Elastomeric matrix based on plasticized PVOH composition and uses thereof

Abstract

Provided herein is an elastomeric matrix comprising poly(vinyl alcohol) (PVOH), at least two plasticizers, neither of which is water, and water, wherein the combined mass ratio of the plasticizers to the PVOH is at least 2:1, and the combined mass content of the PVOH and the plasticizer is at least 70 wt% of the total weight of the matrix excluding water.

Description

[Technical field]

[0001] [Related Applications] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 272,241, filed October 27, 2021, the entire disclosure of which is incorporated herein by reference.

[0002] This application is also related to Israel Patent No. 287646, filed on October 27, 2021, the entire disclosure of which is incorporated herein by reference.

[0003] The present invention in some embodiments thereof relates to materials science, and more particularly, but not exclusively, to polyvinyl alcohol (PVOH) based elastomeric matrices and uses thereof. [Background technology]

[0004] Polyvinyl alcohol (PVOH) is a water-soluble synthetic polymer represented by the formula (C2H4O)n. PVOH is prepared by hydrolysis of polyvinyl acetate, replacing acetate groups with hydroxyl groups. PVOH has many applications, including biomedical and pharmaceutical applications such as the lining of artificial hearts, artificial cartilage, catheters, skin, and membranes for the pancreas. PVOH can be crosslinked chemically or physically (i.e., not covalently).

[0005] During physical crosslinking, hydroxyl groups interact to form intra- and intermolecular hydrogen bonds, resulting in the formation of crystallites. Physical crosslinking is typically performed by freeze-thawing with or without the addition of a solvent, resulting in the well-known cryogel. Alternatively, a solution of polyvinyl alcohol can be dried (Otsuka, E., & Suzuki, A., Journal of Applied Polymer Science, 2009, 114(1), 10-16, doi:10.1002 / app.30546). Various plasticizers can be added to improve flexibility, generally at less than 30%, often less than 10% (Mohsin, M., et al., Journal of Applied Polymer Science, 2011, 122(5), 3102-3109. doi:10.1002 / app.34229; Lim, LY et al., Drug Development and Industrial Pharmacy, 1994, 20(6), 1007-1020. doi:10.3109 / 03639049409038347; and Wu, W. et al., Journal of Polymers and the Environment, 2011, 20(1), 63-69. doi:10.1007 / s10924-011-0364-7).

[0006] Zhang, B. et al., (Ceramics International, 2020, doi:10.1016 / j.ceramint.2020.03.286) teach the beneficial role of the mechanical properties of polyvinyl alcohol films in YSZ tape calendering.

[0007] US Pat. No. 4,874,562 discloses a method for molding polyvinyl alcohol contact lenses.

[0008] U.S. Patent No. 4,663,358 discloses a porous, transparent, hydrated gel prepared from a solution of poly(vinyl alcohol) in a mixed solvent consisting of water and a water-miscible organic solvent. The poly(vinyl alcohol) solution is cooled below room temperature to form a gel as a result of crystallization of the poly(vinyl alcohol) molecules. The organic solvent contained in the gel is exchanged for water to produce a hydrated gel of poly(vinyl alcohol) with high tensile strength, high water content, and high light transmittance.

[0009] US Pat. No. 10,513,588 discloses a water-soluble polyvinyl alcohol film containing a plasticizer blend. Summary of the Invention

[0010] The present disclosure provides an elastomeric matrix formed from polyvinyl alcohol and a plasticizer. The elastomeric matrix disclosed herein is soft and elastic in its dry form. The matrix may enjoy a particularly long shelf life because it can be stored under dry conditions for extended periods of time without losing its softness and plasticity. The matrix may be suitable for applications requiring such stability because its properties such as shape, volume, and elasticity do not substantially change after immersion or exposure to liquids. The elastomeric matrix may be loaded with additional compounds, such as pharmacoactive agents, and may be used as or in ophthalmic devices. Some embodiments of the matrix disclosed herein may be used as implants, for topical application, or for insertion into a body cavity. Some embodiments may be self-applied or may be applied by a physician, for example, during a surgical procedure.

[0011] Thus, according to one aspect of some embodiments of the present invention, there is provided an elastomeric matrix comprising: Poly(vinyl alcohol) (PVOH); At least two plasticizers, neither of which is water; Water, Including, the total mass ratio of plasticizer to PVOH is at least 2:1; An elastomeric matrix is ​​provided, in which the combined mass content of PVOH and plasticizer is at least 70 wt % of the total weight of the matrix, excluding water.

[0012] In accordance with another aspect of some embodiments of the present invention, there is provided an elastomeric matrix for use as an ophthalmic device, comprising:

[0013] Poly(vinyl alcohol) (PVOH); at least one plasticizer which is not water; Water, Including, The weight ratio of plasticizer to PVOH is at least 2:1; An elastomeric matrix is ​​provided, in which the combined mass content of PVOH and plasticizer is at least 70 wt % of the total weight of the matrix, excluding water.

[0014] In some embodiments, the elastomeric matrices provided herein comprise at least two plasticizers, none of which is water.

[0015] In some embodiments, the weight ratio of plasticizer to PVOH is less than 20:1.

[0016] In some embodiments, the elastomeric matrices provided herein swell and contract substantially isotropically.

[0017] In some embodiments, the elastomeric matrices provided herein are characterized as having substantially the same shape under wet and dry conditions (shape stability, shape invariance, shape retention).

[0018] In some embodiments, the elastomeric matrices provided herein are characterized by swelling less than 50% by volume under humid conditions.

[0019] In some embodiments, the elastomeric matrices provided herein are characterized by a crystallinity of less than 50%.

[0020] In some embodiments, the elastomeric matrices provided herein are characterized by a total light transmittance of less than 80%.

[0021] In some embodiments, the PVOH is characterized by a degree of hydrolysis of greater than 90%.

[0022] In some embodiments, the degree of polymerization of PVOH is 500 to 5,000.

[0023] In some embodiments, the plasticizer or plasticizers include at least two hydrogen bond forming functional groups.

[0024] In some embodiments, the molar mass of the one or more plasticizers is characterized as being less than 1,000 g / mol.

[0025] In some embodiments in which the matrix comprises two or more plasticizers, at least one of the plasticizers is an oligomer characterized by a molar mass greater than 1,000 g / mol.

[0026] In some embodiments where the matrix includes two or more plasticizers, the viscosity of at least one of the plasticizers is characterized as being at least 1,000 cp and the viscosity of at least one other of the plasticizers is characterized as being less than 200 cp.

[0027] In some embodiments, the plasticizer is independently selected from the group consisting of polyols, polybasic organic acids, polyamines, alkyl gluceths, aliphatic polyalkylene glycols, ethanolamines, sugars, oligosaccharides, amino acids, polyphenols, tromethamine, urea, tannic acid, and any salts thereof and / or combinations thereof.

[0028] In some embodiments, the polyol is selected from the group consisting of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, propylene glycol, triacetin erythritol, polyglycols, poloxamers and copolymers thereof, and glycerol and its esters.

[0029] In some embodiments, the polybasic organic acid is selected from the group consisting of oxalic acid, maleic acid, citric acid, and any salts thereof.

[0030] In some embodiments, the polyamine is selected from the group consisting of spermine, spermidine, diethylenetriamine, triethylenetetraamine, tris(2-aminoethyl)amine, polyethyleneimine, and any salt thereof.

[0031] In some embodiments, the aliphatic polyalkylene glycol is selected from the group consisting of polyethylene glycol, polypropylene glycol, polyglycol, poloxamer, and polysorbate.

[0032] In some embodiments, the aliphatic polyalkylene glycol is polyethylene glycol.

[0033] In some embodiments, the weight content of PVOH is substantially equal to the weight content of the aliphatic polyalkylene glycol.

[0034] In some embodiments, the aliphatic polyalkylene glycol is selected from the group consisting of polyethylene glycol, polypropylene glycol, and any mixture thereof.

[0035] In some embodiments, the plasticizer is biocompatible.

[0036] In some embodiments, the plasticizer is ophthalmically acceptable.

[0037] According to some embodiments, the plasticizer in the elastomeric matrix provided herein is any one of glycerol, propylene glycol, sugar alcohols such as mannitol and sorbitol, citrate salts, and EDTA salts. In some embodiments, PEG and polypropylene glycol are preferred second plasticizers. Other preferred plasticizers include dicarboxylic acids (e.g., maleic acid, fumaric acid, tannic acid, etc.), sugars (e.g., fructose, maltose, etc.), DMSO, amino acids, triethyl citrate, and dipropylene glycol.

[0038] According to some embodiments, the mechanical properties of the elastomeric matrix provided herein include a Young's modulus of 0.05 MPa to 2 MPa, a tensile strength of 0.05 MPa to 2 MPa, and an elongation at break of 100% to 900%.

[0039] In some embodiments, the weight content of water comprises less than 50 wt% of the total weight content of the elastomeric matrices provided herein.

[0040] In some embodiments, the weight content of PVOH comprises less than 5 wt% of the total weight content of non-water components of the elastomeric matrix provided herein.

[0041] In some embodiments, the elastomeric matrices provided herein are essentially free of covalent crosslinks.

[0042] In some embodiments, the elastomeric matrices provided herein comprise a non-PVOH polymer characterized by a plurality of hydrogen bond forming residues.

[0043] In some embodiments, the weight ratio of PVOH to non-PVOH polymer is at least 2:1.

[0044] In some embodiments, the non-PVOH polymer is selected from the group consisting of polyacrylic acid, polyvinylpyrrolidone, cellulose, chitin, glycogen, starch, gellan, dextran, inulin, pectin, arabinoxylan, and any mixture thereof.

[0045] In some embodiments, the matrices provided herein further comprise a pharma- ceutical active agent.

[0046] According to another aspect of some embodiments of the present invention there is provided an ophthalmic device comprising an elastomeric matrix as provided herein.

[0047] In some embodiments, the elastomeric matrix is ​​comprised of an ophthalmically acceptable component.

[0048] In some embodiments, the elastomeric matrix comprises a pharma- ceutical active agent.

[0049] In some embodiments, the device is configured to be placed on the surface of the eye.

[0050] In some embodiments, the surface is at least partially beneath at least one of the upper and lower eyelids and outside the cornea of ​​the eye.

[0051] In some embodiments, the device is configured to deliver at least one pharma- ceutical active agent to the eye over an extended period of time.

[0052] As used herein, the term "about" means ±10%.

[0053] The terms "comprises," "comprising," "includes," "including," "having" and their conjugations mean "including but not limited to."

[0054] The term "consisting of" means "including and limited to."

[0055] The term "consisting essentially of" means that a composition, method, or structure may include additional ingredients, steps, and / or moieties, but only if the additional ingredients, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0056] As used herein, the phrases "substantially free" and / or "essentially free" in the context of a particular substance refer to a composition that is completely free of the substance or that contains less than about 5%, 1%, 0.5% or 0.1% of the substance based on the total weight or volume of the composition. Alternatively, the phrases "substantially free" and / or "essentially free" in the context of a process, method, property or characteristic refer to a process, composition, structure or article that is completely free of a particular process / method step, or a particular property or characteristic, or a process / method in which a particular process / method step is achieved at less than about 5%, 1%, 0.5% or 0.1% compared to a given standard process / method, or a property or characteristic that is characterized by less than about 5%, 1%, 0.5% or 0.1% of a property or characteristic compared to a given standard.

[0057] As used herein, the term "substantially maintain" when applied to an original, desired, or resulting property of an object or composition means that the property has not changed by more than 20%, 10%, or 5% in the treated object or composition.

[0058] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or to exclude the incorporation of features from other embodiments.

[0059] The words "optionally" or "alternatively" are used herein to mean "provided in some embodiments and not provided in other embodiments." Any particular embodiment of the invention may include multiple "optional" features unless such features are inconsistent.

[0060] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0061] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have specifically disclosed all the possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as the individual numerical values ​​within that range, for example, 1, 2, 3, 4, 5, and 6. This is true regardless of the breadth of the range.

[0062] Whenever a numerical range is given herein, it is intended to include any recited numerical value (fractional or integer) within the specified range. The phrases "ranging / ranges between" a first specified numerical value and a second specified numerical value, and "ranging from" a first specified numerical value to a second specified numerical value, are used interchangeably herein and are meant to include the first specified numerical value and the second specified numerical value, and all fractional and integer numerical values ​​therebetween.

[0063] As used herein, the terms "process" and "method" refer to methods, means, techniques and procedures for accomplishing a given task, including, but not limited to, methods, means, techniques and procedures that are known to those of skill in the chemical, materials, mechanical, computational and digital arts or that are readily developed from known methods, means, techniques and procedures.

[0064] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of embodiments of the present invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not necessarily intended to be limiting. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0065] The present invention, in some embodiments thereof, relates to materials science, and more particularly, but not exclusively, to polyvinyl alcohol (PVOH)-based elastomeric matrices and uses thereof.

[0066] Before describing at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or illustrated by way of examples, as the disclosure is intended to encompass other embodiments or to be practiced or carried out in various ways.

[0067] In devising the present invention, the inventors envisioned a PVOH-based elastomeric matrix that is free of chemical crosslinker residues and stable in shape and consistency during immersion in an aqueous medium. The envisioned elastomeric matrix is ​​soft and elastic under dry and wet conditions and does not substantially change shape after immersion or exposure to liquid. In practicing the present invention, the inventors surprisingly found that such a matrix can be formed by adding a large amount of plasticizer to polyvinyl alcohol. In particular, it is desirable for the amount of plasticizer(s) to be at least twice that of polyvinyl alcohol.

[0068] PVOH-based elastomeric matrix: In optimizing the findings discussed above, the inventors have surprisingly found that an elastomeric matrix containing less than 35 weight percent (wt%) polyvinyl alcohol in its composition maintains elastomeric matrix morphology under dry conditions, swells less than 50% by volume (or less than 15% along each of its three dimensions) under wet conditions, and substantially maintains its size, shape, and morphology when cycling between dry and wet conditions. It has been found that the use of at least two plasticizers is required to manipulate these properties (e.g., to reduce swelling tendency without compromising flexibility).

[0069] Thus, according to one aspect of some embodiments of the present invention, there is provided an elastomeric matrix comprising poly(vinyl alcohol) (PVOH), at least two plasticizers, neither of which is water, and water, wherein the matrix exhibits certain desired properties when the combined mass ratio of plasticizer to PVOH is at least 2:1 and the combined mass content of PVOH and plasticizer is at least 70 wt% of the total weight of the matrix excluding the mass of water, i.e., the combined mass of PVOH and plasticizer(s) is at least 70 wt%, at least 60 wt%, or at least 50 wt% of the mass of all non-water components of the matrix.

[0070] The term "total mass ratio" as used herein refers to the total amount of a plurality of components (e.g., plasticizer) relative to the amount of another component (e.g., PVOH) of the matrix, where all amounts are presented in units of mass (e.g., grams). The total mass ratio is calculated by adding the masses of the plurality of components to obtain a total mass and dividing the total mass by the mass of the other component.

[0071] The term "total mass" as used herein refers to the combined amount of a plurality of components presented in units of mass. The total mass is calculated by adding up the masses of the components that make up the plurality of components.

[0072] According to another aspect of some embodiments of the present invention, there is provided an elastomeric matrix for use as an ophthalmic device, the elastomeric matrix comprising poly(vinyl alcohol) (PVOH), a non-water plasticizer, and water, wherein the weight ratio of the plasticizer to the PVOH is at least 2:1, and the weight content of all non-water components of the matrix is ​​at least 70 wt% of the total weight of the matrix excluding the weight of water. In some embodiments, the elastomeric matrix for use as an ophthalmic device comprises at least two plasticizers, neither of which is water, wherein the combined weight ratio of the plasticizer to the PVOH is at least 2:1, and the combined weight content of the PVOH and the plasticizer is at least 70 wt% of the total weight of the matrix excluding the weight of water, i.e., the combined weight of the PVOH and the plasticizer(s) is at least 70 wt%, at least 60 wt%, or at least 50 wt% of the weight of all non-water components of the elastomeric matrix for use as an ophthalmic device.

[0073] In some embodiments, the weight ratio of the plasticizer(s) to PVOH is less than 5:1, less than 10:1, less than 15:1, less than 20:1, or less than 30:1. In some embodiments, the weight ratio of the plasticizer(s) to PVOH is in the range of 5 to 2:1 (5:1 to 2:1) or 30:1 to 5:1.

[0074] According to some embodiments of the invention, the mass content of PVOH represents less than 5 wt% of the total weight of the non-water components of the matrix. Alternatively, the mass content of PVOH represents less than 10 wt%, less than 15 wt%, less than 20 wt%, less than 25 wt%, or less than 30 wt% of the total weight of the non-water components of the matrix.

[0075] The term "elastomeric matrix" as used herein refers to a crosslinked polymeric structural form that exhibits elastomeric elasticity, undergoes deformation under the influence of a force, and can recover its original shape when the force is removed. In the context of some embodiments of the present invention, the elastomeric matrix is ​​a physically crosslinked polymeric structural form having an open-cell porous microstructure that is sequestered in interconnected voids and can incorporate releasable substances. According to some embodiments of the present invention, the elastomeric matrix is ​​a network of hydrogen-bonded polymers and plasticizers. According to some embodiments of the present invention, the elastomeric matrix is ​​a network of hydrogen-bonded polymers, plasticizers, and water. In some embodiments, the elastomeric matrices provided herein are essentially free of covalent crosslinks.

[0076] In some embodiments, the elastomeric matrices provided herein have a porosity of about 50% to about 90%. In some embodiments, the matrices are characterized by a porosity of at least about 50%, 60%, 70%, 80%, or at least about 90%.

[0077] The consistency of the elastomeric matrices provided herein can be similar to that of hydrogels, but in contrast to hydrogels, the elastomeric matrices provided herein are stable under dry conditions and do not require immersion in water to retain their flexibility. The mechanical properties of the elastomeric matrices provided herein are similar to those of rubber (elastomers) under dry and / or wet conditions (e.g., immersed in an aqueous medium).

[0078] Unless expressly stated otherwise, any reference to the elastomeric matrices provided herein is made to the elastomeric matrices under dry conditions. The term "dry conditions" refers to the elastomeric matrices provided herein themselves, and not to a solution in which the matrices may or may not be immersed. According to embodiments of the present invention, the elastomeric matrices provided herein are definable and shape stable, whether or not immersed in a liquid medium or wetted.

[0079] Water may be structurally fixed within the elastomeric matrix, may be free to evaporate / flow out of the matrix, or may not be present within the matrix. The exact amount of water (fixed and / or free) varies depending on the nature of the components in the matrix and the conditions under which the matrix is ​​stored. When referring to "non-water" elements / components of the elastomeric matrix provided herein, it is intended to refer to all of its components except water. The mass content of "non-water" elements should not be confused with the mass content of the matrix under dry conditions, which may include a mass of water.

[0080] When referring to "dry conditions", it should be understood to refer to conditions in which the elastomeric matrix provided herein is exposed to air at room temperature in an open or closed container and is not immersed in a liquid, such as water or any other aqueous medium or liquid. In the context of ophthalmic devices, "dry conditions" represents a state that is the opposite of how contact lenses are stored. Contact lenses are generally made of hydrogels and must be stored under aqueous media at all times to maintain their shape and ductility. In sharp contrast, the elastomeric matrix provided herein does not need to be kept wet and does not change its shape (although it may change in size) when going between wet and dry conditions.

[0081] Thus, when an elastomeric matrix is ​​said to have less than 35 wt.% polyvinyl alcohol of the total weight of the non-water components of the matrix, it means that the mass content of PVOH accounts for less than 35 wt.% of the total mass content of the matrix, excluding any water (if any) that is structurally fixed within the matrix or freely flows out of the matrix.

[0082] A relatively small amount of water in the matrix allows the matrix to have a longer shelf life and to be stored under dry conditions (i.e., not immersed in liquid), but an excessive amount of water is not required or desirable. Assuming that only water evaporates from the wet elastomeric matrix, the amount of water remaining after conventional drying is considered to form part of the matrix. In the context of the present invention, conventional drying is drying by exposing the outer surface of the matrix to ambient air at room temperature and ambient humidity. The room temperature can range from 15°C to 30°C, and the relative humidity can range from 30% to 75%. The exact conventional drying time can vary depending on the specific content of the matrix, but is typically between 24 hours and 4 days.

[0083] The moisture content can be determined by, among other methods, the Karl Fischer method and the direct measurement of mass loss on drying, i.e., the LOD method. The Karl Fischer method was performed volumetrically using a Karl Fischer apparatus model Titrando 852 (Metrohm) with Hydranal Composite 5 (Honeywell) as the titrant. Methanol was used as the solvent. The LOD test was performed at a temperature of 85 °C on samples of 700 mg or more using an MX-50 moisture meter from A&D Co., Ltd., Japan.

[0084] According to these methods which yield similar results for a given sample, in some embodiments of the invention, the elastomeric matrix contains less than about 50 wt% water therein, hi some embodiments, the amount of water is less than about 40 wt%, less than about 30 wt%, less than about 25 wt%, less than about 20 wt%, less than about 15 wt%, less than about 10 wt%, or less than about 5 wt% of the total mass of the matrix.

[0085] The elastomeric matrices provided herein, due to their unique composition, swell less than 50% by volume under wet conditions while retaining their shape, hi some embodiments, the matrices swell no more than 40% by volume, or less than 35% by volume, or less than 20% by volume, or less than 15% by volume, or less than 10% by volume, or less than 5% by volume under wet conditions.

[0086] It is noted herein that the matrix can be cast, molded, cut, or otherwise fabricated into a well-defined 3D shape, and this shape essentially does not change as conditions change from dry to wet and vice versa. This property is referred to herein as shape retention. In other words, the total volume of a piece of the matrix provided herein may change (swell or shrink) under changing wet conditions, but the overall shape of the piece remains essentially the same without distortion, compression, or deformation. Thus, another characteristic of the elastomeric matrix provided herein is the substantially uniform size variability along all directions and orientations under changing wet conditions. By substantially uniform, it is meant that the size changes by the same amount ±20% along each direction. This characteristic is sometimes referred to herein as isotropic swelling and shrinkage.

[0087] The composition and preparation method of the elastomeric matrix provided herein also determines the crystallinity of the matrix. The degree of crystallinity (DoC) is the percentage of ordered molecules in a polymeric material, and typically ranges from 10% to 80% for many known polymeric materials. Higher values ​​can be achieved for materials with small molecules, or for polymeric materials prepared and / or stored at temperatures just below the melting point. Most methods for evaluating crystallinity assume a mixture of completely crystalline and completely disordered regions, with transition regions expected to be a few percent. These methods include density measurements, differential scanning calorimetry (DSC), X-ray diffraction (XRD), infrared spectroscopy, and nuclear magnetic resonance (NMR).

[0088] The elastomeric matrices provided herein do not need to be cooled below room temperature and, after solidification and drying, do not need to be heated above room temperature. According to some embodiments, the crystallinity of the matrix is ​​less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, or less than 20%.

[0089] The elastomeric matrices provided herein are highly suitable for use as ophthalmic devices in ophthalmic applications, including those in which the matrix needs to be transparent and those in which such requirements are not raised. Thus, the elastomeric matrices provided herein are characterized by relatively low transparency, according to some embodiments. The transparency of a material refers to the optical clarity with which an object can be seen when viewed through a film / sheet made from the material. The transparency of an object made from the elastomeric matrices provided herein can be measured by the total transmittance, which is the ratio of transmitted light to incident light, taking into account the influencing factors of reflection, absorption, and scattering. For example, to subtract absorption / scattering and reflection, the total transmittance of a sample is the incident light (100%) minus the absorption / scattering (X%) and reflection (Y%), or in other words, total transmittance = incident light - (absorption / scattering + reflection). In some embodiments, opaque elastomeric matrices may be preferred, for example, because they are easier to manufacture without compromising functionality. For example, opaque elastomeric matrices can be obtained by using PEG as a plasticizer and / or by manufacturing the matrix at room temperature.

[0090] According to some embodiments of the invention, the elastomeric matrix is ​​characterized by a total light transmittance (transparency) through an optical path length of 0.5 mm of less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, or less than 30%.

[0091] According to some embodiments of the present invention, the PVOH used in the preparation of the elastomeric matrices provided herein is characterized by a degree of hydrolysis (DH) of greater than 80%, greater than 85%, greater than 90%, or greater than 95%. In some embodiments, the degree of hydrolysis of the PVOH is less than 100%.

[0092] The degree of polymerization (DP) of a polymer is estimated by dividing the molecular weight of the polymer by the molecular weight of the monomer unit. In some embodiments of the present invention, the PVOH used in the preparation of the elastomeric matrices provided herein is further characterized by a degree of polymerization ranging from 500 to 5,000. In some embodiments, the PVOH may be a mixture of different degrees of polymerization, for example, one PVOH of high molecular weight (e.g., chain length of 3,000 monomers or more) and one PVOH of low molecular weight (e.g., chain length of 1,000 monomers or less).

[0093] In some embodiments, the elastomeric matrix provided herein is a non-biodegradable matrix. In some embodiments, the elastomeric matrix provided herein is a biodegradable matrix. In some embodiments, the elastomeric matrix is ​​stable in liquid for more than one month at room temperature. In some embodiments, the elastomeric matrix undergoes at least partial and gradual dissolution and / or erosion upon contact with liquid (water, body fluids). In some embodiments, the elastomeric matrix provided herein is bioerodible, i.e., the amount of polymer bulk in the matrix decreases by either physical processes, such as dissolution, and / or chemical processes that occur when the matrix comes into contact with biological tissue and / or body fluids. In some embodiments, the body fluid is tears.

[0094] In some embodiments, the elastomeric matrix provided herein further comprises at least one inorganic ion and / or a salt thereof, and / or at least one organic ion and / or a salt thereof.

[0095] In some embodiments, the elastomeric matrix provided herein further comprises at least one buffering agent, hi some embodiments, the buffering agent is tromethamine, potassium phosphate, citric acid, and any combination thereof.

[0096] In some embodiments, the elastomeric matrix provided herein further comprises at least one surfactant, hi some embodiments, the surfactant is selected from sorbitan esters (Span), sorbitan tristearates (Tween), poloxamers, Triton, Betain, and any combination thereof.

[0097] In some embodiments, the matrices of the present invention are substantially free of chemical (covalent) crosslinks.

[0098] Mechanical properties: The elastomeric matrices provided herein can substantially maintain their mechanical properties, such as rheological properties, elongation at break, tensile strength, yield strength, elongation at yield, modulus, etc., when exposed to wet conditions.

[0099] Reference herein to "dry conditions" should be understood to refer to conditions in which the matrix of the invention is exposed to air at room temperature in an open or closed container and is not immersed in a liquid, in particular an aqueous liquid. Reference herein to "wet conditions" should be understood to refer to conditions in which the matrix of the invention is in direct contact with a liquid (either immersed in the liquid or after immersion in the liquid and before the liquid has evaporated or been wiped off).

[0100] In some embodiments, the liquid is a naturally occurring bodily fluid (including, but not limited to, blood, saliva, tears, feces, biological tissue, interstitial fluid), an aqueous solution (e.g., of at least one plasticizer), a buffer solution, and any combination thereof. In some embodiments, the liquid is naturally occurring or a simulation of a naturally occurring liquid, such as artificial tears. In some embodiments, the artificial tears are based on an aqueous solution containing about 0.67% sodium chloride, about 0.2% sodium bicarbonate, and about 0.008% calcium chloride.

[0101] In some embodiments, the elastomeric matrices provided herein are characterized by an elongation at break of at least 100%, 200%, 300%, 400%, 500%, 700%, at least 800%, or at least 900% under dry conditions, hi some embodiments, the elongation at break of the matrix is ​​at least 100% under wet conditions (immersed in liquid or after immersion in liquid).

[0102] Surprisingly, it has been found that in some embodiments of the present invention, the elongation at break is surprisingly high in those embodiments having a relatively low water content, such that elastomeric matrices having a water content of 30 wt% or less, 25 wt% or less, or 20 wt% or less, according to some embodiments of the present invention, exhibit relatively high elongations at break of 100% or more, and even 300% or more, or 500% or more.

[0103] In some embodiments, the elastomeric matrices provided herein are characterized by a tensile strength in the range of 0.1 MPa to 1.5 MPa or 0.05 MPa to 2 MPa under dry conditions (with additional measurements showing that 0.05 is a more likely lower limit). In some embodiments, the elastomeric matrices provided herein are characterized by a tensile strength in the range of substantially 0.1 MPa to 0.4 MPa under wet conditions. In some embodiments, the tensile strength of the matrix is ​​at least 0.1 MPa under wet conditions (submerged in liquid or after immersion in liquid).

[0104] In some embodiments, the elastomeric matrices provided herein have a yield strength of at least 0.05 MPa to 0.5 MPa under dry conditions. In some embodiments, the elastomeric matrices provided herein have a yield strength of at least 0.01 MPa to 0.5 MPa under wet conditions.

[0105] In some embodiments, the mechanical properties of the elastomeric matrices provided herein are maintained under dry conditions, hi some embodiments, the mechanical properties are maintained under dry conditions for at least one year.

[0106] In some embodiments, the elastic modulus of the elastomeric matrices provided herein is at least 0.05 MPa to 0.5 MPa under dry conditions. In some embodiments, the elastic modulus of the elastomeric matrices provided herein is at least 0.05 MPa to 0.5 MPa under wet conditions. In some embodiments, the elastic modulus of the elastomeric matrices provided herein is at least 0.05 MPa or at least 0.1 MPa or at least 0.2 MPa under dry conditions. In some embodiments, the elastic modulus of the elastomeric matrices provided herein is at least 0.05 MPa or at least 0.1 MPa under wet conditions.

[0107] An exemplary elastomeric matrix according to column 4 of Table 1 below was measured to have a Young's modulus of 0.41 MPa, a tensile strength of 0.51 MPa, and an elongation at break of 456%.

[0108] Plasticizer: The term "plasticizer" as used herein refers to a broad range of substances that, together with PVOH, provide the mechanical properties of the elastomeric matrix provided herein. Without being bound to any particular theory, it is hypothesized that the PVOH and the plasticizer(s) interact to form a hydrogen-bonded network, which allows the matrix to exhibit shape stability and elasticity under wet and dry conditions. The hydrogen-bonded network may include a plasticizer molecule linked to two (or more) PVOH residues.

[0109] In some embodiments of the present invention, the plasticizer is an organic material, ie, a material that contains carbon atoms in various forms.

[0110] According to an embodiment of the invention, at least one of the plasticizers is characterized in that it exhibits at least two hydrogen bond forming functional groups, i.e. at least two H-bond acceptors, at least two H-bond donors, or at least one H-bond acceptor and at least one H-bond donor.

[0111] According to some embodiments of the present invention, the plasticizer exhibits 3 or more H-bond forming functional groups, or 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more H-bond forming functional groups. In some embodiments, the plasticizer comprises a plurality of H-bond forming functional groups.

[0112] According to some embodiments, the plasticizer is characterized by a molar mass of less than 1,000 g / mol or less than 500 g / mol. In some embodiments in which the elastomeric matrix comprises at least two plasticizers, the matrix may comprise at least one plasticizer that is an oligomer characterized by a molar mass of more than 1,000 g / mol. In some embodiments, the oligomer is characterized by a molar mass in the range of 1,000 g / mol to 2,000 g / mol.

[0113] According to some embodiments of the present invention, the plasticizer is characterized by forming non-rigid crosslinks with other elements of the matrix, such as PVOH. In this context, the plasticizer is characterized by not including a bond connecting a hydroxyl group to the molecule and exhibiting at least one or at least two rotatable bonds in its structure. In some embodiments, the plasticizer is characterized by exhibiting at least one bond with a variable dihedral angle. A dihedral angle is the angle between half planes passing through two sets of three atoms, which share two atoms. In some embodiments, a dihedral angle is defined between half planes passing through two sets of three non-hydrogen atoms, which share two non-hydrogen atoms. For example, ethylene glycol exhibits one variable dihedral angle subtended by two sets of three atoms, each having an oxygen and two carbon atoms common to the two sets of non-hydrogen atoms.

[0114] In some embodiments, the plasticizer is biocompatible, i.e., the plasticizer does not cause intolerable local or systemic effects in the recipient / user. In some embodiments, the plasticizer is an ocularly compatible (acceptable) substance, i.e., biocompatible, and in particular does not cause intolerable ophthalmic effects in the recipient / user.

[0115] In the context of the present invention, according to some embodiments, the elastomeric matrix comprises one or more plasticizers, and in other embodiments, the elastomeric matrix comprises at least two plasticizers, it being noted that when reference is made herein to specific characteristics of a plasticizer, it is intended to be taken as referring to a single plasticizer or each of the multiple plasticizers individually.

[0116] According to some embodiments of the present invention, when the matrix includes two or more plasticizers, one is characterized by a viscosity at least 5 times higher than that of the other plasticizers. In some embodiments, at least one of the plasticizers is characterized by a viscosity of at least 1,000 cp, and the other plasticizers are characterized by a viscosity of less than 200 cp. Alternatively, one plasticizer has a viscosity of 500 cp or more, and the other plasticizer has a viscosity of 50 cp or less. For example, in one exemplary matrix, one of the plasticizers is glycerol, exhibiting a viscosity of about 1,400 cp, and the other plasticizer is polyethylene glycol, exhibiting a viscosity of about 100 cp. In another example, one of the plasticizers is glycerol, and the other plasticizer is propylene glycol, exhibiting a viscosity of about 40 cp.

[0117] In some embodiments, the plasticizer comprises at least 30 wt%, 40 wt%, 50 wt%, 60 wt%, 70 wt%, 80 wt%, or at least 90 wt% of the total weight of the matrix, hi some embodiments, the plasticizer comprises between 30 wt% and 90 wt% of the weight of the matrix and any subrange therebetween.

[0118] In some embodiments, the plasticizer is selected from polyols (e.g., ethylene glycol, diethylene glycol (DEG), triethylene glycol (TEG), and tetraethylene glycol), propylene glycol, glycerol, esters of glycerol (e.g., triacetin), polybasic organic acids (e.g., oxalic acid, maleic acid, citric acid, etc.), polyamines (e.g., spermine, spermidine, diethylenetriamine, triethylenetetraamine, tris(2-aminoethyl)amine, polyethyleneimine (PEI; polyaziridine, etc.), trypan blue, alkylgluceths, aliphatic polyether glycols (e.g., polyethylene glycol, polypropylene glycol, polysorbate 80), polyoxyethylene, ethanolamine, erythritol, tromethamine, urea, sugars, amino acids (e.g., glycine, aspartate / aspartic acid, etc.), polyphenols (e.g., tannic acid), and any combination thereof.

[0119] In some embodiments, the plasticizer is an ophthalmic emollient or demulcent as described by the FDA in 21 CFR 349.12.Thus, according to some embodiments of the present invention, the plasticizer is an ophthalmic demulcent selected from the group consisting of cellulose derivatives, sodium carboxymethylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, hemicellulose, dextran, gelatin, liquid polyols, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, povidone, and any combination thereof.

[0120] In some embodiments, the matrix includes glycerol as the sole plasticizer. In some embodiments, the matrix includes propylene glycol as the sole plasticizer. In some embodiments, the matrix includes glycerol and propylene glycol as the plasticizer. In some embodiments, the matrix includes glycerol and propylene glycol as the plasticizer, either alone or in admixture with PEG. In some embodiments, PEG is used as the sole plasticizer, and in some of these embodiments, the amount of PEG and the amount of PVOH are substantially the same.

[0121] Composition of the elastomeric matrix: The present invention further provides compositions of an elastomeric matrix soaked in a liquid and / or in combination with one or more additional elastomeric matrices, each of which is as disclosed herein.

[0122] In some embodiments, the composition of the present invention comprises at least two elastomeric matrices as disclosed herein, which may be similar or different in composition, structure and properties. In some embodiments, one formulation may be cast into a mold and dried to obtain an elastomer, and another solution may be cast on top of the elastomer to obtain a bi-layer elastomeric composition of the matrix. In some embodiments, one (or several) types of micro-elastomers may be mixed with a formulation that settles to provide another type of elastomer, thereby allowing the formulation to settle to provide a "raisin cake" composition of one or more elastomer micro-samples in the "bowl" of another elastomer.

[0123] In some embodiments, the compositions of the present invention comprise a solution comprising at least one plasticizer, and at least one elastomeric matrix is ​​immersed in the solution. In some embodiments, the compositions of the present invention further comprise a fluid selected from water or an aqueous solution or solvent, and at least one elastomeric matrix is ​​immersed in the fluid.

[0124] In some embodiments, the composition is stored under dry conditions prior to its use. In some other embodiments, the composition is stored under moist conditions prior to its use.

[0125] Composite Elastomer Matrix: The elastomeric matrices provided herein can be tailored to meet desired properties, but some applications require the matrix to exhibit unique properties and require the addition of another type of polymer(s) that is not PVOH but is typically made from hydrogen-forming monomers, this type of elastomeric matrix being referred to herein as a composite matrix.

[0126] Generally speaking, a composite material is the product of a connection between two different chemical entities. The connection between the different entities can be through covalent, non-covalent, ionic or other types of bonds. The resulting properties may represent a simple or complex weighted average of the individual properties of each component, resulting in a product with properties quite different from those of the two original components.

[0127] In the context of the present invention, it has been discovered that by adding additional polymers that are not PVOH, new materials can be obtained with a myriad of different properties while maintaining the basic properties of the elastomeric matrices provided herein, namely low polymer content, softness, and shape retention under a variety of dry and wet conditions.

[0128] The addition of non-PVOH polymers can be, for example, Stability under dry and wet conditions, biodegradable, Rheological properties, Bioadhesive, compatibility with active substances, Active substance release profile, as well as Imprinting of active substances, can be used to further improve

[0129] In some embodiments, the composite elastomeric matrix is ​​made by blending PVOH with a non-PVOH polymer capable of hydrogen bonding with PVOH. In some embodiments, the non-PVOH polymer is neutral (uncharged). In some embodiments, the non-PVOH polymer has anionic or cationic functional groups (charged). In some embodiments, the non-PVOH polymer is a synthetic polymer. In some embodiments, the non-PVOH polymer is an oligosaccharide or polysaccharide. In some embodiments, the non-PVOH polymer is an acrylic polymer.

[0130] It is clear to one skilled in the art that composites with PVOH can be made using additional polymers and various types of molecular linkages (e.g., ionic bonds, complexes, etc.) using either covalent or non-covalent interactions to connect the two polymers. The additional polymer that is not PVOH can be selected from a variety of polymers including naturally occurring polymers and macromolecules, synthetic polymers, etc. For example, but not limited to, polymers of hydrogen bond forming monomers that are not PVOH are polyacrylic acid, polyvinylpyrrolidone, cellulose, chitin, glycogen, starch, gellan, dextran, inulin, pectin, arabinoxylan, and any mixtures thereof.

[0131] According to some embodiments of the present invention, the mass content of the non-PVOH polymer in the elastomeric matrix provided herein is less than the mass content of PVOH. In some embodiments, the mass ratio of PVOH to the non-PVOH polymer ranges from about 100:1 to 2:1. Some exemplary embodiments of the composite matrix are presented in the Examples section that follows.

[0132] Medical / Ophthalmic Devices: The present invention further includes embodiments of ophthalmic / ocular devices that can be used in the treatment of ophthalmic / eye pathologies and diseases, the devices comprising or consisting of the elastomeric matrices provided herein.

[0133] In the context of ophthalmic devices, according to some embodiments of the present invention, the matrix comprises or consists of ophthalmically acceptable components, as discussed herein above.

[0134] The elastomeric matrix provided herein is particularly useful for isolating and avoiding pharmacologic agents because it is non-reactive, stable, and non-toxic. The ophthalmic device comprising the elastomeric matrix provided herein is configured for both bolus and sustained release drug delivery. Thus, according to some embodiments, the matrix comprises at least one pharmacologic agent therein or thereon. The pharmacologic agent is preferably selected to treat an ophthalmic condition, disease, or disorder.

[0135] The ocular devices described herein are generally sized and shaped to be placed on the outer surface of the eye and under one or both eyelids such that at least a portion of the ocular device does not contact or interfere with the cornea. In one aspect, the ocular devices provided herein are configured to be placed on the surface of the eye, at least partially, inside at least one of the upper and / or lower eyelids and outside the cornea of ​​the eye, to deliver at least one therapeutic agent to the eye over an extended period of time.

[0136] The elastomeric matrices provided herein are characterized by a porous microstructure that allows for the encapsulation of a liquid therein. The liquid may be, for example, a solution or colloid containing a pharma- ceutical active agent, which may be dispersed in the matrix and / or encapsulated in the pores of the matrix. Thus, in some embodiments, the devices include at least one therapeutic agent dispersed, sequestered, or impregnated within the elastomeric matrices provided herein.

[0137] Pharmaceutically active agents may include, for example, small molecules, macromolecules, cells or tissues.

[0138] In some embodiments, the pharma- ceutical active agent is in liquid form. In some embodiments, the pharma- ceutical active agent is in solid form. In some embodiments, the pharma- ceutical active agent is soluble in water, soluble in organic solvents, or is amphiphilic.

[0139] In some embodiments, the pharma- ceutical active agent is encapsulated or microencapsulated or in microparticulate or nanoparticulate form.

[0140] In the context of the present invention, pharma- ceutical active agents include, but are not limited to, analgesics, antacids, anxiolytics, antiarrhythmics, antibacterials, antibiotics, anticoagulants, thrombolytics, anticonvulsants, antidepressants, antiemetics, antifungals, antihistamines, antihypertensives, anti-inflammatory agents, antineoplastics, antipsychotics, antipyretics, antivirals, barbiturates, bronchodilators, beta-blockers, corticosteroids, cold remedies, cytotoxics, decongestants, diuretics, expectorants, hormones, hypoglycemic agents, immunosuppressants, laxatives, muscle relaxants, sedatives, sex hormones, hypnotics, tranquilizers, vitamins, and any combination thereof.

[0141] In some embodiments, the pharma- ceutical active agent is an ophthalmic active agent, hi some embodiments, the ophthalmic active agent is a lubricant, an angiogenesis inhibitor, a mydriatic, an anesthetic, an anti-infective, an anti-inflammatory, an antihistamine, an antiglaucoma agent, a surgical agent, a diagnostic agent, or any combination thereof.

[0142] Pharmaceutically active agents can include, but are not limited to, bimatoprost, travoprost, latanoprost, tafluprost, NSAIDs, steroids, antihistamines, carbonic anhydrase inhibitors (CAIs), dorzolamide, cyclosporine, antibiotics, doxycycline, tetracycline, azithromycin, fatty acids, long chain fatty acids, fatty alcohols, cetyl alcohol, stearyl alcohol, non-permeating steroids, steroid free acids, lipids, ketorolac, silicone oils, olopatadine, prostaglandins, prostaglandin analogs, prostamides, small molecule integrin antagonists, lifitegrast, loteprednol, and fluorometholone, or combinations thereof.

[0143] The pharma- ceutical active agent may include a prostaglandin analog. The prostaglandin analog may include at least one of bimatoprost, latanoprost, travoprost, and tafluprost. The pharma- ceutical active agent may be for reducing intraocular pressure in the eye. The pharma- ceutical active agent may be for treating dry eye. The pharma- ceutical active agent may include at least one of cyclosporine, steroids, loteprednol, fluorometholone, non-penetrating steroids, free acids of steroids, nonsteroidal anti-inflammatory agents, ketorolac, small molecule integrin antagonists, lifitegrast, doxycycline, azithromycin, lipids, fatty alcohols, cetyl alcohol, stearyl alcohol, fatty acids, long chain fatty acids, oils, or silicone oils. The pharma- ceutical active agent may include a steroid. The steroid may include at least one of loteprednol or fluorometholone.

[0144] When preparing an ophthalmic device comprising an elastomeric matrix according to some embodiments of the present invention, a formulation is prepared according to the preparation procedure presented below. Briefly, a liquid formulation is obtained, which can be used to prepare the final device. A pharma- ceutical active agent can be mixed into the liquid formulation to provide a matrix and device comprising the pharma- ceutical active agent. A hydrophilic pharma- ceutical active agent is readily dissolved in the formulation, and a hydrophobic pharma- ceutical active agent can be suspended (e.g., as a colloid) in the formulation.

[0145] The amount of pharma- ceutical active agent in the matrix varies depending on the pharma- ceutical active agent and the treatment regimen. Depending on the nature and requirements of the matrix, the active agent may comprise up to 30% of the non-aqueous components of the matrix.

[0146] In some embodiments, the matrix of the device further comprises at least one ophthalmically acceptable carrier / auxiliary / adjuvant / additive / non-medicinal agent.

[0147] Drug release profiles vary depending on the pharmacoactive agent and regimen. Those skilled in the art will understand that there are available means and techniques to control the sustained release of drugs from various devices under various conditions. For example, encapsulation of the pharmacoactive agent, addition of materials that modify the interaction between the active agent and the matrix, etc.

[0148] In some embodiments, the pharma- ceutical active agent is released from the matrix in the presence of a liquid, which is defined above. When referring to "the presence of a liquid", it should be understood to refer to a condition in which the matrix of the invention is exposed to a liquid in which it is partially or completely immersed.

[0149] In some embodiments, the pharma- ceutical active agent is maintained within the elastomeric matrix under dry conditions. In some embodiments, the pharma- ceutical active agent is maintained within the matrix during storage. In some embodiments, the pharma- ceutical active agent is maintained within the matrix under dry conditions for at least one year.

[0150] Treatment method: The elastomeric matrix of the present invention can be used to administer a pharma- ceutical active agent to a cell or tissue / membrane. The present invention further provides a method of administering at least one pharma- ceutical active agent to a cell or tissue / membrane, which is accomplished by contacting the cell or tissue / membrane with a therapeutically effective amount of the pharma- ceutical active agent present in an elastomeric matrix disclosed herein. In some embodiments, the tissue is selected from ocular tissue, orthodontic tissue, muscle tissue, mucosal tissue, skin tissue, connective tissue, cardiac tissue, and any combination thereof.

[0151] As used herein, the term "therapeutically effective amount" describes an amount of an active agent administered that alleviates to some extent one or more of the symptoms of the medical condition being treated. In the context of the present embodiment, the term "therapeutically effective amount" describes an amount of a pharmacologic active agent administered and / or re-administered that is at a level that is detrimental to the target cell(s) or microorganism(s) and thereby alleviates to some extent one or more of the symptoms of the pathology being treated and causes disruption in the life cycle of the target cell(s) or microorganism(s).

[0152] In the context of embodiments of the present invention, a therapeutically effective amount may refer to the total pharma- ceutical active agent or the amount of one or more bioactive agents releasably sequestered in a matrix. The efficacy of any pharma-ceutical active agent can be determined by several methodologies known in the art.

[0153] In accordance with another aspect of an embodiment of the present invention, any one of the matrices described herein is identified for use in treating a subject diagnosed with a medical condition treatable by at least a pharma- ceutical active agent that can be sequestered and controllably released from the matrix.

[0154] According to another aspect of an embodiment of the present invention, there is provided a use of any of the elastomeric matrices described herein as a delivery vehicle for use as a medicament, in some embodiments, for treating a subject diagnosed with a medical condition treatable by at least one drug that can be sequestered and controllably released from the matrix.

[0155] In any of the methods and uses described herein, the matrix may be used for medical purposes as part of a medical device.

[0156] Preparation method: The present invention provides a method for preparing the elastomeric matrix disclosed herein, comprising the steps of: (a) dissolving polyvinyl alcohol in water to form a solution; (b) optionally, heating the solution; (c) mixing a plasticizer(s) into the solution to form a mixture; (d) optionally, heating the mixture; (e) adding the mixture to a mold; (f) allowing the mixture to solidify in the mold; thereby forming an elastomeric matrix of the present invention.

[0157] In some embodiments, the solution obtained in (a) has less than 20 wt % PVOH.

[0158] In some embodiments, the plasticizer comprises 30 wt % or more of the mixture formed in (c).

[0159] In some embodiments of the method of preparing a matrix of the present invention, the optional heating is accomplished at a temperature ranging from 60°C to 100°C.

[0160] In further embodiments of the method, step (e) is performed at room temperature, for example, after cooling the mixture with mixing. In some embodiments of the method, step (e) is performed in an open configuration, for example, an open flask or a mold. In some embodiments, the elastomeric matrix is ​​poured into the mold. In some embodiments, the elastomeric matrix is ​​pumped into the mold.

[0161] In some embodiments of the method, the at least one pharma- ceutical active agent is preferably added to the solution when the solution is at about room temperature so as not to promote reactions between the active agent and other components in the solution, which also allows the use of heat-sensitive active agents.

[0162] In some embodiments of the method, the elastomeric matrix formed in step (f) is immersed in a solution containing at least one plasticizer or in water or an aqueous solution or solvent, for example for 5 minutes.

[0163] It is anticipated that many related elastomeric matrices will be developed during the life of the patent which matures from this application, and the scope of the expression "elastomeric matrices" is intended to include a priori all such new technologies.

[0164] It is understood that certain features of the invention that are described for clarity in the context of separate embodiments may also be presented in combination in a single embodiment. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be presented separately or in any suitable subcombination or in any other described embodiment of the invention, as appropriate. Certain features that are described in the context of various embodiments are not considered essential features of those embodiments, unless the embodiment cannot function without those elements.

[0165] Various embodiments and aspects of the present invention as precisely as outlined above and as claimed in the appended claims section find experimental support in the following examples. EXAMPLES

[0166] Reference is now made to the following examples which, together with the above description, illustrate, in a non-limiting manner, certain embodiments of the invention.

[0167] Example 1 Preparation of elastomeric matrices The preparation of an elastomeric matrix according to an embodiment of the present invention can begin with the preparation of a PVOH solution.

[0168] Briefly, 420 ml of purified water was added to a 500 ml round bottom flask equipped with an overhead stirrer. The flask was placed in a heating mantle and 80 grams of PVOH was added in small portions with stirring and heated until all of the PVOH was dissolved.

[0169] The PVOH solution was stirred and heated for an additional 1-2 hours, after which the solution was cooled to room temperature with stirring.

[0170] The plasticizer and 80 grams of the PVOH solution were added to a 500 ml glass beaker to obtain a mixture according to Table 1 (dry basis). Optionally, purified water was added to dilute the concentration of the solutes. The mixture was heated with magnetic stirring until completely dissolved, after which the heat was removed and the mixture was allowed to cool.

[0171] Table 1 shows some exemplary formulations for preparing exemplary elastomeric matrices provided herein. Values ​​represent mass content in % relative to the total weight of non-water components.

[0172] [Table 1]

[0173] Example 2 comparative study To study the importance of the mass ratio between PVOH and plasticizer, 20 grams of PVOH were mixed with 36 grams of glycerol in a 500 ml glass beaker and water was added to achieve a solution of 20 wt% PVOH. It is noted herein that this formulation for producing a matrix is ​​characterized by a mass content ratio of plasticizer to PVOH of 36:20, i.e. 1.8:1, which is outside the scope of the present invention. The mixture was heated until completely dissolved. The heat was turned off and the solution was left to cool.

[0174] The resulting elastomeric matrix exhibits inferior stability under both dry and wet conditions compared to a comparative matrix with a plasticizer to PVOH mass content ratio of 2:1.

[0175] Another comparative example was prepared according to the procedure described above using 35 wt% high molecular weight PVOH, 11 wt% polyethylene glycol, 27 wt% glycerol and 27 wt% propylene glycol.

[0176] This formulation exhibited greater than 20% swelling in water and produced a material that did not retain its shape under dry conditions.

[0177] Example 3 1. Preparation of the Device Each solution of the various formulations specified in Table 1 was poured into the respective molds (open or closed) and allowed to dry. Optionally, a coating machine was used to create a film of the desired thickness. The fill was allowed to dry.

[0178] Example 4 Composite Elastomer Matrix To prepare a composite elastomeric matrix according to some embodiments of the present invention, a formulation according to Table 1 was prepared and 10 grams of the formulation was mixed with a non-PVOH polymer to reach a ratio of polyvinyl alcohol to non-PVOH polymer according to Table 2 below. The mixture was stirred until completely dissolved and further processed to fabricate a device (e.g., a film).

[0179] [Table 2]

[0180] While the present invention has been described in conjunction with specific embodiments thereof, many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0181] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference. Furthermore, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. To the extent section headings are used, they should not be construed as necessarily limiting.

[0182] Additionally, any priority document(s) to this application are hereby incorporated by reference in their entirety.

Claims

1. An ophthalmic device comprising an elastomeric matrix, The elastomeric matrix is poly(vinyl alcohol) (PVOH); at least one plasticizer that is not water; Water and Including, a weight ratio of the plasticizer to the PVOH of at least 2:1; the combined mass content of the PVOH and the plasticizer is at least 70 wt % of the total weight of the elastomeric matrix excluding the water; Ophthalmic devices.

2. The ophthalmic device of claim 1 , wherein the at least one plasticizer comprises at least two plasticizers, none of which is water.

3. The ophthalmic device of claim 1 , wherein the water comprises less than 50 wt % of the total mass content of the elastomeric matrix.

4. The ophthalmic device of claim 1 further comprising a pharmaceutically active agent.

5. The water comprises less than 50 wt% of the total mass content of the elastomeric matrix; the ophthalmic device further comprises a pharmaceutically active agent; The ophthalmic device of claim 1 .

6. The ophthalmic device of claim 1 configured to be placed on the surface of the eye.

7. An ophthalmic device as described in claim 2 configured to be placed on the surface of the eye.

8. An ophthalmic device as described in claim 3 configured to be placed on the surface of the eye.

9. An ophthalmic device as described in claim 4 configured to be placed on the surface of the eye.

10. An ophthalmic device as described in claim 5 configured to be placed on the surface of the eye.

11. A device configured to be placed on the surface of the eye, 6. The ophthalmic device of claim 1, wherein the surface is at least partially inside at least one of the upper and lower eyelids and outside the cornea of ​​the eye.

12. An ophthalmic device described in any one of claims 1 to 10, wherein at least one of the at least one plasticizer contains at least two hydrogen bond-forming functional groups.

13. 11. The ophthalmic device of any one of claims 1 to 10, wherein at least one of the at least one plasticizers is independently selected from the group consisting of polyols, polybasic organic acids, polyamines, alkylgluceths, aliphatic polyalkylene glycols, ethanolamines, sugars, oligosaccharides, amino acids, polyphenols, tromethamine, urea, tannic acid, and any salts thereof and combinations thereof.

14. The ophthalmic device of claim 13 , wherein the aliphatic polyalkylene glycol is selected from the group consisting of polyethylene glycol, polypropylene glycol, polyglycol, poloxamer, and polysorbate.

15. The ophthalmic device of claim 13 , wherein the aliphatic polyalkylene glycol is polyethylene glycol.

16. The ophthalmic device of claim 13 , wherein the mass content of the PVOH is substantially equal to the mass content of the aliphatic polyalkylene glycol.

17. An ophthalmic device described in any one of claims 1 to 10, wherein the mass content of the PVOH is less than 25 wt% of the total weight of the non-water components of the elastomer matrix.

18. The ophthalmic device of any one of claims 1 to 10, which is essentially free of covalent crosslinks.

19. The ophthalmic device of any one of claims 1 to 10, wherein the elastomeric matrix is ​​made of an ophthalmologically acceptable component.

20. 11. The ophthalmic device of any one of claims 1 to 10, which delivers at least one pharmaceutically active agent to the eye over an extended period of time.