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WO2025221979A1 - Écriture laser à empreinte d'arc superposée pour la fabrication de micro-aiguilles creuses - Google Patents

Écriture laser à empreinte d'arc superposée pour la fabrication de micro-aiguilles creuses

Info

Publication number
WO2025221979A1
WO2025221979A1 PCT/US2025/025132 US2025025132W WO2025221979A1 WO 2025221979 A1 WO2025221979 A1 WO 2025221979A1 US 2025025132 W US2025025132 W US 2025025132W WO 2025221979 A1 WO2025221979 A1 WO 2025221979A1
Authority
WO
WIPO (PCT)
Prior art keywords
groove
closed path
laser
arc
forming
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/025132
Other languages
English (en)
Inventor
Sameer Sonkusale
Darian MYERS
Hasika SURESH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tufts University
Original Assignee
Tufts University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tufts University filed Critical Tufts University
Publication of WO2025221979A1 publication Critical patent/WO2025221979A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
    • B29C39/02—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C1/00—Manufacture or treatment of devices or systems in or on a substrate
    • 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
    • A61M2037/0053—Methods for producing microneedles

Definitions

  • methadone and buprenorphine are opioid agonists. They effectively reduce cravings for more potent and addictive drugs such as heroin and fentanyl. Nevertheless, they are not without their own side effects. Some of these are quite dangerous.
  • Naltrexone is a viable alternative to methadone. Instead of being an agonist, naltrexone is an opioid antagonist. Common methods of delivering naltrexone include oral capsules and tablets, intramuscular injections, and extended-release implants.
  • Oral capsules and tablets offer low bioavailability. Extended-release implants require invasive procedures for both implantation and removal.
  • Intramuscular injections avoid the foregoing disadvantages. However, they do involve injections. Since many patients fear needles, this mode tends to have a low patient compliance rate. To some extent, this difficulty can be overcome by reducing the size of the needle.
  • problems that arise in the manufacture of small needles include providing needles with sufficient mechanical strength and fracture resistance, providing a way to achieve convenient loading of a drug and controlled release of that drug, avoiding complexity in the manufacturing process, and avoiding an excessively costly production process.
  • the invention provides a method for manufacturing extremely fine needles for sustained and personalized drug delivery in a way that both provides meaningful doses and avoids implantation. Such needles are so fine that most patients would not realize that the needles are even present.
  • the needles provide a pathway for delivering a drug, such as naltrexone, using a transdermal delivery system. Because it bypasses the digestive system, transdermal delivery offers more consistent and sustained drug release, potentially leading to better control of cravings and reduced risk of relapse.
  • the microneedles are fine enough to offer a pain-free and convenient alternative to injections. This not only improves patient compliance but also reduces the stigma associated with traditional treatment methods.
  • a method for manufacturing the needles uses a commercial laser cutter to make molds for the needles by carrying out cross-over arc lithography. This enables scalable fabrication of microneedles with an embedded drug reservoir.
  • a method includes manufacturing a microneedle by carrying out a step that includes manufacturing a mold for the microneedle. This step is carried out by forming a groove in a substrate. This groove follows a closed path. The groove’s depth varies with position along the closed path.
  • Practices of the method include those in which forming the groove includes ablating the substrate along a first portion of the closed path and ablating the substrate along a second portion of the closed path, the second portion being shorter than the first portion, those in which forming the groove includes ablating the substrate along a first portion of the closed path and ablating a portion of the first portion of the substrate, those in which forming the groove includes ablating the substrate along a first arc of a circle defined by the path and ablating the substrate along a second arc of the circle, the second arc being shorter than the first arc, those in which forming the groove includes ablating the substrate along a first arc of a circle defined by the closed path and ablating a second arc of the circle, the second arc being a portion of the first arc, those in which forming the groove includes ablating the substrate along the closed path, wherein ablating the substrate includes varying an extent of the ablation while ablating the substrate along the closed path, those in which forming the groove includes
  • Still other practices include those in which the closed path defines a circle and wherein forming the groove includes using a laser to ablate the substrate along a first arc of a circle defined by the path and using the laser to ablate the substrate along a second arc of the circle, the second arc being shorter than the first arc and those in which the closed path includes a circle.
  • the closed path defines a circle and wherein forming the groove includes causing a laser to traverse the circle, thereby defining a first region, causing the laser to traverse a first arc along the circle, the first arc being less than the circle’s circumference, thereby defining a second region of the groove, and causing the laser to traverse a second arc along the close path, shorter than the first arc, thereby defining a third region of the groove.
  • the first region forms a base of the micro needle
  • the second region of the groove forms a shaft of the microneedle
  • the third region of the groove forms a tip of the microneedle
  • the second region is between the first region and the third region.
  • Still other practices include those in which manufacturing the mold includes manufacturing a mold for making the microneedle with a diameter of less than half a millimeter.
  • Other practices further include manufacturing a housing for holding a reservoir.
  • manufacturing the microneedle includes causing the microneedle to be integral with a base of the housing to enable a fluid to pass between the reservoir and a space outside the reservoir.
  • the microneedle is a first microneedle
  • the groove is a first groove
  • the closed path is a first closed path
  • the method further includes manufacturing a second microneedle, manufacturing a reservoir having first and second chambers, filling the first chamber with a first drug, and filling the second chamber with a second drug.
  • manufacturing the second microneedle comprises forming a second groove in the substrate, the second groove following a second closed path and having a depth that varies with position in along the second closed path.
  • the first chamber is in fluid communication with the first microneedle and wherein the second chamber is in fluid communication with the second microneedle.
  • the invention features an apparatus for manufacturing a microneedle.
  • Such an apparatus includes a laser, a beam steerer for causing a beam of the laser to illuminate different portions of a substrate, and a controller for causing the laser to form a groove in the substrate. This groove follows a closed path and has a depth that varies with position along the closed path.
  • microneedle As a relative term because “micro” is a relative term.
  • microneedle has acquired a distinct meaning in the art that a layperson may not be familiar with.
  • a microneedle is a very small needle that is used to painlessly and efficiently deliver drugs or vaccines through the skin.
  • microneedle is sufficiently known in the art so that any person who claims to not know what it is or who regards it as somehow being a relative term is very likely to be a person who is unfamiliar with the relevant art.
  • FIG. 1 shows a drug-delivery device
  • FIG. 2 shows an apparatus for making the microneedles shown in the device of FIG. 2;
  • FIG. 3 illustrates operation of the apparatus shown in FIG. 2;
  • FIG. 4 shows an array of microneedles manufactured using the operation shown in FIG.
  • FIG. 5 shows an alternative embodiment of the drug-delivery device for delivery of more than one drug.
  • FIG. 1 shows a drug-delivery device 10 having a reservoir 12 that holds a drug 14 that is to be delivered through microneedles 16 via action of a wireless pump 18.
  • the microneedles 16 are hollow needles that are integral with the reservoir 12.
  • Each microneedle 16 has an opening 20 through which the drug 14 passes out of the reservoir 12 and into the patient. This opening 20 has a diameter that is on the order of half a millimeter.
  • a microneedle 16 extends away from the reservoir’s base by about 1.2 millimeters to its distal tip,
  • the method described herein relies on molding.
  • the process for manufacturing the microneedle 16 thus begins with manufacturing a mold.
  • Suitable materials for the substrate 22 include common plastics and metals.
  • suitable plastics include acrylonitrile butadiene styrene and polymethyl methacrylate.
  • suitable metals include steel and copper.
  • the manufacturing process also requires a laser 24 that produces a beam 26.
  • the laser 24 is one that provides sufficient power to selectively ablate the substrate 22.
  • a suitable laser 24 is one in which the lasing material is carbon dioxide.
  • a suitable substrate 22 is one that comprises acrylic.
  • the manufacturing processes uses a beam steerer 28 for moving the laser’s beam 26 along a circular path 30 on the substrate 22, and control circuitry 32 for modulating various parameters as it traverses arcs 34 of the circular path 30. This results in engraving a path on the substrate.
  • the control circuitry 32 modulates one or more of: the beam’s velocity, the beam’s power, the number of laser pulses per unit distance, and the number of passes made over the circular path 30.
  • the control circuitry 32 modulates the beam’s focus. Control over the beam’s focus has been found to be particularly useful for controlling needle’s sharpness.
  • the circular path 30 defines an inner circle and an outer circle, the diameters of which define the inner and outer diameter of the microneedle’s inner and outer walls, respectively. The difference between them depends on the sharpness of the beam 22. As the beam 22 traverses this circular path 30, it ablates the substrate 22 at different angular positions.
  • ablation by the laser 24 forms a groove 36 that has a depth 38.
  • the depth 38 of this groove 36 at a particular angular position depends on the energy delivered to that angular position by the laser 24 over the course of the process. The more energy that the laser 24 delivers, the deeper the groove 36 will be at that position.
  • the control circuitry 32 and beam steerer 38 cooperate to modulate the beam’s velocity and its power output to carve out a circular groove 36 whose depth 38 is a function of angular position.
  • a circular groove 36 that represents a piecewise approximation of a beveled distal end 40.
  • FIG. 3 shows the process of manufacturing a groove 36 in which the depth 38 of the groove 36 is a step function of angular position.
  • the process includes ablating the circular path 30 along overlapping arcs 42, 44, 46 to form a groove 36 of suitable shape for molding a microneedle 16.
  • the first ablation step is that of ablating along a first arc 42 to form the base 48 of the microneedle 16. This first arc 42 spans the entire circumference of the circular path 30.
  • the process continues with ablating along the second arc 44 to form the shaft 50 of the needle.
  • This second arc 44 spans half of the circumference of the circular path 30.
  • the ablation process concludes with ablating along the third arc 56.
  • This third arc 46 is aligned with the second arc 44 to form the tip 52 of the microneedle 16.
  • the third arc 46 is the shortest of the three arcs 42, 44, 46 and spans half the arclength of the second arc 44.
  • This ablation process is carried out many times to form an array of grooves 36, which then results in an array of corresponding microneedles 16 as shown in FIG. 1.
  • the substrate 22 can now be considered as a mold 22.
  • a cleaning process follows the ablation process. Cleaning is carried out by placing the mold 22, with its array of grooves 36, into an ultrasonic bath to remove any debris remaining in the grooves 36. In most cases, three hours of ultrasonic cleaning yields acceptably clean grooves 36.
  • the next step is to create the mold’s replicate. This is done by casting polydimethylsiloxane with a 5:1 weight ratio of pre-polymer to curing agent on the substrate 22. The resulting casted block is then degassed in a vacuum desiccator using a vacuum pump and subsequently cured in a hot air oven at sixty degrees Celsius for six hours. This results in an array of microneedles 16, as shown in FIG. 4. Suitable materials for use in making microneedles 16 include biocompatible and ultraviolet curable resins.
  • the velocity of the laser’s beam 26, its power density, and its focus distance all cooperate to influence the hollow microneedle's length and its sharpness.
  • Hollow microneedles 16 fabricated using the method described herein are usable for broad spectrum drug delivery, including for delivery of small molecules and proteins. They are also useful for sampling and sensing applications, for example for biomarker sampling applications.
  • the microneedles 16 are suitable for delivery of insulin, peptides, and other small molecule compositions.
  • microneedles 16 are also usable for delivery of larger molecules such as DNA and proteins.
  • microneedles 16 are usable for sampling of interstitial fluid to enable for detection and quantification of a plethora of biomarkers.
  • Such microneedles 16, when used in conjunction with pumps, reservoirs, and actuators, permit both passive and active sampling and drug delivery. This versatility enables such microneedles 16 to play a central role in personalized medicine, offering painless treatment options and improved patient care.
  • the reservoir 12 has a single chamber that is loaded with a single drug 14.
  • An alternative embodiment, shown in FIG. 5, features a multi-chamber reservoir 12 having an annular first chamber 54 and a circular second chamber 56 that are loaded with first and second drugs 58, 60, respectively.
  • the first and second drugs 58, 60 comprise naltrexone and clonidine.
  • first needles 62 which are in fluid communication with the first chamber 54, deliver the first drug 58 and second needles 64, which are in fluid communication with the second chamber 56, deliver the second drug 60.
  • the parameters associated with drug delivery are controllable by making the first needles 62 and the second needles 64 have different geometries. For instance, if the first drug 58 is to be delivered at a slower rate than the second drug 60, the control circuitry 32 manufactures the first needles 62 with a smaller bore than the second needles 64.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Medical Informatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Dermatology (AREA)
  • Anesthesiology (AREA)
  • Manufacturing & Machinery (AREA)
  • Microelectronics & Electronic Packaging (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Pathology (AREA)
  • Molecular Biology (AREA)
  • Surgery (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

La fabrication d'une micro-aiguille comprend la formation d'une rainure dans un substrat. Cette rainure suit un trajet fermé et a une profondeur qui varie avec la position le long du trajet fermé. Le substrat rainuré ainsi obtenu est ensuite utilisé comme moule pour la micro-aiguille.
PCT/US2025/025132 2024-04-18 2025-04-17 Écriture laser à empreinte d'arc superposée pour la fabrication de micro-aiguilles creuses Pending WO2025221979A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463635762P 2024-04-18 2024-04-18
US63/635,762 2024-04-18

Publications (1)

Publication Number Publication Date
WO2025221979A1 true WO2025221979A1 (fr) 2025-10-23

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ID=97404246

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/025132 Pending WO2025221979A1 (fr) 2024-04-18 2025-04-17 Écriture laser à empreinte d'arc superposée pour la fabrication de micro-aiguilles creuses

Country Status (1)

Country Link
WO (1) WO2025221979A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060015061A1 (en) * 2004-07-16 2006-01-19 Shih-Chi Kuo Microneedle array device and its fabrication method
US20200060615A1 (en) * 2016-11-30 2020-02-27 The Regents Of The University Of California Microneedle Fabrication and Device Implantation
US20200238066A1 (en) * 2017-10-16 2020-07-30 Trustees Of Tufts College System and Method for Making Microneedles

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060015061A1 (en) * 2004-07-16 2006-01-19 Shih-Chi Kuo Microneedle array device and its fabrication method
US20200060615A1 (en) * 2016-11-30 2020-02-27 The Regents Of The University Of California Microneedle Fabrication and Device Implantation
US20200238066A1 (en) * 2017-10-16 2020-07-30 Trustees Of Tufts College System and Method for Making Microneedles

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