Packaging system for storing ophthalmic devices

Abstract

A packaging system for storing unused ophthalmic devices is disclosed. The packaging system includes a sealed container for housing one or more unused ophthalmic devices immersed in an aqueous packaging solution comprising hyaluronic acid, or a salt or derivative thereof, and Tremella fuciformis. The aqueous packaging solution has an osmotic pressure of at least about 150 mOsm / kg, a pH of about 6 to about 9, and is sterile.

Description

[Technical Field]

[0001] Claim of priority This application claims priority to U.S. Provisional Patent Application No. 63 / 529,551, “Packaging Solutions,” filed on 28 July 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Blister packs and glass vials are typically used to individually package each soft contact lens for sale to customers. Saline or deionized water is commonly used to store the lenses within the blister packs. Because lens material can tend to stick to itself and to the lens packaging, packaging solutions for blister packs may be formulated with various components to reduce or eliminate lens folding and sticking. [Overview of the project]

[0003] According to one exemplary embodiment, a packaging system for storing unused ophthalmic devices comprises a sealed container containing one or more unused ophthalmic devices immersed in an aqueous packaging solution comprising (a) hyaluronic acid or a salt or derivative thereof, and (b) Tremella fuciformis, wherein the aqueous packaging solution has an osmotic pressure of at least about 150 mOsm / kg, a pH of about 6 to about 9, and is sterile.

[0004] According to yet another exemplary embodiment, a method for preparing a packaging system including a storable sterile ophthalmic device is: (a) To provide unused ocular devices, (b) Immersing an unused ophthalmic device in an aqueous packaging solution comprising (i) hyaluronic acid, or a salt or derivative thereof, and (ii) Tremella fuciformis, wherein the aqueous packaging solution has an osmotic pressure of at least about 150 mOsm / kg and a pH in the range of about 6 to about 9. (c) The aqueous packaging solution and unused ophthalmic devices are packaged in a manner that prevents contamination of unused ophthalmic devices by microorganisms, (d) Sterilizing the packaged solution and unused ophthalmic devices, including: [Modes for carrying out the invention]

[0005] The exemplary embodiments described herein relate to packaging systems for storing ophthalmic devices intended for direct contact with body tissues or bodily fluids, for example, direct contact in the eyes. Ophthalmic devices such as contact lenses are very desirable to be as comfortable as possible for the wearer. Contact lens manufacturers are continuously working to improve lens comfort. Nevertheless, many people who wear contact lenses still experience dryness or eye irritation throughout the day, especially towards the end of the day. Lenses that are not sufficiently moistened will cause significant discomfort to the lens wearer at some point. While moistening solutions can be used as needed to alleviate such discomfort, it is certainly desirable that such discomfort does not occur in the first place.

[0006] Hyaluronic acid is a linear polysaccharide (long-chain biological polymer) formed by repeating disaccharide units consisting of D-glucuronic acid and N-acetyl-D-glucosamine linked by β(1-3) and β(1-4) glycosidic bonds. Hyaluronic acid is a glycosaminoglycan and is distinguished from other glycosaminoglycans because it does not contain covalent bonds to proteins and sulfone groups. Hyaluronic acid is ubiquitous in animals and is found in the highest concentrations in soft connective tissue. It plays an important role in both mechanical and transport purposes within the body, for example, providing elasticity to joints, rigidity to intervertebral discs in vertebrates, and is also an important component of the vitreous humor of the eye.

[0007] Due to its high degree of hydration, hyaluronic acid is likely to play a significant role in increasing the resistance of biological tissues or cells to compression. Furthermore, its viscoelastic properties—low viscosity under small shear forces but rigid elasticity under static conditions—allow it to function essentially as a shock absorber for cells and tissues. The properties of hyaluronic acid depend on its molecular weight, solution concentration, and physiological pH. At low concentrations, individual chains intertwine, forming a continuous network in the solution, which imparts interesting properties to the system, such as the remarkable viscoelasticity and pseudoplasticity characteristic of water-soluble polymers at low concentrations.

[0008] As discussed above, blister packs are typically used to individually package each soft contact lens for sale to customers. Once the blister pack is sealed with the contact lenses immersed in the packaging solution, the sealed blister pack is typically subjected to two sterilization procedures, including autoclaving. However, during the autoclaving procedure, the hyaluronic acid is broken down, thereby reducing its effectiveness.

[0009] Therefore, these problems are overcome by exemplary embodiments disclosed herein, which provide an improved packaging system for ophthalmic devices such as contact lenses, that is more lubricating and comfortable to insert the lens in actual use, thereby enabling prolonged wear of the lens without irritation to the cornea or other harmful effects. In non-limiting exemplary embodiments, the packaging system for ophthalmic devices disclosed herein includes an aqueous packaging solution containing at least hyaluronic acid or a salt thereof and Tremella fuciformis, such that hyaluronic acid or a salt thereof or a derivative decomposes at a slower rate after autoclaving compared to a packaging system comprising an aqueous packaging solution containing hyaluronic acid or a salt thereof or a derivative thereof alone. Thus, the ophthalmic device will be more comfortable to insert in actual use, and the lens will be wearable for extended periods without harmful effects to the cornea. The hydrophilic and / or lubricating surface of the ophthalmic devices herein, such as contact lenses, substantially prevents or inhibits the adsorption of lipids and proteins of tears onto the lens, and their eventual absorption into the lens, thereby maintaining the clarity of the contact lens. This, in turn, helps maintain the performance quality of contact lenses, thereby providing a higher level of comfort to the wearer.

[0010] As used herein, the term “ocular device” refers to a device located in or on the eye. These lenses may provide optical correction, wound healing, drug delivery, diagnostic function, or cosmetic enhancement or effect, or a combination of these properties. Typical examples of such devices include, but are not limited to, soft contact lenses (e.g., soft hydrogel lenses, soft non-hydrogel lenses, etc.), hard contact lenses (e.g., hard gas-permeable lens materials, etc.), intraocular lenses, overlay lenses, intraocular implants, optical implants, etc. As will be understood by those skilled in the art, a lens is considered “soft” if it can be folded and stacked on top of itself without breaking. Any material known to produce ocular devices, including contact lenses, may be used herein.

[0011] An eye device for use in the packaging systems disclosed herein may be any material known in the art capable of forming the eye device described above. In one embodiment, the eye device includes a device formed from a material that is not hydrophilic itself. Such a device is formed from a material known in the art and includes, for example, polysiloxanes, perfluoropolyethers, fluorinated poly(meth)acrylates, or equivalent fluorinated polymers derived from other polymerizable carboxylic acids, polyalkyl(meth)acrylates, or equivalent alkyl ester polymers derived from other polymerizable carboxylic acids, or fluorinated polyolefins, such as fluorinated ethylene propylene polymers, or tetrafluoroethylene, preferably in combination with dioxole, such as perfluoro-2,2-dimethyl-1,3-dioxole. Typical examples of suitable bulk materials include, but are not limited to, lotrafilcon A, neofocon, pasifocon, telefocon, silafocon, fluorsilfocon, paflufocon, silafocon, elastofilcon, fluorofocon, or Teflon® AF. Examples include Teflon® AF materials such as AF)1600 or Teflon® AF2400, which are copolymers of approximately 63 to 73 mol% perfluoro-2,2-dimethyl-1,3-dioxole and approximately 37 to 27 mol% tetrafluoroethylene, or approximately 80 to 90 mol% perfluoro-2,2-dimethyl-1,3-dioxole and approximately 20 to 10 mol% tetrafluoroethylene.

[0012] In another embodiment, the ophthalmic device includes devices formed from materials that are hydrophilic in themselves, since reactive groups, such as carboxy, carbamoyl, sulfate, sulfonate, phosphate, amine, ammonium, or hydroxyl groups, are inherently present in the material and therefore also on the surface of the ophthalmic device manufactured from them. Such devices are formed from materials known in the art, examples of which include polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate (HEMA), polyvinylpyrrolidone (PVP), polyacrylic acid, polymethacrylic acid, polyacrylamide, polydimethylacrylamide (DMA), polyvinyl alcohol, and copolymers thereof, such as copolymers from two or more monomers selected from hydroxyethyl acrylate, hydroxyethyl methacrylate, N-vinylpyrrolidone, acrylic acid, methacrylic acid, acrylamide, dimethylacrylamide, vinyl alcohol, and the like. Typical examples of suitable bulky materials include, but are not limited to, polymacon, tefilcon, metafilcon, deltafilcon, bufilcon, phemfilcon, ocufilcon, focofilcon, etafilcon, hefilcon, vifilcon, tetrafilcon, perfilcon, droxifilcon, dimefilcon, isofilcon, mafilcon, nelfilcon, and atlafilcon. Other suitable bulky materials include balafilcon A, hilafilcon A, alphafilcon A, and bilafilcon B.

[0013] In another embodiment, the eye device includes a device formed from a material that is an amphiphilic segmented copolymer containing at least one hydrophobic segment and at least one hydrophilic segment linked together through a binding or crosslinking member.

[0014] The biocompatible materials described herein, including both flexible and rigid materials commonly used in ophthalmic lenses, including contact lenses, are particularly useful. Generally, non-hydrogel materials or rigid materials are hydrophobic polymer materials that do not contain water in their equilibrium state. Typical non-hydrogel and rigid materials include silicone acrylics, for example, those formed from bulky silicone monomers (e.g., tris(trimethylsiloxy)silylpropyl methacrylate, commonly known as the "TRIS" monomer), methacrylate-terminated poly(dimethylsiloxane) prepolymers, or silicones having fluoroalkyl side groups (polysiloxanes are also commonly known as silicone polymers).

[0015] In another embodiment, the ophthalmic device includes a device that is a hydrogel. Generally, hydrogels are a well-known type of material comprising a hydrated crosslinked polymer system containing water at equilibrium. Thus, a hydrogel is a copolymer prepared from hydrophilic monomers. In the case of silicone hydrogels, the hydrogel copolymer is generally prepared by polymerizing a monomer mixture containing at least one ophthalmic device-forming silicone-containing monomer and at least one ophthalmic device-forming hydrophilic monomer. Either the silicone-containing monomer or the hydrophilic monomer can function as a crosslinker (a crosslinker defined as a monomer having multiple polymerizable functional groups), or a separate crosslinker may be used. Silicone hydrogels typically have a water content of about 10 to about 80 weight percent.

[0016] In some embodiments, the eye device can be obtained from a polymerization product of a monomer mixture containing at least one eye device-forming hydrophilic monomer.

[0017] Suitable one or more hydrophilic comonomers include, for example, unsaturated carboxylic acids, acrylamides, vinyl lactams, hydroxyl-containing (meth)acrylates, hydrophilic vinyl carbonates, hydrophilic vinyl carbamates, hydrophilic oxazolones, and poly(alkene glycols) functionalized with polymerizable groups, as well as mixtures thereof.

[0018] As used herein, the term "(meth)" represents an optional methyl substituent. Thus, terms such as "(meth)acrylate" represent either methacrylate or acrylate, and "(meth)acrylamide" represent either methacrylamide or acrylamide.

[0019] Typical examples of unsaturated carboxylic acids include, but are not limited to, methacrylic acid and acrylic acid, as well as mixtures thereof. Typical examples of acrylamides include, but are not limited to, alkylamides such as N,N-dimethylacrylamide and N,N-dimethylmethacrylamide, as well as mixtures thereof. Typical examples of cyclic lactams include, but are not limited to, N-vinyl-2-pyrrolidone, N-vinylcaprolactam, and N-vinyl-2-piperidone, as well as mixtures thereof. Typical examples of hydroxyl-containing (meth)acrylates include, but are not limited to, 2-hydroxyethyl methacrylate (HEMA) and glycerol methacrylate, as well as mixtures thereof. Additional device-forming hydrophilic comonomers include, for example, the hydrophilic vinyl carbonate or vinyl carbamate monomers disclosed in U.S. Patent No. 5,070,215, and the hydrophilic oxazolone monomers disclosed in U.S. Patent No. 4,910,277. Other suitable device-forming hydrophilic comonomers will be apparent to those skilled in the art. The aforementioned mixture of device-forming hydrophilic comonomers can also be used in the monomer mixtures herein.

[0020] According to one or more additional non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, one or more hydrophilic comonomers may be present in the monomer mixture in an amount ranging from about 20% to about 80% by weight, based on the total weight of the monomer mixture. In another exemplary embodiment, one or more hydrophilic monomers may be present in the monomer mixture in an amount ranging from about 30% to about 60% by weight, based on the total weight of the monomer mixture.

[0021] The monomer mixture may also contain a second eye-device-forming comonomer comprising copolymerizable groups and reactive functional groups. The copolymerizable groups are preferably ethylene-based unsaturated groups, so that this device-forming monomer copolymerizes the hydrophilic eye-device-forming monomer in the initial device-forming monomer mixture with any other device-forming monomer. In addition, the other eye-device-forming comonomer may contain reactive functional groups that react with complementary reactive groups of the copolymer, such as reaction products of one or more polymerizable polyhydric alcohols and one or more polymerizable fluorine-containing monomers. In other words, after the eye-device is formed by copolymerizing the monomer mixture, the reactive functional groups provided by the second device-forming monomer remain to react with complementary reactive moieties of the copolymer.

[0022] In one embodiment, the reactive group of the second eye device-forming monomer includes an epoxide group. Thus, the second eye device-forming comonomer includes both an ethylene-based unsaturated group (which allows the monomer to copolymerize with the hydrophilic eye device-forming monomer) and an epoxide group (which does not react with the hydrophilic eye device-forming monomer but maintains the reaction of the copolymer, for example, the reaction product of one or more polymerizable polyhydric alcohols and one or more polymerizable fluorine-containing monomers). Suitable second eye device-forming monomers include, for example, glycidyl methacrylate, glycidyl acrylate, glycidyl vinyl carbonate, glycidyl vinyl carbamate, and 4-vinyl-1-cyclohexene-1,2-epoxide.

[0023] According to one or more additional non-limiting exemplary embodiments which may be combined with one or more of the preceding paragraphs, one or more second ophthalmic device-forming comonomers may be one or more ophthalmic device-forming silicone comonomers. For example, typical ophthalmic device-forming silicone comonomers for use in the formation of silicone hydrogels are well known in the art, and countless examples are provided in U.S. Patents No. 4,136,250, No. 4,153,641, No. 4,740,533, No. 5,034,461, No. 5,070,215, No. 5,260,000, No. 5,310,779, and No. 5,358,995. Specific examples of materials suitable for use herein include those disclosed in U.S. Patents No. 5,310,779, 5,387,662, 5,449,729, 5,512,205, 5,610,252, 5,616,757, 5,708,094, 5,710,302, 5,714,557, and 5,908,906, the contents of which are incorporated herein by reference.

[0024] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the ophthalmic device-forming silicone comonomer may include one or more non-bulky organosilicon-containing monomers as a representative class of ophthalmic device-forming silicone comonomers. As used herein, “organosilicon-containing monomer” contains at least one [siloxanil] or at least one [silyl-alkyl-siloxanil] repeating unit in the monomer, macromer, or prepolymer. In one exemplary embodiment, an example of a non-bulky organosilicon-containing monomer is presented by the structure of formula Ia, [ka] In the formula, L is an ethylene-based unsaturated polymerizable group, V is a linking group or bond, and R 1 , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , R 8 , and R 9 are each independently hydrogen, an alkyl group, a haloalkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkenyl group, a haloalkenyl group, or an aromatic group, and R 10 and R 11 are each independently hydrogen or alkyl, and at least one of R 10 and R 11 is hydrogen, y is 2 to 7, and n is 1 to 100 or 1 to 20.

[0025] Ethylene unsaturated polymerizable groups are well known to those skilled in the art. Suitable ethylene unsaturated polymerizable groups include, for example, (meth)acrylate, vinyl carbonate, O-vinyl carbamate, N-vinyl carbamate, and (meth)acrylamide.

[0026] The linking group can be any divalent radical or moiety, such as a substituted or unsubstituted C1-C 12 alkyl group, an alkyl ether group, an alkenyl group, an alkenyl ether group, a haloalkyl group, a substituted or unsubstituted siloxane group, and a monomer capable of propagating ring opening.

[0027] In one embodiment, V is (meth)acrylate, L is a C1-C 12 alkylene group, and R<00所00016>, R 2 , R 3 , R 4 , R 5 , R<00000所1>, R 7 , R 8 , and R 9 are each independently a C1-C 12 alkyl group, and R所2]] 10 , and R[[ID=所4]]<000002所> are each independently H or C1-C 12 , and y is 2 to 7, and n is 3 to 8.

[0028] It should be noted that there seems to be an error in the "00所00016" in line 32. It should probably be "0000016". Please check and correct if necessary for a more accurate translation.In one embodiment, V is a (meth)acrylate, L is a C1-C6 alkyl group, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 R is independently a C1-C6 alkyl group. 10 and R 11 is independently H or a C1-C6 alkyl group, y is 2-7, and n is 1-20.

[0029] Non-bulky organosilicon-containing monomers represented by the structure of formula Ia are known in the art; see, for example, U.S. Patents 7,915,323, 7,994,356, 8,420,711, 8,827,447, and 9,039,174, the contents of which are incorporated herein by reference.

[0030] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more non-bulky organosilicon-containing monomers may also include compounds represented by the structure of formula Ib, [ka] In the formula, R 12 However, H is either methyl or X is either O or NR 16 And R 16 However, it is selected from C1-C4 alkyl groups, which may be further substituted with H or one or more hydroxyl groups, and in some embodiments, it is H or methyl, and R 13However, it is a divalent alkyl group that can be further functionalized with a group selected from the group consisting of an ether group, a hydroxyl group, a carbamate group, and combinations thereof, and in another embodiment, it is a C1-C6 alkylene group that can be substituted with an ether, a hydroxyl group, and combinations thereof, and in yet another embodiment, it is a C1 or C3-C4 alkylene group that can be substituted with an ether, a hydroxyl group, and combinations thereof, and each R 14 However, each R is independently a C1-C4 alkyl that can be substituted with phenyl, fluorine, hydroxyl, or ether, and in another embodiment, each R 14 However, independently, the ethyl and methyl groups are selected, and in another embodiment, each R 14 However, it is methyl, and R 15 However, it is a C1-C4 alkyl group, and a is 2-50, and in some embodiments, 5-15.

[0031] Non-bulky organosilicon-containing monomers represented by the structure of formula Ib are known in the art; see, for example, U.S. Patents 8,703,891, 8,937,110, 8,937,111, 9,156,934, and 9,244,197, the contents of which are incorporated herein by reference.

[0032] Typical examples of non-bulky organosilicon-containing monomers include the following: M1EDS6: A compound having the following structure, available from Gelest. [ka] MCR-M11: A compound having the following structure, [ka]

[0033] M1-MCR-C12: Compound having the following structure [ka] (In the formula, n has an average of 12).

[0034] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more bulky silicone-containing monomers as a representative category of ophthalmic device-forming silicone comonomers. Suitable one or more bulky silicone monomers include, for example, one or more bulky siloxane monomers such as polysiloxanyl alkyl (meth)acrylic monomers, bulky polysiloxanyl alkyl carbamate monomers, and mixtures thereof. In one embodiment, a typical example of a bulky silicone-containing monomer is represented by the structure of formula II, [ka] In the formula, X is -O- or -NR 19 - represents each R 19 However, it is hydrogen or a C1-C4 alkyl group, R 17 However, each R independently represents hydrogen or methyl, 18 However, independently, it represents a lower alkyl radical such as a C1-C6 group, a phenyl radical, or a group represented by the following structure: [ka] In the formula, each R 18′ However, independently, it represents a lower alkyl radical or a phenyl radical, where h is 1 to 10, or is represented by the structure of formula III, [ka] In the formula, X is -NR 19 - represents R 19 However, R represents hydrogen or C1-C4 alkyl, 17 However, each R represents hydrogen or methyl, 18However, independently, these represent a lower alkyl radical, a phenyl radical, or a group represented by the following structures: [ka] In the formula, each R 18′ However, each independently represents a lower alkyl radical or a phenyl radical, and h is between 1 and 10.

[0035] Typical examples of bulky silicone-containing monomers include 3-methacryloyloxypropyltris(trimethylsiloxy)silane, or tris(trimethylsiloxy)silylpropyl methacrylate (sometimes referred to as TRIS), and tris(trimethylsiloxy)silylpropyl vinylcarbamate (sometimes referred to as TRIS-VC), pentamethyldisiloxanylmethyl methacrylate, phenyltetramethyldisiloxanyl ethyl acetate, and methyldi(trimethylsiloxy)methacryloxymethylsilane, (3-methacryloxy-2-hydroxypropoxy)propylbis(trimethylsiloxy)methylsilane (sometimes referred to as Sigma), as well as mixtures thereof. In one embodiment, the bulky silicone-containing monomer is a tris(trialkylsiloxy)silylalkyl methacrylate-containing monomer (for example, a tris(trimethylsiloxy)silylpropyl methacrylate-containing monomer).

[0036] Such bulky monomers may be copolymerized with silicone macromonomers, which are poly(organosiloxanes) capped with unsaturated groups at two or more ends of the molecule. U.S. Patent No. 4,153,641 discloses various unsaturated groups, such as acryloxy or methacryloxy groups.

[0037] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more silicone-containing vinyl carbonate or vinyl carbamate monomers, as a typical category of ophthalmic device-forming silicone comonomers. Suitable one or more silicone-containing vinyl carbonate or vinyl carbamate monomers include, for example, 1,3-bis[4-vinyloxycarbonyloxy)buta-1-yl]tetramethyldisiloxane, 3-(trimethylsilyl)propyl vinyl carbonate, 3-(vinyloxycarbonylthio)propyl-[tris(trimethylsiloxy)silane], 3-[tris(trimethylsiloxy)silyl]propyl vinyl carbamate, 3-[tris(trimethylsiloxy)silyl]propyl allyl carbamate, 3-[tris(trimethylsiloxy)silyl]propyl vinyl carbonate, t-butyldimethylsiloxyethyl vinyl carbonate, trimethylsilylethyl vinyl carbonate, trimethylsilylmethyl vinyl carbonate, and mixtures thereof.

[0038] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more polyurethane-polysiloxane macromonomers (sometimes referred to as prepolymers), which may have hard-soft-hard blocks like conventional urethane elastomers. They may be end-capped with hydrophilic monomers such as HEMA. Examples of such silicone urethanes are disclosed in various publications, including Lai, Yu-Chin, "The Role of Bulky Polysiloxanylalkyl Methacryates in Polyurethane-Polysiloxane Hydrogels," Journal of Applied Polymer Science, Vol. 60, 1193-1199 (1996). PCT Publication Application 96 / 31792 discloses examples of such monomers, the disclosure of which is incorporated herein by reference in whole. Further examples of silicone urethane monomers are given by formulas IV and V, i.e., E(*D*A*D*G) a *D*A*D*E', or (IV) E(*D*G*D*A) a *D*A*D*E' (V) Presented by, During the ceremony, D independently represents an alkyl diradical, alkylcycloalkyl diradical, cycloalkyl diradical, aryl diradical, or alkylaryl diradical having 6 to approximately 30 carbon atoms. G independently represents an alkyl diradical, cycloalkyl diradical, alkylcycloalkyl diradical, aryl diradical, or alkylaryl diradical having 1 to about 40 carbon atoms, and may contain ether, thio, or amine bonds in its main chain. * represents a urethane or ureid bond. a is at least 1, A independently represents the divalent polymerizable radical of formula VI: [ka] Each R s However, independently, each represents an alkyl or fluorosubstituted alkyl group having 1 to about 10 carbon atoms that may contain ether bonds between carbon atoms, where m' is at least 1 and p is a number that provides about 400 to about 10,000 partial weights. Each of E and E' independently represents a polymerizable unsaturated organic group represented by formula VII, [ka] R 3 However, it is hydrogen or methyl, R 4 However, hydrogen, alkyl groups having 1 to 6 carbon atoms, or -CO-YR 6 It is a radical, and Y is -O-, -S-, or -NH-. R 5 However, it is a divalent alkylene radical having 1 to approximately 10 carbon atoms. R 6 However, it is an alkyl radical having 1 to approximately 12 carbon atoms. X represents -CO- or -OCO-, Z represents -O- or -NH-, Ar represents an aromatic radical having approximately 6 to 30 carbon atoms. w is between 0 and 6, x is 0 or 1, y is 0 or 1, and z is 0 or 1.

[0039] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more silicone-containing urethane monomers represented by formula VIII, as a typical category of ophthalmic device-forming silicone comonomers. [ka] In the formula, m is at least 1, preferably 3 or 4, a is at least 1, preferably 1, p is a number that provides a portion weight of about 400 to about 10,000, preferably at least 30, R 7 However, it is a diradical of diisocyanate after removal of isocyanate groups such as the diradical of isophorone diisocyanate, and each E'' is a group represented by the following: [ka]

[0040] In another embodiment, the silicone hydrogel material comprises (overall, i.e., in the copolymerized monomer mixture) about 5 to about 50 weight percent (or about 10 to about 25 weight percent) of one or more silicone macromonomers, about 5 to about 75 weight percent (or about 30 to about 60 weight percent) of one or more polysiloxanyl alkyl (meth)acrylic monomers, and about 10 to about 50 weight percent (or about 20 to about 40 weight percent) of hydrophilic monomers. Generally, silicone macromonomers are poly(organosiloxanes) capped with unsaturated groups at two or more ends of the molecule. In addition to the end groups in the above structural formulas, U.S. Patent No. 4,153,641 discloses additional unsaturated groups, including acryloxy or methacryloxy. Fumarate-containing materials, such as those disclosed in U.S. Patents No. 5,310,779, No. 5,449,729, and No. 5,512,205, are also useful substrates for the non-limiting embodiments described herein. The silane macromonomer may be a silicone-containing vinyl carbonate or vinyl carbamate, or a polyurethane-polysiloxane having one or more hard-soft-hard blocks and terminally capped with a hydrophilic monomer.

[0041] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more monomers of formula IX as a typical category of ophthalmic device-forming silicone comonomers. [ka] In the formula, X is a ring-opening agent residue, L is the same or different linking group or bond, V is an ethylene-based unsaturated polymerizable group, R1, R2, R3, R4, R5, and R6 are independently a halogen, alkyl group, haloalkyl group, cycloalkyl group, heterocycloalkyl group, alkenyl group, haloalkenyl group, or aromatic group, R7 and R8 are independently a halogen or alkyl group, at least one of R7 or R8 is hydrogen, y is 2 to 7, and n is 1 to 100.

[0042] Ring-opening agents are well known in the literature. Non-limiting examples of anionic ring-opening agents include alkyllithium, alkoxides, and trialkylsiloxylithium, where the alkyl group may or may not contain a halo atom.

[0043] The linking group can be any divalent radical or moiety and includes substituted or unsubstituted alkyls, alkyl ethers, alkenyls, alkenyl ethers, haloalkyls, substituted or unsubstituted siloxanes, and monomers that can propagate ring opening.

[0044] Ethylene-based unsaturated polymerizable groups are well known to those skilled in the art. Non-limiting examples of ethylene-based unsaturated polymerizable groups include acrylates, methacrylates, vinyl carbonates, O-vinylcarbamates, N-vinylcarbamates, acrylamides, and methacrylamides.

[0045] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more monomers of formula X, as a representative category of ophthalmic device-forming silicone comonomers. [ka] In the formula, L is the same or different linking group or bond, V is the same or different ethylene-based unsaturated polymerizable group, R1, R2, R3, R4, R5, R6, and R9 are independently hydrogen, alkyl group, haloalkyl group, cycloalkyl group, heterocycloalkyl group, alkenyl group, haloalkenyl group, or aromatic group, R7 or R8 is independently halogen or alkyl group, at least one of R7 or R8 is hydrogen, y is 2 to 7, and n is 1 to 100.

[0046] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more monomers from formulas XI and XII, as representative categories of ophthalmic device-forming silicone comonomers. [ka] In the formula, R9, R 10 , and R 11 However, independently, n is a halogen, alkyl group, haloalkyl group, or other substituted alkyl group, where n is as defined above, 1 However, the range is 0 to 10. [ka] In the formula, n is either between 1 and 100, or between 2 and 80, or between 3 and 20, or between 5 and 15.

[0047] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more monomers from formulas XIII to XVII, as a representative category of ophthalmic device-forming silicone comonomers. [ka]

[0048] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may comprise one or more monomers from formulas XVIII to XX, as a representative category of ophthalmic device-forming silicone comonomers. [ka] In the formula, R9, R 10 , and R 11 However, independently, they are halogens, alkyl groups, haloalkyl groups, or other substituted alkyl groups, and n and n 1 However, it is defined as described above.

[0049] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may comprise one or more monomers from formulas XXI to XXIII, as a representative category of ophthalmic device-forming silicone comonomers. [ka] In the formula, n is as defined above, and X - However, it is a counterion that provides an overall neutral charge.

[0050] Counterions capable of providing an overall neutral charge are well known to those skilled in the art, and examples include halide ions.

[0051] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more monomers of formula XXIV as a typical category of ophthalmic device-forming silicone comonomers. [ka]

[0052] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more ophthalmic device-forming silicone comonomers may include one or more polysiloxane prepolymers represented by the structure of formula XXV, as a typical category of ophthalmic device-forming silicone comonomers. [ka] In the formula, each V is independently a reactive functional end group, and includes, for example, a hydroxyl-containing reactive functional end group and an amine-containing reactive functional end group, R 17 ~R 22 However, they are independently linear or branched, and substituted or unsubstituted C1-C 30 Alkyl, substituted or unsubstituted C3-C 30 Cycloalkyl groups, substituted or unsubstituted C4-C 30 Cycloalkylalkyl groups, substituted or unsubstituted C3-C 30 Cycloalkenyl group, substituted or unsubstituted C6-C 30 Aryl groups, and substituted or unsubstituted C7-C 30 It is an arylalkyl group, and L is independently a linking group.

[0053] The hydroxyl-containing reactive functional end groups used herein are groups of the general formula -OH. Typical examples of amine-containing reactive functional end groups used herein include (meth)acrylamide-containing reactive functional end groups.

[0054] The linking group L is independently a linear or branched alkyl group, a cycloalkyl group, an aryl group, an ether or polyether group, and an ester group as defined herein.

[0055] Typical examples of polysiloxane prepolymers are as follows: [ka]

[0056] The methods for preparing the polysiloxane prepolymers described herein are well known and within the realm of common technical knowledge for those skilled in the art. In addition, polysiloxane prepolymers are commercially available from sources such as Gelest, Silar, Shin-Etsu, Momentive, and Siltech.

[0057] Another category of typical ophthalmic device-forming silicone comonomers includes, for example, fluorinated monomers. Such monomers have been used in the formation of fluorosilicone hydrogels to reduce deposit accumulation on contact lenses made from them, as disclosed, for example, in U.S. Patents 4,954,587, 5,010,141, and 5,079,319. Furthermore, the use of silicone-containing monomers having certain fluorinated side groups, namely -(CF2)-H, has been found to improve compatibility between hydrophilic monomer units and silicone-containing monomer units. See, for example, U.S. Patents 5,321,108 and 5,387,662.

[0058] The silicone materials described above are merely examples, and other materials can also be used as substrates, which are disclosed in various publications and are being continuously developed for use in contact lenses and other biomedical devices. For example, contact lenses can be formed from at least cationic monomers, such as cationic silicone-containing monomers or cationic fluorinated silicone-containing monomers.

[0059] Eye devices such as contact lenses can be manufactured using a variety of conventional techniques to obtain molded articles having desired rear and front lens surfaces. Spin casting is disclosed in U.S. Patents 3,408,429 and 3,660,545, and static casting is disclosed in U.S. Patents 4,113,224, 4,197,266 and 5,271,876. Machining operations may be performed following the curing of the monomer mixture to provide a contact lens having a desired final configuration. As an example, U.S. Patent 4,555,732 discloses a process in which an excess amount of monomer mixture is spin-cast in a mold and cured to form a molded article having a front lens surface and a relatively thick surface. The rear surface of the cured spin-cast article is then turned to provide a contact lens with a desired thickness and rear lens surface. Further machining operations, such as edge finishing, may be performed after turning the lens surface.

[0060] As those skilled in the art will readily understand, the surface functional groups of an ophthalmic device may be naturally present on the surface of the device. However, if the ophthalmic device contains few or no functional groups, the surface of the ophthalmic device can be modified by known techniques or by conventional functionalization with groups such as -OH, -NH2, or -CO2H. Suitable surface functional groups for biomedical devices include a wide variety of groups well known to those skilled in the art. Representative examples of such functional groups include, but are not limited to, hydroxyl groups, amino groups, carboxyl groups, carbonyl groups, aldehyde groups, sulfonic acid groups, sulfonyl chloride groups, isocyanate groups, carboxyanhydride groups, lactone groups, azulactone groups, epoxy groups, and groups replaceable by amino or hydroxyl groups, such as halo groups, or mixtures thereof. In one embodiment, the surface functional groups of an ophthalmic device are amino groups and / or hydroxyl groups.

[0061] Next, the resulting ophthalmic devices, such as contact lenses, are immersed in an aqueous packaging solution and stored in a packaging system according to an exemplary embodiment disclosed herein. Generally, a packaging system for storing ophthalmic devices includes at least one sealed container for containing one or more unused ophthalmic devices immersed in an aqueous packaging solution. In one exemplary embodiment, the sealed container is an airtight blister pack, in which a recessed well for containing an ophthalmic device, such as a contact lens, is covered by a metal or plastic sheet adapted to be peelable to open the blister pack. The sealed container may be any suitable generally inert packaging material that provides reasonable protection to the lens, preferably a plastic material such as polyalkylene, PVC, or polyamide.

[0062] According to one or more additional non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, an aqueous packaging solution for use in the packaging systems disclosed herein contains at least hyaluronic acid, or a salt or derivative thereof, and Tremella fuciformis. In exemplary embodiments, the aqueous packaging solution contains about 0.005% to about 5% hyaluronic acid, or a salt or derivative thereof, based on the total weight of the aqueous packaging solution. In exemplary embodiments, the aqueous packaging solution contains about 0.01% to about 1% hyaluronic acid, or a salt or derivative thereof, based on the total weight of the aqueous packaging solution. In exemplary embodiments, the aqueous packaging solution contains about 0.005% to about 5% Tremella fuciformis, based on the total weight of the aqueous packaging solution. In exemplary embodiments, the aqueous packaging solution contains about 0.01% to about 1% Tremella fuciformis, based on the total weight of the aqueous packaging solution.

[0063] Hyaluronic acid is a well-known, naturally occurring, water-soluble, biodegradable polymer composed of two alternately linked sugars, D-glucuronic acid and N-acetylglucosamine, linked via alternating β-(1,4) and β-(1,3) glycosidic bonds. As referred to above herein, hyaluronic acid is a glycosaminoglycan (GAG). In particular, hyaluronic acid is a non-sulfated GAG. This polymer is hydrophilic and has high viscosity in aqueous solutions at relatively low solute concentrations. It often occurs spontaneously as sodium hyaluronate, which is its sodium salt. Another salt of hyaluronic acid is potassium hyaluronate. Methods for preparing commercially available hyaluronan and its salts are well known. Hyaluronan can be purchased from Seikagaku Company, Clear Solutions Biotech, Inc., Pharmacia Inc., Sigma Inc., HTL Biotechnology, Contipro, and Bloomage Biotechnology Corporation, as well as many other suppliers. Hyaluronic acid has repeating units of structure represented by the following formula: [ka] Therefore, the repeating units in hyaluronic acid can be as follows: [ka]

[0064] Generally, hyaluronic acid or its salts can have about 2 to about 1,500,000 disaccharide units. In one embodiment, hyaluronic acid or its salts can have a weight-average molecular weight in the range of about 10,000 to about 4,000,000 Da, with the lower limit being about 10,000, about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, and about 90,000. 0, approximately 100,000 Da, approximately 200,000 Da, approximately 300,000 Da, approximately 400,000 Da, approximately 500,000 Da, approximately 600,000 Da, approximately 700,000 Da, approximately 800,000 Da, approximately 900,000 Da, approximately 1,000,000 Da, approximately 1,100,000 Da, approximately 1,200,000 Da The lower limits are approximately 1,300,000 Da, approximately 1,400,000 Da, and approximately 1,500,000 Da, with the upper limits being approximately 200,000, approximately 300,000, approximately 400,000, approximately 500,000, approximately 600,000, approximately 700,000, approximately 800,000, approximately 900,000, approximately 1,000,000, approximately 1,500,000 Da, approximately maximum 2,000,000 Da, approximately maximum 2,500,000 Da, approximately maximum 2,800,000 Da, maximum approximately 3,000,000 Da, maximum approximately 3,200,000 Da, or maximum approximately 4,0000,000 Da, and any of the lower limits can be combined with any of the upper limits.

[0065] The weight-average molecular weight disclosed herein is determined by size exclusion chromatography.

[0066] According to one or more additional non-limiting exemplary embodiments which may be combined with one or more of the preceding paragraphs, hyaluronic acid or a salt thereof may be a derivative thereof, i.e., a modified hyaluronic acid or a salt thereof. For example, in one exemplary embodiment, hyaluronic acid or a salt thereof may be a crosslinked polymer network comprising a reaction product of hyaluronic acid or a salt thereof, another GAG, and one or more crosslinking agents, wherein hyaluronic acid is different from other glycosaminoglycans. Suitable GAGs that can be used for crosslinking with hyaluronic acid include, for example, chondroitin sulfate (e.g., chondroitin 4- and 6-sulfates), heparan, heparin sulfate, heparosan, dermatan, dermatan sulfate, keratan sulfate, and other disaccharides such as sucrose, lactulose, lactose, maltose, trehalose, cellobiose, mannobiose, and chitobiose. In one exemplary embodiment, the other GAG is chondroitin sulfate. Glycosaminoglycans can be purchased from Sigma and many other biochemical suppliers, such as HTL Biotechnology (France).

[0067] In one exemplary embodiment, other GAGs for use herein may have a weight-average molecular weight in the range of about 10,000 to about 3,000,000 Daltons (Da), with the lower limit being about 10,000, about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or The limit is approximately 100,000 Da, with upper limits of approximately 200,000, 300,000, 400,000, 500,000, 600,000, 700,000, 800,000, 900,000, 1,000,000, or up to approximately 3,000,000 Da, and any of the lower limits can be combined with any of the upper limits.

[0068] Chondroitin sulfate is a linear sulfated polysaccharide composed of repeating units of β-D-glucuronic acid (GlcA) and N-acetyl-β-D-galactosamine (GalNAc) arranged in sequence by GlcA-β(1,3)-GalNAc-β(1,4) glycosidic bonds. In one embodiment, chondroitin sulfate has one or more repeating units of a structure represented by the following formula. [ka]

[0069] In one exemplary embodiment, chondroitin sulfate has repeating units of a structure represented by the following formula. [ka]

[0070] Generally, chondroitin sulfate can have about 2 to about 1,500,000 repeating units. In one embodiment, chondroitin sulfate can have a weight-average molecular weight in the range of about 10,000 to about 3,000,000 Da, with a lower limit of about 5,000, 10,000, about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000 Da, and an upper limit of about 200 Da is approximately 300,000, 400,000, 500,000, 600,000, 700,000, 800,000, 900,000, 1,000,000, or 3,000,000, and any of the lower limits can be combined with any of the upper limits, or any of the upper limits can be combined with any of the upper limits.

[0071] In one exemplary embodiment, dermatan sulfate has repeating units of a structure represented by the following formula. [ka]

[0072] Generally, dermatan sulfate can have about 2 to about 1,500,000 repeating units. In one embodiment, dermatan sulfate can have a weight-average molecular weight in the range of about 1,000 to about 2,000,000 Da, with lower limits being about 1,000, 5,000, 10,000, about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000 Da, and upper limits being about 200 Da is approximately 300,000, 400,000, 500,000, 600,000, 700,000, 800,000, 900,000, 1,000,000, or 2,000,000, and any of the lower bounds can be combined with any of the upper bounds, or any of the upper bounds can be combined with any of the upper bounds.

[0073] In one exemplary embodiment, heparin and heparin sulfate have repeating units of a structure represented by the following formula. [ka]

[0074] Generally, heparin and heparin sulfate can have about 2 to about 1,500,000 repeating units. In one embodiment, heparin and heparin sulfate can have a weight-average molecular weight in the range of about 1,000 to about 3,000,000 Da, with lower limits being about 1,000, 5,000, 10,000, about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000 Da, and upper limits being about 40,000. The values ​​are 100,000, 200,000, approximately 300,000, approximately 400,000, approximately 500,000, approximately 600,000, approximately 700,000, approximately 800,000, approximately 900,000, approximately 1,000,000, or approximately 3,000,000 Da, and any of the lower bounds can be combined with any of the upper bounds, or any of the upper bounds can be combined with any of the upper bounds.

[0075] In one exemplary embodiment, keratan sulfate has repeating units of a structure represented by the following formula. [ka]

[0076] Generally, keratan sulfate can have about 2 to about 1,500,000 repeating units. In one embodiment, keratan sulfate can have a weight-average molecular weight in the range of about 10,000 to about 3,000,000 Da, with lower limits being about 5,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000, or 100,000 Da, and upper limits being about 100,000, 200, The lower limit is approximately 300,000, approximately 400,000, approximately 500,000, approximately 550,000, 600,000, approximately 700,000, approximately 800,000, approximately 900,000, approximately 1,000,000, or approximately 3,000,000Da, and any of the lower limits can be combined with any of the upper limits, or any of the upper limits can be combined with any of the upper limits.

[0077] The reaction product comprises one or more crosslinking agents, for example, to crosslink hyaluronic acid or a salt thereof with other glycosaminoglycans. The crosslinking agent for use herein can be any suitable crosslinking agent known in the art. Generally, suitable crosslinking agents are those having functional groups complementary to hyaluronic acid or a salt thereof and other glycosaminoglycans such as chondroitin sulfate. In one embodiment, suitable crosslinking agents include, for example, bifunctional or polyfunctional crosslinking agents. A bifunctional or polyfunctional crosslinking agent connects a first glycosaminoglycan to a second glycosaminoglycan. Furthermore, the bifunctional or polyfunctional crosslinking agent further acts as a spacer between the first and second glycosaminoglycans. Generally, a bifunctional or polyfunctional crosslinking agent comprises two or more functional groups capable of reacting with the functional groups of hyaluronic acid or a salt thereof and other glycosaminoglycans such as chondroitin sulfate, resulting in the formation of a covalent bond.

[0078] Suitable bifunctional or polyfunctional crosslinking agents include, for example, divinyl sulfone, diepoxide, multiepoxide, dihydrazide, dihydric alcohol, polyhydric alcohol, polyhydric thiol, anhydride, carbodymide, polycarboxylic acid, carboxymethylthiol, cysteine, and cysteine-like amino acids. In one embodiment, the bifunctional or polyfunctional crosslinking agent is a bis or polyepoxide such as a diglycidyl ether derivative. According to one embodiment, the bifunctional or polyfunctional epoxide crosslinking agent contains two or more glycidyl ether functional groups. The glycidyl ether functional groups react with primary hydroxyl groups of hyaluronic acid and chondroitin sulfate to form an ether bond. In one embodiment, suitable bifunctional or polyfunctional crosslinking agents include, for example, 1,4-butanediol diglycidyl ether (BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene (EGDGE), ethylene glycol diglycidyl ether (EGDE), 1,2-ethanediol diglycidyl ether (EDDE), diepoxyoctane, 1,6-hexanediol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether, polyglycerol polyglycidyl ester, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, trimethylolpropane polyglycidyl ether, pentaerythritol polyglycidyl ether, sorbitol polyglycidyl ether, 1,2,7,8-diepoxyoctane, 1,3-butadiene diepoxide, pentaerythritol tetraglycidyl ether, and polyepoxide.

[0079] Suitable dihydrazide crosslinking agents include, for example, succinic acid dihydrazide, glutaric acid dihydrazide, adipic acid dihydrazide, pimelic acid dihydrazide, suberic acid dihydrazide, azalain acid dihydrazide, sebacate acid dihydrazide, undecanedioic acid dihydrazide, dodecanedioic acid dihydrazide, brassic acid dihydrazide, tetradecanedioic acid dihydrazide, pentadecanedioic acid dihydrazide, thapsic acid dihydrazide, and octadecanedioic acid dihydrazide.

[0080] Suitable dihydric alcohol crosslinking agents include, for example, ethylene glycol, propylene glycol, butylene glycol diethylene glycol, dipropylene glycol, neopentyl glycol, 1,3-propanediol, hexylene glycol, pentylene glycol, heptylene glycol, and octylene glycol. Suitable polyhydric alcohol crosslinking agents include, for example, glycerin, pentaerythrite, xylitol, and galactitol. Suitable carbodiimide crosslinking agents include, for example, compounds of the formula XN=C=NX, where each X is independently and optionally substituted with 1 to 2 dialkylamino groups, or a C5 to C6 cycloalkyl group such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and cyclohexylcarbodiimide. Suitable anhydride crosslinking agents include, for example, methacrylic anhydride and octeylsuccinic anhydride. In one embodiment, a suitable crosslinking agent is, for example, an aldehyde crosslinking agent such as formaldehyde, gluteraldehyde, or glutaraldehyde. In another embodiment, suitable crosslinking agents include, for example, acid chlorides, n-hydroxysuccinimide, polyethylene glycol diacrylate, polyethylene glycol diamine, urea, and diisocyanate.

[0081] The crosslinked polymer networks disclosed herein can be obtained by forming a solution of hyaluronic acid or a salt thereof with other glycosaminoglycans and adding one or more of the aforementioned crosslinking agents. The solution is stirred for a suitable time sufficient to crosslink at least the hyaluronic acid or salt thereof with the other glycosaminoglycans. In one embodiment, the crosslinking reaction can be carried out at a temperature of 1°C to about 99°C over a period of about 2 hours to about 24 hours.

[0082] The solution may contain a suitable solvent, such as water, crown ether, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and other aprotic solvents. Generally, the amount of hyaluronic acid or a salt thereof can range from about 0.010 to about 50% by weight, based on the total weight of the solution. In one embodiment, the amount of hyaluronic acid or a salt thereof can range from about 0.1 to about 5% by weight, based on the total weight of the solution. In one embodiment, the amount of other glycosaminoglycans can range from about 0.01 to about 50% by weight, based on the total weight of the solution. In one embodiment, the amount of other glycosaminoglycans can range from about 0.1 to about 5% by weight, based on the total weight of the solution. A crosslinking agent may be added to the solution in an amount ranging from about 0.05 to about 10% by weight, based on the total weight of the solution.

[0083] It will be readily understood and acknowledged to those skilled in the art that the reaction product constitutes a complex mixture of compounds comprising, for example, hyaluronic acid or a salt crosslinked with another glycosaminoglycan, hyaluronic acid or a salt crosslinked with itself, another glycosaminoglycan crosslinked with itself, unreacted hyaluronic acid or a salt, and another unreacted glycosaminoglycan. For example, in one exemplary embodiment, hyaluronic acid or a salt crosslinked with another glycosaminoglycan may have a weight-average molecular weight in the range of about 20,000 to about 6,000,000 Da, with a lower limit of about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000 Da, and an upper limit of about The ranges are 200,000, approximately 300,000, approximately 400,000, approximately 500,000, approximately 600,000, approximately 700,000, approximately 800,000, approximately 900,000, approximately 1,000,000, approximately 2,000,000, approximately 3,000,000, approximately 4,000,000, approximately 5,000,000, or up to approximately 6,000,000 Da, and any of the lower limits can be combined with any of the upper limits. It is not necessary to isolate one or more specific components of the reaction product mixture. In practice, the reaction product mixture can be used as is.

[0084] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the crosslinked polymer network disclosed herein can be further crosslinked with one or more additional glycosaminoglycans. Generally, the one or more additional glycosaminoglycans can be any of the glycosaminoglycans considered above herein. In one embodiment, the one or more additional glycosaminoglycans are hyaluronic acid. In one embodiment, the one or more additional glycosaminoglycans are chondroitin sulfate. In one embodiment, the one or more additional glycosaminoglycans include hyaluronic acid and chondroitin sulfate.

[0085] The crosslinking agent for crosslinking one or more of the same or different additional glycosaminoglycans with the aforementioned crosslinked polymer network may be any of the crosslinking agents considered above. As those skilled in the art will understand, the crosslinking agent may be the same or a different crosslinking agent used in the aforementioned reaction product.

[0086] In general, the crosslinked polymer networks of this disclosure can be further crosslinked with one or more of the same or different additional glycosaminoglycans in substantially the same manner as those considered above.

[0087] In another exemplary embodiment, a derivatized hyaluronic acid or a salt thereof can be obtained by further reacting hyaluronic acid or a salt thereof with one or more phospholipids and, optionally, one or more crosslinking agents to form a glycophospholipid polymer or a crosslinked glycophospholipid polymer network. Suitable phospholipids for reacting with one or more GAGs include, for example, phosphorylcholine, phosphorylhistidine, phosphorylproline, phosphorylserine, α-phosphatidylcholine, α-phosphatidylethanolamine, α-phosphatidyl-L-serine, α-phosphatidylinositol, α-phosphatidylic acid, α-phosphatidyl-DL-glycerol, α-lysophosphatidylcholine, sn-glycero-3-phosphatidylcholine (GPC) (also known as choline alphossert) derived from soy phosphatidylcholine, sphingomyelin, and cardiolipin. The phospholipids described herein are either commercially available or can be prepared by techniques well known in the art; see, for example, Park et al., "Facile Syntheses of L-α-Glycerophosphorylcholine", Bull. Korean Chem. Soc. 2010, Vol. 31, No. pp. 9 2689-2691.

[0088] In one embodiment, the phosphorylcholine-containing phospholipid comprises the following amphoteric groups: [ka] In the formula, n is an integer from 1 to 5, and R', R'', and R'''' are independently a C1-C8 alkyl group, a C1-C8 hydroxyalkyl group, or a heteroatom-containing group such as histidine and proline. As those skilled in the art will readily understand, the phosphorylcholine-containing phospholipids described above further include one or more reactive groups capable of reacting with hyaluronic acid or a salt thereof, such as a hydroxyl-containing group, an epoxide-containing group, an amine-containing group, an aldehyde-containing group, a thiol-containing group, a carboxylic acid-containing group, a cyano-containing group, a halogen-containing group, and the like. Representative examples of suitable phosphorylcholine phospholipids having the aforementioned amphoteric groups include, but are not limited to, glyceryl phosphorylcholine, ethaminonium, 2-[(hydroxy-2-oxyranylmethoxy]phosphinyl)oxy]-N,N,N-trimethyl, intramolecular salt, and hydroxyethyl phosphorylcholine.

[0089] The term "hydroxyl-containing group" should be understood to mean any group containing a hydroxyl moiety. Typical examples of hydroxyl-containing groups for use herein include, for example, a hydroxyl group directly bonded to the rest of the molecule, i.e., -OH, or one or more hydroxyl-containing groups bonded to the rest of the molecule via a linking group, such as alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, or arylalkyl group.

[0090] The term "epoxide-containing group" should be understood to mean any group containing an epoxide moiety. Typical examples of epoxide-containing groups for use herein include, for example, alkylene oxides, in particular lower alkylene oxides such as ethylene oxide, propylene oxide, and butylene oxide, alcohol epoxides such as glycidol, and epihalohydrins such as epichlorohydrin, epibromohydrin, and epiiodohydrin, 1,2-epoxy-4-chlorobutane, 1,2-epoxy-4-bromobutane, 1,2-epoxy-4-iodobutane, 2, Examples of epoxy compounds include 3-epoxy-4-chlorobutane, 2,3-epoxy-4-bromobutane, 2,3-epoxy-4-iodobutane, 2,3-epoxy-5-chloropentane, 2,3-epoxy-5-bromopentane, 1,2-epoxy-5-chloropentane, 2,2-bis(p-1,2-epoxyproxyphenyl)-propane, 1,4-bis(1,2-epoxyproxy)benzene, and N,N'-bis(2,3-epoxypropyl)piperazine.

[0091] The term "amine-containing group" should be understood to mean any group containing an amine moiety. A typical example of an amine-containing group for use herein is, for example, the general formula -R 1 NR 2 R 3 Examples include alkylamine groups or arylamine groups such as amines, where R 1 However, C2~C 30 These are alkylenes, arylenes, or cycloalkylenes, R 2 and R 3 However, independently, for example, C1-C such as alkyl groups, aryl groups, or cycloalkyl groups as defined herein. 30 It is a hydrocarbon.

[0092] The term "aldehyde-containing group" should be understood to mean any group that contains an aldehyde moiety. Typical examples of aldehyde-containing groups for use herein include, for example, aldehyde groups directly bonded to the rest of the molecule, i.e., -CHO, or one or more aldehyde groups bonded to the rest of the molecule via linking groups, such as alkylene, cycloalkyl, cycloalkylalkylene, cycloalkenyl, aryl, or arylalkylene groups.

[0093] The term "thiol-containing group" should be understood to mean any group that contains a thiol moiety. Typical examples of thiol-containing groups for use herein include, for example, thiol groups directly bonded to the rest of the molecule, i.e., -SH groups, or one or more thiol groups bonded to the rest of the molecule via linking groups, such as alkylene, cycloalkyl, cycloalkylalkylene, cycloalkenyl, aryl, or arylalkylene groups.

[0094] The term "carboxylic acid-containing group" should be understood to mean any group containing a carboxylic acid moiety. Typical examples of carboxylic acid-containing groups for use herein include, for example, one or more carboxylic acid groups directly bonded to the rest of the molecule, i.e., -COOH, or bonded to the rest of the molecule via linking groups, such as alkylene, cycloalkyl, cycloalkylalkylene, cycloalkenyl, aryl, or arylalkylene groups.

[0095] The term "cyano-containing group" should be understood to mean any group containing a cyano moiety. Typical examples of cyano-containing groups for use herein include, for example, one or more cyano groups directly bonded to the rest of the molecule, i.e., -CN, or bonded to the rest of the molecule via a linking group, such as an alkylene, cycloalkyl, cycloalkylalkylene, cycloalkenyl, aryl, or arylalkylene group.

[0096] The term "halogen-containing group" should be understood to mean any group containing a halogen moiety. Typical examples of halogen-containing groups for use herein include, for example, halogen groups directly bonded to the rest of the molecule, i.e., F, Cl, B, I, etc., or one or more halogen groups bonded to the rest of the molecule via linking groups, such as alkylene, cycloalkyl, cycloalkylalkylene, cycloalkenyl, aryl, or arylalkylene groups.

[0097] Typical examples of alkyl groups for use herein include, for example, linear or branched hydrocarbon chain radicals containing carbon and hydrogen atoms, having 1 to about 18 carbon atoms relative to the rest of the molecule, whether unsaturated or not, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, and n-pentyl.

[0098] Typical examples of alkylene groups for use herein include, for example, linear or branched alkyl chain radicals containing carbon and hydrogen atoms, having 1 to about 30 carbon atoms or 1 to about 6 carbon atoms relative to the rest of the molecule, whether unsaturated or not, such as methylene and ethylene.

[0099] Typical examples of cycloalkyl groups for use herein include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, perhydronaphthyl, adamantyl, and norbornyl groups, crosslinked cyclic groups or spirodicyclic groups, such as spiro-(4,4)-nonal-2-yl, which are monocyclic or polycyclic systems of about 3 to about 18 carbon atoms, either substituted or unsubstituted, and optionally contain one or more heteroatoms, such as O and N.

[0100] Typical examples of cycloalkylalkyl groups for use herein include substituted or unsubstituted cyclic ring-containing radicals containing about 3 to about 18 carbon atoms, which are directly bonded to an alkyl group and then bonded to the main structure of the monomer with any carbon of the alkyl group, thereby forming a stable structure, such as cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl, where the cyclic ring may optionally contain one or more heteroatoms, such as O and N.

[0101] Typical examples of cycloalkenyl groups for use herein include, for example, substituted or unsubstituted cyclic ring-containing radicals containing about 3 to about 18 carbon atoms and having at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl, where the cyclic ring may optionally contain one or more heteroatoms, such as O and N.

[0102] Typical examples of aryl groups for use herein include, for example, substituted or unsubstituted monocyclic or polycyclic aromatic groups containing about 5 to about 25 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, and biphenyl, which optionally contain one or more heteroatoms, such as O and N.

[0103] Typical examples of arylalkylene groups for use herein include, for example, substituted or unsubstituted aryl groups as defined above, which are directly bonded to the alkylene group as defined herein, such as -CH2C6H5, -C2H5C6H5, etc., and the aryl group may optionally contain one or more heteroatoms, such as O and N.

[0104] The phospholipids used herein are either commercially available or can be prepared by methods known in the art. For example, ethaminonium, 2-[[hydroxy-2-oxyranylmethoxy]phosphinyl)oxy)-N,N,N-trimethyl, intramolecular salt can be prepared by the method described in Example 11 of Lindberg, et al., "Efficient Synthesis of Phospholipids from Glycidyl Phosphates", J. Org. Chemistry, 2002, 67, pp. 194-199, the contents of which are incorporated herein by reference, or according to U.S. Patent No. 7,674,782. In addition, hydroxyethylphosphorylcholine can be prepared according to Zhang et al., "Microscale NMR Screening of New Detergents for Membrane Protein Structural Biology," Journal of the American Chemical Society, 2008, 130(23), pp.7357-7363, the contents of which are incorporated herein by reference, and is also commercially available from Shanghai Chemhere Co., Ltd. (Shanghai, Hong Kong).

[0105] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the reaction product of hyaluronic acid or a salt thereof with one or more phospholipids comprises, for example, one or more crosslinking agents to crosslink hyaluronic acid or a salt thereof with one or more phospholipids to form a crosslinked glycophospholipid polymer network. The crosslinking agent for use herein may be any of the crosslinking agents considered above.

[0106] The glycophospholipid polymer networks disclosed herein can be obtained, when forming a crosslinked polymer network, by forming a solution of hyaluronic acid or a salt thereof with one or more phospholipids and optionally adding one or more crosslinking agents. The solution is stirred for a suitable time sufficient to react and / or crosslink the hyaluronic acid or a salt thereof with one or more phospholipids. In one embodiment, the reaction between hyaluronic acid or a salt thereof with one or more phospholipids can be carried out at a temperature of 1°C to about 99°C over a period of about 2 hours to about 36 hours.

[0107] The solution may contain one or more suitable solvents, such as water, crown ether, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and other aprotic solvents.

[0108] Generally, the amount of hyaluronic acid or its salt in a solution can range from about 0.010 to about 50% by weight, based on the total weight of the solution. In one exemplary embodiment, the amount of hyaluronic acid or its salt in a solution can range from about 0.1 to about 5% by weight, based on the total weight of the solution. In one exemplary embodiment, the amount of one or more phospholipids in a solution can range from about 0.01 to about 50% by weight, based on the total weight of the solution. In one exemplary embodiment, the amount of one or more phospholipids in a solution can range from about 0.1 to about 5% by weight, based on the total weight of the solution. A crosslinking agent can be added to the solution in an amount ranging from about 0.05 to about 20% by weight, based on the total weight of the solution.

[0109] It will be readily understood and acknowledged to those skilled in the art that the reaction products constitute a complex mixture of compounds. For example, the reaction products of hyaluronic acid or a salt thereof with one or more phospholipids and one or more crosslinking agents may include, as examples, polymers obtained from the reaction between hyaluronic acid or a salt thereof and one or more phospholipids, hyaluronic acid or a salt thereof crosslinked with phospholipids, hyaluronic acid or a salt thereof crosslinked with itself, phospholipids crosslinked with itself, unreacted hyaluronic acid or a salt thereof, and unreacted phospholipids. In one exemplary embodiment, hyaluronic acid or a salt thereof crosslinked with a phospholipid may have a weight-average molecular weight in the range of about 20,000 to about 6,000,000 Da, with a lower limit of about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000 Da, and an upper limit of about 200,000 The ranges are 0, approximately 300,000, approximately 400,000, approximately 500,000, approximately 600,000, approximately 700,000, approximately 800,000, approximately 900,000, approximately 1,000,000, approximately 2,000,000, approximately 3,000,000, approximately 4,000,000, approximately 5,000,000, or up to approximately 6,000,000 Da, with any of the lower limits being combined with any of the upper limits. It is not necessary to isolate one or more specific components of the reaction product mixture. In practice, the reaction product mixture can be used as is.

[0110] In an exemplary embodiment, which may be combined with one or more of the preceding paragraphs, to form a grafted hyaluronic acid polymer, the derivatized hyaluronic acid or a salt thereof can comprise hyaluronic acid or a salt thereof having a polymer backbone and one or more side chains grafted to the polymer backbone and containing polyalkylene glycol-containing residues. Generally, the hyaluronic acid or a salt thereof will have a reactive functional group in the polymer backbone for grafting a polymer comprising a polyalkylene glycol chain and at least one reactive end group or a salt thereof. Suitable reactive functional groups in the polymer backbone include carboxylate-containing groups, hydroxyl-containing groups, and other groups containing polymerizable functionality such as allyl, vinyl, acrylate, methacrylate, methacrylamide, and the like. The hyaluronic acid or a salt thereof for use herein can have a weight average molecular weight as discussed above.

[0111] The polyalkylene glycol-containing residues grafted to the reactive functional group in the polymer backbone of the hyaluronic acid or a salt thereof are derived from a polymer comprising a polyalkylene glycol chain and at least one reactive end group or a salt thereof (e.g., HCl). The polyalkylene glycol chain can range from 2 to 10,000 subunits or from 2 to 5,000 subunits. In one embodiment, the polyalkylene glycol chain has the structure: -((CH2) a -O) b -, where "a" is from 2 to 6, or from 2 to 4, and "b" is from 2 to 10,000, or from 2 to 5000. In an exemplary embodiment, the polyalkylene glycol is one or more of a polyethylene glycol chain (e.g., -(CH2CH2O) b -), i.e., PEG, a polypropylene glycol chain (e.g., -(CH2CH2CH2O) b -), a polybutylene glycol chain (e.g., -(CH2CH2CH2CH2O) b -), an ethylene oxide-propylene oxide chain, and an ethylene oxide-butylene oxide chain.

[0112] At least one reactive end group of a polymer containing a polyalkylene glycol chain contains a reactive functional group that can be grafted onto a reactive functional group in the polymer backbone of hyaluronic acid or a salt thereof. Suitable reactive functional groups include, for example, halogens, amino groups, aldehyde groups, carboxylic acid groups, alcohol groups, thiol groups, hydrazide groups, and glycidyl groups. These groups are bonded to the polymer compound by a linker group "X". Examples of reactive functional groups include -X-PDMS-NH2 (wherein PDMS is a polydimethylsiloxane having several molecular weights in the range of about 100 to about 150,000 Da), -X-OH, -X-NH2, -X-SH, and -XC(O)-R' (wherein R' is a hydrogen atom or an organic hydrocarbyl moiety consisting of 1 to 20 carbon atoms, such as a lower alkyl group (e.g., methyl, ethyl, propyl, etc.) or benzyl).

[0113] Suitable linker groups "X" for bonding reactive functional end groups to a polymer include, for example, any of the following: -C(O)-, -NC(O)-NH-CH2-, -NC(O)-NH-CH2-CH2-, -CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-O-CH2-, -CH2-O-CH2-CH2-, -CH2-CH2-CH2-O-CH2-, -C(O)-NH-CH2-, -C(O)-NH-CH2-CH2-, -CH2-C(O)-NH-CH2-, -CH2-CH2-C(O)-NH-, -C(O)-NH-CH2-CH2-CH2-, -CH2-C(O)-NH-CH2-CH2-, -CH2-CH2-C(O)-NH-CH2-, -C(O)-NH-CH2 -CH2-CH2-CH2-, -CH2-C(O)-NH-CH2-CH2-CH2-, -CH2-CH2-C(O)-NH-CH2-CH2-, -CH2-CH2-CH2-C(O)-NH-CH2-, -CH2-CH2-CH2-(Si-O-Si) n -O-Si-CH2-CH2-CH2-(where n=3 to 100), and any two or more combinations of the above.

[0114] Other end groups can be either inert or reactive end groups. Inert end groups are those that do not readily undergo chemical transformation under typical synthetic reaction conditions. Reactive end groups can be used for further crosslinking. Suitable end capping groups include, for example, alkoxy groups, hydroxyl groups, thiol groups, amine groups, and ethylene-based polymerizable groups such as acrylate or methacrylate groups. Alkoxy groups are represented by the general formula -OR, where R is an organic moiety consisting of 1 to 20 carbon atoms, such as a lower alkyl group (e.g., methyl or ethyl) or benzyl. However, R may be saturated or unsaturated and includes aryl, heteroaryl, cyclo, heterocyclo, and any of the aforementioned substitutional forms. For example, the end cap PEG has the structure RO-(CH2CH2O) n - may be included in the formula, where R is as defined above. In an exemplary embodiment, preferred terminal groups include, for example, -OCH3, -OCH2CH3, -OCH2(C6H5), -NH2, -OH, and -SH.

[0115] Polymers comprising polyalkylene glycol chains and at least one reactive end group or a salt thereof for use herein include polymers having a variety of molecular weights, structures, or geometries (e.g., branched, linear, etc.). In one exemplary embodiment, the weight-average molecular weight of a polymer comprising polyalkylene glycol chains and at least one reactive end group or a salt thereof may range from about 100 Da to about 10,000 Da. For example, in one exemplary embodiment, the weight-average molecular weight of a polymer comprising polyalkylene glycol chains and at least one reactive end group or a salt thereof may be greater than about 100 Daltons, or greater than about 250 Da, or greater than about 500 Da, or greater than about 750 Da, or greater than about 1,000 Da, or greater than about 2,000 Da, or greater than about 5,000 Da, or greater than about 7,500 Da. In another exemplary embodiment, the weight-average molecular weight of a polymer comprising a polyalkylene glycol chain and at least one reactive end group or a salt thereof may be less than about 10,000 Da, or less than about 7,500 Da, or less than about 5,000 Da, or less than about 2,000 Da, or less than about 1,000 Da, or less than about 750 Da, or less than about 600 Da. Any molecular weight between those listed above may be used, as will be understood by those skilled in the art.

[0116] The aforementioned polymers are commercially available from various sources such as BroadPharm, Sigma, JenKem, and Advanced Polymer Materials Inc., or can be prepared according to methods well known in the art.

[0117] In one exemplary embodiment, the polymer comprising a polyalkylene glycol chain and at least one reactive end group or a salt thereof is a polymer or salt thereof having the following structure: [ka] In the formula, Z is a terminal cap group, Y is a reactive functional group, a is from 2 to 6, b is from 2 to 10,000, and c is 1 or 2.

[0118] Z can be a terminal cap (or end-capping) group that is an inert or reactive group present at the end of a polymeric compound such as a polyethylene glycol (PEG) polymer. Suitable terminal cap groups include any of those considered above. Y is a reactive functional group capable of grafting onto a reactive functional group in the polymer backbone of GAG. Suitable reactive functional groups include any of those considered above. Suitable linker groups "X" for attaching the reactive functional group include any of those considered above.

[0119] The polymer can be derived from a polyalkylene glycol. Generally, a polyalkylene glycol has the following structure: -((CH2) a -O) b -, where "a" is from 2 to 6, or from 2 to 4, and "b" is from 2 to 10,000, or from 2 to 5000. In an exemplary embodiment, the polyalkylene glycol is polyethylene glycol (e.g., -(CH2CH2O) b -), polypropylene glycol (e.g., -(CH2CH2CH2O) b -), polybutylene glycol (e.g., -(CH2CH2CH2CH2O) b -), ethylene oxide-propylene oxide, and ethylene oxide-butylene oxide, or one or more of them. Polyalkylene glycols for use herein include polyalkylene glycols having various molecular weights, structures, or geometries (e.g., branched, linear, etc.) considered above.

[0120] In one embodiment, representative examples of such polymers for use herein include any of the following:

Chemical formula

[0121] Grafted hyaluronic acid polymers disclosed herein can be obtained by grafting reactive functional groups of one or more polymers containing polyalkylene glycol chains onto reactive functional groups in the polymer backbone of hyaluronic acid or a salt thereof. For example, in one exemplary embodiment, amine-reactive terminal groups of a polymer containing polyalkylene glycol chains can be grafted onto carboxylic acid groups in the polymer backbone of a glycosaminoglycan. The graft polymerization reaction can yield a degree of grafting ranging from about 5 to about 100%, i.e., the number of side chains in the polymer backbone containing polyalkylene glycol residues. In one exemplary embodiment, the degree of grafting can range from about 10 to about 90%. In one exemplary embodiment, the degree of grafting can range from about 20 to about 80%.

[0122] In one exemplary embodiment, hyaluronic acid or a salt thereof may be added to the reaction mixture in an amount ranging from about 0.05% to about 10% by weight, based on the total weight of the reaction mixture. In another exemplary embodiment, hyaluronic acid or a salt thereof may be added to the reaction mixture in an amount ranging from about 0.5% to about 5% by weight, based on the total weight of the reaction mixture.

[0123] In one embodiment, a polymer containing polyalkylene glycol chains may be added to the reaction mixture in an amount ranging from about 0.01% to about 20% by weight, based on the total weight of the reaction mixture. In an exemplary embodiment, a polymer containing polyalkylene glycol chains may be added to the reaction mixture in an amount ranging from about 0.10% to about 0.5% by weight, based on the total weight of the reaction mixture.

[0124] Graft reactions are typically carried out in the presence of a catalytic system. In some embodiments, the catalytic system is a carbodiimide catalytic system, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). In some embodiments, a co-catalyst is used with the carbodiimide catalytic system. Suitable co-catalysts include, for example, hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (NHS), and sulfo-N-hydroxysuccinimide (sulfo-NHS). In some embodiments, the catalytic system includes EDC / NHS. In one embodiment, EDC is added to the reaction mixture in an amount ranging from about 0.01% to about 20% by weight, based on the total weight of the reaction mixture. In one embodiment, NHS is added to the reaction mixture in an amount ranging from about 0.01% to about 20% by weight, based on the total weight of the reaction mixture.

[0125] In one exemplary embodiment, the graft reaction can be carried out by reacting hyaluronic acid or a salt thereof with a polymer under suitable graft conditions, using a catalytic system such as EDC / NHS / or EDC / HOBt coupling, at a pH of about 6.8 with about 1 to about 5 weight percent solid dissolved in water, to form a random copolymer or block copolymer.

[0126] In another embodiment, the graft reaction is carried out by reacting hyaluronic acid or a salt thereof with a monomer capable of forming a polymer in situ that includes a polyalkylene glycol chain and at least one reactive end group or a salt thereof. For example, the reaction can be carried out by first forming a solution containing at least hyaluronic acid or a salt thereof and a cocatalyst system. Next, the hyaluronic acid or a salt thereof is activated by adding an activator to the solution. Suitable activators include, for example, one or more epoxyamines. Epoxyamines are generally molecules that include both at least one amine moiety (e.g., a primary amine, secondary amine, tertiary amine, or quaternary amine) and at least one epoxide moiety. Epoxyamine compounds can be monoepoxyamine compounds and / or polyepoxyamine compounds, i.e., epoxyamines containing one or more amine groups and one or more epoxide groups. In one embodiment, a suitable epoxyamine compound is one in which the amine moiety is C1-C 30 The epoxyamine is linked to the epoxide portion by an alkylene group. Suitable epoxyamine compounds include, for example, epoxyethylamine, epoxypropylamine, epoxybutylamine, and epoxyamylamine. The activation reaction can be carried out at a suitable temperature for a period of time to allow the activator to react with the glycosaminoglycan, for example, at room temperature for a period ranging from about 10 hours to about 48 hours. In one embodiment, the epoxyamine can be added to the reaction mixture in an amount ranging from about 0.01% to about 50% by weight, based on the total weight of the reaction mixture.

[0127] After reacting an activator with hyaluronic acid or a salt thereof, a monomer capable of situ forming a polymer containing a polyalkylene glycol chain and at least one reactive end group or a salt thereof is added to the reaction mixture. In one embodiment, the monomer includes a polyol and an epoxy alcohol. Suitable polyols include, for example, one or more diols. Typical diols include, for example, ethylene glycol, propylene glycol, 1,3-propanediol, 1,2-butanediol, 1,4-butanediol, 2-methyl-1,3-propanediol, poloxamer 407, and other C2-C2 diols. 12 Diols are examples. The epoxy alcohol compound can be a monoepoxy alcohol compound and / or a polyepoxy alcohol compound, i.e., an epoxy alcohol containing one or more alcohol groups and one or more epoxide groups. In one embodiment, a preferred epoxy alcohol compound is one in which the alcohol portion is C1-C 30 Some epoxy alcohol compounds are linked to the epoxide moiety by alkylene and / or alkyne groups. Suitable epoxy alcohol compounds include, for example, glycidyl alcohol, 3-oxyranyl-2-propen-1-ol, 3-(2-oxyranyl)2-propen-1-ol, 1-(2,3-dihydroxypropyl)4-(2-oxyranylmethyl) ester of 2-butenioic acid, and 1-(2-hydroxyethyl)2-(2-oxyranylmethyl) ester of 1,2-benzenedicarboxylic acid.

[0128] Generally, polyols and epoxy alcohols can be added to the reaction mixture sequentially or simultaneously. In one embodiment, a polyol is added to the reaction mixture and reacted with activated hyaluronic acid or a salt thereof, followed by the polyol, to form a polyalkylene glycol-containing residue. This reaction can be carried out at a suitable temperature for a period of time to complete the reaction in order to maximize the yield of the polyalkylene glycol residue, which is the product on the polymer backbone of the glycosaminoglycan, for example, at room temperature for a period ranging from about 10 hours to about 48 hours. In one embodiment, based on the total weight of the reaction mixture, the polyol can be added to the reaction mixture in an amount ranging from about 0.01 to about 50% by weight, and the epoxy alcohol can be added to the reaction mixture in an amount ranging from about 0.01 to about 50% by weight.

[0129] The resulting grafted hyaluronic acid polymer may be a random copolymer or a block copolymer. In one exemplary embodiment, the grafted hyaluronic acid polymer disclosed herein may have a weight-average molecular weight in the range of about 20,000 to about 6,000,000 Da, with a lower limit of about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000 Da, and an upper limit of about 200,000 Da. The ranges are approximately 00, 300,000, 400,000, 500,000, 600,000, 700,000, 800,000, 900,000, 1,000,000, 2,000,000, 3,000,000, 4,000,000, 5,000,000, or up to approximately 6,000,000 Da, and any of the lower limits can be combined with any of the upper limits.

[0130] In another embodiment, the crosslinked polymer network can be formed by either reacting the aforementioned grafted hyaluronic acid polymer with one or more crosslinking agents, or by adding one or more crosslinking agents to the graft reaction mixture. The crosslinking agents used herein may be any of the crosslinking agents considered above, such as bifunctional or polyfunctional crosslinking agents containing two or more functional groups capable of reacting with the functional groups of the grafted hyaluronic acid polymer, resulting in the formation of covalent bonds.

[0131] In one embodiment, the crosslinked polymer network described in the exemplary embodiments herein can be obtained by forming a solution of one or more grafted hyaluronic acid polymers and adding one or more of the aforementioned crosslinking agents. In one embodiment, the crosslinked polymer network described in the exemplary embodiments herein can be obtained by adding one or more of the aforementioned crosslinking agents to a graft solution of one or more hyaluronic acid polymers and one or more polymers. This solution is stirred for a suitable time sufficient to crosslink the reaction mixture. In one embodiment, crosslinking can be carried out at a temperature of 1°C to about 99°C over a period of about 2 hours to about 48 hours.

[0132] The solution may contain a suitable solvent, such as water, crown ether, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and other aprotic solvents. The pH of the solution can be adjusted as needed by adding a hydroxide, such as sodium hydroxide. Generally, the crosslinking agent can be added to the solution in an amount ranging from about 0.01% to about 10% by weight, based on the total weight of the solution. When crosslinking grafted hyaluronic acid polymers, the amount of grafted hyaluronic acid polymer can range from about 0.010% to about 50% by weight, based on the total weight of the solution. In one embodiment, the amount of grafted hyaluronic acid polymer can range from about 0.01% to about 5% by weight, based on the total weight of the solution.

[0133] In one embodiment, one or more glycosaminoglycans can be added to the reaction of a grafted hyaluronic acid polymer with one or more crosslinking agents to form a crosslinked polymer network, i.e., the grafted hyaluronic acid polymer can be crosslinked with one or more glycosaminoglycans. Generally, one or more glycosaminoglycans can be any of the glycosaminoglycans discussed above herein. In one embodiment, one or more glycosaminoglycans are hyaluronic acid or a salt thereof. In one embodiment, one or more glycosaminoglycans are chondroitin sulfate. In one embodiment, one or more glycosaminoglycans comprise hyaluronic acid or a salt thereof and chondroitin sulfate. In an exemplary embodiment, the amount of one or more glycosaminoglycans can range from about 0.010% by weight to about 50% by weight based on the total weight of the solution. In one embodiment, the amount of one or more glycosaminoglycans can range from about 0.01% by weight to about 5% by weight based on the total weight of the solution.

[0134] One or more crosslinking agents have functional groups complementary to the grafted hyaluronic acid polymer and the glycosaminoglycan. For example, suitable crosslinking agents such as bifunctional or polyfunctional crosslinking agents bond the grafted hyaluronic acid polymer to the glycosaminoglycan and also act as spacers between the grafted hyaluronic acid polymer and the glycosaminoglycan.

[0135] It will be readily apparent to those skilled in the art that the reaction product constitutes a complex mixture of compounds comprising, for example, a grafted hyaluronic acid polymer crosslinked with a glycosaminoglycan, a grafted hyaluronic acid polymer crosslinked with another grafted hyaluronic acid polymer, a glycosaminoglycan crosslinked with another glycosaminoglycan, an unreacted grafted hyaluronic acid polymer, and an unreacted glycosaminoglycan. For example, in one exemplary embodiment, the grafted glycosaminoglycan polymer crosslinked with another glycosaminoglycan may have a weight-average molecular weight in the range of about 20,000 to about 6,000,000 Da, with a lower limit of about 20,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 80,000, about 90,000, or about 100,000 Da, and an upper limit of about 100,000 Da The ranges are approximately 200,000, 300,000, 400,000, 500,000, 600,000, 700,000, 800,000, 900,000, 1,000,000, 2,000,000, 3,000,000, 4,000,000, 5,000,000, or up to approximately 6,000,000 Da, with any of the lower limits being combined with any of the upper limits. It is not necessary to isolate one or more specific components of the reaction product mixture. In practice, the reaction product mixture can be used as is. If necessary, any excess crosslinking agent can be removed by dialysis or precipitation in ethanol.

[0136] According to one or more additional non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, an aqueous packaging solution for use in the packaging systems disclosed herein further contains Tremella fuciformis. In one exemplary embodiment, Tremella fuciformis comprises or is a polysaccharide extracted from the Tremella species of mushroom. For example, Tremella fuciformis comprises or is a polysaccharide extracted from a mushroom species selected from the group consisting of Tremella fuciformis, Tremella mesenterica, Tremella aurantia, mixtures thereof, and combinations thereof.

[0137] Tremella fuciformis can also be obtained from a fermentation process. In one exemplary embodiment, Tremella fuciformis is a polysaccharide obtained from a fermentation process. For example, dextrose and mannose are fermented together in a bioreactor and vertical bowl centrifuge for cell separation, followed by washing and filtration. Purification by column chromatography and drying after solvent evaporation yields Tremella fuciformis having a main chain of TFBP-A composed of (1→3)-D-Man-, (1→6)-D-GlcN, (1→4,6)-D-GalA, (1→6)-D-Gal, (1→)-L-Rib, (1→)-L-Xyl, and (1→3)-L-Fuc, with a polysaccharide branching degree of 61.55%.

[0138] According to one or more additional non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, aqueous packaging solutions for use in the packaging systems disclosed herein may further contain ectoin or ophthalmologically acceptable ectoin derivatives, such as hydroxyectoin. Ectoin is a natural substance obtained from microorganisms that inhabit extreme environments (e.g., salt lakes). These microorganisms form the natural substance ectoin to protect themselves from the extreme environmental factors prevalent in their habitats.

[0139] In an exemplary embodiment, ectoyne is L-ectoyne ((S)-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid). In an exemplary embodiment, ophthalmologically acceptable ectoyne derivatives include, for example, hydroxyectoyne ((4S,5S)-5-hydroxy-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid), polyectoyne, its oligogomers, salts, such as sodium or potassium salts of ectoyne, esters that can be obtained by converting the 4-carboxyl group with an alcohol, particularly a linear or branched monovalent or divalent alcohol having 1 to 20 carbon atoms, and / or the 5-hydroxyl group with a carboxylic acid, particularly a linear or branched monovalent or divalent alkylcarboxylic acid having 2 to 20 carbon atoms, such as alkyl monocarboxylic acids, and also esters that can be obtained by acid addition salts with inorganic or organic acids.

[0140] According to one or more additional non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, ectoin or an ophthalmologically acceptable ectoin derivative is present in the aqueous packaging solution in an amount ranging from about 0.01 to about 10 weight percent based on the total weight of the aqueous packaging solution. In another exemplary embodiment, ectoin or an ophthalmologically acceptable ectoin derivative is present in the aqueous packaging solution in an amount ranging from about 0.1 to about 2 weight percent based on the total weight of the aqueous packaging solution.

[0141] According to one or more additional non-limiting exemplary embodiments which may be combined with one or more of the preceding paragraphs, an aqueous packaging solution for use in the packaging system disclosed herein may further contain one or more glycosaminoglycans (GAGs) other than hyaluronic acid or salts thereof that have been considered above. Examples of GAGs other than hyaluronic acid or salts thereof that have a commonly understood structure include, for example, chondroitin sulfate (e.g., chondroitin 4- and 6-sulfates), heparan, heparin sulfate, heparosan, dermatan, dermatan sulfate, keratan sulfate, and other disaccharides such as sucrose, lactulose, lactose, maltose, trehalose, cellobiose, mannobiose, and chitobiose, which have been considered above herein.

[0142] According to one or more additional non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, one or more GAGs can be further derivatized in a manner similar to that considered above with respect to derivatized hyaluronic acid to form modified GAGs.

[0143] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more GAGs or modified GAGs other than hyaluronic acid, its salts, or derivatives discussed above may be present in the aqueous packaging solution in an amount ranging from about 0.01 to about 1 weight percent based on the total weight of the aqueous packaging solution. In another exemplary embodiment, one or more GAGs or modified GAGs discussed above may be present in the aqueous packaging solution in an amount ranging from about 0.01 to about 0.1 weight percent based on the total weight of the aqueous packaging solution.

[0144] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further contains one or more antimicrobial agents. Typical examples of antimicrobial agents for use herein include, but are not limited to, peroxides, polyquaternium, and Purit. Suitable peroxides include, for example, hydrogen peroxide, benzoyl peroxide, t-butyl hydroperoxide, p-menthane hydroperoxide, and mixtures thereof. Suitable polyquaterniums include, for example, polyquaternium-1, polyquaternium-10, and polymer JR.

[0145] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more antimicrobial agents, such as peroxides, are present in the aqueous packaging solution in an amount ranging from about 0.5 ppm to about 20 ppm, based on the total weight of the aqueous packaging solution. In another exemplary embodiment, one or more antimicrobial agents, such as peroxides, are present in the aqueous packaging solution in an amount ranging from about 1 ppm to about 10 ppm, based on the total weight of the aqueous packaging solution.

[0146] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further contains one or more vitamin B5 agents. Suitable vitamin B5 agents include, for example, pantothenic acid, its analogues or derivatives, calcium pantothenate, sodium pantothenate, or pantothenol.

[0147] In one exemplary embodiment, which may be combined with one or more of the preceding paragraphs, one or more vitamin B5 agents are present in the aqueous packaging solution in an amount ranging from about 0.1 to about 2 weight percent based on the total weight of the aqueous packaging solution. In another exemplary embodiment, one or more vitamin B5 agents are present in the aqueous packaging solution in an amount ranging from about 0.5 to about 1 weight percent based on the total weight of the aqueous packaging solution.

[0148] The packaging solutions disclosed herein are physiologically compatible. Specifically, the solutions must be “ophthalmologically safe” for use with lenses such as contact lenses, meaning that contact lenses treated with the solution are generally suitable and safe for direct placement in the eye without rinsing; that is, the solution is safe and comfortable for daily contact with the eye via contact lenses moistened with the solution. An ophthalmologically safe solution contains materials and amounts that have a suitable tonicity and pH for the eye and are non-cytotoxic in accordance with ISO standards and U.S. Food and Drug Administration (FDA) regulations.

[0149] Furthermore, the packaging solution must be sterile in such a way that the absence of microbial contamination in the product must be statistically demonstrated to the extent necessary for such product prior to shipment. The liquid medium useful in the present invention is selected to enable or further facilitate the lens treatment(s) of the present invention without having substantially harmful effects on the lens being treated or cared for. In one embodiment, the liquid medium is aqueous. Particularly useful aqueous liquid mediums are those derived from saline solutions, such as conventional saline solutions or conventional buffered saline solutions.

[0150] The pH of the aqueous packaging solution should be maintained within the range of about 6 to about 9, or about 6.5 to about 7.8. Suitable buffers, such as borate buffers, potassium citrate, citric acid, sodium bicarbonate, TRIS, and various mixed phosphate buffers (including combinations of Na2HPO4, NaH2PO4, and KH2PO4), and mixtures thereof, can be added to the aqueous packaging solution. In an exemplary embodiment, a suitable buffer is tris(hydroxymethyl)aminomethane (2-amino-2-(hydroxymethyl)propane-1,3-diol), (also known as tromethamine and commonly referred to as Tris, Tris buffer, Tris base, or TRIZMA, TRIZMA buffer, or TRIZMA base), or salts thereof such as TRIZMA HCl. In an exemplary embodiment, a suitable buffer is a borate buffer containing one or more of boric acid, sodium borate, potassium tetraborate, potassium metaborate, or mixtures thereof. Buffer combinations are intended herein.

[0151] Generally, the buffer is used in an amount ranging from about 0.005 to about 2.5 weight percent based on the total weight of the aqueous packaging solution. In one embodiment, the buffer is used in an amount ranging from about 0.01 to about 1.5 weight percent based on the total weight of the aqueous packaging solution.

[0152] Typically, aqueous packaging solutions are also adjusted using isotonic agents to approximate the osmotic pressure of normal tears, equivalent to a 0.9 percent sodium chloride solution or a 2.5 percent glycerol solution. If the aqueous packaging solution is made substantially isotonic using saline alone or in combination with other saline, but is not made hypotonic or hypertonic by simply mixing it with sterile water, the lens will lose its desirable optical parameters. Accordingly, excess saline can result in the formation of a hypertonic solution that causes stinging pain and irritation to the eye.

[0153] Suitable tonicity modifiers include, for example, sodium chloride and potassium chloride, dextrose, calcium chloride and magnesium chloride, mannitol, inositol, sorbitol, polyethylene glycol (PEG), glucose (dextrose), glycerin, glutamic acid, proline, stachydrine (also known as N,N-dimethylproline or proline betaine), betaine (also known as trimethylglycine or glycine betaine), taurine, L-carnitine, trehalose, gamma-aminobutyric acid (GABA), alanine, arginine, glycine, glutamine, asparagine, ornithine, isoleucine, leucine, valine, putrescine, spermidine, spermine, homospermine, cadaline, urea, glycerophoscholine, and mixtures thereof.

[0154] These tension modifiers are typically used individually in amounts ranging from about 0.01 to about 2.5% by weight / volume. In one embodiment, the tension modifier is used in amounts ranging from about 0.2 to about 1.5% by weight / volume. The isotonic agent is used in an amount that provides a final effective osmotic value of at least about 150 mOsm / kg. In one embodiment, the tension modifier is used in an amount that provides a final effective osmotic value of about 150 to about 400 mOsm / kg. In one embodiment, the tension modifier is used in an amount that provides a final effective osmotic value of about 150 to about 350 mOsm / kg. In one embodiment, the tension modifier is used in an amount that provides a final effective osmotic value of about 160 to about 220 mOsm / kg.

[0155] If desired, one or more additional components may be included in the packaging solution. Such additional components are selected to impart or provide at least one beneficial or desirable property to the aqueous packaging solution. Generally, the additional components may be selected from components conventionally used in one or more ophthalmic device care compositions. Suitable additional components include, for example, comforters, cleansing agents, wetting agents, nutrients, chelating agents, viscosity enhancers, contact lens adjusters, antioxidants, and mixtures thereof. Each of these additional components may be included in the packaging solution in an amount effective to impart or provide a beneficial or desirable property to the packaging solution. For example, such additional components may be included in the packaging solution in an amount similar to that of other such components used in, for example, conventional contact lens care products.

[0156] In one exemplary embodiment, the aqueous packaging solution further contains one or more comforters to provide additional lubricating and moisturizing properties to the aqueous packaging solution. In one embodiment, preferred comforters are one or more poloxamer comforters. A typical example of a preferred poloxamer comforter is a poloxamer block copolymer. Specific classes of poloxamer block copolymers are available under the trademark Pluronic (BASF Wyandotte Corp., Wyandotte, Michigan). Examples of poloxamers include Pluronic and reverse Pluronic. Pluronic is generally a series of ABA block copolymers consisting of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) blocks represented by formula (XXVI). [ka] In the formula, a is independently at least 1 and b is at least 1. Another typical example of a poloxamer soothing agent is the poloxamer ABA block copolymer, which is generally composed of a poly(ethylene oxide)-poly(butylene oxide)-poly(ethylene oxide) block represented by formula XXVII. [ka]

[0157] Inverse Pluronics are a series of BAB block copolymers, each generally composed of poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) blocks represented by formula (XXVIII). [ka] In the equation, a is at least 1, and b is independently at least 1.

[0158] Another typical example of a poloxamer soothing agent is the poloxamer BAB block copolymer, which is generally composed of a poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block represented by formula XXIX. [ka]

[0159] PEO blocks, which are made of poly(ethylene oxide), are hydrophilic, while PPO blocks, which are made of poly(propylene oxide), and PBO blocks, which are made of poly(butylene oxide), are inherently hydrophobic. Each series of poloxamers has a varying ratio of PEO to PPO or PBO, which ultimately determines the hydrophilic-lipophilic balance (HLB) of the material. That is, the variation in the HLB value is based on the variation in the values ​​of a and b, where a represents the number of hydrophilic poly(ethylene oxide) units (PEO) present in the molecule, and b represents the number of hydrophobic poly(propylene oxide) units (PPO) or hydrophobic poly(butylene oxide) units (PBO) present in the molecule. In one embodiment, the poloxamer has an HLB in the range of about 5 to about 24. In another embodiment, the poloxamer has an HLB in the range of about 1 to about 5.

[0160] Poloxamers and inverse poloxamers have terminal hydroxyl groups that can be terminally functionalized. An example of a terminally functionalized poloxamer is poloxamerized methacrylate (e.g., Pluronic® F127 dimethacrylate) disclosed in U.S. Patent Application Publication No. 2003 / 0044468 and U.S. Patent No. 9,309,357, as discussed herein. Another example is the glycidyl-terminated copolymers of polyethylene glycol and polypropylene glycol disclosed in U.S. Patent No. 6,517,933.

[0161] Poloxamers are functionalized to provide desired reactivity at the end of the molecule. Functionality can be variable and is determined based on the intended use of the functionalized PEO and PPO or PBO-containing block copolymer. That is, the PEO and PPO or PBO-containing block copolymer are reacted to provide end-terminal functionality that is complementary to the intended device-forming monomer mixture. The term "block copolymer" as used herein should be understood to mean a poloxamer having two or more blocks in their polymer backbone.

[0162] In one embodiment, a preferred comforter is one or more polyol comforters. A polyol suitable for use herein is of the formula R''(OH) y The formula has the following characteristics, where R'' is a hydrocarbon radical and y is an integer representing the number of hydroxyl radicals, with a value between 2 and 6. Polyols may contain fewer than approximately 12 carbon atoms. Typical examples of polyol supplements include glycerol, propylene glycol, and erythritol.

[0163] In one embodiment, a preferred stimulant is one or more poloxamine stimulants. Poloxamers and inverse poloxamers are considered to be bifunctional molecules (based on the terminal hydroxyl group), while poloxamine is in a tetrafunctional form, i.e., the molecule is a tetrafunctional block copolymer terminated at a primary hydroxyl group and linked by a central diamine. Specific classes of poloxamine block copolymers are available under the trademark Tetronic (BASF). Examples of poloxamine include Tetronic and inverse Tetronic. Poloxamine has a general structure of the following formula (XXX): [ka] In the equation, a is independently at least 1, and b is independently at least 1.

[0164] Poloxamines are functionalized to provide desired reactivity at the terminal ends of the molecule. Functionality can be variable and is determined based on the intended use of the functionalized PEO and PPO-containing block copolymer. That is, the PEO and PPO-containing block copolymer is reacted to provide terminal functionality that is complementary to the intended device-forming monomer mixture. As used herein, the term block copolymer should be understood to mean poloxamines having two or more blocks in their polymer backbone.

[0165] In one embodiment, suitable comforting agents include water-soluble natural gums and cellulose-derived polymers. Useful natural gums include guar gum and tragacanth gum. Suitable cellulose-derived comforting components include, for example, cellulose-derived polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, and hydroxyethylcellulose.

[0166] In one embodiment, suitable comforters include, for example, polyacrylic acid (PAA)-containing comforters such as PAA-g-amine, PAA-g-lactose, and PAA-co-amine. Another suitable comforter is PDMA-co-mPEG.

[0167] In this specification, any combination of the aforementioned comforters is intended.

[0168] Generally, one or more comforting agents are present in the aqueous packaging solution in an amount ranging from about 0.01 to about 5 weight percent based on the total weight of the aqueous packaging solution. In one exemplary embodiment, one or more comforting agents are present in the aqueous packaging solution in an amount ranging from about 0.1 to about 1 weight percent based on the total weight of the aqueous packaging solution.

[0169] Suitable chelating agents include, for example, disodium ethylenediaminetetraacetate, alkali metal hexametaphosphate, citric acid, sodium citrate, and mixtures thereof.

[0170] Suitable viscosity-enhancing agents include, for example, hydroxyethylcellulose, hydroxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and mixtures thereof.

[0171] Suitable antioxidants include, for example, sodium metabisulfite, sodium thiosulfate, N-acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene, and mixtures thereof.

[0172] A method for packaging and storing ophthalmic devices such as contact lenses according to an exemplary embodiment includes at least packaging an ophthalmic device immersed in an aqueous packaging solution disclosed herein. This method may include immersing the ophthalmic device in the aqueous packaging solution immediately after the manufacture of the contact lens and before delivery to the customer / wearer. Alternatively, packaging and storage in the packaging solution is an intermediate step before delivery to the end customer (wearer), but is performed after the manufacture and transport of the lens in a dry state, and the dry lens is hydrated by immersing the lens in the packaging solution. Consequently, the packaging for delivery to the customer may include a sealed container containing one or more unused contact lenses immersed in the aqueous packaging solution according to the embodiments described herein.

[0173] In an exemplary embodiment, the steps of bringing the packaging system disclosed herein include: (1) molding an ophthalmic device in a mold comprising at least first and second mold portions; (2) optionally hydrating and washing the ophthalmic device in a container comprising at least one of the mold portions; (3) introducing the aqueous packaging solution disclosed herein into the container in which the ophthalmic device is supported; and (4) sealing the container. In an exemplary embodiment, the method further includes the step of sterilizing the contents of the container. Sterilization may be performed before sealing the container or, most conveniently, after sealing, and may be performed by any preferred method known in the art, for example, by autoclaving the sealed container at a temperature of about 120°C or higher.

[0174] The following embodiments are provided to enable those skilled in the art to practice the invention and are merely illustrative of the invention. The embodiments should not be read as limiting the scope of the invention as defined in the claims.

[0175] Examples 1 and 2, and Comparative Examples A and B Aqueous packaging solutions were prepared by mixing the following components, as exemplified in Table 1, in amounts per unit weight. [Table 1]

[0176] Subsequently, the aqueous packaging solutions of Examples 1 and 2 and Comparative Examples A and B were subjected to a first autoclave procedure at 121° C. and a second autoclave procedure at 121° C. The solutions were mixed, placed in sealed glass vials, and then steam sterilized in an autoclave. The results before and after the autoclave procedures are listed in Table 2. [Table 2]

[0177] Comparative Examples C to E An aqueous packaging solution was prepared by mixing the following components exemplified in Table 3 in amounts per weight. [Table 3]

[0178] According to one aspect of the present disclosure, a packaging system for storing an unused ophthalmic device comprises a sealed container containing one or more unused ophthalmic devices immersed in an aqueous packaging solution comprising hyaluronic acid, or a salt or derivative thereof, and a jellyfish, the aqueous packaging solution having an osmotic pressure of at least about 150 mOsm / kg, a pH of about 6 to about 9, and being sterilized.

[0179] In a non-limiting exemplary embodiment that may be combined with one or more of the preceding paragraphs, hyaluronic acid, or a salt or derivative thereof, has a weight average molecular weight of about 10,000 Daltons (Da) to about 4,000,000 Da.

[0180] In a non-limiting exemplary embodiment that may be combined with one or more of the preceding paragraphs, hyaluronic acid, or a salt or derivative thereof, has a weight average molecular weight of about 1,000,000 Da to about 3,200,000 Da.

[0181] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, hyaluronic acid, or a salt or derivative thereof, has a weight-average molecular weight of about 2,000,000 Da to about 2,800,000 Da.

[0182] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, hyaluronic acid, or a salt or derivative thereof, is a hyaluronic acid derivative.

[0183] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the hyaluronic acid derivative comprises a reaction product of hyaluronic acid, a glycosaminoglycan other than hyaluronic acid or a salt thereof, and a first crosslinking agent.

[0184] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the glycosaminoglycan is chondroitin sulfate.

[0185] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, one or more other glycosaminoglycans are crosslinked with the reaction product.

[0186] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the hyaluronic acid derivative comprises a glycophospholipid polymer containing a reaction product of hyaluronic acid with one or more phospholipids.

[0187] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, one or more phospholipids include phosphorylcholine-containing phospholipids.

[0188] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the hyaluronic acid derivative comprises a grafted hyaluronic acid polymer containing hyaluronic acid or a salt thereof, having a polymer backbone and one or more side chains comprising polyalkylene glycol-containing residues grafted onto the polymer backbone.

[0189] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the polyalkylene glycol-containing residue is derived from a polymer compound or a salt thereof having the following structure: [ka] In the formula, Z is a reactive or non-reactive terminal cap group, Y is a reactive functional group, a is 2 to 6, b is 2 to 10,000, and c is 1 or 2.

[0190] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the hyaluronic acid derivative comprises a reaction product of (a) a grafted hyaluronic acid polymer containing hyaluronic acid or a salt thereof, having a polymer backbone and one or more side chains comprising polyalkylene glycol-containing residues grafted onto the polymer backbone, and (b) one or more first crosslinking agents.

[0191] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution comprises, based on the total weight of the aqueous packaging solution, about 0.001% to about 5% by weight of hyaluronic acid, or a salt or derivative thereof, and, based on the total weight of the aqueous packaging solution, about 0.001% to about 5% by weight of Tremella fuciformis.

[0192] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution comprises, based on the total weight of the aqueous packaging solution, about 0.01% to about 1% by weight of hyaluronic acid, or a salt or derivative thereof, and, based on the total weight of the aqueous packaging solution, about 0.01% to about 1% by weight of Tremella fuciformis.

[0193] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises ectoine or an ophthalmologically acceptable ectoine derivative.

[0194] In a non-limiting exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the ectoine is L-ectoine.

[0195] In a non-limiting exemplary embodiment, which may be combined with one or more of the preceding paragraphs, an ophthalmologically acceptable ectoine derivative is hydroxyectoine, polyectoine, a salt thereof, an ester thereof, an oligomer thereof, or a mixture thereof.

[0196] In a non-limiting exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution contains from about 0.01 weight percent to about 10 weight percent of ectoine or an ophthalmologically acceptable ectoine derivative, based on the total weight of the aqueous packaging solution.

[0197] In a non-limiting exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further contains a glycosaminoglycan selected from the group consisting of chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, hyaluronan, and mixtures thereof.

[0198] In a non-limiting exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution contains from about 0.01 weight percent to about 0.05 weight percent of a glycosaminoglycan or a modified glycosaminoglycan, based on the total weight of the aqueous packaging solution.

[0199] In a non-limiting exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further contains one or more antibacterial agents.

[0200] In a non-limiting exemplary embodiment, which may be combined with one or more of the preceding paragraphs, the one or more antibacterial agents include one or more of peroxide, polyquaternium, and purit.

[0201] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the peroxide includes one or more of hydrogen peroxide, benzoyl peroxide, t-butyl hydroperoxide, and p-mentheine hydroperoxide.

[0202] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution contains one or more antimicrobial agents in an amount of about 1 ppm to about 20 ppm, based on the total weight of the aqueous packaging solution.

[0203] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises one or more vitamin B agents.

[0204] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, one or more vitamin B preparations include sodium D-pantothenate.

[0205] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution contains one or more vitamin B preparations in an amount of about 0.01% to about 2% by weight, based on the total weight of the aqueous packaging solution.

[0206] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises one or more comforting agents.

[0207] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises at least one of poloxamer and poloxamine.

[0208] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the packaging system further includes one or more buffers.

[0209] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution does not contain one or more of an effective disinfecting amount of disinfectant and bactericidal compounds.

[0210] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the packaging system is heat-sterilized twice after the packaging system is sealed.

[0211] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the packaging system is thermally sterilized by autoclaving the packaging system.

[0212] According to another aspect of this disclosure, a method for preparing a packaging system including a storable sterile ophthalmic device is: (a) To provide unused ocular devices, (b) Immersing an unused ophthalmic device in an aqueous packaging solution comprising (i) hyaluronic acid, or a salt or derivative thereof, and (ii) Tremella fuciformis, wherein the aqueous packaging solution has an osmotic pressure of at least about 150 mOsm / kg and a pH in the range of about 6 to about 9. (c) The aqueous packaging solution and unused ophthalmic devices are packaged in a manner that prevents contamination of unused ophthalmic devices by microorganisms, (d) Sterilizing the packaged solution and unused ophthalmic devices, including:

[0213] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, hyaluronic acid, or a salt or derivative thereof, has a weight-average molecular weight of about 10,000 daltons (Da) to about 4,000,000 Da.

[0214] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, hyaluronic acid, or a salt or derivative thereof, has a weight-average molecular weight of about 1,000,000 Da to about 3,200,000 Da.

[0215] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, hyaluronic acid, or a salt or derivative thereof, has a weight-average molecular weight of about 2,000,000 Da to about 2,800,000 Da.

[0216] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, hyaluronic acid, or a salt or derivative thereof, is a hyaluronic acid derivative.

[0217] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the hyaluronic acid derivative comprises a reaction product of hyaluronic acid, a glycosaminoglycan other than hyaluronic acid or a salt thereof, and a first crosslinking agent.

[0218] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the glycosaminoglycan is chondroitin sulfate.

[0219] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, one or more other glycosaminoglycans are crosslinked with the reaction product.

[0220] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the hyaluronic acid derivative comprises a glycophospholipid polymer containing a reaction product of hyaluronic acid with one or more phospholipids.

[0221] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, one or more phospholipids include phosphorylcholine-containing phospholipids.

[0222] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the hyaluronic acid derivative includes a grafted hyaluronic acid polymer comprising hyaluronic acid or a salt thereof, having a polymer backbone and one or more side chains comprising polyalkylene glycol-containing residues grafted onto the polymer backbone.

[0223] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the polyalkylene glycol-containing residue is derived from a polymer compound or a salt thereof having the following structure: [ka] In the formula, Z is a reactive or non-reactive terminal cap group, Y is a reactive functional group, a is 2 to 6, b is 2 to 10,000, and c is 1 or 2.

[0224] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the hyaluronic acid derivative comprises a reaction product of (a) a grafted hyaluronic acid polymer containing hyaluronic acid or a salt thereof, having a polymer backbone and one or more side chains comprising polyalkylene glycol-containing residues grafted onto the polymer backbone, and (b) one or more first crosslinking agents.

[0225] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution comprises, based on the total weight of the aqueous packaging solution, about 0.001% to about 5% by weight of hyaluronic acid, or a salt or derivative thereof, and, based on the total weight of the aqueous packaging solution, about 0.001% to about 5% by weight of Tremella fuciformis.

[0226] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution comprises, based on the total weight of the aqueous packaging solution, about 0.1% to about 1% by weight of hyaluronic acid, or a salt or derivative thereof, and, based on the total weight of the aqueous packaging solution, about 0.1% to about 1% by weight of Tremella fuciformis.

[0227] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises ectoine or an ophthalmologically acceptable ectoine derivative.

[0228] In non-exclusive exemplary embodiments, which may be combined with one or more of the preceding paragraphs, ectoin is L-ectoin.

[0229] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, ophthalmologically acceptable ectoine derivatives are hydroxyectoine, polyectoine, salts thereof, esters thereof, oligomers thereof, or mixtures thereof.

[0230] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution comprises, based on the total weight of the aqueous packaging solution, about 0.01% to about 10% by weight of ectoin or an ophthalmologically acceptable ectoin derivative.

[0231] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises one or more glycosaminoglycans selected from the group consisting of chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, hyaluronan, and mixtures thereof.

[0232] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution contains modified glycosaminoglycans in an amount of about 0.01% to about 0.05% by weight, based on the total weight of the aqueous packaging solution.

[0233] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises one or more antimicrobial agents.

[0234] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, one or more antimicrobial agents include one or more peroxides, polyquaternium, and Purit.

[0235] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the peroxide includes one or more of hydrogen peroxide, benzoyl peroxide, t-butyl hydroperoxide, and p-mentheine hydroperoxide.

[0236] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution contains one or more antimicrobial agents in an amount of about 1 ppm to about 20 ppm, based on the total weight of the aqueous packaging solution.

[0237] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises one or more vitamin B agents.

[0238] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, one or more vitamin B preparations include sodium D-pantothenate.

[0239] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution contains one or more vitamin B preparations in an amount of about 0.01% to about 2% by weight, based on the total weight of the aqueous packaging solution.

[0240] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises one or more comforting agents.

[0241] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises at least one of poloxamer and poloxamine.

[0242] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution further comprises one or more buffers.

[0243] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, the aqueous packaging solution does not contain one or more of an effective disinfecting amount of disinfectant and bactericidal compounds.

[0244] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, sterilizing a packaged solution and an ophthalmic device includes heat sterilizing the packaged solution and the ophthalmic device one or more times after the packaging system has been sealed.

[0245] In non-limiting exemplary embodiments, which may be combined with one or more of the preceding paragraphs, sterilizing the packaged solution and ophthalmic device includes autoclaving the packaging system.

[0246] For the sake of brevity, various features disclosed herein are described in the context of a single embodiment, but may also be provided separately or in any preferred partial combination. All combinations of embodiments are specifically encompassed by the exemplary embodiments disclosed herein, as if each and all combinations were individually and expressly disclosed. In addition, all partial combinations enumerated in embodiments describing such variable elements are also specifically encompassed and disclosed herein by the formulation, as if each and all such partial combinations were individually and expressly disclosed herein.

[0247] It will be understood that various modifications can be made to the embodiments disclosed herein. Therefore, the above description should not be construed as restrictive, but rather as illustrative examples of preferred embodiments. For example, the functions described and implemented above as the best mode for making the invention function are for illustrative purposes only. Other configurations and methods can be implemented by those skilled in the art without departing from the scope and spirit of the invention. Furthermore, those skilled in the art will anticipate other modifications within the scope and spirit of the features and advantages accompanying this specification.

Claims

1. A packaging system for storing ophthalmic devices, A packaging system comprising a sealed container for housing one or more unused eye devices immersed in an aqueous packaging solution comprising hyaluronic acid, a salt or derivative thereof, and Tremella fuciformis, wherein the aqueous packaging solution has an osmotic pressure of at least about 150 mOsm / kg, a pH of about 6 to about 9, and is sterile.

2. The packaging system according to claim 1, wherein the hyaluronic acid, or a salt or derivative thereof, has a weight-average molecular weight of about 10,000 Da to about 4,000,000 Da.

3. The packaging system according to claim 1, wherein the hyaluronic acid, or a salt or derivative thereof, has a weight-average molecular weight of about 1,000,000 Da to about 3,200,000 Da.

4. The packaging system according to claim 1, wherein the hyaluronic acid, or a salt or derivative thereof, has a weight-average molecular weight of about 2,000,000 Da to about 2,800,000 Da.

5. The packaging system according to claim 1, wherein the hyaluronic acid derivative comprises a reaction product of hyaluronic acid, a glycosaminoglycan other than hyaluronic acid or a salt thereof, and a first crosslinking agent.

6. The packaging system according to claim 5, wherein the glycosaminoglycan is chondroitin sulfate.

7. The packaging system according to claim 1, wherein the hyaluronic acid derivative comprises a glycophospholipid polymer containing a reaction product of hyaluronic acid and one or more phospholipids.

8. The packaging system according to claim 7, wherein the one or more phospholipids include phosphorylcholine-containing phospholipids.

9. The packaging system according to claim 1, wherein the hyaluronic acid derivative comprises a grafted hyaluronic acid polymer having a polymer backbone and one or more side chains comprising polyalkylene glycol-containing residues grafted onto the polymer backbone, wherein the hyaluronic acid derivative comprises hyaluronic acid or a salt thereof.

10. The polyalkylene glycol-containing residue is derived from a polymer compound or a salt thereof having the following structure: 【Chemistry 1】 In the formula, Z is a reactive or non-reactive terminal cap group, Y is a reactive functional group, a is 2 to 6, b is 2 to 10,000, and c is 1 or 2. The packaging system according to claim 9.

11. The packaging system according to claim 1, wherein the hyaluronic acid derivative comprises (a) a grafted hyaluronic acid polymer containing hyaluronic acid or a salt thereof, having a polymer backbone and one or more side chains containing polyalkylene glycol-containing residues grafted onto the polymer backbone, and (b) a reaction product of one or more first crosslinking agents.

12. The packaging system according to any one of claims 1 to 11, wherein the aqueous packaging solution comprises, based on the total weight of the aqueous packaging solution, about 0.001% to about 5% by weight of hyaluronic acid, or a salt or derivative thereof, and based on the total weight of the aqueous packaging solution, about 0.001% to about 5% by weight of Tremella fuciformis.

13. The packaging system according to any one of claims 1 to 11, wherein the aqueous packaging solution comprises, based on the total weight of the aqueous packaging solution, about 0.01% to about 1% by weight of hyaluronic acid, or a salt or derivative thereof, and based on the total weight of the aqueous packaging solution, about 0.01% to about 1% by weight of Tremella fuciformis.

14. The packaging system according to any one of claims 1 to 13, wherein the aqueous packaging solution further comprises ectoine or an ophthalmologically acceptable ectoine derivative.

15. The packaging system according to claim 14, wherein the aqueous packaging solution contains, based on the total weight of the aqueous packaging solution, about 0.01% by weight to about 10% by weight of the ectoin or the ophthalmologically acceptable ectoin derivative.

16. The packaging system according to any one of claims 1 to 15, wherein the aqueous packaging solution further comprises one or more glycosaminoglycans selected from the group consisting of chondroitin, chondroitin sulfate, dermatan, dermatan sulfate, heparin, heparan sulfate, hyaluronan, and mixtures thereof.

17. The packaging system according to claim 16, wherein the aqueous packaging solution contains the glycosaminoglycan in an amount of about 0.01% by weight to about 0.05% by weight, based on the total weight of the aqueous packaging solution.

18. The packaging system according to any one of claims 1 to 17, wherein the aqueous packaging solution further comprises one or more antimicrobial agents.

19. The packaging system according to claim 18, wherein the one or more antimicrobial agents include one or more of peroxides, polyquaternium, and Purit.

20. The packaging system according to claim 19, wherein the peroxide comprises one or more of hydrogen peroxide, benzoyl peroxide, t-butyl hydroperoxide, and p-menthane hydroperoxide.

21. The packaging system according to any one of claims 18 to 20, wherein the aqueous packaging solution contains one or more antimicrobial agents in an amount of about 1 ppm to about 20 ppm, based on the total weight of the aqueous packaging solution.

22. The packaging system according to any one of claims 1 to 21, wherein the aqueous packaging solution further comprises one or more vitamin B agents.

23. The packaging system according to claim 22, wherein the one or more vitamin B preparations include sodium D-pantothenate.

24. The packaging system according to claim 22 or 23, wherein the aqueous packaging solution contains one or more vitamin B preparations in an amount of about 0.01% to about 2% by weight, based on the total weight of the aqueous packaging solution.

25. The packaging system according to any one of claims 1 to 24, wherein the aqueous packaging solution further comprises one or more comforting agents.

26. The packaging system according to any one of claims 1 to 25, wherein the aqueous packaging solution further comprises at least one of poloxamer and poloxamine.

27. The packaging system according to any one of claims 1 to 26, further comprising one or more buffers.

28. The packaging system according to any one of claims 1 to 27, wherein the packaging system is heat-sterilized twice after the packaging system is sealed.

29. The packaging system according to claim 28, wherein the packaging system is heat-sterilized by autoclaving the packaging system.

30. A method for preparing a packaging system including a storable sterile ophthalmic device, wherein the method is (a) To provide unused ocular devices, (b) Immersing the unused eye device in the aqueous packaging solution according to any one of claims 1 to 27, wherein the aqueous packaging solution has an osmotic pressure of at least about 150 mOsm / kg and a pH in the range of about 6 to about 9. (c) Packaging the aqueous packaging solution and the unused eye device in a manner that prevents contamination of the unused eye device by microorganisms, (d) Sterilizing the packaged solution and the unused eye device, Methods that include...

31. The method according to claim 30, wherein sterilizing the packaged solution and the unused eye device comprises heat sterilizing the packaged solution and the unused eye device once or more after sealing the packaging system.

32. The method according to claim 30 or 31, wherein sterilizing the packaged solution and the unused ophthalmic device comprises autoclaving the packaging system.

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