Controlled release of beneficial agents from contact lenses

Abstract

A beneficial agent-releasing silicone hydrogel contact lens that is capable of taking up and sustaining the release of a releasable beneficial agent and methods of making the contact lens. The contact lens comprises a charged hydrophobic molecule that is embedded in and non-covalently bound to a polymer matrix of a polymeric lens body of the contact lens. A releasable beneficial agent may be complexed to the polymeric lens body via ionic interactions between the beneficial agent and the charged hydrophobic molecule. The charged hydrophobic molecule advantageously facilitates controlled release of the releasable beneficial agent by the polymeric lens body, e.g. during wear.

Description

P10257WO (3038-278-01 PCT)CONTROLLED RELEASE OF BENEFICIAL AGENTS FROM CONTACT LENSESFIELD OF THE INVENTION

[0001] The field of the invention relates to contact lenses and sealed contact lens packages, and particularly, relates to contact lenses having the ability to controllably release one or more releasable beneficial agents. The polymeric lens body of the contact lenses of the present invention incorporate charged hydrophobic molecules that advantageously enhance the ability of the contact lenses to uptake and / or gradually release ionic agents.BACKGROUND

[0002] Efforts have been made to improve contact lens comfort or functionality by introducing a beneficial agent into the lens materials or in the packaging solution so that when the lens is placed on the eye, the beneficial agent is released to the ocular surface. However, it has always been a challenge to achieve sustained release of a beneficial agent during the course of contact lens wear because the beneficial agent may demonstrate a burst release instead of the desired sustained release for the needed period of time, which can be 6 hours or more.

[0003] Thus, there is a need in the industry for new approaches to achieving sustained release of beneficial agents from contact lenses or an improvement in the controlled release of beneficial agents. Further, it would also be desirable to provide such controlled release properties without significantly affecting other properties that are provided by contact lenses.

[0004] One approach to tuning the ability of contact lenses to uptake and release is to include a monomer in the polymerizable formulation from which the polymeric lens body is formed having an opposite charge to the charge of the beneficial agents to be taken up and released by the lens. On polymerisation, the charged monomer becomes covalently bound into the polymerP10257WO (3038-278-01 PCT) matrix of the lens body. The incorporation of such charged monomers into the lens body allows for increased uptake of an oppositely charged beneficial agent and enables its release during the wear to be controlled. However, the addition of charged monomers can cause significant changes in lens properties and stability. Also, only a very limited amount of charged monomer can be added to the lens formulation which in its turn limits the uptake amount of the charged beneficial agents.

[0005] WO 2022 / 129871 Al describes a contact lens that includes at least one acyclic tertiary amine monomer which advantageously facilitates uptake and / or sustained release of the at least one releasable anionic agent, such as a carboxylic acid molecule, by the polymeric lens body.

[0006] As an alternative to modifying lens formulation, the present invention relates to the realisation that the uploading of positively or negatively charged molecules into the polymeric lens body without covalently bonding the charged molecule into the polymer matrix can be used to incorporate charge into the lens in order to facilitate the uptake and controlled release of ionic agents.SUMMARY OF THE INVENTION

[0007] A feature of the present invention is to provide a silicone hydrogel contact lens that can release a beneficial agent during lens wearing and avoid a burst release of the beneficial agent. The beneficial agent is advantageously ionic.

[0008] A further feature of the present invention is to provide a silicone hydrogel contact lens that includes a beneficial agent that is releasable when worn in the eye and has a controlled release for an extended period of time, e.g. 6 hours or more.P10257WO (3038-278-01 PCT)

[0009] An additional feature of the present invention is to provide a silicone hydrogel contact lens that has the ability for a higher uptake and release of a beneficial agent than conventional silicone hydrogel contact lenses.

[0010] An additional feature of the present invention is to provide a silicone hydrogel contact lens that can be loaded or recharged with a beneficial agent by contacting the contact lens with an eye drop or a multi-purpose contact lens care solution that contains the beneficial agent.[Oil] Additional features and advantages of the present invention will be set forth in part in the description that follows, and in part will be apparent from the description, or may be learned by practice of the present invention. The objectives and other advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims.

[0012] The present invention provides a silicone hydrogel contact lens that comprises a polymeric lens body comprising a polymer matrix and a charged hydrophobic molecule present (e.g. embedded) in the polymer matrix. The charged hydrophobic molecule has a hydrophobic group and a charged functional group. The silicone hydrogel contact lens may further comprise a beneficial agent, for example, an ionic beneficial agent. The beneficial agent may be releasably bound to the polymeric lens body through an ionic interaction with the charged hydrophobic molecule.

[0013] In a first aspect, the present invention provides a beneficial agent-releasing silicone hydrogel contact lens that comprises a polymeric lens body comprising a polymer matrix and a charged hydrophobic molecule present in the polymer matrix, and a releasable beneficial agent, wherein the charged hydrophobic molecule includes a hydrophobic group and a charged functional group, wherein the hydrophobic group comprises at least one hydrocarbon chain having at least 8P10257WO (3038-278-01 PCT) carbons, and wherein the releasable beneficial agent has a charge that is opposite to the charge of the charged functional group of the charged hydrophobic molecule. The charged hydrophobic molecule is advantageously embedded in, as opposed to be covalently bound to, the polymer matrix. The charged hydrophobic molecule is advantageously non-covalently bound to the polymer matrix of the polymeric lens body, e.g. via hydrogen bonds or hydrophobic interactions. The releasable beneficial agent is advantageously complexed to the polymeric lens body, for example, by ionic interactions between the charged hydrophobic molecule and the beneficial agent. The beneficial agent is typically an ionic molecule. The charged hydrophobic molecule advantageously facilitates controlled release of the releasable beneficial agent by the polymeric lens body, e.g. during wear.

[0014] The beneficial agent-releasing contact lens comprises a polymeric lens body loaded with an amount of a releasable beneficial agent that advantageously sustains release of the beneficial agent from the lens when in contact with a tear solution. The tear solution can be a human reflex tear or an in vitro release media comprising artificial tear fluid (ATF).

[0015] In a second aspect, the invention provides a packaged silicone hydrogel contact lens immersed in a packaging solution and sealed in a package, wherein the silicone hydrogel contact lens comprises a polymeric lens body having a polymer matrix and a charged hydrophobic molecule present in the polymer matrix, the charged hydrophobic molecule having a hydrophobic group and a charged functional group, wherein the hydrophobic group comprises at least one hydrocarbon chain of at least 8 carbons, and wherein said packaging solution comprises a releasable beneficial agent having a charge that is opposite to the charge of the charged hydrophobic molecule. The charged hydrophobic molecule is advantageously embedded in the polymeric lens body. The charged hydrophobic molecule is advantageously non-covalently boundP10257WO (3038-278-01 PCT) to the polymer matrix of the polymeric lens body. The charged hydrophobic molecule advantageously facilitates uptake of the releasable beneficial agent by the polymeric lens body. Due to the presence of the charged hydrophobic molecule in the polymeric lens body, the silicone hydrogel contact lens of the second aspect of the invention advantageously takes up the releasable beneficial agent. Thus, the packaged silicone hydrogel contact lens that is immersed in a packaging solution and sealed in a package in the second aspect of the invention is advantageously a beneficial agent-releasing silicone hydrogel contact lens of the first aspect of the invention.

[0016] The hydrophobic group of the charged hydrophobic molecule advantageously has a total of no more than 26 carbon atoms present in hydrocarbon chains of least 8 chain carbon atoms. The charged hydrophobic molecule advantageously comprises at least one C10-C26 hydrocarbon chain. Advantageously, the hydrophobic group of the charged hydrophobic molecule contains either a single C12-C26 hydrocarbon chain or two C9-C13 hydrocarbon chains, especially either a single C16-C24 hydrocarbon chain or two C9-C13 hydrocarbon chains.

[0017] The hydrophobic group present in the charged hydrophobic molecule advantageously provides a strong affinity to the lens material through a hydrophobic interaction. The hydrocarbon chain thus acts as an anchor that retains the charged hydrophobic molecule in the lens body during storage and wear. The charged hydrophobic molecule may comprise a hydrophobic group having at least one C8-C26 hydrocarbon chain, for example at least one C10-C24 hydrocarbon chain, especially at least one C12-C20 hydrocarbon chain. The charged hydrophobic molecule optionally comprises more than one hydrocarbon chain, for example 2, 3, or 4 hydrocarbon chains. The hydrophobic group advantageously includes a total of no more than 26 carbon atoms present in C8-C26 hydrocarbon chains, especially no more than 24 carbon atoms in C10-C24 hydrocarbon chains.P10257WO (3038-278-01 PCT)

[0018] In a third aspect, the present invention relates to a method of making the beneficial agent-releasing silicone hydrogel contact lens of the first aspect of the present invention. The method includes the steps of a) polymerizing a polymerizable composition (as described herein) in a contact lens mold to obtain a polymer matrix in the shape of a contact lens, b) removing the polymer matrix from said contact lens mold, c) extracting the polymer matrix in an organic solvent, d) hydrating the polymer matrix in a hydration liquid to obtain the silicone hydrogel contact lens, and optionally e) sealing said hydrated silicone hydrogel contact lens with packaging solution in a package, wherein at least one of the polymerizable composition or the organic solvent contains the charged hydrophobic molecule, and wherein at least one of the organic solvent, the hydration liquid or the optional packaging solution contains the releasable beneficial agent.

[0019] In a fourth aspect, the present invention relates to a method of making the packaged lens of the second aspect of the present invention. The method includes the steps of a) polymerizing a polymerizable composition (as described herein) in a contact lens mold to obtain a polymer matrix in the shape of a contact lens, b) removing the polymer matrix from said contact lens mold, c) extracting the polymer matrix in an organic solvent, d) hydrating the polymer matrix in a hydration liquid to obtain the silicone hydrogel contact lens, e) sealing said hydrated silicone hydrogel contact lens with packaging solution in a package, wherein at least one of the polymerizable composition or the organic solvent contains the charged hydrophobic molecule, and wherein at least one of the organic solvent, the hydration liquid, or the packaging solution contains the releasable beneficial agent.

[0020] In a fifth aspect, the invention provides for the use of a charged hydrophobic molecule to increase the capacity of a silicone hydrogel contact lens to take up a releasableP10257WO (3038-278-01 PCT) beneficial agent and / or the use of a charged hydrophobic molecule to increase the capacity of a silicone hydrogel contact lens to sustain the release of a beneficial agent.

[0021] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide a further explanation of the present invention, as claimed.

[0022] The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate some of the features of the present invention and together with the description, serve to explain the principles of the present invention.DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 shows the release profile of ketotifen from stenfilcon A lenses loaded with the charged hydrophobic molecule 14 PG.

[0024] FIGS. 2A and 2B show the release profile of hyaluronic acid (HA) from stenfilconA lenses loaded with the charged hydrophobic molecule CKC and comparative cationic “IS09” lenses.

[0025] FIGS. 3A and 3B show the release profile of hyaluronic acid (HA) from stenfilconA lenses loaded with charged hydrophobic molecules DDAB and DDMB and comparative cationic “IS09” lenses.

[0026] FIGS. 4A, 4B, 4C, and 4D show the release profile of s-polylysine (ePL) from stenfilcon A lenses loaded with charged hydrophobic molecules 18:0 Lyso PG and 12:0 PG and comparative unmodified stenfilcon A lenses.

[0027] FIGS. 5A and 5B show the release profile of e-polylysine (ePL) from stenfilcon A lenses loaded with different amounts of charged hydrophobic molecule 18:0 Lyso PG.P10257WO (3038-278-01 PCT)DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0028] Contact lenses having polymeric lens bodies comprising embedded charged hydrophobic molecules that provide the lens body with ionic properties and their method of manufacture are described herein. A sealed contact lens package that includes the contact lens is also described herein.

[0029] In the present invention, the contact lens preferably takes up one or more beneficial agents, especially ionic beneficial agents, that can then dissociate from the polymeric lens body during wearing under physiological conditions. The beneficial agent is taken up by the lens in amounts that provide a beneficial effect, such as providing a pharmacological effect and / or a comfort-enhancing effect to the lens wearer, during wear.

[0030] In the present invention, the contact lens preferably provides a controlled release of one or more beneficial agents, especially ionic beneficial agents, that can dissociate from the polymeric lens body during wearing under physiological conditions. The beneficial agent is released from the loaded lens during wear in amounts that provide a beneficial effect, such as providing a pharmacological effect and / or a comfort-enhancing effect to the lens wearer.

[0031] The contact lens is an unworn sterile hydrogel contact lens. In other words, the contact lens is unused and is new. An additional feature of the present invention is to provide a contact lens that can be loaded or recharged with a beneficial agent by contacting the contact lens with an eye drop or a multi-purpose contact lens care solution that contains the beneficial agent.

[0032] The beneficial agent is released from the lens during wear and provides a beneficial effect, such as providing a pharmacological effect and / or a comfort-enhancing effect to the lens wearer. The releasable beneficial agent may be a beneficial fatty acid, an ophthalmic drug, a comfort-enhancing polymer, or an antioxidant.P10257WO (3038-278-01 PCT)

[0033] The beneficial agent is not covalently bound to the polymer matrix of the polymeric lens body and is capable of being released during wear. The presence of a charged hydrophobic molecule in the polymer matrix has been found to facilitate uptake and / or sustained release of the releasable ionic agent by the polymeric lens body. The beneficial agent is advantageously releasable from the contact lens. As used herein, and unless context dictates otherwise, a reference to a lens comprising a releasable beneficial agent, refers to a lens comprising a beneficial agent that is capable of releasing at least 10 pg of the beneficial agent when immersed in 3 mL of an artificial tear fluid (ATF) release media at 35 °C for 3 hours. ATF release media is prepared by adding 60 mg fatty acid-free bovine serum albumin (Akron Biotech, cat.# AK8909), 57 mg Lysozyme (Sigma Aldrich, cat.# L6876), 4.5 mg mucin (Sigma Aldrich, cat.# MJ3895) to a clean class vial then adding 30 ml Dulbecco’s PBS (DPBS) (Sigma Aldrich, cat.# 850725P). The contact lens may release at least 20 pg, for example at least 50 pg, of the beneficial agent when immersed in 3 mL of an artificial tear fluid (ATF) release media at 35 °C for 3 hours. The release may be determined by placing a lens into a 6 mL glass vial containing 3 mL of the in vitro release media (the ATF as described above), shaking the vials at 50 rpm in a 35 °C incubator for 3 hours, removing a 2.5 ml sample of release media from the vial and analysing the sample for beneficial agent content by liquid chromatography-mass spectrometry (LCMS) or other analytical method appropriate for the beneficial agent of interest. 50 pl of the release media from each lens is transferred to HPLC vials and 500 pl isopropanol (IP A) is added and mixed well. Vials are sonicated for 15 minutes and centrifuged. The supernatant is removed for LCMS injection. The supernatants are injected on an LCMS instrument equipped with an ACQUITY UPLC BEH Cl 8 1.7 pg, 2.1 mm x 15 cm column and running a mobile phase gradient from 65% A to 90% B at a flow rate of 0.35 mL / min with A = 40% acetonitrile in water with 10 mM ammonium acetate andP10257WO (3038-278-01 PCT)0.2% (v / v) ammonium hydroxide, and B = 10% acetonitrile in IP A with 10 mM ammonium acetate and 0.2% (v / v) ammonium hydroxide. The peak for the particular beneficial agent of interest in the supernatants is measured.

[0034] The beneficial agent can include one or more different ionic molecules (e.g., one, two, or more). The beneficial agent may provide a beneficial effect following a chemical transformation, for example, the beneficial agent may comprise a pro-drug that decomposes to release a biologically active molecule in vivo or under certain physiological conditions, such as contact with tear film enzymes. The beneficial agent may be adhered to the polymeric lens body by ionic interactions, for example, adhered by ionic interactions with the charged functional group of the charged hydrophobic molecule present in the polymeric lens body that is of the opposite charge to the change of the beneficial agent.

[0035] Examples of releasable beneficial agents that are anionic include, but are not limited to, acids, for example a fatty acid. In a specific example the releasable beneficial agent is an acid that comprises a single carboxylic acid group. In another example, the beneficial agent comprises two or more carboxylic acid groups. In one example, the beneficial agent is a small molecule (i.e. having a molecular weight of less than about 900 Daltons. In some examples beneficial agent, as an option, is not a polymer. Fatty acids can improve contact lens comfort by increasing tear film stability, providing anti-inflammatory effects, and / or inhibiting pain receptors present in ocular tissue such as TRPV1. Examples of fatty acids that may provide a comfort benefit to a contact lens wearer include oleic acid, linoleic acid or a linolenic acid, especially alphalinolenic acid (i.e. (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid, CAS# 463-40-1), ricinoleic acid, or petroselinic acid.P10257WO (3038-278-01 PCT)

[0036] The beneficial agent may be an ophthalmic drug. The contact lenses of the present invention can advantageously be used to provide sustained release of an ophthalmic drug conventionally formulated as ophthalmic solutions or suspensions that are administered as eyedrops several times a day. Non-limiting examples of ophthalmic drugs that can be released from the contact lenses of the present invention may include nonsteroidal anti-inflammatory drugs, such as ketorolac tromethamine, diclofenac and ketoprofen; antibiotics, such as besifloxacin and cyclosporin; antihistamines, such as azelastine, emedastine, ketotifen and olopatadine; muscarinic acetylcholine receptor antagonists, such as atropine and pirenzepine; and antibiotics, such as cyclosporine, ofloxacin and gentamicin.

[0037] Other non-limiting examples of beneficial agents that can be released from the contact lenses of the present invention include y-butyrobetaine and L-carnitine, which can have osmoprotectant and / or antioxidant properties. As an option, the releasable beneficial agent is capable of blocking TRPV 1 receptors and / or is capable of interacting with PPARa receptors, such as on the cornea. In another option, the releasable beneficial agent is a polymer such as a polymer of a disaccharide, for example hyaluronic acid. In another option, the releasable beneficial agent is a peptide, such as a polypeptide, for example polylysine, especially s-polylysine (ePL).

[0038] The present invention provides a silicone hydrogel contact lens that comprises a polymeric lens body comprising a polymer matrix and a charged hydrophobic molecule embedded in the polymer matrix. The charged hydrophobic molecule can be present in the polymeric lens body in amounts of at least 25 pg / lens, for example in an amount of at least 50 pg / lens, or an amount of at least 100 pg / lens, or an amount of at least 250 pg / lens, especially an amount of at least 500 pg / lens.P10257WO (3038-278-01 PCT)

[0039] The hydrophobic group of the charged hydrophobic molecule advantageously provides a strong affinity to the material of the polymer matrix of the lens body through a hydrophobic interaction. The hydrophobic group may act as an anchor that retains the charged hydrophobic molecule in the lens body during storage and wear. The charged hydrophobic molecule may comprise a hydrophobic group having at least one C8-C26 hydrocarbon chain, for example at least one C10-C24 hydrocarbon chain, especially at least one C12-C20 hydrocarbon chain. The hydrocarbon chain may be saturated or unsaturated, straight chain or branched. The hydrocarbon chain may be interrupted by one or two heteroatoms, e.g. oxygen atoms. Preferably, the hydrocarbon chain includes a linear chain of at least 8 carbon atoms uninterrupted by heteroatoms, such as an uninterrupted C10-C24 linear chain. The number of carbon atoms in a hydrocarbon chain includes those present as divalent carbon atoms in methylene (-CH2-) units, monovalent carbon atoms in methyl (-CH3) units and trivalent carbon atoms in present in unsaturated methine units (-CH=CH-). Trivalent carbon atoms in carbonyl groups are not considered to be within the hydrocarbon chain. Thus, for example, a stearoyl group (- C(O)(CH2)i6CH3) has a total of 18 carbon atoms, 17 of which are in a hydrocarbon chain.

[0040] The charged hydrophobic molecule optionally comprises more than one hydrocarbon chain, for example 2, 3, or 4 hydrocarbon chains. Including multiple hydrocarbon chains may increase the affinity of the charged hydrophobic molecule to the lens material. The two or more hydrocarbon chains may be linked to a single head group that includes a charged functional group. The charged hydrophobic molecule may comprise a hydrophobic group including two Cx- C24 hydrocarbon chains, for example, two C10-C20 hydrocarbon chains. Including multiple hydrophobic groups can reduce the amount of charged hydrophobic molecule that can be loaded into the lens. When more than one hydrocarbon chain is present in the hydrophobic molecule, eachP10257WO (3038-278-01 PCT) hydrocarbon chain of at least 8 uninterrupted carbon atoms advantageously includes no more than 13 chain carbon atoms. A hydrophobic group of the charged hydrophobic molecule may, for example, contain two C9-C13 hydrocarbon chains and no further hydrocarbon chains of 8 carbon atoms or more.

[0041] In some examples, the charged hydrophobic molecule advantageously includes a hydrophobic group having a total of no more than 26 carbon atoms present in one or more uninterrupted hydrocarbon chains, each hydrocarbon chain having at least 8 chain carbon atoms, e.g. in C10-C26 hydrocarbon chains, especially no more than 24 carbon atoms present in uninterrupted hydrocarbon chains, each hydrocarbon chain having at least 8 chain carbon atoms, e.g. in C10-C24 hydrocarbon chains. The charged hydrophobic molecule advantageously includes a hydrophobic group with either one or two uninterrupted hydrocarbon chains of at least 8 chain carbon atoms, the one or two hydrocarbon chains having a total of at least 14, especially at least 16, carbon atoms and no more than 26, especially no more than 24, carbon atoms. For example, the charged hydrophobic molecule may have two hydrocarbon chains each having 11 chain carbon atoms (e.g. two lauroyl chains) and thus include a total of 22 carbon atoms in hydrocarbon chains of at least 8 uninterrupted chain carbon atoms. Alternatively, the charged hydrophobic molecule may have a single hydrocarbon chain of 17 chain carbon atoms (e.g. a stearoyl chain) and thus include a total of 17 carbon atoms in hydrocarbon chains of at least 8 uninterrupted chain carbon atoms. Advantageously, the hydrophobic group of the charged hydrophobic molecule contains either a single C12-C26 hydrocarbon chain or two C9-C13 hydrocarbon chains, especially either a single C16-C24 hydrocarbon chain or two C9-C13 hydrocarbon chains.P10257WO (3038-278-01 PCT)

[0042] The charged functional group may include a phosphate group, a tertiary amine group, or a quaternary amine group. The charged hydrophobic molecule may be represented by the formula (I), (II), or (III):(I) (II) (III) wherein R1and R2are each independently H or hydrocarbon chains, with the proviso that at least one of R1and R2is a hydrocarbon chain; X is a charged group, for example, comprising a phosphate and / or phosphate group, a tertiary amine group or a quaternary amine group; and each Ak is independently a C1-4 alkyl group, optionally substituted with one or two hydroxyl groups. One of the Ak groups in compounds of formula (III) may be replaced by a benzyl group.

[0043] When the charged hydrophobic molecule is cationic, the positively charged functional group may be a tertiary amine or a quaternary ammonium group. Examples of suitable positively charged groups X in the compounds of formula (I) and (II) above include a tertiary amine group or a quaternary ammonium group, for example of the formula: -CH2N(Ak)2 or -CH2N(Ak)3+, where Ak is a C1-4 alkyl group, optionally substituted with one or two hydroxyl groups; or a group comprising a tertiary amine group or a quaternary ammonium group, optionally linked to the ethylene glycol residue via a phosphate group, for example, X may be of the formula (IV):P10257WO (3038-278-01 PCT)wherein each Ak is independently a Ci-4 alkyl group, optionally substituted with one or two hydroxyl groups. l,2-dialkoyl-sn-glycero-3-phospho-(l'-rac-glycerol) phospholipids e.g. as sodium salts having two C12-C26 hydrocarbon chains, especially two C14-C20 hydrocarbon chains, each chain having 0 to 4 unsaturated C=C groups have been found to be particularly suitable anionic hydrophobic compounds.

[0044] Examples of cationic hydrophobic compounds found to be suitable include the following compounds: dimethyldioctadecylammonium (18:0 DDA), e.g. as a bromide salt:1 ,2-dipalmitoyl-sn-glycero-3 -ethylphosphocholine (16:0 EPC), e.g. as a chloride salt:l,2-dipalmitoyl-3-trimethylammonium-propane (16:0 TAP), e.g. as a chloride salt:P10257WO (3038-278-01 PCT)l,2-stearoyl-3-trimethylammonium-propane (18:0 TAP), e.g. as a chloride salt:1 ,2-dipalmitoyl-3 -dimethylammonium-propane (16:0 DAP):and,1 ,2-distearoyl-3 -dimethylammonium-propane (18:0 DAP):all available from Avanti Polar Lipids, of Alabaster, Alabama 35007-9105, USA, didodecyldimethylammonium (DDM), e.g. as a bromide salt:ditetradecylbimethylammonium, e.g. as a bromide salt:P10257WO (3038-278-01 PCT)dihexadecyldimethylammonium, e.g. as a bromide salt:all available from Merck KGaA, Darmstadt, Germany, and benzyldimethylhexadecylammonium, e.g. as a chloride salt (cetalkonium chloride or CKC): ci-available from Cambridge Bioscience of Cambridge, United Kingdom.Other suitable cationic hydrophobic compounds may include the following compounds: hexadecyldimethyl(ethylbenzyl)ammonium, e.g. as a chloride salt: ci-(ethylbenzyl)dimethyloctadecylammonium, e.g. as a chloride salt:O,O’-ditetradecanoyl-N-(a-trimethylammonioacetyl)diethanolamine (DC-6-14), e.g. as a chloride salt:P10257WO (3038-278-01 PCT)l,2-di-O-octadecenyl-3 -trimethylammonium propane (DOTMA), e.g. as a chloride salt:l,2-dioleoyl-3-trimethylammonium-propane (DOTAP), e.g. as a methyl sulfate salt:N-(2-hydroxyethyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propan-l-aminium (DORI), e.g. as a bromide salt:all available from Avanti Polar Lipids, of Alabaster, Alabama 35007-9105, USA.

[0045] When the charged hydrophobic molecule is anionic, the negative charged functional group may be a dihydrogen phosphate group, especially a deprotonated dihydrogen phosphate group. Examples of suitable negatively charged groups X in the compounds of formula (I) and (II) above include deprotonated dihydrogen phosphate groups, for example of the formula: -CH2O-P(=O)(-O )-OCH2CH(OH)CH2OH.P10257WO (3038-278-01 PCT)

[0046] Examples of anionic hydrophobic molecules found to be suitable include the following compounds: l,2-distearoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (18:0 PG), e.g. as a sodium salt:l,2-dipalmitoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (16:0 PG), e.g. as a sodium salt:l,2-dipentadecanoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (15:0 PG), e.g. as a sodium salt:l,2-dimyristoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (14:0 PG), e.g. as a sodium salt:l,2-dilauroyl-sn-glycero-3-phospho-(l'-rac-glycerol) (12:0 PG), e.g. as a sodium salt:, andP10257WO (3038-278-01 PCT) l-stearoyl-2-hydroxy-sn-glycero-3-phospho-(l'-rac-glycerol) (18:0 Lyso PG), e.g. as a sodium salt:all available from Avanti Polar Lipids, of Alabaster, Alabama 35007-9105, USA.

[0047] Other suitable anionic hydrophobic molecules may include unsaturated compounds such as: l,2-dioleoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (18: 1 (A9-Cis) PG or DOPG), e.g. as a sodium salt:l,2-dilinoleoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (18:2 PG), e.g. as a sodium salt:l,2-didocosahexaenoyl-sn-glycero-3-[phospho-rac-(l-glycerol)] (22:6 PG or DHAPG), e.g. as a sodium salt:, and l-oleoyl-2-hydroxy-sn-glycero-3-phospho-(l'-rac-glycerol) (18: 1 Lyso PG), e.g. as a sodium salt:P10257WO (3038-278-01 PCT)all available from Avanti Polar Lipids, of Alabaster, Alabama 35007-9105, USA.

[0048] Preferably, the charged hydrophobic molecule (whether anionic or cationic) includes a fully saturated hydrocarbon chain or chains.

[0049] Advantageously, the charged hydrophobic molecule present in the polymeric lens body is not removed when the lens is immersed in deionized water or a standard contact lens packaging solution, such as phosphate buffered saline or phosphate buffered saline containing 75 ppm polyvinylpyrrolidone (PVP). Advantageously, no more than 20% by weight (based on total weight of charged hydrophobic molecule present in lens), especially no more than 10 % by weight, of the charged hydrophobic molecule is extracted from the polymeric lens body into deionized water on immersing the lens in 5 mL deionized water. In one example, a charged hydrophobic molecule is loaded to the polymeric lens body in a loading solution comprising an organic solvent, typically an alcohol, such as ethanol and a charged hydrophobic molecule ranging from 1 to 25 mg / mL, especially from 2 to 20 mg / mL. The loading solution may, for example, comprise approximately 100% ethanol or include a mixture of ethanol and water containing at least 50% ethanol, for example, comprise approximately 60% ethanol (by volume) and approximately 40% water (by volume). In one specific example, the loading solution comprises at least 2 mg / mL charged hydrophobic molecule. The lens may be immersed in the loading solution at 25 °C for 3 hours in order to load the charged hydrophobic molecule to the polymeric lens body.

[0050] For the avoidance of doubt, the charged hydrophobic molecule and the beneficial agent are distinct chemical compounds of different molecular formulae. The beneficial agent may interact with other compounds present in the contact lens body, for example ionic interactions withP10257WO (3038-278-01 PCT) the charged hydrophobic molecule, but is not covalently bound to the polymer matrix or the charged hydrophobic molecule. In the beneficial agent-releasing contact lenses of the first aspect of the invention, the beneficial agent is present in the contact lens body as a distinct compound. The contact lens of the first aspect of the invention comprises two different chemical compounds, one chemical compound which meets the criteria expressed herein for a charged hydrophobic molecule and another distinct chemical compound that is a beneficial agent. Thus, a lens that includes only a single chemical compound which is both a beneficial agent and a charged hydrophobic agent, such as a phospholipid, that can act as a comfort agent, is outside the scope of the present claims. The charged hydrophobic molecule and the beneficial agent are loaded into the polymeric lens body separately as distinct compounds.

[0051] The beneficial agent-releasing silicone hydrogel contact lens and the packaged silicone hydrogel contact lens of the present invention both comprise essentially no compounds in which the beneficial agent is covalently bound to the charged hydrophobic molecule. The molar ratio of free beneficial agent present in the contact lens body to compounds present in the contact lens body in which the beneficial agent (or a precursor to the beneficial agent) is covalently bound to the charged hydrophobic molecule, is advantageously at least 10000:1, especially at least 100000: 1. The charged hydrophobic molecule and the beneficial agent are not decomposition products of a single compound present in the lens body, e.g. a compound in which the charged hydrophobic molecule and the beneficial agent are covalently bound to each other. For example, the charged hydrophobic molecule is not a lysophospholipid derived from the decomposition of a phospholipid that is present in the polymeric lens body or in the packaging solution and the beneficial agent is not a fatty acid derived from the decomposition of the same phospholipid. The beneficial agent is not a decomposition product of a charged hydrophobic molecule present in theP10257WO (3038-278-01 PCT) lens body. Thus, the beneficial agent-releasing silicone hydrogel contact lens of the first aspect of the invention does not merely comprise a charged hydrophobic molecule and a beneficial agent that is a decomposition product of the charged hydrophobic molecule. Likewise, the packaged silicone hydrogel contact lens of the second aspect of the invention does not merely comprise a charged hydrophobic molecule in the lens body and a beneficial agent in the packaging solution that is a decomposition product of the charged hydrophobic molecule. For example, when the charged hydrophobic molecule present in the polymeric lens body is a phospholipid, the beneficial agent is not a fatty acid derived from the decomposition of that phospholipid.

[0052] When the releasable beneficial agent is complexed through ionic interaction with the polymeric lens body (for instance, due to low pH conditions and / or low ionic strength conditions), such as below about 7 pH or below about 6 pH), at that state, the releasable beneficial agent itself is an ionic agent or material that is complexed through ionic interaction with the charged hydrophobic molecules that form part of the polymeric lens body. As an example, the releasable beneficial agent itself is an anionic agent that, once deprotonated, can form a complex with the charged hydrophobic molecule that is present in the polymeric lens body, such as protonated tertiary amine groups present in the charged hydrophobic molecule. A releasable beneficial agent that is complexed through ionic interactions with the charged hydrophobic molecule of the polymeric lens body may be released from the polymeric lens body, by dissociating under physiological conditions through ionic interaction with the counterions in eye tear. The released beneficial agent at that point, may for example, become a salt or ester (e.g., a salt of at least one acid, such as oleic acid or an oleate).

[0053] The beneficial agent-releasing silicone hydrogel contact lens and / or the packaged silicone hydrogel contact lens of the invention advantageously comprises the releasable beneficialP10257WO (3038-278-01 PCT) agent in an amount of at least 25 pg, such as from about 25 pg to 1000 pg, at least 50 pg, such as from 50 pg to 750 pg, or at least 175 pg, such as from 175 pg to 700 pg. As used herein, the phrase “amount of releasable beneficial agent present in the silicone hydrogel contact lens” refers to the total amount of a releasable beneficial agent that can be extracted from the contact lens by an appropriate extraction method, such as the ethanol extraction method described in Example 1 below or the isopropanol (IP A) extraction method described in Example 1 of WO 2022 / 129871, the contents of which are incorporated herein by reference.

[0054] As an option, the releasable beneficial agent can be uniformly distributed throughout the polymeric lens body by way of the ionic interaction described herein. As an option, the releasable beneficial agent can be non-uniformly distributed. The releasable beneficial agent can, for example, be present in a higher amount at the surfaces of the contact lens as compared to the interior portions of the contact lens. For instance, the releasable beneficial agent can be present in a higher amount on a side of the contact lens or on both sides of the contact lens (i.e., the posterior and anterior sides) as compared to the interior portions of the contact lens (the area located between the posterior and anterior sides).

[0055] The beneficial agent-releasing silicone hydrogel contact lens of the first aspect of the invention comprises a releasable beneficial agent. The releasable beneficial agent present within the silicone hydrogel contact lens is not covalently attached to the polymeric lens body, i.e. is not covalently attached to either the polymer matrix or to the charged hydrophobic molecule. The beneficial agent is advantageously complexed to the polymeric lens body. Advantageously, the beneficial agent is complexed to the polymeric lens body via an ionic interaction. In addition to the ionic interaction described herein between the charged hydrophobic molecule present in the polymeric lens body and the beneficial agent, the beneficial agent, as an option, can be consideredP10257WO (3038-278-01 PCT) as embedded, trapped, dispersed, absorbed, and / or located within the contact lens. The beneficial agent is preferably present within and / or on the surface of the contact lens.

[0056] The uptake or loading of the releasable beneficial agent by the silicone hydrogel contact lens can occur during a hydration step and / or during the packaging step. For instance, the uptake of the releasable ionic agent can occur during one or more hydration steps, where the at least one releasable ionic agent is present in the hydration solution.

[0057] The packaged lens of the second aspect of the invention comprises a polymeric lens body comprising a polymer matrix and a charged hydrophobic molecule embedded in the polymer matrix immersed in a packaging solution comprising the releasable beneficial agent. The packaging solution is preferably a typical packaging solution for a contact lens that additionally comprises the beneficial agent. The packaging solution may lack comfort agents other than comfort agents which are charged molecules having the opposite charge to that of the charged hydrophobic molecule that is present in the polymeric lens body. As an option, the packaging solution does not contain any comfort agents. The packaging solution may contain phosphate buffered saline (PBS). The packaging solution may comprise the beneficial agent in a concentration of at least 10 ppm, such as a concentration of at least 100 ppm or 150 ppm, especially a concentration of at least 200 ppm.

[0058] A method of making the beneficial agent-releasing silicone hydrogel contact lens of the present invention typically involves the step of immersing a lens loaded with the charged hydrophobic molecule in an aqueous solution comprising the releasable beneficial agent in a concentration of at least 10 ppm or at least 100 ppm, such as a concentration of at least 150 ppm, especially a concentration of at least 200 ppm.P10257WO (3038-278-01 PCT)

[0059] As used herein, and unless context dictates otherwise, a reference to an amount of beneficial agent released from the beneficial agent-releasing contact lens over a specified duration of time or to a “release profile” of the beneficial agent, refers to the amount of beneficial agent released from the lens as measured using artificial tear fluid (ATF) as an in vitro release media at 35 °C. ATF release media is prepared by adding 60 mg fatty acid-free bovine serum albumin (Akron Biotech, cat.# AK8909), 57 mg Lysozyme (Sigma Aldrich, cat.# L6876), 4.5 mg mucin (Sigma Aldrich, cat.# MJ3895) to a clean class vial then adding 30 ml Dulbecco’s PBS (DPBS) (Sigma Aldrich, cat.# 850725P). The contact lens may have an in vitro beneficial agent release profile of at least 0.05 pg / hr, especially at least 0.1 pg / hr or at least 0.5 pg / hr, such as at least 1 pg / hr beneficial agent from the lens following initial immersion into the release media at 35 °C. For example, the contact lens may have an in vitro release profile of from 0.1 pg / hr to 100 pg / hr of beneficial agent from the lens, such as from 1 pg / hr to 50 pg / hr of beneficial agent from the lens, following initial immersion into the release media at 35 °C. Advantageously, the contact lens sustains the release of the beneficial agent for at least 3 hours, such as for at least 6 hours, optionally for at least 8 hours. Advantageously, the contact lens releases from 0.1 pg / hr to 100 pg / hr of beneficial agent from the lens, such as 0.5 pg / hr to 50 pg / hr, or from 1 pg / hr to 25 pg / hr of beneficial agent for at least the first 3 hours, such as for at least the first 6 hours, optionally for at least the first 8 hours following immersion in the release media at 35 °C. Thus, the contact lens of the invention may have an in vitro beneficial agent release profile of at least 0.5 pg / hr, preferably at least 1 pg / hr, such as 0.5 pg / hr to 100 pg / hr, for example 0.5 pg / hr to 50 pg / hr, or 1 pg / hr to 25 pg / hr beneficial agent from the lens for at least the first 3 hours, such as for at least the first 6 hours, optionally for at least the first 8 hours. The release profile may be determined by placing a lens into a 6 mL glass vial containing 3 mL of the in vitro release media (the ATF as describedP10257WO (3038-278-01 PCT) above), shaking the vials at 50 rpm in a 35 °C incubator, and at increments spanning at least 6 hours removing a 2.5 ml sample of release media from the vial at each increment (e.g. at 1 hr, 3 hr, 6 hr and 24 hr) and analysing the sample for beneficial agent content by liquid chromatographymass spectrometry (LCMS) or other analytical method appropriate for the beneficial agent of interest and replacing 2.5 ml of fresh release media into vial, and continuing to incubate the lens in the vial in the until the next increment. In some examples, the contact lens of the present invention can have a release profile of the beneficial agent of from 0.5 pg to 100 pg, for example from 1 pg to 50 pg, such as from 2 pg to 30 pg, of beneficial agent per hour for a period of at least 3 hours or at least 6 hours.

[0060] The charged hydrophobic molecule present in the polymer matrix has been found to facilitate uptake and / or sustained release of the releasable beneficial agent by the polymeric lens body. Thus, in accordance with the fifth aspect, the invention provides for the use of a charged hydrophobic molecule to increase the capacity of a silicone hydrogel contact lens to take up a releasable beneficial agent and / or the use of a charged hydrophobic molecule to increase the capacity of a silicone hydrogel contact lens to sustain the release of a beneficial agent.

[0061] With respect to the charged hydrophobic molecule present in the polymer matrix facilitating uptake and / or sustained release of the at least one releasable beneficial agent by the polymeric lens body, this means if one compares a ‘control lens’, that is a silicone hydrogel contact lens comprising a polymeric lens body with no charged hydrophobic molecule present but otherwise comprising a polymer matrix formed of the same polymerizable composition, with lens of the invention having a polymeric lens body comprising a polymer matrix and a charged hydrophobic molecule present in the polymer matrix, the amount of beneficial agent taken up by and / or released from the lens of the invention is greater than the amount of beneficial agent taken up by and / orP10257WO (3038-278-01 PCT) released from the control lens. The silicone hydrogel contact lens of the invention advantageously comprises at least 10%, preferably at least 25% more beneficial agent than the control lens (wherein the “%” is by total weight of beneficial agent present in each lens and then compared to each other).

[0062] A lens that facilitates uptake of a releasable beneficial agent takes up a higher amount than the control lens when using the same concentration of releasable beneficial agent in a loading solution. A lens that facilitates uptake of a releasable beneficial agent preferably takes up at least 10%, preferably at least 25% more beneficial agent than the control lens when using the same concentration of releasable beneficial agent in a loading solution (wherein the “%” is by total weight of beneficial agent present in each lens and then compared to each other). Whether a lens facilitates uptake of a beneficial agent can be determined by immersing, e.g. at 25 °C, a lens having charged hydrophobic molecule in the polymeric lens body and a control lens in identical aqueous packaging solutions containing the beneficial agent, e.g. at a concentration of 200 ppm, and measuring the concentration of the beneficial agent in the packaging solutions after 2 hours, e.g. using HPLC. If a lens facilitates uptake of the beneficial agent, the concentration of beneficial agent that remains in the packaging solution into which the lens was immersed will be lower, for example at least 5% lower, especially at least 10% lower, than the concentration of beneficial agent that remains in the packaging solution into which the control lens was immersed (wherein the “%” is by total weight of beneficial agent present in each packaging solution and then compared to each other). The same test can be used to determine if a lens is capable of complexing a beneficial agent, i.e. if more of the beneficial agent is taken up from the packaging solution by a lens having a polymeric lens body comprising a charged hydrophobic molecule than by a control lens it can be concluded that the lens comprising a charged hydrophobic molecule is capable of complexing the beneficial agent.P10257WO (3038-278-01 PCT)

[0063] Similarly, with the facilitating of a sustained release, a lens that sustains release of the releasable beneficial agent, such as the polymeric lens body containing the charged hydrophobic molecule of the present invention, has a longer release period. The lens that sustains release of the releasable beneficial agent may sustain release of at least 0.5 pg / hr, especially at least 1 pg / hr, for at least 25% longer, for example at least 50% longer than the control lens. The lens that sustains release of the releasable beneficial agent may sustain release of at least 0.5 pg / hr, especially at least 1 pg / hr, for 2 hours, such as 4 hours or 6 hours, longer than the control lens, and / or would have a more linear release profile over a period of 4 hours or 6 hours compared to the control lens. As used herein, the term “release profile” refers to the shape of the line when the amount of beneficial agent released from the lens using the release media and release assay method described in Example 2 below is plotted at the 1 hr, 3 hr, 6 hr, and 24 hr time points, such as shown in FIGS. 1, 2 A, and 3 A.

[0064] With the present invention, preferably a burst release of the ionic agent is avoided.An example of a burst release (or burst effect) is where 50 wt.% or more of the ionic agent that is releasable from the contact lens is released in a period of 3 hours or less. Thus, with the present invention, the contact lens of the present invention is capable of providing at least one or more of the following properties: a) a substantially linear release profile of an ionic agent (e.g., as exemplified in one or more the Figures), b) the ability to upload large amounts of an ionic agent (at least 20 pg, or at least 50 pg, or at least 100 pg to the lens), c) a release of an ionic agent over long periods of time (at least 3 hours, such as from 3 hours to 6 hours, or 3 hours to 24 hours), and / or d) avoid any burst release.

[0065] The lens comprises at least 10% more (by weight) of the beneficial agent than a control lens that is a silicone hydrogel contact lens comprising a polymeric lens body with no charged hydrophobic molecule present but otherwise comprising a polymer matrix formed of the sameP10257WO (3038-278-01 PCT) polymerizable composition. In one example, the beneficial agent-releasing silicone hydrogel contact lens of the invention contains at least 25 wt.% more (e.g., by weight) of the releasable beneficial agent than a control lens, such as at least 50 wt.% more, or at least 75 wt.% more. A silicone hydrogel contact lens of the invention loaded with an anionic hydrophobic molecule may contain at least 25 wt.% more (e.g., by weight) of a cationic releasable beneficial agent, such as s- poly lysine, than a control lens, such as at least 50 wt.% more, or at least 75 wt.% more. A silicone hydrogel contact lens of the invention loaded with a cationic hydrophobic molecule may contain at least 25 wt.% more (e.g., by weight) of an anionic releasable beneficial agent, such as sodium cromolyn, than a control lens, such as at least 50 wt.% more, or at least 75 wt.% more. The beneficial agent-releasing silicone hydrogel contact lens of the invention and the control lenses may be prepared by sealing the lenses in a blister package in a 1.3 mL solution of phosphate buffered saline comprising 200 ppm of the beneficial agent for two hours, then autoclaving and storing for 3 days.

[0066] As described further below, an unworn contact lens after an extraction and hydration step is generally placed in a base member that contains a packaging solution and then the base member with contact lens and packaging solution is sealed and subjected to a sterilization process (e.g., autoclaving). As an option, the packaging solution can contain an amount of the releasable beneficial agent so that this agent is uploaded to the contact lens upon packaging. Preferably, the sterilization step does not affect the uploading nor the stability of the beneficial agent in the contact lens or in the packaging solution.

[0067] As an option, eye drops and / or a multi-purpose contact lens care solution (MPS) can contain the releasable beneficial agent. This option is particularly effective to recharge the contact lens with further releasable beneficial agent. Thus, a further aspect of the present inventionP10257WO (3038-278-01 PCT) is the ability to recharge the contact lens with an uploading solution that contains the releasable beneficial agent.

[0068] Any liquid used as an uploading solution for the releasable ionic agent can contain a concentration of releasable beneficial agent of at least 50 ppm beneficial agent. This concentration can be at least 100 ppm of beneficial agent. For instance, the concentration can be from 50 ppm to 2000 ppm or more of beneficial agent in an uploading solution (or a solution used for uploading of the beneficial agent to the contact lens).

[0069] In some examples, the releasable beneficial agent, once adhered to the polymeric lens body is stable and does not substantially release from the polymeric lens body or degrade during autoclaving of the sealed contact lens package that contains the unworn silicone hydrogel contact lens in a packaging solution, or during storage in its packaging solution, but does release during lens wear. Thus, the packaging solution that the contact lens is immersed in, before autoclaving, or immediately after autoclaving, or after 1 day thereafter, or after 30 days thereafter, has less than 10 ppm releasable beneficial agent released into the packaging solution from the contact lens or less than 5 ppm released from the contact lens into the packaging solution. Whether the releasable beneficial agent is released from a contact lens during autoclave or storage can be determined by testing for the presence of the releasable beneficial agent in the packaging solution using HPLC, LCMS or other suitable analytical method.

[0070] With the present invention, one of the features that can be achieved, is to improve the comfort level of a soft contact lens, which includes reducing corneal sensitivity by releasing agents that block TRPV1 receptors or interact with PPARa receptors on the cornea.

[0071] Furthermore, the present invention relates to a method of making the sealed contact lens package of the present invention or the unworn sterile silicone hydrogel contact lens thatP10257WO (3038-278-01 PCT) includes a polymeric lens body. The method includes the steps of a) polymerizing a polymerizable composition (as described herein) in a contact lens mold to obtain a hydrogel contact lens, b) removing the hydrogel contact lens from the contact lens mold, c) extracting and hydrating the removed hydrogel contact lens one or more times, wherein at least one of the extraction solvents include the charged hydrophobic molecule, d) sealing said hydrated silicone hydrogel contact lens with packaging solution in a package, wherein the hydrating solution contains the releasable beneficial agent, and e) autoclaving said package.

[0072] A silicone hydrogel material that is molded into the shape of a contact lens can be typically formed by curing a polymerizable composition (i.e. a monomer mixture) comprising the at least one siloxane monomer, the at least one hydrophilic monomer, and optionally at least one hydrophobic monomer.

[0073] Conventional methods can be used to manufacture the contact lens of the invention.As an example, a polymerizable silicone hydrogel composition is dispensed into a female mold member having a concave surface that defines the front surface of the contact lens. A male mold member having a convex surface that defines the back surface of the contact lens, i.e. the corneacontacting surface, is combined with the female mold member to form a contact lens mold assembly that is subjected to curing conditions, such as UV or thermal curing conditions, under which the curable composition is formed into a polymeric lens body. The female and male mold members can be non-polar molds or polar molds. The mold assembly is disassembled (i.e. demolded) and the polymeric lens body is removed from the mold and contacted with a solvent, for instance, an organic solvent, such as ethanol, to extract unreacted components from the lens body. The charged hydrophobic molecule may be loaded to the lens by including the charged hydrophobic molecule in the extraction solvent. After extraction, the lens body is hydrated in aP10257WO (3038-278-01 PCT) hydration liquid such as water or an aqueous solution. As indicated, the releasable beneficial agent may be included in a hydration liquid used for the hydration step.

[0074] If a charged hydrophobic molecule is included in the extraction solvent, the hydration step will displace the solvent with the hydration liquid, thereby hydrating the polymeric lens body to form a silicone hydrogel lens, and the charged hydrophobic molecule (or portion thereof) can remain, e.g. through hydrophobic interaction with the polymer matrix, within the resulting silicone hydrogel lens body Exemplary methods of manufacturing silicone hydrogel contact lenses are described in U.S. Pat. No. 8,865,789.

[0075] The silicone hydrogel contact lens is a reaction product of a polymerizable composition. The polymerizable composition typically includes no, or low levels, of ionic monomers. For example, the polymerizable composition may include no more than 1 wt.% ionic monomers, such as no more than 0.8 wt.% ionic monomers, especially no more than 0.5 wt.% ionic monomers. The ionic properties are advantageously imparted to the polymeric lens body of the contact lens of the present invention by the presence of a charged hydrophobic molecule that is embedded within the polymer matrix, but which is separate to the material of the polymer matrix, i.e. is not covalently bound into the polymer matrix.

[0076] As an example, the silicone hydrogel contact lens is a reaction product of a polymerizable composition that includes at least one siloxane monomer and at least one non-ionic hydrophilic monomer.

[0077] As an example, the silicone hydrogel contact lens is a reaction product of a polymerizable composition that includes at least one siloxane monomer, at least one non-ionic hydrophilic monomer, and optionally at least one hydrophobic monomer.P10257WO (3038-278-01 PCT)

[0078] In general, a “monomer” can include or refer to a molecule comprising a polymerizable carbon-carbon double bond (i.e. a polymerizable group) capable of reacting with other polymerizable group-containing molecules that are the same or different, to form a polymer or copolymer. The term monomer encompasses polymerizable pre-polymers and macromers, there being no size constraint of the monomer unless indicated otherwise. The monomer may comprise a single polymerizable carbon-carbon double bond, or more than one polymerizable group, and thus have cross-linking functionality. The term “ionic monomers” encompasses cationic, anionic and zwitterionic monomers.

[0079] Referring to the reaction product of the polymerizable composition, at least one siloxane monomer can be one siloxane monomer or two or three or more siloxane monomers.

[0080] As used herein, the term “siloxane monomer” is a molecule that contains at least one Si-0 group and at least one polymerizable group. “Siloxane macromers” refers to a silicon- containing molecule with at least one polymerizable functional group which, although used as monomers, possess sufficiently high molecular weight and enough internal monomer units to be considered polymeric. Typically, siloxane macromers contain a siloxane chain with at least 5 siloxane (-Si-O-) units and / or have a molecular weight of at least 500 daltons. Siloxane monomers used in contact lens compositions are well-known in the art (see, e.g., US Pat No. 8,658,747 and US Pat No. 6,867,245). (All patents and publications mentioned here and throughout are incorporated in their entirety by reference.)

[0081] In some examples, the polymerizable composition comprises a total amount of siloxane monomer of at least 10 wt.%, 15 wt.%, 20 wt.%, 25 wt.% or 30 wt.% upto about 40 wt.%, 45 wt.%, 50 wt.%, 55 wt.%, 60 wt.%, or 65 wt.%. For instance, the at least one siloxane monomerP10257WO (3038-278-01 PCT) can be present in an amount of from 15 wt.% to about 65 wt.%, based on the weight of the polymerizable composition.

[0082] In general, unless specified otherwise, as used herein, a given weight percentage(wt.%) of a component of the polymerizable composition is relative to the total weight of all polymerizable ingredients (and any optional polymers or other components that may be present) in the polymerizable composition. The weight of the polymerizable composition contributed by components, such as diluents, that do not incorporate into the final contact lens product are not included in the wt.% calculation.

[0083] Exemplary siloxane monomers are those used in the following FDA-approved silicone hydrogel materials: asmofilcon A, balafilcon A, comfilcon A, delefilcon A, enfilcon A, fanfilcon A, galyfilcon A, kalifilcon A, lotrafilcon A, lotrafilcon B, narafilcon A, narafilcon B, olifilcon A, riofilcon A, samfilcon A, senofilcon A, senofilcon B, senofilcon C, somofilcon A, and stenfilcon A.

[0084] The non-ionic hydrophilic monomer can be present in the reaction product of the polymerizable composition in amounts of at least 10 wt.%, 15 wt.%, 20 wt.%, 25 wt.% or 30 wt.% up to about 40 wt.%, 45 wt.%, 50 wt.%, 55 wt.%, 60 wt.%, 65 wt.%, 70 wt.%, or 75 wt.% based on the weight of the polymerizable composition. For instance, the at least one non-ionic hydrophilic monomer can be present in an amount of from 25 wt.% to about 70 wt.%, based on the weight of the polymerizable composition.

[0085] With respect to the non-ionic hydrophilic monomer, as used herein, the at least one non-ionic hydrophilic monomer can be understood to comprise a single hydrophilic monomer, or to comprise a hydrophilic monomer component composed of two or more hydrophilic monomers, such as two, three, or four or more.P10257WO (3038-278-01 PCT)

[0086] The hydrophilicity or hydrophobicity of a monomer or compound can be determined using conventional techniques, such as, for example, based on the monomer’s or compound’s aqueous solubility. For purposes of the present disclosure, a hydrophilic monomer is a monomer that is visibly soluble in an aqueous solution at room temperature (e.g. about 20-25 degrees C). For example, a hydrophilic monomer can be understood to be any monomer for which 50 grams of the monomer are visibly fully soluble in 1 litre of water at 20° C (i.e., > 5% soluble in water) as determined using a standard shake flask method as known to persons of ordinary skill in the art. A hydrophobic monomer or hydrophobic compound, as used herein, is a monomer or compound that is visibly insoluble in an aqueous solution at room temperature, such that separate, visually identifiable phases are present in the aqueous solution, or such that the aqueous solution appears cloudy and separates into two distinct phases over time after sitting at room temperature. For example, a hydrophobic monomer or hydrophobic compound can be understood to be any monomer or compound for which 50 grams of the monomer are not visibly fully soluble in 1 litre of water at 20° C. The charged hydrophobic molecule loaded to the lens body in the lenses of the invention is such a hydrophobic compound.

[0087] Non-silicon non-ionic hydrophilic monomers which can be used as the hydrophilic monomer or the hydrophilic monomer component in the polymerizable compositions disclosed herein include, for example, acrylamide-containing monomers, or acrylate-containing monomers, or acrylic acid-containing monomers, or methacrylate-containing monomers, or methacrylic acidcontaining monomers, or vinyl-containing monomer or any combination thereof. It is understood that the hydrophilic monomer or hydrophilic monomer component is a non-silicon monomer.

[0088] Examples of the non-ionic hydrophilic monomer include, but are not limited to,N,N-dimethylacrylamide (DMA), or 2-hydroxyethyl acrylate, or 2-hydroxyethyl methacrylateP10257WO (3038-278-01 PCT)(HEMA), or ethoxyethyl methacrylamide (EOEMA), or 2-hydroxypropyl methacrylate, or 2- hydroxybutyl methacrylate (HOB), or 2-hydroxybutyl acrylate, or 4-hydroxybutyl acrylate glycerol methacrylate, or 2-hydroxyethyl methacrylamide, or polyethyleneglycol monomethacrylate, or methacrylic acid, or acrylic acid, ethylene glycol methyl ether methacrylate (EGMA), or any combinations thereof.

[0089] The non-ionic hydrophilic monomer can be at least one hydrophilic vinyl monomer.As used-herein, a “hydrophilic vinyl monomer” is any siloxane-free (i.e. contains no Si-0 groups) hydrophilic monomer having a polymerizable carbon-carbon double bond (i.e., a vinyl group) present in its molecular structure that is not part of an acryl group, where the carbon-carbon double bond of the vinyl group is less reactive than the carbon-carbon double bond present in a polymerizable methacrylate group under free radical polymerization. As used herein, the term “acryl group” refers to the polymerizable group present in acrylate, methacrylates, acrylamides, etc. Thus, while carbon-carbon double bonds are present in acrylate and methacrylate groups, as used herein, such polymerizable groups are not considered to be vinyl groups.

[0090] Examples of hydrophilic vinyl-containing monomers which can be provided in the polymerizable compositions include, without limitation, N-vinyl formamide, or N-vinyl acetamide, or N-vinyl-N-ethyl acetamide, or N-vinyl isopropylamide, or N-vinyl-N-methyl acetamide (VMA), or N-vinyl pyrrolidone (NVP), or N-vinyl caprolactam, or N-vinyl-N-ethyl formamide, or N-vinyl formamide, or N-2 -hydroxyethyl vinyl carbamate, or N-carboxy-P-alanine N-vinyl ester, 1,4-butanediol vinyl ether (BVE), or ethylene glycol vinyl ether (EGVE), or diethylene glycol vinyl ether (DEGVE), or any combination thereof. In one example, the hydrophilic monomer or hydrophilic monomer component comprises VMA, NVP, or both VMA and NVP.P10257WO (3038-278-01 PCT)

[0091] In one example, the polymerizable composition comprises at least 10 wt.%, 15 wt.%, 20 wt.%, or 25 wt.% up to about 45 wt.%, 50 wt.%, 55 wt.%, 60 wt.%, 65 wt.%, or 75 wt.% of a hydrophilic vinyl monomer. As used herein, a given weight percentage of a particular class of component (e.g., hydrophilic vinyl monomer, siloxane monomer, or the like) in the polymerizable composition equals the sum of the wt.% of each ingredient in the composition that falls within the class. Thus, for example, a polymerizable composition that comprises 5 wt.% BVE and 25 wt.% NVP and no other hydrophilic vinyl monomer, is said to comprise 30 wt.% hydrophilic vinyl monomer.

[0092] In one example, the hydrophilic vinyl monomer is an N-vinyl amide monomer.Exemplary hydrophilic N-vinyl amide monomers are VMA and NVP. In a specific example, the polymerizable composition comprises at least 25 wt.% (e.g., from 25 wt.% to 55 wt.%) of at least one vinyl amide monomer. In a further specific example, the polymerizable composition comprises from about 25 wt.% up to about 75 wt.% (e.g., from 25 wt.% to 55 wt.%) of VMA or NVP, or a combination thereof.

[0093] As an option, one or more hydrophobic monomers can be present as part of the polymerizable composition. Examples of suitable hydrophobic monomers include, but are not limited to, one or more non-silicon containing hydrophobic monomers. Examples of suitable hydrophobic monomers include methyl acrylate, or ethyl acrylate, or propyl acrylate, or isopropyl acrylate, or cyclohexyl acrylate, or 2-ethylhexyl acrylate, or methyl methacrylate (MMA), or ethyl methacrylate, or propylmethacrylate, or butyl acrylate, or 2-hydroxybutyl methacrylate, or vinyl acetate, or vinyl propionate, or vinyl butyrate, or vinyl valerate, styrene, or chloroprene, or vinyl chloride, or vinylidene chloride, or acrylonitrile, or 1 -butene, or butadiene, or methacrylonitrile, or vinyltoluene, or vinyl ethyl ether, or perfluorohexylethylthiocarbonylaminoethyl methacrylate,P10257WO (3038-278-01 PCT) or isobornyl methacrylate (IBM), or trifluoroethyl methacrylate, or hexafluoroisopropyl methacrylate, or tetrafluoropropyl methacrylate, or hexafluorobutyl methacrylate, or any combinations thereof.

[0094] The hydrophobic monomer, if used, can be present in the reaction product of the polymerizable composition in amounts of from 1 wt.% to about 30 wt.%, such as from 1 wt.% to 25 wt.%, from 1 wt.% to 20 wt.%, from 1 wt.% to 15 wt.%, from 2 wt.% to 20 wt.%, from 3 wt.% to 20 wt.%, from 5 wt.% to 20 wt.%, from 5 wt.% to 15 wt.%, from 1 wt.% to 10 wt.%, based on the total weight of the polymerizable composition.

[0095] In addition, or as an alternative to, a hydrophilic monomer, the polymerizable composition may comprise a non-polymerizable hydrophilic polymer, which results in a polymeric lens body comprising an interpenetrating polymer network (IPN) with the non-polymerizable hydrophilic polymer interpenetrating the silicone hydrogel polymer matrix. In this example, the non-polymerizable hydrophilic polymer is referred to as an IPN polymer, which acts as an internal wetting agent in the contact lens. In contrast, polymer chains within the silicone hydrogel network that form by polymerization of monomers present in the polymerizable composition are not considered to be IPN polymers. The IPN polymer may be a high molecular weight hydrophilic polymer, for example from about 50,000 to about 500,000 Daltons, e.g., weight-average molecular weight. In a specific example, the IPN polymer is polyvinylpyrrolidone (PVP). In other examples, the polymerizable composition is substantially free of polyvinyl pyrrolidone or other IPN polymer.

[0096] The polymerizable composition may additionally comprise at least one crosslinking agent. As used herein, a “cross-linking agent” is a molecule having at least two polymerizable groups. Thus, a cross-linking agent can react with functional groups on two or more polymer chains so as to bridge one polymer to another. A variety of cross-linking agents suitableP10257WO (3038-278-01 PCT) for use in silicone hydrogel polymerizable compositions are known in the field (see, e.g., U.S. Pat. No. 8,231,218, incorporated herein by reference). Examples of suitable cross-linking agents include, without limitation, lower alkylene glycol di(meth)acrylates such as triethylene glycol dimethacrylate and diethylene glycol dimethacrylate; poly(lower alkylene) glycol di(meth)acrylates; lower alkylene di(meth)acrylates; allyl methacrylate, divinyl ethers such as triethylene glycol divinyl ether, di ethylene glycol divinyl ether, 1 ,4-butanediol divinyl ether and 1 ,4-cyclohexanedimethanol divinyl ether; divinyl sulfone; di- and trivinylbenzene; trimethylolpropane tri(meth)acrylate; pentaerythritol tetra(meth)acrylate; bisphenol A di(meth)acrylate; methylenebis(meth)acrylamide; triallyl phthalate; l,3-bis(3- methacryloxypropyl)tetramethyldisiloxane; diallyl phthalate; triallyl isocyanurate and combinations thereof.

[0097] The polymeric lens body may optionally have an equilibrium water content (EWC) of at least 20%, such as at least 25% or at least 30%. The polymeric lens body typically has an equilibrium water content (EWC) of at least 40%, such as at least 45%. The contact lens may be a US Food and Drug Administration (FDA) group II, non-ionic high water content lens that is a silicone hydrogel contact lens having an EWC of at least 40% or at least 45%.

[0098] As will be appreciated by those skilled in the art, the polymerizable composition may comprise additional polymerizable or non-polymerizable ingredients conventionally used in contact lens formulations such as one or more of a polymerization initiator, an oxygen scavenger, a chain transfer agent, a diluent, or the like. In some examples, the polymerizable composition may include an organic diluent in an amount to prevent or minimize phase separation between the hydrophilic and hydrophobic components of the polymerizable composition, so that an optically clear lens is obtained. Diluents commonly used in contact lens formulations include hexanol,P10257WO (3038-278-01 PCT) ethanol, and / or other primary, secondary or tertiary alcohols. In other examples, the polymerizable composition is free or substantially free (e.g., less than 500 ppm) of an organic diluent. In such examples, the use of siloxane monomers containing hydrophilic moieties such as polyethylene oxide groups, pendant hydroxyl groups, or other hydrophilic groups, may make it unnecessary to include a diluent in the polymerizable composition. Non-limiting examples of these and additional ingredients that may be included in the polymerizable composition are provided in U.S. Pat. No. 8,231,218.

[0099] The polymer matrix of the polymeric lens body is typically the reaction product of a polymerizable composition that includes from about 15 wt.% to about 65 wt.% of at least one siloxane monomer, from about 25 wt.% to about 75 wt.% of at least one non-ionic hydrophilic monomer, and optionally from about 1 wt.% to about 20 wt.% of a hydrophobic monomer. The polymeric lens body may comprise from 0.01 wt.% to 15 wt.% of a charged hydrophobic molecule, typically from 0.1 to 3 wt.% of a charged hydrophobic molecule.

[0100] The polymer matrix of the polymeric lens body may, for example, be the reaction product of a polymerizable composition comprising from 25 wt.% to 55 wt.% of a siloxane monomer(s), from 30 wt.% to 55 wt.% of a vinyl monomer selected from N-vinyl pyrrolidone (NVP), N-vinyl-N-methyl acetamide (VMA), or combinations thereof. The polymeric lens body may optionally comprise from about 1 wt.% to about 20 wt.% of a hydrophilic monomer selected from N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxyethyl methacrylamide (EOEMA), or ethylene glycol methyl ether methacrylate (EGMA), or any combination thereof. The polymeric lens body may alternatively or additionally optionally comprise from about 1 wt.% to about 20 wt.% of a hydrophobic monomer selected from methyl methacrylate (MMA), isobornyl methacrylate (IBM), or 2-hydroxybutyl methacrylate (HOB) orP10257WO (3038-278-01 PCT) any combination thereof. Silicone hydrogel materials made from such polymerizable composition include stenfilcon A, comfilcon A, somofilcon A, fanfilcon A, and enfilcon A.

[0101] The contact lens in the present invention can be considered a soft silicone hydrogel contact lens. The contact lens sealed in the contact lens package of the present disclosure may be of any lens wear modality. Lens wear modality refers to the how many days and nights in a row the lens can be worn without removal. In one example, the contact lens sealed in the contact lens package of the present disclosure is a daily disposable lens. Daily disposable lenses are indicated for single use, up to about 12 or 16 hours of continuous wear and should be discarded after the single use. In another example, the contact lens sealed in the contact lens package of the present disclosure is a daily wear lens. Daily wear lenses are worn during the waking hours, typically up to about 12 to 16 hours, and are removed before sleep. Daily wear lenses are typically stored in a contact lens case containing a contact lens care solution for cleaning and disinfecting the lens during the hours of non-use. Daily wear lenses are typically discarded after a maximum of 30 days wear. In yet another example, the contact lens is an extended wear lens. Extended wear lenses are typically worn continuously for up to 6, 14, or 30 consecutive days and nights.

[0102] The polymeric lens body of the invention comprising a polymer matrix and a charged hydrophobic molecule present in the polymer matrix, may be prepared by loading the charged hydrophobic molecule into the polymer matrix once formed or by including the charged hydrophobic molecule into the polymerizable composition from which the polymer matrix is formed. Advantageously, the polymeric lens body of silicone hydrogel contact lens of the invention are obtained, or are obtainable by, loading the charged hydrophobic molecule into the polymer matrix once formed. The charged hydrophobic molecule may be loaded into the polymer matrix of the polymeric lens body by exposing the polymer matrix to a loading solution comprisingP10257WO (3038-278-01 PCT) the charged hydrophobic molecule, typically by immersing the polymer matrix in the solution. The loading solution may comprise an organic solvent capable of swelling the polymer matrix of the polymeric lens body, such as a Ci-6 alcohol, for example methanol, ethanol or propanol, especially ethanol. The loading solution may be a mixture, such as a mixture of ethanol and water, e.g. a 50:50 or 60:40 (by volume) mixture of ethanol / water. It has been found that once loaded into the polymer matrix of the polymeric lens body by exposing the polymer matrix to a solution comprising the charged hydrophobic molecule, for example, by soaking the polymer matrix of the lens body in ethanol or ethanol / water, the charged hydrophobic molecule adheres to the polymer matrix material and a significant quantity (e.g. at least 70 wt% of the amount loaded to the lens, such as 90 wt% of the amount loaded to the lens or more) may remain bound in the lens body during storage in typical contact lens storage solutions prior to wear. It has also been found that no or minimal qualities (e.g. no more than 10 wt.%, especially no more than 2 wt.%) of the charged hydrophobic molecule typically become detached from the lens body during the lens wear.

[0103] The packaging solution sealed within the contact lens package of the present disclosure may be any conventional contact-lens compatible solution. In one example, the packaging solution comprises, consists, or consists essentially, of an aqueous solution of a buffer, and / or a tonicity agent. In another example, the packaging solution contains additional agents such as one or more additional antimicrobial agents, and / or a comfort agent, and / or a hydrophilic polymer, and / or a surfactant and / or other additive that prevents the lens from sticking to the package. The packaging solution can have a pH in the range of about 6.8 or 7.0 up to about 7.8 or 8.0. In one example, the packaging solution comprises phosphate buffer or borate buffer. In another example, the packaging solution comprises a tonicity agent selected from sodium chloride or sorbitol in an amount to maintain osmolality in the range of about 200 to 400 mOsm / kg, andP10257WO (3038-278-01 PCT) typically from about 270 mOsm / kg up to about 310 mOsm / kg. In some examples, the packaging solution may comprise polysaccharides (e.g. hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxy ethyl cellulose, etc.) or other high molecular weight polymers, such as polyvinyl pyrrolidone, which are commonly used as comfort polymers or thickening agents in ophthalmic solutions and contact lens packaging solutions. The releasable beneficial agent may be included in the packaging solution and introduced to the lens during storage. Ionic interactions between an ionic beneficial agent and the charged hydrophobic molecule present in the polymeric lens body advantageously facilitates uptake of the beneficial agent from the packaging solution into the lens.

[0104] The packaged lens of the second aspect of the invention is typically prepared by immersing a silicone hydrogel contact lens that comprises a polymeric lens body and a charged hydrophobic molecule present in the polymeric lens body into a packaging solution comprising the releasable beneficial agent and sealing the package. Alternatively, the packaged lens of the second aspect of the invention may be prepared by immersing a beneficial agent-releasing lens of the first aspect of the invention in a packaging solution that does not contain the releasable beneficial agent such that a quality of releasable beneficial agent leaches from the lens body into the packaging solution, or by immersing a beneficial agent-releasing lens of the first aspect of the invention in a packaging solution that comprises an additional quality of the beneficial agent, and sealing the package.

[0105] With respect to the contact lens package, this package can include or comprise a base member, such as a plastic base member, comprising a cavity configured to retain the contact lens and packaging solution and a flange region extending outwardly around the cavity. A removable foil or seal is attached to the flange region to provide a sealed contact lens package.P10257WO (3038-278-01 PCT)Such contact lens packages, which are commonly referred to as “blister packs”, are well-known in the art (see e.g. U.S. Pat. No. 7,426,993).

[0106] It will be appreciated that conventional manufacturing methods can be used to manufacture the sealed contact lens package. Thus, one aspect of the present disclosure is a method of manufacturing a contact lens package including the step of placing an unworn contact lens and a contact lens packaging solution in a receptacle, placing a cover on the receptacle, and sealing the cover on the receptacle. Generally, the receptacle is configured to receive a single contact lens and an amount of packaging solution sufficient to completely cover the contact lens, typically about 0.5 to 1.5 ml. The receptacle may be made from any suitable material, such as glass or plastic. In one example, the receptacle comprises a plastic base member comprising a cavity configured to retain the contact lens and packaging solution and a flange region extending outwardly around the cavity, and the cover comprises a removable foil attached to the flange region to provide the sealed contact lens package. The removable foil may be sealed by any conventional means such as heat sealing or gluing. In another example, the receptacle is in the form of a plastic base member comprising a plurality of threads and the cover comprises a plastic cap member comprising a compatible set of thread for engagement with the threads of the base member thereby providing a resealable cover. It will be appreciated that other types of packaging can also be used to provide a resealable package. For example, the contact lens package may comprise a plastic cover comprising features that engage with compatible features of the receptacle to form an interference fit.

[0107] In the method of manufacturing, the sealed contact lens package may further comprise sterilizing the unworn contact lens by autoclaving the sealed contact lens package. Autoclaving generally involves subjecting the sealed contact lens package to temperatures of atP10257WO (3038-278-01 PCT) least 121° C for at least 20 minutes. The final product is a sterile, packaged silicone hydrogel contact lens having ophthalmically-acceptable surface wettability. In a specific example, the invention provides a contact lens package, comprising a base member having a cavity for accommodating a packaging solution and a contact lens; an unworn silicone hydrogel contact lens in the cavity of the base member; and a packaging solution in the cavity of the base member.EXAMPLES

[0108] The following Examples illustrate certain aspects and advantages of the present invention, which should be understood not to be limited thereby.Example 1. Sodium Cromolyn Uptake and release by DDAB Loaded Lenses

[0109] Stenfilcon A silicone hydrogel contact lenses were prepared by curing a polymerizable composition in polypropylene contact lens molds, dry demolded and immersed in an ethanol solution containing 2 mg / mL of 18:0 DDAB (dimethyldioctadecylammonium bromide salt) for 215 minutes without prior extraction or hydration. The loaded lenses were immersed in deionised water for 6 minutes, immersed in fresh deionised water for 30 minutes and then immersed in a further batch of fresh deionised water for a further 30 minutes to hydrate the lenses.

[0110] 18:0 DDAB bromide salt loaded lenses and unmodified stenfilcon A lenses were sealed in a blister package in a 1.3 mL solution of phosphate buffered saline comprising 200 ppm sodium cromolyn (sodium 5,5'-(2-hydroxypropane-l,3-diyl) / >A(oxy) / >A(4-oxo-4 / 7-chromene-2- carboxylate) for two hours, then autoclaved and stored for a few days.

[0111] Sodium cromolyn was extracted from the lenses by removing the lenses from the blisters, soaking the lenses in a 6 mL glass vial containing 2 mL of ethanol and shaking overnight (~16 hours) in a bench top shaker at room temperature. The extracted residual amount of sodiumP10257WO (3038-278-01 PCT) cromolyn (pg) was determined by multiplying the concentration of sodium cromolyn in the extraction media (pg / mL), determined by liquid chromatography-mass spectrometry (LCMS) using a linear regression of chromatography analysis method, by the volume of the extraction media. The extracted residual amount of sodium cromolyn in the unmodified stenfilcon A lens was determined to be 22 pg / lens and the amount of sodium cromolyn in the stenfilcon A lens loaded with 18:0 DDAB bromide salt was determined to be 31 pg / lens.

[0112] The release of sodium cromolyn was determined by liquid chromatography-mass spectrometry (LCMS) by removing the lenses from the blisters, blotting dry and transferring to 6 mL glass vials containing 2 mL of PBS preheated to 35 °C in a bench top shaker at 120 rpm. At 1, 3, 4, and 24 hour time points 1.5 mL of PBS was removed and exchanged for 1.5 mL of fresh PBS. The release amount at each time point (AT) is determined according to the following equation:Arn= [Crnko]_[ n^ CPo_^)] where CTnis the concentration of release sample at Tntime point, determined by linear regression of chromatography analysis method (pg / mL); Kois the initial fluid volume; and S is the exchange fluid volume. The cumulative amount sodium of cromolyn released in pg / lens at least time point (i.e. the sum of the amount released at Tnand all preceding time points) is shown in Table 1 :Table 1.P10257WO (3038-278-01 PCT)

[0113] From the above results, it can be seen that the loading of a lens with the charged hydrophobic molecule DDAB both increased the amount of ionic beneficial agent sodium cromolyn that was taken up by the lens. Furthermore, the amount of beneficial agent released from the lens was increased and the rate of release (as a percentage of the total available for release) was slowed for lens that include the charged hydrophobic molecule compared to unmodified, neutral lenses.Example 2. Ketotifen Uptake and Release from PG Loaded Lenses

[0114] Stenfilcon A silicone hydrogel contact lenses were prepared by curing a polymerizable composition in polypropylene contact lens molds, dry demolded and immersed in an ethanol solution containing either 1 mg / mL of 14:0 PG(l,2-dimyristoyl-sn-glycero-3-phospho- (l'-rac-glycerol)) sodium salt or 3 mg / mL of 14:0 PG sodium salt for 215 minutes without prior extraction or hydration. The loaded lenses were immersed in deionised water for 6 minutes, immersed in fresh deionised water for 30 minutes and then immersed in a further batch of fresh deionised water for a further 30 minutes to hydrate the lenses.

[0115] Both sets of 14:0 PG sodium loaded lenses and unmodified stenfilcon A lenses were sealed in a blister package in a 1.2 mL solution of TRIS-sorbitol buffered saline comprising 200 ppm ketotifen (4-(l-methylpiperidin-4-ylidene)-4,9-dihydro-10 / f-benzo[4,5]cyclohepta[l,2- / >]thi ophen- 10-one) then autoclaved and stored for a few days.

[0116] The amount of ketotifen taken up into the lenses was determined by measuring the amount of ketotifen that remained in the TRIS-sorbitol buffered saline after the lenses had been removed. Unmodified stenfilcon A lenses were found to have taken up 27 pg / lens of ketotifen, lenses modified with a 1 mg / mL solution of 14:0 PG were found to have taken up 27 pg / lens of ketotifen and lenses modified with a 3 mg / mL solution of 14:0 PG were found to have taken upP10257WO (3038-278-01 PCT)41 pg / lens of ketotifen. Therefore, the inclusion of the charged hydrophobic molecule 14:0 PG increased the ability of the lenses to take up ketotifen a charged beneficial agent.

[0117] Release of ketotifen into a phosphate buffered saline release media was then determined at 1, 3, 6, and 24 hour timepoints using liquid chromatography -mass spectrometry (LCMS). Three lenses of each type were removed from the blister solution, briefly rinsed in 4 mL deionized (DI) water, repeated four times with fresh DI water, using a hydration tray. The lenses were then each immersed in 3.0 mL of phosphate buffered saline (PBS) release media that had been pre- warmed to 35 °C in separate 6 mL glass vials in an incubator. The vials were shaken at 125 rpm and maintained at 35 °C. At each time point, 2.5 mL of release medium was removed from the vial and analysed to determine the concentration of ketotifen present. 2.5 mL of fresh PBS that had been pre- warmed to 35 °C was added to the vials to replenish the release media that had been removed for analysis. The release amount at each time point (AT) is determined according to the following equation:Ayn=[nko]—[^^(ko—5')] where CTnis the concentration of release sample at Tntime point, determined by linear regression of chromatography analysis method (pg / mL); Kois the initial fluid volume; and S is the exchange fluid volume. The cumulative release amount at least time point (i.e. the sum of the amount released at Tnand all preceding time points) is shown in FIG. 1.

[0118] As can be seen from FIG. 1, the amount of ketotifen released from lenses loaded with 1 mg / mL of 14:0 PG sodium salt at each time point is about 1.7 times the amount released from unmodified stenfilcon A lenses. And, the amount pf ketotifen released from lenses loaded with 3 mg / mL of 14:0 PG sodium salt at each time point is about 2 times the amount released fromP10257WO (3038-278-01 PCT) unmodified stenfilcon A lenses. The data also shows that release of ketotifen is sustained for at least 6 hours using the lenses loaded with 14:0 PG sodium salt.Example 3. s-Polylysine Uptake by PG Loaded Lenses

[0119] Stenfilcon A silicone hydrogel contact lenses were prepared by curing a polymerizable composition in polypropylene contact lens molds, dry demolded and immersed in an ethanol solution containing 3 mg / mL of 14:0 PG sodium salt for 215 minutes without prior extraction or hydration. The loaded lenses were immersed in deionised water for 6 minutes, immersed in fresh deionised water for 30 minutes and then immersed in a further batch of fresh deionised water for a further 30 minutes to hydrate the lenses.

[0120] 14:0 PG sodium salt loaded lenses and unmodified stenfilcon A lenses were sealed in a blister package in a 1.2 mL solution of TRIS-sorbitol buffered saline comprising 200 ppm sPL (s-polylysine) then autoclaved and stored for a few days.

[0121] sPL was then extracted from the lenses by soaking the lenses in a 15 mL plastic vial containing 5 mL of a, 11.7 mg / mL solution of NaCl + 0.1% Trifluoracetic Acid (TFA) in water, sonicating for 30 minutes and the shaking overnight. The extracted residual amount of sPL (pg) was determined by multiplying the concentration of sPL in the extraction media (pg / mL), determined by liquid chromatography-mass spectrometry (LCMS) using a linear regression of chromatography analysis method, by the volume of the extraction media. The extracted residual amount of sPL in the unmodified stenfilcon A lens was determined to be 2.69 pg / lens and the amount of sPL in the stenfilcon A lens loaded with 14:0 PG sodium salt was determined to be 21.65 pg / lens.Example 4. Maximum LoadingsP10257WO (3038-278-01 PCT)

[0122] In addition to loading lenses with 18:0 DDAB bromide salt and 14:0 PG sodium salt, stenfilcon A lenses were loaded with l,2-dipalmitoyl-s7?-glycero-3 -ethylphosphocholine (16:0 EPC), e.g. as a chloride salt and l,2-dipalmitoyl-3-dimethylammonium-propane (16:0 DAP) using the same procedure as for 18:0 DDAB bromide salt and 14:0 PG sodium salt described in Examples 1 and 3 above.

[0123] For each charged hydrophobic loaded to the lens body, the maximum amount of loading was determined by screening different loading concentrations and observing at what concentration a precipitate will start forming on the lens surface after storage for a few days (e.g. 4 days). The highest concentration that did not lead to the formation of precipitate was considered to be the maximum loading. For example, 16:0 DAP could be loaded at a concentration of 3 mg / mL without precipitation occurring immediately after loading, some precipitation was noticed on the lens after a few days. Thus, the loading obtained by soaking a stenfilcon A lens in a 3 mg / mL solution of 16:0 DAP in ethanol was considered to exceed the maximum loading level. The highest loading concentration for solutions of 18:0 DDAB bromide salt and 14:0 PG sodium salt without forming precipitate was 2 mg / mL.

[0124] Staining with a dye after loading was used to gauge the efficiency of the charged hydrophobic molecule incorporation in lens. Orange II dye was used to stain lenses loaded with cationic hydrophobic compounds and TBO used to stain lenses loaded with anionic hydrophobic compounds. A darker stain indicates a higher density of charged species that are capable to binding to the dye molecule.

[0125] For 16:0 EPC chloride salt, a 20 mg / mL loading solution was used which resulted in light orange II staining compared to a darker orange II staining with 1 mg / mL 18:0 DDAB bromide salt loading solution. The lighter staining of 16:0 EPC chloride salt loaded lens indicatesP10257WO (3038-278-01 PCT) that the lens had taken up a lower amount of charged hydrophobic compounds than the 18:0 DD AB bromide salt loaded lens despite the significantly more concentrated loading solution.

[0126] It was investigated whether charged compounds with a higher water solubility, i.e. less hydrophobic compounds, could be loaded into lenses in greater quantities. Stenfilcon A silicone hydrogel contact lenses were prepared and dry demolded and immersed in an ethanol solution containing various concentrations of cetalkonium chloride (CKC) for 215 minutes without prior extraction or hydration. The loaded lenses were immersed in deionised water for 6 minutes, immersed in fresh deionised water for 30 minutes and then immersed in a further batch of fresh deionised water for a further 30 minutes to hydrate the lenses.

[0127] It was found that when that more highly water-soluble charged compound cetalkonium chloride (CKC) was loaded into stenfilcon A lenses instead of 18:0 DDAB bromide salt and 14:0 PG sodium salt, the loading concentration could be increased up to 25 mg / ml resulting in the incorporation of a significant number of charged molecules into the lens.

[0128] The cetalkonium chloride loaded lenses were extracted by immersing 3 lenses in 3 separate vials containing 5 ml of ethanol and shaking at 350 rpm at room temperature overnight (~19 hours). 4.5 mL of the extraction solvent was withdrawn from each vial, 2.5 mL of fresh ethanol was added, and the vials were shaken at 350 rpm at room temperature for a further 3 hours. 2.5 mL of the extraction solvent was withdrawn from each vial, 2.5 mL of fresh ethanol was added, and the vials were shaken at 350 rpm at room temperature for a further 1 hour. The amount of CKC in each extraction medium was determined using HPLC. Only trace amounts of CKC were detected as having been released in the third extractions confirming that the CKC had been removed from the lenses in the first and second extractions. The average cumulative amount ofP10257WO (3038-278-01 PCT)CKC extracted from lenses that had been loaded with CKC using a loading solution having a concentration of 25 mg / ml was 1440 pg / lens.Example 5. HA Uptake by Cetalkonium Chloride Loaded Lenses

[0129] Comparative cationic “IS09” hydrogel contact lenses modified to incorporate a cationic monomer in the lens body, were prepared by curing a polymerizable composition for stenfilcon A modified to contain 4.5 wt.% of N-(3-(dimethylamino)propyl) methacrylamide (DMAPMA). The polymerizable compositions were cured in polypropylene contact lens molds. The polymeric lens bodies were removed from the molds and extracted by immersing them for 215 minutes in ethanol (EtOH), removed from the EtOH and washed in a mixture of 50 / 50 EtOH / water for approximately 30 minutes followed by three exchanges of DI water for approximately 6 minutes, 30 minutes, and 30 minutes, respectively.

[0130] Cetalkonium chloride loaded lenses and comparative IS09 lenses were sealed in a blister package in a 3 mL solution of phosphate buffered saline (PBS) containing mannitol and 0.1 wt% 3 million Da hyaluronic acid (HA) for two hours, then autoclaved and stored for a few days. The PBS-mannitol solution used contained 0.52% sodium phosphate dibasic dodecahydrate (Acros), 0.09% sodium phosphate monobasic dihydrate (Spectrum), 4.25% mannitol (Sigma) and 95.14% DI water and had a pH of 7.3.

[0131] The uptake amount0of HA in CKC loaded lenses was estimated using the differences between packaging solution without vs. with charged loaded lens, using the following formula:•4Q—l^org ~ ens] X VP10257WO (3038-278-01 PCT) where Corgis the concentration of autoclaved original packaging solution, determined by linear regression of chromatography analysis method (pg / mL), Ciensis the concentration of autoclaved packaging solution with charged loaded lens, determined by linear regression of chromatography analysis method (pg / mL) and V is the volume of packaging solution with a charged loaded lens (mL). The uptake amount in each lens was as follows:Table 2

[0132] Release of HA was then determined at 0.5, 1, 3, 6, and 24 hour timepoints using a chromatography analysis method. Three lenses of each type were removed from the blister solution, briefly rinsed in 4 mL deionized (DI) water, repeated four times with fresh DI water, using a hydration tray. The lenses were then each immersed in 2.0 mL of phosphate buffered saline (PBS) release media that had been pre- warmed to 35 °C in separate 6 mL glass vials. The vials were shaken at 125 rpm and maintained at 35 °C. At each time point, 1.5 mL of PBS release medium was removed from the vial and analysed by liquid chromatography-mass spectrometry (LCMS) to determine the concentration of HA present. 1.5 mL of fresh PBS that had been prewarmed to 35 °C was added to the vials to replenish the release media that had been removed for analysis. The release amount at each time point (AT) is determined according to the following equation:P10257WO (3038-278-01 PCT) where CTnis the concentration of release sample at Tntime point, determined by linear regression of chromatography analysis method (pg / mL); Kois the initial fluid volume; and S is the exchange fluid volume. The cumulative release amount at each time point (i.e. the sum of the amount released at Tnand all preceding time points) is shown in FIG. 2A.

[0133] From the estimated total loading of HA, the proportion of HA released from the lens as a percentage at each time point was calculated using the following formula: 100where Tnis the time point, ATnis the release amount at time point Tn, and d0is the uptake amount. The results are shown in in FIG. 2B.

[0134] When CKC was loaded to lenses at concentrations of 10 mg / mL and above, the amounts of HA released from the lens were significantly greater than the amounts released from IS09 lenses that had been modified to incorporate charged DMAPMA monomers.

[0135] Trace amounts of CKC were observed in all the release samples along with the HA.Example 6. Comparison of HA Uptake with Different Hydrophobic Compounds

[0136] A study was carried out to optimize the lipophilic portion of the charged hydrophobic molecule such that the molecule remains permanently with the lens but can be loaded in sufficient amounts to enable the lens to take up and release substantial quantities of charged beneficial agents.

[0137] Didodecyldimethylammonium bromide (DDMB) has 24 carbon atoms present in hydrocarbon chains of least 8 chain carbon atoms, i.e. two C12 hydrocarbon chains. DDMB was loaded at using an ethanol solution having a concentration of 2 mg / mL, 4 mg / mL and 25 mg / mL. No precipitation was observed with loading concentrations of 25 mg / mL.P10257WO (3038-278-01 PCT)

[0138] Dihexadecyldimethylammonium bromide has 32 carbon atoms present in hydrocarbon chains of least 8 chain carbon atoms, i.e. two Ci6 hydrocarbon chains. Dihexadecyldimethylammonium bromide was loaded at using an ethanol solution having a concentration of 5 mg / mL, 10 mg / mL, and 15 mg / mL. Precipitation was observed with loading concentrations of 15 mg / mL.

[0139] Dimethyldioctadecylammonium bromide (18:0 DDAB) has 36 carbon atoms present in hydrocarbon chains of least 8 chain carbon atoms, i.e. two Cis hydrocarbon chains. 18:0 DDAB is more hydrophobic and less water soluble than CKC. The highest loading was achieved using an ethanol solution having a 18:0 DDAB concentration of 2 mg / mL.

[0140] The lenses loaded with 18:0 DDAB and DDMB were autoclaved in 0.1 wt.% million Da HA solution and HA uptake and release were tested in accordance with the procedures of Example 5 above. The uptake amount in each lens was as follows:Table 3

[0141] Amounts of HA released are shown in FIG. 3 A and the proportion of HA released is shown in FIG. 3B. The HA uptake achieved by loading a stenfilcon A lens using a 4 mg / mL solution of DDMB was comparable to that achieved using IS09 lenses in which the polymer matrix of the lens material had been modified. Thus, the present invention provides a simpler way ofP10257WO (3038-278-01 PCT) adapting a lens such that it is effective for the delivery of beneficial agents without requiring a change to the chemical composition of the polymer matrix which can lease to instability.Example 7. g-Polylysine Uptake by Depending on Concentration

[0142] A study was undertaken to ascertain whether higher concentrations of beneficial agent could be used to increase the amount taken up by and released from lenses that include charged hydrophobic compounds.

[0143] Stenfilcon A silicone hydrogel contact lenses were prepared by curing a polymerizable composition in polypropylene contact lens molds, dry demolded, and immersed in 2.5 mL of an ethanol solution containing no charge hydrophobic molecule to provide control stenfilcon A lenses, in a solution containing 2.68 mg / mL of 18:0 Lyso PG (l-stearoyl-2-hydroxy- sn-glycero-3-phospho-(l'-rac-glycerol) sodium salt) or in a solution containing 2.67 mg / mL 12:0 PG (l,2-dilauroyl-sn-glycero-3-phospho-(l'-rac-glycerol) sodium salt) overnight (~16 hours) in a sealed 6 mL glass vial without prior extraction or hydration. The loaded lenses were immersed in deionised water for 6 minutes, immersed in fresh deionised water for 30 minutes and then immersed in a further batch of fresh deionised water for a further 30 minutes to hydrate the lenses. No precipitation was observed at these loading levels suggesting that higher loadings may be tolerated.

[0144] Staining with a toluene blue dye after loading produce a dark blue coloration for both 18:0 Lyso PG and 12:0 PG loaded lenses indicating that the loaded lenses carried a significant negative charge.

[0145] Stenfilcon control lenses, 18:0 Lyso PG loaded lenses, and 12:0 PG loaded lenses were each sealed in a separate blister package in a 1.3 mL solution of TRIS-sorbitol bufferedP10257WO (3038-278-01 PCT) saline comprising 200 ppm sPL (s-polylysine) or 600 ppm sPL, then autoclaved and stored for a few days.

[0146] The amount of sPL taken up into the lenses was determined by measuring the amount of sPL present in the packaging solutions before introduction of the lens and after autoclaving and storage of the lens for a few days.Table 4

[0147] Release of sPL into a phosphate buffered saline release media was then determined at 1, 3, 6, and 24 hour timepoints using a liquid chromatography-mass spectrometry (LCMS). Three lenses of each type were removed from the blister solution, briefly rinsed in 4 mL deionized (DI) water, repeated four times with fresh DI water, using a hydration tray. The lenses were then each immersed in 3.0 mL of phosphate buffered saline (PBS) release media that had been prewarmed to 35 °C in separate 6 mL glass vials in an incubator. The vials were shaken at 125 rpm and maintained at 35 °C. At each time point, 2.5 mL of release medium was removed from the vial and analysed to determine the concentration of ketotifen present. 2.5 mL of fresh PBS that had been pre- warmed to 35 °C was added to the vials to replenish the release media that had been removed for analysis. The release amount at each time point (AT) is determined according to the following equation:P10257WO (3038-278-01 PCT)^Tn~ [^Tn^o]—[^Tn-j C )—^)] where CTnis the concentration of release sample at Tntime point, determined by linear regression of chromatography analysis method (pg / mL); Kois the initial fluid volume; and S is the exchange fluid volume. The cumulative release amount of sPL at least time point (i.e. the sum of the amount released at Tnand all preceding time points) from the control and loaded lenses is shown in FIGS. 4A and 4B with the proportion of sPL released shown in FIGS. 4C and 4D.Example 8. s-Polylysine Uptake Depending on 18:0 Lyso PG Loading

[0148] A study was carried out to determine the correlation between the level of loading of charged hydrophobic molecules and the uptake of beneficial agents.

[0149] Stenfilcon A silicone hydrogel contact lenses were prepared by curing a polymerizable composition in polypropylene contact lens molds, dry demolded, and immersed in 2.5 mL of an ethanol solution containing 2.67 mg / mL, 4.01 mg / mL, or 8.01 mg / mL of 18:0 Lyso PG (l-stearoyl-2-hydroxy-sn-glycero-3-phospho-(l'-rac-glycerol) sodium salt) for 215 minutes in a sealed 6 mL glass vial without prior extraction or hydration. The loaded lenses were immersed in deionised water for 6 minutes, immersed in fresh deionised water for 30 minutes and then immersed in a further batch of fresh deionised water for a further 30 minutes to hydrate the lenses. No precipitation was observed at these loading levels.

[0150] 18:0 Lyso PG loaded lenses were sealed in a blister package in a 1.3 mL solution of TRIS -sorbitol buffered saline comprising 600 ppm sPL, then autoclaved and stored for a few days.P10257WO (3038-278-01 PCT)

[0151] The amount of sPL taken up into the lenses was determined by measuring the amount of sPL present in the packaging solution before introduction of the lens and after autoclaving and storage of the lens for a few days. The sPL uptake was as follows:Table 5

[0152] It was found that sPL uptake is directly proportional to the 18:0 Lyso PG loading solution concentration indicating that the negatively charges lipid in the lens body increases the uptake of positive charged beneficial agent through ionic interactions.

[0153] Release of sPL from each lens was determined using the procedure described in Example 8 above and the results are shown in FIGS. 5 A and 5B. Release was sustained for at least 6 hours.Example 9. DOPG-Loaded Lenses

[0154] l,2-Dioleoyl-sn-glycero-3-phospho-rac-(l -glycerol) sodium salt (DOPG) from Sigma-Aldrich was dissolved into a 50% by volume ethanol (EtOH) 50% by volume deionised water solution and sonicated until the DOPG was fully dissolved to provide DOPG loading solutions ranging in concentration from 1 mg / ml to 10 mg / ml.

[0155] Silicone hydrogel contact lenses were prepared by curing the formulation for stenfilcon A in polypropylene contact lens molds. The cured stenfilcon A was removed from the molds, and each lens was extracted in EtOH to remove unreacted monomer. The lenses were then placed in the DOPG loading solutions for about 90 minutes and then hydrated in several exchanges of DI water. The lenses were packaged in plastic blisters with about 1.2 ml of a packaging solution comprising phosphate buffered saline (PBS) and autoclaved.P10257WO (3038-278-01 PCT)

[0156] The amount of DOPG in each lens was determined by extracting the lens with isopropanol (IP A) and measuring DOPG in the extract by LCMS. Briefly, each lens was removed from its blister pack, lightly blotted to remove excess packaging solution, and placed in a 20 mL glass vial containing 10 mL 100% IPA. The vials were placed on a bench top shaker at 300 rpm overnight (~16 hours) at room temperature. For stenfilcon A, a single 2-hour extraction step is sufficient to extract substantially all the DOPG from the lens. The amount of DOPG in the IPA extract from each lens is determined by LCMS compared to a DOPG standard solution. The DOPG loading concentrations and average DOPG in each lens are shown in Table 6.Table 6.Example 10. Stenfilcon A and Somofilcon A Lenses Loaded with DHAPG

[0157] Contact lenses prepared by curing the formulation for stenfilcon A and somofilcon A lenses. Both types of lenses were soaked in a 3 mg / mL DHAPG (1,2-didocosahexaenoyl-sn- glycero-3-[phospho-rac-(l-glycerol)] sodium salt) dissolved in 50 vol% ethanol (an ethanol-water mixture). Both lens types absorbed over 60 pg of DHAPG demonstrating the above results obtained with stenfilcon A lenses can be expected to be achieved with other types of silicone hydrogel contact lenses.P10257WO (3038-278-01 PCT)

[0158] The above Examples 1 to 10 demonstrate that incorporation of charged hydrophobic molecules into the polymeric lens body of a silicone hydrogel lens through a simple soaking process leads to a significant uptake of the oppositely charged beneficial agents followed by controlled release of these agents. No chemical changes in lens formulation were necessary.

[0159] The disclosure herein refers to certain illustrated examples, it is to be understood that these examples are presented by way of example and not by way of limitation. The intent of the foregoing detailed description, although discussing exemplary examples, is to be construed to cover all modifications, alternatives, and equivalents of the examples as may fall within the spirit and scope of the invention as defined by the additional disclosure.

[0160] The entire contents of all cited references in this disclosure, to the extent that they are not inconsistent with the present disclosure, are incorporated herein by reference.

[0161] Other embodiments of the present invention will be apparent to those skilled in the art from consideration of the present specification and practice of the present invention disclosed herein. It is intended that the present specification and examples be considered as exemplary only with a true scope and spirit of the invention being indicated by the following claims and equivalents thereof.

Claims

P10257WO (3038-278-01 PCT)CLAIMS1. A silicone hydrogel contact lens that comprises a polymeric lens body and a releasable beneficial agent, wherein the polymeric lens body comprises a polymer matrix and a charged hydrophobic molecule embedded in the polymer matrix, wherein the charged hydrophobic molecule includes a hydrophobic group and a charged functional group, wherein the hydrophobic group comprises at least one hydrocarbon chain having at least 8 carbon atoms, and wherein the releasable beneficial agent has a charge that is opposite to the charge of the charged functional group of the charged hydrophobic molecule.

2. The silicone hydrogel contact lens of claim 1, wherein the charged hydrophobic molecule facilitates controlled release of the releasable beneficial agent by the polymeric lens body.

3. The silicone hydrogel contact lens of claim 1 or claim 2 that releases at least 0.5 pg / hr of beneficial agent from the lens for at least 3 hours following immersion into an artificial tear fluid (ATF) release media at 35 °C.

4. The silicone hydrogel contact lens of any preceding claim that sustains the release of at least 0.5 pg / hr of beneficial agent from the lens for at least 25% longer than a control lens that is a silicone hydrogel contact lens comprising a polymeric lens body with no charged hydrophobic molecule present but otherwise comprising a polymer matrix formed of the same polymerizable composition following immersion into an artificial tear fluid (ATF) release media at 35 °C.

5. The silicone hydrogel contact lens of any preceding claim, wherein the charged hydrophobic molecule is present in an amount of at least 100 pg / lens.

6. The silicone hydrogel contact lens of any preceding claim, wherein the charged hydrophobic molecule comprises at least one C10-C26 hydrocarbon chain.P10257WO (3038-278-01 PCT)7. The silicone hydrogel contact lens of claim 6, wherein the charged hydrophobic molecule comprises at least one C12-C20 hydrocarbon chain.

8. The silicone hydrogel contact lens of any preceding claim, wherein the charged hydrophobic molecule contains a single hydrocarbon chain having 14 carbons or more or contains two hydrocarbon chains each having 13 carbon atoms or fewer.

9. The silicone hydrogel contact lens of any preceding claim, having a total of no more than 26 carbon atoms present in hydrocarbon chains of least 8 chain carbon atoms.

10. The silicone hydrogel contact lens of any preceding claim, comprising at least 50 pg / lens of the beneficial agent.

11. The silicone hydrogel contact lens of any preceding claim, wherein the lens comprises at least 10% more (by weight) of the beneficial agent than a control lens that is a silicone hydrogel contact lens comprising a polymeric lens body with no charged hydrophobic molecule present but otherwise comprising a polymer matrix formed of the same polymerizable composition.

12. A method of preparing the silicone hydrogel contact lens of any preceding claim, comprising the step of immersing a silicone hydrogel contact lens comprising a polymeric lens body having a charged hydrophobic molecule in a polymer matrix, into a solution comprising the releasable beneficial agent.

13. The method of claim 12, further comprising the step of loading the charged hydrophobic molecule into the polymeric lens body, in which the polymer matrix is immersed into a loading solution comprising the charged hydrophobic molecule.

14. The method of claim 13, wherein the loading solution includes 1 to 25 mg / mL of the charged hydrophobic molecule in an organic solvent.P10257WO (3038-278-01 PCT)15. A silicone hydrogel contact lens immersed in a packaging solution and sealed in a package, wherein the silicone hydrogel contact lens comprises a polymeric lens body having a polymer matrix and a charged hydrophobic molecule, the charged hydrophobic molecule having a hydrophobic group and a charged functional group, wherein the hydrophobic group comprises at least one hydrocarbon chain of at least 8 carbon atoms, and wherein said packaging solution comprises a releasable beneficial agent having a charge that is opposite to the charge of the charged hydrophobic molecule.

16. The silicone hydrogel contact lens of claim 15, wherein the charged hydrophobic molecule facilitates uptake of a releasable beneficial agent by the polymeric lens body and / or controlled release of the releasable beneficial agent by the polymeric lens body.

17. The silicone hydrogel contact lens of claim 15 or claim 16 that releases at least 0.5 pg / hr of beneficial agent from the lens for at least 3 hours following immersion into an artificial tear fluid (ATF) release media at 35 °C.

18. The silicone hydrogel contact lens of any one of claims 15 to 17 that sustains the release of at least 0.5 pg / hr of beneficial agent from the lens for at least 25% longer than a control lens following immersion into an artificial tear fluid (ATF) release media at 35 °C, wherein the control lens is a silicone hydrogel contact lens comprising a polymeric lens body with no charged hydrophobic molecule present but otherwise comprising a polymer matrix formed of the same polymerizable composition immersed in an identical packaging solution comprising the releasable beneficial agent.

19. The silicone hydrogel contact lens of any one of claims 15 to 18, comprising the charged hydrophobic molecule in an amount of at least 100 pg / lens.P10257WO (3038-278-01 PCT)20. The silicone hydrogel contact lens of any one of claims 15 to 19, wherein the charged hydrophobic molecule comprises at least one C10-C26 hydrocarbon chain.

21. The silicone hydrogel contact lens of claim 20, wherein the charged hydrophobic molecule comprises at least one C12-C20 hydrocarbon chain.

22. The silicone hydrogel contact lens of any one of claims 15 to 21, wherein the charged hydrophobic molecule contains a single hydrocarbon chain having 14 carbons or more or comprises two hydrocarbon chains each having 13 carbon atoms or fewer.

23. The silicone hydrogel contact lens of any one of claims 15 to 22, having a total of no more than 26 carbon atoms present in hydrocarbon chains of least 8 chain carbon atoms.

24. The silicone hydrogel contact lens of any one of claims 15 to 23, wherein the polymeric lens body comprises at least at least 50 pg / lens of the beneficial agent.

25. The silicone hydrogel contact lens of any one of claims 15 to 24, wherein the packaging solution comprises the beneficial agent in a concentration of at least 100 ppm.

26. A method of preparing the silicone hydrogel contact lens of any one of claims 15 to 25, comprising the step of immersing a silicone hydrogel contact lens comprising a polymeric lens body having a charged hydrophobic molecule in a polymer matrix, into a packaging solution comprising the releasable beneficial agent and sealing the silicone hydrogel contact lens immersed in the packaging solution in a package.

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