CONTACT LENS LOADED WITH A GLYCEROPHOSPHOLIPID
FIELD OF THE INVENTION
[001] The field of the invention relates to contact lenses that release a beneficial agent when worn.
BACKGROUND OF THE INVENTION
[002] 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 or do not sustain release for the needed period of time, which can be 8 hours or more. There is a need in the industry for new approaches to achieving sustained release of beneficial agents from contact lenses.
SUMMARY OF THE INVENTION
[003] A feature of the present invention is to provide a hydrogel contact lens that can sustain release of beneficial agents from contact lenses during lens wear.
[004] 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.
[005] To achieve these and other advantages, and in accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention, in part relates to a hydrogel contact lens comprising a polymeric lens body loaded with phospholipid, wherein the phospholipid is a glycerophospholipid comprising a residue of a beneficial agent at the sn-2 position.
The terms “beneficial agent” and “target molecule” are used interchangeably herein and refer to any molecule for which sustained release from a contact lens is desired.
[006] The glycerophospholipid may be of the Formula (I):
Formula (I) in which X is either -O- or -O(CO)-, Ri is a Cn-25 alkyl group, A is a residue of a beneficial agent, -L- is a linking group or a covalent bond, and Z is H or a phospholipid head group. In some examples Z is selected from C1-10 polyol (such as glycerol or inositol); ethanolamine (- CH2CH2NH2); and serine (-CH2CH(NH2)COOH). In all examples, reference to a glycerophospholipid is intended to encompass the glycerophosphopholipid and salts thereof (e.g. where Z in Formula 1 has a negative charge, or the ethanolamine is protonated as -CH2CH2NH3+) unless context dictates otherwise.
[007] The glycerophospholipid present in the contact lens body is advantageously susceptible to digestion by secretory phospholipase 2-acylhydrolase (SPLA2) enzymes found in human tears, especially group IIA secretory phospholipase 2-acylhydrolase (SPLA2-IIA) when present in the polymeric lens body of a hydrogel contact lens, especially a silicone hydrogel contact lens, such as a stenfilcon A contact lens. A glycerophospholipid comprising a residue of a target molecule at the sn- 2 position may be considered to be susceptible to digestion by SPLA2 enzymes when the amount of target molecule derived from the digestion of the sn-2 position acyl group that is released from a stenfilcon A lens loaded with at least 200 pg of the glycerophospholipid to an artificial tear fluid (ATF) release medium containing SPLA2 enzyme, is at least 3 times the amount of target molecule released to an otherwise identical control ATF release medium lacking phospholipase A2 enzymes, following immersion of identical stenfilcon A contact lenses each loaded with said glycerophospholipid in each release media for 4 hours at 35 °C. An exemplary ATF release medium containing SPLA2 enzyme may be that defined in Table 2 below, additionally containing 50 ppm recombinant human SPLA2-IIA. The control release medium lacking phospholipase A2 enzymes may be an otherwise identical ATF release medium lacking phospholipase A2 enzymes. Alternatively, the release medium containing SPLA2 enzyme may be reflex tear solution and the control release medium may be an ATF, such as the ATF of Table 2 below. For the avoidance of doubt, while the determination of whether a glycerophospholipid is susceptible to digestion by SPLA2 enzymes may be carried out by loading the glycerophospholipid to a stenfilcon A lens, the contact lens of the invention, including contact lenses comprising glycerophospholipids that have been determined to be susceptible to digestion by SPLA2 enzymes need not be stenfilcon A lenses. In all aspects of the invention the contact lens into which a glycerophospholipid that is susceptible to digestion by SPLA2 enzymes may be any contact lens described herein.
[008] In one example, the hydrogel contact lens is capable of releasing a target molecule for at least 1 hour following immersion in an ATF release media containing 50 ppm SPLA2-IIA enzyme solution in phosphate buffered saline (PBS) at 35 °C.
[009] Furthermore, the present invention relates to a method of making the hydrogel contact lens 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 polymeric lens body, b) removing the polymeric lens body from the contact lens mold, c) extracting the polymeric lens body in an organic solvent comprising a glycerophospholipid comprising a residue of a target molecule at the sn-2 position, d) hydrating the polymeric lens body in a hydration liquid to obtain the hydrogel contact lens, e) sealing said hydrogel contact lens with packaging solution in a package, and f) autoclaving said package. Hydration step d) may occur prior to extraction step c) in which phospholipid is loaded to the polymeric lens body. If hydration step d) occurs prior to extraction step c) in which phospholipid is loaded to the polymeric lens body, additional hydration steps may be performed after step c).
[010] Furthermore, the present invention relates to a method of delivering a beneficial agent to a contact lens wearer by providing to the contact lens wearer a target molecule-releasing hydrogel contact lens, especially a target molecule-releasing hydrogel contact lens, comprising a polymeric lens body loaded with a glycerophospholipid comprising a residue of a target molecule at the sn-2 position. Advantageously, the target molecule-releasing hydrogel contact lens sustains release of the target molecule for at least 1 hour, preferably for at least 4, for at least 8, for at least 12, or for at least 16 hours.
[Oil] Further aspects of the invention are provided in the following numbered clauses:
1. An unworn hydrogel contact lens sealed in a package, the contact lens comprising a polymeric lens body loaded with a glycerophospholipid of formula (I): Formula (I) in which Ri is a C11-25 alkyl group, X is either -O- or -O(CO)-, A is a residue of a target molecule, -L- is a linking group or a covalent bond, and Z is H or a phospholipid head group, wherein the silicone hydrogel contact lens releases the target molecule or salts thereof when in contact with a solution comprising SPLA2-IIA, wherein the target molecule is a digestion product of the glycerophospholipid, provided that when -L- is a covalent bond and the target molecule is a fatty acid, the fatty acid is not oleic acid, myristic acid, palmitic acid, stearic acid, pentadecanoic acid, heptadic- 12-enoic acid, nonadec- 10-enoic acid or docosahexaenoic acid. 2. The contact lens of clause 1 , wherein Z is a residue of ethanolamine, serine, inositol or glycerol.
3. The contact lens of clause 1 or clause 2, wherein the polymeric lens body is loaded with an amount of from 1 pg to 1000 pg, preferably at least 300 pg, of the phospholipid.
4. The contact lens of any preceding clause, wherein the contact lens is a silicone hydrogel contact lens.
5. The contact lens of any preceding clause, wherein the hydrogel is neutral or cationic.
6. The contact lens of any preceding clause, wherein the polymeric lens body is a reaction product of a polymerisable composition that comprises at least one hydrophilic monomer comprising a vinyl group. The contact lens of any preceding clause, wherein the polymeric lens body is a reaction product of a polymerisable composition that comprises a first siloxane having the structure represented by Formula (II), Formula (II) and a second siloxane having the structure represented by Formula (III)
Formula (III). The contact lens of any preceding clause, wherein the hydrogel contact lens releases the target molecule or salts thereof when in contact with a solution comprising SPLA2-IIA, wherein the target molecule is a digestion product of the glycerophospholipid. The contact lens of any preceding clause, wherein when immersed in a release media comprising artificial tear fluid containing 50 ppm SPLA2-IIA at 35 °C, the contact lens sustains release of the target molecule for at least 4 hours, such as for at least 8 hours, optionally for at least 10 hours. The contact lens of any preceding clause, wherein -L- is a covalent bond. The contact lens of any one of clauses 1 to 9, wherein -L- is a linking group. 12. The contact lens of clause 11, wherein -L- comprises a substituted or unsubstituted hydrocarbon chain having from 2 to 15 carbon atoms.
13. The contact lens of any one of clauses 1 to 10, wherein the target molecule is alphalinolenic acid, ricinoleic acid, or petroselinic acid.
14. The contact lens of any one of clauses 1 to 12, wherein the target molecule is an osmoprotectant.
15. The contact lens of any one of clauses 1 to 12, wherein the target molecule is a nonsteroidal anti-inflammatory agent, an antihistamine, a muscarinic acetylcholine receptor antagonist, or an antibiotic.
16. The contact lens of preceding clause, wherein the package comprises: a. a base member having a cavity that retains a packaging solution; and b. a cover that forms a liquid-tight seal with the base member.
17. A method of making the hydrogel contact lens of any preceding clause, the method comprising: a) polymerizing a polymerisable composition in a contact lens mold to obtain the polymeric lens body, b) removing the polymeric lens body from the contact lens mold, c) extracting the polymeric lens body in an organic solvent comprising the glycerophospholipid, d) hydrating the polymeric lens body in a hydration liquid to obtain the hydrogel contact lens, e) sealing the hydrogel contact lens with packaging solution in a package and, optionally, f) autoclaving the package. 18. A method of delivering a beneficial agent to a contact lens wearer, the method comprising applying the contact lens of any one of clauses 1 to 15 to the lens wearer, whereby the contact lens sustains release of the target molecule for at least 4 hours during wear, such as for at least 8 hours, optionally for at least 10 hours.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 depicts the enzymatic hydrolysis of a glycerophospholipid at the sn-2 ester bond by PLA2 to yield a target molecule and lysophospholipid (LPG).
FIG. 2 depicts the oleic acid release profile of a 5 mg/mL DOPG-loaded silicone hydrogel contact lens (lens A) in ATF with 50 ppm PLA2 enzyme solution.
DETAILED DESCRIPTION
[012] Hydrogel contact lenses that sustain release of a beneficial agent during wear and their method of manufacture are described herein. The contact lens can be referred to, herein, as a target molecule-releasing contact lens. The target molecule is released from the lens during wear in amounts that provide a beneficial effect, such as enhancing the comfort of contact lens wear in contact lens wearers or providing a pharmacological effect to the lens wearer.
[013] The present disclosure advantageously provides for sustained target molecule release from hydrogel contact lenses whereby glycerophospholipid associated with hydrogel contact lenses decompose to release the target molecule. For an effective target molecule release rate, the target molecule-group must occupy the sn-2 (middle) position in the glycerophospholipid structure. A C12-C26 fatty alcohol- or fatty acid-group may occupy the sn-1 (end) position in the glycerophospholipid structure.
[014] Glycerophospholipids comprising an acyl group at the sn-2 position may be degraded by the group IIA secretory phospholipase A2 (SPLA2-IIA) enzymes found in human tears. The glycerophospholipid may, for example, be phosphatatidic acid, phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol or bisphosphatidyl glycerol. Preferably the glycerophospholipid is other than a phosphocholine. Phosphocholines have been found to be less susceptible to degradation by the group IIA SPLA2-IIA enzymes found in human tears than other glycerophospholipids. Advantageously, the glycerophospholipid is selected from phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol and phosphatidylglycerol, especially phosphatidylethanolamine or phosphatidylglycerol. The pKa of the amino-group of phosphatidylethanolamine (PE) or phosphatidylserine (PS) is preferably in the range of 8 - 10, preferably in the range of 8.5 - 9.8. Further information on the activity of SPLA2 enzymes is found in Chem Rev. 2011 October 12; 111(10): 6130-6185, “Phospholipase A2 Enzymes: Physical Structure, Biological Function, Disease Implication, Chemical Inhibition, and Therapeutic Intervention” , by Dennis et al.
[015] By “susceptible to digestion” the SPLA2 present in human tears will hydrolyze the acyl group at the sn2 position of the glycerophospholipid resulting in a free target molecule and a lysophospholipid as depicted in Fig. 1.
[016] The target molecule at the sn-2 position is advantageously released and eluted from the lens, while the remainder of the glycerophospholipid is retained within the lens. The release rate of the target molecule may depend on the kinetic of the enzymatic reaction of the phospholipid, in addition to the diffusion rate of the target molecule itself.
[017] In one embodiment, the hydrogel contact lens comprises a polymeric lens body loaded with a glycerophospholipid of the formula (I):
Formula (I) in which X is either -O- or -O(CO)-, Ri is a C11-25 alkyl, Z is H or a phospholipid head group, A is a residue of a target molecule, and -L- is a linking group or a covalent bond, provided that when -L- is a covalent bond and the target molecule is a fatty acid, the fatty acid is not oleic acid, myristic acid, palmitic acid, stearic acid, pentadecanoic acid, heptadic- 12-enoic acid, nonadec- 10- enoic acid or docosahexaenoic acid. The term “alkyl” as used herein encompasses both aliphatic groups having a saturated alkyl chain and to groups having an unsaturated alkenyl chain unless otherwise stated. In examples where Z is a phospholipid head group, Z may be selected from Ci- 10 polyol, ethanolamine (-CH2CH2NH2) and serine (-CH2CH(NH2)COOH). Z is advantageously selected from -CH2CH2NH2, -CH2CH(NH2)COOH and -CH2CH(OH)CH2OH, especially - CH2CH(OH)CH2OH. R1 may, for example, be selected from oleoyl, myristoyl, pentadecanoyl, palmitoyl or stearoyl.
[018] In one example, the glycerophospholipid comprises a fatty acid residue at the sn-2 position other than a fatty acid selected from oleic acid, myristic acid, palmitic acid, stearic acid, pentadec- 12-enoic acid, heptadec- 12-enoic acid, nonadec- 10-enoic acid or docosahexaenoic acid. In a further example, the glycerophospholipid comprises a fatty acid residue in the sn-2 position other than a Cl 2, Cl 4, C22, C24 or C26 fatty acid. Thus, the glycerophospholipid may comprise a fatty acid residue at the sn-2 position other than a fatty acid selected from oleic acid, palmitic acid, stearic acid, pentadec- 12-enoic acid, heptadec- 12-enoic acid, nonadec- 10-enoic acid, a C12 fatty acid, a C14 fatty acid, a C22 fatty acid, a C24 fatty acid or a C26 fatty acid. In one example, the glycerophospholipid comprises an unsaturated fatty acid residue at the sn-2 position other than an unsaturated fatty acid selected from oleic acid, pentadec- 12-enoic acid, heptadec- 12-enoic acid, nonadec-10-enoic acid or docosahexaenoic acid. In a further example the glycerophospholipid comprises an unsaturated fatty acid residue at the sn-2 position other than an unsaturated Cl 2 fatty acid, an unsaturated Cl 4 fatty acid, an unsaturated C22 fatty acid, an unsaturated C24 fatty acid or an unsaturated C26 fatty acid. Thus, the glycerophospholipid may comprise an unsaturated fatty acid residue at the sn-2 position other than an unsaturated fatty acid selected from oleic acid, pentadec- 12-enoic acid, heptadec- 12-enoic acid, nonadec- 10-enoic acid, an unsaturated C12 fatty acid, an unsaturated Cl 4 fatty acid, an unsaturated C22 fatty acid, an unsaturated C24 fatty acid or an unsaturated C26 fatty acid. In one example, the fatty acid residue in the sn-2 position is an unsaturated Cl 5 to C21 fatty acid other than pentadec- 12-enoic acid, heptadec- 12-enoic acid, nonadec-10-enoic acid or oleic acid. In a further example, the fatty acid residue in the sn-2 position is an unsaturated Cl 8 fatty acid other than oleic acid (i.e. (9Z)-octadec-9-enoic acid). In a specific example, the glycerolphospholipid comprises a fatty acid residue in the sn-2 position selected from alpha-linolenic acid, ricinoleic acid, or petroselinic acid.
[019] The target molecule-releasing contact lens comprises a polymeric lens body loaded with an amount of a glycerophospholipid comprising a target molecule at the sn-2 position that sustains release of the target molecule from the lens when in contact with a tear solution comprising SPLA2- IIA. The tear solution can be human reflex tear or an in vitro release media comprising ATF comprising group IIA SPLA2 enzyme solution, e.g., at a concentration of 50 ppm. [020] As an option, one or more glycerophospholipids as described herein can be present in the target molecule-releasing contact lens of the present invention (e.g., two different, three different or more glycerophospholipids as described herein).
[021] When the target molecule is a beneficial fatty acid, -L- of formula I is typically a covalent bond. Fatty acids can improve contact lens comfort by increasing tear film stability, providing anti-inflammatory effects, or inhibiting pain receptors present in ocular tissue such as TRPV 1. Examples of fatty acids that may provide a comfort benefit to a contact lens wearer include linoleic acid or a linolenic acid, especially alpha-linolenic acid (i.e. (9Z,12Z,15Z)-octadeca-9,12,15- trienoic acid, CAS# 463-40-1), ricinoleic acid, or petroselinic acid. Thus, in one example, the invention provides an unworn hydrogel contact lens, preferably a silicone hydrogel contact lens, sealed in a package, comprising a polymeric lens body loaded with a glycerophospholipid of formula (I) in which Ri is a C11-25 alkyl group, X is either -O- or -O(CO)-, A is a residue of a fatty acid, -L- is a covalent bond, and Z is H or a phospholipid head group, wherein the fatty acid is linoleic acid or a linolenic acid, especially alpha-linolenic acid, ricinoleic acid, or petroselinic acid, and where the contact lens releases the fatty acid when in contact with a solution comprising SPLA2- IIA, wherein the fatty acid is a digestion product of the glycerophospholipid.
[022] Non-limiting examples of glycerophospholipids that can be loaded into a contact lens to sustain release of linolenic acid when in contact with a solution comprising SPLA2-IIA include 1- palmitoleoyl-2-linolenoyl phosphatidylethanolamine, 1 -oleoyl-2-linolenoyl phosphatidylethanolamine, 1,2-dilinolenoyl phosphatidylethanolamine, 1 -octadecyl-2-linolenoyl phosphatidylethanolamine, l-palmitoyl-2-linolenoyl phosphatidylglycerol, 1 -oleoyl-2-linolenoyl phosphatidylinositol, and l-oleoyl-2-linolenoyl phosphatidylserine. In the above examples the linolenoyl group is preferably alpha-linolenoyl, such that the contact lens sustains release of alpha- linolenic acid. Non-limiting examples of glycerophospholipids that can be loaded into a contact lens to sustain release of ricinoleic acid when in contact with a solution comprising SPLA2-IIA include 1- palmitoleoyl-2-ricinoleoyl phosphatidylethanolamine, 1 -oleoyl-2-ricinoleoyl phosphatidylethanolamine, 1 ,2-ricinoleoyl phosphatidylethanolamine, 1 -octadecyl-2-ricinoleoyl phosphatidylethanolamine, 1 -palmitoyl-2-ricinoleoyl phosphatidylglycerol, l-oleoyl-2- ricinoleoyl phosphatidylinositol, and l-oleoyl-2-ricinoleoyl phosphatidylserine. Non-limiting examples of glycerophospholipids that can be loaded into a contact lens to sustain release of petroselinic acid when in contact with a solution comprising SPLA2-IIA include 1 -palmitoleoyl-2- petroselinoyl phosphatidylethanolamine, l-oleoyl-2-petroselinoyl phosphatidylethanolamine, 1,2- petroselinoyl phosphatidylethanolamine, 1 -octadecyl-2-petroselinoyl phosphatidylethanolamine, l-palmitoyl-2- petroselinoyl phosphatidylglycerol, l-oleoyl-2-petroselinoyl phosphatidylinositol, and l-oleoyl-2- petroselinoyl phosphatidylserine. The foregoing glycerophospholipids can be synthesized by routine acylation reaction between the desired target molecule fatty acid and a suitable host lysophospholipid.
[023] When the target molecule lacks a hydrocarbon chain of at least two carbons linked to a terminal carboxylic acid group, -L- may be a linking group that reduces the steric hindrance a target molecule may otherwise cause in the absence of the linking group on the enzymatic cleavage of the ester bond at position sn-2 of the glycerophospholipid. Prodrugs comprising a glycerophospholipid covalently linked, via a linking group at the sn2 position, to a small molecule drug are well known in the pharmaceutical industry. Linking groups that enable phospholipases, such as SPLA2 to digest the ester bond at the sn-2 position of a glycerophospholipid of formula (I) are known. In one example, -L- is a saturated or unsaturated, straight-chain or branched, substituted or unsubstituted hydrocarbon chain having from 2 to 15 carbon atoms, which may include cyclic elements, and optionally is interrupted by one or more atoms selected from oxygen and sulfur atoms. A terminal CH or CH2 of the linking group may be covalently bound to the target molecule residue (A) of formula (I). Alternatively, a terminal O, S, NH or C(O) group of the linking group may be covalently bound to the target molecule residue (A) of formula (I). Methods for synthesizing glycerophospholipids containing hydrocarbon linking groups at the sn2 position and their reactions with target molecules to form glycerophospholipids of formula (I) where -L- is a linking group are known in the art (see e.g. U.S. Pat. No. 6,774,121 by Kozak etal.,- Markovic et al., Pharmaceutics 2022, 14:675; Dahan et al., Eur. J. Pharm. Sci. 2017, 108, 78-85; and Pedersen et al., J. Med. Chem. 2010, 53, 3782-3792). Oligopeptides and oligo(ethylene glycol) spacers are additional types of linking groups that can reduce steric hindrance by a target molecule residue to permit SPLA2 digestion of the ester bond at the sn-2 position of a glycerophospholipid of formula (I) (see e.g. Rosseto, R. and Hajdu, J. Chem. Phys. Lipids 2014, 183, 110-116, and Rosseto, R., and Hajdu, J. Chem. Phys. Lipids 2010, 163, 110-116). Computational simulation methods are available to guide the selection of linking groups to link a target molecule of interest to the sn2 position of a glycerophospholipid whilst preserving enzymatic site recognition by SPLA2 enzyme (see e.g. Markovic et al. “Computation Simulations to Guide Enzyme-Mediated Prodrug Activation”, Int. J. Mol. Sci. 2020, 21, 3621).
[024] 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 (i.e. target molecule residues) that can be attached either directly or via a linking group at the sn2 position of a glycerophospholipid of formula (I) include nonsteroidal anti-inflammatory agent such as ketorolac tromethamine, diclofenac, and ketoprofen, antihistamines such as azelastine, emedastine, ketotifen, and olopatadine, muscarinic acetylcholine receptor antagonists such as atropine and pirenzepine, and antibiotics such as besifloxacin, cyclosporine, ofloxacin, and gentamicin. Accordingly, the target molecule may be a nonsteroidal anti-inflammatory agent, an antihistamine, a muscarinic acetylcholine receptor antagonist, or an antibiotic.
[025] In one example the target molecule is an osmoprotectant. Non-limiting examples of osmoprotectants include betaine and derivatives thereof (e.g. glycine betaine, L-proline betaine, P-alanine betaine, N-alkyl modified betaine derivatives having an alkyl spacer between the oppositely charged ends including y-butyrobetaine, et al.), amino acids (e.g. glutamine, proline and alanine), sugars (e.g. trehalose, mannitol, and sucrose), L-carnitine including acyl modified L- carnitines, and taurine, and derivatives of the foregoing.
[026] Other classes of beneficial agents (i.e. target molecules) that may be released from the glycerophospholipid of formula (I) include nutraceuticals such as alpha lipoic acid, lutein, and zeaxanthin, and antimicrobial agents such as epsilon poly-L-lysine.
[027] As one example, the contact lens is a non-silicone hydrogel that contains no or essentially no silicon-containing components, which is a reaction product of a polymerisable composition for a non-silicone hydrogel. A hydrogel containing less than 3 wt%, especially less 2 wt%, preferably less than 1 wt%, of units derived from monomers or macromers that contain than silicon is a non- silicone hydrogel that contains essentially no silicon-containing components. Non-silicone hydrogel contact lenses are typically formed from polymerization of one or more hydrophilic monomers such as 2-hydroxyethyl methacrylate (HEMA) or vinyl alcohol, optionally in combination with other monomers, and contains no siloxane molecule. The polymeric lens body of the hydrogel contact lens may, for example, be a reaction product of a polymerisable composition that comprises at least one monomer of N-vinylpyrrolidone, (hydroxyethyl)methacrylate, glycidyl methacrylate, ethylene glycol dimethacrylate and/or polycarbonates or any combination thereof, wherein the composition optionally contains no siloxane monomers or macromers.
[028] The hydrogel contact lens may be a silicone hydrogel. As an example, the silicone hydrogel contact lens comprises a polymeric lens body that is the reaction product of a polymerisable composition comprising at least one siloxane monomer or macromer and at least one hydrophilic monomer and/or at least one hydrophilic polymer. Conveniently, as described in more detail below, a cured polymeric lens body for a silicone hydrogel may be extracted in an extraction solvent containing the glycerophospholipid. Consequentially, the desired amount of glycerophospholipid becomes associated with the polymeric lens body. The glycerophospholipid may be adhered to the polymeric lens body by electrostatic and/or hydrophobic interaction, and/or may be physically entrapped by the polymer network of the polymeric lens body. Alternatively, or additionally, the glycerophospholipid may be added to the polymerisable composition, e.g. prior to curing.
[029] Advantageously, the hydrogel, i. e the conventional hydrogel or silicone hydrogel, is neutral or positively charged (i.e. cationic), preferably neutral. The term ‘neutral’ refers to units derived from non-ionic or zwitterionic molecules. The presence of an overall negative charge has been found to inhibit the activity of the SPLA2 enzyme and thus reduce the release of target molecule from the glycerophospholipid-containing contact lens. Preferably the contact lens does not contain anionic units such as units derived from methacrylic acid (MAA) or 2-methacryloxy ethyl phosphate (MOEP).
[030] The polymeric lens body typically may optionally have an equilibrium water content (EWC) of at least 20%, such as at least 25% or at least 30%. In some examples, the polymeric lens body typically has an equilibrium water content (EWC) of at least 40%, such as at least 45%. Advantageously, hydrogel contact lens is a high water content contact lens having polymeric lens body with an EWC of at least 50%. The contact lens may be a US Food and Drug Adminstration (FDA) group II, non-ionic high water conent lens or an FDA group IV, ionic high water conent lens that is cationic or a silicone hydrogel contact lens having an EWC of at least 40% or at least 45%. Advantageously the contact lens is an FDA group II, non-ionic high water content lens or a silicone hydrogel contact lens having an EWC of at least 40% or at least 45%. It has been found that EWC of greater than 40 % leads to increased SPLA2 enzyme activity leading to fatty acid release.
[031] The amount of glycerophospholipid “loaded to” or “associated with” the polymeric lens body refers to the total amount of glycerophospholipid that can be extracted from the contact lens by an isopropyl alcohol (IP A) extraction method as described in Example 2 below. The glycerophospholipid associated with the polymeric lens body may be embedded within the matrix of the polymeric material or attached to the polymeric material, e.g. via hydrogen bonds or electrostatic interactions. Advantageously, glycerophospholipid associated with 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, especially no more than 10 % by weight, of the glycerophospholipid is extracted from the polymeric lens body into deionized water on immersing the lens in 5 mL deionized water. In one example, glycerophospholipid is loaded to the polymeric lens body in a loading solution comprising an alcohol, such as ethanol and a glycerophospholipid ranging from 1 - 10 mg/mL. The loading solution may, for example, comprise approximately 60% ethanol and approximately 40% water. In one specific example, the loading solution comprises 2 mg/mL glycerophospholipid. The lens may be immersed in the loading solution at 25 °C for 3 hours in order to load the glycerophospholipid to the polymeric lens body. In another example, the amount of glycerophospholipid associated with the polymeric lens body can be at least about 1 pg, 25 pg, 50 pg, 100 pg, 200 pg or 300 pg up to about 400 pg, 500 pg, 600 pg, 700 pg, 800 pg, 900 pg or 1000 pg, such as from about 300 pg to about 1000 pg. Preferably the amount of glycerophospholipid associated with the polymeric lens body is from 100 pg, to 1000 pg, especially from 300 pg to 800 pg.
[032] As used herein, and unless context dictates otherwise, a reference to an amount of target molecule released from the target molecule-releasing contact lens over a specified duration of time or to a “release profile” of the target molecule, refers to the amount of target molecule released from the lens as measured using the in vitro release media (the ATF as described in Table 2 below with the addition of 50 ppm PLA2-IIA, e.g. recombinant human, group IIA, phospholipase 2- acylhydrolase enzyme or bee venom SPLA2, as described in Example 4 below). The contact lens may have an in vitro target molecule release profile of at least 0.05 pg/hr or from 0.05 pg/hr to 50 pg/hr target molecule from the lens, such as 0.1 pg/hr to 25 pg/hr, or from 0.5 pg/hr to 10 pg/hr, or from 1 pg/hr to 5 pg/hr target molecule from the lens, following initial immersion into the release media at 35 °C. Advantageously, the contact lens sustains the release of the target molecule for at least 4 hours, such as for at least 8 hours, optionally for at least 10 hours. Advantageously, the contact lens releases from 0.05 pg/hr to 50 pg/hr target molecule from the lens, such as 0.01 pg/hr to 25 pg/hr, or from 0.5 pg/hr to 10 pg/hr, or from 1 pg/hr to 5 pg/hr target molecule per hour for at least the first 10 hours following immersion in the release media at 35 °C. Thus, the contact lens of the invention loaded with the glycerophospholipid of the formula (I) may have an in vitro target molecule release profile of at least 0.05 pg/hr, preferably at least 0.1 pg/hr, such as 0.1 pg/hr to 25 pg/hr, for example 0.5 pg/hr to 10 pg/hr, or 1 pg/hr to 5 pg/hr target molecule from the lens for at least 4 hours, such as for at least 8 hours, optionally for at least 10 hours, determined by placing the lens into a 6 mb glass vial containing 3 mL of the in vitro release media (the ATF as described in Table 2 with the addition of 50 ppm SPLA2), shaking the vials at 50 rpm in a 35 °C incubator, and at 2 hour increments (e.g. 2 hr, 4 hr, 6 hr, 8 hr and 10 hr) removing a 2.5 ml sample of release media from the vial and analyzing the sample for target molecule content by liquid chromatography- mass spectrometry (LCMS) or other analytical method appropriate for the target molecule of interest and replacing 2.5 ml of fresh release media into vial, and continuing to incubate the lens in the vial in the shaker for a further 2 hours until the next increment.
[033] As an option, the packaging solution as described herein does not contain any comfort agents.
[034] As an option, the only phospholipid present in the contact lens or associated with the contact lens is a glycerophospholipid of formula (I).
[035] As an option, the only source of a target molecule released or present with the contact lens is from the glycerophospholipid present.
[036] The present invention has the ability to provide an improved controlled release of a target molecule compared to a free target molecule being associated with the contact lens (i.e., not sourced from a glycerophospholipid). For instance, the release can be more linear compared to a free target molecule being only used/associated with the contact lens.
[037] The release of the target molecule from the digestion of the glycerophospholipid can be considered a tear-controlled release of the target molecule. [038] The polymeric lens body may comprise any hydrogel material suitable for use as a contact lens material. Advantageously, the hydrogel, i.e. the conventional hydrogel or silicone hydrogel, is neutral or positively charged (i.e. cationic), preferably neutral. The term ‘neutral’ refers to units derived from non-ionic or zwitterionic molecules. The presence of an overall negative charge has been found to inhibit the activity of the SPLA2 enzyme and thus reduce the release of target molecule from the glycerophospholipid-containing contact lens. Preferably the contact lens does not contain anionic units such as units derived from methacrylic acid (MAA) or 2-methacryloxy ethyl phosphate (MOEP).
[039] The polymeric lens body typically has an equilibrium water content (EWC) of at least 40%, such as at least 45%. Advantageously, hydrogel contact lens is a high water content contact lens having polymeric lens body with an EWC of at least 50%. The contact lens may be a US Food and Drug Adminstration (FDA) group II, non-ionic high water content lens or an FDA group IV, ionic high water content lens that is cationic or a silicone hydrogel contact lens having an EWC of at least 40% or at least 45%. Advantageously the contact lens is an FDA group II, non-ionic high water content lens or a silicone hydrogel contact lens having an EWC of at least 40% or at least 45%. It has been found that EWC of greater than 40 % leads to increased SPLA2 enzyme activity leading to fatty acid release.
[040] As one example, the contact lens is a non-silicone (i.e. “conventional”) hydrogel that contains no or essentially no silicon-containing components, which is a reaction product of a polymerizable composition for a non-silicone hydrogel. A hydrogel containing less than 3 wt%, especially less 2 wt%, preferably less than 1 wt%, of units derived from monomers or macromers that contain silicon is a non-silicone hydrogel that contains essentially no silicon-containing components. Non-silicone hydrogel contact lenses are typically formed from polymerization of one or more hydrophilic monomers such as 2-hydroxyethyl methacrylate (HEMA) or vinyl alcohol, optionally in combination with other monomers, and contains no siloxane molecule. The polymeric lens body of the hydrogel contact lens may, for example, be a reaction product of a polymerisable composition that comprises at least one monomer of N-vinylpyrrolidone, (hydroxyethyl)methacrylate, glycidyl methacrylate, ethylene glycol dimethacrylate and/or polycarbonates or any combination thereof, wherein the composition optionally contains no siloxane monomers or macromers.
[041] A silicone hydrogel material for contact lenses is typically formed by curing a polymerisable composition (i.e., a monomer mixture) comprising at least one siloxane monomer or macromer and at least one hydrophilic monomer or at least one hydrophilic polymer, or a combination thereof. Conveniently, as described in more detail below, a cured polymeric lens body for a silicone hydrogel may be extracted in an extraction solvent containing the glycerophospholipid. Consequentially, the desired amount of glycerophospholipid becomes associated with the polymeric lens body. The glycerophospholipid may be adhered to the polymeric lens body by electrostatic and/or hydrophobic interaction, and/or may be physically entrapped by the polymer network of the polymeric lens body. Alternatively, or additionally, the glycerophospholipid may be added to the polymerisable composition, e.g. prior to curing. As used herein, the terms “siloxane monomer” refers to molecules that contains at least one Si-0 group and at least one polymerisable functional group. “Siloxane macromers” refers to a silicon- containing molecule with at least one polymerisable 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. [042] Siloxane monomers and macromers 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.) In some examples, the polymerisable composition comprises a total amount of siloxane monomer or macromer of at least 10 wt.%, 20 wt.%, or 30 wt.% up to about 40 wt.%, 50 wt.%, 60 wt.%, or 70 wt.%. Unless specified otherwise, as used herein, a given weight percentage (wt.%) of a component of the polymerisable composition is relative to the total weight of all polymerisable ingredients and interpenetrating polymer network (IPN) polymers (as described further below) in the polymerisable composition. The weight of the polymerisable composition contributed by components, such as diluents, that do not incorporate into the final contact lens product are not included in the wt.% calculation.
[043] In a specific example, the polymerisable composition comprises a 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 polymerisable carbon-carbon double bond (i.e., a vinyl group) present in its molecular structure that is not part of an acryl group, where the carboncarbon double bond of the vinyl group is less reactive than the carbon-carbon double bond present in a polymerisable methacrylate group under free radical polymerization. As used herein, the term “acryl group” refers to the polymerisable group present in acrylate, methacrylates, acrylamides, etc. Thus, while carbon-carbon double bonds are present in acrylate and methacrylate groups, as used herein, such polymerisable groups are not considered to be vinyl groups. Further, as used herein, a monomer is “hydrophilic” if at least 50 grams of the monomer are fully soluble in 1 liter of water at 20 °C (i.e., ~ 5% soluble in water) as determined visibly using a standard shake flask method. In various examples, the hydrophilic vinyl monomer is N-vinyl-N-methylacetamide (VMA), or N-vinyl pyrrolidone (NVP), or 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 polymerisable composition comprises at least 10 wt.%, 15 wt.%, 20 wt.%, or 25 wt.% up to about 45 wt.%, 60 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 polymerisable composition equals the sum of the wt.% of each ingredient in the composition that falls within the class. Thus, for example, a polymerisable 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. In one example, the hydrophilic vinyl monomer is a vinyl amide monomer. Exemplary hydrophilic vinyl amide monomers are VMA and NVP. In a specific example, the polymerisable composition comprises at least 25 wt.% of a vinyl amide monomer. In a further specific example, the polymerisable composition comprises from about 25 wt.% up to about 75 wt.% of VMA or NVP, or a combination thereof. Additional hydrophilic monomers that may be included in the polymerisable composition are N,N-dimethylacrylamide (DMA), 2-hydroxyethyl methacrylate (HEMA), ethoxy ethyl methacrylamide (EOEMA), ethylene glycol methyl ether methacrylate (EGMA), and combinations thereof.
[044] In addition, or as an alternative to a hydrophilic monomer, the polymerisable composition may comprise a non-polymerisable hydrophilic polymer, which results in a polymeric lens body comprising an interpenetrating polymer network (IPN) with the non-polymerisable hydrophilic polymer interpenetrating the silicone hydrogel polymer matrix. In this example, the non- polymerisable 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 polymerisable 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. In a specific example, the IPN polymer is polyvinylpyrrolidone (PVP). In other examples, the polymerisable composition is free or substantially free of polyvinylpyrrolidone or other IPN polymer.
[045] As an option, one or more non-silicon containing hydrophobic monomers can be present as part of the polymerisable composition. A hydrophobic monomer can be understood to be any monomer for which 50 grams of the monomer are not visibly fully soluble in 1 liter of water at 20 °C as determined using a standard shake flask method. 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, or isobornyl methacrylate (IBM), or trifluoroethyl methacrylate, or hexafluoroisopropyl methacrylate, or tetrafluoropropyl methacrylate, or hexafluorobutyl methacrylate, or any combinations thereof.
[046] The hydrophobic monomer, if used, can be present in the reaction product of the polymerisable 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 polymerisable composition. [047] The polymerisable composition may additionally comprise at least one cross-linking agent. As used herein, a “cross-linking agent” is a molecule having at least two polymerisable 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. The cross-linking agent may comprise an acryl group or a vinyl group, or both an acryl group and a vinyl group. In certain examples, the cross-linking agent is free of siloxane moieties, i.e., it is a non-siloxane cross-linking agent. A variety of cross-linking agents suitable for use in silicone hydrogel polymerisable compositions are known in the field (see, e.g., U.S. Pat. No. 8,231,218, incorporated herein by reference). Examples of suitable crosslinking agents include, without limitation, lower alkylene glycol di(meth)acrylates such as triethylene glycol dimethacrylate, diethylene glycol dimethacrylate, poly(lower alkylene) glycol di(meth)acrylates and lower alkylene di(meth)acrylates; divinyl ethers such as triethyleneglycol divinyl ether, di ethyleneglycol 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; and combinations thereof.
[048] As will be appreciated by those skilled in the art, the polymerisable composition may comprise additional polymerisable or non-polymerisable ingredients conventionally used in contact lens formulations such as one or more of a polymerization initiator, a UV absorbing agent, a tinting agent, an oxygen scavenger, a chain transfer agent, or the like. In some examples, the polymerisable composition may include an organic diluent in an amount to prevent or minimize phase separation between the hydrophilic and hydrophobic components of the polymerisable composition, so that an optically clear lens is obtained. Diluents commonly used in contact lens formulations include hexanol, ethanol, and/or other primary, secondary or tertiary alcohols. In other examples, the polymerisable 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 polymerisable composition. Non-limiting examples of these and additional ingredients that may be included in the polymerisable composition are provided in U.S. Pat. No. 8,231,218.
[049] Non-limiting examples of silicone hydrogels that may be used include comfilcon A, fanfilcon A, stenfilcon A, senofilcon A, senofilcon C, somofilcon A, narafilcon A, delefilcon A, narafilcon A, lotrafilcon A, lotrafilcon B, balafilcon A, samfilcon A, galyfilcon A, and asmofilcon A.
[050] A specific example of a hydrogel contact lens of the present invention is one that is based on a polymerisable composition comprising from 25 wt.% to 55 wt.% of siloxane monomer(s) or macromer(s), from 30 wt.% to 55 wt.% of a vinyl monomer selected from NVP, VMA, or combinations thereof, and optionally 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, and optionally 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) or any combination thereof. Silicone hydrogel materials made from this specific embodiment of polymerisable composition include stenfilcon A, comfilcon A, somofilcon A, fanfilcon A, and enfilcon A. In a further example, the above-described polymerizable composition comprises the siloxanes of stenfilcon A, specifically a first siloxane having the structure represented by Formula (II),
Formula (II) and a second siloxane having the structure represented by Formula (III),
Formula (III).
[051] Conventional methods can be used to manufacture the contact lens of the invention. As an example, a polymerisable composition for a 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. After extraction, the lens body is hydrated in one or more hydration liquids such as water or an aqueous solution and packaged. Exemplary methods of manufacturing silicone hydrogel contact lenses are described in U.S. Pat. No. 8,865,789.
[052] The glycerophospholipid is typically loaded into the polymeric lens during the extraction step. Generally, after curing, the polymeric lens body is swelled in an extraction solvent, such as ethanol, which contains the glycerophospholipid. When the extracted polymeric lens body is subsequently placed in a hydration solution, such as deionized (DI) water, the extraction solvent is removed, and the glycerophospholipid remains associated with the polymeric lens body.
[053] Examples of the extraction solvents and hydration liquids used in an extraction and hydration process can consist of denatured ethanol, a 50/50 (by vol) mixture of denatured ethanol and deionized water, and deionized water. As an example, the extraction and hydration process can involve at least one extraction step in denatured ethanol followed by a 50: 50 mixture of ethanol water followed by at least one hydration step in deionized water, and wherein each extraction and hydration step can last from about 15 minutes to about 3 hours at a temperature of from about 20 °C and to about 30 °C. An extraction solvent can contain the glycerophospholipid to achieve uploading of the glycerophospholipid to the polymeric lens body.
[054] Any extraction solvent used as an uploading solution for the glycerophospholipid can contain a concentration of glycerophospholipid of 1 - 50 mg/mL, such as from 2 to 20 mg/mL. This concentration can be at least 1 mg/mL, at least 3 mg/mL, at least 5 mg/mL, or at least 10 mg/mL of glycerophospholipid. In one example, the concentration of glycerophospholipid in the extraction solvent is from about 2 mg/mL to about 20 mg/mL, such as from 3 to 10 mg/ml. The amount of glycerophospholipid loaded to the polymeric lens body can be from 1 pg to 1000 pg. The amount glycerophospholipid loaded to the polymeric lens body can be at least 100 pg, at least 200 pg, or at least 500 pg. Preferably, the amount of glycerophospholipid loaded to the polymeric lens body is at least 300 pg, e.g., from 300 pg to 1000 pg.
[055] In some examples, the glycerophospholipid, once loaded 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 hydrogel contact lens in a packaging solution, or during storage in its packaging solution. Thus, the packaging solution that the contact lens is immersed in, before autoclaving, or immediately after autoclaving, or after 1 day thereafter at 25 °C, or after 30 days thereafter at 25 °C, or after 60 days thereafter at 25 °C, or after 120 days thereafter at 25 °C, has less than 10 ppm glycerophospholipid comprising a target molecule residue at the sn-2 position released into the packaging solution from the contact lens or less than 5 ppm or less than 1 ppm or 0 ppm released from the contact lens into the packaging solution. Advantageously, no more than 20% by weight, especially less than 10% by weight, preferably less than 5% by weight, of the glycerophospholipid associated with the polymeric lens body is released into the packaging solution after storage for at least 1 day at 25 °C. Whether the glycerophospholipid is released from a contact lens during autoclave or storage can be determined by testing for the presence of the glycerophospholipid in the packaging solution using LCMS or other suitable analytical method.
[056] As part of the present invention, the contact lens can be sealed in a contact lens package. The packaging solution sealed within the contact lens package may be any conventional contactlens 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 beneficial agent. In some examples, the packaging solution may comprise polysaccharides (e.g., hyaluronic acid, 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. In other examples, the packaging solution may comprise an ophthalmic drug. 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 mOsm/kg to 400 mOsm/kg, and typically from about 270 mOsm/kg up to about 310 mOsm/kg.
[057] It will be appreciated that conventional manufacturing methods can be used to manufacture the sealed contact lens package. In a method of manufacturing a contact lens package, the method can include 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 0.5-1.5 ml. The receptacle may be made from any suitable material, such as glass or plastic. 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 at least 121° C for at least 20 minutes.
EXAMPLES [058] The following examples illustrate certain aspects and advantages of the present invention, which should be understood not to be limited thereby.
[059] Example 1. Assay for testing susceptibility of phospholipid digestion by sPLV-IIA.
[060] Each phospholipid-loaded lens is removed from its package and placed in a 6 mL glass vial containing 5 mL of the ATF described in Example 2 at room temperature on a shaker at 125 rpm overnight to wash the lens.
[061] Each lens is rinsed in a 6 ml glass vial containing a fresh aliquot of 5 mL ATF for 30 minutes prior to running the digestion assay.
[062] A 50 ppm solution of sPLAz is prepared in ATF by adding 200 pl ATF to a tube containing 10 pg recombinant human PLA2G2A (Creative BioMart, Cat. No. PLA2G2A-669H). The solution is referred to as ATF+sPLA?. As an option, human reflex tear may be used instead of ATF+sPLA?. Two 4 mm pieces are cut from each lens. One piece of each lens is placed in a tube with 100 pL ATF and the other piece is placed in a tube containing 100 pL ATF+sPLA?. The tubes are incubated at 35±2 °C for 4 hours with no shaking.
[063] 50 pl of the release media from each lens at T=4 hr (“T” meaning “time”) is transferred to HPLC vials and 500 pl isopropanol (IP A) is added and mixed well. T=0 hr HPLC vials are also prepared (50 pl ATF + 500 pl IP A). All vials are sonicated for 15 minutes and centrifuged. The supernatant is removed for LCMS injection.
[064] 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 and 0.2% (v/v) ammonium hydroxide, and B = 10% acetonitrile in IPA with 10 mM ammonium acetate and 0.2% (v/v) ammonium hydroxide. The mass spec detector is run at negative electrospray mode. The peak for the particular target molecule of interest in the supernatants (i.e., the beneficial agent that is released from the sn-2 position of the phospholipid in the contact lens) is measured. The ratio of target molecule peak area in ATF with and without SPLA2 is calculated.
[065] Example 2. sPLA -mediated phospholipid digestion from stenfilcon A lenses loaded with different phospholipids.
[066] The phospholipids shown in Table 1 were obtain from Avanti Polar Lipids. 3 mg/ml loading solutions of the phospholipids shown in Table 1 were prepared by adding 2.4 mL ethanol to 9 mg of phospholipid, sonicating (up to 14 minutes) then adding 0.6 mL DI water and sonicating again (up to 15 minutes) to dissolve the phospholipid.
[067] Table 1.
[068] Hydrated contact lenses made from stenfilcon A were washed three times in 3 mL purified water for 30 minutes each time. Each washed lens was placed in 3 mL of a phospholipid loading solution and incubated at room temperature with gentle shaking at 75 rpm for 3 hours. The loaded lenses were then rinsed and hydrated in several exchanges of DI water. The lenses were packaged in a buffered saline contact lens packaging solution and autoclaved.
[069] An artificial tear fluid (ATF) was prepared by adding the first three ingredients listed in Table 2 to a clean class vial and then adding 30 mL of the fourth ingredient.
[070] Table !.
[071] After autoclaving, each lens was tested for susceptibility to phospholipid digestion by SPLA2-IIA using the method described in Example 1. The peak for oleic acid (OA) in the supernatants sent for LCMS analysis were measured (m/z trace = 281.24). The ratio of OA in ATF with and without SPLA2 was calculated. The results are shown in Table 3.
[072] Table 3 Oleic acid peak areas in ATF with and without SPLA2.
[073] Example 3. DOPG-Loaded Stenfilcon A Contact Lenses
[074] 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.
[075] 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.
[076] 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 lense. Silicone hydrogel lens materials that are more hydrophobic may require a second overnight extraction in order to extract all the DOPG, in which case the IPA from the first extraction step is removed and replaced with 3 mL fresh IPA and shaken overnight at 300 rpm at room temperature. 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 4.
[077] Table 4.
[078] Example 4. Determining Target Molecule Release Profiles [079] To determine the release profile of a target molecule from a silicone hydrogel contact lens loaded with a glycerophospholipid comprising a target molecule linked at the sn-2 position, the lens is removed from its package and placed in a 6 mL glass vial containing 5 mL of ATF (described in Example 1) at room temperature on a shaker at 125 rpm overnight to wash the lens.
[080] Each lens is then transferred to a 6 mL glass vial containing 3 mL of the ATF+SPLA2 in vitro release media described in Example 1 at 35 °C. As an alternative, phospholipase A2 from honeybee venom (CAS No. 9001-84-7) may be used in place of the recombinant human PLA2G2A at the same concentration (50 ppm). The vials are placed on a shaker at 50 rpm in a 35 °C incubator, and at 2-hour increments (e.g., 2 hr, 4 hr, 6 hr, 8 hr and 10 hr). 2.5 ml of the in vitro release media is removed from each vial and submitted for analysis. If the release media is not to be analysed right away at that specific time point, a sample is taken and mixed with IPA (1: 10 v/v ratio) to stop enzymatic activity. Following that, 2.5 ml of fresh ATF+SPLA2 in vitro release media is added back to each vial and the lens is continued to be incubated. At the end of the release experiment, the amount of target molecule in the release media at each timepoint is determined by a suitable analytical method.
[081] Example 5. Oleic Acid Release from a 5 mg/mL DOPG-Loaded Contact Lens (Lens A) and from a 3 mg/mL DOPG-Loaded Contact Lens (Lens B).
[082] Silicone hydrogel contact lenses were prepared as in Example 2 using 5 mg/mL DOPG loading concentration (lens A) and 3 mg/mL DOPG loading concentration (lens B). The oleic acid release rate of lenses A and B was determined using the method of Example 4 with ATF release medium contained 50 ppm bee venom SPLA2 enzyme (CAS No. 9001-84-7). The oleic acid release into the in vitro release media samples were tracked every 2 hours. The release profile for lens A is shown in FIG. 2. Results for both lenses are shown in Table 5, where the cumulative oleic acid release (from T=0) at each time point is given.
Table 5. [084] The results demonstrate that sustained SPLA2 -mediated release of a target molecule from a contact lens loaded with a glycerophospholipid is achievable.
[085] 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.
[086] References herein to “an example” or “a specific example” or “an aspect” or “an embodiment” or similar phrase, are intended to introduce a feature or features of the target molecule-releasing hydrogel contact lens of the invention or components thereof, the sealed contact lens package or components thereof, or method of manufacturing the target moleculereleasing hydrogel contact lens of the invention (depending on context) that can be combined with any combination of previously-described or subsequently-described examples, aspects, embodiments (i.e. features), unless a particular combination of features is mutually exclusive, or if context indicates otherwise. Further, as used in this specification, the singular forms “a,” “an,” and “the” include plural referents (e.g., at least one or more) unless the context clearly dictates otherwise. Thus, for example, reference to a “contact lens” includes a single lens as well as two or more of the same or different lenses.
[087] 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.
[088] The present invention can include any combination of the various features or embodiments described above including the above numbered clauses and/or in the claims below as set forth in sentences and/or paragraphs. Any combination of disclosed features herein is considered part of the present invention and no limitation is intended with respect to combinable features.
[089] 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.