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WO2018143481A1 - Dispositif de libération prolongée de médicament pouvant être réinjecté avec le médicament, et gel injectable pour remplissage - Google Patents

Dispositif de libération prolongée de médicament pouvant être réinjecté avec le médicament, et gel injectable pour remplissage Download PDF

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Publication number
WO2018143481A1
WO2018143481A1 PCT/JP2018/004278 JP2018004278W WO2018143481A1 WO 2018143481 A1 WO2018143481 A1 WO 2018143481A1 JP 2018004278 W JP2018004278 W JP 2018004278W WO 2018143481 A1 WO2018143481 A1 WO 2018143481A1
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sustained
drug
release
pdms
reservoir
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PCT/JP2018/004278
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English (en)
Japanese (ja)
Inventor
阿部　俊明
早絢 西條
展裕 永井
山下　哲郎
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国立大学法人東北大学
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Priority to JP2018566173A priority Critical patent/JPWO2018143481A1/ja
Publication of WO2018143481A1 publication Critical patent/WO2018143481A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

Definitions

  • the present invention relates to the field of drug delivery devices. Specifically, the present invention relates to a drug sustained-release device that can be implanted in a living body, and more specifically to a device that can be sustainedly released at a constant sustained rate over a long period of time and can be re-injected with a drug.
  • DDS drug delivery system
  • instillation is a common administration method, but it is effective for anterior segment diseases, but it is sufficient for posterior segment diseases by clearance with the corneal barrier and tears, etc. Since a certain amount of drug may not transfer to the posterior segment, it is difficult to obtain a therapeutic effect. Therefore, vitreous injection is performed in the treatment of age-related macular degeneration, which is an intractable posterior segment (retinal) disease.
  • CV port There is a septum in the CV port, and it is possible to repeatedly inject a drug by inserting a dedicated needle into the septum.
  • a peripheral vein indwelling needle when the blood vessel is thin or fragile, it may be painful because the needle needs to be re-stabbed many times. There is no need to do it.
  • this CV port does not have a drug sustained release function, and the injected drug quickly flows into the blood vessel, so that frequent injection is required depending on the treatment.
  • Non-Patent Document 2 In addition to re-injection-type devices, devices filled with drugs in titanium alloy cube holes and covered with membranes (Non-Patent Document 2), devices using MEMS (Non-Patent Documents 3, 4, 5, 6), A device using a silicone tube (Non-patent Document 7), a device using an implantable pump (Non-patent Document 8), a device using a silicone reservoir (Non-patent Document 9), a silicone reservoir type device of a scleral placement type (Non-Patent Document 10). In either case, a non-decomposable base material using metal or silicone is used.
  • a number of reinjection-type administration devices have been developed, but there is no example of a device that imparts long-term sustained release, and there is no example of a re-injection type device that aims to control release. In addition, there is no example in which a mechanism capable of freely changing the shape is provided. Considering practical use, the administration period, dosage, and administration site vary depending on the disease and individual differences, and a device that can be controlled to release for a long period of time and can be closely attached to the shape of the target site is useful. .
  • the present invention provides an implantable and refillable drug sustained release device that achieves drug delivery with controllable drug release rate at a desired release rate over a long period of time of several months or more, and reinfusion It is an object of the present invention to provide an injectable gel for refilling that can contain various drugs and can provide sustained release over a long period of time.
  • the present inventors previously developed a sustained release device using polyethylene glycol dimethacrylate (PEGDM) or triethylene glycol dimethacrylate (TEGDM) as a material (WO2011 / 021594).
  • PEGDM polyethylene glycol dimethacrylate
  • TEGDM triethylene glycol dimethacrylate
  • PEGDM polydimethylsiloxane
  • TEGDM triethylene glycol dimethacrylate
  • a reservoir-type device with micropores on the sustained release surface Since PDMS (silicone) is a flexible material, it is possible to repeatedly pierce the needle and reinject the drug into the inside. Further, by filling the above device with an injectable gel (iGel) containing a drug, gelatin, chitosan and a cross-linking agent, it is found that the drug gels in the reservoir to obtain sustained release, thereby completing the present invention. It came. Moreover, it discovered that a liquid agent was sustained-released by installing PEGDM and iGel double in a capsule as a sustained-release film
  • a sustained drug sustained release device capable of reinjecting a drug using a syringe and a needle in a state of being implanted in the body, which is implanted in the body, and is a box-shaped polydimethyl capable of encapsulating the drug
  • a sustained drug sustained release device capable of reinjecting a drug comprising a siloxane (PDMS) reservoir and a PDMS sheet lid and having a sustained release surface with pores.
  • PDMS siloxane
  • the device further has a sustained-release film on the sustained-release surface, and the sustained-release film is PEGDM, TEGDM, or a sustained-release film of a mixture of chitosan, gelatin, and a crosslinking agent, and is crosslinked by ultraviolet rays or by a crosslinking agent.
  • a sustained-release sustained-release device capable of reinjecting the drug of [1], which is a sustained-release membrane formed into a sheet by cross-linking or freeze-drying.
  • a sustained-release drug sustained-release device having a dual structure of a siloxane (PDMS) sustained-release surface and a triethylene glycol dimethacrylate (TEGDM) sustained-release surface having a pore and capable of reinjecting the drug of [1] or [2].
  • PDMS siloxane
  • TAGDM triethylene glycol dimethacrylate
  • It has a double structure having a triethylene glycol dimethacrylate (TEGDM) reservoir having a pore inside a polydimethylsiloxane (PDMS) reservoir having a pore, and further has no pore on the sustained-release surface of the reservoir
  • TOGDM triethylene glycol dimethacrylate
  • PDMS polydimethylsiloxane
  • a sustained-release membrane without pores can be re-injected with the drug of [5] located between a polydimethylsiloxane (PDMS) reservoir with pores and a triethylene glycol dimethacrylate (TEGDM) reservoir with pores Sustained drug sustained release device.
  • PDMS polydimethylsiloxane
  • TEGDM triethylene glycol dimethacrylate
  • the drug according to [5] or [6], wherein the sustained-release membrane having no pore is selected from the group consisting of polyethylene glycol dimethacrylate (PEGDM), a mixture of PEGDM and water, and a crosslinked product of gelatin and chitosan A re-injectable sustained drug sustained release device.
  • a sustained drug sustained-release device capable of reinjecting the drug according to any one of [1] to [7], wherein a liquid agent can be contained in a reservoir as a drug.
  • a long-lasting drug capable of reinjecting a drug as set forth in any one of [1] to [7], wherein an injectable gel comprising a mixture of a drug, chitosan, gelatin and a crosslinking agent can be encapsulated in the reservoir Sustained release device.
  • a sustained drug sustained-release device capable of reinjecting the drug according to any one of [2] to [8], wherein the crosslinking agent is a water-soluble carbodiimide.
  • Reinjectable sustained drug sustained release device A sustained drug sustained-release device capable of reinjecting the drug of any one of [1] to [11], wherein a metal wire for incorporating and stabilizing the shape is incorporated.
  • a long-acting drug capable of reinjecting a drug according to any one of [1] to [12], which incorporates a metal sheet for preventing accidental puncture to prevent the needle during drug injection from penetrating the device Sustained release device.
  • a sustained drug sustained-release device capable of reinjecting the drug according to any one of [1] to [13], which is a scleral indwelling device for transplantation into the sclera.
  • a sustained drug sustained release device capable of reinjecting the drug according to any one of [1] to [13], which is a subcutaneous implantable device for subcutaneous implantation.
  • An injectable gel containing a drug, gelatin, chitosan and a cross-linking agent for sustained release of the drug [19] An injectable gel for sustained release of the drug of [18], wherein the crosslinking agent is a water-soluble carbodiimide. [20] The drug can be reinjected, including a sustained drug sustained-release device capable of reinjecting the drug of any one of [1] to [15] and an injectable gel of any of [16] to [19]
  • This is a sustained drug sustained release system that has a structure in which an injectable gel is encapsulated in a reservoir of the device, and the drug in the gel encapsulated through the injectable gel and the pore is gradually released, and is released from the injectable gel.
  • sustained drug sustained release system capable of reinjecting drug, in which the release rate is controlled in two stages, outward release through the pore and the injectable gel can be reinjected.
  • the sustained-release drug sustained-release device capable of reinjecting the drug of the present invention uses soft polydimethylsiloxane (PDMS) as a main material, the needle can be repeatedly inserted and the drug can be reinjected. . Further, by using a TEGDM hard material partially, the material prevents the needle from penetrating the device. Further, when a gel composition is used as the drug composition, the sustained drug sustained release device capable of reinjection of the drug of the present invention is provided with a sustained release membrane having pores, so that the drug encapsulated through the membrane is gradually released. Released.
  • PDMS soft polydimethylsiloxane
  • a liquid composition when used as the drug composition, it is gradually released through the membrane by providing a PEGDM membrane or the like having no pore on the sustained release surface of the device.
  • a sustained drug sustained-release device capable of reinjecting the drug of the present invention
  • the action and device of the injectable gel iGel
  • the injectable gel have Sustained release of the drug over a long period of time can be achieved by the action of the micropore.
  • the drug release from iGel can be controlled by changing the pore density and pore diameter of the sustained release surface, or by filling the pore with a mixture of PEGDM or TEGDM or a mixture of PEGDM and water.
  • the drug release can be changed by changing the mixing ratio of iGel gelatin and chitosan or the concentration of the cross-linking agent.
  • a double membrane in the device it is possible to install a hard TEGDM membrane (with pores) or a stainless steel sheet for preventing puncture caused by needle puncture during reinjection.
  • FIG. 6 is a graph showing the fluorescence intensity in plasma by sustained release of FL mixed with iGel in a rat subcutaneous implantation test of iGel.
  • FIG. 5 is a diagram showing the fluorescence intensity in urine by sustained release of FL mixed with iGel in an iGel subcutaneous implantation test in rats. It is the histological photograph of the implantation site
  • FIG. 22A shows a state after one week after device implantation in which the interior is empty
  • FIG. 22B shows a method of injecting FL-iGel with a 25G needle
  • FIG. 22C is a photograph showing a state of FL in the injected device. It is. It is a figure which shows each component in preparation of PDMS capsule (Type1).
  • the unit of the diameter of the pore in FIG. 23B is mm.
  • FIG. 1 It is a figure which shows the blood glucose level change of the diabetic mouse when the reinjectable PDMS capsule which inject
  • a mold (A left) for preparing PDMS pellets mixed with NaCl particles and a photograph (A right) of the prepared NaCl particle-containing PDMS pellets adhered to a PDMS stage are shown.
  • a photograph (A) and an illustration (B) of a flexible capsule containing the fluorescent dye FD150 (5% gelatin pellet) are shown (NaCl particle size 70 ⁇ m, 0.5 g / mL). It is a figure which shows the sustained release property from the flexible capsule containing fluorescent dye FD150 (5% gelatin pellet). A shows a particle size of 70 ⁇ m, and B shows a particle size of 40 ⁇ m.
  • a photograph of a flexible capsule containing a Calpain inhibitor (P20W80 pellet) is shown. The sustained release property of the flexible capsule containing the Calpain inhibitor (P20W80 pellet) was shown. The results showed that the particle diameters of NaCl particles were 100 ⁇ m (A) and 70 ⁇ m (B).
  • a photograph (A) and a sustained release property (B) of a flexible capsule containing a calpain inhibitor (5% gelatin [G5] pellet) were shown.
  • the present invention is a sustained drug sustained release device for implantation into the body that contains a drug inside and can release the drug, and can be refilled, that is, refilled. Reinjectable sustained drug sustained release device.
  • the device of the present invention is also a drug delivery device for delivering a drug. Since the device of the present invention is a capsule-like device that can be filled with a drug, it is also referred to as a capsule.
  • the present invention is an injectable gel for mixing and filling a drug in the internal reservoir of the reinjectable sustained drug sustained release device.
  • the injectable gel is a refillable injectable gel for obtaining a sustained release property for a long time. 1.
  • Injectable gel is a mixture of gelatin and chitosan and crosslinked with a crosslinking agent. That is, the injectable gel is composed of gelatin and chitosan cross-linked with a cross-linking agent, and the drug is mixed and filled in the injectable gel, thereby gelling in the reservoir and acquiring the sustained release property.
  • Gelatin is extracted by applying heat to collagen, which is the main component of connective tissue such as skin, bones, and tendons of animals such as pigs, cows, and fish.
  • collagen which is the main component of connective tissue such as skin, bones, and tendons of animals such as pigs, cows, and fish.
  • the origin of gelatin used in the present invention is not limited, for example, gelatin derived from pig skin can be used.
  • the gelatin for example, Sigma's G2500-100G can be used.
  • Chitosan is a kind of polysaccharide and refers to poly- ⁇ 1 ⁇ 4-glucosamine, and its molecular formula is (C 6 H 11 NO 4 ) Represented by n.
  • the molecular weight is from several thousands to several hundred thousand, and the molecular weight is not limited, but the viscosity is about 5 to 600 mPa ⁇ s, preferably about 25 to 100 mPa ⁇ s. Further, the degree of deacetylation (% DA) is 80% or more, preferably 90% or more, more preferably 98% or more.
  • Daiichi Sedan 100D manufactured by Dainichi Seika Kogyo can be used.
  • cross-linking agent When a cross-linking agent is added to a mixture of gelatin and chitosan, gelatin and chitosan, and gelatin and chitosan are cross-linked and gelled.
  • the crosslinking agent is not particularly limited as long as it can crosslink proteins and sugars and has water solubility.
  • aldehyde-based, carbodiimide-based, epoxide-based, and imidazole-based crosslinking agents are preferably used from the viewpoints of economy, safety, and operability.
  • water-soluble carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 1-cyclohexyl-3- (2-morpholinyl-4-ethyl) carbodiimide sulfonate are used. It is preferable to do this.
  • the amount of gelatin and chitosan mixed is, for example, 100: 1 to 1:50 by weight.
  • a 5% (w / v) gelatin solution and a 2.5% (w / v) chitosan solution may be mixed in a volume of 50: 1 to 1:10.
  • it is 3: 2.
  • gelatin alone or chitosan alone may be used.
  • the gelatin concentration is 0.01 to 20% (w / v), preferably 1 to 10% (w / v).
  • the concentration of chitosan is 0.01% to 10% (w / v). Preferably, it is 0.1 to 5% (w / v).
  • a cross-linking agent may be added after mixing gelatin and chitosan.
  • the concentration of the crosslinking agent is not particularly limited. Since the iGel biodegradability rate and sustained release rate may change depending on the concentration of the cross-linking agent, the concentration may be determined according to the application.
  • the final concentration is in the range of 0.01 mg / mL to 1 g / mL, preferably 1 mg / mL to 100 mg / mL, and more preferably 10 mg / mL.
  • the crosslinking agent affects the activity of the drug, the crosslinking agent need not be added. In this case, the stabilizing effect of the gel due to crosslinking becomes weak, but it can be used as an injectable gel for reinjection.
  • the solvent for producing iGel in the case of an acidic solvent, water that is safe and widely used for industrial use from the viewpoint of end use, or an aqueous solution of acetic acid, hydrochloric acid, citric acid, fumaric acid or the like is preferable.
  • the drug to be sustained-released may be added to a mixture of gelatin and chitosan and then gelled by adding a crosslinking agent.
  • the amount of drug to be added may be appropriately determined depending on the type of drug, the type and severity of the disease to be treated.
  • the gelation base of the injectable gel of the present invention is an in situ gel in which a mixture of gelatin and chitosan is crosslinked with a water-soluble carbodiimide. be able to.
  • chitosan is preferably 1.5% to 0.5% / gelatin 2% to 4%, more preferably chitosan 1% / gelatin 3%.
  • gelatin alone, chitosan alone, or a gelled substrate without a crosslinking agent can be used.
  • Gelatinization of a mixture of gelatin and chitosan, a cross-linking agent, and a drug may be performed by cross-linking in situ in a device reservoir in order to refill a capsule placed in a living body.
  • a mixture of gelatin, chitosan and a cross-linking agent can be gelled and used as a sustained-release film of a sustained-release sustained-release device capable of reinjecting the drug of the present invention.
  • Sustained drug sustained release device capable of reinjecting drug is a device that can be implanted into the body, and after all of the initially infused drug has been released, the drug can be reinjected while implanted in the body.
  • the sustained drug sustained-release device capable of reinjecting a drug has a capsule structure in which a box-shaped reservoir is closed with a sheet-like lid (cover), and can be filled with the drug inside the capsule.
  • the box shape refers to a shape in which a substance can be contained, but is not limited to this, and a cylindrical shape, a spherical shape, a bag can be used as long as the substance can be contained in the inside.
  • the shape may be a shape, a bag shape, or the like.
  • the drug may be a single drug, a mixture of a plurality of drugs, or a mixture with another substance such as a gelling substance. For example, 1. It is possible to enclose an injectable gel mixed with a drug. It is necessary to use a material that does not adhere to a living body as a material for a sustained drug sustained-release device capable of reinjecting the drug of the present invention.
  • the material that does not adhere to the living body is a substance that does not dissolve in the living body and does not adhere to or bind to the living tissue.
  • a substance that does not dissolve in the living body and does not adhere to or bind to the living tissue For example, gelatin-based hydrogels, agarose gels, and the like can be dissolved in vivo, so that they can be used as compounds impregnated with substances to be contained, but cannot be used as device materials.
  • the device is flexible and plastic to allow drug re-injection, and the needle used for re-injection can be pierced, and even when the needle is punctured, the hole is immediately closed and repeatedly Need to be able to pierce the needle.
  • examples of the material of the box-shaped reservoir and the sheet-like lid constituting the outside include polydimethylsiloxane (PDMS) which is a silicone-based thermosetting resin.
  • PDMS polydimethylsiloxane
  • the thickness of the membrane forming the reservoir and the sheet-like lid is 0.01 to 5 mm, preferably 0.2 to 0.6 mm.
  • the box-type device of the present invention can be provided with a box or a film on the inner side to form a double or triple sustained-release surface.
  • the “sustained release surface of the device” refers to a surface that allows sustained release through a drug among a plurality of surfaces of the device. On the sustained release surface of the device, there is a single to multiple, preferably single to triple sustained release film.
  • the sustained release membrane for example, a portion of the membrane located in the sustained release surface portion of a polydimethylsiloxane (PDMS) reservoir having pores, or triethylene glycol having or not having pores provided on the device sustained release surface
  • PDMS polydimethylsiloxane
  • examples thereof include dimethacrylate (TEGDM) and polyethylene glycol dimethacrylate (PEGDM), a mixture of gelatin, chitosan and a crosslinking agent, a crosslinked product of gelatin and chitosan, and a film of a mixture of PEGDM and water.
  • TOGDM dimethacrylate
  • PEGDM polyethylene glycol dimethacrylate
  • the release rate can be controlled by changing the mixing ratio of PEGDM and water.
  • the sustained release rate decreases.
  • a film of triethylene glycol (TEG) such as PEGDM or TEGDM or polyethylene glycol (PEG) is provided on the double or triple film, and the drug is reinjected from the surface opposite to the surface where the outer membrane is present. It is preferable to stab a needle for the purpose. It is difficult to determine how far the needle implanted with a device implanted under the skin or the like reaches the reservoir.
  • the needle Since the film such as TEGDM is hard, even if the needle for reinjecting the drug is inserted too deeply, unlike the PDMS and PEGDM, the needle does not pierce and the needle stops. As a result, it is possible to prevent the needle from penetrating through the entire reservoir of the device and pointing to the internal organs. If the device has a surface made of TEGDM, a stainless steel sheet or the like, the needle may be stabbed toward the surface, and iGel or a liquid agent may be injected when the needle is stabbed and stopped, thereby facilitating the reinjection operation.
  • the box-shaped reservoir constituting the outside is manufactured by putting a thermosetting resin (PDMS prepolymer) in a PDMS mold having the shape of a reservoir and curing it by heat.
  • the PDMS mold is prepared by putting a thermosetting resin (PDMS prepolymer) on an acrylic plate whose device shape has been cut and curing it by heat. Further, the PDMS mold is subjected to oxygen plasma treatment and silanization treatment so that the cast material (PDMS) is easily peeled off.
  • the device shape can be cut on the acrylic plate by, for example, cutting with a CAD-CAM micromachining machine or by three-dimensional molding with a 3D printer.
  • the lid of the box-shaped reservoir constituting the outside is produced by putting the above-mentioned thermosetting resin (PDMS prepolymer) into a PDMS mold having the shape of a lid and curing it by heat.
  • the PDMS template is produced in the same manner as described above.
  • the material of the inner box-shaped reservoir and the sustained-release film include TEGDM and PEDGM of photocurable resins, chitosan of biomaterials, gelatin, and a crosslinking agent.
  • the thickness of the membrane forming the reservoir and the sustained-release membrane is 0.01 to 5 mm, preferably 0.2 mm to 0.6 mm.
  • the reservoir on the box side constituting the inside is prepared by putting a photocurable resin (TEGDM prepolymer) in a PDMS mold having the shape of a reservoir and curing it by ultraviolet irradiation.
  • the PDMS template is produced in the same manner as described above.
  • the sustained-release membrane constituting the inner side is prepared by putting a sustained-release membrane component such as PEGDM into a PDMS template having the shape of a sustained-release membrane, and curing and forming a sheet by ultraviolet irradiation, crosslinking, and freeze-drying.
  • the PDMS template is produced in the same manner as described above.
  • the shape of the sustained-release sustained-release device capable of reinjecting the drug is preferably a substantially disc shape having an upper surface, a lower surface and a side surface, the upper surface and the lower surface being substantially circular, or a substantially cubic shape having an approximately rectangular shape on the upper and lower surfaces.
  • the shape is not limited as long as it has a surface for gradually releasing the substance contained therein, and may have a flat shape, a substantially spherical shape, a substantially cylindrical shape, or the like.
  • the diameters of the upper and lower surfaces of the substantially circular shape are several tens mm, preferably 5 to 500 mm, more preferably 10 to 300 mm, and particularly preferably 20 to 300 mm.
  • the length of one piece of the substantially rectangular upper and lower surfaces is several tens mm, preferably 5 to 500 mm, more preferably 10 to 300 mm, and particularly preferably 20 to 300 mm.
  • the area of the upper and lower surfaces is about 20 mm 2 ⁇ 200000mm 2
  • the thickness is several mm, preferably 1 to 7 mm, and more preferably 2 to 5 mm.
  • the above size is an example, and the size of the device can be appropriately designed according to the amount of drug loaded according to the implantation site and therapeutic purpose.
  • the reinjectable sustained drug sustained release device has a pore (micropore) for sustained release of the drug.
  • the pore may be provided only on one specific surface of the device, or may be provided on a plurality of surfaces. Moreover, you may provide so that it may exist in the whole surface, and you may provide in a part of surface. Since the drug is gradually released from the surface having pores, the surface having pores is referred to as a sustained release surface.
  • the pore size is 0.001 ⁇ m to 10 mm, and the density of the pores is 1 to 2000 holes / cm. 2 It is.
  • the pores can be formed by providing needle-like protrusions on the upper surface or the lower surface of the mold for producing the component of the capsule device, or on the upper and lower surfaces.
  • the pores formed using these protrusions as a mold suppress the release of the drug. Therefore, the smaller the pore diameter and density, the more the drug release is suppressed.
  • the diameter of the needle-like protrusion is 0.001 mm to 10 mm. Preferably, it is 0.1 mm to 1 mm. More preferably, it is 0.3 to 0.5 mm.
  • a hole may be made using a needle, laser light, biopsy trepan, or the like.
  • a 0.5 mm biopsy trepan can open a 0.5 mm pore at any location.
  • the pores may be opened by a salt elution method (Salt leaching method) or a sugar elution method (Sugar leaching method).
  • Salt leaching method Salt leaching method
  • sugar elution method Sugar leaching method
  • the salt concentration is 0.01-2 g / mL.
  • it is 0.1 to 1 g / mL.
  • As the salt particles it is better to use salt particles having a uniform particle size by sieving.
  • the particle size of the salt is 0.1 to 100 ⁇ m. This is preferably 40 to 100 ⁇ m.
  • the PDMS pellet mixed with the salt may be sliced with a microtome or the like to form a thin film sheet and then eluted.
  • the salt can be easily eluted because the salt is exposed on the sliced surface.
  • the thickness of the sheet is 0.01 mm to 1 mm. Preferably, it is 0.1 mm to 0.2 mm.
  • the portion having a pore can be called a sustained-release membrane because the drug inside the reservoir is gradually released from the pore.
  • a sheet-like lid which is similarly produced using a container that is a mold, may be joined to a box-shaped reservoir using PDMS prepolymer as an adhesive by thermosetting.
  • the PDMS prepolymer may be thinly applied by spin coating.
  • the spin coating conditions are 1000 to 5000 revolutions and 5 to 20 seconds. Preferably, it is 10 seconds at 3000 revolutions. Further, in order to enhance the adhesion between the box and the lid, a groove may be carved on the adhesive surface on the box side.
  • TEGDM is used to make a reservoir with an open pore as described above. The outer and inner pores are designed to overlap so that they can enter the box without any gaps. However, the pore positions do not necessarily have to overlap.
  • the outer reservoir and lid are joined using a thermosetting resin.
  • the lid may or may not be open on the lid.
  • This device assumes iGel injection.
  • a metal sheet may be incorporated in the device (reservoir) in order to stop needle puncture at the bottom of the device during reinjection and prevent penetration.
  • the sheet may be used according to the size of the device. Preferably, it may be attached to the bottom surface (sustained release surface) of the reservoir.
  • the sheet and the reservoir may be pasted using PDMS or TEGDM as glue.
  • the thickness of the sheet is preferably from 0.01 mm to 0.5 mm, more preferably from 0.25 mm to 0.5 mm.
  • the sheet is preferably coated on both sides with PDMS.
  • the sheet is preferably made of stainless steel or copper, and more preferably made of stainless steel.
  • a sustained-release membrane having no pore is installed on the bottom surface of the TEGDM reservoir. Also, use an outer lid that does not have pores. By doing so, the internal sealing is maintained.
  • the sustained-release membrane is prepared using a dedicated mold, bonded to the bottom surface of the inner TEGDM reservoir, and then stored in the outer PDMS reservoir, and finally capped with a thermosetting resin. In order to maintain hermeticity, it is necessary to bring the TEGDM reservoir and the sustained-release membrane into close contact.
  • the sustained-release membrane In the case of using PEGDM and a mixture of PEGDM and water for the sustained-release membrane, it can be bonded by irradiating with ultraviolet rays while keeping the TEGDM reservoir and the sustained-release membrane in close contact.
  • chitosan or gelatin is used for the sustained-release membrane, a chitosan / gelatin prepolymer is cast and crosslinked on the bottom and inside of the TEGDM reservoir to seal the TEGDM reservoir pore surface from above and below. Thereafter, the TEGDM reservoir is placed in the outer PDMS reservoir and finally capped with a thermosetting resin.
  • Reinjectable sustained drug sustained-release devices can be separated from the point of use, for example, a scleral indwelling type for the purpose of administering sclera into the eye using the sclera of the eye There are subcutaneous implantable devices for the purpose of device and subcutaneous systemic administration. Hereinafter, the structure and usage of these devices will be described.
  • the scleral indwelling device is a device for treating eye diseases, and is implanted or implanted as an implant in the sclera.
  • the sclera refers to a portion above the choroid and below the conjunctiva, that is, the subsclera, in the sclera, on the sclera, below the conjunctiva, and on the choroid. Transplantation does not require vitrectomy and can be performed safely and simply.
  • the scleral indwelling device may be implanted so as to be placed in the sclera outside the eye.
  • the scleral indwelling device only needs to have a pore on one surface of the reservoir, and the sustained-release surface having the pore may be implanted so as to contact the sclera.
  • the drug released from the scleral indwelling device reaches the inside of the eye through the sclera without diffusing to other parts.
  • a stainless steel sheet on the bottom surface of the device, it is possible to prevent needle puncture and safely inject a drug into the device implanted on the sclera.
  • the shape of the sclera indwelling device is shown in FIGS.
  • a flexible capsule (flexible device) that can be injected with a syringe can be created as a device that can be easily placed in a minimally invasive manner on the sclera. It is a thin disk capsule.
  • the sustained release surface has micropores formed by the salt elution method.
  • Subcutaneous implantable device are implantable devices that can be implanted into subcutaneous tissue and have voids that function as reservoirs for containing substances therein. Also called a subcutaneous implantable device.
  • the sustained-release membrane portion having the reservoir pore may be doubled.
  • a sustained-release membrane made of triethylene glycol dimethacrylate (TEGDM) having a pore may be superimposed on the inside of a membrane having a pore of a reservoir made by PDMS.
  • TAGDM triethylene glycol dimethacrylate
  • the pore size provided in the inner TEGDM sustained-release membrane may be made smaller than the pore size provided in the outer PDMS sustained-release membrane (FIG. 23B).
  • the sustained release surface portion having a pore of the reservoir has a PDMS sustained release surface having a pore and a triethylene glycol dimethacrylate (TEGDM) sustained release having a pore from the outside.
  • TEGDM triethylene glycol dimethacrylate
  • Examples include sustained drug sustained release devices that have a double-faced structure and can be reinjected with drug.
  • the reservoir may have a double structure. Thus, by making the reservoir portion double, the release of the drug in the reservoir can be controlled.
  • a stab prevention film is obtained. That is, as one aspect of the subcutaneous implantable device of the present invention, reinjection having a double structure having a triethylene glycol dimethacrylate (TEGDM) reservoir having a pore inside a polydimethylsiloxane (PDMS) reservoir having a pore.
  • TEGDM triethylene glycol dimethacrylate
  • PDMS polydimethylsiloxane
  • Possible sustained drug sustained release devices for example, the outer reservoir is made of polydimethylsiloxane (PDMS), and the inner reservoir is made of a photocurable resin.
  • Examples of the photocurable resin used for the material of the inner reservoir include triethylene glycol (TEG), triethylene glycol dimethacrylate (TEGDM), which is a derivative obtained by adding a methacrylate group to an ethylene glycol monomer, and tetraethylene glycol dimethacrylate. It is done.
  • a reservoir made of TEGDM may be placed inside an outer reservoir made of PDMS.
  • a sustained-release membrane made of PEGDM, a mixture of PEGDM and water, a cross-linked product of chitosan and gelatin or the like may be provided between the outer reservoir made of PDMS and the inner reservoir made of TEGDM. This sustained-release membrane is also provided to control the release of the drug in the reservoir, in particular, the liquid drug.
  • FIG. 25 shows the shape of a subcutaneous implantable device in which the reservoir portion is doubled.
  • FIG. 25A shows a subcutaneous implantable device where the reservoir is a dual reservoir of an outer reservoir made of PDMS and an inner reservoir made of TEGDM. In this device, the pores of the inner and outer reservoirs are connected. Furthermore, there are also pores in the sheet portion that becomes the lid.
  • FIG. 25A shows a subcutaneous implantable device where the reservoir is a dual reservoir of an outer reservoir made of PDMS and an inner reservoir made of TEGDM. In this device, the pores of the inner and outer reservoirs are connected. Furthermore, there are also pores in the sheet portion that becomes the lid.
  • FIG. 25B shows a subcutaneous implantable device where the reservoir is a dual reservoir of an outer reservoir made of PDMS and an inner reservoir made of TEGDM, with a PEGDM membrane between the two reservoirs.
  • the two reservoirs have pores, but the PEGDM membrane has no pores.
  • the subcutaneous implantable device shown in FIG. 25B is suitable for placing a solution inside the reservoir. That is, the connection between the inside of the reservoir and the outside is blocked by the PEGDM membrane, and since it is not connected through the pore, it is not easily released even if it is a liquid agent, and is slowly released through the sustained release membrane.
  • the device of the present invention is a drug reservoir type DDS (Drug delivery system) device that enables long-term sustained release with an initial burst suppressed.
  • the invention also encompasses a sustained drug sustained release system comprising a reinjectable sustained drug sustained release device and an injectable gel (iGel). 3.
  • the pore of the sustained drug sustained release device capable of reinjecting the drug of the present invention is filled with polyethylene glycol dimethacrylate (PEGDM), triethylene glycol dimethacrylate (TEGDM), a mixture of PEGDM and water, or a mixture of PEGDM and TEGDM. It may be closed.
  • PEGDM and TEGDM a mixture of 30 to 70% (w / w) PEGDM and 70 to 30% (w / w) TEGDM, preferably 40% (w / w) PEGDM and 60% (w / w)
  • release property can be controlled by mixing PEGDM with water.
  • Examples of the mixture of PEGDM and water include a mixture of 1 to 99% (w / w) PEGDM and 99 to 1% (w / w) water.
  • the resin may be cast into the pores of the device and cured by UV irradiation. By filling the pores of the device with resin, the drug release within the device can be controlled more precisely.
  • sustained drug sustained release devices that can be reinjected with a drug may incorporate copper or stainless steel wires to stabilize the shape.
  • the reservoir may be cured by sinking a wire bent into the shape of the reservoir in a container that becomes a mold when the reservoir is manufactured.
  • the shape of the device can be freely deformed, deformed according to the complex shape of the living body, and transplanted so as to contact the sclera and subcutaneous tissue without gaps it can.
  • Devices incorporating the wires are shown in FIGS. 4).
  • Sustained release from a sustained drug sustained release device capable of reinjecting the drug
  • the drug of the present invention is released at a constant rate through a pore of a sustained-release membrane having a pore of a sustained-release drug sustained-release device that can be re-injected. Can be achieved.
  • a liquid composition (solution)
  • a PEGDM membrane or the like that does not have pores on the sustained release surface of the device
  • the solution is released through the membrane, and sustained release can be achieved.
  • an injectable gel the drug in the injectable gel loaded into a sustained drug sustained release device that can be re-injected with the drug is slowly released from the gel into the reservoir of the device. Further, it is slowly discharged from the inside of the reservoir through the pore. That is, the release rate is controlled in two steps: release from the injectable gel and release to the outside through the pore, so that a constant release can be obtained and sustained release of the drug can be achieved.
  • the release property can be changed by changing the mixing ratio of the gelatin and chitosan of the injectable gel and the concentration of the crosslinking agent.
  • drug release can be controlled by changing the pore density and pore diameter of the sustained release surface, or by filling the pore with a mixture of PEGDM or TEGDM.
  • the release rate of the drug can also be controlled by installing a double membrane. In this way, the drug is gradually released from the device over a long period of time, and the drug can be continuously administered locally to the diseased site, or can be administered systemically. Furthermore, as shown in FIG.
  • the reinjectable sustained drug sustained-release device of the present invention can reinject an injectable gel or solution containing the drug when all of the internal drug has been released. Reinjection may be performed with a syringe and a needle (syringe). That is, an injectable gel or solution containing a drug can be placed in a syringe, and the needle of the syringe can be pierced into the device and reinjected into a reservoir inside the device.
  • a thin needle is suitable for puncturing the skin, but a 14G to 32G needle can be used.
  • the needle is 18G to 25G.
  • the shape of the needle may be selected according to the transplant site. Long needles and short needles, bend-type and blunt needles, and Huber needles suitable for repeated punctures can be used.
  • the needle may be stabbed into a surface made only of PDMS having flexibility among each surface of the device.
  • the drug can be continuously administered and the treatment of the disease can be continued.
  • the device of the present invention uses TEGDM or PDMS, which has a weak reaction with the living body, adhesion is weak and easy to remove, and when treatment is no longer necessary or side effects occur, surgery is performed. Can be removed without That is, the device of the present invention is an easily removable device.
  • the dose and administration period of the drug may be appropriately set depending on the degree of control of release from the device.
  • 0.01 to 10 g of drug is at least 1 month, preferably at least 3 months, more preferably at least 6 months, more preferably at least 1 year, more preferably at least 2 years, More preferably, it is administered over at least 3 years, more preferably at least 4 years, more preferably at least 5 years. 5).
  • Drug The target disease of the present invention is not particularly limited, and examples thereof include diseases for which continuous drug administration is desired in the body, particularly diseases for which local continuous administration is desired. Such diseases include cancer, inflammatory diseases, degenerative diseases and the like.
  • ophthalmic diseases can be mentioned, and a scleral indwelling device can be used for treating ocular diseases.
  • eye diseases for example, retinal pigment degeneration, age-related macular degeneration, glaucoma, etc. involving multiple factors such as genes and environmental factors, retinal vascular lesions such as retinal artery occlusion, branch retinal vein occlusion, diabetic retinopathy, Examples of the disease include inflammation and damage to the choroid, retina, and vitreous body such as uveitis.
  • Retinitis pigmentosa is a disease in which retinal neurons are progressively impaired for unknown reasons, and is designated as an intractable disease (specific disease).
  • Retinitis pigmentosa is an eye disease in which photoreceptor cells progressively degenerate, and photoreceptor cells undergo apoptosis (cell death) due to various genetic abnormalities, inflammation, immune reactions, and the like.
  • Age-related macular degeneration is an eye disease in which new blood vessels and the like appear in the macular region with age, and is a specific disease in which new blood vessels are generated from the choroid outside the retina, blood leaks, and the retina is damaged.
  • Glaucoma is a progressive disease with characteristic optic disc changes and visual field abnormalities.
  • intraocular pressure is the largest risk factor for progression of glaucoma, and the basic treatment for glaucoma is to stop the progression of visual field impairment by lowering the intraocular pressure with drugs. Recently, it has become the leading cause of blindness in Japan.
  • treatment-resistant retinal artery occlusion, retinal vein branch occlusion, diabetic retinopathy, uveitis and the like are also targeted.
  • the drugs used for the treatment of diseases such as the above-mentioned eye diseases include drugs that suppress angiogenesis, drugs that promote the growth of nerve cells, drugs that protect nerve cells, and cell death (apoptosis). Examples include drugs to suppress, steroids, anti-glaucoma drugs, anti-inflammatory agents, antifungal agents, anticancer agents, immunosuppressive agents and the like.
  • isopropyl unoprostone (UNO) is exemplified as a therapeutic agent for retinitis pigmentosa.
  • Pegaptanib, Avastin, Ranibizmab, Afribercept, Vasohibin and the like as vascularization inhibitors include BDNF (Brain).
  • drugs that suppress cell death (apoptosis) such as -derived neurotrophic factor
  • examples of drugs that suppress cell death (apoptosis) include calpain inhibitor
  • examples of steroid agents include betamethasone and hydrocortisone.
  • prostaglandin-related drugs lact, travoprost, tafluprost, unoprostone, etc.
  • sympathomimetic blockers timolol maleate, timolol maleate, hydrochloric acid
  • drugs that mainly focus on lowering intraocular pressure are drugs that mainly focus on lowering intraocular pressure.
  • Carteolol betaxolol hydrochloride, levobunolol hydrochloride, nipradilol, bunazosin hydrochloride, etc.), carbonic anhydrase inhibitors (dorzolamide hydrochloride, brinzolamide, etc.) and the like.
  • an angiogenesis inducing factor for forming a blood vessel bed for creating a space for cell transplantation can be mentioned.
  • the angiogenesis inducing factor is not particularly limited as long as it can induce angiogenesis.
  • an immunosuppressant may be contained so as not to be rejected when allogeneic transplantation is performed.
  • the immunosuppressant include cyclosporin A, tacrolimus, sirolimus, and derivatives thereof.
  • physiologically active substance examples include insulin for controlling blood glucose level.
  • the drug is: It may be contained in other injectable gels, and may contain other pharmaceutically acceptable carriers, excipients, lubricants, binders, disintegrants, coating agents and the like. Excipients include lactose, glucose, corn starch, sorbit, crystalline cellulose, etc. Lubricants include talc, magnesium stearate, hydrogenated vegetable oil, etc., and binders include dimethylcellulose, polyvinyl alcohol. , Polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, hydroxypropyl cellulose, polyvinyl pyrrolidone and the like.
  • the disintegrant examples include starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin and the like.
  • the drug when it is a liquid, it may contain a buffer solution, physiological saline and the like. Moreover, you may use the pellet which dried the thing containing the said substance.
  • the drug is also referred to as a drug composition.
  • iGel creation 1-1 Preparation of gelatin iGel (examination of cross-linking concentration) 1-1-1.
  • the powder of FL was shattered with a pestle and mixed well.
  • a 500 mg / mL (50%) EDC solution was mixed at 40 ° C. to a final concentration of 1%, 4%, and 10% (v / v) in a gelatin solution mixed with FL.
  • 2 mL of phosphate buffer (PBS, WAKO) was added to each well containing the gel and incubated at 37 ° C.
  • the whole amount of PBS was periodically collected, and fresh PBS was added to continue the incubation.
  • FIG. 1 shows a photograph of an EDC cross-linked gelatin gel. The results on day 2 (FIG. 1A), day 4 (FIG. 1B) and day 5 (FIG. 1C) are shown. Under the crosslinking condition of EDC 10%, the gel quickly dissolved on the second day.
  • FIG. 2 shows the FL release from an EDC cross-linked gelatin gel. EDC 4% released most continuously. 1-2. Creation of gelatin / chitosan iGel 1-2-1.
  • iGel gel compressive strength measurement (1) iGel shown in Table 1 was prepared in a 48-well plate (660 ⁇ L / well). (2) Vertical Functional Type Motorized Test Stand (EMX-1000N, IMADA)) and Standard Type Digital Force Gauge (Standard Model Digital TS Gauge TSZ-NZ5) Gel strength was measured with the combined device. The sample was compressed at a speed of 1 mm / min, and the compression strength was measured. 1-2-3. In vitro biodegradability of iGel (1) The tube weight used for the test was measured. (2) iGel described in Table 1 was prepared in a 5 mL tube with a known weight (1 mL / vial).
  • FIG. 3 shows a photograph of EDC cross-linked gelatin / chitosan gel.
  • FIG. 3-1 shows the state before PBS addition
  • 3-2, 3-3 and 3-4 show the state after 1 hour, 1 day and 4 days after PBS addition, respectively.
  • the gel of chitosan only dissolved in 1 hour.
  • Gelatin-only gels dissolved on the fourth day. Gels of 3% gelatin / 1% chitosan were the slowest to dissolve.
  • FIG. 4 shows the release of FL.
  • the chitosan-only gel burst in 1 hour, and the gelatin-only gel collapsed and burst within 1 day. Mixing chitosan and gelatin stabilized the gel and sustained release.
  • FIG. 35 shows gel compressive strength and in vitro degradability.
  • the compressive strength showed high values under the conditions of D, E, and F in Table 1.
  • In vitro degradability was the slowest degradation at D in Table 1. From the above, the condition having gel strength and biostability was determined to be D (chitosan 1% / gelatin 3%). 1-3. Sustained release of isopropyl unoprostone (UNO) from gelatin / chitosan iGel 1-3-1.
  • FIG. 5 shows a photograph of EDC cross-linked gelatin / chitosan gel containing UNO. A to C in the figure indicate A to C in Table 2. The left (0d) in FIG. 5 is a photograph on day 0, and the right (9d) in FIG. 5 is a photograph on day 9.
  • iGel implantation test 2-1 Method 2-1-1. iGel production and implantation in rats (1) Gelatin (Sigma, G2500-100G) was mixed with MilliQ water at 50 mg / mL (5%) and dissolved at 40 ° C.
  • the FL powder was pulverized with a pestle and mixed well.
  • a 50% EDC solution was mixed with the FL mixed solution at 40 ° C. to a final concentration of 1 (v / v)% (0.35 mL gelatin / chitosan mixture + 7 ⁇ L 50% EDC).
  • (7) After mixing for 3 seconds with a Voltex mixer, it was filled into a 1 mL syringe and injected subcutaneously into a rat (250 g) using an 18G needle.
  • the needle was removed, and ointment was applied to the puncture site, and the procedure was completed. 2-1-2.
  • Fig. 9 shows photographs of the tissue of the implanted sites on the third and eighth days after implantation. On the third day after implantation, both FL-iGel (fluorescein-containing iGel) and placebo iGel (fluorescein-free iGel) were confirmed. Many inflammatory cells were found around iGel.
  • IGel could not be confirmed on the 8th day after implantation, and it was considered that it was digested.
  • Method 3-1-1 Fabrication of a scleral indwelling device 3-1.
  • Method 3-1-1 PDMS mold creation (1) The shape of the device was cut on an acrylic plate (10 cm square, 0.5 cm thickness) (FIG. 10A). (2) A polydimethylsiloxane (PDMS, SILPOT-184, Toray Dow Corning) prepolymer was cast on an acrylic plate and cured at 80 ° C. for 3 hours. (3) PDMS was removed from the acrylic plate, and oxygen plasma treatment was performed (FIG. 10B).
  • PDMS polydimethylsiloxane
  • PDMS was placed at room temperature for 1 hour in a 1H, 1H, 2H, 2H-perfluorotrichlorosilane (FOTS, Wako) atmosphere (silanized PDMS template).
  • a new PDMS prepolymer was cast on a silanized PDMS mold and cured at 80 ° C. for 3 hours.
  • PDMS was removed and oxygen plasma treatment was performed.
  • PDMS was placed at room temperature for 1 hour in a 1H, 1H, 2H, 2H-perfluorotrichlorosilane (FOTS, Wako) atmosphere (silanized PDMS template).
  • the shape cut into the acrylic plate was transferred to PDMS (FIG. 10C).
  • a push-type PDMS mold was prepared in the same manner (FIG. 10D).
  • the molds C and D were combined as shown in FIG. 10E. 3-1-2.
  • Capsule production method 1 (Agarose gel sacrificial layer method) (1) A PDMS prepolymer was cast on the PDMS mold prepared in 3-1-1 and a stamp was placed thereon, and then cured at 80 ° C. for 3 hours. (2) PDMS was removed to obtain a PDMS reservoir (FIG. 11A). (3) After casting 50 ⁇ L of agarose gel (10% concentration) mixed with fluorescein 100 mg / mL in a PDMS reservoir, the PDMS mold was placed and cured at 4 ° C.
  • FIG. 14 is a diagram showing the shape of a flexible device incorporating a wire and the method of reinjection. 3-1-5. Production of capsules with pores filled with PEGDM / TEGDM (1) 100% PEGDM and 40% PEGDM / 60% TEGDM containing 0.05 mg / mL rhodamine B were cast into the pores of the reservoir prepared in 3-1-3, and cured by UV irradiation (240 seconds). ).
  • the FL powder was pulverized with a pestle and mixed well.
  • a 50% EDC solution was mixed with the FL mixed solution at 40 ° C. to a final concentration of 1 (v / v)% (0.35 mL gelatin / chitosan mixture + 7 ⁇ L 50% EDC).
  • (7) After mixing for 3 seconds with a Voltex mixer, using a 25G needle, the PDMS capsule was pierced with 32 ⁇ L (FIG. 16).
  • FIG. 16A shows a state before filling
  • FIG. 16B shows a state after filling. 3-1-7.
  • iGel-UNO unoprostone-containing iGel filling
  • Gelatin Sigma, G2500-100G
  • MilliQ water 50 mg / mL (5%) and dissolved at 40 ° C.
  • Chitosan (Daiichi Seika Kogyo, Daichitosan 100D, deacetylation degree 98%) was mixed with 1% acetic acid at 25 mg / mL (2.5%) and dissolved at 40 ° C.
  • a mixed solution of 3% (v / v) gelatin / 1% (v / v) chitosan was prepared.
  • FIG. 17A shows a state before filling
  • FIG. 17B shows a state after filling. 3-1-8.
  • Sustained release test iGel-FL (fluorescein-containing iGel)
  • iGel refill (1) The PDMS capsule after the sustained release was stirred in PBS at 80 ° C. for 1 hour or more, and the inside of the capsule was washed with vortex. (2) The capsule was refilled with iGel-FL by the method shown in 3-1-6. 3-1-11.
  • V79 cytotoxicity test Culture medium (1) Cells were subcultured 3 to 5 times using a 10 cm dish in a medium in which an antibiotic was added to MEM10 medium (Eagle's MEM medium adjusted to 10% fetal calf serum). (2) M05 medium (Eagle's MEM medium supplemented with fetal bovine serum 5 vol%, sodium pyruvate, and antibiotics) was used for the test and preparation of the test solution.
  • Test solution preparation (1) Finely cut test material (PDMS sheet / iGel / 0.25% zinc dibutyldithiocarbamate (ZDBC) -containing polyurethane film) to 0.1 g / mL was placed in M05 medium. The test solution was allowed to stand for 24 hours in a 37 ° C. carbon dioxide incubator. (2) After standing for 24 hours, the test medium was centrifuged and filtered (centrifugation; 2500 rpm, 5 min / filter hole diameter; 0.4 ⁇ m). The test medium obtained at this time was used as a 100% test medium. (3) The obtained 100% test medium was diluted with fresh M05 medium to prepare test solutions (25%, 50%, 75%, 100%) having different concentrations.
  • Disposable syringe made of polypropylene (Terumo Corporation) with a general anesthetic solution [mixture of ketamine (90 mg / kg as ketamine hydrochloride) and Seractal (10 mg / kg as xylazine hydrochloride)] attached with a 25G injection needle (Terumo Corporation) And administered into the thigh muscle.
  • ketamine 90 mg / kg as ketamine hydrochloride
  • Seractal 10 mg / kg as xylazine hydrochloride
  • a sheet having a silicon coating on one side was prepared by curing at 80 ° C. for 3 hours.
  • (3) The stainless steel sheet coated with silicon was cut to fit the bottom of the capsule reservoir.
  • (4) PDMS was further cast on the sheet cut to the size of the bottom, and spin coated at 3000 rpm for 10 seconds. At this time, the surface to be coated was the opposite side to that in the step (1).
  • the surface coated in (4) was placed so as to face the bottom surface of the PDMS reservoir, and cured at 80 ° C. for 3 hours.
  • the PDMS sheet with wire and the PDMS reservoir with slenless sheet prepared in 3-1-4 were bonded with PDMS as glue to complete the capsule. 3-1-14.
  • iGel-FD150 fluorescent dextran 150 kDa containing iGel
  • Gelatin Sigma, G2500-100G
  • Chitosan Daiichi Seika Kogyo, Daichitosan 100D, degree of deacetylation 98%) was mixed with 1% acetic acid at 25.5 mg / mg and dissolved at 40 ° C.
  • a mixed solution of 3% (v / v) gelatin / 1% (v / v) chitosan was prepared.
  • PDMS capsule was stabbed and filled with 29 to 32 uL. 3-1-15.
  • Sustained release test (iGel-FD150) (1) PDMS capsules filled with iGel-FD150 were immersed in 10 mL of PBS and incubated at 37 ° C. (2) Periodically, PBS was collected and replaced with fresh PBS. (3) The collected PBS was appropriately diluted and measured with a fluorescent plate reader (ex.485 mm / em.538 nm). (4) The concentration was calculated from the calibration curve of FD150. 3-1-16.
  • Rabbit scleral implantation test (drug injection into a capsule with stainless steel sheet) (1) The animal was general anesthetized. Disposable syringe made of polypropylene (Terumo Corporation) with a general anesthetic solution [mixture of ketamine (90 mg / kg as ketamine hydrochloride) and Seractal (10 mg / kg as xylazine hydrochloride)] attached with a 25G injection needle (Terumo Corporation) And administered into the thigh muscle. (2) After general anesthesia, the area around the left eye was shaved and washed with physiological saline. The right eye was not treated.
  • the device was placed using a surgical microscope (OME-1000, Olympus Optical Co., Ltd.). (4) After applying 1 to 2 drops of Benokishir to the left eye, it was opened with a crusher. (5) Thereafter, a control thread was applied to the superior rectus muscle with 4-0 thread to rotate the eyeball downward to expose the bulbar conjunctiva near 12:00. (6) An ophthalmic scissor was used to make an approximately 4 ⁇ 4 mm scissor-ball conjunctival incision on the nose side, and one device (inside the sky) was inserted between the bulb conjunctiva and the sclera using a sushi.
  • the position of the device was fixed on the sclera with 7-0 suture with the tip between the eye equator and the optic nerve. (7) After fixing the device, the incised part of the bulbar conjunctiva was sutured with 9-0 suture. (8) After indwelling, Talivid eye ointment was spotted. (9) Three weeks after implantation, the state of the device was confirmed. If there was no problem, the animal was anesthetized by the method of (1). (10) After the treatment from (2) to (5), iGel containing 50 mg / mL FD150 (see 3-1-14 for the preparation method) was injected into the device using a 25G needle.
  • Rat scleral implantation test evaluation of biodegradability of iGel and PDMS (1) The animal was general anesthetized. Disposable syringe made of polypropylene (Terumo Corporation) with a general anesthetic solution [mixture of ketamine (90 mg / kg as ketamine hydrochloride) and Seractal (10 mg / kg as xylazine hydrochloride)] attached with a 25G injection needle (Terumo Corporation) And administered into the thigh muscle.
  • ketamine 90 mg / kg as ketamine hydrochloride
  • Seractal 10 mg / kg as xylazine hydrochloride
  • FIG. 19 shows the state of the capsules on the 8th, 16th, 18th and 22nd days before the test.
  • the release curve of UNO is shown in FIG. Encapsulation suppressed burst release and a constant release was observed.
  • the result of the V79 cell colony formation test using the device extract obtained in (1) of “Test solution preparation” of 3-1-11 is shown in FIG.
  • FIG. 21A shows the colony formation rate when each device extract is used
  • FIG. 21B shows the state of the colonies.
  • the extract solution of iGel and PDMS sheet has a control colony formation rate of 97% or higher in any of 100% to 25%, and is not cytotoxic in consideration of the medical device GLP standard that 80% or higher is not toxic It was confirmed.
  • FIG. 21A shows the colony formation rate when each device extract is used
  • FIG. 21B shows the state of the colonies.
  • the extract solution of iGel and PDMS sheet has a control colony formation rate of 97% or higher in any of 100% to
  • FIG. 22 shows a photograph of the rabbit sclera implantation. After implanting an empty flexible device (FIG. 22A), it was possible to inject FL-iGel with a 25G needle one week later (FIGS. 22B and C).
  • FIG. 28 shows a diagram of a flexible device in which a stainless steel sheet is placed.
  • FIG. 28A shows a schematic diagram, where the left shows a sustained release surface and the right shows a non-sustained release surface.
  • FIG. 28B shows a photograph, showing a sustained release surface, a non-sustained release surface, and a photograph after bending from above. When the needle was punctured into the capsule during implantation, the sclera was prevented from being pierced.
  • FIG. 29 shows a state of implantation of a flexible device containing a stainless steel sheet (FIG. 29A) and a state of injection of iGel-FD150 (FIG. 29B).
  • FIG. 29A shows the state before implantation, conjunctival incision, device placement, and conjunctival suture (after implantation) from the left.
  • the device extracted after the injection was filled with iGel-FD150 (upper part of FIG. 29C), and strong fluorescence was observed in the device (lower part of FIG. 29C).
  • FIG. 30 shows the sustained release properties when iGel-FD150 and iGel-FD150 are filled in a flexible capsule.
  • FIG. 31 shows the state of the rabbit eyeballs after 1 week, 4 weeks, and 12 weeks after implantation of the flexible capsule filled with iGel-FD150.
  • FIG. 31 shows a photograph and a fluorescent photograph of the eyeball before removal of the device (flexible capsule), and a photograph and a fluorescence photograph of the eyeball after removal of the device (flexible capsule). Since strong fluorescence was observed in the sclera after removing the flexible capsule, sustained release to the sclera was confirmed.
  • FIG. 32 shows rabbit eyeball specimens (fluorescence imaging) after 1 week (FIG. 32A), 4 weeks (FIG. 32B), and 12 weeks (FIG.
  • FIG. 33 shows the biodegradability of iGel and the surrounding tissues after implantation on the rat sclera (A: before implantation, B: 1 day later, C: 8 weeks later, D: 16 weeks later, E: 24 weeks later).
  • the upper photo shows the entire eyeball, the center shows the subconjunctival tissue near the implantation site, and the lower photo shows the retinal tissue near the implantation site.
  • FIG. 34 shows the biodegradability of PDMS and the surrounding tissue after implantation on the rat sclera (A: before implantation, B: 1 day, C: 8 weeks, D: 16 weeks, E: 24 weeks later).
  • the upper photo shows the entire eyeball, the center shows the subconjunctival tissue near the implantation site, and the lower photo shows the retinal tissue near the implantation site.
  • the arrow part of the upper photograph shows implanted PDMS. PDMS did not degrade in 24 weeks. There was no abnormality in retinal tissue.
  • Subcutaneous implantable device 4-1 Subcutaneous implantable device 4-1.
  • Method 4-1-1 PDMS mold production
  • the shape of the device was cut into an acrylic plate (10 cm square, 0.5 cm thickness).
  • a polydimethylsiloxane (PDMS, SILPOT-184, Toray Dow Corning) prepolymer was cast on an acrylic plate and cured at 80 ° C. for 3 hours.
  • PDMS was removed from the acrylic plate, and oxygen plasma treatment was performed.
  • PDMS was placed at room temperature for 1 hour in a 1H, 1H, 2H, 2H-perfluorotrichlorosilane (FOTS, Wako) atmosphere (silanized PDMS template).
  • a new PDMS prepolymer was cast on a silanized PDMS mold and cured at 80 ° C. for 3 hours.
  • PDMS was removed and oxygen plasma treatment was performed.
  • PDMS was placed at room temperature for 1 hour in a 1H, 1H, 2H, 2H-perfluorotrichlorosilane (FOTS, Wako) atmosphere (silanized PDMS template).
  • FOTS, Wako 1H, 1H, 2H, 2H-perfluorotrichlorosilane
  • a push-type PDMS mold was produced in the same manner. 4-1-2. Preparation of capsule 1 (Type 1; for gel injection) (1) A PDMS prepolymer was cast on the PDMS mold for reservoir prepared in 4-1-1, and a stamping die was placed thereon, and then cured at 100 ° C. for 1 hour to obtain a PDMS reservoir (FIG. 23A).
  • FIG. 23A shows a schematic diagram of a PDMS capsule. 4-1-3.
  • capsule 2 (Type 2; for gel injection)
  • a PDMS prepolymer was cast on a PDMS mold for an outer reservoir and a stamping die was placed thereon, followed by curing at 80 ° C. for 3 hours.
  • (3) A TEGDM reservoir was obtained by casting TEGDM on a PDMS mold (with pores) for inner reservoir and UV irradiation (40 seconds).
  • the TEGDM reservoir was placed inside the PDMS reservoir (outside).
  • the PDMS prepolymer was cast on a PDMS mold for the cover and placed on a pressing mold, and then cured at 80 ° C. for 3 hours.
  • PDMS was removed to obtain a PDMS cover (with pores).
  • PDMS was cast on the PDMS reservoir (outside) cage, placed with a PDMS cover, and cured at 80 ° C. for 3 hours.
  • a PDMS capsule (for gel injection) was completed by the above treatment (FIG. 25A). 4-1-4. Preparation of capsule 3 (Type 3; for liquid injection) (1) A PDMS prepolymer was cast on a PDMS mold for an outer reservoir and a stamping die was placed thereon, followed by curing at 80 ° C. for 3 hours. (2) PDMS was removed to obtain a PDMS reservoir (outside).
  • a TEGDM reservoir was obtained by casting TEGDM on a PDMS mold (with pores) for inner reservoir and UV irradiation (40 seconds).
  • PEGDM was cast on a PDMS template for sustained release film and UV irradiation (240 seconds) was performed to obtain a PEGDM film.
  • a PEGDM membrane was placed in the PDMS reservoir.
  • the TEGDM reservoir was placed inside the PDMS reservoir (outside) and on the PEGDM membrane.
  • a PDMS prepolymer was cast on a PDMS mold for a cover and placed on a stamping die, and then cured at 80 ° C. for 3 hours.
  • PDMS was removed to obtain a PDMS cover (no pore).
  • the FL powder was pulverized with a pestle and mixed well.
  • a 50% EDC solution was mixed with the FL mixed solution at 40 ° C. to a final concentration of 1 (v / v)% (0.35 mL gelatin / chitosan mixture + 7 ⁇ L 50% EDC).
  • the port needle 24G was stabbed and then filled with 420 ⁇ L in a PDMS capsule using a 20G needle. 4-1-6.
  • iGel-FL Sustained release test
  • the capsule filled with iGel-FL was immersed in 25 mL of PBS and incubated at 37 ° C.
  • PBS was collected and replaced with fresh PBS.
  • the collected PBS was appropriately diluted and measured with a fluorescent plate reader (ex.485 nm / em.538 nm).
  • the concentration was calculated from the calibration curve of FL. 4-1-7.
  • Capsule subcutaneous implantation and drug injection test (1) A 2 cm incision was made on the right back of an SD rat (250 g, heel), a pocket was created between the subcutaneous and muscle, and an empty capsule (Type 2; for gel injection and Type 3; for liquid injection) was detained.
  • untreated capsules were prepared in the pores.
  • the PEGDM / Water solution constituting the sustained release membrane was cast into a TEGDM reservoir and cured by UV irradiation.
  • the P50W50 film was immediately frozen at -80 ° C.
  • P30W70 and P15W85 membranes were frozen at ⁇ 80 ° C. by adding an appropriate amount of water used during the production of the membrane.
  • lyophilized for 24 hours or more After freezing for 4 hours or more, lyophilized for 24 hours or more.
  • a TEGDM reservoir prepared by lyophilization was placed in a PDMS reservoir.
  • the PDMS prepolymer was cast on a PDMS mold for cover and the mold was placed thereon, and then cured at 80 ° C.
  • cyclosporin A (neoral) was injected intramuscularly every day (2 conditions of 25 ⁇ L and 50 ⁇ L).
  • the body weight was measured regularly until the 14th day of administration.
  • lipopolysaccharide LPS; WAKO
  • LPS lipopolysaccharide
  • plasma was collected, and IL1-beta concentration in the plasma was measured by ELISA (# 27193, IBL). 4-1-11.
  • iGel-insulin preparation (1) Gelatin (Sigma, G2500-100G) was mixed with MilliQ water at 50 mg / mL (5%) and dissolved at 40 ° C.
  • Human recombinant insulin (WAKO, 097-06474) was mixed with gelatin / chitosan solution so as to be 100, 50, 10 mg / mL (40 ° C.).
  • a 50% EDC solution was mixed at 40 ° C. to a final concentration of 1 (v / v)% (0.35 mL gelatin / chitosan mixture + 7 ⁇ L 50% EDC). 4-1-12.
  • Preparation of capsule for liquid injection and insulin filling (1) A PDMS prepolymer was cast on a PDMS mold for an outer reservoir and a stamping die was placed thereon, followed by curing at 80 ° C. for 3 hours. (2) PDMS was removed to obtain a PDMS reservoir (outside).
  • a TEGDM reservoir was obtained by casting TEGDM on a PDMS mold (with pores) for inner reservoir and UV irradiation (40 seconds).
  • the pores of the TEGDM reservoir were filled with PEGDM 50% / Water 50% (P50W50), PEGDM 30% / Water 70% (P30W70), PEGDM 20% / Water 80% (P20W80), PEGDM 15% / Water 75% (P15W75) (hereinafter, gradually) Abbreviated as release).
  • An untreated capsule was created in the pore as a control.
  • the PEGDM / Water solution constituting the sustained release membrane was cast into a TEGDM reservoir and cured by UV irradiation.
  • the P50W50 film was immediately frozen at -80 ° C.
  • the P30W70, P20P80, and P15W85 membranes were frozen at ⁇ 80 ° C. after adding an appropriate amount of water used during the production of the membrane.
  • lyophilized for 24 hours or more.
  • a TEGDM reservoir prepared by lyophilization was placed in a PDMS reservoir.
  • the PDMS prepolymer was cast on a PDMS mold for cover and the mold was placed thereon, and then cured at 80 ° C. for 3 hours.
  • PDMS was removed to obtain a PDMS cover (no pore).
  • the PDMS was cast on the cage of the PDMS reservoir of (8), the PDMS cover was placed, and cured at 80 ° C. for 3 hours. (12) Trimming unnecessary PDMS. (13) A PDMS capsule (for liquid injection) was completed by the above treatment. (14) Using a 20G needle, 350 ⁇ L of an insulin solution (100 mg / mL) was filled in the capsule. 4-1-13. Sustained release test (iGel-insulin) (1) The iGel-insulin prepared in 4-1-11 (3 conditions of 100, 50, and 10 mg / mL) was incubated at 37 ° C. in a solvent (2.4% Tween 80, 4% Cremophor-containing PBS).
  • Diabetic rats were anesthetized and iGel-insulin (4 conditions of 100, 50, 10, 0 mg / mL) prepared in 4-1-11 was injected subcutaneously.
  • iGel-insulin 4 conditions of 100, 50, 10, 0 mg / mL
  • an aqueous insulin solution (27.5, 2.75, 0.275 Unit / 3 conditions) was intramuscularly injected.
  • blood glucose level was measured (Glucose pilot). 4-1-15.
  • FIG. 26 shows the sustained release of FL from double sustained release membrane capsule (Type; for gel injection 2) + iGel.
  • FIG. 27 shows a photograph of a capsule (B) in which iGel (A) and fluorescein (solution) were injected into the capsule implanted subcutaneously. It was confirmed that the TEGDM membrane prevented puncture and the capsule was easily filled with the drug.
  • FIG. 36 shows the sustained release properties of cyclosporin A. The examination was performed three times by changing the ratio of PEGDM to Water in the PEGDM / Water solution cast into the pores of the TEGDM reservoir (P15W85, P30W70, P50W50). The results of Study 1, Study 2 and Study 3 are shown in FIGS. 36A, 36B and 36C, respectively.
  • FIG. 37 shows the results of a pharmacological test for cyclosporin A-DDS.
  • FIG. 37A shows the weight change rate
  • FIG. 37B shows the plasma IL-b concentration.
  • Body weight was reduced by cyclosporin A administration (FIG. 37A). The decrease was significant in DDS (without film), which has a high release.
  • FIG. 38A shows the sustained release of iGel (chitosan 1%, gelatin 3%)-insulin. The higher the insulin concentration, the longer the sustained release period. The released amount was about 1 to 18 Unit / day.
  • FIG. 38B shows the sustained release when an insulin solution is injected into a subcutaneously implantable capsule. A constant sustained release was observed in the capsule with the sustained release membrane.
  • FIG. 39 shows changes in blood glucose level when insulin solution (FIG. 39A) and iGel (chitosan 1%, gelatin 3%)-insulin (FIG. 39B) were administered.
  • the optimum amount of insulin showing a decrease in blood glucose level in diabetic rats was determined to be 2.75 Units or more and 27.5 Units or less.
  • the sustained release of iGel was suggested.
  • NaCl particles were sieved using a cell strainer (100 ⁇ m, 70 ⁇ m, 40 ⁇ m; BD falcon, REF 352360, REF 352350, REF 352340) to obtain NaCl particles of 100 ⁇ m, 70 ⁇ m, 40 ⁇ m.
  • (3) NaCl particles were mixed with the PDMS prepolymer at an arbitrary concentration (0.025 g / mL to 1 g / mL) and mixed well. (4) It deaerated until the foam disappeared at 0.08 MPa or less.
  • An NaCl-containing PDMS prepolymer was cast into a PDMS mold (diameter) (diameter 16 mm, depth 4 mm, left in FIG.
  • PDMS prepolymer was cast on an acrylic plate on which a 0.05 mm stainless steel spacer was placed, sandwiched with another acrylic plate, and cured at 80 ° C. for 3 hours.
  • a PDMS sheet (2 cm ⁇ 2 cm) having a thickness of 0.05 mm was obtained.
  • (2) 0.2 mL of PDMS prepolymer was cast on a PDMS sheet and spin-coated (3000 rpm, 10 seconds).
  • the PDMS sheet was placed on a PDMS mold having a recess ( ⁇ 2 mm, depth 0.5 mm) (FIG. 43B).
  • FIG. 43A illustrates the procedure for creating a flexible capsule by way of illustration. 5-1-4.
  • Porous PDMS sheet containing NaCl particles having particle sizes of 100 ⁇ m, 70 ⁇ m, and 40 ⁇ m at a concentration of 0.025 g / mL to 1 g / mL was prepared by the method of 5-1-1.
  • Calpain inhibitor molecular weight 2839
  • P20W80 or 5% gelatin aqueous solution Calpain inhibitor concentration: 100 mg / mL.
  • the P20W80 mixture was cured by irradiation with ultraviolet rays for 240 seconds.
  • Each mixture (drug pellet) was air-dried in a draft at room temperature for 2 hours.
  • FIG. 41A shows a PDMS mold (left) for producing NaCl particle-containing PDMS pellets and a produced NaCl particle-containing PDMS pellet (right).
  • FIG. 41B A photograph of a porous PDMS sheet sliced with a microtome is shown in FIG. 41B. From the left, the concentration of NaCl particles (particle size 40 ⁇ m) is 0.5 g / mL, 0.25 g / mL, and 0.1 g / mL. The higher the particle density, the whiter the sheet. In the case of the PDMS pellet of FIG. 41A, it was difficult to elute the salt even when immersed in water. It was considered that the salt particles were not exposed on the surface of the PDMS pellet. Therefore, we devised a method of slicing and exposing the salt particles to elution into water. By this method, a PDMS porous sheet can be produced easily and reliably.
  • FIG. 42 shows SEM photographs of porous PDMS sheets that were salt-eluted with NaCl having a particle size of 100 ⁇ m (A) and 70 ⁇ m (B). The dotted line indicates the boundary between the surface and the cross section. A porous structure was observed on the surface and cross section of the sheet.
  • FIG. 44-1A shows a photograph of a flexible capsule containing FD150 (5% gelatin pellet), and FIG. 44-1B shows a configuration image of the flexible capsule (NaCl particle size 70 ⁇ m, 0.5 g / mL). In FIG. 44-1A, it can be seen that the drug reservoir portion is filled with the fluorescent dye FD150 (yellow).
  • FIGS. 44-2A and 44-2B show the sustained release properties of FD150.
  • the results showed that the particle size of the NaCl particles was 70 ⁇ m (A) and 40 ⁇ m (B). In any result, it was found that the lower the concentration of NaCl particles, the more the release can be suppressed. This indicates that the release can be suppressed by the pore density. Also, the release was suppressed more than 70 ⁇ m at a particle size of 40 ⁇ m.
  • FIG. 45 shows a photograph of a flexible capsule containing a Calpain inhibitor (P20W80 pellet).
  • FIG. 45A it can be seen that the drug reservoir portion is filled with calpain inhibitor (blue).
  • FIG. 46 shows the sustained release properties of the flexible capsule containing the Calpain inhibitor (P20W80 pellet). The results showed that the particle diameters of NaCl particles were 100 ⁇ m (A) and 70 ⁇ m (B). In any result, it was found that the lower the concentration of NaCl particles, the more the release can be suppressed.
  • FIG. 47 shows a photograph (A) and sustained release (B) of a flexible capsule containing Calpain inhibitor (5% gelatin [G5] pellet).
  • the particle size of NaCl particles was 70 ⁇ m and 40 ⁇ m.
  • FIG. 45 it was found that the release can be suppressed by the size and density of the pores.
  • the reinjectable sustained drug sustained release device of the present invention can be utilized for long-term sustained administration of drugs. All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety.

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Abstract

L'invention concerne un dispositif d'administration de médicament pouvant être enfoncé et rechargeable qui permet une administration de médicament avec la vitesse de libération de médicament pouvant être commandée à une vitesse de libération souhaitée sur de longues périodes de temps d'au moins plusieurs mois. Pour une implantation dans le corps, ce dispositif de libération prolongée de médicament peut être réinjecté avec le médicament à l'aide d'une seringue dans un état implanté dans le corps, et comprend un réservoir en polydiméthylsiloxane (PDMS) en forme de boîte et un couvercle en feuille de PDMS encapsulant le médicament, et a une surface de libération progressive poreuse.
PCT/JP2018/004278 2017-02-01 2018-02-01 Dispositif de libération prolongée de médicament pouvant être réinjecté avec le médicament, et gel injectable pour remplissage WO2018143481A1 (fr)

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JP2020156968A (ja) * 2019-03-28 2020-10-01 国立大学法人東北大学 ４層構造を利用した展開制御可能な薬剤徐放シート
WO2021020252A1 (fr) 2019-07-26 2021-02-04 国立大学法人東北大学 Dispositif de libération continue de médicament pouvant être rempli de médicaments
WO2023159169A1 (fr) * 2022-02-18 2023-08-24 The Board Of Trustees Of The University Of Illinois Induction d'une infertilité irréversible chez les mammifères femelles à l'aide d'un seul implant de progestérone

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