Patent Application
20150168605
The present invention relates generally to methods, compositions, and articles comprising polymeric materials, and particularly for use of these materials in contact lenses.
Photochromic compounds undergo a color change upon irradiation, and the photoproduct can be reversed back to the initial state thermally and/or by subsequent irradiation at a suitable wavelength of light. This interesting effect can be used in applications such as ophthalmic lenses, nonlinear device components, optical waveguides and shutters, light modulators, optical storage media and delay generators, as well as other optical devices depending on the response time and other properties of the photochromic compounds.
The use of photochromic compounds to produce a variety of tinted articles is known. For example, photochromic spectacles have found some success, providing the wearer the convenience of visible light absorbing lenses (sunglasses) only when exposed to bright light (e.g., daylight). Under low light conditions, the lenses are generally substantially colorless and provide optimal night and indoor vision. Photochromic spectacles eliminate the need for switching between sunglasses and regular spectacles.
However, existing photochromic compounds and methods for producing very thin photochromic articles, such as contact lenses, have been met with limited success. In some cases, the articles do not provide enough darkening to produce a noticeable difference to the wearer, and/or the existing photochromic compounds and manufacturing methods are not compatible with the materials and/or processes used for ophthalmic devices. In addition, the timescale of the thermal back-fading of the colored form of the photochromic compound to the colorless form is usually minutes to hours, which is too slow for certain applications.
In addition, it would be desirable for contact lenses and other ophthalmic applications to block ultraviolet radiation.
Accordingly, improved compositions, methods, and articles are needed.
In some embodiments, a method of forming a polymeric material is provided comprising polymerizing a bicontinuous microemulsion comprising water, a monomer, and a surfactant copolymerizable with said monomer, to form a porous polymeric material comprising a polymer matrix defining interconnected pores at least partially filled by water, wherein said microemulsion further comprises at least one ultraviolet blocking agent.
In some embodiments, a photochromic polymeric material for use in an ophthalmic device is provided comprising a polymer matrix defining interconnected pores, said interconnected pores containing water and said polymer matrix being substantially hydrophobic; and wherein the polymeric material further comprises at least one ultraviolet blocking agent.
In some embodiments, a composition is provided comprising between about 20 wt % and about 22.5 wt % 2-hydroxylethyl methacrylate (HEMA); between about 8 wt % and about 9 wt % glycidyl methacrylate (GMA); between about 29 wt % and about 31 wt % ω-methoxy poly(ethylene oxide)40 undecyl α-methacrylate macromonomer (C1-PEO-C11-MA-40); between about 33 wt % and about 36 wt % H2O; between about 0.3 wt % and about 3.5 wt % ethylene glycol dimethacrylate (EDGMA); between about 0.1 wt % and about 0.35 wt % 2,2-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (AIPH); between about 0.025 wt % and about 4 wt % hydroxybenzotriazole (HBT); between about 0.025 wt % and about 1 wt % benzophenone (BP); and between about 0 wt % and about 0.1 wt % hydroxyphenyl triazine (HPT).
Other aspects, embodiments, and features of the invention will become apparent from the following detailed description when considered in conjunction with the accompanying drawings. The accompanying figures are schematic and are not intended to be drawn to scale. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the invention shown where illustration is not necessary to allow those of ordinary skill in the art to understand the invention. All patent applications and patents incorporated herein by reference are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
The present invention relates generally to polymeric materials, and related methods and articles. In some embodiments, an article is an ophthalmic lens, more particularly, a contact lens. A polymeric material may comprise a polymer matrix defining a plurality of interconnected pores. In some embodiments, the polymeric material may comprise at least one photochromic agent and/or a ultraviolet-absorbing (UV-absorbing) agent. The photochromic agent and/or UV-absorbing agent may be substantially contained in the polymer matrix. In some cases, an ophthalmic lens may be used to protect eyes from strong light (e.g., UV-light).
Photochromic materials are materials which change color upon exposure to light (e.g., UV-light). Upon exposure to light, a photochromic material changes from a first colored state (e.g., colorless) to a second colored state (e.g., darkened), which is referred to as direct chromism. The reverse transition is referred to as reverse photochromism. In some cases, reverse chromism may be may be accelerated by heating. In addition, reverse photochromism may be inhibited due to stabilizing interactions of a photochromic agent with a polymer matrix or other component or material. Advantageously, the photochromic polymeric materials described herein may exhibit rapid reverse photochromism as compared to currently known materials. Without wishing to be bound by theory, this may be due, at least in part, to the ability to control the nano- or micro-environment surrounding the photochromic agent. The microenvironment may be controlled by varying the components provided in a bicontinuous microemulsion, as described herein. In some cases, the nano- or micro-environment may have an effect on the fast and ultrafast events undergone by a trapped photochromic agent. Generally, the degree of confinement of a photochromic agent may be affected by various factors including the structure, the orientation of the photochromic agent, the rigidity of the complex, and the polarity of a nano- or microcavity. The relatively hydrophilic interior and hydrophobic exterior of the molecular pockets may aid in providing a suitable and facilitating host for a photochromic agent, and additionally may offer a unique opportunity for studying size-controlled nano- and microenvironment effects such as reduced degrees of freedom of the photochromic agents.
In some embodiments, the inventors have discovered that it is beneficial to include a UV-absorbing agent in a composition, e.g., for use as a contact lens, in addition to a photochromic agent. The UV-absorbing agent should be selected so as to not interfere with the photochromic agent transitions. In addition, incorporation of more than one UV-absorbing agent may be useful to provide optimal UV-blocking over the desired UV-range (e.g., all or substantially all of the UV light range). In addition, the UV-absorbing agents and/or photochromic agents, in some embodiments, should be selected so as to not affect the transparency of the composition.
In some embodiments, a polymeric article of the present invention comprises a polymeric material and at least one photochromic agent and/or a UV-absorbing agent, wherein the polymeric material comprises a polymer matrix defining a plurality of interconnecting pores. The term, “polymeric material,” as used herein, refers to a material comprising a polymer matrix and a plurality of interconnecting pores. For example, a non-limiting example of a contact lens of the present invention is depicted in
In some embodiments, a polymeric material may be formed from a bicontinuous microemulsion. A bicontinuous microemulsion may comprise water, a monomer, and a surfactant copolymerizable with the monomer, and optionally, at least one photochromic agent and/or UV-absorbing agent. The bicontinuous microemulsion may be polymerized to form a polymer matrix defining interconnected pores. For example, a polymer matrix may be prepared by polymerizing a bicontinuous microemulsion of one or more copolymerizable monomers, one or more surfactants copolymerizable with at least one of the monomers, and water, such that the resulting polymeric material has interconnected pores filled with water. The bicontinuous microemulsion may also include a polymerization initiator or a cross-linker, or both.
An exemplary structure of a bicontinuous microemulsion 30 is illustrated in
In some cases, a method of forming a polymeric material comprises polymerization a bicontinuous microemulsion comprising a first continuous phase comprising water and a second continuous phase comprising a monomer and a surfactant copolymerization with said monomer to form a porous polymeric material. The polymeric material may comprise a polymer matrix portion formed from the second phase and a water portion (e.g., aqueous domains) formed from the first phase, the water phase forming interconnected pores defined in the polymer matrix. The polymeric material may comprise at least one photochromic agent and/or UV-absorbing agent. The at least one photochromic agent and/or UV-absorbing agent may be dispersed in the first and/or second continuous phase prior to polymerization. Alternatively, the at least one photochromic agent and/or UV-absorbing agent may be provided to a polymeric material following polymerization.
A photochromic agent and/or UV-absorbing agent may be incorporated into the polymeric material. The photochromic agent and/or UV-absorbing agent may be substantially contained within the polymer matrix and/or the interconnecting pores of the polymeric material. The photochromic agent and/or UV-absorbing agent may be substantially contained within the polymer matrix (or the interconnecting pores) due to hydrophobic/hydrophilic interactions, and/or due to the formation at least one bond between the photochromic agent and/or UV-absorbing agent and the polymer matrix. For example, in embodiments where the polymer matrix is substantially hydrophobic as compared to the interconnecting pores (e.g., comprising water), a hydrophobic photochromic agent and/or UV-absorbing agent may be substantially contained within the polymer matrix due to hydrophobic/hydrophilic interactions. It should be understood, however, that in some embodiments, the photochromic agent and/or UV-absorbing agent may be substantially contained in the interconnecting pores of the polymeric material. In such embodiments, the photochromic agent and/or UV-absorbing agent may not leach from the polymer matrix so long as some internal sections of the interconnecting pores or the surface openings are narrow such that the photochromic agent and/or UV-absorbing agent is substantially trapped inside these internal sections and may be retained during use. International Patent Application No. PCT/SG2009/000245, filed Jul. 9, 2009, entitled “Trapping Glucose Probe in Pores of Polymer,” published as WO/2010/005398 on Jan. 14, 2010, herein incorporated by reference, describes suitable methods and compositions for forming a polymeric material with selected pore size.
In some cases, a photochromic agent and/or UV-absorbing agent may be associated with a polymer matrix by the formation of at least one bond (e.g., covalent bond). In other instances, a least a portion of a photochromic agent and/or UV-absorbing agent may be cross-linked with a polymer matrix. As used herein, a component is “cross-linked” with a polymer matrix when the component comprises at least one bond (e.g., a covalent bond) to two or more adjacent chains of polymer. Those of ordinary skill in the art will be aware of methods for covalently linking a photochromic agent and/or UV-absorbing agent with the polymer matrix. For example, the photochromic group and/or UV-absorbing group may be functionalized with at least one polymerizable group (e.g., a group that may be polymerized). The structure of the polymerizable group will depend on the structure of the polymer matrix being form. Non-limiting examples of polymerizable groups include p-vinylbenzene, a compound comprising an acrylate moiety (e.g., (methyl)acrylate), or the like. In some cases, a monomer may be functionalized with a photochromic group and/or UV-absorbing group, and the ratio of the photochromic group and/or UV-absorbing group in the polymer may be controlled by varying the ratio of unfunctionalized monomers to functionalized monomers. In such embodiments, the ratio of the unfunctionalized monomer to the functionalized monomer may be about 5:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about 40:1, about 50:1, about 100:1, or greater, or may be between about 10:1 and about 100:1, or between about 20:1 and about 70:1, or between about 20:1 and about 40:1, or the like.
A UV-absorbing agent may be any UV-absorbing compound known to those of ordinary skill in the art. The term “UV-absorbing agent” is given its ordinary meaning in the art and generally refers to a compound or composition that inherently absorbs ultraviolet radiation. Ultraviolet radiation or ultraviolet wavelengths include UV-A radiation (325 nm-390 nm), UV-B radiation (295 nm-325 nm) and UV-C radiation (200 nm-295 nm). The percentage of radiation absorbed in the UV region can vary depending on the wavelength of radiation.
In some embodiments, a UV-absorbing agent and/or a material comprising at least one UV-absorbing agent absorbs UV radiation substantially throughout the UV wavelength region, i.e., from 200 nm to 390 nm. In some embodiments, the UV-absorbing agent absorbs UV radiation in the UV-A region, or the UV-B region, or the UV-C region, or in the UV-A and UV-B regions, or in the UV-B and UV-C regions.
In some embodiments, a UV-absorbing agent and/or a material comprising at least one UV-absorbing agent absorbs radiation from about 200 nm to about 390 nm, or from about 210 nm to about 390 nm, or from about 220 nm to about 390 nm, or from about 200 nm to about 380 nm, or from about 200 nm to about 370 nm, or from about 200 nm to about 360 nm, or from about 220 nm to about 370 nm.
In some embodiments, the UV-absorbing agent transmits less than about 90%, less than about 50%, less than about 40%, less than about 20%, less than about 10%, less than about 5% or less than about 3% of the radiation at 200 nm. In some embodiments, the UV-absorbing agent and/or a material comprising at least one UV-absorbing agent transmits less than about 90%, less than about 50%, less than about 40%, less than about 20%, less than about 10%, less than about 5% or less than about 3% of the radiation at 295 nm. In some embodiments, the UV-absorbing agent and/or a material comprising at least one UV-absorbing agent transmits less than about 90%, less than about 50%, less than about 40%, less than about 20%, less than about 10%, less than about 5% or less than about 3% of the radiation at 300 nm. In some embodiments, the UV-absorbing agent and/or a material comprising at least one UV-absorbing agent transmits less than about 90%, less than about 50%, less than about 40%, less than about 20%, less than about 10%, less than about 5% or less than about 3% of the radiation at 325 nm. In some embodiments, the UV-absorbing agent and/or a material comprising at least one UV-absorbing agent transmits less than about 90%, less than about 50%, less than about 40%, less than about 20%, less than about 10%, less than about 5% or less than about 3% of the radiation at 390 nm.
One of ordinary skill in the art will be aware that the extent of absorption of a UV-absorbing agent and/or a material comprising at least one UV-absorbing agent at specific wavelength may vary depending on a number of parameters, including but not limited to, the nature of the UV-absorbing compound/composition, concentration of the UV-absorbing compound/composition, the pathlength of the sample cell, and/or intensity of the radiation. Non-limiting examples of UV-absorbing agents and stabilizers include benzophenone (BP), hydroxybenzotriazole (HBT), and hydroxyphenyl triazine (HPT). Other non-limiting examples of UV-absorbing agents and/or classes thereof include benzotriazoles, triazines, hydroxybenzophenones, cyanoacrylates, aromatic carboxylic esters, aromatic azines, benziminazole, benzoxazole, benzthiazole, pyridines, oxides, titanium oxide, zinc oxide, barium titanate, carbon black, hindered amines, nickel quenchers, DNA bases, melanin, menthyl anthranilate, and octyl methoxycinnamate.
In some embodiments, a composition comprises more than one UV-absorbing agent. In some embodiments, a composition comprises one, two, three, four, five, or more, UV-absorbing agents. In some embodiments, a composition comprises BP, HBT, and HPT. In some embodiments, a composition comprises HBT and BP. The amount of each UV-absorbing agent present in the composition may be selected so as to prevent precipitation and/or any other undesirable affects caused by the specific UV-blocking agent and/or the combination of UV-absorbing agents. In some cases, the amount of each UV-blocking agent(s) may be selected so that there is no or essentially no precipitation of the UV-blocking agent(s) and a high and/or maximum UV-absorption is obtained. Suitable amounts of UV-blocking agents are described herein.
One of skill in the art will realize that the term “UV-absorbing agent” is not limited to agents that only absorb radiation in the UV region. Thus, UV agents are capable of absorbing radiation at other wavelengths in addition to UV wavelengths. Those of ordinary skill in the art will be aware of methods and systems for determining the UV-absorption of a UV-absorbing agent and/or a material comprising a UV-absorbing agent, including, but not limited to, spectrophotometry. In some embodiments, the UV-absorbance of a polymeric material may be determined using a UV-visible spectrophotometer. For example, strips of polymeric material may be prepared and light transmission from 200-800 nm wavelengths may be measured through the strips to determine the UV-absorption wavelengths.
A photochromic agent may be any photochromic compound known to those of ordinary skill in the art. The term “photochromic agent” is given its ordinary meaning in the art and refers to any compound which exhibits a reversible change of color upon exposure to light. In some cases, the light is ultraviolet light. A photochromic agent may include the following classes of materials: chromenes (e.g., naphthopyrans, benzopyrans, indenonaphthopyrans, phenanthropyrans), spiropyrans (e.g., spiro(benzindoline) naphthopyrans, spiro(indoline)benzopyrans, spiro(indoline)naphthopyrans, spiro(indoline)quinopyrans, spiro(indoline)pyrans), oxazines (e.g., spiro(indoline)naphthoxazines, spiro(indoline)pyridobenzoxazines, spiro(benzindoline)pyridobenzoxazines, spiro(benzindoline)naphthoxazines, spiro(indoline)benzoxazines), mercury dithizonates, fulgides, fulgimides, or the like, or combinations thereof. In a particular embodiment, the photochromic agent is 6′-(2,3-dihydro-1H-indole-1-yl)-1,3-dihydro-3,3-dimethy 1-1-propyl-spiro[2H-indole-2,3′-(3H)-naphtho(2,1-b)(1,4)oxazine, a spiro-naphthoxazine (e.g., Reversacol™ Midnight Grey). In some cases, the photochromic agent is a naphthopyran (e.g., Reversacol™ Sunflower Yellow). In some cases, the photochromic agent is purchased from a commercial source Reversacol™ Oxford Blue (napthoxazine), Reversacol™Palatinate Purple (napthoxazine), Reversacol™Midnight Grey (napthoxazine), Reversacol™ Sunflower Yellow (napthopyran).
As used herein, a “photochromic amount” means an amount of a photochromic agent that is at least sufficient to produce a photochromic effect discernible to the naked eye upon activation. The concentration of photochromic agent in the polymerizable mixture may be selected based on a number of considerations such as the photochromic efficiency of the photochromic compound, the solubility of the photochromic compound (e.g., in the polymerizable material, in the fluid contained in the pores of the polymeric material, etc.), the thickness of the material or article (e.g., lens), and the desired darkness of the material or article (e.g., lens) when exposed to light. Typically, the more photochromic agent incorporated into an article, the greater the color intensity is up to a certain limit. Generally, there may be a point after which the addition of more photochromic agent does not have a noticeable effect. The polymerizable mixture or article may include more than one photochromic agent.
The concentration of the photochromic agent and/or UV-absorbing agent in the article or material may be varied in different locations of the article, as described herein. It will be appreciated that, by increasing the concentration of a photochromic agent and/or UV-absorbing agent in a given location of an article (e.g., lens), the percentage of light that is blocked at that location is generally increased as compared to locations where the concentration has not been increased. The term “photochromic region” or “UV-absorbing region” refers to a portion of the article or material lens that includes one or more photochromic agents or one or more UV-absorbing agents, respectively.
Photochromic materials for use with embodiments of the present invention generally at least partially block light in at least a portion of the visible spectrum (approximately 400 nm-700 nm). However, health advantages may be gained if a material blocks at least some light in either the ultraviolet or infrared portions of the spectrum. In some embodiments, a material may comprise one or more additives which assist in further blocking the ultraviolet and/or infrared portions of the spectrum. In some cases, as described herein, a material comprises at least one UV-absorbing agent.
In some embodiments, a photochromic material exhibits a color change upon exposure to any suitable light source which emits ultraviolet radiation. In one embodiment, the light source is sunlight. In another embodiment, the light source may be a mercury lamp or a xenon lamp. The exposure time required to exhibit a visible color change may vary depending upon various factors including, but not limited to, wavelength and/or intensity of the light.
Those of ordinary skill in the art will be aware of methods and techniques for determining both direct and reverse photochromism response times for a photochromic material. In some cases, the response time may be presented as a lifetime, T, where T may be calculated according to the following equation
T=1/k
where k is the rate constant. In some cases, the rate constant for reverse photochromism and/or direct photochromism of a material of the present invention is at least about 0.01 s−1, about 0.02 s−1 about 0.03 s−1, about 0.05 s−1, about 0.07 s−1, about 0.10 s−1, about 0.12 s−1, about 0.15 s−1 about 0.20 s−1, about 0.3 s−1, or greater. In some cases, the rate constant may be between about 0.01 s−1 and about 0.4 s−1, between about 0.02 s−1 and about 0.25 s−1, between about 0.05 s−1 and about 0.15 s−1, between about 0.08 s−1 and about 0.12 s−1, or the like. In some cases, the photochromic agent is selected and utilized so that the agent achieves forward and reverse transitions with quick response times (e.g., less than about 1 minute, less than about 45 seconds, less than about 30 seconds, less than about 15 seconds, etc.) in response to changing light conditions.
Those of ordinary skill in the art will be aware of methods and techniques for preparing a microemulsion. The term “microemulsion,” is given its ordinary meaning in the art and refers to a thermodynamically stable dispersion of one liquid phase into another liquid phase. The microemulsion may be stabilized by an interfacial film of surfactant. Generally, one of the two liquid phases is hydrophilic or lipophobic (such as water) and the other is hydrophobic or lipophilic (such as oil). Typically, the droplet or domain diameters in microemulsions are about 100 nanometers or less, and thus the microemulsions are transparent (e.g., prior to a change in the color of a photochromic agent contained within the microemulsion). A microemulsion can be continuous or bicontinuous.
A microemulsion may be prepared, for example, by dispersing a mixture of components (e.g., monomer, surfactant, water) using standard techniques such as sonication, vortexing, or other agitation techniques for creating microdroplets of the different phases within the mixture. Alternatively, the mixture may be passed through a filter having pores on the nanometer scale so as to create fine droplets. Depending on the proportions of various components and the hydrophile-lipophile value of the surfactant, the droplets can be swollen with oil and dispersed in water (referred to as normal or O/W microemulsion), or swollen with water but dispersed in oil (referred to as inverse or W/O microemulsion), or the microemulsion can be bicontinuous.
As will be understood by one of ordinary skill in the art, a nanoporous and, in some cases, transparent polymer matrix may be obtained when the components of the microemulsion are in appropriate ratios and the droplets or domains have appropriate sizes. As is known to persons skilled in the art, to determine the appropriate proportions of the components suitable for forming a bicontinuous microemulsion, a ternary phase diagram for the monomer, water and the surfactant may be prepared. The region on the diagram corresponding to single-phase microemulsion may be identified and the proportions of the components may be so chosen such that they fall within the identified region. A person skilled in the art will be able to adjust the proportions according to the diagram in order to achieve a certain desirable property in the resulting polymeric material. Further, the formation of a bicontinuous microemulsion may be confirmed using techniques known to persons skilled in the art. For example, the conductivity of the mixture may increase substantially when the microemulsion is bicontinuous. The conductivity of the mixture may be measured using a conductivity meter after titrating a 0.1 M sodium chloride solution into the mixture. The water in the microemulsion can be pure water or a water-based liquid. The water may optionally contain various additives, as described herein.
Persons skilled in the art will understand how to combine different monomers and surfactants in different ratios to achieve the desired effect on the various properties of the resulting polymeric material, for example to improve the mechanical strength or hydrophilicity of the resulting polymeric material. Generally, the choice and weight ratio of the particular components (e.g., monomer and surfactant) depends on the application of the resulting polymeric material. The ratios may be selected such that the resulting polymeric material is suitable and compatible with the environment in which the polymeric material is to be used and has the desired properties. In some cases, the water content in the bicontinuous emulsion is between about 10 wt % to about 50 wt %, between about 15 wt % and about 45 wt %, between about 15 wt % and about 40 wt %, between about 20 wt % and about 35 wt %, or between about 20 wt % and about 30 wt %. The surfactant may be present in an amount between about 10 wt % and about 50 wt %, between about 15 wt % and about 45 wt %, between about 20 wt % and about 40 wt %, between about 30 wt % and about 50 wt %, between about 10 wt % and about 30 wt %, between about 20 wt % and about 30 wt %, or between about 15 wt % and about 25 wt %. The one or more monomers may be present in an amount between about 20 wt % and about 70 wt %, between about 30 wt % and about 70 wt %, between about 40 wt % and about 70 wt %, between about 40 wt % and about 60 wt %, or the like. A cross-linker may be present in an amount between about 0.1 wt % and about 10 wt %, between about 1 wt % and about 10 wt %, between about 5 wt % and about 10 wt %, between about 5 wt % and about 15 wt %, between about 3 wt % and about 8 wt %, between about 0.1 wt % and about 5 wt %, between about 0.1 wt % and about 3 wt %, between about 0.5 wt % and about 2 wt %, between about 0.5 wt % and about 1.5 wt %, or about 1.0 wt % about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, or more.
The at least one photochromic agent and/or UV-absorbing agent may be present in an amount between about 0.01 wt % and about 5 wt %, between about 0.1 wt % and about 5 wt %, between about 0.01 wt % and about 3 wt %, between about 0.01 wt % and about 2 wt %, between about 0.01 wt % and about 1 wt %, between about 0.01 wt % and about 0.5 wt %, between about 0.01 wt % and about 0.2 wt %, or about 0.1 wt %.
In some embodiments, when the UV-absorbing agents are HBT and BP and optionally HPT, HBT is present in an amount between about 0.025 wt % and about 3.9 wt %, BP is present in an amount between about 0.025 wt % and about 0.8 wt %, and HPT is present in an amount between about 0 wt % and about 0.025 wt %. In some cases, HBT is present in about 1 wt %, BP is present in an amount about 0.75 wt %, and HPT is present in about 0.025 wt %.
The emulsion may additionally comprise one or more additives (e.g., including a polymerization initiator, as described herein) in an amount between 0.01 wt % and about 5 wt %, between about 0.1 wt % and about 5 wt %, between about 0.01 wt % and about 3 wt %, between about 0.01 wt % and about 2 wt %, between about 0.01 wt % and about 1 wt %, between about 0.01 wt % and about 0.5 wt %, between about 0.01 wt % and about 0.2 wt %, or about 0.1 wt %, about 0.5 wt %, about 1.0 wt %, about 2.0 wt %, about 2.5 wt %, about 3.0 wt %, about 4.0 wt %, about 0.5 wt %, or more. In a particular embodiment, a bicontinuous microemulsion comprises from about 15 to about 50 wt % for water, from about 5 wt % to about 40 wt % for the monomer, and from about 10 wt % to about 50 wt % for the surfactant.
In some embodiments, the water content of a polymeric material may determined as the equilibrium water content. Those of ordinary skill in the art will be aware of methods for determining an equilibrium water content. The equilibrium water content (Q) of a polymeric material may be calculated as follows:
Q=(WS−Wd)×100/WS, (1)
where WS is the saturation weight and Wd is the dry weight. The saturation weight may be measured after immersing the polymeric material in water for a period of time so that the total weight will no longer increase significantly upon further immersion.
Various other measurable factors may be determined and/or tuned for the polymeric material by varying the ratio of components. In some cases, the polymeric material may have a light transmission percentage higher than about 80%, about 85%, about 88%, about 90%, about 92%, about 95%, or greater, or between about 80% and about 100%, between about 80% and about 95%, between about 85% and about 95%, or between about 88% and about 93%. The refractive index of the polymeric material may be about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, or greater, or between about 0.5 and about 1.5, between about 0.7 and about 1.4, or between about 0.9 and about 1.3. The polymeric material may have a glucose diffusion permeability coefficient of at least about 1×10−6 cm−2/s, about 2×10−6 cm−2/s, about 3×10−6 cm−2/s, about 4×10−6 cm−2/s, about 5×10−6 cm−2/s, or greater, or between about 2.1×10−6 cm−2/s to about 3.2×10−6 cm−2/s, between about 1×10−6 cm−2/s to about 5×10−6 cm−2/s, between about 2×10−6 cm−2/s to about 4×10−6 cm−2/s, between about 1×10−6 cm−2/s to about 7×10−6 cm−2/s, or between about 0.1×10−6 cm−2/s to about 10×10−6 cm−2/s. The polymeric material may have an albumin diffusion permeability coefficient of at least about 1.0×10−7 cm−2/s, about 1.2×10−7 cm−2/s, about 1.4×10−7 cm−2/s, about 1.6×10−7 cm2/s, about 1.8×10−7 cm−2/s, about 2.0×10−7 cm−2/s, or greater, or between about 1.4×10−7 cm−2/s and about 1.8×10−7 cm−2/s, between about 1.0×10−7 cm−2/s and about 2.0×10−7 cm−2/s, between about 1.2×10−7 cm−2/s and about 2.0×10−7 cm−2/s, between about 1.4×10−7 cm−2/s and about 2.0×10−7 cm2/s, between about 1.4×10−7 cm−2/s and about 1.6×10−7 cm−2/s. The polymeric material may have a tensile strength of at least about 1 MPa, about 1.5 MPa, about 2 MPa, about 2.5 MPa, about 3 MPa, about 4 MPa, or greater, or between about 1 MPa and about 10 MPA, between about 1 MPa and about 5 MPA, between about 2 MPa and about 5 MPA, between about 1 MPa and about 3 MPA, or between about 2 MPa and about 4 MPA. The polymeric material may have a Young's modulus of at least about 60 MPa, about 80 MPa, about 90 MPa, about 100 MPa, about 110 MPa, or greater, or between about 50 MPa and about 150 MPa, between about 60 MPa and about 140 MPa, between about 80 MPa and about 120 MPa, or between about 60 MPa and about 110 MPa. Those of ordinary skill in the art will be aware of methods and devices for determining the above parameters for a polymeric material. For example, oxygen permeability may be measured using a Polarographic method, also known as the FATT method named after Dr. Irving Fatt. This method may be performed with a Model 201T Oxygen Permeometer, available from Rehder™, M201T.
For medical applications, the polymeric material should be safe and biocompatible with human cells. For use as contact lenses, it is desirable that the polymeric material is permeable to fluids such as gases (e.g., O2 and CO2), various salts, nutrients, water and diverse other components of the tear fluid. The presence of interconnecting pores distributed throughout the polymeric material may facilitate the transport of gases, molecules, nutrients, and/or minerals through the eye and the surroundings.
The interconnecting pores of the polymeric material may have a pore diameter of between about 10 nm and about 100 nm, between about 20 nm and about 90 nm, or between about 30 and about 80 nm. The pores may have round or other cross-sectional shapes and may have different sizes. As used herein, a pore diameter refers to the average or effective diameter of the cross-sections of the pores. The effective diameter of a cross-section that is not circular equals the diameter of a circular cross-section that has the same cross-sectional area as that of the non-circular cross-section. In some embodiments, such as when the polymeric material is swellable when the pores are filled with water, the sizes of the pores may change depending on the water content in the polymeric material. When the polymeric material is dried, some or all of the pores may be filled or partially filled by a gas such as air. The polymeric material may thus behave like a sponge. In alternative embodiments, the pore diameter may be in the range from about 10 nm to 100 nm when the polymeric material is in a dry condition wherein the water content of the polymeric material is at or near minimum.
The pores may be randomly distributed. Some of the pores may be closed pores, meaning that they are not connected or joined with other pores or open to the surfaces of the polymeric material. It is not necessary that all of the pores are interconnected. Depending on use, the polymeric material can be prepared to have more or less interconnected pores as would be understood by an ordinary person skilled in the art.
In some cases, the polymeric material (e.g., comprising the photochromic agent and/or the UV-blocking agent) is substantially transparent (e.g., prior to a color change in the photochromic material). As used herein, the term “transparent” broadly describes the degree of transparency that is acceptable for a contact lens or like devices, for example the degree of transmission of visible light through the polymeric material equivalent to that of other materials employed in the manufacture of contact lenses or other ophthalmic devices.
A bicontinuous microemulsion may be polymerized by standard techniques known to those of ordinary skill in the art. For example, it may be polymerized by heat, the addition of a catalyst, by irradiation of the microemulsion or by introduction of free radicals into the microemulsion. The method of polymerization chosen will be dependent on the nature of the components of the microemulsion.
The monomers for forming bicontinuous microemulsion can be any suitable monomer known to those of ordinary skill in the art, which is capable of copolymerizing with another monomer (e.g., a surfactant) to form a polymeric material. While the monomer is copolymerizable with another monomer such as the surfactant, the monomer may also be polymerizable with itself. The type and amount of the monomer that may be employed to prepare a suitable bicontinuous microemulsion will be known to a person of ordinary skill in the art. Exemplary monomers are ethylenically unsaturated monomers including methyl methacrylate (MMA), 2-hydroxylethyl methacrylate (HEMA), 2-hydroxylethyl acrylate, monocarboxylic acids such as acrylic acid (AA) and methacrylic acid (MA), glycidyl methacrylate (GMA), and silicone-type monomers, or the like. Suitable combinations of these monomers can also be used.
In some embodiments, more than one monomer may be provided. In some cases, a combination of monomers comprises a first monomer more hydrophilic than 2-hydroxyethyl methacrylate (HEMA), and a second monomer as hydrophilic as, or less hydrophilic than, HEMA. The monomers in the bicontinuous microemulsion may be polymerized to form a porous polymeric material. In exemplary embodiments of the present invention, the combination of the first and second monomers and their concentrations may be conveniently selected so that the resulting polymeric material has the desired properties for a particular application.
In some cases, the first monomer may comprise N-vinylpyrrolidone (NVP) or methacrylic acid (MAA) and the second monomer may comprise HEMA or methyl methacrylate (MMA) 2-hydroxylethyl acrylate, monocarboxylic acids, glycidyl methacrylate (GMA), and silicone-based monomers. In other embodiments, NVP or MAA may be replaced with one or more other highly hydrophilic monomers. A monomer is considered to be “highly” hydrophilic herein when it is more hydrophilic than HEMA. Typically, the more hydrophilic terminal groups a monomer has, the more hydrophilic the monomer. Thus, a highly hydrophilic monomer can have more hydrophilic terminal groups in its base structure than HEMA does. Alternatively, the hydrophilic groups in a highly hydrophilic monomer may be individually more hydrophilic than the hydrophilic groups of HEMA. The hydrophilicity of a material may be measured by its equilibrium water content. As can be appreciated, NVP and MAA are highly hydrophilic. There are other materials, such as silicone-based monomers, which are also highly hydrophilic. NVP and MA may thus be replaced by such other materials. A highly hydrophilic material may be amphiphilic. International Patent Application No. PCT/SG2009/000097, filed Mar. 19, 2009, entitled “Forming Copolymer from Bicontinuous Microemulsion Comprising Monomers of Different Hydrophilicity,” published as WO/2010/107390 on Sep. 23, 2010, herein incorporated by reference, describes suitable combinations of monomers and methods for forming a polymeric material.
As will be understood by those of ordinary skill in the art, a polymerizable surfactant may be capable of polymerizing with itself and/or with other monomeric compounds to form a polymeric material. The surfactant for the mixture can be any suitable surfactant that can co-polymerize with at least one of the monomers in the microemulsion. As can be appreciated, when the surfactant is copolymerized into the polymeric material, there is no need to separate the surfactant from the polymeric material after polymerization. This can be advantageous as the polymeric material formation process is simplified. The surfactant can be anionic, non-ionic, or zwitterionic. In a particular embodiment, the surfactant is non-ionic. Exemplary surfactants include poly(ethylene oxide)-macromonomer (PEO-macromonomer), such as ω-methoxy poly(ethylene oxide)40 undecyl α-methacrylate macromonomer denoted herein as C1-PEO-C11-MA-40. The chain length of the macromonomer can be varied. For example, the macromonomer may be in the form of R1O(CH2CH2O)n—(CH2)—V, where R1 is either hydrogen or an alkyl group (e.g., C1-C5 alkyl), n is an integer between about 5 and about 200, or between about 10 and about 110, and V is a polymerizable group. The structure of the polymerizable group will depend on the type of polymer matrix being formed. In some cases, the polymerizable group is p-vinylbenzene, a compound comprising an acrylate moiety (e.g., (methyl)acrylate), or the like. In some embodiments, the surfactant may be a zwitterionic surfactant such as {SO3−}{(CH2)m+}NCHCHCHN(CH2)pV, where m is an integer ranging from 1 to 20, n is an integer ranging from 6 to 20, p is an integer ranging from 10 to 110, and V is copolymerizable group.
Polymerization of the microemulsion may involve the use of a catalyst. The catalyst may be any catalyst or polymerization initiator that promotes polymerization of the monomers and the surfactant. The specific catalyst chosen may depend on the particular monomers, and polymerizable surfactant used or the method of polymerization. For example, polymerization can be achieved by subjecting the microemulsion to ultraviolet (UV) radiation if a photo-initiator is used as a catalyst. Exemplary photo-initiators include 2,2-dimethoxy-2-phenyl acetophenone (DMPA) and dibenzylketone. A redox-initiator may also be used. Exemplary redox-initiators include ammonium persulphate and N,N,N′,N′-tetramethylethylene diamine (TMEDA). A combination of photo-initiator and redox-initiator may also be used. In this regard, including in the mixture an initiator can be advantageous. The polymerization initiator may be present in an amount between about 0.1 wt % and about 5 wt %, between about 1 wt % and about 5 wt %, between about 0.1 wt % and about 4 wt %, between about 0.1 wt % and about 3 wt %, between about 0.1 wt % and about 1 wt %, between about 2 wt % and about 4 wt %, between about 0.1 wt % and about 0.5 wt %, or between about 0.1 wt % to about 0.4 wt % of the microemulsion.
To promote cross-linking between polymer molecules in the resulting polymeric material, a cross-linker may be added to the mixture. Suitable cross-linkers include ethylene glycol dimethacrylate (EGDMA), diethylene glycol dimethacrylate, diethylene glycol diacrylate, or the like. As can be understood, the more the polymer molecules are cross-linked, the more difficult it for an additive (e.g., drug) or photochromic agent and/or UV-absorbing agent to diffuse or migrate through the polymeric material, thereby resulting in a slower release of the additive or photochromic agent and/or UV-absorbing agent. The content of the cross-linker can therefore be selected to adjust the release rate. Increasing the overall concentration of the cross-linker can also improve the mechanical strength of the resulting polymeric material.
The microemulsion may be formed into a desired end shape and size prior to polymerization. For example, a sheet material may be formed by pouring or spreading the mixture into a layer of a desired thickness or by placing the mixture between glass plates prior to polymerization. The mixture may also be formed into a desired shape such as a rod, for example, by pouring the mixture into a mold or cast prior to polymerizing. In some cases, however, following polymerization, the polymeric material may be formed into a desired end shape using cutting techniques (e.g., using lasers). In some cases, the microemulsion may be stored (e.g., at low temperatures) for a period of time, prior to forming the desired end-shape article and/or prior to polymerization. For example, the microemulsion may be stored at a suitable temperature (e.g., about 0° C., about 2° C., about 4° C., about 6° C., about 8° C., etc.) for at least about 1 day, about 2 days, about 3 days, about 4 days, about 1 week, about 1 month, prior to forming the desired end-shape article, with essentially no substantial changes in the end properties of the end-shape article as compared to an article formed of the material at a time point essentially immediately after forming the end-shape article.
In some embodiments, a microemulsion may be formed into a desired end shape and size prior to polymerization. In one embodiment, contact lens 10 may be formed from the microemulsion according to the process illustrated in
The polymeric materials may also be used, in some cases, for the preparation of pinhole lenses. Pinhole lenses will be known to those of ordinary skill in the art. These lenses utilize theories of pinhole imaging, commonly understood in optics as a method to reduce geometrical aberrations, e.g., astigmatism, spherical aberration, and coma. By restricting a person's vision to a small “pinhole” aperture, visual deficiencies are greatly reduced, or even effectively removed. Non-limiting types of pinhole lenses are shown in
After polymerization, the polymeric material may be rinsed and/or equilibrated with water to remove un-reacted monomers and/or other components that have not been incorporated into the polymeric material. In some cases, a small percentage of the additives incorporated in the polymeric material may be lost during rinsing but the amount lost can be limited by controlling the duration of rinsing. A rinsed polymeric material may be optionally dried and sterilized in preparation for use in a medical or clinical application. Both drying and sterilization can be accomplished in any suitable manner, which is known to person of skill in the art. In some embodiments, both drying and sterilization can be affected at a low temperature so as not to adversely affect the additive or photochromic agent and/or UV-absorbing agent, for example using ethyleneoxide gas or UV radiation.
In some embodiments, the polymeric material may comprise one or more additives. In some cases, an additive may be sufficiently contained within the polymer matrix, of the water in the interconnected pores, or both. Such additives can be selected for achieving one or more desired properties in the resulting polymeric material, and can include one or more of a drug, a protein, an enzyme, a filler, a dye, an inorganic electrolyte, a pH adjuster, or the like.
In some embodiments, a drug such as an ophthalmic drug may be incorporated into the microemulsion. The drug may be dispersed in the aqueous domains or in the oil domains of the microemulsion, or in both domains including at the interface of the two domains. When the drug is initially dispersed in the oil domains, it is likely dispersed in the polymer matrix after polymerization. When the drug is initially dispersed in the aqueous domains, it is likely dispersed in the water in the pores after polymerization. Drugs that can be incorporated in the polymeric material can vary and can be either hydrophilic or hydrophobic, water soluble or water insoluble. Those of ordinary skill in the art will understand how different drugs will be dispersed in the microemulsion depending on their properties such as hydrophilicity or lipophilicity. International Patent Application No. PCT/SG2004/000237, filed Aug. 3, 2004, entitled “Polymer having Interconnected Pores for Drug Delivery and Method,” published as WO 2006/014138 on Feb. 9, 2006, herein incorporated by reference, describes suitable drugs, and methods for incorporating a drug into a polymer matrix.
Non-limiting examples of ophthalmic drugs include anti-glaucoma agents such as a beta adrenergic receptor antagonist, e.g., timolol maleate, and other therapeutic agents such as antibiotic agents, antibacterial agents, anti-inflammatory agents, anaesthetic agents, anti-allergic agents, polypeptides and protein groups, lubricating agents, any combination or mixture of the above, and the like.
The amount of the drug to be included may be determined based on various factors. In general, the drug should have a concentration suitable for providing the desired therapeutic dosage, as would be known in the art. For ophthalmic drug delivery, the transparency and clarity of the resulting polymeric material is one of the factors may depend on the concentration of the drug in the polymeric material.
In some cases, a polymeric material may comprise a glucose probe. A glucose probe can be any compound that generates a detectable spectral signal, such as a change in fluorescence response, in the presence of glucose. For instance, the glucose probe may react with glucose on contact, thus forming a new compound structure which has a fluorescence spectrum different from that of the original probe molecule. A glucose probe may be trapped in the interconnecting pores of a polymer material and/or with bond the probe to the polymer. When internal pores in the polymer are connected with one another and to surface pores, glucose may travel through the connected pores to interact with the probe in the pores during use. To prevent leaching of the probe, the pores can be connected through openings sized to restrict passage of the probe through the openings. A suitable glucose probe may be a boronic acid probe, such as a boronic acid-based fluorophore. For example, a boronic acid may be used. The boronic acid may have the formula of R—B(OH)2, where R is alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxyalkyl, alkoxyalkenyl, or aryl arylakyl. Suitable boronic acids include 1,3-diphenylprop-2-en-1-one, or alternatively expressed as 3-[4′(dimethylamino)phenyl]-1-(4″-boronophenyl)-prop-2-en-1-one; and 1,5-diphenylpenta-2,4-dien-1-one, alternatively expressed as 5-[4″-(dimethylamino)phenyl]-1-(4′-boronophenyl)-pent-2,4-dien-1-one. International Patent Application No. PCT/SG2009/000245, filed Jul. 9, 2009, entitled “Trapping Glucose Probe in Pores of Polymer,” published as WO/2010/005398 on Jan. 14, 2010, herein incorporated by reference, describes suitable glucose probes and methods for containing a glucose probe in a polymeric material.
In some embodiments, a polymeric material may comprise a wetting agent. A wetting agent may be any suitable wetting agent, subject to constraints in any given particular application. For example, for contact lens applications, the wetting agent should be compatible with human eye. In a contact lens application, suitable wetting agents may include hyaluronic acid (HA), acrylated HA (AHA), methacrylated hyaluronic acid (MeHA), polyvinylpyrrolidone (PVP), dextran, or other wetting agents that are suitable for ophthalmic applications. In some applications, wetting agents such as carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), glycerine, chitosan, polyvinylalcohol, or the like, may be suitable.
Hyaluronic acid may also be referred to as hyaluronate or hyaluronan. A hyaluronic acid is a glycosaminoglycan, also called mucopolysaccharide, which is a polymer of disaccharides, composed of D-glucuronic acid and D-N-acetylglucosamine, linked together via alternating β-1,4 and β-1,3 glycosidic bonds. An exemplary hyaluronic acid A is a sodium hyaluronate. In some cases, a wetting agent may be cross-linked with the polymer matrix. International Patent Application No. PCT/SG2007/000398, filed Nov. 17, 2007, entitled “Porous Polymeric Material with Cross-Linkable Wetting Agent,” published as WO 2008/060249 on May 22, 2008, herein incorporated by reference, describes suitable wetting agents including wetting agents for cross-linking with the polymer matrix, and methods for incorporating wetting agents into a polymer matrix.
Conveniently, the polymeric materials according to various embodiments of the invention can be made compatible with human dermal fibroblasts cells and mechanically strong and can be advantageously used to manufacture contact lenses for placement on the eye.
The polymeric materials described above are useful not only for contact lens applications, but also useful in other applications. For example, the exemplary materials and processes described herein, or similar materials or processes, may be utilized to prepare hydrophilic, nanoporous materials for use in applications such as prescription lenses, 3-D (dimensional) tissue engineering scaffolds, artificial cornea, or the like. In some embodiments, since only one polymerization step is required, in some cases, to prepare the polymeric material incorporating a photochromic agent and/or UV-absorbing agent, the process can be simple and inexpensive.
In some embodiments, the present invention provides an optical device comprising a photochromic agent rendering the device switchable from a first, relatively transparent state to a second, at least partially opaque state, whereby transmission of visible light through the optical pathway can change by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, upon switching of the device from the first state to the second state, and from the second state to the first state, each within a period of time of no more than about 1 second, about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 50 seconds, about 60 seconds, about 90 seconds, about 120 seconds, or the like upon exposure to appropriate electromagnetic radiation and/or thermal relaxation. The optical device may have an optical pathway through the device with a maximum length of less than about 0.5 mm, about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 4 mm, about 5 mm, or the like. The optical device may be a contact lens.
In some embodiments, a composition comprises between about 15 wt %, and about 25 wt % ω-methoxy poly(ethylene oxide)40 undecyl α-methacrylate macromonomer (PEO-R-MA-40), between about 15 wt % and about 20 wt % glycidyl methacrylate (GMA), between about 30 wt % and about 50 wt % 2-hydroxyethyl methacrylate (HEMA), between about 15 wt % and about 25 wt % water, between about 0.1 wt % and about 10 wt % ethyleneglycol dimethacrylate (EGDMA), between about 0.1 wt % and about 5 wt % 2,2-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (AIPH), and between about 0.05 wt % and about 5 wt % 6′-(2,3-dihydro-1H-indole-1-yl)-1,3-dihydro-3,3-dimethy 1-1-propyl-spiro[2H-indole-2,3′-(3H)-naphtho(2,1-b)(1,4)oxazine (SPO). In a particular embodiment, a composition comprises about 20 wt % PEO-R-MA-40, about 17 wt % GMA, about 43 wt % HEMA, about 20 wt % water, about 1.0 wt % EGDMA, about 0.3 wt % AIPH, and about 0.1 wt % SPO. In another particular embodiment, a composition comprises about 18.2 wt % PEO-R-MA-40, about 14.1 wt % GMA, about 37.9 wt % HEMA, about 18.2 wt % water, about 8.8 wt % EGDMA, about 2.7 wt % AIPH, and about 0.1 wt % SPO. In some embodiments, a composition comprises between about 20.9 wt % and about 21.9 wt % HEMA, between about 8.2 wt % and about 8.7 wt % GMA, between about 29 wt % and about 30.5 wt % C1-PEO-C11-MA-40, between about 33.9 wt % and about 35.6 wt % H2O, between about 2.9 wt % and about 3.05 wt % EDGMA, between about 0.29 wt % and about 0.31 wt % AIPH, between about 0.02 wt % and about 3.9 wt % HBT, between about 0.02 wt % and about 0.8 wt % BP, and between about 0 wt % and about 0.1 wt % HPT. In some embodiments, a composition comprises between about 20 wt % and about 22.5 wt % HEMA, between about 8 wt % and about 9 wt % GMA, between about 29 wt % and about 31 wt % C1-PEO-C11-MA-40, between about 33 wt % and about 36 wt % H2O, between about 0.3 wt % and about 3.5 wt % EDGMA, between about 0.1 wt % and about 0.35 wt % AIPH, between about 0.025 wt % and about 4 wt % HBT, between about 0.025 wt % and about 1 wt % BP, and between about 0 wt % and about 0.1 wt % HPT. In some embodiments, a composition comprises between about 20 wt % and about 22 wt % HEMA, between about 8 wt % and about 9 wt % GMA, between about 29 wt % and about 31 wt % C1-PEO-C11-MA-40, between about 33 wt % and about 36 wt % H2O, between about 2.5 wt % and about 3.5 wt % EDGMA, between about 0.25 wt % and about 0.35 wt % AIPH, between about 0.025 wt % and about 4 wt % HBT, between about 0.025 wt % and about 1 wt % BP, and between about 0 wt % and about 0.025 wt % HPT. In some embodiments, a composition comprises between about 20.8 wt % and about 21.9 wt % HEMA, between about 8.2 wt % and about 8.7 wt % GMA, between about 29.0 wt % and about 30.6 wt % C1-PEO-C11-MA-40, between about 33.9 wt % and about 35.6 wt % H2O, between about 2.9 wt % and about 3.1 wt % EDGMA, between about 0.29 wt % and about 0.31 wt % AIPH, between about 0.025 wt % and about 3.9 wt % HBT, between about 0.025 wt % and about 0.8 wt % BP, and between about 0 wt % and about 0.025 wt % HPT. In some embodiments, a composition comprises about 21.5 wt % HEMA, about 8.5 wt % GMA, about 30 wt % C1-PEO-C11-MA-40, about 35 wt % H2O, about 3 wt % EDGMA, about 0.3 wt % AIPH, about 1 wt % HBT, about 0.75 wt % BP, and about 0.025 wt % HPT. In some embodiments, a composition comprises about 22.1 wt % HEMA, about 8.7 wt % GMA, about 30.25 wt % C1-PEO-C11-MA-40, about 36 wt % H2O, about 0.4 wt % EDGMA, about 0.1 wt % AIPH, about 1.6 wt % HBT, about 0.4 wt % BP, about 0.02 wt % HPT, and about 0.4 wt % dye. In some embodiments, a composition comprises about 21.5 wt % HEMA, about 8.5 wt % GMA, about 30 wt % C1-PEO-C11-MA-40, about 35 wt % H2O, about 3.0 wt % EDGMA, about 0.3 wt % AIPH, about 1.0 wt % HBT, about 0.75 wt % BP, and about 0.02 wt % HPT. In some embodiments, a composition comprises the components outlined in Table A (amounts given in wt %). In some embodiments, each of the above compositions may optionally comprise at least one photochromic agent. The photochromic agent may be present in any suitable amount, for example, between about 0.01 wt % and about 5 wt %, or between about 0.1 wt % and about 0.4 wt %. Other amounts are possible.
A “polymer,” as used herein, is given its ordinary meaning as used in the art, i.e., a molecular structure comprising one or more repeat units (monomers), connected by covalent bonds. The repeat units may all be identical, or in some cases, there may be more than one type of repeat unit present within the polymer.
The terms “hydrophobic” and “hydrophilic” are given their ordinary meaning in the art and, as will be understood by those of ordinary skill in the art, in many instances herein, these are relative terms. Although specific parameters or limitations on the meaning of a “hydrophobic material” (e.g., polymer matrix) would be inappropriate given different relative hydrophobicities, in general, a hydrophobic polymer matrix is one that, when formed into a material suitable for a contact angle measurement, will result in a water contact angle of greater than about 50°.
As used herein, “substantially,” in connection with a component (e.g., a photochromic agent and/or UV-absorbing agent) being contained within a polymer matrix (or interconnecting cores), means that at least about 25%, at least about 35%, at least about 50%, at least about 60%, at least about 75%, at least about 85%, or at least about 90%, at least about 95%, or more, of the component is encapsulated in and/or compounded with the polymeric material.
As used herein, a “subject” or a “patient” refers to any mammal (e.g., a human). Examples include a human, a non-human primate, a cow, a horse, a pig, a sheep, a goat, a dog, a cat, or a rodent such as a mouse, a rat, a hamster, or a guinea pig. Generally, or course, the invention is directed toward use with humans. A subject may be a subject needing corrective lenses.
These polymeric materials can have various desirable physical, chemical, and biochemical properties. To illustrate, the preparation and properties of sample polymeric materials are described below. The following examples are intended to illustrate certain embodiments of the present invention, but do not exemplify the full scope of the invention.
The following describes the preparation and characterization of a non-limiting photochromic polymeric material of the present invention.
The photochromic agent used in this example is 6′-(2,3-dihydro-1H-indole-1-yl)-1,3-dihydro-3,3-dimethy 1-1-propyl-spiro[2H-indole-2,3′-(3H)-naphtho(2,1-b)(1,4)oxazine, a spiro-naphthoxazine (SPO). The structure of SPO and one of its open forms is shown in
The nanostructured lenses were typically prepared by polymerizing the bicontinuous microemulsion precursor derived via the self-assembly of amphiphilic templates that consisted of ω-methoxy poly(ethylene oxide)40 undecyl α-methacrylate macromonomer (C1-PEO-C11-MA-40 or PEO-macromonomer), 2-hydroxyethyl methacrylate (HEMA), glycidyl methacrylate (GMA) and water. The resulting bicontinuous phase offered exceptional control over the nanostructure, yielding an architecture that was well-suited for the incorporation of photochromic dye. The compositions of selected microemulsions are listed in Table 1. The resulting lenses were molded using a mold-casting technique. They lenses were substantially transparent and showed improved hydrophilicity and oxygen permeability (Dk) (from 13 to 21) with increasing water content. The Young's modulus varied from 0.44 to 0.63 MPa with decreasing water content. No significant amount of the tensile strength was lost when the water content of these materials was further increased to 50-60 wt %. The Young's modulus and tensile strength (0.20-0.26 MPa) suggested that these materials were sufficiently durable for contact lens applications (see Table 1).
Time-dependent response curves were obtained by following the signal at the peak wavelength in the transient absorption spectra. Spectra of solutions (not shown) and as-synthesized lenses were obtained with an Agilent 5453 UV-visible spectrophotometer. The solutions from which the lenses were prepared were colorless. The lenses were completely transparent in the visible range, with transmissions of ˜97% indicating that the dye was present in their closed form. SEM micrographs (
The transmission of the dye-doped lenses did not decrease after several weeks. Typical spectra of the lenses during UV exposure are depicted in
As previously stated, SPO photochromics have important applications in ophthalmic lenses due to their dark coloration, large extinction coefficients in the open form, inherent fatigue resistance, and moderately good switching performance. In testing the switching performance, the coloration of the lenses prepared with different water contents was found to be approximate 2 times greater than that of the control (PMMA) after 5 min of irradiation (
In the nanostructured materials investigated here, the SPO was located within the organic domains based on the conclusions that the response was very much faster than that observed in the non-nanostructured polymeric material (i.e. PMMA) that was reported previously. Secondly, upon drying, pure PMMA would become colored and begin to exhibit reverse photochromism. Samples that were stored at ambient conditions for varying periods after their synthesis were analyzed and there was no indication of reverse photochromism. Another interesting feature was evident from the fits of the bleaching curves for the SPO-doped materials. Fresh samples (PEO-20) that has been stored for ˜40 h showed a slightly slower response (k=0.06 s−1) as compared than a 3 week-old sample (k=0.10 s−1). This was in contrast to the pure PMMA system, whereby the matrix environment became more restricted with aging, and the open molecular forms became stabilized by contact with the pore walls. In our case, the increased rate of photobleaching with increasing water content suggested that the nanoporous environment reduced the number of sites available in the polymer matrix domains for the open forms of the SPO to stabilize, resulting in faster bleaching kinetics. This also reflected a homogeneous dye environment at the nanometer-scale, confirming that the photochromic species were located predominantly within the organic domains of the biphasic nanocomposites.
In summary, that nanostructured bicontinuous microemulsions were shown to be excellent hosts for photochromic dyes. The SPO dye investigated showed direct photochromism, becoming colored upon UV illumination and was bleached thermally back to their colorless closed forms in the absence of UV irradiation. The response times of SPO-doped lens materials were very fast, amongst the best values reported so far for solid state composites. The materials also showed long-term stability, with no obvious competition between direct and reverse photochromism over time. As these nanostructured photochromic materials derived from bicontinuous microemulsion could be processed easily into any desired shape, they would be of interest for applications as ophthalmic lenses and optical devices
The following describes methods used in combination with Example 1.
The polymer membrane morphology was studied with field emission scanning electron microscopy (FESEM) (JEOL 6700). The membranes were freeze-fractured in liquid nitrogen to expose their cross-sections. Prior to examination, they were vacuum dried at room temperature for 24 h, and then coated with a thin layer of gold (JEOL ion-sputter JFC-1100). The thermal behavior of the polymer samples (˜10 mg each) was evaluated for 30-600° C. (ramp=10° C./min) under dry nitrogen flow using a Perkin Elmer TGA7 thermal gravimetric analyzer. To measure the water content of the polymer membranes, pre-weighed dry samples were immersed in deionized water at various temperatures. After the excess surface water was removed with a piece of filter paper, the weight of each fully swollen sample was recorded. The wt % of water was determined using the following equation:
EWC(%)=(Ws−Wd)/Wd×100
where Wd refers to the dry sample weight before swelling, and Ws is the wet sample weight after immersing in water for at least 24 h. The strain, Young's modulus and tensile strength of the polymer membranes were measured by an Instron 4502 microforce tester. Samples of standard size were used according to ASTM 638. The light transmission of the polymer membranes was examined by Agilent 5453 UV-visible spectrophotometer. Refractive indices of materials, fully hydrated in phosphate buffered saline (PBS), were measured with a refractometer. Oxygen permeabilities of the materials were measured by Rehder 201T permeometer.
UV-visible absorption spectra were obtained using an Agilent 5453 UV-visible spectrophotometer. The UV source of irradiation was a 20-W Hg lamp (Philips) with a maximum wavelength of 365 nm. First, the polymer films were irradiated with the Hg lamp, the absorbance spectra were recorded until the maximum absorbance decreased to that of the non-irradiated films; the variation in maximum absorbance was plotted against time. Next, the polymer films were irradiated multiple times until no change in the photochromic properties of the polymer films was recorded. The UV light excitation was performed for 5-10 min; the plots of maximum absorbance with time were obtained. Rate constants for the thermally activated reaction to convert from the open form back to the closed form of SPO was determined by monitoring the temporal change in the absorption at 620 nm of the open form.
The following describes the preparation and characterization of non-limiting photochromic polymeric materials of the present invention. The two materials employed in this example have formulations as provided in Table 2.
In this example, Material A was formed using 200 mg PEO-R-MA-40, 170 mg GMA, 430 mg HEMA, 200 uL (microliters) water, 10 mg EGDMA, 3 mg AIPH, and 1 mg SPO, and Material B was formed using 200 mg PEO-R-MA-40, 156 uL GMA, 418 uL HEMA, 200 uL water, 97 uL EGDMA, 30 mg AIPH, and 1 mg SPO.
The materials were prepared as follows. PEO-R-MA-40, GMA, and HEMA were vortexed to form a first mixture. Water, EGDMA, and AIPH were then added to the first mixture, and addition vortexing was carried out until a second mixture was formed. SPO was added to the second mixture, and the resulting material was sonicated in ice to form a third mixture. Any solid material from the third mixture was separated from the third mixture (e.g., by centrifuging, for example, 30 seconds at 5 ref). The liquid portion of the third mixture was isolated and poured into molds. The liquid portion of the third mixture was left of polymerize overnight at 60° C. The unpolymerized material (e.g., the liquid portion of the third mixture) may be stored at 4° C. with no or essentially no loss of function. Material B exhibited about 10 times the tensile strength and 100 times the tensile modulus of Material A (see
The following describes the characterization of photochromic, UV-absorbing contact lenses with high water content and oxygen permeability. Various UV-absorbing agents are comprised in the materials, including benzophenone, hydroxybenzotriazole, and hydroxyphenyl triazine. The resulting contact lenses have superior UV-absorbing abilities as compared to current commercial contact lenses. Furthermore, the polymeric compositions comprise a higher water content and oxygen permeability comparable to commercial contact lens.
A non-limiting material in this example comprises 21.4 wt % HEMA, 8.4 wt % GMA, 34.8 wt % H2O, 29.8 wt % PEO, 3.3 wt % EDGMA, 0.9 wt % AIPH, 0.1 wt % dye (e.g., Reversacol™ Oxford Blue (napthoxazine), Reversacol™Palatinate Purple (napthoxazine), Reversacol™Midnight Grey (napthoxazine), Reversacol™ Sunflower Yellow (napthopyran)); 1.0 wt % HBT (e.g., from Aldrich, CAS#123333-53-9), 0.7 wt % BP (e.g., from Aldrich, CAS#119-61-9), and 0.02 wt % HPT (e.g., from BASF, TINUVIN® 460), wherein HEMA, GMA, EDGMA, and AIPH are as described herein; HBT is hydroxy-benzotriazol, e.g., 1-hydroxybenzotriazole hydrate:
BP is benzo-phenone:
HPT is hydroxy-phenyltriazine:
and
The material was prepared using similar methods as described in Example 3, wherein the UV-absorbing agents were mixed/sonicated with the HEMA/GMA phase. Generally, and oil phase is prepared comprising all the oil soluble components and a water phase is prepared comprising all the water soluble components, with the exception of the initiator. The oil and the water phases are then mixed together with the surfactant (e.g., agitation, sonication, etc.) to form a solution (e.g., a transparent solution). The initiator (e.g., AIPH) is then added to the mixed solution. A resulting material had an O2 permeability of 23.1, water content of 52.9 wt %, was photochromic, had UV-blocking ability (see
A) No UV-absorbing agent material comprising 20.0 wt % HEMA, 7.9 wt % GMA, 40.7 wt % H2O, 30.6 wt % PEO, 0.4 wt % EDGMA, 0.1 wt % AIPH, and 0.4 wt %;
B) Comp-HBT material comprising 19.7 wt % HEMA, 7.8 wt % GMA, 40.1 wt % H2O, 30.1 wt % PEO, 0.4 wt % EDGMA, 0.1 wt % AIPH, 1.5 wt % HBT and 0.4 wt % dye;
C) Comp-BP material comprising 22.7 wt % HEMA, 9.0 wt % GMA, 40.0 wt % H2O, 29.6 wt % PEO, 0.4 wt % EDGMA, 0.1 wt % AIPH, 0.8 wt % BP and 0.4 wt % dye; and
A) Comp-HBT material comprising 19.7 wt % HEMA, 7.8 wt % GMA, 40.1 wt % H2O, 30.1 wt % PEO, 0.4 wt % EDGMA, 0.1 wt % AIPH, 1.5 wt % HBT and 0.4 wt % dye;
B) Comp-(HBT+BP) material comprising 19.6 wt % HEMA, 7.8 wt % GMA, 40.0 wt % H2O, 30.0 wt % PEO, 0.4 wt % EDGMA, 0.1 wt % AIPH, 1.5 wt % HBT, 0.4 wt % BP and 0.4 wt % dye; and
C) Comp-(HBT+BP+HPT) material comprising 19.6 wt % HEMA, 7.7 wt % GMA, 39.9 wt % H2O, 30 wt % PEO, 0.4 wt % EDGMA, 0.1 wt % AIPH, 0.4 wt % dye, 1.5 wt % HBT, 0.4 wt % BP, 0.1 wt % HPT.
Cell test result (100% cell activity means the cells all survived using tissue culture plastic (TCP) a control), indicating that the UV-absorbing agent HBT is non-toxic. Generally, the materials comprise a lower amount of UV-absorbing agents BPs and HPTs.
This example described the synthesis and characterization of UV-blocking photochromic soft contact lenses via bicontinuous nanoemulsion polymerization. These lenses have good oxygen permeability, water content, stiffness and strength comparable to commercial soft contact lenses. They have greater UV-blocking ability compared to commercial UV-blocking soft contact lenses, and a faster response to UV light particularly in reverse transition from colored to colorless state compared to traditional photochromic spectacle lenses. They are non-toxic to human primary conjunctival epithelial cells in the eye, and are safe for in vivo use based on pilot tests with a live rabbit model. For individuals with chronic eye conditions that require long-term glare protection, photochromic contact lenses potentially combine the advantages of traditional photochromic spectacles and soft contact lenses.
The ability to block glare from sunlight when outdoors, in particular the harmful effects of ultraviolet (UV) radiation on the eye, is of great concern, particularly because long-term exposure of the eyes to UV can result in photokeratitis, photoconjunctivitis, pterygium, cataracts and carcinoma of the cornea and conjunctiva. While the pupil is naturally able to constrict to modulate the amount of sunlight entering the eye, this effect is limited on cloudy days when UV radiation is still high, and may not function perfectly in individuals with disease conditions such as albinism, caratacts, macular degeneration and uveitis, or oculomotor nerve damage. One solution is to use lenses that contain both photochromic compounds and UV blockers. Upon exposure to UV light, photochromic compounds can change via structural rotation or conformational changes from a first colored state (e.g., colorless) to a second colored state (e.g., darkened), and this color transition is reversible upon removal of the UV stimulus. In particular, photochromic spectacles provide the wearer with the glare protection of visible light absorbing lenses (sunglasses) only when exposed to UV light. Under indoor or night time conditions, the lenses are generally colorless and provide optimal night and indoor vision. Photochromic spectacles thus eliminate the need for switching between sunglasses and regular spectacles. However, even with combined with additional UV-protective compounds or coatings, photochromic spectacles do not completely block UV and glare, allowing light in around the lenses. Unlike contact lenses which completely cover the pupil, they are also cumbersome and subjected to issues such as fogging and perspiration, thus are less desirable for use in outdoor or water sports, where contact lenses are preferred.
Therefore, it is desirable to have a photochromic compound incorporated into a soft, transparent and non-toxic matrix suitable for use as contact lens material. In this case, not only should there be sufficient darkening of the contact lens so as to block glare for the wearer, the timescale of the reverse transition from the colored form of the photochromic lens back to its original colorless form should also be fast, preferably within seconds, in order to provide quick response under changing lighting conditions. Thus, a soft flexible contact lens matrix should provide a superior host environment for the structural changes required of the photochromic dye molecule to respond quickly under changing UV stimulus, as there is sufficient free volume compared to a rigid spectacle lens matrix where the speed of reverse photochromism in particular is restricted. In addition, appropriate UV-blockers need to be incorporated in order to ensure that the eye is protected from UV even as the contact lens itself darkens to block glare. These UV-blockers not only have to be stably polymerized within the contact lens matrix so as not to cause toxicity or irritation to the eye from leaching, they also need to perform the UV-blocking function without hindering the performance of the UV-activated photochromic dye molecule.
This example describes transparent bicontinuous nanoemulsion systems (
In
The transparent nanoemulsion polymers were subjected to oxygen permeability (
In
In
The optical properties of these transparent nanoemulsion polymers were also evaluated by demonstrating the effect of the UV-blockers incorporated (
In vitro testing showed that the photochromic UV-blocking soft contact lenses were non-toxic to human primary conjunctival epithelial (HCEP) cells (
In
Synthesis, Optical Characterization and FESEM Imaging of Transparent UV-Blocking Photochromic Contact Lens:
2-hydroxyethyl methacrylate (HEMA, Tokyo Chemical Industry, Japan), glycidyl methacrylate (GMA, Fluka, USA), and ethylene glycol dimethacrylate (EDGMA, Aldrich, USA) was distilled to remove inhibitor before use. Napthoxazine and napthopyran photochromic dyes (PD, Reversacol, USA) as well as the UV-blockers 1-hydroxybenzotriazole (HBT, Aldrich), benzophenone (BP, Alfa Aesar, USA) and hydroxyphenyltriazine (HPT, BASF, Germany) were selected in order to impart photochromic and UV-blocking properties to the lens. The polymerizable non-ionic surfactant ω-methoxy poly(ethylene oxide)40 undecyl α-methacrylate macromonomer (PEO-40) was synthesized according to a procedure modified from Liu, J., Chew, C. H. & Gan, L. M. Synthesis and polymerization of a nonionic surfactant: poly(ethylene oxide) macromonomer. J. Macromol. Sci. Pure Appl. Chem. 33, 337-352 (1996). Polymerization was achieved using a water-soluble thermal initiator 2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (AIPH, Wako, Japan).
The oil phase comprising HEMA, GMA, EDGMA, PD, HBT, BP and HBT was first mixed with the PEO-40 surfactant by vortexing and ultrasonication. It was then titrated with the aqueous phase comprising deionized water and AIPH under further ultrasonication so as to obtain a homogenous emulsion. Ultrasonication was performed in an ice bath to prevent premature polymerization of the emulsion mixture. Successful nanoemulsion synthesis was determined by measuring an optical transmission near 100% in the visible range. The optical transparency of the emulsion for each composition tested was determined by measuring transmission in the visible range using ultraviolet-visible (UV-Vis) spectroscopy (Agilent 8453 UV-Visible Spectrophotometer) and plotted accordingly in a ternary phase diagram (FIG. 18A(i)). Each emulsion mixture was then cast between 2 glass plates separated by a spacer and subjected to polymerization in a 60° C. oven for 1 h in order to obtain a solid fully-polymerized sheet. For the purposes of the in vivo tests, oxygen transmissibility, and water content measurements, the emulsion mixture was instead cast into lens-shaped molds so as obtain a curved contact lens. After polymerization, the sheets were then soaked in deionized water and subjected to further transmission tests with the UV-Vis in order to obtain the compositions that remained transparent after polymerization (FIG. 18A(ii)). Selected transparent polymerized sheets were then cut, dried, and sputter-coated with platinum before imaging under field emission scanning electron microscopy (FESEM, JEOL, JSM-7400F), operating at an accelerating voltage of 5 kV. FESEM micrographs of the transparent polymer cross-section were obtained to show its bicontinuous nanostructure with interconnected nanometer-sized channels formed by separate water and polymer domains (
Comparison of Oxygen Permeability, Equilibrium Water Content and Mechanical Properties of Transparent Photochromic UV-Blocking Contact Lens with Commercial Soft Contact Lens:
Oxygen permeability (Dk) measurements (
Equilibrium water content (EWC) of the contact lenses (
Mw was measured from the hydrated contact lens after removal of excess water and obtaining a stable current (i) with the oxygen permeometer. Md was measured from the dehydrated contact lens after 15 h drying in a vacuum oven at 37° C.
To obtain the tensile stiffness (Et) and yield strength (σy) (
Video and Lens Transmission Tests to Demonstrate UV Blocking and Photochromic Response Properties of Lenses:
To demonstrate the effects of incorporated UV blockers on the light transmission properties of the photochromic lenses (
To demonstrate the photochromic response of the photochromic UV-blocking contact lens before and after UV irradiation, and especially showing the reverse photochromic transition from colored to colorless state at different time intervals after UV irradiation (
To demonstrate the effect of different photochromic dyes on reverse photochromic transition times from colored to colorless state after UV irradiation, transparent nanoemulsion polymer sheets were prepared according to composition 4 using either blue (naphthoxazine), green (naphthoxazine) or yellow (naphthopyran) photochromic dye. The sheets were then hydrated and cut into 15 mm discs. A set of 3 discs containing 1 each of blue, green and yellow were then subjected to 5 min UV irradiation. The subsequent removal of the discs from the UV lamp and ensuing reverse photochromic transition from colored to colorless state was then captured on video.
In Vitro and In Vivo Testing of Transparent Photochromic UV-Blocking Soft Contact Lens:
Human primary corneal epithelial (HCEP) cells were purchased from CELLnTEC (Switzerland) and cultivated using CnT-20 medium (CELLnTEC, Switzerland) with 5% CO2 and humidified atmosphere. The medium was changed every 2 days. The effects of materials on HCEP cell viability was examined using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Cells were seeded in 24-well plates in 1 mL of CnT-20 medium. Polymerized sheets of nanoemulsion polymer composition 4 were prepared i) without UV blockers and photochromic dye; ii) with all 3 UV blockers only; or iii) with both photochromic dye and UV blockers. The sheets were cut into discs using a 10 mm biopsy punch and placed in cell culture inserts. The inserts containing the photochromic UV-blocking polymer discs were then cultured together with the HCEP cells. 200 μL of MTS solution was added after 12 h. After 3 h of incubation at 37° C. in 5% CO2, the light absorbance was measured at 490 nm with a microplate reader. The cell viability was expressed as the percentage of viable cells in wells containing nanoemulsion polymer compared to control wells without polymer. Experiments were repeated in triplicates, and consistent results were obtained and reported as mean±standard deviation (
New Zealand rabbits (3-6 months, 2-2.5 kg) were used for animal studies. All experiments involving animals were performed in accordance with the protocol approved by the Institutional Animal Care and Use Committee of Biological Research Centre, Agency for Science, Technology and Research (A*STAR), Singapore. The New Zealand rabbits were randomly grouped. In each group, a total of 3 rabbits were used. The transparent nanoemulsion polymer composition 4 containing both photochromic dye and UV blockers was cast into contact lens shape and worn on the eye of the rabbits. The eyelid was then sutured shut to prevent the contact lens from being dislodged by animal activity. After 7 days, the treated eyeballs were collected and fixed in 4% neutral buffered formalin. The fixed eyeballs were embedded in paraffin, sectioned and stained with hematoxylin (nucleus, blue) and eosin (cytoplasma, purple) using standard protocols (
The following described a non-limiting synthesis of polymerizable non-ionic surfactant of ω-methoxypoly(ethyleneoxide)40undecyl-α-methacrylate (C1-PEO-C11-MA-40).
The synthesis of the macromonomer (C1-PEO-C11-MA-40) featuring the four steps is shown in
The hydrolysis of the THP-ether to the corresponding alcohol (PEO-R-OH) was done by refluxing and was achieved almost quantitatively. The final step of the reaction scheme was to introduce methacrylate group into the PEO-R-OH, thus producing the macromonomer (PEO-R-MA-40) with a α-polymerizable group located at the “tail” of the molecule. A relatively high yield (˜90%) is attainable.
Synthesis of Bromoundecyl-THP Ether (BU-THP):
To a magnetically stirred solution of 11-bromoundecanol (0.2 mol) and ptoluenesulfonic acid monohydrate (2 mmol) dissolved in dried THF (100 ml) at 0° C., DHP (0.7 mol) was added in a dropwise manner over 30 minutes. The solution, kept at a constant temperature of 28° C., was stirred further for another 30 minutes. The reaction mixture was stirred overnight at ambient temperature. The THF and excess reagent (DHP) were then removed in a rotary evaporator. The residue was dissolved in ether and washed twice with saturated brine to remove any p-toluenesulfonic acid and dried overnight with anhydrous magnesium sulfate. The solution was filtered by suction filtration and the ether was subsequently evaporated. The resulting yellowish liquid (˜100% yield) could be used directly for the next step, but a purified product (60% yield) was obtained by vacuum distillation.
Synthesis of ω-Methoxy Poly(Ethylene Oxide)Undecyl-THP Ether (PEO-R-THP):
Potassium hydroxide (0.06 mol) mol was pounded into fine powder and added with bromoundecyl-THP ether (0.06 mol) to a magnetically stirred solution of poly(ethylene glycol) methyl ether (0.02 mol) in 200 ml of dried THF (NOTE: poly(ethylene glycol) methyl ether was first be dissolved in THF completely at 50° C. thereafter potassium hydroxide and bromoundecyl-THP ether were added). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 1 day and then filtered. After evaporation of both THF and benzene, the residue was collected in ether at 0° C., and the milky white precipitate was centrifuged at 1,500 rpm using the Kubota 5100 centrifuge. The precipitate was dried in a vacuum oven at ambient temperature and then re-dissolved in distilled chloroform followed by washing with brine to remove KOH as well as any unreacted PEG. The chloroform solution was again dried overnight with magnesium sulphate, which was later filtered off. Chloroform was evaporated and the white solid product (85% yield) obtained was further dried in the vacuum oven for two days at ambient temperature.
Synthesis of ω-Methoxy Poly(Ethylene Oxide)Undecanol (PEO-R-OH):
PEO-R-OH was obtained by refluxing PEO-R-THP in ethanol acidified with HCl (pH 3.0) using an oil bath for 4 hours. After evaporating off the ethanol, the residue was dissolved in distilled chloroform, washed thrice with brine and left to dry overnight by magnesium sulfate. A white solid product (95% yield) was obtained after evaporation of the chloroform and dried to a constant weight in vacuum.
Synthesis of ω-Methoxy Poly(Ethylene Oxide)Undecyl α-Methacrylate (C1-PEO-C11-MA-40):
The final macromonomer of C1-PEO-C11-MA-40 was prepared by adding methacryloyl chloride (MAC, 0.065 mol) dropwise under nitrogen over a period of half an hour to a magnetically stirred solution of PEO-R-OH (0.013 mol) and 8 ml of triethylamine in 80 ml of dried CH2Cl2 at 0° C. Upon the addition of MAC, a solid salt was formed immediately, and it was kept in the ice-bath for another hour. The reacting mixture was further stirred overnight at room temperature. After the excess methacryloyl chloride and triethylamine were removed, the residue was dissolved in distilled chloroform and washed twice with saturated sodium bicarbonate solution followed by saturated brine. A solid product was recovered from the chloroform solution after rotary evaporation. The pure product of C1-PEO-C11-MA-40 (90% yield) was obtained by reprecipitating the crude product thrice from chloroform and ether (as before in Step 2). The precipitate was dried to a constant weight and stored in darkness.
While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and/or structures for performing the functions and/or obtaining the results and/or one or more of the advantages described herein, and each of such variations and/or modifications is deemed to be within the scope of the present invention. More generally, those of ordinary skill in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and/or configurations will depend upon the specific application or applications for which the teachings of the present invention is/are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and/or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and/or methods, if such features, systems, articles, materials, kits, and/or methods are not mutually inconsistent, is included within the scope of the present invention.
The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”
The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and/or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.
As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.
This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. No. 61/915,471, entitled “NANOSTRUCTURED CONTACT LENSES AND RELATED OPHTHALMIC MATERIALS” filed on Dec. 12, 2013, which is herein incorporated by reference in its entirety. This application is also a continuation-in-part and claims the benefit under 35 U.S.C. §120 of U.S. application Ser. No. 13/387,014, entitled “FAST-RESPONSE PHOTOCHROMIC NANOSTRUCTURED CONTACT LENSES” filed on Jan. 25, 2012, which is herein incorporated by reference in its entirety. U.S. application Ser. No. 13/387,014 filed on Jan. 25, 2012, is a national stage filing under 35 U.S.C. §371 of International Application No. PCT/US2010/054244, filed Oct. 27, 2010, which was published under PCT Article 21(2) in English, and claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application Ser. No. 61/255,474, entitled “FAST-RESPONSE PHOTOCHROMIC NANOSTRUCTURED CONTACT LENSES” filed on Oct. 27, 2009, each of which are herein incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61915471 | Dec 2013 | US | |
| 61255474 | Oct 2009 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13387014 | Aug 2012 | US |
| Child | 14569253 | US |
