a stainless-steel rod which is well-fitted into a stainless- steel holder tube.
  • the spring is made of a -0.8 mm stainless-steel wire, and has an outer-diameter of 9 mm, a length of 40 mm, an effective coil-number of 10, a k value of -0.09 kgf/mm, and a loading force of -1.4 kgf.
  • the porcine tissue was then excised and photographed to analyze the embedded MLs inside the tissue (insertion depth and trajectory).
  • the tissues were fixed with 4% paraformaldehyde solution for 24 hours, and cryoprotected with 30% sucrose solution for 1-2 days, before embedding in FSC22 Frozen Section Media (Leica Microsystem).
  • the tissue sections (10 pm) were sliced using a cryostat (CM 1950 cryostat, Leica Microsystems) before staining with the hematoxylin and eosin solutions (Sigma- Aldrich), and images were taken using a digital microscope (Leica DVM6).
  • CM 1950 cryostat Leica Microsystems
  • Leica DVM6 digital microscope
  • MLs were inserted vertically into the agarose hydrogel (4% w/v, in DI water, pH 7.4) using the applicator.
  • the bright-field images of the agarose hydrogel with the embedded MLs were then analyzed using the ImageJ software (NIH.gov).
  • MLs differently loaded with CL316,243 or Cy5 molecules were immersed in the phosphate buffer solution (PBS, pH 7.4), and placed in an incubator shaker (100 rpm, 37 °C). Fluorescent molecules released from MLs were determined using a fluorescence spectrometer (SpectraMax M5, Molecular Devices).
  • CL316,243 molecules released from MLs were measured by a gradient reverse-phase high performance liquid chromatography (Agilent 1100 HPLC-DAD system) using an Agilent Poroshell 120 EC-C18 column (with a mobile phase of water and methanol, a flow rate of 0.5 mL/min and UV detection at 285 nm) and quantified based on the linear calibration curve created with different known concentrations.
  • the real-time visualization of fluorescent molecules releases from MLs in agarose hydrogel (4% w/v, in DI water, pH 7.4) were also analyzed using a confocal microscopy.
  • mice C57BL/6J, 7 - 8-week-old male. Briefly, after shaving the mouse hairs around the inguinal region (lower left or right quadrant of dorsolateral area, adjacent to the hind limbs), MLs differently loaded with Cy5 molecules (1 pg in the PLGA-core or CMC- shell) were applied obliquely ( ⁇ 45 0 angle from the skin surface) on the skin around the inguinal region using the applicator. The mice were then imaged immediately (dayO) or at day 1 or day7 using an in vivo imaging system (IVIS Spectrum, Perkin Elmer).
  • IVIS in vivo imaging system
  • mice treated with either ML insertion (1 pg Cy5 in the PLGA-core or CMC-shell) or intraperitoneal (IP) injection (1 pg in 50 pi PBS) were euthanized at 2-hour post treatment or at day7, and the white adipose tissue (WATs) and other major organs (liver, heart, kidney and lung) were dissected and visualized by IVIS imaging system.
  • ML insertion (1 pg Cy5 in the PLGA-core or CMC-shell
  • IP intraperitoneal
  • Example ID Animal Experiments (In Vivo Studies of Polymeric Microlances)
  • mice C57BL/6J were housed in light and temperature-controlled facility (12-hr light/12-hr dark cycle, 22 °C), and allowed free access of water and standard or high- fat diet. After shaving the hairs around the inguinal region, a ML was applied using the applicator. Low-dose inhaled isoflurane was used to constrain the mice during ML application. Mice were then returned to their cages and imaged immediately to access the penetration sites.
  • mice After ⁇ 5 mins, mice were recovered from anaesthesia and their behaviours were monitored to access their possible pain using Grimace scoring based on orbital tightening, nose bulge, check bulge, and ear position. The body weight and food intake were also recorded (day 1, 4 and 7). In some tested mice groups, mice were euthanized immediately after ML insertion or at dayl or day30, and skin tissue and IgWATs were collected to examine the histological changes and biocompatibility of MLs. The in vivo fluorescence from Cy5 molecules released from MLs was imaged using an in vivo imaging system (IVIS Spectrum, Perkin Elmer).
  • IVIS in vivo imaging system
  • mice 6-7 weeks old male fed on high-fat diet (60% kcal from fat, Testdiet) for 3 weeks to induce obesity
  • high-fat diet 60% kcal from fat, Testdiet
  • mice were randomly divided into 5 groups for different treatments.
  • Each ML contains 10 pg CL316,243 in the core and 5 pg CL316,243 in the shell.
  • One ML was applied at each left and right inguinal region once every 1 week, or 2 MLs at each region once every 2 weeks (both equivalent to 1 mg/kg/week).
  • mice Lour to five mice were used in each treatment or control group, and mice were fed with high-fat diet throughout the experiments. After 5 weeks treatment, the glucose tolerance test was performed as described previously. Briefly, the overnight-fasted mice (16 hrs) were injected with glucose solution (2 g per kg in PBS) via IP route, and blood glucose was monitored over time. After 6 weeks treatment, body surface temperature was monitored on the shaved skin under fully awake condition, using infrared thermal imaging camera (LLIR T420). The mice were then euthanized by a lethal dose of carbon dioxide. After measuring the body weights, fat tissues (inguinal WAT, epididymal WAT and interscapular BAT) were excised, weighted and collected for histological analyses.
  • LLIR T420 infrared thermal imaging camera
  • IgWATs immunoblot analyses. Briefly, tissue samples with equal amount of proteins (as the loading control) were separated on 12% SDS-PAGE before being transferred onto a nitrocellulose membrane.
  • the membrane was then blocked with Superblock blocking buffer (ThermoFisher Scientific) (2 hr at RT) and incubated with specific primary antibody (1: 200-400 dilutions, 12 hr at RT), before washing (Tris-buffered saline- Tween solution- TBST, 3 x 15 min each) and incubation with horseradish peroxidase- conjugated secondary antibody (Sigma- Aldrich) (1: 2000 - 4000; 6 hr at RT).
  • Superblock blocking buffer ThermoFisher Scientific 2 hr at RT
  • specific primary antibody 1: 200-400 dilutions, 12 hr at RT
  • Tris-buffered saline- Tween solution- TBST 3 x 15 min each
  • horseradish peroxidase- conjugated secondary antibody Sigma- Aldrich
  • the excised tissues were immediately fixed with 4% paraformaldehyde solution for 24 hrs, washed with PBS, and immersed in 30% sucrose solution for 2 days to cryoprotect the tissues. After embedding in FSC22 Frozen Section Media (Leica Microsystem), tissues were frozen and sliced (10-20 pm thick) using a cryostat (CM1950 cryostat, Leica Microsystems). The tissue sections were finally stained with hematoxylin and eosin solutions (Sigma- Aldrich), and images were taken using a digital microscope (Leica DVM6).
  • Example 1G Assessment on serological parameters
  • Serum levels of cholesterol, triglycerides, free fatty acids, and glucose were measured by the standard assay kits from Sigma-Aldrich. Serum level of insulin was determined by a mouse insulin ELISA kit from ThermoFisher Scientific.
  • Example 2A Discussion on Fabrication of Core-Shelled Micro-Lances
  • lance-shaped polymeric micro-implants (termed herein micro lances, MLs) were fabricated using a simple hot-embossing micro-molding method (FIG. 1H).
  • PLGA biodegradable and biocompatible polymer poly (lactic-co-glycolic acid)
  • CMC carboxymethyl cellulose
  • shell MLs
  • PLGA and CMC are also widely used in many US-FDA approved medical and food products, respectively. Combining the merits of slow-releasing PLGA and fast-releasing CMC, herein developed is the core- shell MLs for localized and controlled drug delivery into subcutaneous tissue.
  • salt particles as porogens were mixed in PLGA (50:50) to realize the porous structure of MLs in the tissues, as the leaching of salt particles by tissue interstitial fluid could create pores, and hence accelerate the degradation rate and release kinetic of PLGA.
  • salt-mixed PLGA with or without therapeutic compounds, were casted into the mold by applying a load of ⁇ 50 pounds per square inch at ⁇ 80 °C for 1 hour. It was known that glass transition temperature (Tg) of PLGA is ⁇ 55 °C.
  • the fabricated MLs are long cylindrical in shape with the diameter of -250 pm and length of -4 mm (FIG. 2A and FIG. IB).
  • the ML has a sharp-pointed tip at one end, with the diameter of ⁇ 10 pm and a single bevel angle of -75°, and a flat-blunted one at the other end (FIG. IB).
  • the ML design is based on the previous findings that sharp-tapered and thinner needles cause less pain, skin penetration force and trauma comparing to large and obtuse needles.
  • the average pore diameter of the porous PLGA- based MLs after leaching of the salt particles is ⁇ 4 pm, with the maximum pore size of ⁇ 10 pm (FIG. ID to 1G).
  • the confocal fluorescence imaging confirms that different fluorescence molecules, as the model therapeutic compounds, can be differently loaded in the inner PLGA core and outer coating layer (FIG. 2A). Consistent with the well- known biocompatibilities of PLGA and CMC polymers, the fabricated MLs are highly biocompatible to human cells, as evidenced by the preserved morphology and viability of human white adipocytes (FIG. 5H and 51).
  • PLGA poly (lactic-co-glycolic acid)
  • the biodegradation rate of PLGA can be tailored by varying the monomer ratio (PLA/PGA).
  • PLGA with 50:50 PLA/PGA monomer ratio exhibits the fastest hydrolytic degradation at the physiological condition.
  • salt micro-particles (10 - 50 pm, FIG. 1A) as porogens are added to PLGA polymer matrix.
  • Tg of PLGA melting temperature
  • a dry homogeneous mixture of PLGA molecules, drug compounds, and NaCl micro-particles was first placed on top of a negative mold made of polydimethylsiloxane (PDMS), and subsequently heated at 90 °C for 10 mins to make it rubbery and pressed into the mold with a compression force of ⁇ 20 kg for 2 hrs. After cooling at room temperature (e.g. 20 - 28 °C) for 30 mins, PLGA-MLs were demolded.
  • PDMS polydimethylsiloxane
  • CMC carboxymethyl cellulose
  • Example 2B Present Micro-Lances for Bi-phasic Drug Delivery and Strong Mechanical Strength
  • confocal fluorescence imaging confirms the ability of the MLs to pack different fluorescence molecules as the model drug molecules (red cy5 in inner PLGA core, green fluorescein in outer CMC shell).
  • MLs differently loaded with fluorescence dyes were inserted into agarose hydrogel as the skin mimics, and continuously monitored under confocal microscopy.
  • fast-dissolving outer-shell of CMC quickly released its cargo within 5 mins (FIG. 2B and 1C), while the salt-mixed PLGA inner-core (50% salt) gradually degraded, and discharged its cargo over several weeks (4 - 6 week, FIG. 2B).
  • FIG. 3L and 3M show the corresponding mechanical strength performance.
  • MLs with 75% salt may be too brittle for skin penetration and suitable for applications that require such properties.
  • Additional CMC coating does not reinforce the mechanical strength (FIG. 3N), indicating that the mechanical property is dictated by the PLGA inner core.
  • drug loading (10%) does not significantly compromise the mechanical properties of MLs (FIG. 30).
  • Example 2C Lancing MLs into sWAT
  • lateral bending which may be a typical mechanical failure mode for the needles, particularly the polymeric ones
  • the lateral bending when the axial compressive force exceeds the critical load of the needles.
  • the presence of lateral support can largely increase the critical buckling load.
  • the lateral support of mosquito’s labium increases the critical load of fascicle (a microneedle made of chitin) by a factor of 5.
  • a straight fascicle can penetrate more easily.
  • ML can be laterally supported by a rigid tube to resist buckling during skin insertion.
  • a high-speed lancing- device or applicator can be included, which involves a spring and a shaft connected with a stainless-steel rod.
  • the rod is fitted into a stainless-steel tube holder, into which a ML can be snugly loaded (FIG. 41).
  • the compressive force of the spring is released, the rod instantly strikes the ML, lancing ML swiftly into skin.
  • the lancing speed is ⁇ 1 m/s, and duration is only ⁇ 50 ms (FIG. 4J).
  • a core- shelled ML can be easily lanced into skin- mimicking agarose gel (4%), without buckling or fracture (FIG. 4K).
  • the distance between the penetration point on the surface and the blunted end of ML is 2-3 mm (greater than the thickness of human skin of ⁇ 2 mm at abdominal area), suggesting that MLs can be embedded deep into sWAT.
  • the embedded ML is titled -22°, because of the resistive force from the tissue acted on the bevelled tip of the ML (FIG. 4K to 4N). This is consistent with the observation that the insertion trajectory of bevel- tipped needles is curved.
  • Porcine skin closely resembles human skin and is the widely used skin model. Similar to human sWAT, porcine sWAT is continuously associated with dermal layer. As demonstrated in FIG. 3A, ML can be easily lanced into sWAT (tip reaches 5 - 6 mm deep from the skin surface). Subsequent histological study shows the narrow insertion path, and the implanted ML (FIG. 3B). The insertion force for ML upon its penetration into the porcine skin is ⁇ 0.1 N (FIG. 3P) as indicated by a small dip in the force-displacement curve followed by a steeper slope. Taken together, these experiments demonstrate that MLs are strong enough to pierce the skin and reach into the subcutaneous fat, where the implanted MLs can function as the micro-drug- reservoirs for the localized and controlled drug release.
  • Example 2D Safe, Painless and Minimally Invasive Implantation of MLs as Embedded Drug Reservoirs
  • the safety and drug releases of core-shell MLs were further investigated in vivo mouse model.
  • the MLs were inserted into the skin around the inguinal area using the applicator at the angle of -45° from the skin surface to embed the MLs within the underlying subcutaneous white adipose tissue (WAT; also called inguinal WAT).
  • WAT subcutaneous white adipose tissue
  • Inguinal WAT which lies just 1 - 2 mm below the skin, is the largest subcutaneous WAT in rodents, and comparable in terms of location to the large gluteofemoral subcutaneous WAT in humans.
  • the insertion site, body weight and food intake were monitored over 1 week.
  • the fabricated MLs are highly biocompatible to human cells, as evidenced by the well-preserved morphology and viability of human white adipocytes (FIG. 5H and 51).
  • MLs were administrated by the applicator at the inguinal area to implant MLs into the sWAT (inguinal WAT — IgWAT).
  • IgWAT which lies just 1 - 2 mm below the skin, is the largest sWAT in rodents. As shown in FIG.
  • FIG. 13 A and 13B show, in the upper lane, representative bright field and corresponding confocal images of gutter-like ML made of poly(D, L-lactide-co- glycolide) (PLGA, 50:50, Mw 54,000-69,000), loaded with cells.
  • PLGA poly(D, L-lactide-co- glycolide)
  • FIG. 13C and 13D show, in the lower lane, representative bright field and corresponding confocal images of cell-loaded PLGA-based gutter-like ML inserted in a 4% agarose hydrogel.
  • Scale bar denotes 50 pm.
  • the fabricated MLs are long cylindrical gutter-like in shape with the diameter of -250 pm and length of -4 mm.
  • the ML has a sharp-pointed tip at one end, with the diameter of -30 pm and a single bevel angle of -75°, and a flat-blunted one at the other end.
  • the central channel has a diameter of -150 pm, and provides a reservoir space for cell loading.
  • the volume of the central channel was 0.05 to 0.1 mm 3 (pL) (5 x 10 6 - 10 x 10 7 pm 3 ).
  • the maximal dosage of cells in each ML ranges from 6 x 10 3 to 3 x 10 5 cells.
  • Such MLs attain the mechanical force of more than 1 N per needle (stiffness of -3.5 N/mm) without breaking or deformation.
  • Such MLs are also strong enough to penetrate porcine skin.
  • the porous PLGA-based lateral wall of the ML core ( ⁇ 0.5 - 5 pm pore size) allows nutrient and gas exchange to the surrounding environment.
  • the surface modification and cell loading of PLGA-based gutter- like MLs are discussed below.
  • Coating with Poly-L-Lysine (PLL) - Poly-L-Lysine (PLL) is a biocompatible cationic polyamino acid that facilitates the attachment of cells and proteins to solid surfaces in biological application, hence promoting cell adhesion, proliferation and regeneration at the interface of the biomaterial.
  • PLL demonstrates exceptional antimicrobial property, water solubility, stability and safety.
  • PLL improves cell adhesion by enhancing the electrostatic interaction between the positive charges on the PLL surface and negative charges on the cell membrane surface. When adsorbed to the biomaterial, it increases the number of positively charged sites available for cell binding. This surface modification strategy is convenient, simple and displays great potential in biomaterial applications.
  • PLL coating was performed as followed.
  • MLs e.g. solid or hollow or gutter like MLs
  • MLs were immersed in 0.1 M NaOH solution for 30 minutes at room temperature (e.g. 20 - 28 °C) to introduce -COOH groups onto the MLs’ surface.
  • MLs were washed with distilled water five times to remove the remaining NaOH solution.
  • PLL solution P4707, Sigma Aldrich
  • Oxygen Plasma Treatment is another surface modification strategy to enhance cell adhesion.
  • Gas plasma treatment is used for chemical modification of PLGA surface by creating reactive groups and increasing its hydrophilicity to improve cell adhesion.
  • surface roughness may also influences cell spreading and growth as cells may orientate themselves along the grooves of a surface, a phenomenon known as contact guidance. Studies showed that oxygen plasma-treated samples had significantly higher cell attachment.
  • MLs solid, hollow or gutter-like MLs
  • a plasma cleaner Hard Plasma
  • high power setting ⁇ 45 W
  • treated for different durations e.g. 10 - 60 minutes
  • MLs - Cells were loaded into MLs (solid, hollow or gutter like MLs) by simply mixing MLs with cell suspension solution before incubating overnight in the C02 incubator at 37 °C.
  • cells may be loaded with centrifugal forces (e.g. ⁇ 100 - 400 g) using a centrifuge.
  • Example 3A Present Device and Treatment/Prevention of Diseases
  • the present device and method provides a new transdermal delivery technique and demonstrated its use to directly deliver browning and insulin sensitizing agents into subcutaneous white adipose tissue (sWAT).
  • Ultrathin, core-shelled, and lance-shaped polymeric drug reservoirs were readily fabricated by thermal pressing molding and subsequent dip-coating. They can be rapidly lanced through the skin and totally implanted into sWAT for localized and biphasic drug release.
  • the excellent therapeutic effectiveness to prevent development of obesity and associated metabolic diseases was demonstrated using an obese mouse model induced by high-fat diet.
  • the present device provides a self-administrable and minimally-invasive ML approach, which can also be employed for long-term home-based treatment of other chronic diseases.
  • obesity is a serious epidemic health problem that can cause many other diseases including type 2 diabetes and cardiovascular diseases.
  • Existing approaches to combat obesity suffer from low effectiveness and adverse side effects.
  • the present device provides for a self-administrable and minimally-invasive transdermal drug delivery strategy for home-based long-term treatment of obesity and other diseases.
  • ultrathin, core-shelled, and lance-shaped polymeric drug- reservoirs were readily fabricated by a thermal pressing molding method and totally implanted into subcutaneous fat by lancing through the skin.
  • Obesity is increasingly prevalent worldwide and it may often be a root cause to many diseases such as diabetes, cardiovascular diseases, and cancers.
  • Lifestyle intervention diet and physical activity alone may be insufficient to combat obesity because of problematic long-term patient compliance, body adaptation, and the fact that obesity may be a consequence of definite biological reasons.
  • surgical intervention may be effective, there are concerns about risks, side-effects, high cost, and long-term efficacy.
  • weight management medications may be available, but they all act indirectly with limited efficacy, e.g. either by reducing fat absorption in gastrointestinal tract or suppressing appetite in brain. The adverse side- effects and high cost limit their use.
  • WAT White adipose tissue
  • WAT stores energy in the form of triglycerides.
  • WAT is excessively accumulated and releases various deleterious factors (e.g. free fatty acids- FFA, inflammatory cytokines, reactive oxygen species) which lead to various metabolic problems, such as insulin resistance.
  • brown adipose tissue (BAT) specializes in burning energy using glucose and FFA as the major fuels. Studies have demonstrated BAT as a negative regulator of adiposity and insulin resistance.
  • BAT is scarce in adults and even less in obese people, brown-like (or beige) adipocytes have been identified in WAT, particularly in subcutaneous fat depot.
  • white adipocytes can transform into brown-like adipocytes (termed as browning) upon induction by some agents, (e.g. b3 -adrenergic receptor agonist). Therefore, stimulating browning of subcutaneous WAT (sWAT) may be more effective strategy to combat obesity and associated metabolic diseases. Nevertheless, the clinical use of browning or anti-obesity agents is prevented by the issues associated with the conventional drug delivery methods (e.g. oral intake, intravenous injection). Using these systemic delivery methods, the bioavailability at WAT is low due to poor GI absorption, hepatic first pass effect, renal clearance, enzymatic degradation and lack of ability to specifically target on WAT.
  • sWAT subcutaneous WAT
  • microneedle skin patches for localized and controlled transdermal delivery of browning agents to sWAT have been demonstrated. Such a method offers outstanding anti-obesity efficacy with low effective dosage (thus presumably low side-effects) and minimal invasiveness (thus suitable for home-based healthcare).
  • the microneedle approach still faces several limitations. Firstly, microneedle patches are typically fabricated using micro-molding method which is time-consuming and not easy to be scaled up due to involvement of centrifugation and lengthy drying process. Secondly, the length of microneedles is usually limited to be less than 1 mm in order to ensure painless penetration and possibility to demold microneedles without breaking.
  • Example 3B Effective Anti- Obesity Treatment Enabled by Present ML Approach
  • adipose browning could potentially increase energy expenditure, reduce adiposity, and improve metabolic health.
  • Many browning molecules have been discovered (e.g. b-adrenergic hormone, apelin, etc.), however, their low bioavailability in adipose tissue, enzymatic degradation in circulation, rapid renal clearance and off-target effects associated with systemic administration (e.g. intravenous injection) dissuade their practical usage in metabolic diseases.
  • systemic administration e.g. intravenous injection
  • CL316,243 a p3-adrenergic receptor agonist
  • a US-FDA approved human b3 -adrenergic receptor agonist is clinically used for overactive bladder syndrome. Therefore, repurposing it for anti-obesity will largely lower the translational hurdle because its toxicity is well characterized.
  • mice continuously fed with high-fat diet gained -23% of body weight (FIG. 4A to 4C) and -70% of the gain was due to the increase of white fat mass including IgWAT and epididymal WAT - EpiWAT (FIG. 4D to 4E).
  • IP injection of CL316,243 failed to significantly suppress weight gain. Specifically, -14% and 18% of weight gain were still observed in the groups received IP injection once a week or once two weeks (FIG. 4C). Fluctuation of body weight changes was observed in the latter group presumably because doubled dosage caused weight loss in the initial a few days, and weight gain then restored quickly afterwards.
  • ML treatment can suppress the development of obesity and associated metabolic diseases by inducing browning of sWAT through localized and controlled delivery of browning agent.
  • fat browning and reduction effects from biphasic delivery of CL316,243 are much better than those from fast releasing of CL316,243 (same amount but in shell only).
  • -14% weight gain was still observed in the group received with the latter treatment (FIG. 8A).
  • larger fat mass (FIG. 8B) and lesser brown like adipocytes (FIG. 8C) were observed in this group than in the group treated with biphasic delivery of CL316,243.
  • Example 3C Combination Therapy for Obesity and Metabolic Disorders
  • Combination therapy that involves co-delivery of several drugs for synergistic or multiple therapeutic effects are highly desired.
  • core and shell of MLs are differentially loaded with adipose browning agent (CL316,243) and insulin- sensitizing drug (rosiglitazone which is an agonist of the peroxisome proliferator-activated receptor-g, PPARy). Rosiglitazone not only is a US-FDA approved anti-diabetic drug but also is recognized as a browning agent by some studies. As shown in FIG.
  • mice treated once every 2 weeks for 6 weeks, with MLs loaded with 40 pg CL316,243 in inner-core and 20 pg rosiglitazone in outer-shell significantly reduced weight gain induced by high-fat diet (only -8% weight gain vs. -24% in control group).
  • Subcutaneous injection of both CL316,243 and rosiglitazone with the same dosage and frequency failed to exert obvious weight control effect (-20% weight gain).
  • the ML treatment with CL316,243 in the shell and rosiglitazone in the core failed to control the weight gain (-19% gain, FIG. 6A).
  • Skin which is the largest organ, contains a vast network of capillaries and lymphatic vessels and has various tissues lying underneath including subcutaneous fat (sWAT), muscles, tendons, ligments, and fibrous joint capsules. As the outer covering of the body, it offers an conveniently accessible interface for drug administration. Transdermal drug delivery can bypass gastrointestinal tract absorption and hepatic first pass effect, and be locally applied at the site just above the targeted or suitable tissues.
  • MLs lancing polymeric micro-lances
  • the present disclosure demonstrates the use of such paradiagm-shifting approach for combating obesity and associated metabolic diseases via inducing adipose browning and increasing insulin sensitivity.
  • Using an obese mouse model the outstanding therapeutic effects are evidenced by halted weight gain under high-fat diet, reduced fat masses, appearance of multilocular brown-like adipocytes, upregulated expression of brown- specific proteins including thermogenic UCP1, elevated body surface temperature, increased glucose clearance rate, as well as decreased serum levels of cholesterol, triglycerides and insulin.
  • the present ML approach significantly outperforms the conventional systemic administration methods (IP or subcutaneous injection) because of high drug bioavailability owing to localized and direct delivery, as well as biphasic drug release kinetics and combination therapy enabled by core- shelled MLs. It is also superior to reported microneedle-based transdermal delivery approach in terms of much less frequent treatment (here only once every 2 weeks) and less weight gain using the same weekly dosage of CL316,243. This is attributable to the total implantation of ML inside sWAT and more desirable drug release profiles. [00270] The human clinical studies of both b3 -adrenergic receptor agonists (CL316,243 and mirabegron) using conventional systemic delivery were disappointing.
  • the present ML approach may make mirabegron as well as other browning agents clinically feasible by reducing the effective dosage because of high drug bioavailability and optimal release kinetics.
  • Abdominal and gluteofemoral areas are suitable sites for ML application because they are the largest sWAT depots in human and the least pain sensitive compared to other body parts.
  • Lancing ML into these fat depots should be more patient friendly than lancing the stainless-steel lancets into the most pain- sensitive fingertips for blood sampling. For the latter, a study reported that >90% patients considered painless. In addition to frequent blood sampling, diabetes patients also need to do insulin injection using an insulin needle (e.g. 33G x 4 mm) several times a day. Owing to its sustainable releasing property, ML treatment can be much less frequent (e.g. once every 2 weeks). Using a simple applicator, ML can be easily self-administrated. ML wholly implanted in sWAT can then serve as micro-drug-reservoir.
  • insulin needle e.g. 33G x 4 mm
  • sWAT total implantation of ML in sWAT ensures a higher loading capacity, 100% bioavailability in the subcutaneous tissues, precise drug dosage, and minimized skin reactions.
  • implantation depth can be controlled by simply adjusting the applicator’s spring force or injection angle into the skin.
  • Powder or liquid jet injection has been demonstrated for transdermal delivery. But for these methods, -10% of sprayed drugs are loss at the skin surface and the majority of the remaining are dispersed in epidermis and dermis, which are easily adsorbed into circulation before reaching subcutaneous tissues (e.g., sWAT).
  • ML approach promises for other diseases as well, for examples, implanting anti-diabetic agents (e.g. sulfonylureas- glimepiride) for diabetes, synthetic hormonal agents (e.g. levonorgestrel) for contraception and hormone replacement therapy, anti psychotic agents (e.g. risperidone) for schizophrenia and other mental disorders, anticancer drugs to tumor tissues (e.g., tamoxifen for breast cancer). It may also be useful for intraocular drug delivery by bypasing anatomical barriers (e.g. cornea, sclera).
  • anatomical barriers e.g. cornea, sclera
  • MLs can be implanted into sclera for sustained delivery of corticosteriods for uveitis or b-adrenergic receptor blockers for glaucoma.
  • such safe, painless and convenient transdermal delivery method may provide unprecedented long-term home-based solution for obesity and many other diseases.
  • Example 5 Commercial and Potential Applications
  • IDD devices including drug infusion pumps, intraocular drug delivery devices, and contraceptive drug delivery devices can be replaced by the present patient-friendly self-administrable and implantable micro-lance therapeutics delivery devices, because those conventional devices may inconveniently require surgery and clinic visit.
  • the present device can be applied in home -based care of people with obesity or overweight. It has enormous potential to replace currently- available obesity treatments (liposuction, lipolysis), or FDA-approved “anti-obesity drugs”, because it is safe, cost-effective, and patient-friendly.

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Abstract

L'invention concerne un dispositif d'administration de produits thérapeutiques implantable dans un tissu biologique, comprenant un noyau qui est biodégradable, le noyau comprenant une première composition polymère, le noyau ayant une hauteur d'au moins 1 mm, et le noyau ayant une extrémité en forme de pointe acérée suffisante pour pénétrer dans le tissu biologique, la pointe acérée comprenant une forme à angle de biseau unique, une forme à double biseau, un bord chiselé, une forme de balle, ou une forme tronconique. Le noyau peut être revêtu d'une ou de plusieurs enveloppes. Dans un mode de réalisation préféré, le dispositif d'administration de produits thérapeutiques comprend un noyau de poly(acide lactique-co-glycolique) (PLGA) revêtu d'une enveloppe de carboxyméthylcellulose (CMC). L'invention concerne également un applicateur utilisable pour implanter le dispositif d'administration de produits thérapeutiques, un procédé de production du dispositif d'administration de produits thérapeutiques, et des applications du dispositif d'administration de produits thérapeutiques.
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CN113230402A (zh) * 2021-05-20 2021-08-10 厦门大学 一种聚吡咯纳米片及其制备方法与应用
CN113230402B (zh) * 2021-05-20 2022-06-21 厦门大学 一种聚吡咯纳米片及其制备方法与应用
CN113984811A (zh) * 2021-12-29 2022-01-28 中国工程物理研究院流体物理研究所 表面微喷射颗粒相态演化的动态x射线衍射装置及方法
CN113984811B (zh) * 2021-12-29 2022-03-04 中国工程物理研究院流体物理研究所 表面微喷射颗粒相态演化的动态x射线衍射装置及方法

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