WO2023171360A1

WO2023171360A1 - Administration device and administration method

Info

Publication number: WO2023171360A1
Application number: PCT/JP2023/006137
Authority: WO
Inventors: 眞▲崎▼賢治; 有延学; 密岡拓心
Original assignee: テルモ株式会社
Priority date: 2022-03-08
Filing date: 2023-02-21
Publication date: 2023-09-14

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

Administration device and method

The present invention relates to an administration device and administration method for releasing a drug into the eye.

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.

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).

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.

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.

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.

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.

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, and 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, and 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, 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. 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. 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, and 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, and 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, and 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, 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. FIG. 10 is a plan view of the administration device according to the third embodiment.

(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.

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.

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.

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.

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.). Such a cylindrical body 12 can reduce invasiveness.

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.

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.

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.

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. 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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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

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.

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.

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.

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.

(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.

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.

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.

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.

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.

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.

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.

(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.

The above embodiments can be summarized as follows.

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.

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.

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.

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.

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.

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.

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.

In the above administration device, the cylindrical body may be annular. This administration device can be stably placed along the circumference of the eyeball.

In the above administration device, the cylindrical body may be made of a flexible material. This administration device can reduce irritation to surrounding tissue.

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.

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.

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.

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.

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.

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.

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.

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

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. 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. 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. 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.
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.
The administration device according to claim 4 or 5, wherein the cannula has a withdrawal prevention structure protruding from the side.
Dosing device.
The administration device according to any one of claims 1 to 6, wherein the cylindrical body is annular.
The administration device according to any one of claims 1 to 7, wherein the cylindrical body is made of a flexible material.
The administration device according to any one of claims 1 to 8, wherein the administration product is an ophthalmic VEGF inhibitor.
Dosing device.
The administration device according to claim 9,
the dosage comprises aflibercept at a concentration of 40-160 mg/ml;
Dosing device.
The administration device according to claim 9,
the dosage comprises ranibizumab at a concentration of 10-80 mg/ml;
Dosing device.
The administration device according to claim 9,
the dosage comprises brolucizumab at a concentration of 120-320 mg/ml;
Dosing device.
The administration device according to claim 9,
the dosage comprises faricimab at a concentration of 120-240 mg/ml;
Dosing device.
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. The method of administration according to claim 14,
the pump is an osmotic pump operated by lachrymal fluid;
Method of administration.