Administration device and administration method

Abstract

To provide an administration device which can continuously administer an administration substance into the eye over a long period of time, which can bring about a stable effect and which can reduce the frequency of a treatment, and an administration method.SOLUTION: An administration device comprises: a cylindrical body 12 which has a curved shape along a clearance between an eye surface and the eyelid and within which an inner cavity 12c for housing an administration substance is provided; a channel part 14 which protrudes the cylindrical body 12 and which is inserted into the eyeball so as to administer the administration substance into the eye; and a pump 16 which delivers the administration substance into the channel part 14 from the inner cavity 12c. The cylindrical body 12 is arranged within the conjunctival sac so as to discharge the administration substance into the eye.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to an administration device and method for delivering a drug into the eye. [Background technology]

[0002] 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 vision. It is known that these diseases involve VEGF (vascular endothelial growth factor) in the body, which promotes the proliferation of new blood vessels and worsens macular edema. Anti-VEGF treatment is used to treat such diseases. Anti-VEGF treatment is a treatment that improves macular edema and inhibits the progression of the disease by administering therapeutic drugs such as VEGF inhibitors, which suppress the action of VEGF, into the eye.

[0003] Current anti-VEGF treatments place a heavy burden on patients because the drug is administered through a syringe needle, and there is a limit to the number of times it can be administered. In addition, there are periods when the drug is not present in sufficient concentrations inside the vitreous (inside the eye), which can lead to a gradual decline in vision.

[0004] To solve such problems, Patent Document 1 discloses an intraocular device that has a drug solution tank that is implanted in the eye and a connection port for refilling, and gradually releases a therapeutic drug. This device can continuously administer the drug solution into the vitreous body by performing a procedure to refill the drug solution tank every six months. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent No. 5577354 Summary of the Invention [Problem to be solved by the invention]

[0006] However, the device of Patent Document 1 requires a procedure involving incision of the conjunctiva and sclera for placement in the eye, and requires large-scale equipment, so that the procedure cannot be performed in a short time in a consultation room like intravitreal injection. In addition, conventional devices are highly invasive to the patient when placed in the eye, and often cause adverse events such as conjunctival inflammation and bleeding, which places a heavy burden on the patient.

[0007] Furthermore, the above problems are not limited to anti-VEGF therapy, but also commonly occur in the continuous intraocular administration of various biologics and / or small molecule drugs, such as inhibitors such as antibody drugs and antagonists, agonists, nucleic acid drugs, peptide drugs, gene therapy drugs, and therapeutic cells.

[0008] Therefore, there is a demand for a device that can complete the treatment with the same burden as an injection, thereby reducing the burden on patients and doctors.

[0009] An object of the present invention is to solve the above-mentioned problems. [Means for solving the problem]

[0010] One aspect of the disclosure below is an administration device that is placed in the conjunctival sac and releases an administration substance into the eye, the administration device comprising: a tubular body having a curved shape that fits the gap between the ocular surface and the eyelid and having an internal cavity for containing the administration substance; a flow path portion that protrudes from the tubular body and punctures the eyeball to administer the administration substance into the eye; and a pump that delivers the administration substance from the internal cavity to the flow path portion.

[0011] Another aspect is an administration method using the administration device of the above aspect, in which the tubular body is placed in the conjunctival sac and the flow path portion is inserted into the eye, and the pump is operated to administer the substance contained in the inner cavity of the tubular body into the eye. Effect of the Invention

[0012] The administration device of the above aspect does not require incision of the conjunctiva or sclera and can be attached to the patient through minimally invasive procedures. In addition, the administration device can continuously administer the substance into the eye for a long period of time, so that a stable effect can be obtained and the frequency of treatment can be reduced. Therefore, the administration device can reduce the burden on the patient and the doctor. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1A is a plan view of a dispensing device according to a first embodiment, and FIG. 1B is a cross-sectional view of the dispensing device of FIG. 1A. [Diagram 2] FIG. 2A is an explanatory diagram of a cylindrical body used in the manufacture of the administration device of FIG. 1A, and FIG. 2B is a plan view of a connecting member. [Diagram 3] FIG. 3A is an explanatory diagram of a processing step for the cylindrical body of FIG. 1, and FIG. 3B is an explanatory diagram of a step of connecting a connecting member to the cylindrical body that has been subjected to the processing step of FIG. 3A. [Figure 4] FIG. 4 is an illustration of a method of using the administration device of FIG. 1A. [Diagram 5] 5A is a cross-sectional view of the vicinity of a flow path portion of the administration device of FIG. 4, and FIG. 5B is a diagram for explaining the operation of the administration device of FIG. [Figure 6] FIG. 6A is a plan view of a dispensing device according to a second embodiment, and FIG. 6B is a cross-sectional view of the dispensing device of FIG. 6A. [Figure 7] FIG. 7A is an explanatory diagram of a cylindrical body used in the production of the administration device of FIG. 6A, and FIG. 7B is an explanatory diagram (part 1) of bending the cylindrical body. [Figure 8] FIG. 8A is an explanatory diagram (part 2) of bending a cylindrical body, and FIG. 8B is an explanatory diagram of a step of connecting a flow path portion to the cylindrical body of FIG. 8A. [Figure 9] 9A is an explanatory diagram of a process of inserting a drug solution, a gasket, an osmotic pressure generating material, and a semipermeable membrane into the cylindrical body of FIG. 8B, and FIG. 9B is an explanatory diagram of a process of connecting a connecting member to the cylindrical body of FIG. 9A. [Figure 10] FIG. 10 is a plan view of the administration device according to the third embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] (First embodiment) The administration device 10 of this embodiment shown in Fig. 1A is a device that continuously administers a medicinal liquid M (administered substance) into a patient's eye (see Fig. 4) using an osmotic pump. The administration device 10 has a cylindrical body 12, a flow path section 14, and a pump 16.

[0015] The cylindrical body 12 has a shape in which flexible tubes are connected in an annular shape. A first end 12a and a second end 12b of the cylindrical body 12 are connected by a connecting member 18. As shown in FIG. 1B, the cylindrical body 12 has an inner cavity 12c inside. The inner cavity 12c has a hollow shape with a circular cross section and a smooth inner circumferential 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 to communicate the inner cavity 12c with the outside space.

[0016] The material of the cylindrical body 12 in this embodiment is preferably a flexible material. The cylindrical body 12 is made of, for example, 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 stored in the gap between the eyelid and the eyeball. Specifically, the diameter D of the ring formed by the cylindrical body 12 is a circular shape 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 retained for a long period of time in the conjunctival sac, which is the gap between the eyeball and the eyelid.

[0017] It is desirable that the cylindrical body 12 has an internal volume sufficient for supplying the medicinal liquid M to the lumen 12c for a long period of time. Therefore, the cylindrical body 12 can be formed into a cylindrical shape with an outer diameter dimension φ1 of 1 to 3.2 mm. The cylindrical body 12 having such an outer diameter dimension φ1 can be accommodated in the conjunctival sac. 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 cylindrical body 12 having an inner diameter dimension φ2 of, for example, 1.1 to 1.2 mm has a volume of the lumen 12c of 60 to 106 μL. Such a cylindrical body 12 can accommodate the medicinal liquid M in an amount (for example, 40 μL) required for sustained release for about six months and the pump 16 in the lumen 12c.

[0018] The inner cavity 12c of the cylindrical body 12 is divided by a partition wall 22 provided in the connecting member 18. The partition wall 22 divides the inner cavity 12c into a first end 12a and a second end 12b in a liquid-tight and air-tight manner. The partition wall 22 is disposed between the flow path portion 14 and the moisture inlet 20.

[0019] The cylindrical body 12 may be covered with a soft biocompatible material such as silicone resin or a swelling polymer (CMC-Na, HPMC, PVP, etc.) on the entire outer circumferential surface or the part that contacts the eyeball. Such a cylindrical body 12 can reduce invasiveness.

[0020] The flow path portion 14 is provided in the connecting member 18. The position of the flow path portion 14 does not have to be the connecting member 18, and may be disposed near the second end 12b of the cylindrical body 12. The flow path portion 14 has 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 center line of the cylindrical body 12. The base end of the cannula 24 is joined to the connecting member 18 (or the cylindrical body 12). The cannula 24 has a flow path 24a inside. The cannula 24 of this embodiment is formed so that the tip is almost without a step with the puncture needle 26. The state of having almost without a step includes a state in which the outer circumferential side of the tip of the cannula 24 is smoothly chamfered, or a state in which the tip of the cannula 24 has a shape inclined at an obtuse angle. The cannula 24, which has almost no step at its tip with the puncture needle 26, has little puncture resistance and can be smoothly inserted into the eyeball. The cannula 24 is also made of a flexible material, which can reduce irritation to the eyeball. The flow path 24a of the cannula 24 communicates with the lumen 12c of the cylindrical body 12 via a filter 28.

[0021] The cannula 24 has a diameter 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 the cannula 24 can penetrate the sclera and choroid of the eyeball to reach the vitreous body. The cannula 24 has a retaining structure 25 protruding outward from the side. The retaining structure 25 is a protrusion that engages with the tissue of the eyeball when the cannula 24 is inserted into the eyeball to prevent the cannula 24 from being pulled out. The retaining structure 25 is not limited to a protrusion, and may be a recess. The retaining structure 25 is not limited to engagement with the tissue, and may be an appropriate structure that prevents the cannula 24 from being pulled out by fitting or frictional resistance.

[0022] When the administration device 10 is used to administer the medicinal solution M to the sclera or choroid, the protruding length of the cannula 24 may be shorter than the above example. The protruding length of the cannula 24 is appropriately selected depending on the site to which the medicinal solution M is to be administered.

[0023] Such a 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 base end of the cannula 24 is joined to the connecting member 18. A sealant 32 is disposed at the boundary between the cannula 24 and the connecting member 18 by coating or the like. The sealant 32 is made of a silicone resin or a swelling polymer, and seals the gap at the joint between the cannula 24 and the connecting member 18 liquid-tight and air-tight.

[0024] Filter 28 is disposed within connecting member 18 inside cannula 24. Filter 28 is located between flow path 24a and lumen 12c. Filter 28 removes contaminants from the dosage delivered from lumen 12c to flow path 24a.

[0025] In an initial state, which is a product delivery state, the puncture needle 26 is inserted through the flow path 24a of the cannula 24. The puncture needle 26 has an inner diameter slightly smaller than the inner diameter of the flow path 24a. The puncture needle 26 is formed longer than the cannula 24. The needle tip 26a of the puncture needle 26 protrudes from the tip of the cannula 24, and the base 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 by puncturing the eyeball when introducing the cannula 24 into the interior of the eyeball. The puncture needle 26 is removed from the base end side after the cannula 24 is introduced into the interior of the eyeball.

[0026] The packing 30 is joined to the connecting member 18. The packing 30 is disposed in a portion of the connecting member 18 through which the puncture needle 26 is inserted. In an initial state, the puncture needle 26 penetrates the packing 30. The packing 30 is formed 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 passed, and closes the portion of the connecting member 18 through which the puncture needle 26 passes in a liquid-tight and air-tight manner.

[0027] The connecting member 18 is a cylindrical member having approximately the same inner diameter and outer diameter as the cylindrical body 12. One end 18a of the connecting member 18 is fitted 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 and joined to the outer periphery or inner cavity 12c of the second end 12b of the cylindrical body 12. The connecting member 18 maintains the cylindrical body 12 in an annular shape. The connecting member 18 is made of the same material as the cylindrical body 12.

[0028] The pump 16 (pressurizing mechanism) is an osmotic pump that is driven by osmotic pressure. The pump 16 includes a semipermeable membrane 34, a gasket 36, and an osmotic pressure generating material 38.

[0029] The gasket 36 is disposed in the cavity 12c. The gasket 36 divides the cavity 12c into a storage chamber 40 (storage area) on the second end 12b side and a pressure generating chamber 42 (pressurized area) on the first end 12a side in a liquid-tight and air-tight manner. The gasket 36 is movable while sliding inside the cavity 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 formed of a rubber material such as, for example, a styrene-based elastomer, an olefin-based elastomer, a urethane elastomer, a butyl rubber, or a mixture of these. The gasket 36 has a cylindrical shape with an outer diameter slightly larger than the cavity 12c.

[0030] 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. The sodium chloride dissolves in the water supplied through the semipermeable membrane 34 to generate saturated saline solution. 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 the tear fluid and the osmotic pressure of the saturated saline solution. The pressure in the pressure generating chamber 42 displaces the gasket 36, causing the administration substance in the storage chamber 40 to be delivered.

[0031] The semipermeable membrane 34 is a cylindrical member, and fills the lumen 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 having a porous membrane. The semipermeable membrane 34 has pores with an average pore size of, for example, 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 through. The administration device 10 is capable of adjusting the release rate of the administered substance by adjusting the thickness of the semipermeable membrane 34.

[0032] The release rate dm / dt of the administered substance is expressed as dm / dt = (A / h) × k × ΔΠ × c, where h is the thickness of semipermeable membrane 34, A is the cross-sectional area, k is the effective permeability of semipermeable membrane 34, ΔΠ is the osmotic pressure difference between pressure generating chamber 42 and the surrounding tissue, and c is the concentration of the administered substance inside storage chamber 40.

[0033] In the above formula, the effective permeability k of the semipermeable membrane 34 is a constant value determined by the material. Furthermore, since a large excess of sodium chloride is enclosed inside the pressure generating chamber 42, the concentration inside is a saturated concentration, and the osmotic pressure difference ΔΠ is an approximately constant value. Furthermore, the concentration c of the drug solution M, which is the administered substance, is constant when decomposition due to instability is not taken into consideration. Therefore, the release rate of the administered substance can be adjusted by the thickness of the semipermeable membrane 34.

[0034] The storage chamber 40 of the lumen 12c is filled with a drug solution M, which is an administration product. The drug solution M may contain an ophthalmic VEGF inhibitor. Examples of the drug solution M include biopharmaceuticals, antibody drugs, nucleic acid drugs, peptide drugs, therapeutic genes, therapeutic cell-containing liquids, and low-molecular drugs. Examples of antibody drugs include ranibizumab, bevacizumab, brolucizumab, and faricimab. Examples of nucleic acid drugs include aptamers, such as pegaptanib sodium, siRNA, antisense oligonucleotides, and decoys. Examples of other VEGF inhibitors include aflibercept and abiciper pegol. The storage chamber 40 may contain an AAV vector (for gene introduction). Examples of therapeutic cell-containing liquids include photoreceptor cell-containing liquids. Examples of low molecular weight drugs include sirolimus, triamcinolone acetonide, dexamethasone, bimatoprost, travoprost, latanoprost, tafluprost, omidenepag, cepetaprost, netarsudil, fasudil, timolol, levobunolol, brimonidine, dorzolamide, and brinzolamide.

[0035] The drug solution M contains antibiotics such as tetracycline, chlortetracycline, neomycin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampicin, ciprofloxacin, tobramycin, gentamicin, erythromycin, and penicillin; antifungal agents such as amphotericin B and miconazole; antibacterial agents such as sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole, nitrofurazone, and sodium propionate; idoxuridine, trifluridine, and the like. antiviral agents such as fluorocymidine, acyclovir, ganciclovir, interferon, etc.; antiallergic agents such as sodium cromoglycate, antazoline, methapyrilene, chlorpheniramine, pyrilamine, cetirizine, profenpyridamine, etc.; anti-inflammatory agents such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone, prednisolone 21-phosphate, prednisolone acetate, fluorometholone, betamethasone, triamcinolone, etc.; Nonsteroidal anti-inflammatory drugs such as salicylic acid, indomethacin, ibuprofen, diclofenac, flurbiprofen and piroxicam; decongestants such as phenylephrine, naphazoline and tetrahydrozoline; miotics and anticholinesterase drugs such as pilocarpine, salicylic acid, acetylcholine chloride, physostigmine, eserine, carbachol, diisopropylfluorophosphate, phosphonaphthalene iodide and demecarium bromide; atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine and mydriatics such as hydroxyamphetamine and hydroxyamphetamine; sympathomimetics such as epinephrine; antineoplastic agents such as carmustine, cisplatin and fluorouracil; immunological drugs such as vaccines and immunostimulants; hormonal agents such as estrogen, estradiol, progestational, progesterone, insulin, calcitonin, parathyroid hormone and peptides and vasopressin hypothalamic releasing factor; beta adrenergic blockers such as timolol maleate, levobunolol Hcl and betaxolol Hcl;Growth factors such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta, somatotropin and fibronectin; carbonic anhydrase inhibitors such as dichlorphenamide, acetazolamide and methazolamide, as well as prostaglandins, antiprostaglandins and prostaglandin precursors;

[0036] In addition, as the drug solution M for anti-VEGF treatment, for example, aflibercept, ranibizumab, brolucizumab, or faricimab is suitable as an antibody drug. 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 for 180 days by setting the release rate at 222 nL / day. From the viewpoint of the limited capacity of the storage chamber 40 and improving the stability of the antibody drug, it is preferable to set the concentration of the antibody drug to a higher concentration than that of existing formulations. The upper limit of the concentration of the drug solution M can be set so that the concentration does not exceed the exposure amount (AUC) of existing intravitreal injections at a release rate of 222 nL / day.

[0037] If the drug solution M is aflibercept, the concentration is preferably 40 to 160 mg / ml. If the 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 the drug solution M is faricimab, the concentration is preferably 120 to 240 mg / ml. Since antibody drugs tend to become less stable 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 administered continuously for a long period of time, such as six months or more.

[0038] The administration device 10 of this embodiment is configured as described above. The administration device 10 is manufactured by the following method.

[0039] 2A, the manufacturing method of the administration device 10 includes a step of producing a tubular body 12 made of a hollow cylindrical tube. This step includes a process of cutting the tube to a predetermined length to obtain the tubular body 12. In addition, a moisture inlet 20 is formed by drilling a peripheral wall 12e near a first end 12a of the tubular body 12.

[0040] As shown in FIG. 2B, the manufacturing method of the administration device 10 includes a manufacturing step of a connecting member 18 having a flow path portion 14. A filler constituting the partition wall 22 and a filter 28 are inserted inside the connecting member 18. A packing 30 is also joined to the connecting member 18. Then, a puncture needle 26 is inserted so as to penetrate the packing 30 and the filter 28. Next, a cannula 24 is joined to the cylindrical connecting member 18 by a method such as fitting. Then, 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.

[0041] Next, the cylindrical body 12 of Fig. 2A and the connecting member 18 of Fig. 2B are subjected to a sterilization treatment. Thereafter, in a sterile environment, a gasket 36, an osmotic pressure generating material 38, and a 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 disposed at a location adjacent to the moisture inlet 20. Then, the medicinal liquid M is filled into the inner cavity 12c on the second end 12b side of the gasket 36. Although not particularly shown, the medicinal liquid M is also filled into the space of the connecting member 18.

[0042] Next, as shown in Fig. 3B, the manufacturing method proceeds to a process of assembling the tubular body 12 and the connecting member 18. In this process, the other end 18b of the connecting member 18 is connected to the second end 12b of the tubular body 12. Then, one end 18a of the connecting member 18 is connected to the first end 12a of the tubular body 12. Through the above processes, the manufacturing process of the administration device 10 of this embodiment is completed.

[0043] The administration device 10 of this embodiment is used as follows.

[0044] As shown in Fig. 4, the cannula 24 of the flow path section 14 of the administration device 10 is inserted into the vitreous body. The cannula 24, together with the puncture needle 26 (see Fig. 1A), penetrates the sclera and choroid and is inserted into the vitreous body. The puncture needle 26 is then removed from the administration device 10. The cannula 24 has a retention structure 25 that engages with the inside of the eyeball. The retention structure 25 prevents the cannula 24 from being unintentionally pulled out.

[0045] 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. The above operations complete the procedure for placing the administration device 10 in the patient. In this way, placement of the administration device 10 does not require an incision in the sclera, and is a minimally invasive and simple procedure.

[0046] As shown in FIG. 5A, the tip of the cannula 24 is located inside the vitreous body, and administers the administration substance to the vitreous body through the flow path 24a. As shown in FIG. 5B, the pump 16 is driven by the tear fluid. The tear fluid comes into contact with the semipermeable membrane 34 through the water inlet 20. The water in the tear fluid permeates the semipermeable membrane 34 and flows into the pressure generating chamber 42. The water comes into contact with the osmotic pressure generating material 38 of 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. Due to the movement of the gasket 36, the administration substance (medicinal solution M) in the storage chamber 40 is administered to the vitreous body through the flow path 24a of the cannula 24.

[0047] The administration rate of the drug solution M by the administration device 10 is determined by the thickness of the semipermeable membrane 34. The administration device 10 continues administration of the drug substance for at least 15 days to half a year. Therefore, frequent treatment is not required, and the burden on the patient can be reduced.

[0048] 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 a circular ring shape with a first end 12a and a second end 12b connected via the connecting member 18A. The cylindrical body 12A of this embodiment is made of a highly rigid metal tube such as stainless steel or nitinol. The cylindrical body 12A has an inner cavity 12c therein. In addition, the cylindrical body 12A has a moisture inlet 20 near the first end 12a.

[0049] 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 by a partition wall 22 in a liquid-tight and air-tight manner.

[0050] The cylindrical body 12A has a mounting hole 12f near the second end 12b. The base end of the cannula 24A constituting the flow path portion 14A is joined to the mounting hole 12f. The base end of the cannula 24A fits into the mounting hole 12f. The connection between the cannula 24A and the mounting hole 12f may be sealed with a sealant 32 (see FIG. 1). The cannula 24A in this embodiment is formed of a hard material such as stainless steel. The cannula 24A has a sharp needle tip 46 at its tip. The cannula 24A can puncture the needle tip 46 into the eyeball. The cannula 24A has a stop structure 25 that bulges out from the side. The cannula 24A also has a flow path 24a inside 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.

[0051] 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 provided. This cylindrical body 12A has a moisture inlet 20 and an attachment hole 12f. Next, as shown in Fig. 7B, a support rod 48 for maintaining the inner diameter is inserted into the cylindrical body 12A.

[0052] Next, as shown in Fig. 8A, a process is performed in which the cylindrical body 12A with the support rod 48 inserted therein is plastically deformed together with the support rod 48 to bend it into an annular shape. This causes the cylindrical body 12A to be shaped into an annular shape. Thereafter, the support rod 48 is pulled out and removed from the cylindrical body 12A.

[0053] Next, as shown in Fig. 8B, a step of fitting the base end of the cannula 24A into the mounting hole 12f is performed. Through this step, the cannula 24A is joined to the cylindrical body 12A. Thereafter, as shown in Fig. 9A, a gasket 36, an osmotic pressure generating material 38 (salt), and a semipermeable membrane 34 are inserted in this order from the first end 12a of the cylindrical body 12A. Furthermore, a medicinal solution M is filled from the second end 12b of the cylindrical body 12A.

[0054] Next, as shown in Fig. 9B, a step of fitting a connecting member 18A to the first end 12a and the second end 12b of the cylindrical body 12A is performed. Through the steps described above, the administration device 10A of the present embodiment is obtained.

[0055] In the administration device 10A described above, since the cannula 24A has a sharp needle tip 46, the operation of removing the puncture needle 26 (FIG. 1A) is not necessary, and the operation of attaching the device to the eyeball is simplified.

[0056] Third embodiment The administration device 10B of this embodiment 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. In the lumen 12c, a semipermeable membrane 34, an osmotic pressure generating material 38, and a gasket 36 are arranged in order from the side closer to the first end 12a. The cylindrical body 12B has an end wall 50 at the second end 12b. The end wall 50 closes the lumen 12c. The cylindrical body 12B has a flow path portion 14A near the second end 12b. The flow path portion 14A of this embodiment is similar to the flow path portion 14A of FIG. 6A. The administration device 10B of this embodiment can also provide the same effect.

[0057] The above embodiment can be summarized as follows.

[0058] One aspect of the above is an administration device 10, 10A, 10B that is placed in the conjunctival sac and releases an administration substance into the eye, comprising a tubular body 12, 12A, 12B that has a curved shape that follows the gap between the ocular surface and the eyelid and has an inner cavity 12c that contains the administration substance, a flow path portion 14, 14A that protrudes from the tubular body and punctures the eyeball to administer the administration substance into the eye, and a pump 16 that sends the administration substance from the inner cavity to the flow path portion.

[0059] The administration device does not require a procedure involving incision of the conjunctiva or sclera for placement in the eye, and can perform treatment with minimal invasiveness in a short time. In addition, the administration device is less invasive to the patient, reducing the burden on the patient.

[0060] In the administration device, the pump may be movably disposed in the inner cavity of the cylindrical body, and may include a gasket 36 that divides the inner cavity into a storage area in which the substance to be administered is stored and a pressurizing area, and a pressurizing mechanism that pressurizes the pressurizing area. Since the pump in this administration device can be made compact and stored inside the cylindrical body, it is easy to place the pump in the narrow gap between the eyeball and the eyelid.

[0061] In the administration device, the pressurizing mechanism may include a water inlet 20 formed in the cylindrical body for introducing water into the cavity, a semipermeable membrane 34 disposed between the water inlet and the pressurized region, and an osmotic pressure generating material 38 sealed in the pressurized region for increasing the internal pressure of the pressurized region by contacting with water. This administration device can administer the administration substance into the eyeball by generating osmotic pressure using the water in the tears. Eye drops may be used as a supplement to the tears, or the eye drops may be used as the main water supply source when the secretion of tears is insufficient for administration. This administration device can perform stable administration operation for a long period of time because it generates high pressure.

[0062] In the administration device, the flow path may include a flexible cannula 24 protruding from the cylindrical body, and a puncture needle 26 that passes through the inside of the cannula and has a sharp needle tip 26a at its tip. By using a flexible cannula, this administration device can reduce irritation to biological tissue.

[0063] In the administration device described above, 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. Since this administration device can directly puncture the cannula into the eyeball, the placement work of the administration device can be simplified.

[0064] In the administration device described above, the cannula may have a pull-out prevention structure 25 protruding from the side. This administration device can prevent the cannula from being pulled out when placed in place or during use.

[0065] In the administration device, the cylindrical body may be annular, so that the administration device can be stably placed along the periphery of the eyeball.

[0066] In the administration device, the tubular body may be made of a flexible material, which can reduce irritation to surrounding tissue.

[0067] In the administration device, the substance to be administered may be an ophthalmic VEGF inhibitor. This administration device can continuously administer the ophthalmic VEGF inhibitor into the interior of the eyeball, and therefore can be suitably used for anti-VEGF treatment of retinal diseases such as age-related macular degeneration, retinal vein occlusion, and diabetic retinopathy.

[0068] In the administration device, the administration product may contain aflibercept at a concentration of 40 to 160 mg / ml. Since the administration device contains a relatively high concentration of the biological preparation, the administration product can be administered for a long period of time. In addition, the administration device is used in a harsh body temperature environment as a storage environment for the biological preparation. By setting the concentration as described above, the administration device can increase the stability of the biological preparation, and can perform anti-VEGF treatment for a long period of time.

[0069] In the administration device, the administration product may contain ranibizumab at a concentration of 10 to 80 mg / ml. Since this administration device contains a relatively high concentration of antibody drug, the administration product can be administered over a long period of time. In addition, the administration device is used under a harsh body temperature environment as a storage environment for the antibody drug. By setting the above concentration, this administration device can increase the stability of the antibody drug, and anti-VEGF treatment can be performed over a long period of time.

[0070] In the administration device, the administration product may contain brolucizumab at a concentration of 120 to 320 mg / ml. Since this administration device contains a relatively high concentration of the antibody drug, the administration product can be administered over a long period of time. In addition, the administration device is used in a harsh body temperature environment as a storage environment for the antibody drug. By setting the above concentration, this administration device can increase the stability of the antibody drug, and can perform anti-VEGF treatment over a long period of time.

[0071] In the administration device, the administration material may contain faricimab at a concentration of 120 to 240 mg / ml. Since this administration device contains a relatively high concentration of antibody drug, the administration material can be administered over a long period of time. In addition, the administration device is used in a harsh body temperature environment as a storage environment for the antibody drug. By setting the above concentration, this administration device can increase the stability of the antibody drug, and anti-VEGF treatment can be performed over a long period of time.

[0072] Another aspect is an administration method using the administration device, in which the cylindrical body is placed in the conjunctival sac, the flow path portion is inserted into the eye, and the pump is operated to administer the substance contained in the inner cavity of the cylindrical body into the eye. According to this administration method, the substance can be continuously administered into the eye for a long period of time.

[0073] In the above administration method, the pump may be an osmotic pump that is operated by tears. According to this administration method, the substance can be administered without maintenance for a long period of time, further reducing the burden on the patient.

[0074] The present invention is not limited to the above-described embodiment, and various configurations can be adopted without departing from the gist of the present invention. [Explanation of symbols]

[0075] 10, 10A, 10B...administration device 12, 12A, 12B...cylindrical body 12c... Lumen 14, 14A... Flow passage portion 16... Pump 20... Moisture inlet 24, 24A: Cannula 25: Anti-pullout structure 26...Puncture needle 34...Semipermeable membrane 36...Gasket 38...Osmotic pressure generating material

Claims

1. 1. An administration device for placement in the conjunctival sac to deliver a dosage into the eye, comprising: A cylindrical body having a curved shape that fits the gap between the eye surface and the eyelid and having an internal cavity for accommodating the administration material therein; a flow path portion that protrudes from the cylindrical body and punctures an eyeball to administer the administration substance into the eye; A pump for delivering the administration substance from the lumen to the flow path portion. Dosing device.

2. 2. The administration device according to claim 1, wherein the pump is movably disposed in the inner cavity of the cylindrical body, and includes a gasket that divides the inner cavity into a storage region in which the substance is stored and a pressurizing region, and a pressurizing mechanism that pressurizes the pressurizing region. Dosing device.

3. 3. The administration device according to claim 2, wherein the pressurizing mechanism is formed in the cylindrical body and includes a water inlet for introducing water into the lumen, a semipermeable membrane disposed between the water inlet and the pressurized region, and an osmotic pressure generating material that is enclosed in the pressurized region and increases the internal pressure of the pressurized region by contacting with water. Dosing device.

4. The administration device according to any one of claims 1 to 3, wherein the flow path portion has a flexible cannula protruding from the cylindrical body and a puncture needle that is inserted through the inside of the cannula and has a sharp needle tip at its tip. Dosing device.

5. 4. The administration device according to claim 1, wherein the flow path portion has a hard cannula protruding from the cylindrical body, and the cannula has a sharp needle tip at a tip. Dosing device.

6. 6. The administration device according to claim 4 or 5, wherein the cannula has a retaining structure protruding from a side portion. Dosing device.

7. 7. An administration device according to any one of claims 1 to 6, wherein the cylindrical body is annular.

8. 8. An administration device according to any one of claims 1 to 7, wherein the tubular body is made of a flexible material.

9. The administration device according to any one of claims 1 to 8, wherein the administered product is an ophthalmic VEGF inhibitor. Dosing device.

10. 10. The administration device of claim 9, The dosage contains aflibercept at a concentration of 40 to 160 mg / ml; Dosing device.

11. 10. The administration device of claim 9, The dosage contains ranibizumab at a concentration of 10-80 mg / ml. Dosing device.

12. 10. The administration device of claim 9, The dosage contains brolucizumab at a concentration of 120-320 mg / ml. Dosing device.

13. 10. The administration device of claim 9, The dosage contains faricimab at a concentration of 120-240 mg / ml. Dosing device.

14. A method of administration using the administration device according to claim 1, The cylindrical body is placed in the conjunctival sac, and the pump is operated in a state in which the flow path portion is inserted into the eye, to administer the administration substance contained in the inner cavity of the cylindrical body into the eye. Method of administration.

15. 15. The method of claim 14, comprising: The pump is an osmotic pump operated by tear fluid. Method of administration.

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