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WO2024245992A1 - Implant pour œil - Google Patents

Implant pour œil Download PDF

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Publication number
WO2024245992A1
WO2024245992A1 PCT/EP2024/064496 EP2024064496W WO2024245992A1 WO 2024245992 A1 WO2024245992 A1 WO 2024245992A1 EP 2024064496 W EP2024064496 W EP 2024064496W WO 2024245992 A1 WO2024245992 A1 WO 2024245992A1
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WO
WIPO (PCT)
Prior art keywords
group
implant
independently
bis
thermoplastic elastomer
Prior art date
Application number
PCT/EP2024/064496
Other languages
English (en)
Inventor
Inês Carolina FIGUEIREDO PEREIRA
Jacob Marinus Jan Den Toonder
Helena Jacqueline Maria BECKERS
Patricia Yvonne Wilhelmina Dankers
Henricus Marie Janssen
Original Assignee
Universiteit Maastricht
Academisch Ziekenhuis Maastricht
Technische Universiteit Eindhoven
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universiteit Maastricht, Academisch Ziekenhuis Maastricht, Technische Universiteit Eindhoven filed Critical Universiteit Maastricht
Publication of WO2024245992A1 publication Critical patent/WO2024245992A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/64—Polyesters containing both carboxylic ester groups and carbonate groups
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G64/00—Macromolecular compounds obtained by reactions forming a carbonic ester link in the main chain of the macromolecule
    • C08G64/02—Aliphatic polycarbonates
    • C08G64/0208—Aliphatic polycarbonates saturated
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/26—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from polyamines and polycarboxylic acids

Definitions

  • the present invention relates to an implant for implantation in an eye and a production process thereof.
  • Glaucoma is a neurodegenerative disease of the optic nerve and the leading cause of irreversible vision loss worldwide. Elevated intraocular pressure (IOP) is considered to be the major risk factor for glaucoma and is associated with a disbalance between the production and drainage of aqueous humor (AqH, internal eye fluid), due to an increased resistance to AqH outflow. Lowering the IOP remains the only proven treatment to halt progression of the disease and visual field loss. Ophthalmologists use a variety of approaches to lower IOP, including medication (eye drops), laser procedures, and incisional surgeries.
  • IOP Elevated intraocular pressure
  • MIGS minimally invasive glaucoma surgery
  • Schlemm’s canal MIGS devices using this approach are typically called Schlemm’s canal MIGS devices.
  • Schlemm’s canal MIGS devices the two most commonly used Schlemm’s canal MIGS devices are the iStent inject® (Glaukos Corporation, California, USA) and the Hydrus® Microstent (Ivantis, Inc., California, USA).
  • the iStent inject® is made of heparin-coated implant-grade titanium and is inserted ab interno through a microincision made in the anterior chamber using an injector device.
  • the iStent inject® has been shown in numerous publications to be a safe and effective procedure in the treatment of different types of open-angle glaucoma, either as a standalone procedure or combined with cataract surgery. In these clinical studies, most patients experienced a clinically significant reduction in IOP and a reduction in reliance on glaucoma medication, with a low incidence of postoperative complications.
  • US10271989 discloses an implant for implantation in an eye, preferably made of one or more biocompatible materials. Suitable examples of polymers and metals are mentioned. US10271989 discloses that the implant can further include a biodegradable material in or on the implant such as poly(caprolactone). US10271989 discloses that the implants can be manufactured by sintering, micro machining, laser machining, and/or electrical discharge machining.
  • MIGS devices Known issues with existing MIGS devices are that sometimes they are blocked or overgrow in time with a fibrotic capsule, thereby closing the direct opening into systemic circulation leading to an increase in IOP and further progression of the disease.
  • a new implant is injected in the trabecular meshwork, leaving the old implant. This causes problems for future implants since the location of an overgrown device is not known and no other glaucoma drainage implant can be placed near the same location due to an active fibrotic response.
  • the present invention provides an implant for implantation in an eye, wherein the implant comprises a thermoplastic elastomer according to the formula [AB]n, wherein: n represents the number of repeats of the AB segment and is an integer of 2 to 100; A represents a soft block according to formula (I):
  • K is a Ci - C36 alkylene group, a Ce - C24 arylene group, a C7 - C24 alkarylene group or a C7 - C24 arylalkylene group;
  • L is a Ci - C36 alkylene group, a Ce - C24 arylene group, a C7 - C24 alkarylene group or a C7 - C24 arylalkylene group or L is absent;
  • M is a Ci - C36 alkylene group, a Ce - C24 arylene group, a C7 - C24 alkarylene group or a C7 - C24 arylalkylene group or M is absent; o, p, q, r, s and t are independently 0 - 50; provided that:
  • HBG is a simple hydrogen bonding unit independently selected from the group consisting of amide, urea and urethane groups;
  • S is a Ci - C36 alkylene group, a Ce - C24 arylene group, a C7 - C24 alkarylene group or a C7 - C24 arylalkylene group or S is absent; and x is 1 , 2 or 3.
  • the present invention further provides a process for making the implant, comprising hot embossing of the thermoplastic elastomer to obtain the implant.
  • the implant according to the invention is biodegradable and therefore has an advantage that it will be naturally absorbed into the body.
  • the implant degrades slowly, which offers enough time for a proper and sufficient remodeling of the trabecular meshwork to occur around the implant.
  • the extra outflow site created by the implant remains patent, thus creating a long-term modification of the trabecular meshwork without the need for a permanent implant that may further scar and lose effectiveness.
  • Being biodegradable is additionally advantageous in case the implant is mispositioned or becomes dislodged. As the implant will degrade over time, there will be no accumulation of “lost” implants inside the eye. For the same reason, if at some point the implant becomes non-functional, it is less of a concern to reoperate the eye and implant a new implant.
  • thermoplastic elastomer (TPE) used according to the invention has good processibility (e.g. good solubility, easy to melt), shape persistency (no or very little creep) and elasticity suitable for making an eye implant.
  • the TPE is also a soft material, and it is biodegradable and non-toxic, so it is suitable for application in the biomedical field.
  • thermoplastic elastomer used according to the invention can withstand high temperature and high pressure without its polymer structure and mechanical properties being significantly affected. This allows the thermoplastic elastomer to be subjected to a hot embossing process for producing the implant according to the invention, which process is particularly suitable due to the shape and size of the implant. In contrast, other types of polymers such as polycaprolactone were found to be unsuitable for hot embossing as they cannot be reliably formed into an implant without substantial deformation.
  • the hot embossing processing allows producing a non-porous, dense implant.
  • the nonporosity of the implant allows the implant to provide an effective fluid flow path.
  • the nonporosity of the implant further results in the implant according to the invention to degrade slower than e.g. a porous scaffold.
  • thermoplastic elastomer used according to the invention is a slow degrading polymer that mainly degrades through hydrolysis of the carbonate and amide groups, either through interaction with water or from enzymatic reactions. Carbonate and amide groups degrade slower than esters, which are very common in other biodegradable polymers such as polycaprolactone and polylactic acid.
  • thermoplastic elastomer used according to the invention is non-cytotoxic.
  • WO2015/194961 discloses the thermoplastic elastomer used according to the invention, but WO2015/194961 does not disclose its application to an implant for implantation in an eye and does not disclose hot embossing.
  • the implant according to the invention may have forms and dimensions described in US10271989, the contents of which are fully incorporated herein by reference. As described in US10271989, the implant according to the invention can have the following features.
  • implant refers to ocular implants which can be implanted into any number of locations in the eye.
  • the ocular implants are drainage implants designed to facilitate or provide for the drainage of aqueous humor from the anterior chamber of an eye into a physiologic outflow pathway in order to reduce intraocular pressure.
  • the implant can be sized and shaped to provide a fluid flow path for draining aqueous humor from the anterior chamber through the trabecular meshwork and into Schlemm's canal.
  • implant as used herein is a broad term, and is to be given its ordinary and customary meaning to a person of ordinary skill in the art (and it is not to be limited to a special or customized meaning), and refers without limitation to drainage shunts, stents, sensors, drug delivery implants, drugs, therapeutic agents, fluids, or any other device or substance capable of being inserted within an eye.
  • implant can be interchanged with the words “stent” or “shunt” in various embodiments.
  • one or more of the implants are ocular implants for purposes other than drainage (for example, a drug delivery device or an ocular sensor for measuring intraocular pressure or components of ocular fluid, such as glucose).
  • an implant comprises two sections or portions tethered together, such as a sensor tethered to a drainage implant, a sensor tethered to an anchor.
  • drainage implants define one or more fluid passages.
  • the fluid passage(s) in some embodiments remains patent and, in other embodiments, the passage(s) is fully or partially occluded under at least some circumstances (e.g., at lower intraocular pressure levels).
  • the implants may feature a variety of characteristics which facilitate the regulation of intraocular pressure.
  • the implant is configured to provide a fluid flow path for draining aqueous humor from the anterior chamber through the trabecular meshwork and into Schlemm's canal when implanted.
  • the implant has a proximal portion, an intermediate portion and a distal portion, wherein the proximal portion is configured to reside in the anterior chamber and the distal portion is configured to reside in the Schlemm’s canal, wherein a lumen extends from a proximal end of the proximal portion through the intermediate portion to a distal end of the distal portion to provide fluid communication between the proximal end and the distal end.
  • the distance between the proximal end and the distal end is 0.01 to 1.0 mm.
  • the implant according to the invention can have the structure as described in detail in column 21, lines 20 to column 23, line 21 and Figure 18 of US10271989, incorporated herein by reference.
  • thermoplastic elastomer used according to the invention has the formula [AB] n , wherein: n represents the number of repeats of the AB segment and is an integer of 2 to 100; A represents a soft block according to formula (I):
  • K is a Ci - C36 alkylene group, a Ce - C24 arylene group, a C7 - C24 alkarylene group or a C7 - C24 arylalkylene group;
  • L is a Ci - C36 alkylene group, a Ce - C24 arylene group, a C7 - C24 alkarylene group or a C7 - C24 arylalkylene group or L is absent;
  • M is a Ci - C36 alkylene group, a Ce - C24 arylene group, a C7 - C24 alkarylene group or a C7 - C24 arylalkylene group or M is absent; o, p, q, r, s and t are independently 0 - 50; provided that:
  • HBG is a simple hydrogen bonding unit independently selected from the group consisting of amide, urea and urethane groups;
  • S is a Ci - C36 alkylene group, a Ce - C24 arylene group, a C7 - C24 alkarylene group or a C7 - C24 arylalkylene group or S is absent; and x is 1 , 2 or 3.
  • thermoplastic elastomer may be prepared by a process wherein a prepolymer according to formula (III- A) or (lll-B): is reacted with a reactive compound according to formula (IV): wherein n, K, L, M, o, p, q, r, s, t, S and HBG have the meaning according to above;
  • FG is a functional group selected from the group consisting of hydroxy, azide, activated hydroxy, carboxylic acid, activated carboxylic acid, isocyanate, activated amine, ester, alkenyl, alkynyl and amine; and
  • FG* is a complementary functional group selected from the group consisting of isocyanate, amine, activated amine, carboxylic acid, activated carboxylic acid, ester, hydroxy, activated hydroxy, azide, alkenyl and alkynyl; a is 0, 1 , 2, 3 or 4; and c is 0 or 1.
  • the soft block A does not display a melting transition or has a melting transition T m -sB of lower than 15 °C, and the hard block B displays a melting transition T m -
  • thermoplastic elastomer Suitable examples of the thermoplastic elastomer and the process for preparing the thermoplastic elastomer used according to the invention are described in detail in WO201 5/194961 , the contents of which are fully incorporated herein by reference.
  • A is a (co)poly-carbonate, a (co)poly-ester or a co-poly(ester-carbonate). More preferably, A is a (co)poly-carbonate or a co-poly(ester-carbonate). Most preferably A is a (co)poly-carbonate.
  • the thermoplastic elastomer has particularly beneficial mechanical properties that are required for making the eye implant according to the invention.
  • (co)poly-carbonates have a preferred biodegradability, as degradation is usually slow.
  • soft block A may be a random polymer, a block-copolymer or a sequence controlled polymer.
  • soft block A is then a random polymer.
  • soft block A may be a homo-polymer or a co-polymer of monomeric components, where the monomeric units can either be randomly distributed over the chain, present in blocks or in a sequenced controlled fashion.
  • soft block A is then a homo-polymer.
  • the soft block A has a number average molecular weight Mn of 100 to 10,000 Dalton, preferably 500 to 5000 Dalton, wherein the number average molecular weight Mn of soft block A is for example determined by 1 H-NMR analysis. These ranges result in good mechanical properties of the implant according to the invention.
  • K is selected from the group consisting of cyclic, linear or branched C2 - Cis alkylene groups, more preferably from cyclic, linear or branched C4 - C12 alkylene groups.
  • L is absent or an alkylene selected from the group of cyclic, linear or branched C2 - Cis alkylene groups. More preferably, L is selected from cyclic, linear or branched C4 - C10 alkylene groups.
  • M is selected from the group of cyclic, linear or branched Ci - C17 alkylene groups. More preferably, M is selected from cyclic, linear or branched C5 - C10 alkylene groups.
  • soft blocks A are selected from the group consisting of:
  • f, g and j are independently in the range of 1 -100, more preferably in the range of 1 - 50, most preferably in the range of 1 - 25.
  • Formula (V-A) represents a (co) poly-carbonate and formula (V-B) represents a polycarbonate with ester terminal groups.
  • the K and M spacers may be independently selected for every K and M in the soft block A and are alkylene, arylene, alkylarylene or arylalkylene groups, preferably alkylene groups.
  • the M-spacer may also be a radical.
  • K is a linear, branched or cyclic C4 -
  • the two M-spacers in formula (V-B) are identical and are selected from Ci - C12 linear, branched or cyclic alkylenes.
  • all K groups are the same, and in this case (V-A) represents a homo-polycarbonate.
  • K is preferably selected from the group of linear, branched or cyclic C4 - C12 alkylenes, more preferably from C4 - C7 and C9 linear alkylenes or C5 - C10 branched alkylenes that are derived from primary diols. Most preferably K is then selected from C4 - C7 linear alkylenes.
  • Soft block A may have the formula (VI):
  • hard block B is selected from the group consisting of bis-urea hard blocks, bisamide hard blocks, tri-amide hard blocks, mono-urea-bis-amide hard blocks, bis- urethane-bis-amide hard blocks and tetra-amide hard block. Most preferably, hard block B is a bis-urea or a bis-amide hard block.
  • hard block B is the same hard block for every hard block unit in the [AB] n polymer.
  • hard block B is preferably monodisperse, so the molecular weight of hard block B is a single molecular weight, and it is not a number averaged molecular weight (as is the case for the soft block A).
  • the molecular structure of the hard block is iso-merically pure, so the connectivity of the atoms in the hard block is such that the hard block is one isomer or stereo-isomer.
  • the molecular weight of the hard block B is preferably between about 85 and about 1000 Dalton, more preferably between about 85 and about 530, even more preferably between about 105 and 350, and most preferably between 115 and about 270 Dalton.
  • the formula weight of the hard block B is not too high, and preferably it is lower than about 530 Dalton, more preferably it is lower than about 300 Dalton.
  • S is absent or S is an alkylene selected from the group of cyclic, linear or branched Ci - C12 alkylene groups. More preferably, S is selected from linear or cyclic C2 - Ce alkylenes that do not contain heteroatoms, where then n-ethylene, n-propylene, n- butylene, n-pentylene, n-hexylene, and 1 ,4-trans-cyclohexylene spacers are more preferred.
  • This has an advantage that the thermoplastic elastomer has good processing and thermal properties suitable hot embossing which is particularly suitable for making an eye implant.
  • the hard block is a bis-amide and S is 1 ,4-trans- cyclohexylene.
  • the hard block is a bis-urea and S is n-ethylene, n- propylene, n-butylene, n-pentylene or n-hexylene, more preferably n-butylene or n- hexylene.
  • x is 1 or 2.
  • Examples of preferred bis-amide hard blocks B are shown below. The asterisks represent the radical connections between these hard blocks B and the soft block A. These are bis-amide (or di-amide) hard blocks B.
  • Hard block 2A is derived from trans 1 ,4- cyclohexylene diamine, and is therefore not a mixture of isomers, but is a single isomeric form.
  • Hard block 2B may either be derived from trans 1 ,2-cyclohexylene diamine or from cis 1 ,2-cyclohexylene diamine, not from both, and is therefore a single isomeric form.
  • Hard block 2E has a radical (i.e.
  • hard blocks 2F, 2G and 2H have n-ethylene, n-propylene and n-butylene S spacers, respectively.
  • preferred hard blocks are 2A, 20, 2D and 2H and the most preferred hard block is 2A. This has an advantage that the thermoplastic elastomer has good processing properties suitable for hot embossing, particularly suitable for making an eye implant.
  • the thermoplastic elastomer according to the formula [AB] n has a number average molecular weight Mn of 500 to 500,000 Dalton, preferably 1 ,000 to 100,000 Dalton, more preferably 10,000 to 50,000 Dalton, wherein the number average molecular weight Mn is determined by gel permeation chromatography. These ranges result in good mechanical properties of the implant according to the invention.
  • Soft block A is polymeric with a distribution in molecular weight.
  • hard block B is the same molecular structure throughout the [AB] n material and has a single specific molecular weight.
  • blocks A and B are strictly alternating in the [AB] n polymer.
  • the weight percentage of the hard block B in the [AB] grip polymer according to the invention is preferably between about 1 w/w% and about 60 w/w%, based on the total weight of the [AB] grip polymer. More preferably, it is between about 2 w/w% and about 25 w/w%, even more preferably between about 3 w/w% and about 16 w/w%, yet even more preferably between about 4 w/w% and about 12 w/w% and most preferably between about 5 w/w% and about 10 w/w%.
  • thermoplastic elastomer is a poly(hexyl carbonate bis-amide represented by the below formula, where the cyclohexyl-diamine is iso-merically pure trans:
  • thermoplastic elastomer [AB] n used according to the invention has good processibility (e.g. good solubility, easy to melt), shape persistency (no or very little creep) and elasticity suitable for making an eye implant.
  • the TPE is also a soft material, and it is biodegradable and non-toxic, so it is suitable for application in the biomedical field.
  • the [AB] spreading materials of the invention may be solubilized at room temperature in chloroform/methanol (10 v/v% methanol) at a concentration of at least 1 (w/v)%, preferably at a concentration of at least 5 (w/v)%, most preferably at a concentration of at least 10 (w/v)%, thereby producing homogeneous, clear and free flowing solutions (viscous or low viscous solutions). Accordingly, the formation of gels or jellies or inhomogeneities is avoided.
  • homogeneous, clear and free flowing solutions are acquired at room temperature in chloroform/methanol (1 v/v% methanol) using a concentration of the [AB] groove material of at least 1 (w/v)%, preferably using a concentration of at least 5 (w/v)%, and most preferably using a concentration of at least 10 (w/v)%.
  • the mechanical properties of the [AB] n polymer can be checked by performing uniaxial tensile testing experiments and/or by performing Dynamic Mechanical Thermal Analysis (DMTA) experiments.
  • DMTA Dynamic Mechanical Thermal Analysis
  • the Youngs’ modulus (E) of the [AB] groove material at room temperature is between about 0.2 MPa and about 200 MPa, more preferably between about 1 MPa and about 100 MPa.
  • the Young’s modulus is preferably higher than about 5 MPa, more preferably it is higher than about 10 MPa, and most preferably it is higher than about 15 MPa.
  • DMTA measurements provide storage moduli (E’) and loss moduli (E”) as a function of temperature.
  • the storage modulus (E 1 ) of the [AB] crust material at 37 °C is between about 0.2 MPa and about 200 MPa, and more preferably between about 1 MPa and about 100 MPa.
  • This modulus is preferably higher than about 5 MPa, more preferably it is higher than about 10 MPa, and most preferably it is higher than about 15 MPa.
  • this storage modulus shows little dependence on temperature between about 20 °C and about 80 °C.
  • the Young’s modulus (E), the storage modulus (E’) and the loss modulus (E”) show the mechanical properties of the material.
  • the indicated preferred ranges for the E and E’ moduli indicate that the [AB]n material is a soft material.
  • the tan(8) as determined with DMTA at 37 °C is lower than about 1.
  • this tan (8) is lower than about 0.2, more preferably, the tan(8) is lower than about 0.1, even more preferably it is about 0.06 or lower, and most preferably it is about 0.04 or lower.
  • the tan(8) is a measure for the elasticity of a material at a certain temperature.
  • the tan(8) value is indicative of the elasticity of the material at a certain temperature.
  • the indicated preferred ranges for tan(8) indicate that the [AB] n material is an elastic and shape- persistent material.
  • DMTA can also be used to determine the flow temperature (T-flow) of a material, where this is the temperature at which the storage E'-modulus suddenly decreases, and here it is defined as the temperature at which the E'-modulus has fallen below about 0.1 MPa.
  • the T-flow of the materials according to the invention is preferably higher than about 100 °C, more preferably higher than about 115 °C and most preferably higher than about 125 °C.
  • the T-flow is preferably lower than about 250 °C, more preferably lower than about 200 °C, and most preferably it is lower than about 180 °C.
  • the flow temperature is indicative of the temperature at which a material can be processed from the melt.
  • the thermal properties of the [AB] n material can be assessed by performing differential scanning calorimetry (DSC) measurements. These measurements provide information on melt and crystallization temperatures (or temperature ranges) as well as on glass transition temperatures.
  • DSC differential scanning calorimetry
  • the invention further provides a process for producing the implant according to the invention by hot embossing.
  • Hot embossing is a micro-fabrication technique in which micron-scale structures on mold is replicated on to a polymer substrate by application of pressure and temperature.
  • the invention provides a process for producing the implant according to the invention comprising hot embossing of the thermoplastic elastomer in a mold to obtain the implant.
  • the hot embossing involves placing a melt of the thermoplastic elastomer having a temperature of 100 to 150 °C in the mold by applying a pressure of 1 to 10 tons, and solidifying the thermoplastic elastomer in the mold.
  • the process may comprise melting the thermoplastic elastomer in a mold made by femtosecond laser-assisted chemical wet etching of a fused silica glass and solidifying the thermoplastic elastomer.
  • Femtosecond laser-assisted chemical wet etching is based on a two-step process of ultrashort-pulsed laser radiation in transparent materials, followed by chemical wet etching to selectively remove the exposed material. This is further described in Suthisomboon, T., Bargiel, S., Rabenorosoa, K. & Pengwang, E. Design and Simulation of XZ MEMS Micropositioning with 3D-Complex Structure, in 2020 Symposium on Design, Test, Integration and Packaging of MEMS and MOEMS (DTIP) 1-5 (2020).
  • Femtosecond laser-assisted chemical wet etching is advantageous for the production of the mold due to its shape and size which would be extremely difficult to achieve using classical micro-manufacturing techniques, such as photolithography or micro-milling.
  • the mold has been subjected to a process for facilitating the release (demolding) of the implants after the hot embossing step.
  • the mold Before the hot embossing step, the mold may be coated with a superhydrophobic layer e.g. of fluorosilane (e.g.
  • the hot embossing is performed on a mold which has been provided with a fluorosilane coating.
  • the mold may undergo an oxygen plasma treatment performed immediately before coating with the fluorosilane.
  • the mold has at least two cavities corresponding to the shapes of the implants and at least two implants are produced by one hot embossing step.
  • the term ‘comprising’ does not exclude the presence of other elements.
  • a description on a product/composition comprising certain components also discloses a product/composition consisting of these components.
  • the product/composition consisting of these components may be advantageous in that it offers a simpler, more economical process for the preparation of the product/composition.
  • a description on a process comprising certain steps also discloses a process consisting of these steps.
  • the process consisting of these steps may be advantageous in that it offers a simpler, more economical process.
  • Figure 1 A schematic view of an example of the implant according to the invention.
  • Figure 2 A scheme of polycarbonate bisamide (PC-BA) synthesis starting with converting poly(hexamethylene carbonate) diol to a poly(hexamethylene carbonate) di-carboxylic acid (95% yield), and then reacting to a poly(hexamethylene carbonate) di-(tetra- fluorophenol active ester) (80% yield), which was reacted with trans-1,4- diaminocyclohexane to obtain the final polymer with a yield of 91%;
  • PC-BA polycarbonate bisamide
  • Figure 3 Characterization of the hot embossed polycarbonate bisamide (PC-BA).
  • b Second heating run of the hot embossed polymer measured with differential scanning calorimetry (DSC)
  • Figure 4 Fabrication process of Schlemm’s canal MIGS implant and its final shape and dimensions
  • a Representation of the PC-BA molecular structure as well as schematic illustration of the stacking of the PC-BA polymer due to hydrogen bonds
  • b Schematic representation of the implant fabrication by replica molding using hot embossing, with femtosecond laser-machined fused silica glass molds
  • c Schematic illustration of the femtosecond laser machining process used to fabricate the glass molds
  • d Picture of the glass mold, made using femtosecond laser machining, used in the hot embossing of the implants, e, Demolded array of implants.
  • Figure 5 a, Injector design and its components; the zoomed figure shows the injector tip reloaded with one of the implant according to the invention, b, Front and back view of the injector device - the back view reveals the “window” created in the housing of the injector to facilitate manipulating the rotating cam.
  • Figure 6 Post-mortem study. Picture showing the proper placement of the implant according to the invention into the trabecular meshwork, after being delivered by the modified injector device.
  • Figure 7 Polycarbonate bisamide (PC-BA) characterization after degradation, a, Mass loss measured after 2, 30 and 60 days for the samples exposed to a hydrolytic environment through incubation with a PBS solution (pH 7.4) at 70 °C, and after 2, 7 and 14 days for the samples in enzymatic and in oxidative environments both at 37 °C.
  • PC-BA Polycarbonate bisamide
  • Figure 8 A photograph of implants made from PCL.
  • Figure 9 The table compiles DMTA-data on the PC-BA [AB] n material.
  • the data indicate that PC-BA is a soft elastic material, given its E’ value, its low tan(8) value and its nearly temperature independent storage modulus E’ between 20 °C and 80 °C.
  • PC-BA can be processed from the melt at lower temperatures, given its low flow temperature.
  • Figure 1 shows a schematic view of an example of the implant according to the invention.
  • the implant has radial symmetry, and is 420 pm-long and 360 pm-wide. It is composed of three parts: a conical-shaped head designed to seat within Schlemm’s canal; a wider flange, which faces the anterior chamber; and the thorax, which is retained by the trabecular meshwork.
  • the central lumen of the device through which the aqueous humor will flow has a diameter of 100 pm. With this device, a direct connection between the anterior chamber and the Schlemm’s canal/collector channel is made, thus bypassing the trabecular meshwork.
  • the implant contains one central outlet.
  • a poly(hexyl carbonate bisamide (hereinafter sometimes referred as PC-BA) was synthesized by reacting trans-1,4-diaminocyclohexane with the prepolymer poly(hexamethylene carbonate) di-(tetra-fluorophenol active ester), as schematically depicted in Figure 2.
  • the activated prepolymer was synthesized by first converting a poly(hexamethylene carbonate) diol to a poly(hexamethylene carbonate) di-carboxylic acid with a yield of 95% and subsequently activating this telechelic di-acid with 2, 3,5,6- tetrafluorophenol (80% yield).
  • the apparent number averaged molecular weight (M n ) of the hot embossed PC-BA polymer is 14.0 kg/mol and the weight averaged molecular weight (M w ) is 27.4 kg/mol, as determined from the GPC measurement ( Figure 3a, Table S1).
  • a differential scanning calorimetry (DSC) measurement revealed that the polymer has a glass transition temperature for the PC soft block around -39.6 °C and three different melting transitions around 8.2, 97 and 152.7 °C in the second heating run (Figure 3b, Table S1).
  • the melting transitions have enthalpies of 5.7, 0.09 and 2.9 J/g, respectively.
  • the first melting peak originates from the soft polycarbonate block and the other two melting peaks originate from the melting of the amide hard block.
  • the hard block has strong hydrogen bonding interactions resulting in a higher melting transition compared to the much weaker dipole interactions of the soft block.
  • the molecular weights, glass transition temperature and melting transitions of the polymer before hot embossing are similar to the values after the polymer has been hot embossed (Table S1). Looking into the thermal stability of the polymer with th e rm ogravi metric analysis reveals that the PC-BA starts to quickly degrade at a temperature around 270 °C. The mechanical behavior of the hot embossed material was determined with tensile testing and showed a typical curve of a thermoplastic elastomer (Figure 3c). The PC-BA has a Young’s modulus of 45.8 ⁇ 3.6 MPa.
  • the cytotoxicity of the embossed PC-BA on primary human tenon fibroblasts was investigated by means of a lactate dehydrogenase (LDH) release assay. LDH is released into the cell culture medium upon damage to the cell’s plasma membrane. The percentage of cytotoxicity obtained for all test conditions is shown in Figure 3d. This experiment reveals that the PC-BA polymer is non-cytotoxic.
  • LDH lactate dehydrogenase
  • PC-BA polycarbonate bisamide
  • Gel permeation chromatography was performed on Varian/Polymer Laboratories PL-GPC 50 equipment using a Shodex GPC KD-804 column that was operated at 50°C using dimethylformamide, or DMF (with 10 mM Li Br and 0.3% water), as the eluent or on a Shimadzu LC-10ADVP system with a Shimadzu RID-10A refractive index detector, a Shimadzu SPD-M10AVP UV-Vis detector, and a combination of a PLgel 5-pm mixed-C column and a PLgel 5-pm mixed-D column, using tetrahydrofuran, or THF, as eluent.
  • GPC Gel permeation chromatography
  • MeO-TEMPO (0.1 g, 0.5 mmol) was added to this DCM solution, as well as a solution of NaBr (0.7 g, 7 mmol) in 200 mL 1M NaHCOs.
  • the resulting two-phase system was stirred vigorously and cooled in an ice bath.
  • Aqueous NaOCI (13%, approx. 3.7 M, 60 mL) was added slowly to the reaction mixture, which was allowed to warm to room temperature after addition of the hypochlorite.
  • Telechelic poly(hexamethylene carbonate) di-carboxylic acid 1 (20 g, 8.7 mmol) was dissolved in DCM (75 mL) with 2,3,5,6-tetrafluorophenol (3.6 g, 22 mmol) and DMAP (89 mg).
  • N,N’-diisopropylcarbodiimide (DiC, 3.6 mL, 23 mmol) was added to the reaction mixture, causing almost immediate formation of a crystalline precipitate. After 3 hours, NMR confirmed full conversion of the two carboxylic acid end groups to active ester end groups.
  • the reaction mixture was filtered, evaporated to dryness, stirred with n-pentane and decanted (2x) to afford crude product as a white solid.
  • the material was weighed and sealed in Tzero aluminum pans before differential scanning calorimetry (DSC) measurements were done on a DSC Q2000 (TA instruments, United States).
  • DSC differential scanning calorimetry
  • the samples were first brought to an isotropic state at 40 °C and then heated to 180 °C at 10 °C/min, which marked the first heating run, and cooled to -70 °C at the same rate. Then the material was further subjected to two heating/cooling cycles from -70 to 180 °C with a heating/cooling rate of 10 °C/min.
  • the data was quantified and analysed using Universal Analysis software (V4.5A, TA Instruments).
  • a mechanical tensile test was performed on PC-BA thin films using a tensile test machine (ZwickRoell Z010) with a crosshead speed of 20 mm/min and a 100 N static load cell.
  • a tensile test machine ZwickRoell Z010
  • a crosshead speed 20 mm/min
  • a 100 N static load cell 100 N static load cell.
  • a 200 pm-thick film was fabricated in a hot embossing machine (Specac limited). We used 130 °C to melt the polymer and 5 tons of pressure press the polymer into the shape of a film. The demolding took place after the hot embossing had cooled down to room temperature. Thereafter, the film obtained was cut into three small rectangular specimens of approximately 30x10x0.2 mm (length x width x thickness). The Young’s modulus was determined as the slope of the linear portion of the obtained stress-strain curve.
  • PC-BA was also analyzed by DMTA.
  • the samples were then sterilized by immersing in 70% ethanol for 20 minutes and treated with UV for 15 minutes, after which they were rinsed in phosphate-buffered saline (PBS, pH 7.4) before transferring to a sterile 96-well plate.
  • PBS phosphate-buffered saline
  • the cells were then seeded at 3.2x10 cells/well into the well plate containing the test samples (three replicates) using complete Advanced Dulbecco’s modified Eagle Medium (DM EM) supplemented with 10% of Fetal Bovine Serum (FBS), 100 U/mL penicillin and streptomycin, and 0.2 mM L-glutamine (now referred to as culture medium).
  • DM EM Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • penicillin and streptomycin 100 U/mL penicillin and streptomycin
  • 0.2 mM L-glutamine now referred to as culture medium.
  • Femtosecond laser-assisted chemical wet etching is based on a two-step process of ultrashort-pulsed laser radiation in transparent materials, followed by chemical wet etching to selectively remove the exposed material (Figure 4c).
  • the laser beam focused inside the glass, locally modifies its refractive index and chemical properties, and patterns written by the laser are then chemically etched to form three-dimensional structures with high precision, aspect ratio and complexity.
  • the complexity of the shape of our implant would be extremely difficult to achieve using classical micro-manufacturing techniques, such as photolithography or micro-milling.
  • the glass slide was immersed in a concentrated solution of 45% potassium hydroxide (KOH, Sigma-Aldrich) diluted in water to remove the exposed material. Finally, the mold was rinsed thoroughly with acetone and DI water to remove all debris.
  • the femtosecond laser-machined glass mold was first coated with a superhydrophobic layer of fluorosilane (Trichloro(1H,1 H,2H,2H-perfluorooctyl)silane, Sigma-Aldrich). To improve the adhesion of this coating, the mold underwent an oxygen plasma treatment performed immediately before the fluorosilane vapor deposition. After the silanization treatment, the mold was ready to be used in the hot embossing machine together with the PC-BA pellets to fabricate the implants.
  • fluorosilane Terichloro(1H,1 H,2H,2H-perfluorooctyl
  • FIG. 4d A picture of the fabricated glass mold is shown in Figure 4d, which also includes a zoomed microscopic view of the features in the mold showing the 100 pm-diameter glass pillar used to form the central lumen of the implant. Using this mold, many implants can be fabricated in one single hot embossing step.
  • the polymer was heated to a temperature of 130 °C to provide a melt of the polymer and 5 tons of pressure was applied to help the melted polymer to flow into the cavities of the mold ( Figure 4b).
  • the demolding took place after the hot embossing had cooled down to room temperature.
  • Figure 4e shows a microscopic image of the fabricated implants.
  • the design and components that comprise the injector device are represented in Figure 5a.
  • the working principle of the injector is explained in the patent no. US10271989B2.
  • the injector is designed to deliver the stents automatically through the trabecular meshwork and into Schlemm’s canal when activated by the surgeon.
  • the portion of the injector that enters the anterior chamber is a 23-gauge stainless steel insertion sleeve.
  • the sleeve of the injector is retracted using the insertion sleeve retraction button, revealing the micro-insertion tube and the trocar.
  • the surgeon then advances the micro-insertion tube across the anterior chamber to the desired site of implantation, while visualizing the tube through direct gonioscopy (using a gonioprism). After locating the trabecular meshwork and selecting the implant location, the trabecular meshwork is penetrated with the trocar. By pressing the surgeon-activated delivery button on the housing, the stent moves over the small guiding trocar to exit the injector. A single audible click will indicate that the first stent has been delivered.
  • Two stents can be implanted with a single entry into the eye, and they should be separated by 2-3 clock hours apart (separated by an angle of 60 to 90 degrees). A total of four positions are available on the injector to position the two stents.
  • a rotating cam hidden within the housing of the injector rotates in a clockwise manner to deploy the stents when the release button is pressed. After the stent delivery button has been pressed for the fourth time, the rotating cam will no longer rotate, and the injector will no longer function. Therefore, in order to have a functioning injector again, the cam has to be manually rotated counter-clockwise (up to four times). This rotation was possible by releasing the engagement between the trigger stop and the first cam flat, which thereby allows the cam to freely rotate.
  • PC- BA hot embossed polycarbonate bisamide
  • PCL Polycaprolactone

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Prostheses (AREA)

Abstract

L'invention concerne un implant destiné à être implanté dans un œil, l'implant comprenant un élastomère thermoplastique selon la formule [AB]n, dans laquelle : n représente le nombre de répétitions du segment AB et est un nombre entier de 2 à 100 ; A représente un bloc mou selon la formule (I) : B représente un bloc dur selon la formule (II) : K étant un groupe alkylène en C1 - C36, un groupe arylène en C6 - C24, un groupe alkarylène en C7 - C24 ou un groupe arylalkylène en C7 - C24 ; L étant un groupe alkylène en C1 - C36, un groupe arylène en C6 - C24, un groupe alkarylène en C7 - C24 ou un groupe arylalkylène en C7 - C24 ou L étant absent ; M étant un groupe alkylène en C1 - C36, un groupe arylène en C6 - C24, un groupe alkarylène en C7 - C24 ou un groupe arylalkylène en C7 - C24 ou M étant absent ; o, p, q, r, s et t valant indépendamment de 0 - 50 ; à condition que : (a) lorsque o, q, r et t valent 0, alors p et s valent indépendamment de 1 - 50 ; (b) lorsque p et s valent 0, alors o, q, r et t valent indépendamment de 1 - 50 ; (c) lorsque o et t valent 0, alors p, q, r et s valent indépendamment de 1 - 50 ; (d) lorsque q et r valent 0, alors o, p, s et t valent indépendamment de 1 - 50 ; (e) lorsque o, p, s et t valent 0, q et r valent indépendamment de 1 - 50 ; (f) lorsque p, q, r et s valent 0, alors o et t valent indépendamment de 1 - 50 ; HBG étant une simple unité de liaison à l'hydrogène indépendamment choisie dans le groupe constitué par les groupes amide, urée et uréthane ; S étant un groupe alkylène en C1 - C36, un groupe arylène en C6 - C24, un groupe alkarylène en C7 - C24 ou un groupe arylalkylène en C7 - C24 ou S étant absent ; et x valant 1, 2 ou 3.
PCT/EP2024/064496 2023-06-02 2024-05-27 Implant pour œil WO2024245992A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120251587A1 (en) * 2009-08-17 2012-10-04 Academisch Ziekenhuis Leiden H.O.D.N. Lumc Diabetes treatment
WO2015194961A1 (fr) 2014-06-19 2015-12-23 Symo-Chem B.V. Élastomères thermoplastiques segmentés de manière stricte en tant que biomatériaux biodégradables
US20190046696A1 (en) * 2016-03-11 2019-02-14 The Johns Hopkins University Partially degradable stents for controlled reduction of intraocular pressure
US10271989B2 (en) 2012-03-26 2019-04-30 Glaukos Corporation System and method for delivering multiple ocular implants
US20200390601A1 (en) * 2019-06-14 2020-12-17 Iantrek Implantable biologic stent and system for biologic material shaping and preparation in the treatment of glaucoma

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120251587A1 (en) * 2009-08-17 2012-10-04 Academisch Ziekenhuis Leiden H.O.D.N. Lumc Diabetes treatment
US10271989B2 (en) 2012-03-26 2019-04-30 Glaukos Corporation System and method for delivering multiple ocular implants
WO2015194961A1 (fr) 2014-06-19 2015-12-23 Symo-Chem B.V. Élastomères thermoplastiques segmentés de manière stricte en tant que biomatériaux biodégradables
US20190046696A1 (en) * 2016-03-11 2019-02-14 The Johns Hopkins University Partially degradable stents for controlled reduction of intraocular pressure
US20200390601A1 (en) * 2019-06-14 2020-12-17 Iantrek Implantable biologic stent and system for biologic material shaping and preparation in the treatment of glaucoma

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