WO2023171360A1 - Administration device and administration method - Google Patents

Administration device and administration method Download PDF

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Publication number
WO2023171360A1
WO2023171360A1 PCT/JP2023/006137 JP2023006137W WO2023171360A1 WO 2023171360 A1 WO2023171360 A1 WO 2023171360A1 JP 2023006137 W JP2023006137 W JP 2023006137W WO 2023171360 A1 WO2023171360 A1 WO 2023171360A1
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WO
WIPO (PCT)
Prior art keywords
administration
cylindrical body
administration device
cannula
dosing device
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PCT/JP2023/006137
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French (fr)
Japanese (ja)
Inventor
眞▲崎▼賢治
有延学
密岡拓心
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テルモ株式会社
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Publication of WO2023171360A1 publication Critical patent/WO2023171360A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to an administration device and administration method for releasing a drug into the eye.
  • VEGF vascular endothelial growth factor
  • Anti-VEGF treatment is performed for such diseases.
  • Anti-VEGF treatment is a treatment method that improves macular edema and suppresses the progression of the disease by intraocularly administering a therapeutic agent such as a VEGF inhibitor that suppresses the action of VEGF.
  • Japanese Patent No. 5577354 discloses an intraocular device that has a drug solution tank to be implanted in the eye and a connection port for refilling, and gradually releases a therapeutic drug. .
  • This device can continuously administer a drug solution into the vitreous by refilling the drug tank with the therapeutic drug every six months.
  • Japanese Patent No. 5577354 requires a procedure that involves incision of the conjunctiva and sclera for intraocular placement, requires large-scale equipment, and requires a short time in the examination room like intravitreal injection. Unable to perform treatment on time. Further, conventional devices have the problem of being highly invasive to the patient during placement, causing many adverse events such as conjunctival inflammation and bleeding, and placing a large burden on the patient.
  • the above-mentioned problems are not limited to anti-VEGF therapy, but include various biological treatments such as inhibitors such as antibody drugs and antagonists, agonists, nucleic acid drugs, peptide drugs, gene therapy drugs, and therapeutic cells. Continuous administration of formulations and/or small molecule drugs into the eye is also a common occurrence.
  • the present invention aims to solve the above problems.
  • One aspect of the following disclosure is an administration device that is disposed within the conjunctival sac and releases a dose into the eye, the device having a curved shape along the gap between the ocular surface and the eyelid, and having the dose inside the device.
  • a cylindrical body having a lumen for accommodating the drug; a flow path portion that protrudes from the cylindrical body and is punctured into the eyeball to administer the administration into the eye; and a pump for delivering the substance.
  • Another aspect is an administration method using the administration device according to the above aspect, in which the pump is operated in a state where the cylindrical body is placed in the conjunctival sac and the flow path is punctured into the eye.
  • the administration method comprises administering the drug contained in the inner cavity of the cylindrical body into the eye.
  • the administration device of the above aspect does not require incision of the conjunctiva or sclera, and can be attached to the patient with a minimally invasive procedure. Moreover, since the administration device can continuously administer the drug into the eye over a long period of time, stable effects can be obtained and the frequency of treatment can be reduced. Therefore, the administration device can reduce the burden on patients and doctors.
  • FIG. 1A is a plan view of the administration device according to the first embodiment
  • FIG. 1B is a cross-sectional view of the administration device of FIG. 1A
  • FIG. 2A is an explanatory diagram of a cylindrical body used for manufacturing the administration device of FIG. 1A
  • FIG. 2B is an explanatory diagram of a connecting member.
  • FIG. 3A is an explanatory diagram of the processing steps for the cylindrical body of FIG. 1A
  • FIG. 3B is an explanatory diagram of the process of connecting a connecting member to the cylindrical body that has undergone the processing steps of FIG. 3A.
  • FIG. 4 is an illustration of how to use the administration device of FIG. 1A
  • 5A is a sectional view of the vicinity of the flow path of the administration device of FIG. 4, and FIG.
  • FIG. 5B is a diagram illustrating the operation of the administration device of FIG. 4.
  • FIG. 6A is a plan view of the administration device according to the second embodiment
  • FIG. 6B is a cross-sectional view of the administration device of FIG. 6A.
  • FIG. 7A is an explanatory diagram of a cylindrical body used for manufacturing the administration device of FIG. 6A
  • FIG. 7B is an explanatory diagram (part 1) of bending of the cylindrical body.
  • FIG. 8A is an explanatory diagram (part 2) of the bending process of the cylindrical body
  • FIG. 8B is an explanatory diagram of the process of connecting the flow path portion to the cylindrical body in FIG. 8A.
  • FIG. 9A is an explanatory diagram of the process of inserting the chemical solution, gasket, osmotic pressure generating material, and semipermeable membrane into the cylindrical body of FIG. 8B
  • FIG. 9B is an explanatory diagram of the process of connecting the connecting member to the cylindrical body of FIG. 9A. It is a diagram.
  • FIG. 10 is a plan view of the administration device according to the third embodiment.
  • the administration device 10 of this embodiment shown in FIG. 1A is a device that continuously administers a medical solution M (administration) into a patient's eye (see FIG. 4) using an osmotic pump.
  • the administration device 10 includes a cylindrical body 12, a flow path section 14, and a pump 16.
  • the cylindrical body 12 has a shape in which flexible tubes are connected in an annular shape.
  • the cylindrical body 12 has a first end 12a and a second end 12b connected by a connecting member 18.
  • the cylindrical body 12 has an internal cavity 12c.
  • the inner cavity 12c has a hollow shape with a circular cross section and a smooth inner peripheral surface 12d.
  • the cylindrical body 12 has a moisture inlet 20 near the first end 12a. The moisture inlet 20 penetrates the peripheral wall 12e of the cylindrical body 12 and communicates the inner cavity 12c with the external space.
  • the material of the cylindrical body 12 of this embodiment is preferably a flexible material.
  • the cylindrical body 12 is made of a resin material such as silicone elastomer, PFA resin, polypropylene resin, polyethylene resin, COP resin, and COC resin, or a metal material such as tungsten, stainless steel, and nitinol.
  • the cylindrical body 12 has a curve that allows it to be accommodated in the gap between the eyelid and the eyeball.
  • the diameter D of the ring formed by the cylindrical body 12 is circular with a diameter of 20 to 35 mm.
  • the diameter D can be more preferably 20 to 30 mm.
  • the cylindrical body 12 having such a curved shape can be left in the conjunctival sac, which is the gap between the eyeball and the eyelid, for a long period of time.
  • the cylindrical body 12 has an internal volume sufficient to supply the drug solution M to the inner cavity 12c over a long period of time. Therefore, the cylindrical body 12 can have a cylindrical shape with an outer diameter ⁇ 1 of 1 to 3.2 mm.
  • the cylindrical body 12 having such an outer diameter size ⁇ 1 can be accommodated in the conjunctival sac.
  • the inner diameter dimension ⁇ 2 of the cylindrical body 12 can be, for example, 0.1 to 3 mm, more preferably 0.2 to 2 mm, and even more preferably 0.5 to 1.5 mm.
  • the diameter D of the cylindrical body 12 is 20 to 30 mm
  • the volume of the inner cavity 12c of the cylindrical body 12 having an inner diameter ⁇ 2 of, for example, 1.1 to 1.2 mm is 60 to 106 ⁇ L.
  • Such a cylindrical body 12 can accommodate the pump 16 and an amount (for example, 40 ⁇ L) of the drug solution M required for sustained release for about 6 months in the inner cavity 12c.
  • the inner cavity 12c of the cylindrical body 12 is partitioned by a partition wall 22 provided on the connecting member 18.
  • the partition wall 22 partitions the first end 12a and the second end 12b of the inner cavity 12c in a liquid-tight and air-tight manner.
  • the partition wall 22 is arranged between the flow path section 14 and the moisture inlet 20.
  • the entire outer peripheral surface of the cylindrical body 12 or the portion that contacts the eyeball may be covered with a flexible biocompatible material such as a silicone resin or a swellable polymer (CMC-Na, HPMC, PVP, etc.).
  • a flexible biocompatible material such as a silicone resin or a swellable polymer (CMC-Na, HPMC, PVP, etc.).
  • the flow path section 14 is provided in the connecting member 18. Note that the flow path section 14 does not have to be located at the connecting member 18 and may be located near the second end 12b of the cylindrical body 12.
  • the flow path section 14 includes a cannula 24, a puncture needle 26, a filter 28, and a packing 30.
  • the cannula 24 of this embodiment protrudes in a direction perpendicular to the centerline of the cylindrical body 12. The proximal end of the cannula 24 is joined to the connecting member 18 (or the cylindrical body 12).
  • Cannula 24 has a flow path 24a inside.
  • the cannula 24 of this embodiment is formed so that its tip is substantially flush with the puncture needle 26.
  • the state with almost no level difference includes a state in which the outer peripheral side of the distal end of the cannula 24 is smoothly chamfered, or a state in which the distal end of the cannula 24 is inclined at an obtuse angle.
  • the cannula 24, which has almost no level difference between the tip and the puncture needle 26, has little puncture resistance and can be smoothly punctured into the eyeball.
  • the cannula 24 is made of a flexible material, which can suppress irritation to the eyeballs.
  • the flow path 24a of the cannula 24 communicates with the lumen 12c of the cylindrical body 12 via the filter 28.
  • the cannula 24 has a thickness of, for example, 30G to 34G (outer diameter 0.3 to 0.2 mm, inner diameter 0.2 to 0.1 mm).
  • the tip of the cannula 24 protrudes from the connecting member 18 by 2 mm to 2.5 mm.
  • the tip of such a cannula 24 can penetrate the sclera and choroid of the eyeball to reach the vitreous body.
  • the cannula 24 has an outwardly projecting retaining structure 25 on its side.
  • the retaining structure 25 is a protrusion that engages with the tissue of the eyeball to prevent the cannula 24 from being pulled out when the cannula 24 is inserted into the eyeball.
  • the retaining structure 25 is not limited to a protrusion, but may be a recess.
  • the pull-out prevention structure 25 is not limited to engagement with tissue, and may adopt any suitable structure that prevents pull-out by fitting or frictional resistance.
  • the protrusion length of the cannula 24 may be shorter than in the above example.
  • the protruding length of the cannula 24 is appropriately selected depending on the region to which the medical solution M is to be administered.
  • the cannula 24 is made of a material such as stainless steel, polypropylene resin, polyethylene resin, polyimide resin, PES resin, SIBS resin, ETFE resin, polyurethane resin, or PTFE resin.
  • the proximal end of cannula 24 is joined to coupling member 18 .
  • a sealing material 32 is placed at the boundary between the cannula 24 and the connecting member 18 by coating or the like.
  • the sealing material 32 is made of silicone resin or a swellable polymer, and seals the gap between the joint between the cannula 24 and the connecting member 18 in a liquid-tight and air-tight manner.
  • the filter 28 is placed inside the coupling member 18 inside the cannula 24. Filter 28 is located between flow path 24a and lumen 12c. Filter 28 removes foreign substances from the dose supplied from lumen 12c to channel 24a.
  • the puncture needle 26 is inserted through the flow path 24a of the cannula 24 in the initial state, which is the product provision state. Puncture needle 26 has an inner diameter slightly smaller than the inner diameter of flow path 24a. Puncture needle 26 is formed longer than cannula 24. A needle tip 26a of the puncture needle 26 protrudes from the distal end of the cannula 24, and a proximal end of the puncture needle 26 penetrates the connecting member 18.
  • the puncture needle 26 has a sharp needle tip 26a and can puncture the sclera of the eyeball.
  • the puncture needle 26 is used to puncture the eyeball when introducing the cannula 24 into the eyeball.
  • the puncture needle 26 is removed from the proximal end after the cannula 24 is introduced into the eyeball.
  • the packing 30 is joined to the connecting member 18.
  • the packing 30 is arranged at a portion of the connecting member 18 through which the puncture needle 26 is inserted. In the initial state, the puncture needle 26 penetrates the packing 30.
  • the packing 30 is made of an elastically deformable material such as a rubber material. When the puncture needle 26 is pulled out, the packing 30 closes the hole through which the puncture needle 26 has passed, and fluid-tightly and airtightly closes the portion of the connecting member 18 through which the puncture needle 26 is inserted.
  • the connecting member 18 is a cylindrical member having substantially the same inner and outer diameters as the cylindrical body 12. One end 18a of the connecting member 18 is fitted into and joined to the outer periphery or inner cavity 12c of the first end 12a of the cylindrical body 12. The other end 18b of the connecting member 18 is fitted into and joined to the outer periphery or inner cavity 12c of the second end 12b of the cylindrical body 12. The connecting member 18 keeps the cylindrical body 12 in an annular shape.
  • the connecting member 18 is made of the same material as the cylindrical body 12.
  • the pump 16 (pressurizing mechanism) is an osmotic pump driven by osmotic pressure.
  • the pump 16 includes a semipermeable membrane 34, a gasket 36, and an osmotic pressure generating material 38.
  • the gasket 36 is placed in the inner cavity 12c.
  • the gasket 36 liquid-tightly and airtightly partitions the inner cavity 12c into a storage chamber 40 (accommodation area) on the second end 12b side and a pressure generation chamber 42 (pressurization area) on the first end 12a side.
  • the gasket 36 is movable while sliding inside the lumen 12c.
  • the gasket 36 is displaced toward the second end 12b by the osmotic pressure generated in the pressure generating chamber 42.
  • the gasket 36 is made of a rubber material such as styrene elastomer, olefin elastomer, urethane elastomer, butyl rubber, or a mixture thereof.
  • the gasket 36 has a cylindrical shape with an outer diameter slightly larger than the inner cavity 12c.
  • the osmotic pressure generating material 38 is filled in the pressure generating chamber 42.
  • the osmotic pressure generating material 38 is, for example, sodium chloride. Sodium chloride is dissolved by water supplied through the semipermeable membrane 34 to generate saturated saline.
  • the osmotic pressure generating material 38 generates a pressure increase in the pressure generating chamber 42 due to the difference between the osmotic pressure of tear fluid and the osmotic pressure of saturated saline.
  • the gasket 36 is displaced by the pressure in the pressure generating chamber 42, causing the administration in the storage chamber 40 to be delivered.
  • the semipermeable membrane 34 is a cylindrical member, and is filled in the inner cavity 12c in a portion adjacent to the moisture inlet 20.
  • the semipermeable membrane 34 is a porous filter made of polyvinylidene fluoride resin (PVDF), polyethylene furanoate resin (PEF), or cellulose.
  • PVDF polyvinylidene fluoride resin
  • PEF polyethylene furanoate resin
  • cellulose cellulose
  • the semipermeable membrane 34 has, for example, pores with an average pore size of 0.22 ⁇ m.
  • the semipermeable membrane 34 supplies moisture to the osmotic pressure generating material 38 by allowing moisture in the tear fluid to pass therethrough. In the administration device 10, the release rate of the drug can be adjusted by adjusting the thickness of the semipermeable membrane 34.
  • the effective transmittance k of the semipermeable membrane 34 is a constant value determined by the material. Furthermore, since a large excess of sodium chloride is sealed inside the pressure generating chamber 42, the concentration inside is a saturated concentration, and the osmotic pressure difference ⁇ is approximately a constant value. Furthermore, the concentration c of the drug solution M to be administered is constant unless decomposition due to instability is taken into consideration. Therefore, the rate of release of the dose can be adjusted by the thickness of the semipermeable membrane 34.
  • the storage chamber 40 of the lumen 12c is filled with a medicinal solution M, which is a drug to be administered.
  • Medical solution M may contain an ophthalmological VEGF inhibitor.
  • the drug solution M include biopreparations, antibody drugs, nucleic acid drugs, peptide drugs, therapeutic genes, therapeutic cell-containing solutions, and low-molecular drugs.
  • antibody drugs include ranibizumab, bevacizumab, brolucizumab, faricimab, and the like.
  • Nucleic acid drugs include aptamers typified by pegaptanib sodium, siRNA, antisense oligonucleotides, decoys, and the like.
  • Other VEGF inhibitors include, for example, aflibercept and abiciperpegol.
  • the storage chamber 40 may contain an AAV vector (for gene introduction).
  • the therapeutic cell-containing solution includes a photoreceptor cell-containing solution.
  • low-molecular drugs include sirolimus, triamcinolone acetonide, dexamethasone, bimatoprost, travoprost, latanoprost, tafluprost, omidenepag, sepetaprost, netarsudil, fasudil, timolol, levobunolol, brimonidine, dorzolamide, brinzolamide, and the like.
  • Drug solution M includes antibiotics such as tetracycline, chlortetracycline, neomycin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampicin, ciprofloxacin, tobramycin, gentamicin, erythromycin, and penicillin; antifungals such as amphotericin B and miconazole; Antibacterial agents such as sulfonamide, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole and nitrofurazone and sodium propionate; Antiviral agents such as idoxuridine, trifluorothymidine, acyclovir, ganciclovir, interferon; Antiallergic agents such as sodium cromoglycate, antazoline, metapyrylene, chlorpheniramine, pyrilamine, cetirizine and prophenpyridamine; hydrocortisone, hydrocortis
  • suitable antibody drugs include, for example, aflibercept, ranibizumab, brolucizumab, or faricimab.
  • the administration device 10 can continuously release the drug solution M over 180 days by setting the release rate to 222 nL/day.
  • the concentration of the antibody drug be higher than that of existing formulations.
  • the upper limit of the concentration of drug solution M can be set so that the concentration does not exceed the exposure amount (AUC) of existing intravitreal injection at a release rate of 222 nL/day.
  • the concentration is preferably 40 to 160 mg/ml. If drug solution M is ranibizumab, the concentration is preferably 10 to 80 mg/ml. If the drug solution M is brolucizumab, the concentration is preferably 120 to 320 mg/ml. If drug solution M is faricimab, the concentration is preferably 120 to 240 mg/ml. In addition, since the stability of antibody drugs tends to decrease at human body temperature, the drug solution M may contain an appropriate stabilizer. By setting the concentration within the above range, the drug solution M can be continuously administered over a long period of time, such as half a year or more.
  • the administration device 10 of this embodiment is configured as described above.
  • the above administration device 10 is manufactured by the following method.
  • the method for manufacturing the administration device 10 includes a step of manufacturing a cylindrical body 12 made of a hollow cylindrical tube. This step includes cutting the tube into a predetermined length to form the cylindrical body 12. Further, a moisture inlet 20 is formed in the peripheral wall 12e near the first end 12a of the cylindrical body 12 by drilling.
  • the method for manufacturing the administration device 10 includes a process for manufacturing a connecting member 18 having a flow path section 14.
  • a filler forming the partition wall 22 and a filter 28 are inserted inside the connecting member 18 .
  • a packing 30 is joined to the connecting member 18.
  • the puncture needle 26 is inserted so as to penetrate the packing 30 and the filter 28.
  • the cannula 24 is joined to the cylindrical connecting member 18 by fitting or the like.
  • a sealant 32 is applied to the boundary between the cannula 24 and the connecting member 18.
  • the connecting member 18 is formed by the above steps.
  • the cylindrical body 12 in FIG. 2A and the connecting member 18 in FIG. 2B are sterilized. Thereafter, in a sterile environment, the gasket 36, the osmotic pressure generating material 38, and the semipermeable membrane 34 are inserted into the inner cavity 12c of the cylindrical body 12, as shown in FIG. 3A.
  • the semipermeable membrane 34 is placed adjacent to the moisture inlet 20 .
  • the inner cavity 12c closer to the second end 12b than the gasket 36 is filled with the medical solution M.
  • the space of the connecting member 18 is also filled with the chemical solution M.
  • the manufacturing method proceeds to the step of assembling the cylindrical body 12 and the connecting member 18.
  • the other end 18b of the connecting member 18 is connected to the second end 12b of the cylindrical body 12.
  • one end 18a of the connecting member 18 is connected to the first end 12a of the cylindrical body 12.
  • the administration device 10 of this embodiment is used as follows.
  • the cannula 24 of the flow path section 14 punctures the vitreous body.
  • the cannula 24 and the puncture needle 26 penetrate the sclera and choroid and puncture the vitreous body. Thereafter, the puncture needle 26 is removed from the administration device 10.
  • the cannula 24 has a retaining structure 25 that engages inside the eyeball. The retaining structure 25 prevents the cannula 24 from being unintentionally pulled out.
  • the cylindrical body 12 of the administration device 10 is placed in the gap between the ocular surface and the eyelid. Since the cylindrical body 12 is formed in an annular shape, it is placed in contact with the ocular surface so as to surround the cornea. With the above operations, the procedure for placing the administration device 10 in the patient is completed. In this way, indwelling the administration device 10 does not require incision of the sclera, and is a minimally invasive and simple procedure.
  • the tip of the cannula 24 is located inside the vitreous body, and administers the drug into the vitreous body through the channel 24a.
  • pump 16 is powered by lachrymal fluid.
  • the tear fluid contacts the semipermeable membrane 34 through the water inlet 20.
  • the water in the tear fluid passes through the semipermeable membrane 34 and flows into the pressure generating chamber 42 .
  • the water comes into contact with the osmotic pressure generating material 38 in the pressure generating chamber 42 to generate an aqueous solution.
  • the gasket 36 is driven by the osmotic pressure of the aqueous solution in the pressure generating chamber 42 .
  • the gasket 36 slowly moves through the inner cavity 12c of the cylindrical body 12 toward the second end 12b.
  • the drug (medicinal solution M) in the storage chamber 40 is administered into the vitreous body through the channel 24a of the cannula 24.
  • the speed at which the drug solution M is administered by the administration device 10 is determined by the thickness of the semipermeable membrane 34.
  • the administration device 10 continues to administer the dose for at least 15 days to six months. Therefore, frequent treatments are not required and the burden on the patient can be reduced.
  • the administration device 10A of this embodiment includes a cylindrical body 12A, a flow path section 14A, a pump 16, and a connecting member 18A.
  • the cylindrical body 12A has an annular shape in which a first end 12a and a second end 12b are connected via a connecting member 18A.
  • the cylindrical body 12A of this embodiment is made of a highly rigid metal tube made of stainless steel, nitinol, or the like.
  • the cylindrical body 12A has a lumen 12c inside. Further, the cylindrical body 12A has a moisture inlet 20 near the first end 12a.
  • the configuration of the pump 16 is similar to that of the pump 16 in FIG. 1A, and includes a gasket 36, an osmotic pressure generating material 38, and a semipermeable membrane 34.
  • the connecting member 18A is made of the same metal material as the cylindrical body 12A.
  • the inside of the connecting member 18A is partitioned off by a partition wall 22 in a liquid-tight and air-tight manner.
  • the cylindrical body 12A has a mounting hole 12f near the second end 12b.
  • a proximal end portion of a cannula 24A constituting the flow path portion 14A is joined to the attachment hole 12f.
  • the proximal end of the cannula 24A fits into the attachment hole 12f.
  • the connection between the cannula 24A and the attachment hole 12f may be sealed with a sealant 32 (see FIG. 1A).
  • the cannula 24A of this embodiment is made of, for example, a hard material such as stainless steel.
  • the cannula 24A has a sharp needle tip 46 at its distal end. The cannula 24A is capable of puncturing the eyeball with the needle tip 46.
  • the cannula 24A has a retaining structure 25 bulging from the side.
  • the cannula 24A also has a flow path 24a inside thereof that communicates with the lumen 12c.
  • a filter 28 is disposed in the lumen 12c at a portion corresponding to the base of the cannula 24A.
  • the administration device 10A of this embodiment is manufactured by the following manufacturing method. First, as shown in FIG. 7A, a linear cylindrical body 12A is supplied. This cylindrical body 12A has a moisture inlet 20 and a mounting hole 12f. Next, as shown in FIG. 7B, a support rod 48 for maintaining the inner diameter is inserted into the cylindrical body 12A.
  • a step is performed in which the cylindrical body 12A into which the support rod 48 is inserted is plastically deformed together with the support rod 48 to curve into an annular shape. Thereby, the cylindrical body 12A is shaped into an annular shape. Thereafter, the support rod 48 is pulled out and removed from the cylindrical body 12A.
  • a step of fitting the proximal end of the cannula 24A into the attachment hole 12f is performed.
  • the cannula 24A is joined to the cylindrical body 12A.
  • the gasket 36, the osmotic pressure generating material 38 (salt), and the semipermeable membrane 34 are inserted in this order from the first end 12a of the cylindrical body 12A.
  • the chemical solution M is filled from the second end 12b of the cylindrical body 12A.
  • the administration device 10B of this embodiment shown in FIG. 10 has a cylindrical body 12B.
  • the cylindrical body 12B has a first end 12a and a second end 12b that are not connected and has an arc shape.
  • a lumen 12c opens.
  • a semipermeable membrane 34, an osmotic pressure generating material 38, and a gasket 36 are arranged in the inner cavity 12c in this order from those closest to the first end 12a.
  • the cylindrical body 12B has a terminal wall 50 at the second end 12b. Terminal wall 50 closes lumen 12c.
  • the cylindrical body 12B has a flow path portion 14A near the second end portion 12b.
  • the flow path section 14A of this embodiment is similar to the flow path section 14A of FIG. 6A. Similar effects can also be obtained with the administration device 10B of this embodiment.
  • the administration device 10, 10A, 10B which is disposed in the conjunctival sac and discharges a drug into the eye, has a curved shape along the gap between the ocular surface and the eyelid, and has the above-mentioned drug inside.
  • Cylindrical bodies 12, 12A, and 12B each having a lumen 12c that accommodates a dose; flow path portions 14 and 14A that protrude from the tube and puncture the eyeball to administer the dose into the eye;
  • a pump 16 is provided for delivering the drug from the lumen to the flow path section.
  • the above-mentioned administration device does not require a procedure that involves incision of the conjunctiva or sclera when it is placed in the eye, and the treatment can be performed in a minimally invasive manner in a short time. Furthermore, the above-described administration device is less invasive to the patient and can reduce the burden on the patient.
  • the pump includes a gasket 36 which is movably arranged in the lumen of the cylindrical body and partitions the lumen into a storage area in which the dose is accommodated and a pressurization area; It may also include a pressurizing mechanism that pressurizes the pressurizing area.
  • This administration device can be easily placed in a narrow gap between the eyeball and the eyelid because the pump is miniaturized and can be housed inside the cylindrical body.
  • the pressurizing mechanism is formed in the cylindrical body and is arranged between a moisture inlet 20 that introduces moisture into the inner cavity and between the moisture inlet and the pressurizing area.
  • the device may include a semipermeable membrane 34 and an osmotic pressure generating material 38 that is sealed in the pressurized region and increases the internal pressure of the pressurized region when it comes into contact with water.
  • This administration device can administer a drug into the eyeball by generating osmotic pressure using the water content of lachrymal fluid. Eye drops may be used as a supplement to the lacrimal fluid, or if the secretion of lachrymal fluid is insufficient for the administration operation, the eye drops may be used as the main source of water.
  • This dosing device generates high pressure and can perform stable dosing operations over a long period of time.
  • the flow path section includes a flexible cannula 24 protruding from the cylindrical body, and a puncture needle 26 that is inserted through the cannula and has a sharp needle tip 26a at its tip. You can. By using a flexible cannula, this administration device can reduce stimulation to living tissue.
  • the flow path portion has a hard cannula 24A protruding from the cylindrical body, and the cannula may have a sharp needle tip 46 at its tip.
  • This administration device allows the cannula to be directly punctured into the eyeball, thereby simplifying the operation of indwelling the administration device.
  • the cannula may have a retaining structure 25 protruding from the side. This administration device can prevent the cannula from being pulled out during indwelling or use.
  • the cylindrical body may be annular. This administration device can be stably placed along the circumference of the eyeball.
  • the cylindrical body may be made of a flexible material. This administration device can reduce irritation to surrounding tissue.
  • the administration product may be an ophthalmological VEGF inhibitor. Since this administration device can continuously administer an ophthalmic VEGF inhibitor into the inside of the eyeball, it can be suitably used for anti-VEGF treatment of retinal diseases such as age-related macular degeneration, retinal vein occlusion, and diabetic retinopathy.
  • retinal diseases such as age-related macular degeneration, retinal vein occlusion, and diabetic retinopathy.
  • the dosage may contain aflibercept at a concentration of 40 to 160 mg/ml.
  • This administration device contains a relatively high concentration of the biologic agent and thus can administer the dose over an extended period of time. Furthermore, the administration device is used in a harsh temperature environment as a storage environment for biologics. With this administration device, the stability of the biopreparation can be increased by setting the above concentration, and anti-VEGF treatment can be performed over a long period of time.
  • the dosage may contain ranibizumab at a concentration of 10 to 80 mg/ml. Since this administration device contains a relatively high concentration of antibody drug, it is possible to administer the dose over an extended period of time. Furthermore, the administration device is used in a harsh temperature environment as a storage environment for antibody drugs. With this administration device, the stability of the antibody drug can be increased by setting the above concentration, and anti-VEGF treatment can be performed over a long period of time.
  • the dosage may contain brolucizumab at a concentration of 120 to 320 mg/ml. Since this administration device contains a relatively high concentration of antibody drug, it is possible to administer the dose over an extended period of time. Furthermore, the administration device is used in a harsh temperature environment as a storage environment for antibody drugs. With this administration device, the stability of the antibody drug can be increased by setting the above concentration, and anti-VEGF treatment can be performed over a long period of time.
  • the dosage may contain faricimab at a concentration of 120-240 mg/ml. Since this administration device contains a relatively high concentration of antibody drug, it is possible to administer the dose over an extended period of time. Furthermore, the administration device is used in a harsh temperature environment as a storage environment for antibody drugs. With this administration device, the stability of the antibody drug can be increased by setting the above concentration, and anti-VEGF treatment can be performed over a long period of time.
  • Another aspect is an administration method using the above-mentioned administration device, in which the pump is operated with the cylindrical body disposed in the conjunctival sac and the flow path portion punctured into the eye.
  • the method of administration includes intraocularly administering the drug housed in the lumen of the cylindrical body. According to this administration method, the drug can be continuously administered into the eye over a long period of time.
  • the pump may be an osmotic pump operated by lachrymal fluid.
  • the drug can be administered over a long period of time without maintenance, further reducing the burden on the patient.

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Abstract

An administration device (10) and an administration method comprise: a tubular body (12) that has a lumen (12c) having a curved shape configured to conform to a gap between the eye surface and eye lid and that holds therein a substance to be administered; a flow path unit (14) that protrudes from the tubular body (12) and administers a substance to be administered into the eye by piercing the eyeball; and a pump (16) that sends, from the lumen (12c) to the flow path unit (14), the substance to be administered. The substance to be administrated is discharged into the eye with the tubular body (12) placed inside the conjunctival sac.

Description

投与装置及び投与方法Administration device and method
　本発明は、薬物を眼内に放出する投与装置及び投与方法に関する。 The present invention relates to an administration device and administration method for releasing a drug into the eye.
　加齢黄斑変性や網膜静脈閉塞症、糖尿病網膜症等の網膜の疾患は、視野のゆがみ、中心暗点、及び視力低下等の症状を発生させる。これらの疾患は、体内のＶＥＧＦ（血管内皮増殖因子）が、新生血管の増殖や黄斑浮腫の悪化に関与していることが知られている。このような疾患に対して、抗ＶＥＧＦ治療が行われる。抗ＶＥＧＦ治療はＶＥＧＦの働きを抑えるＶＥＧＦ阻害薬等の治療薬を眼内に投与することにより、黄斑浮腫を改善させ、病気の進行を抑制する治療法である。 Retinal diseases such as age-related macular degeneration, retinal vein occlusion, and diabetic retinopathy cause symptoms such as visual field distortion, central scotoma, and decreased visual acuity. It is known that in these diseases, VEGF (vascular endothelial growth factor) in the body is involved in the growth of new blood vessels and worsening of macular edema. Anti-VEGF treatment is performed for such diseases. Anti-VEGF treatment is a treatment method that improves macular edema and suppresses the progression of the disease by intraocularly administering a therapeutic agent such as a VEGF inhibitor that suppresses the action of VEGF.
　現行の抗ＶＥＧＦ治療は、注射器の注射針より治療薬を投与するため患者への負担が大きく、注射による投与回数に限りがある。また、硝子体の内部（眼内部）で治療薬が充分な濃度で存在しない期間が生じることで、徐々に視力が低下する問題がある。 Current anti-VEGF treatments place a heavy burden on patients because the therapeutic agent is administered through the needle of a syringe, and the number of times the drug can be administered by injection is limited. Furthermore, there is a problem in that visual acuity gradually deteriorates due to a period in which the therapeutic agent is not present at a sufficient concentration inside the vitreous body (inside the eye).
　このような問題を解消するため、特許第５５７７３５４号公報は、眼内に埋め込まれる薬液タンクと再充填用の接続ポートを有し、治療薬を徐々に放出する眼内留置用のデバイスを開示する。このデバイスは、６か月ごとに薬液タンクに治療薬を再充填する手技を行うことで継続的に薬液を硝子体内に投与できる。 In order to solve such problems, Japanese Patent No. 5577354 discloses an intraocular device that has a drug solution tank to be implanted in the eye and a connection port for refilling, and gradually releases a therapeutic drug. . This device can continuously administer a drug solution into the vitreous by refilling the drug tank with the therapeutic drug every six months.
　しかしながら、特許第５５７７３５４号公報のデバイスは、眼内への留置に、結膜や強膜の切開を伴う手技が必要とされ、大がかりな設備が必要であり、硝子体内注射のように診察室で短時間に処置を行うことができない。また、従来のデバイスは、留置の際の患者への侵襲が大きく、結膜の炎症及び出血等の有害事象を多く生じさせ、患者への負担も大きいという問題がある。 However, the device disclosed in Japanese Patent No. 5577354 requires a procedure that involves incision of the conjunctiva and sclera for intraocular placement, requires large-scale equipment, and requires a short time in the examination room like intravitreal injection. Unable to perform treatment on time. Further, conventional devices have the problem of being highly invasive to the patient during placement, causing many adverse events such as conjunctival inflammation and bleeding, and placing a large burden on the patient.
　また、上記の問題は、抗ＶＥＧＦ治療に限定されるものではなく、抗体薬や拮抗薬等の阻害薬、作動薬、核酸薬、ペプチド薬、遺伝子治療薬、治療用細胞、等の種々のバイオ製剤及び／又は低分子薬の眼内への継続的な投与についても共通に生じる。 Furthermore, the above-mentioned problems are not limited to anti-VEGF therapy, but include various biological treatments such as inhibitors such as antibody drugs and antagonists, agonists, nucleic acid drugs, peptide drugs, gene therapy drugs, and therapeutic cells. Continuous administration of formulations and/or small molecule drugs into the eye is also a common occurrence.
　そのため、注射をするのと同程度の負担で処置が完結し、患者及び医師への負担を軽減できるデバイスが望まれる。 Therefore, there is a need for a device that can complete the treatment with the same burden as administering an injection, reducing the burden on patients and doctors.
　本発明は、上記した課題を解決することを目的とする。 The present invention aims to solve the above problems.
　以下の開示の一観点は、結膜嚢内に配置され、投与物を眼内に放出する投与装置であって、眼表面と、瞼との隙間に沿った湾曲形状を有し、内部に前記投与物を収容する内腔を有する筒状体と、前記筒状体から突出し、眼球に穿刺されて前記投与物を前記眼内に投与する流路部と、前記内腔から前記流路部に前記投与物を送出するポンプと、を備えた、投与装置にある。 One aspect of the following disclosure is an administration device that is disposed within the conjunctival sac and releases a dose into the eye, the device having a curved shape along the gap between the ocular surface and the eyelid, and having the dose inside the device. a cylindrical body having a lumen for accommodating the drug; a flow path portion that protrudes from the cylindrical body and is punctured into the eyeball to administer the administration into the eye; and a pump for delivering the substance.
　別の一観点は、上記観点の投与装置を用いた投与方法であって、前記筒状体が結膜嚢に配置され、前記流路部が眼内に穿刺された状態で、前記ポンプを作動させて前記筒状体の内腔に収容された投与物を眼内に投与する、投与方法にある。 Another aspect is an administration method using the administration device according to the above aspect, in which the pump is operated in a state where the cylindrical body is placed in the conjunctival sac and the flow path is punctured into the eye. The administration method comprises administering the drug contained in the inner cavity of the cylindrical body into the eye.
　上記観点の投与装置は、結膜や強膜の切開が不要であり、低侵襲な処置で患者に取り付けることができる。また、投与装置は、長期間にわたって連続的に投与物を眼内に投与できるため、安定した効果が得られるとともに、処置の頻度を減らすことができる。したがって、投与装置は、患者及び医師の負担を軽減できる。 The administration device of the above aspect does not require incision of the conjunctiva or sclera, and can be attached to the patient with a minimally invasive procedure. Moreover, since the administration device can continuously administer the drug into the eye over a long period of time, stable effects can be obtained and the frequency of treatment can be reduced. Therefore, the administration device can reduce the burden on patients and doctors.
図１Ａは、第１実施形態に係る投与装置の平面図であり、図１Ｂは図１Ａの投与装置の断面図である。FIG. 1A is a plan view of the administration device according to the first embodiment, and FIG. 1B is a cross-sectional view of the administration device of FIG. 1A. 図２Ａは、図１Ａの投与装置の製造に用いる筒状体の説明図であり、図２Ｂは連結部材の説明図である。FIG. 2A is an explanatory diagram of a cylindrical body used for manufacturing the administration device of FIG. 1A, and FIG. 2B is an explanatory diagram of a connecting member. 図３Ａは、図１Ａの筒状体に対する加工工程の説明図であり、図３Ｂは図３Ａの加工工程を経た筒状体に連結部材を接続する工程の説明図である。FIG. 3A is an explanatory diagram of the processing steps for the cylindrical body of FIG. 1A, and FIG. 3B is an explanatory diagram of the process of connecting a connecting member to the cylindrical body that has undergone the processing steps of FIG. 3A. 図４は、図１Ａの投与装置の使用方法の説明図である。FIG. 4 is an illustration of how to use the administration device of FIG. 1A. 図５Ａは、図４の投与装置の流路部付近の断面図であり、図５Ｂは図４の投与装置の動作を説明する図である。5A is a sectional view of the vicinity of the flow path of the administration device of FIG. 4, and FIG. 5B is a diagram illustrating the operation of the administration device of FIG. 4. 図６Ａは、第２実施形態に係る投与装置の平面図であり、図６Ｂは図６Ａの投与装置の断面図である。FIG. 6A is a plan view of the administration device according to the second embodiment, and FIG. 6B is a cross-sectional view of the administration device of FIG. 6A. 図７Ａは、図６Ａの投与装置の製造に用いる筒状体の説明図であり、図７Ｂは、筒状体の曲げ加工の説明図（その１）である。FIG. 7A is an explanatory diagram of a cylindrical body used for manufacturing the administration device of FIG. 6A, and FIG. 7B is an explanatory diagram (part 1) of bending of the cylindrical body. 図８Ａは、筒状体の曲げ加工の説明図（その２）であり、図８Ｂは図８Ａの筒状体に対する流路部の接続工程の説明図である。FIG. 8A is an explanatory diagram (part 2) of the bending process of the cylindrical body, and FIG. 8B is an explanatory diagram of the process of connecting the flow path portion to the cylindrical body in FIG. 8A. 図９Ａは、図８Ｂの筒状体に対する薬液、ガスケット、浸透圧発生材、及び半透膜の挿入工程の説明図であり、図９Ｂは図９Ａの筒状体に対する連結部材の接続工程の説明図である。FIG. 9A is an explanatory diagram of the process of inserting the chemical solution, gasket, osmotic pressure generating material, and semipermeable membrane into the cylindrical body of FIG. 8B, and FIG. 9B is an explanatory diagram of the process of connecting the connecting member to the cylindrical body of FIG. 9A. It is a diagram. 図１０は、第３実施形態に係る投与装置の平面図である。FIG. 10 is a plan view of the administration device according to the third embodiment.
（第１実施形態）
　図１Ａに示す本実施形態の投与装置１０は、浸透圧ポンプを利用して患者の眼内（図４参照）に薬液Ｍ（投与物）を継続的に投与するデバイスである。投与装置１０は、筒状体１２と、流路部１４と、ポンプ１６と、を有する。 (First embodiment)
The administration device 10 of this embodiment shown in FIG. 1A is a device that continuously administers a medical solution M (administration) into a patient's eye (see FIG. 4) using an osmotic pump. The administration device 10 includes a cylindrical body 12, a flow path section 14, and a pump 16.
　筒状体１２は、可撓性のチューブを円環状に繋いだ形状を有する。筒状体１２は、その第１端部１２ａと第２端部１２ｂとが連結部材１８で連結されている。図１Ｂに示すように、筒状体１２は、内部に内腔１２ｃを有する。内腔１２ｃは、断面が円形の中空形状であり、滑らかな内周面１２ｄを有する。筒状体１２は、第１端部１２ａの近くに水分導入口２０を有する。水分導入口２０は、筒状体１２の周壁１２ｅを貫通して、内腔１２ｃと外部空間とを連通する。 The cylindrical body 12 has a shape in which flexible tubes are connected in an annular shape. The cylindrical body 12 has a first end 12a and a second end 12b connected by a connecting member 18. As shown in FIG. 1B, the cylindrical body 12 has an internal cavity 12c. The inner cavity 12c has a hollow shape with a circular cross section and a smooth inner peripheral surface 12d. The cylindrical body 12 has a moisture inlet 20 near the first end 12a. The moisture inlet 20 penetrates the peripheral wall 12e of the cylindrical body 12 and communicates the inner cavity 12c with the external space.
　本実施形態の筒状体１２の材料は、柔軟性材料とすると好適である。筒状体１２は、例えばシリコーンエラストマ、ＰＦＡ樹脂、ポリプロピレン樹脂、ポリエチレン樹脂、ＣＯＰ樹脂、及びＣＯＣ樹脂等の樹脂材料、又はタングステン、ステンレス及びニチノール等の金属材料よりなる。筒状体１２は、瞼と眼球の隙間に収納可能な湾曲を有する。具体的には、筒状体１２が形成する円環の直径Ｄは、２０～３５ｍｍの円形状である。直径Ｄは、より好ましくは２０～３０ｍｍとすることができる。このような湾曲形状の筒状体１２は、眼球と瞼の隙間である結膜嚢内に長期間にわたって留置可能である。 The material of the cylindrical body 12 of this embodiment is preferably a flexible material. The cylindrical body 12 is made of a resin material such as silicone elastomer, PFA resin, polypropylene resin, polyethylene resin, COP resin, and COC resin, or a metal material such as tungsten, stainless steel, and nitinol. The cylindrical body 12 has a curve that allows it to be accommodated in the gap between the eyelid and the eyeball. Specifically, the diameter D of the ring formed by the cylindrical body 12 is circular with a diameter of 20 to 35 mm. The diameter D can be more preferably 20 to 30 mm. The cylindrical body 12 having such a curved shape can be left in the conjunctival sac, which is the gap between the eyeball and the eyelid, for a long period of time.
　筒状体１２は、内腔１２ｃに長期間にわたる薬液Ｍの供給に充分な内部容積を有することが望ましい。そのため、筒状体１２は、外径寸法φ１を１～３．２ｍｍの円筒形状とすることができる。このような外径寸法φ１を有する筒状体１２は、結膜嚢に収容可能である。また、筒状体１２の内径寸法φ２は、例えば０．１～３ｍｍ、より好ましくは、０．２～２ｍｍ、更に好ましくは０．５～１．５ｍｍとすることができる。筒状体１２の直径Ｄを２０～３０ｍｍとした場合に、内径寸法φ２が例えば１．１～１．２ｍｍの筒状体１２は、内腔１２ｃの容積が６０～１０６μＬとなる。このような筒状体１２は、内腔１２ｃに、６か月程度の徐放に必要な量（例えば、４０μＬ）の薬液Ｍと、ポンプ１６とを収容できる。 It is desirable that the cylindrical body 12 has an internal volume sufficient to supply the drug solution M to the inner cavity 12c over a long period of time. Therefore, the cylindrical body 12 can have a cylindrical shape with an outer diameter φ1 of 1 to 3.2 mm. The cylindrical body 12 having such an outer diameter size φ1 can be accommodated in the conjunctival sac. Further, the inner diameter dimension φ2 of the cylindrical body 12 can be, for example, 0.1 to 3 mm, more preferably 0.2 to 2 mm, and even more preferably 0.5 to 1.5 mm. When the diameter D of the cylindrical body 12 is 20 to 30 mm, the volume of the inner cavity 12c of the cylindrical body 12 having an inner diameter φ2 of, for example, 1.1 to 1.2 mm is 60 to 106 μL. Such a cylindrical body 12 can accommodate the pump 16 and an amount (for example, 40 μL) of the drug solution M required for sustained release for about 6 months in the inner cavity 12c.
　筒状体１２の内腔１２ｃは、連結部材１８に設けられた仕切壁２２によって仕切られている。仕切壁２２は、内腔１２ｃの第１端部１２ａと第２端部１２ｂとを液密及び気密に仕切る。仕切壁２２は、流路部１４と水分導入口２０との間に配置される。 The inner cavity 12c of the cylindrical body 12 is partitioned by a partition wall 22 provided on the connecting member 18. The partition wall 22 partitions the first end 12a and the second end 12b of the inner cavity 12c in a liquid-tight and air-tight manner. The partition wall 22 is arranged between the flow path section 14 and the moisture inlet 20.
　筒状体１２は、その外周面の全域又は、眼球と接触する部分が、シリコーン樹脂又は膨潤性ポリマ（ＣＭＣ－Ｎａ、ＨＰＭＣ、ＰＶＰ等）といった柔軟な生体適合性材料で覆われてもよい。このような筒状体１２は、侵襲性を低減できる。 The entire outer peripheral surface of the cylindrical body 12 or the portion that contacts the eyeball may be covered with a flexible biocompatible material such as a silicone resin or a swellable polymer (CMC-Na, HPMC, PVP, etc.). Such a cylindrical body 12 can reduce invasiveness.
　流路部１４は、連結部材１８に設けられている。なお、流路部１４の位置は、連結部材１８でなくてもよく、筒状体１２の第２端部１２ｂの近傍に配置されてもよい。流路部１４は、カニューレ２４と、穿刺針２６と、フィルタ２８と、パッキン３０とを有する。本実施形態のカニューレ２４は、筒状体１２の中心線に直交する方向に突出する。カニューレ２４は、その基端が連結部材１８（又は筒状体１２）に接合される。カニューレ２４は、内部に流路２４ａを有する。本実施形態のカニューレ２４は、先端が穿刺針２６と段差がほぼない状態に形成される。段差がほぼない状態とは、カニューレ２４の先端の外周側が滑らかに面取りされた形状、又は、カニューレ２４の先端が鈍角に傾斜した形状を有する状態を含む。先端に穿刺針２６との段差がほぼない状態のカニューレ２４は、穿刺抵抗が少ないため、眼球内に円滑に穿刺できる。また、カニューレ２４は柔軟な素材によって形成されており、眼球への刺激を抑制できる。カニューレ２４の流路２４ａは、フィルタ２８を介して筒状体１２の内腔１２ｃと連通する。 The flow path section 14 is provided in the connecting member 18. Note that the flow path section 14 does not have to be located at the connecting member 18 and may be located near the second end 12b of the cylindrical body 12. The flow path section 14 includes a cannula 24, a puncture needle 26, a filter 28, and a packing 30. The cannula 24 of this embodiment protrudes in a direction perpendicular to the centerline of the cylindrical body 12. The proximal end of the cannula 24 is joined to the connecting member 18 (or the cylindrical body 12). Cannula 24 has a flow path 24a inside. The cannula 24 of this embodiment is formed so that its tip is substantially flush with the puncture needle 26. The state with almost no level difference includes a state in which the outer peripheral side of the distal end of the cannula 24 is smoothly chamfered, or a state in which the distal end of the cannula 24 is inclined at an obtuse angle. The cannula 24, which has almost no level difference between the tip and the puncture needle 26, has little puncture resistance and can be smoothly punctured into the eyeball. Furthermore, the cannula 24 is made of a flexible material, which can suppress irritation to the eyeballs. The flow path 24a of the cannula 24 communicates with the lumen 12c of the cylindrical body 12 via the filter 28.
　カニューレ２４は、太さが例えば、３０Ｇ～３４Ｇ（外径０．３～０．２ｍｍ、内径０．２～０．１ｍｍ）である。カニューレ２４の先端は、連結部材１８から、２ｍｍ～２．５ｍｍ突出する。このようなカニューレ２４は、先端が眼球の強膜及び脈絡膜を貫通して硝子体に到達することができる。カニューレ２４は、側部に外方に突出した抜止構造２５を有する。抜止構造２５は、カニューレ２４を眼球に挿入した際に、眼球の組織に係合して、カニューレ２４の引き抜けを防止する突起である。なお、抜止構造２５は、突起に限定されず、凹部であってもよい。また、抜止構造２５は、組織との係合に限定されず、嵌め合い、又は摩擦抵抗によって引き抜けを防止する適宜の構造を採用し得る。 The cannula 24 has a thickness of, for example, 30G to 34G (outer diameter 0.3 to 0.2 mm, inner diameter 0.2 to 0.1 mm). The tip of the cannula 24 protrudes from the connecting member 18 by 2 mm to 2.5 mm. The tip of such a cannula 24 can penetrate the sclera and choroid of the eyeball to reach the vitreous body. The cannula 24 has an outwardly projecting retaining structure 25 on its side. The retaining structure 25 is a protrusion that engages with the tissue of the eyeball to prevent the cannula 24 from being pulled out when the cannula 24 is inserted into the eyeball. Note that the retaining structure 25 is not limited to a protrusion, but may be a recess. Further, the pull-out prevention structure 25 is not limited to engagement with tissue, and may adopt any suitable structure that prevents pull-out by fitting or frictional resistance.
　なお、投与装置１０が強膜又は脈絡膜への薬液Ｍの投与に使用される場合には、カニューレ２４の突出長さは、上記の例よりも短くてもよい。カニューレ２４の突出長さは、薬液Ｍを投与したい部位に応じて適宜選択される。 Note that when the administration device 10 is used to administer the drug solution M to the sclera or choroid, the protrusion length of the cannula 24 may be shorter than in the above example. The protruding length of the cannula 24 is appropriately selected depending on the region to which the medical solution M is to be administered.
　このような、カニューレ２４は、例えば、ステンレス鋼、ポリプロピレン樹脂、ポリエチレン樹脂、ポリイミド樹脂、ＰＥＳ樹脂、ＳＩＢＳ樹脂、ＥＴＦＥ樹脂、ポリウレタン樹脂、又はＰＴＦＥ樹脂等の材料で構成される。カニューレ２４の基端は、連結部材１８に接合されている。カニューレ２４と連結部材１８との境界部分にはシール材３２が塗布等により配置されている。シール材３２は、シリコーン樹脂又は膨潤性ポリマよりなり、カニューレ２４と連結部材１８との接合部分の隙間を液密及び気密に封止する。 The cannula 24 is made of a material such as stainless steel, polypropylene resin, polyethylene resin, polyimide resin, PES resin, SIBS resin, ETFE resin, polyurethane resin, or PTFE resin. The proximal end of cannula 24 is joined to coupling member 18 . A sealing material 32 is placed at the boundary between the cannula 24 and the connecting member 18 by coating or the like. The sealing material 32 is made of silicone resin or a swellable polymer, and seals the gap between the joint between the cannula 24 and the connecting member 18 in a liquid-tight and air-tight manner.
　フィルタ２８は、カニューレ２４の内側の連結部材１８の内部に配置される。フィルタ２８は、流路２４ａと内腔１２ｃとの間に位置する。フィルタ２８は、内腔１２ｃから流路２４ａに供給される投与物から、異物を除去する。 The filter 28 is placed inside the coupling member 18 inside the cannula 24. Filter 28 is located between flow path 24a and lumen 12c. Filter 28 removes foreign substances from the dose supplied from lumen 12c to channel 24a.
　穿刺針２６は、製品提供状態である初期状態において、カニューレ２４の流路２４ａを挿通する。穿刺針２６は、流路２４ａの内径よりも僅かに小さな内径を有する。穿刺針２６は、カニューレ２４よりも長く形成されている。穿刺針２６の針先２６ａはカニューレ２４の先端から突出し、穿刺針２６の基端は、連結部材１８を貫通する。穿刺針２６は、鋭利な針先２６ａを有し、眼球の強膜に穿刺可能である。穿刺針２６は、カニューレ２４を眼球の内部に導入する際に眼球に穿刺して使用される。穿刺針２６は、カニューレ２４を眼球の内部に導入した後に、基端側から抜去される。 The puncture needle 26 is inserted through the flow path 24a of the cannula 24 in the initial state, which is the product provision state. Puncture needle 26 has an inner diameter slightly smaller than the inner diameter of flow path 24a. Puncture needle 26 is formed longer than cannula 24. A needle tip 26a of the puncture needle 26 protrudes from the distal end of the cannula 24, and a proximal end of the puncture needle 26 penetrates the connecting member 18. The puncture needle 26 has a sharp needle tip 26a and can puncture the sclera of the eyeball. The puncture needle 26 is used to puncture the eyeball when introducing the cannula 24 into the eyeball. The puncture needle 26 is removed from the proximal end after the cannula 24 is introduced into the eyeball.
　パッキン３０は、連結部材１８に接合される。パッキン３０は、連結部材１８の穿刺針２６が挿通する部分に配置されている。初期状態において穿刺針２６は、パッキン３０を貫通する。パッキン３０は、ゴム素材等の弾性変形可能な材料によって形成される。穿刺針２６が引き抜かれると、パッキン３０は穿刺針２６が通過した孔を閉塞し、連結部材１８の穿刺針２６の挿通部分を液密及び気密に閉塞する。 The packing 30 is joined to the connecting member 18. The packing 30 is arranged at a portion of the connecting member 18 through which the puncture needle 26 is inserted. In the initial state, the puncture needle 26 penetrates the packing 30. The packing 30 is made of an elastically deformable material such as a rubber material. When the puncture needle 26 is pulled out, the packing 30 closes the hole through which the puncture needle 26 has passed, and fluid-tightly and airtightly closes the portion of the connecting member 18 through which the puncture needle 26 is inserted.
　連結部材１８は、筒状体１２とほぼ同一の内径及び外径を有する筒状部材である。連結部材１８の一端１８ａは、筒状体１２の第１端部１２ａの外周又は内腔１２ｃに嵌め込まれて接合される。連結部材１８の他端１８ｂは、筒状体１２の第２端部１２ｂの外周又は内腔１２ｃに嵌め込まれて接合される。連結部材１８により、筒状体１２が円環状の形状に保たれる。連結部材１８は、筒状体１２と同様の材料によって形成される。 The connecting member 18 is a cylindrical member having substantially the same inner and outer diameters as the cylindrical body 12. One end 18a of the connecting member 18 is fitted into and joined to the outer periphery or inner cavity 12c of the first end 12a of the cylindrical body 12. The other end 18b of the connecting member 18 is fitted into and joined to the outer periphery or inner cavity 12c of the second end 12b of the cylindrical body 12. The connecting member 18 keeps the cylindrical body 12 in an annular shape. The connecting member 18 is made of the same material as the cylindrical body 12.
　ポンプ１６（加圧機構）は、浸透圧により駆動する浸透圧ポンプである。ポンプ１６は、半透膜３４と、ガスケット３６と、浸透圧発生材３８と、を有する。 The pump 16 (pressurizing mechanism) is an osmotic pump driven by osmotic pressure. The pump 16 includes a semipermeable membrane 34, a gasket 36, and an osmotic pressure generating material 38.
　ガスケット３６は、内腔１２ｃに配置される。ガスケット３６は、内腔１２ｃを第２端部１２ｂ側の収容室４０（収容領域）と、第１端部１２ａ側の圧力発生室４２（加圧領域）とに液密及び気密に仕切る。ガスケット３６は、内腔１２ｃの内部を摺動しつつ移動可能である。ガスケット３６は、圧力発生室４２で発生した浸透圧によって第２端部１２ｂに向けて変位する。ガスケット３６は、例えば、スチレン系エラストマ、オレフィン系エラストマ、ウレタンエラストマやブチルゴムあるいはこれらの混合物等のゴム素材によって形成される。ガスケット３６は、内腔１２ｃよりも僅かに大きな外径を有する円柱状を有する。 The gasket 36 is placed in the inner cavity 12c. The gasket 36 liquid-tightly and airtightly partitions the inner cavity 12c into a storage chamber 40 (accommodation area) on the second end 12b side and a pressure generation chamber 42 (pressurization area) on the first end 12a side. The gasket 36 is movable while sliding inside the lumen 12c. The gasket 36 is displaced toward the second end 12b by the osmotic pressure generated in the pressure generating chamber 42. The gasket 36 is made of a rubber material such as styrene elastomer, olefin elastomer, urethane elastomer, butyl rubber, or a mixture thereof. The gasket 36 has a cylindrical shape with an outer diameter slightly larger than the inner cavity 12c.
　浸透圧発生材３８は、圧力発生室４２に充填されている。浸透圧発生材３８は、例えば塩化ナトリウムである。塩化ナトリウムは、半透膜３４を通じて供給される水分によって溶解し、飽和食塩水を発生させる。浸透圧発生材３８は、圧力発生室４２に涙液の浸透圧と飽和食塩水との浸透圧との差による圧力上昇を発生させる。この圧力発生室４２の圧力により、ガスケット３６が変位し、収容室４０の投与物を送出させる。 The osmotic pressure generating material 38 is filled in the pressure generating chamber 42. The osmotic pressure generating material 38 is, for example, sodium chloride. Sodium chloride is dissolved by water supplied through the semipermeable membrane 34 to generate saturated saline. The osmotic pressure generating material 38 generates a pressure increase in the pressure generating chamber 42 due to the difference between the osmotic pressure of tear fluid and the osmotic pressure of saturated saline. The gasket 36 is displaced by the pressure in the pressure generating chamber 42, causing the administration in the storage chamber 40 to be delivered.
　半透膜３４は、円柱状の部材であり、水分導入口２０に隣接する部分の内腔１２ｃに充填されている。半透膜３４は、多孔質膜を有するポリフッ化ビニリデン樹脂（ＰＶＤＦ）、ポリエチレンフラノエート樹脂（ＰＥＦ）又はセルロースからなる多孔質フィルタである。半透膜３４は、例えば平均ポアサイスが０．２２μｍの気孔を有する。半透膜３４は、涙液中の水分を通過させることで、浸透圧発生材３８に水分を供給する。投与装置１０は、半透膜３４の厚さを調整することで、投与物の放出速度の調整が可能である。 The semipermeable membrane 34 is a cylindrical member, and is filled in the inner cavity 12c in a portion adjacent to the moisture inlet 20. The semipermeable membrane 34 is a porous filter made of polyvinylidene fluoride resin (PVDF), polyethylene furanoate resin (PEF), or cellulose. The semipermeable membrane 34 has, for example, pores with an average pore size of 0.22 μm. The semipermeable membrane 34 supplies moisture to the osmotic pressure generating material 38 by allowing moisture in the tear fluid to pass therethrough. In the administration device 10, the release rate of the drug can be adjusted by adjusting the thickness of the semipermeable membrane 34.
　投与物の放出速度ｄｍ／ｄｔは、半透膜３４の厚さをｈ、断面積をＡとし、半透膜３４の有効透過率をｋ、圧力発生室４２と周辺組織との浸透圧差をΔΠ、収容室４０の内部の投与物の濃度をｃとすると、ｄｍ／ｄｔ＝（Ａ／ｈ）×ｋ×ΔΠ×ｃと表される。 The release rate dm/dt of the administered substance is calculated as follows: where the thickness of the semipermeable membrane 34 is h, the cross-sectional area is A, the effective permeability of the semipermeable membrane 34 is k, and the osmotic pressure difference between the pressure generating chamber 42 and the surrounding tissue is ΔΠ. , when the concentration of the dose inside the storage chamber 40 is c, it is expressed as dm/dt=(A/h)×k×ΔΠ×c.
　上記の式において、半透膜３４の有効透過率ｋは、材質により定まる一定値である。また、圧力発生室４２の内部では塩化ナトリウムが大過剰に封入されているため、内部の濃度は飽和濃度であり、浸透圧差ΔΠは概ね一定の値となる。更に、投与物である薬液Ｍの濃度ｃは不安定性による分解を考慮しない場合は一定である。したがって、投与物の放出速度は、半透膜３４の厚さによって調整できる。 In the above equation, the effective transmittance k of the semipermeable membrane 34 is a constant value determined by the material. Furthermore, since a large excess of sodium chloride is sealed inside the pressure generating chamber 42, the concentration inside is a saturated concentration, and the osmotic pressure difference ΔΠ is approximately a constant value. Furthermore, the concentration c of the drug solution M to be administered is constant unless decomposition due to instability is taken into consideration. Therefore, the rate of release of the dose can be adjusted by the thickness of the semipermeable membrane 34.
　内腔１２ｃの収容室４０には、投与物である薬液Ｍが充填されている。薬液Ｍは、眼科用ＶＥＧＦ阻害剤を含んでもよい。薬液Ｍとしては、バイオ製剤、抗体薬、核酸薬、ペプチド薬、治療用遺伝子、治療用細胞含有液、及び低分子薬が挙げられる。抗体薬としては、例えば、ラニビズマブ、ベバシズマブ、ブロルシズマブ、ファリシマブ等が挙げられる。核酸薬としては、ペガプタニブナトリウムで代表されるアプタマー、ｓｉＲＮＡ、アンチセンスオリゴヌクレオチド、デコイ等が挙げられる。その他のＶＥＧＦの阻害薬として、例えば、アフリベルセプト及びアビシパーペゴル等がある。収容室４０は、ＡＡＶベクター（遺伝子導入用）を含んでもよい。治療用細胞含有液としては、視細胞含有液が挙げられる。低分子薬としては、例えばシロリムス、トリアムシノロンアセトニド、デキサメタゾン、ビマトプロスト、トラボプロスト、ラタノプロスト、タフルプロスト、オミデネパグ、セペタプロスト、ネタルスジル、ファスジル、チモロール、レボブノロール、ブリモニジン、ドルゾラミド、ブリンゾラミド等が挙げられる。 The storage chamber 40 of the lumen 12c is filled with a medicinal solution M, which is a drug to be administered. Medical solution M may contain an ophthalmological VEGF inhibitor. Examples of the drug solution M include biopreparations, antibody drugs, nucleic acid drugs, peptide drugs, therapeutic genes, therapeutic cell-containing solutions, and low-molecular drugs. Examples of antibody drugs include ranibizumab, bevacizumab, brolucizumab, faricimab, and the like. Nucleic acid drugs include aptamers typified by pegaptanib sodium, siRNA, antisense oligonucleotides, decoys, and the like. Other VEGF inhibitors include, for example, aflibercept and abiciperpegol. The storage chamber 40 may contain an AAV vector (for gene introduction). The therapeutic cell-containing solution includes a photoreceptor cell-containing solution. Examples of low-molecular drugs include sirolimus, triamcinolone acetonide, dexamethasone, bimatoprost, travoprost, latanoprost, tafluprost, omidenepag, sepetaprost, netarsudil, fasudil, timolol, levobunolol, brimonidine, dorzolamide, brinzolamide, and the like.
　薬液Ｍは、テトラサイクリン、クロルテトラサイクリン、ネオマイシン、セファレキシン、オキシテトラサイクリン、クロラムフェニコール、カナマイシン、リファンピシン、シプロフロキサシン、トブラマイシン、ゲンタマイシン、エリスロマイシン及びペニシリン等の抗生物質；アムホテリシンＢ及びミコナゾール等の抗真菌剤；スルホンアミド、スルファジアジン、スルファセタミド、スルファメチゾール、スルフイソキサゾール及びニトロフラゾン及びプロピオン酸ナトリウム等の抗菌剤；イドクスウリジン、トリフルオロサイミジン、アシクロビル、ガンシクロビル、インターフェロン等の抗ウイルス剤；クロモグリク酸ナトリウム、アンタゾリン、メタピリレン、クロルフェニラミン、ピリラミン、セチリジン及びプロフェンピリダミン等の抗アレルギー剤；ヒドロコルチゾン、酢酸ヒドロコルチゾン、デキサメタゾン、デキサメタゾン２１－ホスフェート、フルオシノロン、メドリゾン、プレドニゾロン、プレドニゾロン２１－ホスフェート、酢酸プレドニゾロン、フルオロメトロン、ベタメタゾン及びトリアムシノロン等の抗炎症剤；サリチル酸、インドメタシン、イブプロフェン、ジクロフェナク、フルルビプロフェン及びピロキシカム等の非ステロイド性抗炎症剤；フェニレフリン、ナファゾリン及びテトラヒドロゾリン等の鬱血除去薬；ピロカルピン、サリチル酸、塩化アセチルコリン、フィゾスチグミン、エゼリン、カルバコール、ジイソプロピルフルオロリン酸、ヨウ化ホスホリン及び臭化デメカリウム等の縮瞳薬及び抗コリンエステラーゼ薬；硫酸アトロピン、シクロペントラート、ホマトロピン、スコポラミン、トロピカミド、ユーカトロピン及びヒドロキシアンフェタミン等の散瞳薬；エピネフリン等の交感神経摸倣薬；カルムスチン、シスプラチン及びフルオロウラシル等の抗悪性腫瘍薬；ワクチン及び免疫刺激剤等の免疫学的薬物；エストロゲン、エストラジオール、プロゲステロン作用薬（progestational）、プロゲステロン、インスリン、カルシトニン、副甲状腺ホルモン及びペプチド及びバソプレシン視床下部放出因子等のホルモン剤；マレイン酸チモロール、レボブノロールＨｃｌ及びベタキソロールＨｃｌ等のベータアドレナリン遮断薬；上皮細胞増殖因子、線維芽細胞増殖因子、血小板由来増殖因子、トランスフォーミング増殖因子ベータ、ソマトトロピン及びフィブロネクチン等の増殖因子；ジクロルフェナミド、アセタゾラミド及びメタゾラミド等の炭酸脱水素酵素阻害剤、ならびに、プロスタグランジン、抗プロスタグランジン及びプロスタグランジン前駆体であってもよい。 Drug solution M includes antibiotics such as tetracycline, chlortetracycline, neomycin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampicin, ciprofloxacin, tobramycin, gentamicin, erythromycin, and penicillin; antifungals such as amphotericin B and miconazole; Antibacterial agents such as sulfonamide, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole and nitrofurazone and sodium propionate; Antiviral agents such as idoxuridine, trifluorothymidine, acyclovir, ganciclovir, interferon; Antiallergic agents such as sodium cromoglycate, antazoline, metapyrylene, chlorpheniramine, pyrilamine, cetirizine and prophenpyridamine; hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone, prednisolone 21-phosphate, acetic acid Anti-inflammatory agents such as prednisolone, fluorometholone, betamethasone and triamcinolone; non-steroidal anti-inflammatory agents such as salicylic acid, indomethacin, ibuprofen, diclofenac, flurbiprofen and piroxicam; decongestants such as phenylephrine, naphazoline and tetrahydrozoline; pilocarpine, Miotic and anticholinesterase drugs such as salicylic acid, acetylcholine chloride, physostigmine, eserine, carbachol, diisopropylfluorophosphate, phosphorine iodide and demecarium bromide; atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine and hydroxyamphetamine mydriatics such as; sympathomimetics such as epinephrine; antineoplastic agents such as carmustine, cisplatin, and fluorouracil; immunological drugs such as vaccines and immunostimulants; estrogen, estradiol, progestational agents, Hormones such as progesterone, insulin, calcitonin, parathyroid hormone and peptides and vasopressin hypothalamic releasing factor; beta-adrenergic blockers such as timolol maleate, levobunolol Hcl and betaxolol Hcl; epidermal growth factor, fibroblast growth factor, platelets Growth factors such as derived growth factor, transforming growth factor beta, somatotropin and fibronectin; carbonic anhydrase inhibitors such as dichlorphenamide, acetazolamide and methazolamide, and prostaglandins, anti-prostaglandins and prostaglandin precursors. It may be the body.
　なお、抗ＶＥＧＦ治療のための薬液Ｍとしては、抗体薬として、例えば、アフリベルセプト、ラニビズマブ、ブロルシズマブ又はファリシマブが好適である。収容室４０の薬液Ｍの充填容量を４０μＬとしたときに、投与装置１０は、２２２ｎＬ／日の放出速度とすることで、１８０日間にわたって継続的に薬液Ｍを放出できる。限られた収容室４０の容量と、抗体薬の安定性向上の観点から、抗体薬の濃度を既存製剤よりも高い濃度とすることが好ましい。薬液Ｍの濃度の上限値は、２２２ｎＬ/日の放出速度において、既存の硝子体内注射の曝露量（ＡＵＣ）を越えない範囲の濃度となるように、設定され得る。 As the drug solution M for anti-VEGF treatment, suitable antibody drugs include, for example, aflibercept, ranibizumab, brolucizumab, or faricimab. When the filling volume of the drug solution M in the storage chamber 40 is 40 μL, the administration device 10 can continuously release the drug solution M over 180 days by setting the release rate to 222 nL/day. In view of the limited capacity of the storage chamber 40 and from the viewpoint of improving the stability of the antibody drug, it is preferable that the concentration of the antibody drug be higher than that of existing formulations. The upper limit of the concentration of drug solution M can be set so that the concentration does not exceed the exposure amount (AUC) of existing intravitreal injection at a release rate of 222 nL/day.
　薬液Ｍがアフリベルセプトであれば、濃度を４０～１６０ｍｇ／ｍｌとすることが好ましい。薬液Ｍがラニビズマブであれば、濃度を１０～８０ｍｇ／ｍｌとすることが好ましい。薬液Ｍがブロルシズマブであれば、濃度を１２０～３２０ｍｇ／ｍｌとすることが好ましい。薬液Ｍがファリシマブであれば、濃度を１２０～２４０ｍｇ／ｍｌとすることが好ましい。なお、抗体薬は人の体温で安定性が低下する傾向があるため、薬液Ｍは、適宜の安定剤を含有してもよい。上記の濃度範囲とすることで、半年あるいはそれ以上といった長期間に亘って、持続的に薬液Ｍを投与することができる。 If the drug solution M is aflibercept, the concentration is preferably 40 to 160 mg/ml. If drug solution M is ranibizumab, the concentration is preferably 10 to 80 mg/ml. If the drug solution M is brolucizumab, the concentration is preferably 120 to 320 mg/ml. If drug solution M is faricimab, the concentration is preferably 120 to 240 mg/ml. In addition, since the stability of antibody drugs tends to decrease at human body temperature, the drug solution M may contain an appropriate stabilizer. By setting the concentration within the above range, the drug solution M can be continuously administered over a long period of time, such as half a year or more.
　本実施形態の投与装置１０は以上のように構成される。上記の投与装置１０は、以下の方法で製造される。 The administration device 10 of this embodiment is configured as described above. The above administration device 10 is manufactured by the following method.
　図２Ａに示すように、投与装置１０の製造方法は、中空円筒状のチューブよりなる筒状体１２の作製工程を有する。この工程は、チューブを所定の長さで切断して筒状体１２とする加工が含まれる。また、筒状体１２の第１端部１２ａ寄りの周壁１２ｅに、穴あけ加工により水分導入口２０が形成される。 As shown in FIG. 2A, the method for manufacturing the administration device 10 includes a step of manufacturing a cylindrical body 12 made of a hollow cylindrical tube. This step includes cutting the tube into a predetermined length to form the cylindrical body 12. Further, a moisture inlet 20 is formed in the peripheral wall 12e near the first end 12a of the cylindrical body 12 by drilling.
　図２Ｂに示すように、投与装置１０の製造方法は、流路部１４を有する連結部材１８の製造工程を有する。連結部材１８の内側に仕切壁２２を構成する充填体と、フィルタ２８とが挿入される。また、連結部材１８にパッキン３０が接合される。その後、穿刺針２６が、パッキン３０及びフィルタ２８を貫通するように挿入される。次に、円筒状の連結部材１８に、カニューレ２４が嵌合等の方法で接合される。その後、カニューレ２４と連結部材１８との境目にシール材３２が塗布される。以上の工程により連結部材１８が形成される。 As shown in FIG. 2B, the method for manufacturing the administration device 10 includes a process for manufacturing a connecting member 18 having a flow path section 14. A filler forming the partition wall 22 and a filter 28 are inserted inside the connecting member 18 . Further, a packing 30 is joined to the connecting member 18. Thereafter, the puncture needle 26 is inserted so as to penetrate the packing 30 and the filter 28. Next, the cannula 24 is joined to the cylindrical connecting member 18 by fitting or the like. Thereafter, a sealant 32 is applied to the boundary between the cannula 24 and the connecting member 18. The connecting member 18 is formed by the above steps.
　次に、図２Ａの筒状体１２及び図２Ｂの連結部材１８に対して滅菌処理が行われる。その後、無菌環境下にて、図３Ａに示すように筒状体１２の内腔１２ｃに、ガスケット３６と、浸透圧発生材３８と、半透膜３４とが挿入される。半透膜３４は、水分導入口２０に隣接する部位に配置される。その後、ガスケット３６よりも第２端部１２ｂ側の内腔１２ｃに薬液Ｍが充填される。特に図示しないが、連結部材１８のスペースにも薬液Ｍが充填される。 Next, the cylindrical body 12 in FIG. 2A and the connecting member 18 in FIG. 2B are sterilized. Thereafter, in a sterile environment, the gasket 36, the osmotic pressure generating material 38, and the semipermeable membrane 34 are inserted into the inner cavity 12c of the cylindrical body 12, as shown in FIG. 3A. The semipermeable membrane 34 is placed adjacent to the moisture inlet 20 . Thereafter, the inner cavity 12c closer to the second end 12b than the gasket 36 is filled with the medical solution M. Although not particularly illustrated, the space of the connecting member 18 is also filled with the chemical solution M.
　次に、図３Ｂに示すように、製造方法は、筒状体１２と連結部材１８との組み立て工程に進む。この工程では、筒状体１２の第２端部１２ｂに連結部材１８の他端１８ｂが接続される。その後、筒状体１２の第１端部１２ａに連結部材１８の一端１８ａが接続される。以上の工程により、本実施形態の投与装置１０の製造工程が完了する。 Next, as shown in FIG. 3B, the manufacturing method proceeds to the step of assembling the cylindrical body 12 and the connecting member 18. In this step, the other end 18b of the connecting member 18 is connected to the second end 12b of the cylindrical body 12. Thereafter, one end 18a of the connecting member 18 is connected to the first end 12a of the cylindrical body 12. Through the above steps, the manufacturing process of the administration device 10 of this embodiment is completed.
　本実施形態の投与装置１０は、以下のように使用される。 The administration device 10 of this embodiment is used as follows.
　図４に示すように、投与装置１０の流路部１４は、流路部１４のカニューレ２４が硝子体に穿刺される。カニューレ２４は、穿刺針２６（図１Ａ参照）とともに、強膜及び脈絡膜を貫通して硝子体に穿刺される。その後、穿刺針２６は、投与装置１０から抜去される。カニューレ２４は、抜止構造２５が眼球の内部に係合する。抜止構造２５は、カニューレ２４の意図しない引き抜けを防止する。 As shown in FIG. 4, in the flow path section 14 of the administration device 10, the cannula 24 of the flow path section 14 punctures the vitreous body. The cannula 24 and the puncture needle 26 (see FIG. 1A) penetrate the sclera and choroid and puncture the vitreous body. Thereafter, the puncture needle 26 is removed from the administration device 10. The cannula 24 has a retaining structure 25 that engages inside the eyeball. The retaining structure 25 prevents the cannula 24 from being unintentionally pulled out.
　その後、投与装置１０の筒状体１２が眼表面と瞼との隙間に配置される。筒状体１２は、円環状に形成されているため、角膜の周囲を取り囲むようにして眼表面に当接して配置される。以上の操作により、投与装置１０の患者への留置手技が完了する。このように、投与装置１０の留置は、強膜の切開が不要であり、低侵襲で簡易な処置で済む。 Thereafter, the cylindrical body 12 of the administration device 10 is placed in the gap between the ocular surface and the eyelid. Since the cylindrical body 12 is formed in an annular shape, it is placed in contact with the ocular surface so as to surround the cornea. With the above operations, the procedure for placing the administration device 10 in the patient is completed. In this way, indwelling the administration device 10 does not require incision of the sclera, and is a minimally invasive and simple procedure.
　図５Ａに示すように、カニューレ２４の先端は、硝子体の内部に位置し、流路２４ａを通じて投与物を硝子体に投与する。図５Ｂに示すように、ポンプ１６は、涙液によって駆動される。涙液は、水分導入口２０を通じて半透膜３４に接触する。涙液中の水分は、半透膜３４を透過して圧力発生室４２に流入する。水分は、圧力発生室４２の浸透圧発生材３８と接して水溶液を生成する。ガスケット３６は、圧力発生室４２の水溶液の浸透圧により駆動される。ガスケット３６は、ゆっくりと筒状体１２の内腔１２ｃを第２端部１２ｂに向けて移動する。ガスケット３６の移動によって、収容室４０の投与物（薬液Ｍ）がカニューレ２４の流路２４ａを通じて硝子体に投与される。 As shown in FIG. 5A, the tip of the cannula 24 is located inside the vitreous body, and administers the drug into the vitreous body through the channel 24a. As shown in FIG. 5B, pump 16 is powered by lachrymal fluid. The tear fluid contacts the semipermeable membrane 34 through the water inlet 20. The water in the tear fluid passes through the semipermeable membrane 34 and flows into the pressure generating chamber 42 . The water comes into contact with the osmotic pressure generating material 38 in the pressure generating chamber 42 to generate an aqueous solution. The gasket 36 is driven by the osmotic pressure of the aqueous solution in the pressure generating chamber 42 . The gasket 36 slowly moves through the inner cavity 12c of the cylindrical body 12 toward the second end 12b. By the movement of the gasket 36, the drug (medicinal solution M) in the storage chamber 40 is administered into the vitreous body through the channel 24a of the cannula 24.
　投与装置１０による薬液Ｍの投与速度は、半透膜３４の厚さによって決まる。投与装置１０は、少なくとも１５日～半年間にわたって投与物の投与を継続する。したがって、頻繁な処置が不要となり、患者への負担を軽減できる。 The speed at which the drug solution M is administered by the administration device 10 is determined by the thickness of the semipermeable membrane 34. The administration device 10 continues to administer the dose for at least 15 days to six months. Therefore, frequent treatments are not required and the burden on the patient can be reduced.
（第２実施形態）
　図６Ａに示すように、本実施形態の投与装置１０Ａは、筒状体１２Ａと、流路部１４Ａと、ポンプ１６と、連結部材１８Ａと、を備える。筒状体１２Ａは、第１端部１２ａと第２端部１２ｂとが連結部材１８Ａを介して連結された円環状の形状を有する。本実施形態の筒状体１２Ａは、ステンレス鋼、ニチノール等の剛性の高い金属チューブによって構成される。筒状体１２Ａは、内部に内腔１２ｃを有する。また、筒状体１２Ａは、第１端部１２ａの近くに水分導入口２０を有する。 (Second embodiment)
As shown in FIG. 6A, the administration device 10A of this embodiment includes a cylindrical body 12A, a flow path section 14A, a pump 16, and a connecting member 18A. The cylindrical body 12A has an annular shape in which a first end 12a and a second end 12b are connected via a connecting member 18A. The cylindrical body 12A of this embodiment is made of a highly rigid metal tube made of stainless steel, nitinol, or the like. The cylindrical body 12A has a lumen 12c inside. Further, the cylindrical body 12A has a moisture inlet 20 near the first end 12a.
　図６Ｂに示すように、ポンプ１６の構成は、図１Ａのポンプ１６と同様であり、ガスケット３６と、浸透圧発生材３８と、半透膜３４とを有する。連結部材１８Ａは、筒状体１２Ａと同様の金属材料によって構成される。連結部材１８Ａの内部は、仕切壁２２により液密及び気密に仕切られている。 As shown in FIG. 6B, the configuration of the pump 16 is similar to that of the pump 16 in FIG. 1A, and includes a gasket 36, an osmotic pressure generating material 38, and a semipermeable membrane 34. The connecting member 18A is made of the same metal material as the cylindrical body 12A. The inside of the connecting member 18A is partitioned off by a partition wall 22 in a liquid-tight and air-tight manner.
　筒状体１２Ａは、第２端部１２ｂの近くに、取付孔１２ｆを有する。取付孔１２ｆには、流路部１４Ａを構成するカニューレ２４Ａの基端部が接合されている。カニューレ２４Ａの基端は、取付孔１２ｆに嵌合している。カニューレ２４Ａと取付孔１２ｆとの接続部は、シール材３２（図１Ａ参照）で封止されてもよい。本実施形態のカニューレ２４Ａは、例えば、ステンレス鋼等の硬質の材料によって形成される。カニューレ２４Ａは、その先端に鋭利な針先４６を有する。カニューレ２４Ａは、針先４６を眼球に穿刺可能である。カニューレ２４Ａは、側部から膨出した抜止構造２５を有する。また、カニューレ２４Ａは、内部に内腔１２ｃに連通する流路２４ａを有する。カニューレ２４Ａの基部に対応する部分の内腔１２ｃには、フィルタ２８が配置されている。 The cylindrical body 12A has a mounting hole 12f near the second end 12b. A proximal end portion of a cannula 24A constituting the flow path portion 14A is joined to the attachment hole 12f. The proximal end of the cannula 24A fits into the attachment hole 12f. The connection between the cannula 24A and the attachment hole 12f may be sealed with a sealant 32 (see FIG. 1A). The cannula 24A of this embodiment is made of, for example, a hard material such as stainless steel. The cannula 24A has a sharp needle tip 46 at its distal end. The cannula 24A is capable of puncturing the eyeball with the needle tip 46. The cannula 24A has a retaining structure 25 bulging from the side. The cannula 24A also has a flow path 24a inside thereof that communicates with the lumen 12c. A filter 28 is disposed in the lumen 12c at a portion corresponding to the base of the cannula 24A.
　本実施形態の投与装置１０Ａは、以下の製造方法で作製される。まず、図７Ａに示すように、直線状の筒状体１２Ａが供給される。この筒状体１２Ａは、水分導入口２０及び取付孔１２ｆを有する。次に、図７Ｂに示すように、筒状体１２Ａに内径保持のための支持棒４８が挿入される。 The administration device 10A of this embodiment is manufactured by the following manufacturing method. First, as shown in FIG. 7A, a linear cylindrical body 12A is supplied. This cylindrical body 12A has a moisture inlet 20 and a mounting hole 12f. Next, as shown in FIG. 7B, a support rod 48 for maintaining the inner diameter is inserted into the cylindrical body 12A.
　次に、図８Ａに示すように、支持棒４８を挿入した筒状体１２Ａを支持棒４８とともに塑性変形させて、円環状の形状に湾曲させる工程が行われる。これにより、筒状体１２Ａが円環状に形づけられる。その後、支持棒４８は、筒状体１２Ａから引き抜かれて除去される。 Next, as shown in FIG. 8A, a step is performed in which the cylindrical body 12A into which the support rod 48 is inserted is plastically deformed together with the support rod 48 to curve into an annular shape. Thereby, the cylindrical body 12A is shaped into an annular shape. Thereafter, the support rod 48 is pulled out and removed from the cylindrical body 12A.
　次に、図８Ｂに示すように、取付孔１２ｆにカニューレ２４Ａの基端部を嵌合させる工程が行われる。この工程により、筒状体１２Ａにカニューレ２４Ａが接合される。その後、図９Ａに示すように、筒状体１２Ａの第１端部１２ａからガスケット３６、浸透圧発生材３８（塩）、及び半透膜３４がこの順に挿入される。また、筒状体１２Ａの第２端部１２ｂからは、薬液Ｍが充填される。 Next, as shown in FIG. 8B, a step of fitting the proximal end of the cannula 24A into the attachment hole 12f is performed. Through this step, the cannula 24A is joined to the cylindrical body 12A. Thereafter, as shown in FIG. 9A, the gasket 36, the osmotic pressure generating material 38 (salt), and the semipermeable membrane 34 are inserted in this order from the first end 12a of the cylindrical body 12A. Moreover, the chemical solution M is filled from the second end 12b of the cylindrical body 12A.
　次に、図９Ｂに示すように、筒状体１２Ａの第１端部１２ａと第２端部１２ｂとに連結部材１８Ａを嵌合させる工程が行われる。以上の工程により、本実施形態の投与装置１０Ａが得られる。 Next, as shown in FIG. 9B, a step of fitting the connecting member 18A into the first end 12a and second end 12b of the cylindrical body 12A is performed. Through the above steps, the administration device 10A of this embodiment is obtained.
　上記の投与装置１０Ａは、カニューレ２４Ａが鋭利な針先４６を有するため、穿刺針２６（図１Ａ）を抜去する操作が不要となり、眼球への取り付け作業が簡略化される。 In the above administration device 10A, since the cannula 24A has a sharp needle tip 46, there is no need to remove the puncture needle 26 (FIG. 1A), and the work of attaching it to the eyeball is simplified.
（第３実施形態）
　図１０に示す、本実施形態の投与装置１０Ｂは、筒状体１２Ｂを有する。筒状体１２Ｂは、第１端部１２ａと第２端部１２ｂとが連結されておらず、円弧形状を有する。第１端部１２ａにおいて、内腔１２ｃが開口する。内腔１２ｃには、第１端部１２ａに近い方から順に、半透膜３４、浸透圧発生材３８、及びガスケット３６が配置されている。筒状体１２Ｂは、第２端部１２ｂに終端壁５０を有する。終端壁５０は内腔１２ｃを閉塞する。筒状体１２Ｂは、第２端部１２ｂの近くには流路部１４Ａを有する。本実施形態の流路部１４Ａは、図６Ａの流路部１４Ａと同様である。本実施形態の投与装置１０Ｂによっても、同様の効果が得られる。 (Third embodiment)
The administration device 10B of this embodiment shown in FIG. 10 has a cylindrical body 12B. The cylindrical body 12B has a first end 12a and a second end 12b that are not connected and has an arc shape. At the first end 12a, a lumen 12c opens. A semipermeable membrane 34, an osmotic pressure generating material 38, and a gasket 36 are arranged in the inner cavity 12c in this order from those closest to the first end 12a. The cylindrical body 12B has a terminal wall 50 at the second end 12b. Terminal wall 50 closes lumen 12c. The cylindrical body 12B has a flow path portion 14A near the second end portion 12b. The flow path section 14A of this embodiment is similar to the flow path section 14A of FIG. 6A. Similar effects can also be obtained with the administration device 10B of this embodiment.
　上記の実施形態は、以下のようにまとめられる。 The above embodiments can be summarized as follows.
　上記の一観点は、結膜嚢内に配置され、投与物を眼内に放出する投与装置１０、１０Ａ、１０Ｂであって、眼表面と瞼との隙間に沿った湾曲形状を有し、内部に前記投与物を収容する内腔１２ｃを有する筒状体１２、１２Ａ、１２Ｂと、前記筒状体から突出し、眼球に穿刺されて前記投与物を前記眼内に投与する流路部１４、１４Ａと、前記内腔から前記流路部に前記投与物を送出するポンプ１６と、を備える。 One aspect of the above is the administration device 10, 10A, 10B which is disposed in the conjunctival sac and discharges a drug into the eye, has a curved shape along the gap between the ocular surface and the eyelid, and has the above-mentioned drug inside. Cylindrical bodies 12, 12A, and 12B each having a lumen 12c that accommodates a dose; flow path portions 14 and 14A that protrude from the tube and puncture the eyeball to administer the dose into the eye; A pump 16 is provided for delivering the drug from the lumen to the flow path section.
　上記の投与装置は、眼内への留置に、結膜や強膜の切開を伴う手技が不要であり、低侵襲で短時間に処置を行うことができる。また、上記の投与装置は、患者への侵襲が小さくなり、患者の負担を軽減できる。 The above-mentioned administration device does not require a procedure that involves incision of the conjunctiva or sclera when it is placed in the eye, and the treatment can be performed in a minimally invasive manner in a short time. Furthermore, the above-described administration device is less invasive to the patient and can reduce the burden on the patient.
　上記の投与装置において、前記ポンプは、前記筒状体の前記内腔に移動可能に配置され、前記内腔を前記投与物が収容される収容領域と加圧領域とに仕切るガスケット３６と、前記加圧領域を加圧する加圧機構とを有してもよい。この投与装置は、ポンプを小型化して筒状体の内部に収容できるため、眼球と瞼との狭い隙間への留置が容易である。 In the above-mentioned administration device, the pump includes a gasket 36 which is movably arranged in the lumen of the cylindrical body and partitions the lumen into a storage area in which the dose is accommodated and a pressurization area; It may also include a pressurizing mechanism that pressurizes the pressurizing area. This administration device can be easily placed in a narrow gap between the eyeball and the eyelid because the pump is miniaturized and can be housed inside the cylindrical body.
　上記の投与装置において、前記加圧機構は、前記筒状体に形成され、水分を前記内腔に導入する水分導入口２０と、前記水分導入口と前記加圧領域との間に配置された半透膜３４と、前記加圧領域に封入され、水に接することで前記加圧領域の内圧を高める浸透圧発生材３８と、を有してもよい。この投与装置は、涙液の水分を利用して浸透圧を発生させることで、投与物を眼球内に投与できる。涙液の補助として点眼液を用いてもよいし、涙液の分泌が投与動作に足りない場合は点眼液を主たる水分の供給源としてもよい。この投与装置は、高い圧力を発生させるため長期間にわたって安定した投与動作を行える。 In the above-mentioned administration device, the pressurizing mechanism is formed in the cylindrical body and is arranged between a moisture inlet 20 that introduces moisture into the inner cavity and between the moisture inlet and the pressurizing area. The device may include a semipermeable membrane 34 and an osmotic pressure generating material 38 that is sealed in the pressurized region and increases the internal pressure of the pressurized region when it comes into contact with water. This administration device can administer a drug into the eyeball by generating osmotic pressure using the water content of lachrymal fluid. Eye drops may be used as a supplement to the lacrimal fluid, or if the secretion of lachrymal fluid is insufficient for the administration operation, the eye drops may be used as the main source of water. This dosing device generates high pressure and can perform stable dosing operations over a long period of time.
　上記の投与装置において、前記流路部は、前記筒状体から突出した柔軟なカニューレ２４と、前記カニューレの内部を挿通し、先端に鋭利な針先２６ａを有する穿刺針２６と、を有してもよい。この投与装置は、柔軟なカニューレを用いることで、生体組織への刺激を軽減できる。 In the above administration device, the flow path section includes a flexible cannula 24 protruding from the cylindrical body, and a puncture needle 26 that is inserted through the cannula and has a sharp needle tip 26a at its tip. You can. By using a flexible cannula, this administration device can reduce stimulation to living tissue.
　上記の投与装置において、前記流路部は、前記筒状体から突出した硬質なカニューレ２４Ａを有し、前記カニューレは、先端に形鋭な針先４６を有してもよい。この投与装置は、カニューレを直接眼球に穿刺できるため、投与装置の留置作業を簡素化できる。 In the above administration device, the flow path portion has a hard cannula 24A protruding from the cylindrical body, and the cannula may have a sharp needle tip 46 at its tip. This administration device allows the cannula to be directly punctured into the eyeball, thereby simplifying the operation of indwelling the administration device.
　上記の投与装置において、前記カニューレは、側部から突出した抜止構造２５を有してもよい。この投与装置は、留置時や使用中のカニューレの引き抜けを防止できる。 In the above administration device, the cannula may have a retaining structure 25 protruding from the side. This administration device can prevent the cannula from being pulled out during indwelling or use.
　上記の投与装置において、前記筒状体は環状であってもよい。この投与装置は、眼球の周縁部に沿って安定して配置できる。 In the above administration device, the cylindrical body may be annular. This administration device can be stably placed along the circumference of the eyeball.
　上記の投与装置において、前記筒状体は、柔軟性材料で構成されてもよい。この投与装置は、周辺の組織への刺激を軽減できる。 In the above administration device, the cylindrical body may be made of a flexible material. This administration device can reduce irritation to surrounding tissue.
　上記の投与装置において、前記投与物は眼科用ＶＥＧＦ阻害剤であってもよい。この投与装置は、眼球の内部に継続的に眼科用ＶＥＧＦ阻害剤を投与できるため、加齢黄斑変性や網膜静脈閉塞症、糖尿病網膜症等の網膜の疾患の抗ＶＥＧＦ治療に好適に使用できる。 In the above administration device, the administration product may be an ophthalmological VEGF inhibitor. Since this administration device can continuously administer an ophthalmic VEGF inhibitor into the inside of the eyeball, it can be suitably used for anti-VEGF treatment of retinal diseases such as age-related macular degeneration, retinal vein occlusion, and diabetic retinopathy.
　上記の投与装置において、前記投与物は４０～１６０ｍｇ／ｍｌの濃度でアフリベルセプトを含んでもよい。この投与装置は、比較的高い濃度のバイオ製剤を含むため、長期間にわたって投与物の投与を行うことができる。また、投与装置は、バイオ製剤の保存環境として過酷な体温環境下で使用される。この投与装置は、上記の濃度とすることでバイオ製剤の安定性を高めることができ、長期間にわたって抗ＶＥＧＦ治療を行うことができる。 In the above administration device, the dosage may contain aflibercept at a concentration of 40 to 160 mg/ml. This administration device contains a relatively high concentration of the biologic agent and thus can administer the dose over an extended period of time. Furthermore, the administration device is used in a harsh temperature environment as a storage environment for biologics. With this administration device, the stability of the biopreparation can be increased by setting the above concentration, and anti-VEGF treatment can be performed over a long period of time.
　上記の投与装置において、前記投与物は１０～８０ｍｇ／ｍｌの濃度でラニビズマブを含んでもよい。この投与装置は、比較的高い濃度の抗体薬を含むため、長期間にわたって投与物の投与を行うことができる。また、投与装置は、抗体薬の保存環境として過酷な体温環境下で使用される。この投与装置は、上記の濃度とすることで抗体薬の安定性を高めることができ、長期間にわたって抗ＶＥＧＦ治療を行うことができる。 In the above administration device, the dosage may contain ranibizumab at a concentration of 10 to 80 mg/ml. Since this administration device contains a relatively high concentration of antibody drug, it is possible to administer the dose over an extended period of time. Furthermore, the administration device is used in a harsh temperature environment as a storage environment for antibody drugs. With this administration device, the stability of the antibody drug can be increased by setting the above concentration, and anti-VEGF treatment can be performed over a long period of time.
　上記の投与装置において、前記投与物は１２０～３２０ｍｇ／ｍｌの濃度でブロルシズマブを含んでもよい。この投与装置は、比較的高い濃度の抗体薬を含むため、長期間にわたって投与物の投与を行うことができる。また、投与装置は、抗体薬の保存環境として過酷な体温環境下で使用される。この投与装置は、上記の濃度とすることで抗体薬の安定性を高めることができ、長期間にわたって抗ＶＥＧＦ治療を行うことができる。 In the above administration device, the dosage may contain brolucizumab at a concentration of 120 to 320 mg/ml. Since this administration device contains a relatively high concentration of antibody drug, it is possible to administer the dose over an extended period of time. Furthermore, the administration device is used in a harsh temperature environment as a storage environment for antibody drugs. With this administration device, the stability of the antibody drug can be increased by setting the above concentration, and anti-VEGF treatment can be performed over a long period of time.
　上記の投与装置において、前記投与物は１２０～２４０ｍｇ／ｍｌの濃度でファリシマブを含んでもよい。この投与装置は、比較的高い濃度の抗体薬を含むため、長期間にわたって投与物の投与を行うことができる。また、投与装置は、抗体薬の保存環境として過酷な体温環境下で使用される。この投与装置は、上記の濃度とすることで抗体薬の安定性を高めることができ、長期間にわたって抗ＶＥＧＦ治療を行うことができる。 In the above administration device, the dosage may contain faricimab at a concentration of 120-240 mg/ml. Since this administration device contains a relatively high concentration of antibody drug, it is possible to administer the dose over an extended period of time. Furthermore, the administration device is used in a harsh temperature environment as a storage environment for antibody drugs. With this administration device, the stability of the antibody drug can be increased by setting the above concentration, and anti-VEGF treatment can be performed over a long period of time.
　別の一観点は、上記の投与装置を用いた投与方法であって、前記筒状体が結膜嚢に配置され、前記流路部が眼内に穿刺された状態で、前記ポンプを作動させて前記筒状体の内腔に収容された投与物を眼内に投与する、投与方法にある。この投与方法によれば、長期間にわたって、継続的に眼内に投与物を投与できる。 Another aspect is an administration method using the above-mentioned administration device, in which the pump is operated with the cylindrical body disposed in the conjunctival sac and the flow path portion punctured into the eye. The method of administration includes intraocularly administering the drug housed in the lumen of the cylindrical body. According to this administration method, the drug can be continuously administered into the eye over a long period of time.
　上記の投与方法において、前記ポンプは涙液によって動作する浸透圧ポンプであってもよい。この投与方法によれば、長期間に亘ってメンテナンスを行うことなく投与物を投与でき、患者の負担を更に軽減できる。 In the above administration method, the pump may be an osmotic pump operated by lachrymal fluid. According to this administration method, the drug can be administered over a long period of time without maintenance, further reducing the burden on the patient.
　なお、本発明は、上記した開示に限らず、本発明の要旨を逸脱することなく、種々の構成を採り得る。 Note that the present invention is not limited to the above disclosure, and can take various configurations without departing from the gist of the present invention.

Claims (15)

  1. 　結膜嚢内に配置され、投与物を眼内に放出する投与装置であって、
    　眼表面と、瞼との隙間に沿った湾曲形状を有し、内部に前記投与物を収容する内腔を有する筒状体と、
    　前記筒状体から突出し、眼球に穿刺されて前記投与物を前記眼内に投与する流路部と、
    　前記内腔から前記流路部に前記投与物を送出するポンプと、を備えた、
    　投与装置。     A dosing device positioned within the conjunctival sac and delivering a dose into the eye, the dosing device comprising:
    a cylindrical body having a curved shape along the gap between the ocular surface and the eyelid, and having a lumen therein for accommodating the administration;
    a channel portion that protrudes from the cylindrical body and punctures the eyeball to administer the drug into the eye;
    a pump that delivers the drug from the lumen to the flow path section;
    Dosing device.
  2. 　請求項１記載の投与装置であって、前記ポンプは、前記筒状体の前記内腔に移動可能に配置され、前記内腔を前記投与物が収容される収容領域と加圧領域とに仕切るガスケットと、前記加圧領域を加圧する加圧機構とを有する、
    　投与装置。     2. The administration device according to claim 1, wherein the pump is movably arranged in the lumen of the cylindrical body, and partitions the lumen into a storage area where the administration product is accommodated and a pressurization area. comprising a gasket and a pressurizing mechanism that pressurizes the pressurized area;
    Dosing device.
  3. 　請求項２記載の投与装置であって、前記加圧機構は、前記筒状体に形成され、水分を前記内腔に導入する水分導入口と、前記水分導入口と前記加圧領域との間に配置された半透膜と、前記加圧領域に封入され、水に接することで前記加圧領域の内圧を高める浸透圧発生材と、を有する、
    　投与装置。     3. The administration device according to claim 2, wherein the pressurizing mechanism is formed in the cylindrical body and includes a moisture inlet for introducing moisture into the inner cavity, and a gap between the moisture inlet and the pressurizing area. and an osmotic pressure generating material that is sealed in the pressurized region and increases the internal pressure of the pressurized region when it comes into contact with water,
    Dosing device.
  4. 　請求項１～３のいずれか１項に記載の投与装置であって、前記流路部は、前記筒状体から突出した柔軟なカニューレと、前記カニューレの内部を挿通し、先端に鋭利な針先を有する穿刺針と、を有する、
    　投与装置。     4. The administration device according to claim 1, wherein the flow path section includes a flexible cannula protruding from the cylindrical body, and a needle inserted through the inside of the cannula and having a sharp tip. a puncture needle having a tip;
    Dosing device.
  5. 　請求項１～３のいずれか１項に記載の投与装置であって、前記流路部は、前記筒状体から突出した硬質なカニューレを有し、前記カニューレは、先端に鋭利な針先を有する、
    　投与装置。     4. The administration device according to claim 1, wherein the flow path section has a hard cannula protruding from the cylindrical body, and the cannula has a sharp needle tip at its tip. have,
    Dosing device.
  6. 　請求項４又は５記載の投与装置であって、前記カニューレは、側部から突出した抜止構造を有する、
    　投与装置。     The administration device according to claim 4 or 5, wherein the cannula has a withdrawal prevention structure protruding from the side.
    Dosing device.
  7. 　請求項１～６のいずれか１項に記載の投与装置であって、前記筒状体は環状である、投与装置。 The administration device according to any one of claims 1 to 6, wherein the cylindrical body is annular.
  8. 　請求項１～７のいずれか１項に記載の投与装置であって、前記筒状体は、柔軟性材料で構成される、投与装置。 The administration device according to any one of claims 1 to 7, wherein the cylindrical body is made of a flexible material.
  9. 　請求項１～８のいずれか１項に記載の投与装置であって、前記投与物は眼科用ＶＥＧＦ阻害剤である、
    　投与装置。     The administration device according to any one of claims 1 to 8, wherein the administration product is an ophthalmic VEGF inhibitor.
    Dosing device.
  10. 　請求項９記載の投与装置であって、
    　前記投与物は４０～１６０ｍｇ／ｍｌの濃度でアフリベルセプトを含む、
    　投与装置。     The administration device according to claim 9,
    the dosage comprises aflibercept at a concentration of 40-160 mg/ml;
    Dosing device.
  11. 　請求項９記載の投与装置であって、
    　前記投与物は１０～８０ｍｇ／ｍｌの濃度でラニビズマブを含む、
    　投与装置。     The administration device according to claim 9,
    the dosage comprises ranibizumab at a concentration of 10-80 mg/ml;
    Dosing device.
  12. 　請求項９記載の投与装置であって、
    　前記投与物は１２０～３２０ｍｇ／ｍｌの濃度でブロルシズマブを含む、
    　投与装置。     The administration device according to claim 9,
    the dosage comprises brolucizumab at a concentration of 120-320 mg/ml;
    Dosing device.
  13. 　請求項９記載の投与装置であって、
    　前記投与物は１２０～２４０ｍｇ／ｍｌの濃度でファリシマブを含む、
    　投与装置。     The administration device according to claim 9,
    the dosage comprises faricimab at a concentration of 120-240 mg/ml;
    Dosing device.
  14. 　請求項１記載の投与装置を用いた投与方法であって、
    　前記筒状体が結膜嚢に配置され、前記流路部が眼内に穿刺された状態で、前記ポンプを作動させて前記筒状体の内腔に収容された投与物を眼内に投与する、
    　投与方法。     An administration method using the administration device according to claim 1, comprising:
    With the cylindrical body disposed in the conjunctival sac and the flow path portion punctured into the eye, the pump is operated to administer the drug contained in the lumen of the cylindrical body into the eye. ,
    Method of administration.
  15. 　請求項１４記載の投与方法であって、
    　前記ポンプは涙液によって動作する浸透圧ポンプである、
    　投与方法。     15. The method of administration according to claim 14,
    the pump is an osmotic pump operated by lachrymal fluid;
    Method of administration.
PCT/JP2023/006137 2022-03-08 2023-02-21 Administration device and administration method WO2023171360A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6251090B1 (en) * 1994-12-12 2001-06-26 Robert Logan Avery Intravitreal medicine delivery
JP2014530044A (en) * 2011-09-14 2014-11-17 フォーサイト・ビジョン５・インコーポレイテッドＦｏｒｓｉｇｈｔｖｉｓｉｏｎ５，Ｉｎｃ． Eye insertion device and method
WO2016031093A1 (en) * 2014-08-28 2016-03-03 株式会社ユニバーサルビュー Ocular insert device
US20160243288A1 (en) * 2015-02-23 2016-08-25 Tissuetech, Inc. Apparatuses and methods for treating ophthalmic diseases and disorders
US20180092776A1 (en) * 2016-09-30 2018-04-05 Sara Heikali Method and device for treating and managing diseased ocular tissue

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6251090B1 (en) * 1994-12-12 2001-06-26 Robert Logan Avery Intravitreal medicine delivery
JP2014530044A (en) * 2011-09-14 2014-11-17 フォーサイト・ビジョン５・インコーポレイテッドＦｏｒｓｉｇｈｔｖｉｓｉｏｎ５，Ｉｎｃ． Eye insertion device and method
WO2016031093A1 (en) * 2014-08-28 2016-03-03 株式会社ユニバーサルビュー Ocular insert device
US20160243288A1 (en) * 2015-02-23 2016-08-25 Tissuetech, Inc. Apparatuses and methods for treating ophthalmic diseases and disorders
US20180092776A1 (en) * 2016-09-30 2018-04-05 Sara Heikali Method and device for treating and managing diseased ocular tissue

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