WO2019068136A1 - Dispositif et procédé d'utilisation d'un dispositif pour recevoir et/ou délivrer une substance in vivo - Google Patents

Dispositif et procédé d'utilisation d'un dispositif pour recevoir et/ou délivrer une substance in vivo Download PDF

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Publication number
WO2019068136A1
WO2019068136A1 PCT/AU2018/051033 AU2018051033W WO2019068136A1 WO 2019068136 A1 WO2019068136 A1 WO 2019068136A1 AU 2018051033 W AU2018051033 W AU 2018051033W WO 2019068136 A1 WO2019068136 A1 WO 2019068136A1
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WO
WIPO (PCT)
Prior art keywords
stimuli
membrane
responsive
opening
magnetic
Prior art date
Application number
PCT/AU2018/051033
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English (en)
Inventor
Gursel ALICI
Hao Zhou
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University Of Wollongong
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Publication date
Priority claimed from AU2017903980A external-priority patent/AU2017903980A0/en
Application filed by University Of Wollongong filed Critical University Of Wollongong
Publication of WO2019068136A1 publication Critical patent/WO2019068136A1/fr

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Classifications

    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/07—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of capsules or similar small containers for oral use
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of 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
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/00147—Holding or positioning arrangements
    • A61B1/00158—Holding or positioning arrangements using magnetic field
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B1/00—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor
    • A61B1/04—Instruments for performing medical examinations of the interior of cavities or tubes of the body by visual or photographical inspection, e.g. endoscopes; Illuminating arrangements therefor combined with photographic or television appliances
    • A61B1/041—Capsule endoscopes for imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/02—Instruments for taking cell samples or for biopsy
    • A61B10/0233—Pointed or sharp biopsy instruments
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0272—Electro-active or magneto-active materials

Definitions

  • the present invention relates to a device and a method for using a device to receive and/or deliver a substance in vivo.
  • a site-specific drug delivery device can be designed to carry and release a desired medication to the area of interest only in vivo, by which a planned payload of medication can be exclusively applied to the intended tissue(s) and/or organ(s) while causing minimal side effects to the surrounding tissue.
  • a planned payload of medication can be exclusively applied to the intended tissue(s) and/or organ(s) while causing minimal side effects to the surrounding tissue.
  • the InteliSiteTM capsule (Innovative Devices, Raleigh, US) is an FDA-approved radiofrequency (RF) activated, drug delivery device configured to carry a drug payload stored within a reservoir to a site specific location in the gastrointestinal tract in vivo.
  • RF radiofrequency
  • the InteliSiteTM capsule must be of a particular size (10 mm in diameter and 32 mm in length) to be able to carry the mechanical components associated with the spring loaded release mechanism as well as the drug payload. Such dimensions are not desirable for good patient compliance.
  • the InteliSiteTM capsule is solely reliant on the natural peristalsis within the gastrointestinal tract to move in vivo, and has no means by which to anchor the capsule at the drug delivery site in order to really be considered a true site specific drug delivery device.
  • the movement and control of such a capsule through a lumen such as the gastrointestinal tract (Gl tract) is very much at the mercy of the natural peristalsis associated with the intestinal tract.
  • Gl tract the gastrointestinal tract
  • the present invention seeks to provide a device and a method for using a device to receive and/or deliver a substance in vivo, which will overcome or substantially ameliorate at least some of the deficiencies of the prior art, or to at least provide an alternative.
  • a device including:
  • At least one stimuli-responsive membrane mounted to and substantially around an internal surface of the wall to define at least one chamber that is in fluid communication with the at least one opening and is configured to receive and/or deliver a substance via the at least one opening when an external stimulus is applied in proximity to the at least one stimuli-responsive membrane.
  • the at least one stimuli-responsive membrane includes a plurality of magnetic particles, and wherein the external stimulus is a magnetic field.
  • the plurality of magnetic particles is selected from the group consisting of particles of Fe, Co, Ni, and oxides thereof.
  • the concentration of magnetic particles within the at least one stimuli-responsive membrane falls within the range of about 60 wt. % to about 90 wt. %.
  • the concentration of magnetic particles within the at least one stimuli-responsive membrane falls within the range of about 70 wt. % to about 80 wt. %.
  • the at least one stimuli-responsive membrane includes a biocompatible polymer modified with said plurality of magnetic particles.
  • the biocompatible polymer is selected from the group of medical grade polymers consisting of silicone elastomer, polydimethylsiloxane (PDMS), polyethylene (PE), polypropylene (PP) and polyurethane (PU), or any combination thereof.
  • PDMS polydimethylsiloxane
  • PE polyethylene
  • PP polypropylene
  • PU polyurethane
  • the at least one stimuli-responsive membrane has a thickness that falls within the range of about 0.9 mm to about 1 .2 mm.
  • the at least one stimuli-responsive membrane has a thickness that falls within the range of about 1 .0 mm to about 1 .1 mm.
  • the at least one stimuli-responsive membrane has a diameter that falls within the range of about 1 1 .0 mm to about 12.5 mm.
  • the at least one stimuli-responsive membrane has a diameter that falls within the range of about 1 1 .5 mm to about 12.0 mm.
  • the body is manufactured from, or at least coated on an internal and external surface thereof with, a biocompatible material.
  • the biocompatible material is selected from the group biocompatible polymer consisting of polyethylene (PE), polyvinylchloride (PVC), polyether ether ketone (PEEK), polycarbonate, polyethyleneimine (PEI), polysulfone (PS), polypropylene (PP) and polyurethane (PU), or any combination thereof
  • the device further includes a hollow member operably connected to the at least one stimuli-responsive membrane and in fluid communication with the at least one chamber to enable the substance to be fluidly communicated from the at least one chamber to a site specific location in vivo via the at least one opening when the external stimulus is applied in proximity to the at least one stimuli-responsive membrane.
  • the at least one stimuli-responsive membrane includes at least two stimuli-responsive membranes mounted to and substantially around the internal surface of the wall in spaced apart arrangement to define the at least one chamber substantially therebetween, wherein, when mounted, a first of the at least two stimuli- responsive membranes is located substantially between a second of the at least two stimuli-responsive membranes and the at least one opening, and wherein the device further includes a hollow member operably connected to the first of the at least two stimuli-responsive membranes and in fluid communication with the at least one chamber to enable the substance to be fluidly communicated from the at least one chamber to a site specific location in vivo via the at least one opening when the external stimulus is applied in proximity to at least the second stimuli-responsive membrane.
  • the first stimuli-responsive membrane has a thickness that falls within the range of about 1 .0 mm to about 1 .1 mm.
  • the first stimuli-responsive membrane has a diameter that falls within the range of about 1 1 .5 mm to about 12 mm.
  • the second stimuli-responsive membrane has a thickness that falls within the range of about 0.65 mm to about 0.8 mm.
  • the second stimuli-responsive membrane has a diameter that falls within the range of about 7.5 mm to about 8.0 mm.
  • the device further includes a membrane mounted to and substantially around the internal surface of the wall in spaced apart arrangement to the at least one stimuli-responsive membrane to define the at least one chamber substantially therebetween, wherein the membrane is mounted between the at least one stimuli-responsive membrane and the at least one opening, and wherein the device further includes a hollow member operably connected to the membrane and in fluid communication with the at least one chamber to enable the substance to be fluidly communicated from the at least one chamber to a site specific location in vivo via the at least one opening when the external stimulus is applied in proximity to the at least one stimuli-responsive membrane.
  • the hollow member in response to an external stimulus being applied in proximity to or removed from the at least one stimuli-responsive membrane, is configured to transition, respectively, between an extended position, in which at least a tip of the hollow member protrudes from the at least one opening to enable a body tissue at the site specific location to be penetrated by the tip, and a retracted position, in which the tip is retracted substantially within the at least one opening or the internal volume of the hollow body.
  • the tip when in the delivery positon, is configured to protrude from the at least one opening by a distance that falls within a range of about 0.5 mm to about 1 .0 mm from an external surface of the body.
  • the hollow member is a needle.
  • the hollow member is a biopsy punch.
  • the body is shaped to promote locomotion of the device within a lumen in vivo.
  • the body is generally spherical in shape to allow the device to roll within the lumen.
  • the body includes a stimuli-responsive means to facilitate active locomotion of the device within a lumen in vivo in response to an external stimulus being applied in proximity to the stimuli-responsive means.
  • the stimuli-responsive means includes at least one magnet located at an external surface of the body and the external stimulus is a magnetic field.
  • the at least one magnet is located at a circumference of the body.
  • the at least one magnet is located distal to the at least one opening.
  • the stimuli-responsive means includes a plurality of magnets located at a circumference of the body in spaced apart arrangement.
  • the substance is selected from the group consisting of: a drug, a bioadhesive, a biomarker, a fluid, and a bodily fluid.
  • the body is a two-part construction including a first part and a second part, each part defined by a corresponding wall portion that is configured at an end portion thereof to allow the two parts to couple together to define the internal volume of the body.
  • the wall portion of at least one of the first and second parts of the two-part construction includes the at least one opening extending substantially therethrough.
  • the first and second parts of the two-part construction are generally hemispherical in shape.
  • the device further includes a non-return valve located at the at least one opening to control a flow of the substance into and/or out of the at least one chamber in response to an external stimulus being applied in proximity to or removed from the at least one stimuli-responsive membrane.
  • a non-return valve located at the at least one opening to control a flow of the substance into and/or out of the at least one chamber in response to an external stimulus being applied in proximity to or removed from the at least one stimuli-responsive membrane.
  • the device further includes a plug located at the at least one opening to temporarily seal the at least one chamber until the external stimulus is applied in proximity to the at least one stimuli-responsive membrane.
  • a method for the delivery or removal of a substance to a site specific location in vivo including:
  • FIG. 1 shows a schematic representation of a magnetically controlled spherical drug delivery device according to a first embodiment of the present invention
  • Fig. 2 shows a schematic cross-sectional representation of a magnetically controlled spherical drug delivery device configured with a single chamber and a magnetically-responsive membrane according to a second embodiment of the present invention
  • FIG. 3 shows a schematic cross-sectional representation of a magnetically controlled spherical drug delivery device configured with a single chamber defined by two magnetically-responsive membranes according to a third embodiment of the present invention
  • Fig. 4 shows a schematic cross-sectional representation of a part of the magnetically controlled spherical drug delivery device of Fig. 3, illustrating a range of movement (mm) of a needle when the magnetically-responsive membranes are stimulated by an external magnetic field;
  • FIG. 5 shows a schematic cross-sectional representation of a magnetically controlled spherical drug delivery device configured with two chambers, each defined by two magnetically-responsive membranes according to a fourth embodiment of the present invention
  • Fig. 6 shows plots of attraction force (imN) versus magnetic flux (imT) to illustrate the attraction measurements for five (5) magnetically modified polymer membranes of different thicknesses (mm) that have an equal diameter of: (a) 12 mm, and (b) 8 mm;
  • Fig. 7 shows plots of deflection (mm) versus magnetic flux (imT) to illustrate the deflection measurements for magnetically modified polymer membranes of (a) 8 mm diameter and 0.8 mm thickness, and (b) 12 mm diameter and thicknesses of 0.65 mm, 0.8 mm and 1 .1 .mm;
  • Fig. 8 shows a plot of attraction force (imN) versus magnetic flux (imT) to illustrate the attraction measurements for two magnetically modified polymer membranes that have the same diameter of 12 mm and thickness (0.6 mm) but different concentrations of iron particles;
  • Fig. 9 shows a plot of deflection (mm) versus magnetic flux (imT) to illustrate the deflection measurements for two (2) magnetically modified polymer membranes that have the same diameter of 12 mm and thickness (0.6 mm) but different concentrations of iron particles;
  • FIG. 10 shows a schematic representation of a magnetically controlled spherical drug delivery device according to any one of the preferred embodiments of Figs. 1 to 3 and 5 caused to undergo active locomotion within a lumen by rolling (clockwise) in the X-direction when stimulated by an external magnet (rotating anticlockwise) linearly translated in the same X-direction.
  • the present invention is predicated on the finding of a device 10 that is configured to receive and/or deliver a substance at a site specific location in vivo in response to an external stimulus being applied in proximity to at least one stimuli- responsive membrane mounted within the device 10. Moreover, the device 10 is further configured for active locomotion through the gastrointestinal tract to the site specific location as well as for active anchoring at the site specific location, thereby realising a true site-specific drug delivery means.
  • the device 10, and its variants 10A, 10B according to the preferred embodiments of the present invention described herein are to be used for application in vivo as part of a strategy that involves a patient firstly swallowing a capsule equipped with imaging capability in order to identify the site specific location in vivo, and to anchor itself at the site while sending real-time video to an operator.
  • the operator is able to actively orient and guide the device 10, 10A, 10B to the site specific location in real time, and once there, activate the anchoring mechanism to anchor the device 10, 10A, 10B at the desired location.
  • the operator is then able to apply the external stimulus to the stimuli-responsive membrane mounted within the device 10, 10A, 10B to either receive a substance such as a biopsy sample from the site specific location, or site specifically delivery a substance such as a drug to the site specific location.
  • FIG. 1 shows a schematic representation of a magnetically controlled device 10 according to a first preferred embodiment of the present invention.
  • the device 10 includes a generally spherical hollow body 20 that is a two- part construction including a first hemispherical part 22 and a second hemispherical part 24.
  • Each hemispherical part 22, 24 is defined by a corresponding wall portion 25 that is configured at an end portion thereof (not shown) with complementary coupling means to allow the two parts 22, 24 to be coupled together to form a water- and airtight seal, as well as define an internal volume of the body 20.
  • the wall 25 comprises an opening 30 that extends substantially through the wall 25 from an internal surface 26 of the wall 25 to an external surface 27 thereof to facilitate access to the internal volume of the body 20 when the two parts 22, 24 are coupled together.
  • the two parts 22, 24 of the body 20 are ideally manufactured from a biocompatible material, or at least coated with a biocompatible material to ensure the device 10 meets the necessary safety requirements for in-vivo applications.
  • the two parts 22, 24 of the body 20 of the device 10 are manufactured from a biocompatible polymer such as medical grade polyethylene (PE), polyvinylchloride (PVC), polyether ether ketone (PEEK), polycarbonate, polyethyleneimine (PEI), polysulfone (PS), polypropylene (PP) and polyurethane (PU), or indeed any suitable combination thereof.
  • a biocompatible polymer such as medical grade polyethylene (PE), polyvinylchloride (PVC), polyether ether ketone (PEEK), polycarbonate, polyethyleneimine (PEI), polysulfone (PS), polypropylene (PP) and polyurethane (PU), or indeed any suitable combination thereof.
  • PE polyethylene
  • PVC polyvinylchloride
  • PEEK polyether ether ketone
  • PES polycarbonate
  • PEI polyethyleneimine
  • PS polysulfone
  • PP polypropylene
  • PU polyurethane
  • the two parts 22, 24 of the body 20 may simply be manufactured from a material that is then coated with a biocompatible material such that the external surface 27 of the device 10 is biocompatible.
  • the two parts 22, 24 of the body 20 are manufactured from medical grade polymer, where the surface of the polymer is then treated with a long chain alkyl or oligo(ethylene glycol) ligand suitably functionalised at one of the terminal ends thereof to form a covalent linkage with the hydroxyl groups on the surface of the polymer to produce a self-assembled monolayer (SAM) of the ligand around the body 20 of the device 10.
  • SAM self-assembled monolayer
  • Such ligands may include but are not limited to: a trialkoxy(alkyl)silane such as triethoxy(ethyl)silane or trimethoxy(methyl)silane, or a trialkoxy(oligo(ethylene glycol)silane to PEGylate the surface of the polymer to render it biocompatible.
  • a trialkoxy(alkyl)silane such as triethoxy(ethyl)silane or trimethoxy(methyl)silane
  • oligo(ethylene glycol)silane to PEGylate the surface of the polymer to render it biocompatible.
  • the device 10 has the ability to roll in any direction. This is a particularly important consideration when the device 10 is to be used in a confined space in vivo, such as in a lumen like the gastrointestinal tract (hereinafter referred to as the Gl tract), where the ability to roll along the lumen provides a number of benefits.
  • Gl tract the gastrointestinal tract
  • a sphere since the diameter of an intestinal lumen is not uniform, on account of the curved and deflated structure, and the possibility of polyps/tumours that may be positioned on such an irregular surface, a sphere has an inherent lower risk of being caught and/or retained within the folded tissues of the lumen than say the cylindrical shape of a conventional endoscope device (assuming the length of the cylinder is much larger than its diameter). Similarly, a sphere would also have a better turning radius in vivo than a cylinder, and would be subject to less friction due to there being less surface contact with the wall of the lumen.
  • Size is another major practical consideration when designing a device 10 for in vivo applications. Since the device 10 described herein is proposed to be administrated via the oral route, it needs to be swallowable. However, while a small device 10 will make swallowing easier, the internal volume of such a small device 10 will reduce the amount of payload that can be used. Indeed, if the payload is a drug, then the device 10 needs to be of a particular size to ensure that the correct dosage of the drug payload can be received within the device 10 and delivered at the site specific location. Therefore, the size of the device 10 is a trade-off between these two factors.
  • the inventors have looked to the size of conventional capsule endoscopes, which falls within the range of 1 1 mm to 13 mm in diameter, as a practical range to adopt for the diameter of the device 10 of the various embodiments described herein.
  • the external diameter of the device 10 is preferably set as 13 mm to ease swallowing.
  • the device 10 has been manufactured using 3D printing.
  • the wall 25 of the body 20 has been printed with a thickness of 0.5 mm. Given these dimensions, the internal diameter of the spherical device 10 is 12 mm at the centre.
  • the body 20 includes a stimuli-responsive means by which to enable active locomotion and orientation of the spherical device 10 in vivo.
  • the stimuli-responsive means is provided in the form of a permanent ring magnet 90 that is located at the external surface 27 of the body 20 around the circumference of the device 10, with north and south poles labelled (N)orth and (S)outh, respectively.
  • the external wall 25 of the body 20 has been formed with a groove that extends substantially around the circumference at the external surface 27 of the body 20.
  • each part 22, 24 of the body 20 is hemispherical in shape, each part 22, 24 is shaped at their respective end portion (not shown) accordingly to provide the groove once the two parts 22, 24 are coupled together.
  • the as-formed groove has a depth that corresponds to the same dimension of the ring magnet 90 such that when the ring magnet 90 is embedded within the groove, the ring magnet 90 is flush with the external surface 27 of the body 20 to ensure a continuous surface to reduce friction in vivo.
  • the ring magnet 90 is positioned at the circumference of the spherical device 10, the ring magnet 90 is substantially orthogonal to, and sufficiently distanced from the opening 30 to ensure that in the presence of an external magnetic field, it becomes possible to selectively orient the spherical device 10 in vivo.
  • Another key feature for the various configurations of the device 10 described in the following embodiments of the present invention is the use of one or membranes mounted within the internal volume of the device 10 that have been modified with a plurality of magnetic particles to render the membrane(s) susceptible to deflection when the device 10 is placed inside an external magnetic field.
  • the resultant stimuli-responsive membrane is able to change its shape in response to an external magnetic field, thereby rendering it suitable for use as an actuator.
  • the ability to cause the magnetic membrane to deflect in vivo in a controllable manner provides a convenient means by which to control the flow of a substance to and/or from a reservoir or chamber defined within the internal volume of the device 10.
  • the controlled deflection of the magnetic membrane provides a means by which to make the process of drug delivery controllable in vivo.
  • a magnetic membrane as an actuator in this way is particularly advantageous, as unlike conventional devices which rely on an on-board micro-motor and battery or inductive coil to establish locomotion and/or delivery of a drug payload in vivo, this stimuli-responsive membrane actuator takes up very little space within the internal volume of the device 10, thereby enabling a greater payload to be transported and delivered in vivo without compromising the size of the overall device 10. Moreover, a magnetic membrane that can be actuated in response to an external magnetic field means that there is little risk of losing power for operation as would be the case for conventional devices.
  • the degree of deflection of this magnetic membrane in response to an external magnetic field will largely be dependent on several factors, including but not limited to, the choice of polymer, the thickness of the membrane, the concentration of magnetic particles used in the membrane, as well as the strength of the external magnetic field used to list but a few. To this end, it has been necessary to fine tune these parameters in order to identify conditions, whereby the deflection of the magnetic membrane is sufficient to ensure the maximum amount of a particular payload within the chamber can be delivered to a site specific location in vivo, or conversely, that a sufficient volume of a particular sample such as a bodily fluid can be collected from the site specific location and received within the chamber.
  • polymer With regards to the choice of polymer, it will be widely appreciated by those persons skilled in the relevant art that a range of polymers may be suited to this particular application. A good candidate needs to be flexible enough to acquire sufficient deflection while its rigidity needs to be high enough to support its own weight.
  • the polymer must also be biocompatible to ensure it meets the necessary criteria for use in vivo.
  • the biocompatible polymer is ideally selected from the group of medical grade polymers consisting of silicone elastomers, polydimethylsiloxane (PDMS), polyethylene (PE), polypropylene (PP) and polyurethane (PU), or any suitable combination thereof.
  • membranes produced from a combination of silicone rubber and silicone oil having a thickness that falls within a range of about 0.65 mm to about 1 .1 mm have the desired rigidity and flexibility to undergo a high degree of deflection.
  • magnetic particles are typically formed from one or more of the following, iron (Fe), cobalt (Co) and nickel (Ni). More often than not, the magnetic particles are prepared from the magnetic iron oxides, such as magnetite (Fe.3G 4 ), gamma ferric oxide (Fe Qa) and magnetic ferrites, but carbonyl iron (Fe(COs)) can also be used. These magnetic particles are available in finely divided form, having particle sizes generally between about 0.2 microns and 44 microns in maximum dimension. Carbony! iron, specifically, is obtainable in spherical particle form of about 1 micron to about 5 microns in diameter.
  • membranes comprising a dispersion of magnetic particles with a concentration of about 70 wt. % to about 80 wt. % exhibit a desirable deflection when exposed to an externally applied magnetic field.
  • a stimuli- responsive membrane with excellent magnetic properties can be produced using a combination of a silicon elastomer such as silicone rubber and silicone oil in a 1 :1 ratio that is then mixed with a plurality of carbonyl iron particles in a concentration of 70 wt. % of the polymer to, once cured, obtain a magnetic membrane with a plurality of well dispersed particles throughout.
  • the spherical device 10 may be configured in any one of a number of ways to fulfil a host of different roles. What follows, is a description of preferred embodiments of the present invention in which the spherical device 10 has been configured to suit a particular role.
  • the spherical device 10 has been configured with a single magnetic membrane 40 mounted within the internal volume to define a chamber 60 that is in fluid communication with the opening 30.
  • the magnetic membrane 40 is affixed substantially around its periphery to the internal surface 26 of the wall 25 using a suitable adhesive or sealant to establish a water- and air-tight seal between the periphery of the magnetic membrane 40 and the internal surface 26 to which it is adhered.
  • the chamber 60 is thus configured to receive and/or deliver a substance via the opening 30 of the device 10 when an external magnetic field is applied in proximity thereto to cause the magnetic membrane 40 to deflect in a corresponding direction.
  • a permanent magnet (not shown) is applied in proximity to the device 10 at a position directly below the opening 30, the external magnetic field generated by the permanent magnet has a nonuniform magnetic gradient that translates into a non-zero net force that attracts the magnetic particles within the magnetic membrane 40 causing the magnetic membrane 40 to deflect in the direction towards the opening 30, as represented by arrow H-i . This deflection reduces the size of the chamber 60 causing any substance within the chamber 60 to be forced out through the opening 30.
  • the magnetic particles within the magnetic membrane 40 are attracted towards the permanent magnet as a result of the non-zero net force produced by the non-uniform magnetic gradient, thereby causing the magnetic membrane 40 to deflect away from the opening 30 in the direction of arrow H 2 .
  • the deflection increases the size of the chamber 60 thereby causing any substance located outside of the device 10 to be drawn into the chamber 60 through the opening 30 for the purpose of acting as a biopsy device that can be expelled from the body of the subject once a sample of the substance has been taken for subsequent analysis ex vivo.
  • the substance to be received, transported and delivered to a site specific location in vivo is a drug, or a suitable, pharmaceutically acceptable solution thereof.
  • the drug may be labelled with a suitable biomarker such as a fluorescent dye or fluorescent particle(s) or a radio marker, as required.
  • the substance may take another form.
  • the substance may take the form of a bioadhesive to be delivered to a site specific location in vivo.
  • the bioadhesive may be selectively delivered by itself, or in combination with another substance such as a drug that can then be selectively adhering to a body tissue at the site specific location via the bioadhesive.
  • Suitable bioadhesive materials may be selected from a range of bioadhesive polymers including but not limited to, cellulosed based compounds such as carboxy methyl cellulose, hydroxy ethyl cellulose, polyacrylic acid based polymers such as those sold under the commercial trade name, CarbopolTM and PolycabophilTM, as well as other compounds such as gelatin, sodium alginate and the like.
  • the substance may take the form of a bodily fluid that when the permanent magnet is applied in proximity to the opposite side of the device 10, the magnetic membrane 40 is caused to deflect in the direction of arrow H 2 , as shown in Fig. 2, thereby creating at least a partial vacuum in the chamber 60 that draws the bodily fluid into the chamber 60 through the opening 30.
  • the device 10 further includes a plug 70 located at the opening 30 to temporarily seal the chamber 60 until such time as it is necessary to apply an external magnetic stimulus to the stimuli-responsive magnetic membrane 40.
  • plug 70 it is possible to preclude inadvertent diffusion and/or convection of a substance carried within the chamber 60 occurring through the opening 30 before reaching the site specific location in vivo.
  • the plug 70 ensures that when the device 10 is being used to deliver a drug payload to a site specific location in vivo, the drug is not contaminated in transit.
  • the plug 70 For the plug 70 to be an effective temporary sealing measure, it must be able to remain in place within the opening 30 in transit, but then be easily displaced from the opening 30 in response to a displacement force caused by the deflection of the magnetic membrane 40 when an external magnetic field is applied.
  • the plug 70 is a biocompatible oil that does not mix with the substance to be carried within the chamber 60, or mix with a bodily fluid that the device 10 may become exposed to during transit to the site specific location in vivo such as, for example, the gastro-intestinal fluid. Similarly, the oil should not break down in vivo to produce by-products that would be toxic to the subject.
  • suitable oils may include but are not limited to: a mineral oil or castor oil.
  • FIGs. 3 and 4 show schematic representations of a spherical device 10A configured according to another preferred embodiment of the present invention.
  • FIG. 3 shows a cross-sectional schematic representation of the spherical device 10A in which the internal volume has been configured with two magnetic membranes 40, 50 mounted within the internal volume in a vertically spaced apart arrangement to define a chamber 65 substantially therebetween.
  • the magnetic membranes 40, 50 are affixed substantially around their respective peripheries to the internal surface 26 of the wall 25 using a suitable adhesive or sealant to establish a water- and air-tight seal.
  • the device 10A further includes a hollow member in the form of a needle 80 that is operably connected to the smaller magnetic membrane 50.
  • a needle 80 that is operably connected to the smaller magnetic membrane 50.
  • the needle 80 is pushed down through the second magnetic membrane 50 in the direction of the opening 30, such that a flange portion located distal to a tip of the needle 80 can be adhered to an inner surface of the magnetic membrane 50, thereby precluding the needle 80 from passing straight through the second magnetic membrane 50.
  • the needle 80 is securely mounted to the magnetic membrane 50 and importantly, it is in fluid communication with the chamber 65.
  • the first magnetic membrane 40 is then adhered to the internal surface 26 of part 24 of the body 20 and then the two parts 22, 24 are then coupled together to complete the construction of the spherical device 10A. It will be appreciated by those skilled in the relevant art, however, that in an alternative construction method, the first magnetic membrane 40 is already adhered to the other part 22 of the body 20 such that the two parts 22, 24 can simply be coupled together to the complete the construction of the spherical device 10A.
  • the needle 80 is mounted generally at the centre of the magnetic membrane 50 so that the tip of the needle 80 is substantially aligned with the opening 30.
  • the gauge of the needle 80 is selected to conform as closely to the internal diameter of the opening 30 to ensure that the tip of the needle 80 can extend through the opening 30 without hindrance.
  • Fig. 4 shows a schematic cross-sectional representation of one part 24 of the spherical drug delivery device 10A.
  • the thickness (w) of the wall 25 of the body 20 is selected as 0.5 mm so that the internal diameter of the spherical device 10 is 12 mm.
  • the distance (z) by which the tip of the needle 80 is allowed to protrude through the opening 30 and beyond the external surface 27 of the spherical device 10A should be no more than 1 mm to avoid the risk of tissue perforation.
  • the second magnetic membrane 50 is required to have a maximum deflection (y) of 1 mm, which means that the second magnetic membrane 50 must be fixed to the internal surface 26 of the wall 25 at a distance that is 1 mm from the opening 30.
  • the second magnetic membrane 50 is required to have a diameter of 8 mm. Since the first magnetic membrane 40 is affixed to the internal surface 26 of the wall 25 at the centre of the body 20, the first magnetic membrane 40 will have the same diameter (12 mm) as the internal diameter of the spherical device 10A. To ensure a minimum drug payload of 0.3 ml, the two magnetic membranes 40, 50 should each have a thickness of no more than 1 mm.
  • the deflection of the second magnetic membrane 50 causes the needle 80 to transition from a retracted position, in which the tip of the needle 80 is located substantially within the opening 30 or even a little further back inside the internal volume of the body 20, to an extended position, in which the tip of the needle 80 extends through and protrudes out from an end of the opening 30 such that the tip extends outwardly beyond the external surface 27 of the body 20 of the spherical device 10A, where it can then penetrate a body tissue at a site specific location in vivo and deliver by injection the substance fluidly communicated from the chamber 65 via the needle 80.
  • the needle 80 is caused to transition from the extended position back to the retracted position such that the tip of the needle 80 is back inside the opening 30 or at least back within the internal volume of the body 20.
  • the drug payload is designed to be expelled from the chamber 65 by the first magnetic membrane 40 when the first magnetic membrane 40 is caused to deflect in the presence of an external magnetic field.
  • the first magnetic membrane 40 should be deflected to take up all the space of the chamber 65 so that the entire drug payload can be expelled from the chamber 65 when a full dosage is needed.
  • the minimum deflection (x) of the first magnetic membrane 40 is required to be 4.5 mm.
  • the other requirement is the magnetic force, which can be calculated based on the injection pressure.
  • the required injection pressure can be found by solving Poiseuille's equation (1 ), expressed as follows: [01 12] Q - AP ⁇ 4 (1 )
  • the needle 80 chosen for use in the spherical device 10A has a diameter of 0.337 mm and a length of 2 mm.
  • the viscosity of the drug is assumed to be 0.705 x 10 "3 Pa»s, based on the viscosity of water at 36 °C.
  • the pressure drop is calculated to be 27.8 Pa.
  • the interstitial hydrostatic pressure of normal submucosal tissue is taken to be negative, which means that the required injection pressure is smaller than 27.8 Pa and possibly even negative.
  • the interstitial pressure at a depth of 1 mm inside a tumour is taken to be approximately 1333 Pa.
  • the required injection pressure can be calculated by adding together the interstitial pressure and the calculated pressure drop, which equals 1360.8 Pa.
  • the first factor is the delivered force and the second factor is the degree of deflection of the magnetic membranes 40, 50 within an external magnetic field. These factors will directly affect how much drug payload can be ejected out of the chamber 65 by the magnetic membranes 40, 50, which is essential to evaluate the performance of the spherical device 10A for this particular application. Attraction Force Tests
  • the magnetic force strongly depends on the distance between the permanent magnet (PM) and the magnetic membrane sample. For instance, as the magnetic membrane sample deforms due to the attraction force, part of the magnetic membrane is drawn closer to the permanent magnet, which leads to an increase in the magnetic force for further deflection. For this reason, the magnetic force is strongest when the magnetic membrane sample is at full deflection, and weakest at the point before the magnetic membrane sample begins to deform. To ensure that each of the two magnetic membranes 40, 50 has the capability to act as an actuator to perform its respective function, the weakest magnetic force measurements are used as the baseline for each membrane.
  • FIG. 6 shows the attraction measurements taken for the magnetic membrane samples having a diameter of 12 mm (see Fig. 6(a)) and 8 mm (see Fig. 6(b)).
  • the thickness of the magnetic membrane sample (of diameter of 12 mm) would need to be 1 .1 mm to have a magnetic force more than the required amount: 154 imN when the local magnetic field is 250 mT. All the magnetic membrane samples tested in these two sets have a concentration of iron particles of 70 wt. %.
  • the thickness of the magnetic membrane sample (of diameter 8 mm) would need to be at least 0.8 mm when the external magnetic field is 250 mT, in order to achieve a minimum puncturing force of 50 mN for the tip of a needle 80 to enter the intestinal tissue in the Gl tract.
  • a magnetic membrane with a diameter of 12 mm is designed as the actuator to eject the drug payload.
  • the inventors conducted a series of tests on a set of magnetic membrane samples with diameters of either 12 mm or 8 mm, and a thickness ranging between 0.65 mm and 1 .1 mm.
  • Each magnetic membrane sample was affixed onto a linear stage (not shown), and then a permanent magnet was mounted above the magnetic membrane sample at a distance that could be adjusted.
  • the magnetic membrane samples were moved successively closer to the permanent magnet and the amount of deflection was measured using a laser displacement sensor (not shown). The inventors observed that the magnitude of deflection for each magnetic membrane sample is affected by the distance between the sample and the permanent magnet, and that this determines the magnetic force exerted on the magnetic membrane samples.
  • Fig. 7(a) shows the results of the deflection tests conducted for the magnetic membrane sample with a diameter of 8 mm, a thickness of 0.8 mm and a 70 wt. % concentration of iron particles.
  • the magnetic membrane sample experiences a greater deflection.
  • the local magnetic flux density needs to be at least 250 mT for such a magnetic membrane sample to achieve the required puncturing force.
  • the deflection is approximately 3.7 mm, which is much more than the required stroke of 1 mm for extending the tip of the needle 80 through the opening 30.
  • Fig. 7(b) shows the deflection measurements of the magnetic membrane samples with a diameter of 12 mm, but different thickness (0.65 mm, 0.8 mm and 1 .1 mm).
  • the magnetic membrane sample with the thinnest thickness (0.65 mm) experiences the greatest deflection when the magnetic field intensity is relatively low.
  • the magnetic membrane sample with the greatest thickness (1 .1 . mm) shows greater increments in deflection.
  • the deflection observed for the thickest magnetic membrane sample of the study becomes larger than the deflection observed for the thinnest magnetic membrane sample (0.65 mm).
  • the required stroke (x) for the first magnetic membrane 40 (of 12 mm diameter) would need to be 4 mm.
  • the first magnetic membrane 40 when the magnetic flux density is over 140 mT, the first magnetic membrane 40 would need to have a thickness of 1 .1 mm in order to achieve a deflection of 4 mm and thus meet the requirement needed for actuation purposes in the drug delivery application.
  • Fig. 8 shows the attraction measurements taken for two magnetic membrane samples of the same diameter (12 mm) and thickness (0.6 mm), but with two different concentrations of iron particles (70 wt. % and 80 wt.%).
  • the magnetic membrane sample with a concentration of 80 wt. % iron particles exhibits a greater attraction force under the same external magnetic field. It is also observed that as the magnetic field intensity becomes larger, the difference between the attraction forces for the two magnetic membrane samples increases concomitantly.
  • Fig. 9 shows the results of the deflection tests conducted for the same two magnetic membrane samples of diameter (12 mm) and thickness (0.6 mm), but with two different concentrations of iron particles (70 wt.% and 80 wt.%).
  • the magnetic membrane sample with the higher iron concentration (80 wt. %) exhibits a greater deflection when the magnetic field intensity is within a relatively low range and a relatively high range, but not within the mid-range.
  • This result indicates that the magnetic force does not increase enough to compensate for the increased elastic modulus for deformation, within that range of magnetic field intensity.
  • the increased concentration of iron particles causes the elastic modulus of the magnetic membrane to increase, thereby making it harder to deform the magnetic membrane.
  • the inventors have found that for the spherical device 10A having a chamber 65 defined by the two magnetic membranes 40, 50, good results can be obtained when the first magnetic membrane 40 has a diameter of 12 mm and a thickness of 1 .1 mm and the second magnetic membrane 50 has a diameter of 8 mm and a thickness of 0.8 mm, and that each magnetic membrane 40, 50 has a concentration of 70 wt. % iron particles. These dimensions were found to be effective for receiving and subsequently delivering a minimum drug payload of 0.3 ml.
  • FIG. 5 shows a schematic cross-sectional representation of a spherical device 10B configured according to another preferred embodiment of the present invention.
  • the spherical device 10B has been configured with an additional opening 35 that extends through the wall 25 of the body 20, and two chambers 65a, 65b, each chamber being defined by a corresponding pair of magnetically-responsive membranes 40, 50 and 45, 55, respectively.
  • the additional opening 35 is located distal to the first opening 30 and is configured to receive a tip of a second needle 85 that is mounted to the magnetic membrane 55 in the same manner described above in respect of the device 10 configured with a single chamber 65, and as shown in Figs. 3 and 4.
  • the two chambers 65a, 65b are substantially isolated from each other such that it is possible for each chamber 65a, 65b of the spherical device 10B to receive the same drug payload or a different drug payload as required.
  • each chamber 65a, 65b is the same, then it would be possible to deliver a double dose of the drug payload to the site specific location in vivo, or deliver one dose at one location and the second dose at a separate location.
  • Locomotion tests were conducted inside a sample of porcine small intestine 80 to investigate the performance in controlling both movement and orientation of the spherical device 10 for use in in vivo applications.
  • the spherical device 10 was first inserted inside the intestine sample 80 and the pre-loaded intestine sample 80 was then mounted onto a plastic or glass platform (not shown). Located beneath the platform is a DC motor 100 that is mounted on to a motorised linear stage (not shown) to allow the DC motor 100 to be linearly translated relative to the platform above in an X- direction.
  • the DC motor 100 is configured with a spindle (not shown) upon which is mounted a permanent magnet 1 10 that is caused to rotate when power is applied to the DC motor 100.
  • the inventors then conducted a second test whereby power was applied to the DC motor 100 shown in the schematic representation in Fig. 10(i) to cause the external permanent magnet 1 10 to rotate about rotational axis 1 15 in an anticlockwise manner.
  • the DC motor 100 was then linearly translated in the X-direction while the external permanent magnet 1 10 was rotating, such that the magnetic attraction between the ring magnet 90 and the external permanent magnet 1 10 caused the spherical device 10 to roll in a clockwise manner within the intestine sample 80 in the same X-direction.
  • the anticlockwise rotating external permanent magnet 1 10 can be linearly translated along the X-direction until the clockwise rolling spherical device 10 reaches the site specific location in vivo.
  • the inventors found that the spherical device 10 could move more freely within the intestine sample 80 on account of the reduced friction.
  • the method includes, according to a first step, the step of preloading the chamber 65 of the spherical device 10A (see Fig. 3) with a suitable substance such as a drug, and then providing the pre-loaded spherical device 10A to a subject to swallow.
  • the preloaded spherical device 10A can be tracked by any one of a number of suitable tracking methods.
  • the preloaded spherical device 10A can be modified with a suitable biomarker such as a fluorescent dye or fluorescent particles, or even using a radio- labelled marker that can be tracked using suitable equipment.
  • an external magnetic field is applied in proximity to the site specific location using an electromagnet to cause the second magnetic membrane 50 of the spherical device 10A to deflect in the direction of the opening 30, thereby causing the tip of the needle 80 to extend through the opening 30 to penetrate a body tissue at the site specific location and the first magnetic membrane 40 is caused to deflect in the same direction thereby causing the drug to be expelled from the chamber 65 where it is then fluidly communicated by injection through the needle 80 into the body tissue of the subject at the site specific location .
  • the external magnetic field is then removed, causing the second magnetic membrane 50 to be released from its magnetic attraction to the external magnetic field and subsequently the tip of the needle 80 to be withdrawn from the body tissue and retracted back into the internal volume of the body 20 of the spherical device 10A.
  • the inventors devised an experiment whereby a sample of porcine small intestine 80 was first mounted to a plastic or glass platform (not shown). Located beneath the platform is an electromagnet (not shown). The inventors then pre-loaded the chamber 65 of the spherical device 10A with coloured water and mounted the pre-loaded spherical device 10A to a holder (not shown) such that the pre-loaded spherical device 10A was positioned directly above the intestine sample 80 with the opening 30 being located substantially against the surface of the intestine sample 80.
  • the inventors observed that the magnetic attraction between the second magnetic membrane 50 of the pre-loaded spherical device 10A and the electromagnet caused the second magnetic membrane 50 to deflect towards the electromagnet by the required 1 mm. This caused the tip of the needle 80 to extend and protrude through the opening 30 by the required 1 mm from the external surface 27 of the spherical device 10A, causing it to penetrate the intestine sample 80.
  • the first magnetic membrane 40 was also magnetically attracted by the external magnetic field, which caused the first magnetic membrane 40 to deflect in the direction of the electromagnet by the required 4 mm. The deflection caused the coloured water to be expelled from the chamber 65 and fluidly communicated through the needle 80 into the intestine sample 80.
  • the ring magnet 90 must be configured to respond to an external magnetic field that is lower than the threshold value required to cause deflection of the magnetic membrane(s) 40, 50 to prevent an inadvertent triggering of the drug delivery mechanism during the active locomotion stage.
  • the two hemispherical parts 22, 24 of the body 20 of the device 10, 10A, 10B were fabricated using a 3D printer (3D Printing Systems, Model: UP Plus 2) equipped with a PVC or PE filament as desired.
  • the thickness of the wall 25 of the 3D printed shell was 0.5 mm, which results in an overall diameter of 13 mm.
  • the end portion of each of the two parts 22, 24 was printed with a complementary thread or snap-fit arrangement to enable the two parts 22, 24 to be coupled together.
  • the end portion of each of the two parts 22, 24 was also printed with an external groove, such that when the two parts 22, 24 are coupled together, the two grooves combine to provide a single groove around the external circumference of the body 20 to which a ring magnet 90 can be mounted.
  • the materials employed in this work were silicone rubber (type clear silicone sealant, Selleys Pty. Ltd), silicone oil (type 378364, Sigma-Aldrich Pty. Ltd), and carbonyl iron particles (type C3518, Sigma- Aldrich Pty. Ltd.).
  • silicone rubber 15 wt. %), silicone oil (15 wt. %), and iron particles (70 wt. %) were mixed together and stirred in a beaker for two hours at room temperature to obtain a good dispersion of particles within the polymer. After they were fully mixed, the resulting polymer mixture was placed under a vacuum (pressure at -450 mm Hg) to remove any air bubbles.
  • the final mixture was then poured between a pair of flat vertically spaced apart plates (Teflon) separated by a gap, the distance of which is adjusted using a micrometer according to the desired thickness of the cured magnetic membrane 40.
  • the polymer mixture was then cured in this configuration at room temperature for 48 hours. After curing, the resultant magnetic membrane could be cut to any size according to the internal dimensions of the delivery device 10, 10A, 10B.
  • the spherical devices 10, 10A, 10B produced according to the preferred embodiments of the present invention described above provide a number of benefits, including:
  • the devices 10, 10A, 10B according to the embodiments of the present invention are configured with a spherical shape to achieve better performance in locomotion and ease of orientation adjustment.
  • a spherical shape is also easier to swallow, thereby realising patient compliance.
  • device 10B By virtue of device 10B being configured with two reservoirs or chambers 60, 65, this allows two drug payloads to be stored separately. Such payloads can be of the same medication or of two entirely different medications, as may be required. By being able to selectively orient this particular device 10B in vivo, means that the required drug payload can be easily selected and delivered at the site specific location, which leads to a better flexibility of the drug delivery.
  • the devices 10, 10A and 10B being configured in the manner in which they have been described above, these devices 10, 10A, 10B do not require an on-board motor and associated energy source to enable the devices 10, 10A, 10B to move. This has certain benefits in that the devices 10, 10A, 10B are cheaper to manufacture, and can be made much smaller than conventional devices with onboard motors without comprising on the volume available for the drug payload.
  • the embodiments of the present invention above are not limited to what has been described.
  • the membrane located in closest proximity to the opening 30 does not need to be a magnetic membrane if the first membrane has a suitable thickness and concentration of magnetic particles such that it can be sufficiently deflected in an external magnetic field to cause the second membrane to deflect merely by way of the change in pressure within the chamber 65.
  • the stimuli-responsive means to facilitate locomotion of the device 10 is not limited to just one magnet being located at the circumference of the body 20 as described above, but may include a plurality of magnets (not shown) located at the circumference of the body 20 in spaced apart arrangement.
  • the hollow member is not limited to being a needle 80 as described in the embodiments above.
  • the hollow member may be a biopsy punch (not shown) that can be selectively transitioned between extended position and a retracted position in much the same manner as described above. That is, once the second magnetic membrane 50 is caused to deflect in response to an external magnetic field being applied in proximity thereto, the biopsy punch is caused to transition from the retracted position within the body 20 of the device 10 to the extended position, whereby the force of the deflection and thus the extent of protrusion of the biopsy punch from the external surface 27 of the device 10 is sufficient to puncture and extract a sample of body tissue at the site selection location in vivo.
  • the external magnetic field can be removed to cause the biopsy punch to be transitioned back to the retracted positon substantially within the body 20 of the device 10, complete with the extracted sample of body tissue.
  • the device 10 can then be expelled from the body of the subject naturally and the extracted biopsy sample analyzed ex vivo.
  • the device 10 may further include a valve (not shown) located at the opening 30 to control a flow of the substance into and/or out of the chamber 60 in response to a corresponding external magnetic field being applied in proximity to or removed from the magnetic membrane 40.
  • a valve located at the opening 30 to control a flow of the substance into and/or out of the chamber 60 in response to a corresponding external magnetic field being applied in proximity to or removed from the magnetic membrane 40.
  • a reference to "A and/or B", when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

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Abstract

L'invention concerne un dispositif et un procédé d'utilisation d'un dispositif pour recevoir et/ou délivrer une substance in vivo. Le dispositif comprend un corps creux ayant une paroi qui définit un volume interne, la paroi comprenant au moins une ouverture s'étendant sensiblement à travers celle-ci pour faciliter l'accès au volume interne, et au moins une membrane sensible aux stimuli montée sur une surface interne de la paroi et sensiblement autour de celle-ci pour définir au moins une chambre qui est en communication fluidique avec ladite au moins une ouverture et est configurée pour recevoir et/ou délivrer une substance par l'intermédiaire de l'au moins une ouverture lorsqu'un stimulus externe est appliqué à proximité de l'au moins une membrane sensible aux stimuli.
PCT/AU2018/051033 2017-10-03 2018-09-21 Dispositif et procédé d'utilisation d'un dispositif pour recevoir et/ou délivrer une substance in vivo WO2019068136A1 (fr)

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AU2017903980A AU2017903980A0 (en) 2017-10-03 A device and a method for using a device to receive and/or deliver a substance in vivo

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113476670A (zh) * 2021-05-19 2021-10-08 李富财 一种自恢复型整形吸脂方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10018323A1 (de) * 2000-04-13 2001-02-08 Herbert Naarmann Bio-Depots zur Freisetzung von Wirkstoffen
US20050197652A1 (en) * 2002-05-13 2005-09-08 Fluidigm Corporation Drug delivery system
US20060015088A1 (en) * 2003-03-07 2006-01-19 Fachhochschule Jena Arrangement for remote-controlled release of active ingredients
JP2008125642A (ja) * 2006-11-17 2008-06-05 Matsushita Electric Works Ltd 投薬装置

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10018323A1 (de) * 2000-04-13 2001-02-08 Herbert Naarmann Bio-Depots zur Freisetzung von Wirkstoffen
US20050197652A1 (en) * 2002-05-13 2005-09-08 Fluidigm Corporation Drug delivery system
US20060015088A1 (en) * 2003-03-07 2006-01-19 Fachhochschule Jena Arrangement for remote-controlled release of active ingredients
JP2008125642A (ja) * 2006-11-17 2008-06-05 Matsushita Electric Works Ltd 投薬装置

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113476670A (zh) * 2021-05-19 2021-10-08 李富财 一种自恢复型整形吸脂方法

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