Degradable elastomer matrix, composition comprising a degradable elastomer matrix, method of making a degradable elastomer matrix, and uses thereof

Abstract

Provided herein is an elastomeric matrix comprising poly(vinyl alcohol) (PVOH), water, and one or more organic plasticizers. The mass ratio of the one or more organic plasticizers to the PVOH in combination is at least 2: 1; and the PVOH comprises two or more types of PVOH that differ from one another in one or both of hydrolysis degree (HD) and chain length.

Description

[0001] Related applications

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 462,269, filed April 27, 2023, and U.S. Provisional Patent Application No. 63 / 463,034, filed April 30, 2023, the contents of which are incorporated herein by reference in their entirety.

[0003] Field and background of the invention

[0004] In some embodiments of the present invention, the present invention relates to polyvinyl alcohol (PVOH)-based elastomer matrices and their uses, and more specifically, but not exclusively, to degradable PVOH-based elastomer matrices and their uses.

[0005] U.S. Patent No. 4,874,562 discloses a method for molding polyvinyl alcohol contact lenses.

[0006] U.S. Patent No. 4,663,358 discloses a porous and transparent hydrated gel prepared from a poly(vinyl alcohol) solution in a mixed solvent consisting of water and a water-miscible organic solvent.

[0007] U.S. Patent No. 10,513,588 discloses a water-soluble polyvinyl alcohol film having a plasticizer blend.

[0008] International Patent Application No. WO2022 / 016268 discloses a biocompatible polyvinyl alcohol (PVA) matrix comprising blends of PVA with different hydrolysis.

[0009] U.S. Patent Application Publication No. US20220168142A1 discloses an implantable, bioerectible insert for delivering an active pharmaceutical ingredient to the eye. The present invention also relates to treatment methods using such inserts and methods of manufacturing such inserts.

[0010] U.S. Patent Application Publication No. US20170226298A1 discloses a water-soluble film comprising a polyvinyl alcohol (PVOH) resin blend and optionally one or more other components such as plasticizers, fillers, surfactants and other additives. Invention Overview

[0011] The following is a non-exclusive list of some examples including embodiments of the present invention. The invention also includes embodiments that include fewer than all features in the examples and embodiments that use features from multiple examples, whether or not explicitly listed below.

[0012] Example 1. An elastomer matrix comprising:

[0013] a. Poly(vinyl alcohol) (PVOH);

[0014] b. One or more organic plasticizers; wherein the mass ratio of the one or more organic plasticizers to the PVOH is at least 2:1; and

[0015] c. Water;

[0016] The PVOH mentioned therein includes two or more types of PVOH that differ from each other in one or both of the degree of hydrolysis (HD) and chain length.

[0017] Example 2. The elastomer matrix according to Example 1, wherein the PVOH comprises two or more types of PVOH that differ from each other in terms of degree of hydrolysis (HD).

[0018] Example 3. An elastomer matrix according to Example 1 or Example 2, wherein the two types of PVOH differ by at least 1000 in chain length and have similar degrees of hydrolysis, both between 97% and 100%.

[0019] Example 4. An elastomeric matrix according to any one of Examples 1-3, wherein the first type of the two or more types has a degree of hydrolysis from 97% to 100%.

[0020] Example 5. An elastomeric matrix according to any one of Examples 1-4, wherein the second type of the two or more types has a degree of hydrolysis of less than 93%.

[0021] Example 6. An elastomeric matrix according to any one of Examples 1-5, wherein the second type of the two or more types has a degree of hydrolysis from 80% to 93%.

[0022] Example 7. An elastomeric matrix according to any one of Examples 1-6, wherein the first type of the two or more types has a chain with more than 2,500 units.

[0023] Example 8. An elastomeric matrix according to any one of Examples 1-7, wherein the second type of the two or more types has a chain with fewer than 1,500 units.

[0024] Example 9. An elastomer matrix according to any one of Examples 1-8, wherein the relationship between the first type of PVOH and the second type of PVOH in the two or more types is from about 3:1 to about 1:3.

[0025] Example 10. An elastomeric matrix according to any one of Examples 1-9, wherein the first type of the two or more types has chains with more than 2,500 units and a degree of hydrolysis of 97% to 100%, and the second type of the two or more types has chains with less than 1,000 units and a degree of hydrolysis of 80% to 93%.

[0026] Example 11. The elastomer matrix according to Example 3, wherein the second type of PVOH accounts for more than 50% of the PVOH.

[0027] Example 12. An elastomeric matrix according to any one of Examples 1-11, wherein the at least two types of PVOH determine the degradation time of the elastomeric matrix.

[0028] Example 13. The elastomer matrix according to Example 12, wherein the degradation includes changes in mechanical properties under humid conditions.

[0029] Example 14. The elastomer matrix according to Example 12, wherein the degradation includes changes in shape under humid conditions.

[0030] Example 15. An elastomeric matrix according to any one of Examples 1-14, wherein the at least two types of PVOH determine the mechanical properties of the elastomeric matrix over time under humid conditions.

[0031] Example 16. An elastomeric matrix according to any one of Examples 1-15, wherein the mass content of the combination of said PVOH and said one or more organic plasticizers is at least 70% wt of the total weight of the matrix excluding said water.

[0032] Example 17. An elastomeric matrix according to any one of Examples 1-16, wherein the elastomeric matrix is ​​used as an ophthalmic device.

[0033] Example 18. An elastomeric matrix according to any one of Examples 1-17, wherein the mass ratio of the combination of the one or more organic plasticizers to the PVOH is less than 20:1.

[0034] Example 19. An elastomeric matrix according to any one of Examples 1-18 is characterized by substantially isotropic expansion and contraction.

[0035] Example 20. An elastomeric matrix according to any one of Examples 1-19, wherein the elastomeric matrix expands by less than 50% by volume under wet conditions.

[0036] Example 21. An elastomer matrix according to any one of Examples 1-20, wherein the one or more organic plasticizers are independently selected from the group consisting of: polyols, polyacids, polyamines, alkylgluceth, aliphatic polyalkylene glycols, ethanolamines, sugars, oligosaccharides, amino acids, polyphenols, tromethamine, urea, tannic acid and any salts thereof and / or combinations thereof.

[0037] Example 22. The elastomer matrix according to Example 21, wherein the polyol is selected from the group consisting of: ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, propylene glycol, triacetin erythritol, polyethylene glycol, poloxamer and copolymers thereof, and glycerol and its esters.

[0038] Example 23. The elastomer matrix according to Example 21, wherein the polybasic organic acid is selected from the group consisting of oxalic acid, maleic acid, citric acid and any salt thereof.

[0039] Example 24. The elastomer matrix according to Example 21, wherein the polyamine is selected from the group consisting of spermine, spermidine, diethylenetriamine, triethylenetetramine, tri(2-aminoethyl)amine, polyethyleneimine and any salt thereof.

[0040] Example 25. The elastomer matrix according to Example 21, wherein the aliphatic polyalkylene glycol is selected from the group consisting of: polyethylene glycol, polypropylene glycol, polydiol, poloxamer, and polysorbate.

[0041] Example 26. The elastomer matrix according to Example 21, wherein the aliphatic polyalkylene glycol is polyethylene glycol.

[0042] Example 27. The elastomer matrix according to any one of Examples 24-25, wherein the mass content of the PVOH is substantially equal to the mass content of the aliphatic polyalkylene glycol.

[0043] Example 28. The elastomer matrix according to Example 27, wherein the aliphatic polyalkylene glycol is selected from the group consisting of polyethylene glycol, polypropylene glycol, and any mixture thereof.

[0044] Example 29. An elastomeric matrix according to any one of Examples 1-28, wherein the water constitutes a total mass content of less than 50% wt of the matrix.

[0045] Example 30. An elastomeric matrix according to any one of Examples 1-29, wherein the mass content of said PVOH is less than 25% wt of the total weight of the non-aqueous components of the matrix.

[0046] Example 31. An elastomer matrix according to any one of Examples 1-30, wherein the mass content of said PVOH is less than one-third of the total weight of said one or more organic plasticizers.

[0047] Example 32. The elastomeric matrix according to any one of Examples 1-31 is substantially free of covalent crosslinking.

[0048] Example 33. The elastomer matrix according to any one of Examples 1-32 further comprises a pharmaceutically active agent.

[0049] Example 34. An ophthalmic device comprising an elastomeric matrix according to Example 1.

[0050] Example 35. An ophthalmic device according to Example 34, wherein the elastomeric matrix is ​​composed of ophthalmologically acceptable components.

[0051] Example 36. An ophthalmic device according to Example 34 or Example 35, wherein the weight of the device is between 3 mg and 50 mg.

[0052] Example 37. An ophthalmic device according to any one of Examples 34-36, wherein the elastomer matrix comprises a pharmaceutically active agent.

[0053] Example 38. An ophthalmic device according to any one of Examples 34-37, wherein the ophthalmic device is configured to be positioned on the surface of the eye.

[0054] Example 39. The ophthalmic device according to Example 38, wherein the surface is at least partially located below at least one of the upper eyelid and lower eyelid and outside the cornea of ​​the eye.

[0055] Example 40. An ophthalmic device according to any one of Examples 34-39, wherein the ophthalmic device is configured to deliver at least one pharmaceutically active agent to the eye for an extended period of time between 5 minutes and 24 hours.

[0056] Example 41. A medical device comprising two elastomeric matrices, each of which is according to claim 1, wherein the two matrices differ from each other in one or more of the following aspects:

[0057] a. The ratio between the mass content of PVOH contained in the matrix and the mass content of the matrix;

[0058] b. The ratio between the mass content of PVOH contained in the matrix and the mass content of a combination of one or more plasticizers;

[0059] c. Types of PVOH; and

[0060] d. Mass ratio between types of PVOH.

[0061] Example 42. The medical device according to Example 41, wherein the two substrates are in contact across a contact surface.

[0062] Example 43. The medical device according to Example 42, wherein the contact surface is a closed surface.

[0063] Example 44. A medical device according to any one of Examples 41-43, wherein the two matrices degrade at different rates under humid conditions.

[0064] Example 45. A medical device according to any one of Examples 41-44, wherein the two matrices exhibit different mechanical properties under dry conditions.

[0065] Example 46. An elastomer matrix comprising:

[0066] a. Poly(vinyl alcohol) (PVOH);

[0067] b. One or more organic plasticizers; wherein the mass ratio of the one or more organic plasticizers to the PVOH is at least 2:1; and

[0068] c. Water;

[0069] The PVOH described herein comprises only PVOH with chains having fewer than 2000 or 1000 units and a degree of hydrolysis of less than 90%, and

[0070] The water content of the substrate is less than 10% or less than 5%.

[0071] 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 pertains. While methods and materials similar to or equivalent to those described herein are used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including its definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0072] Brief description of several views in the attached figure

[0073] This document describes some embodiments of the invention by way of example only, with reference to the accompanying drawings. Referring now to the drawings in detail, it should be emphasized that the details shown are by way of example and for the purpose of illustratively discussing embodiments of the invention. In this respect, the description using the drawings makes it apparent to those skilled in the art how embodiments of the invention can be practiced.

[0074] In the attached diagram:

[0075] Figure 1 This is a diagram illustrating exemplary degradation characteristics of three different elastomeric matrix compositions according to some embodiments of the present invention as they evolve over time under humid conditions;

[0076] Figure 2 This is a diagram illustrating the degradation of some substrates during wet and dry cycles according to some embodiments of the present invention;

[0077] Figure 3 This is a simplified schematic cross-sectional view of a medical device according to some embodiments of the present invention;

[0078] Figures 4a-4b This is a simplified schematic cross-sectional view of a medical device according to some embodiments of the present invention;

[0079] Figure 5 , Figure 6 , Figure 7 , Figure 8 , Figure 9 and Figure 10 This is a simplified schematic cross-sectional view of a portion of an ophthalmic device according to some embodiments of the present invention; and

[0080] Figures 11a-11b This is a simplified schematic cross-sectional view of an apparatus on the surface of an eye according to some embodiments of the present invention.

[0081] Description of specific embodiments of the present invention

[0082] In some embodiments of the invention, the present invention relates to polyvinyl alcohol (PVOH)-based elastomeric matrices and their uses, and more specifically, but not exclusively, to degradable, biodegradable, or bioerodible PVOH-based elastomeric matrices. The terms “biodegradable” and “bioerodible” (and their morphological variations, such as biodegradable and bioerodible) are used interchangeably herein. For example, a matrix may be considered biodegradable if it undergoes mechanical erosion in vivo, regardless of whether any component of the matrix undergoes chemical decomposition.

[0083] Overview

[0084] Some embodiments of the present invention relate to an elastomeric matrix (hereinafter referred to simply as "matrix" or "matrices / matrixes") containing one or more types of PVOH to achieve a matrix having defined and / or desired mechanical properties. In some embodiments, the elastomeric matrix is ​​PVOH-based, and in a sense, the PVOH is the sole or dominant film-forming polymer in the matrix.

[0085] In some embodiments, the matrix is ​​designed to dissolve and / or degrade under humid conditions according to predetermined timeline requirements. In some embodiments, the degradation timeline is controlled by selecting the composition of one or more types of PVOH in the matrix. In some embodiments, the composition is optionally characterized by the multiple types of PVOH contained in the composition and their relative masses or by the mass fraction of total PVOH provided by each type.

[0086] In some embodiments, when "wet conditions" is referred to, it should be understood to refer to conditions in which the matrix of the present invention is in direct contact with a liquid (immersed in the liquid or after immersion in the liquid and before the liquid evaporates or is wiped away). In some embodiments, the liquid is a naturally occurring bodily fluid (including but not limited to blood, saliva, tears, excrement, body tissue, tissue fluid), an aqueous solution (e.g., an aqueous solution of one or more organic plasticizers), a buffer solution, and any combination thereof. In some embodiments, the liquid is a naturally occurring fluid or a fluid that mimics a naturally occurring fluid, such as artificial tears. In some embodiments, 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. In some embodiments, "wet conditions" refers to conditions when the matrix is ​​applied to human mucosal tissue, such as on the surface of oral tissue or the eye.

[0087] In some implementations, the term matrix degradation is defined as the change in the properties of the matrix over time under humid conditions, and “degradability” is defined as the tendency or rate of degradation.

[0088] In some embodiments, changes in properties may include, for example, changes or loss in the mass of one or more of the matrix components or the matrix as a whole. For example, while plasticizers leaving an ophthalmic device may be replaced by water, in some embodiments, the PVOH itself leaves the ophthalmic device, and therefore, the device is lighter. Alternatively or additionally, changes may include changes in the mechanical properties, shape, and / or size of the matrix. Alternatively or additionally, degradation may be represented by the dissolution, rupture, tearing, and / or fragmentation of the matrix. Generally, degradation may be due to the breaking of bonds between the different components of the matrix (e.g., PVOH, plasticizer, and water), while each component remains intact. In some embodiments, for example, when the matrix is ​​used for medical purposes, degradation allows the ophthalmic device or its contained elastomeric matrix to be washed out of the body. For example, when used in an ophthalmic device, degradation of the matrix may allow residues of the matrix to be washed out of the eye through tears.

[0089] In some embodiments, the type of degradation, such as a change from a soft solid to a slime, dissolution, mass loss, or change in tearability, can depend on the type of PVOH contained in the matrix. For example, the inventors have found that some matrices comprising long-chain fully hydrolyzed (LCFH) PVOH and short-chain partially hydrolyzed (SCPH) PVOH tend to become “slimy” when immersed in simulated tear fluid (STF). In such embodiments, increased sliminess can be accompanied by a decrease in compressive modulus over time under the STF. In some embodiments, some matrices comprising LCFH PVOH and long-chain partially hydrolyzed (LCPH) PVOH tend to become more soluble in the STF; in a sense, they can dissolve to a clear solution in cold water. In some embodiments, some matrices comprising LCFH PVOH and short-chain fully hydrolyzed (SCFH) PVOH tend to be more easily torn the longer they are immersed in the STF. In some embodiments, increased tear susceptibility of such matrices can be accompanied by a decrease in compressive strength over time under the STF.

[0090] See also the exemplary mechanical properties in Example 7 below.

[0091] In some implementations, degradation can eliminate the need to remove the matrix from the body. For example, degradation products can be naturally eliminated from the body, such as through tears (if the matrix is ​​used in the eye), through urea (if the matrix is ​​used in the bladder), etc. In the case of ophthalmic devices, after a period of time in the eye, the ophthalmic device made of a biodegradable matrix can leave the eye naturally without requiring active removal. For example, the device can completely dissolve and leave the eye with tears, or disintegrate into small portions that can be expelled from the eye like any other foreign object.

[0092] In some implementations, a slight press on the biodegradable matrix (e.g., as an ophthalmic device) can immediately change the form or integrity of the matrix, so that the ophthalmic device can be naturally expelled shortly after the press.

[0093] In some embodiments, degradation causes the matrix to acquire a shape and / or consistency adapted to the anatomical site where it is used, thus allowing the matrix to remain at that site. For example, an ophthalmic device may acquire a shape conforming to the space between the conjunctiva and the tarsal plate, within which the device can be placed without causing patient discomfort until the matrix degrades and is discharged from the eye. In some embodiments, the degraded device may come into contact with the cornea and cause temporary discomfort en route from the eye.

[0094] In some embodiments, the terms "dissolution" and "degradation" are used interchangeably and refer to the process by which an elastomeric matrix changes, for example, under humid conditions. The change can be, for example, from a solid state to a fully degraded state. The change can be, for example, a loss of mass. In some embodiments, a fully degraded state can be defined as, for example, the degradation state of the matrix when it is not visible to the naked eye, e.g., because the matrix has disintegrated into very small particles, and / or the state of the matrix when, for example, the matrix elastically changes shape and / or does not maintain a defined form under certain external pressures, such as the pressure exerted on the matrix from the eyelids in a matrix used in or applied to any tissue (e.g., in the eye). The terms "shape" and "geometry" are used interchangeably and refer to the form of the matrix.

[0095] In some embodiments, the matrix comprises a mixture of two or more types of PVOH. In some embodiments, the types of PVOH differ in one or more of the degree of hydrolysis and chain length of the PVOH. In some embodiments, the higher the amount of highly hydrolyzed PVOH in the matrix, the longer the time required for complete degradation of the matrix. In some embodiments, the PVOH comprises two or more types of PVOH that differ from each other in one or both of the degree of hydrolysis (HD) and chain length. In some embodiments, each of the two or more types of PVOH constitutes at least 10% of the total amount of PVOH in the matrix. In some embodiments, the two or more types of PVOH include one type having a long chain and being completely hydrolyzed, and one type having at least one of the following: short chain and partially hydrolyzed; long chain and partially hydrolyzed; short chain and completely hydrolyzed. In some embodiments, the short chain has 200 to 2000 monomer units; the long chain has 2200 to 5000 monomer units; the completely hydrolyzed PVOH has a degree of hydrolysis of 97% or higher; and the partially hydrolyzed PVOH has a degree of hydrolysis of 95% or lower.

[0096] In some implementations, the number of PVOH types is three or more.

[0097] In some embodiments, the two types of PVOH have different chain lengths, for example, differing by at least 1000 or 1500 units. In some such embodiments, the two types of PVOH have similar degrees of hydrolysis, for example, between 97% and 100%.

[0098] In some embodiments, the two types of PVOH have different degrees of hydrolysis; for example, one type has 97% or higher DH, and the other type has 93%, 90%, or lower DH. In some such embodiments, the two types of PVOH also have different chain lengths, for example, differing by at least 1000 or 1500 units. For example, the PVOH type with a higher degree of hydrolysis may have a longer chain. In another example, the PVOH type with a higher degree of hydrolysis may have a shorter chain. In some embodiments where the two types of PVOH have different degrees of hydrolysis, the two types of PVOH have similar lengths, differing from each other by, for example, less than 500 units.

[0099] In some embodiments, the short-chain PVOH has an average chain length between about 200 and about 2000 monomer units; and the long-chain PVOH has an average chain length between about 2200 and about 5000 monomer units. In some embodiments, the fully hydrolyzed PVOH has a degree of hydrolysis of 97% or higher; and the partially hydrolyzed PVOH has a degree of hydrolysis of 94% or lower. In some embodiments, the short-chain PVOH has a molecular weight of less than about 50 kg / mol to about 80 kg / mol, while the long-chain PVOH has a molecular weight of more than about 50 kg / mol to about 80 kg / mol.

[0100] In some embodiments, the substrates are specifically designed to maintain their geometry / shape under moist conditions prior to the initiation of the degradation process. In some embodiments, the degradation process may begin after 1 minute under moist conditions, and in other embodiments after several hours under moist conditions, or at an intermediate time. The substrates that maintain their geometry can be shaped externally to the body (e.g., the eye), and are known to retain the same shape for at least a period of time after contact with the body.

[0101] In some embodiments, the elastomeric matrix comprises PVOH, one or more organic plasticizers, and optionally water. In some embodiments, the elastomeric matrix is ​​characterized by the ratio between the mass of a combination of one or more plasticizers (at least 2:1) and the mass of a combination of multiple types of PVOH.

[0102]

[0103] This ratio is referred to in this paper as the "combined mass ratio".

[0104] In some implementations, the elastomer matrix contains more than one type of plasticizer.

[0105] In some embodiments, the matrix is ​​characterized by maintaining its geometry when exposed to a moist environment, such as when placed in contact with an eye or other body tissue. In some embodiments, in addition to maintaining its geometry when exposed to a moist environment, the matrix optionally increases its volume. In some embodiments, the volume increase does not exceed 50%. In some embodiments, the expansion is the same in all directions, such that the volume changes but the geometry remains unchanged. In some embodiments, the elastomeric matrix is ​​characterized by substantially isotropic expansion when immersed in simulated tear fluid for 5, 10, or 15 minutes at room temperature. In some embodiments, the elastomeric matrix expands by less than 50% by volume when immersed in simulated tear fluid for 5, 10, or 15 minutes at room temperature.

[0106] In some embodiments, the mechanical properties and / or degradability of the elastomeric matrix depend on the type and mass of the PVOHs used to form the matrix. For example, when the PVOHs comprise predominantly fully hydrolyzed long-chain PVOHs (hereinafter LCFH) and a small amount of partially hydrolyzed short-chain PVOHs (hereinafter SCPH), the matrix degrades more slowly than when LCFH PVOHs constitute a small fraction of the PVOHs in the matrix and SCPH PVOHs constitute the majority.

[0107] The table below (Table 1) provides examples of some commercially available PVOH types. This list is taken from the brand Mowiol™, but similar materials are available from other sources. PVOH types labeled "30k" in Table 1 are not branded with Mowiol. All PVOH types used in the examples and measurements described herein were performed using PVOH sold under the brand Emprove™ or 30k PVOH (Sigma Aldrich 8.21039).

[0108] Table 1

[0109]

[0110] In some embodiments, the elastomeric matrix is ​​used as a medical device. For example, the matrix can be used as an ophthalmic device or incorporated into an ophthalmic device. In some embodiments, the ophthalmic device can be configured to be positioned on the surface of the eye, preferably on the sclera, optionally not covering any part of the cornea so as not to obstruct vision. In some embodiments, options for positioning the ophthalmic device include one or more of the following: local (sclera, cornea), subconjunctival, conjunctival, suprachoroidal, vitreous, anterior chamber, subretinal, or any other means of delivery to the eye. In some embodiments, the medical device is applied to or into a body part other than the eye, such as a body cavity, (e.g., bladder, stomach), joint, etc. In some embodiments, the matrix can be administered to the body part by intramuscular injection. In some embodiments, a potential advantage of positioning on the sclera is that the sclera is potentially less sensitive than the cornea (to pain, irritation, etc.), therefore designing the matrix to contact only the sclera potentially results in a more user-friendly matrix. In some embodiments, depending on the type of PVOH included in the elastomer matrix, complete degradation occurs, for example, between 0.5 hours and 12 hours from contact with the eye. Alternatively, complete degradation occurs between 0.5 hours and 24 hours. Alternatively, complete degradation occurs between 0.5 hours and 48 hours. Alternatively, complete degradation occurs over a period longer than 48 hours. In some embodiments, a potential advantage of controlling the degradation time is that it allows the user to use the ophthalmic device at a convenient and / or selected time (e.g., when the user is sleeping, or, for example, allowing the device to function within a desired time window).

[0111] In some embodiments, the elastomeric matrix is ​​characterized under dry conditions by tensile strength below 10 MPa, 4 MPa, 3 MPa, and preferably below 2 MPa. Alternatively or additionally, the elastomeric matrix is ​​characterized under dry conditions by elasticity (also known as Young's modulus) of 0.01 MPa to 10 MPa, 0.01 MPa to 4 MPa, or 0.01 MPa to 3 MPa, and preferably 0.01 MPa to 2 MPa. Alternatively or additionally, the elastomeric matrix is ​​characterized under dry conditions by elongation at break of at least 50%, for example, 50% to 900% or 50% to 1000%. In some embodiments, a potential advantage of a matrix having the mechanical properties described above is that it potentially reduces user discomfort, thereby potentially increasing compliance.

[0112] Before explaining at least one embodiment of the invention in detail, it should be understood that the invention is not necessarily limited in its application to the details of the construction and arrangement of the components and / or methods set forth in the following description and / or shown in the drawings and / or examples. The invention is capable of other embodiments, or can be practiced or carried out in various ways.

[0113] Exemplary basic composition of an exemplary elastomer matrix

[0114] In some embodiments, an exemplary elastomeric matrix used as, but not limited to, ophthalmic devices comprises poly(vinyl alcohol) (PVOH), one or more, two or more, or three or more plasticizers (none of which are water), and water. In some embodiments, each of the one or more, two or more, or three or more plasticizers is an organic plasticizer. In some embodiments, the mass ratio of the combination (i.e., the ratio between the mass of the combination of one or more plasticizers and the mass of the combination of multiple types of PVOH included in the matrix) is at least 2:1, for example, 2.5:1, 3:1, 4:1, or a higher or intermediate ratio. In some embodiments, the mass content of all non-aqueous components of the matrix is ​​at least 70% wt of the total weight of the matrix excluding water, i.e., the total mass of PVOH and plasticizers is at least 70% wt, at least 80% wt, or at least 90% wt of the mass of all non-aqueous components of the matrix.

[0115] In some embodiments, the mass ratio of plasticizer to PVOH is less than 5:1, less than 10:1, less than 15:1, less than 20:1, or less than 30:1. For example, 5.6:1. In some embodiments, the mass ratio of plasticizer to PVOH is in the range of 10-2:1 (from 10:1 to 2:1) or 30:1 to 3:1.

[0116] In some embodiments, the mass content of PVOH (all types of PVOH in combination) constitutes less than 33% wt of the total non-aqueous components of the matrix. For example, in some embodiments, the mass content of PVOH constitutes between 3% wt and 10% wt or less, between 5% wt and 15% wt, less than 20% wt, less than 25% wt, or less than 30% wt of the total weight of PVOH and plasticizer (the non-aqueous components of the matrix).

[0117] As used herein, the term "combination mass ratio" refers to the combined amount of one or more components of the first class (e.g., one or more plasticizers) relative to one or more other components of the matrix (e.g., the type of PVOH), wherein all amounts are provided in mass (e.g., grams). The combination mass ratio is calculated by adding the masses of one or more components of the first class to obtain the mass of the first combination; adding the masses of one or more components of the second class to obtain the mass of the second combination; and dividing the mass of the first combination by the mass of the second combination.

[0118] As used in this paper, the term "mass of a combination" refers to the quantity of a combination of more than one component provided in units of mass. The mass of a combination is calculated by adding the masses of the components in the combination.

[0119] As used herein, the term "elastomeric matrix" refers to a cross-linked polymer structure that exhibits rubber-like elasticity and can undergo deformation under force, returning to its original shape once the force is removed. In some embodiments, the cross-linking is purely physical, i.e., the matrix is ​​not covalently cross-linked. The absence of covalent cross-linking can be expressed as soluble in hot water. The exact temperature and amount of hot water required to dissolve a particular matrix can depend on the size of the matrix and its specific formulation, including the type of PVOH contained in the formulation. In some embodiments, the solubility of the matrix is ​​approximately the solubility of the less soluble PVOH type.

[0120] In some embodiments, an elastomeric matrix comprising less than 33% (%wt) of polyvinyl alcohol has the advantages of: maintaining its elastomeric matrix form under dry conditions; expanding by less than 50% by volume (or less than 15% along each of its three dimensions) under wet conditions; and substantially maintaining its geometry when moved from dry to wet conditions. It has been found that manipulating these properties requires the use of at least two plasticizers.

[0121] In the context of some embodiments of the present invention, the elastomeric matrix is ​​in the form of a physically cross-linked polymer structure that can release one or more of its components (e.g., plasticizers and / or active pharmaceutical ingredients (APIs)) into water (or any humid environment) without alteration to its mechanical properties, such as having an open-cell porous microstructure incorporating chelated and / or added releasable substances within its interconnected voids. 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. 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 matrix provided herein is substantially free of covalent cross-linking. Substantially free of covalent cross-linking can be expressed as water solubility in hot water. The amount of water and temperature required to dissolve the matrix depends on the size of the matrix and its formulation, which includes a specific type of PVOH contained in the matrix. In some embodiments, the solubility of the matrix is ​​approximately the solubility of the less soluble PVOH type.

[0122] In some embodiments, the elastomeric matrix provided herein has a porosity of about 50% to 90%. In some embodiments, the matrix is ​​characterized by a porosity of at least about 50%, 60%, 70%, 80%, or at least about 90%.

[0123] In some embodiments, the PVOH-based elastomer matrix is ​​free of chemical crosslinking agent residues and is stable in geometry and consistency during immersion in an aqueous medium, at least during the first phase in the aqueous medium, such as the first 1 to 2 minutes after insertion, or for longer periods, such as up to several hours, depending on the formulation. In some embodiments, the elastomer matrix is ​​soft and elastic under both dry and wet conditions.

[0124] In some embodiments, the consistency of the elastomeric matrix provided herein may be similar to that of a hydrogel; however, unlike a hydrogel, the elastomeric matrix provided herein has a low water content (less than 50% wt), is stable under dry conditions, and does not need to be immersed in water to maintain its flexibility. In some embodiments, under wet conditions, the water content may reach no more than 150% of the mass of the non-PVOH components present in the matrix under dry conditions.

[0125] In some embodiments, the mechanical properties of the elastomeric matrix provided herein are similar to those of rubber (elastomeric) under dry and / or wet conditions (e.g., immersion in an aqueous medium).

[0126] Unless otherwise expressly stated, any reference to the elastomer matrix provided herein refers to the elastomer matrix under dry conditions. The term "dry conditions" refers to the elastomer matrix provided herein itself, and not to a solution in which the matrix may be immersed / soaked or not immersed / not soaked.

[0127] In some embodiments, water is structurally fixed within the elastomeric matrix, freely evaporates / flows out of the matrix, or is not present in the matrix. In some embodiments, the exact amount of water (fixed water and / or free water) varies depending on the nature of the components in the matrix and the conditions under which the matrix is ​​stored. In some embodiments, when referring to the “non-aqueous” element / component of the elastomeric matrix provided herein, it means all its components other than water. In some embodiments, the mass content of the “non-aqueous” element should not be confused with the mass content of the matrix under dry conditions, where the matrix may include a significant amount of water.

[0128] When “drying conditions” are mentioned, it should be considered to refer to conditions in which the elastomeric matrix, as described 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.

[0129] In some implementations, within the context of ophthalmic devices, "dry conditions" describes the opposite of how contact lenses are stored; contact lenses are typically made of hydrogels, which should always be kept in an aqueous medium to maintain their shape and elasticity. In stark contrast, the elastomeric matrix provided herein does not need to be kept moist to maintain its shape and elasticity, and does not change its shape (although its dimensions may change) when moving from wet to dry conditions and back.

[0130] Therefore, in some embodiments, when the elastomeric matrix is ​​said to have less than a certain %wt of polyvinyl alcohol by weight of the total non-aqueous components of the matrix, this means that the mass content of PVOH constitutes less than a certain %wt of the total mass content of the matrix that does not contain any water, which is either structurally fixed in the matrix (if present) or freely flows out of the matrix.

[0131] In some embodiments, a relatively small amount of water in the matrix allows for a longer shelf life and allows for storage under dry conditions (i.e., without immersion in liquid), while excess water is unnecessary and undesirable. In some embodiments, it is assumed that only water evaporates from the wet elastomeric matrix, and the amount of water remaining after conventional drying is considered part of the matrix formation. In the context of this invention, conventional drying is achieved by exposing the outer surface of the matrix to ambient air at room temperature and ambient humidity. In some embodiments, the room temperature may be in the range of 15°C to 30°C, and the relative humidity may be in the range of 30% to 75%. In some embodiments, the precise conventional drying time may vary depending on the specific content of the matrix, but is typically between 24 hours and 4 days. In some embodiments, drying is accelerated, for example, by heating to approximately 60°C, and the drying time is correspondingly shortened. In some embodiments, drying is slowed, for example, by drying the solution in a closed mold and / or by cooling to, for example, approximately 10°C.

[0132] In some implementations, the amount of water can be determined, among other methods, by the Karl Fischer method and by direct measurement of mass loss after drying or the LOD method. The Karl Fischer method uses a Karl Fischer instrument model Titrando 852 (Metrohm) with Hydranal Composite 5 (Honeywell) as the titrant for volumetric analysis. Methanol is used as the solvent. LOD testing is performed at 85°C using an MX-50 moisture analyzer manufactured by A&D Company Ltd., Japan, on samples of 700 mg or larger.

[0133] Based on these methods that yield similar results for a given sample, in some embodiments of the invention, the elastomeric matrix contains less than about 50% wt of water. In 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. In some embodiments, the elastomeric matrix comprises between about 50% wt and about 5% wt of water.

[0134] In some embodiments, due to its unique composition, the elastomeric matrix provided herein expands under wet conditions while maintaining its shape, with the expansion being less than 50% by volume. In some embodiments, the matrix expands under wet conditions by 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.

[0135] It should be noted herein that in some embodiments, the matrix may be cast, molded, cut, or otherwise formed to have a distinct 3D shape that substantially does not change when conditions change from dry to wet, and vice versa. This property is referred to herein as shape retention. In other words, while the total volume of the matrix sheet provided herein may change (expand or contract) under varying wet conditions, the overall shape of the sheet remains substantially the same without distortion, compression, or deformation. Therefore, in some embodiments, another characteristic of the elastomeric matrix provided herein is substantially uniform dimensional variability along all directions and orientations under varying wet conditions. Substantially uniform means that the dimensions change by the same amount ±20% along each direction. This characteristic may also be referred to herein as isotropic expansion and contraction. In some embodiments, the elastomeric matrix is ​​characterized by substantially isotropic expansion when immersed in simulated tear fluid for 5, 10, or 15 minutes at room temperature. In some embodiments, the elastomeric matrix expands by less than 50% by volume when immersed in simulated tear fluid for 5, 10, or 15 minutes at room temperature.

[0136] In some embodiments, the composition and preparation method of the elastomeric matrix provided herein also determine the crystallinity of the matrix. Crystallinity (DoC) is the fraction of ordered molecules in a polymeric material, and for many known polymeric materials, this fraction is typically in the range of 10% to 80%. Higher values ​​can be obtained in materials with small molecules, or in polymeric materials prepared and / or stored at temperatures just below their melting point. Most methods for assessing crystallinity assume a mixture of perfectly crystalline and completely disordered regions; a transition region is expected to reach a few percent. These methods include density measurements, differential scanning calorimetry (DSC), X-ray diffraction (XRD), infrared spectroscopy, and nuclear magnetic resonance (NMR).

[0137] In some embodiments, the elastomeric matrix provided herein does not require cooling to below room temperature and, once solidified and dried, does not require heating to above room temperature. In some embodiments, the elastomeric matrix contains an active pharmaceutical ingredient (API) and is available without heating the API or any mixture or solution containing the API. In some embodiments, the matrix has a crystallinity of less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, or less than 20%. In some embodiments, the matrix does not change its shape after freezing to -18°C or lower and thawing to room temperature. In some embodiments, a potential advantage is that it may allow the use of matrices containing active pharmaceutical ingredients (APIs) that require deep freezing.

[0138] In some embodiments, the elastomeric matrix provided herein is well-suited for use in ophthalmic devices for ophthalmic applications, including applications requiring the matrix to be transparent and applications that do not make such a requirement. Therefore, the elastomeric matrix provided herein according to some embodiments is characterized by relatively low transparency. The transparency of a material refers to the optical clarity of an object visible when viewed through a film / sheet made of that material. The transparency of an object made from the elastomeric matrix provided herein can be measured by its total transmittance, which is the ratio of transmitted light to incident light, taking into account influencing factors: reflection, absorption, and dispersion. For example, subtracting absorption / dispersion and reflection, the total transmittance of a sample is incident light (100%) minus absorption / dispersion (X%) and subtracting reflection (Y%); in other words, total transmittance = incident light - (absorption / dispersion + reflection). In some embodiments, for example, an opaque elastomeric matrix may be preferred because it is easier to manufacture without compromising functionality, and additionally, an opaque elastomeric matrix facilitates user manipulation because it potentially allows users to better visualize the matrix. For example, an opaque elastomeric matrix can be obtained using PEG as a plasticizer and / or by producing the matrix at room temperature.

[0139] According to some embodiments of the invention, the elastomeric matrix is ​​characterized by its total transmittance (transparency) over an optical length of 0.5 mm, wherein the total transmittance (transparency) is 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% of the total transmittance of light through the elastomeric matrix.

[0140] In some embodiments, the elastomer matrix provided herein further comprises at least one inorganic ion and / or its salt, and / or at least one organic ion and / or its salt.

[0141] In some embodiments, the elastomer matrix provided herein further comprises at least one buffer. In some embodiments, the buffer is tromethamine, phosphate, citrate, or any combination thereof.

[0142] In some embodiments, the elastomer matrix provided herein further comprises at least one surfactant. In some embodiments, the surfactant is selected from sorbitan esters (Spans), sorbitan tristearate (Tweens), poloxamer, triton, betaine, and any combination thereof.

[0143] In some embodiments, the matrix of the present invention is substantially free of chemical (covalent) crosslinks. Chemical or covalent crosslinks are covalent bonds between monomers of the same polymer chain, between two (or more) polymer chains, or between a monomer of a polymer chain and another molecule (e.g., a plasticizer). The substantial absence of covalent crosslinks can be expressed as water solubility in hot water. The amount of water and temperature required to dissolve the matrix depend on the size of the matrix and its formulation, which includes the specific PVOH types contained in the matrix. In some embodiments, the solubility of the matrix is ​​approximately the solubility of the less soluble PVOH types.

[0144] Exemplary degree of hydrolysis (DH), degree of polymerization (DP), degradation time, and combinations thereof

[0145] The inventors have discovered surprising effects when combining two types of PVOH with different degrees of hydrolysis in an elastomeric matrix as described herein. These effects can be beneficial, for example, for medical applications of the matrix, such as ophthalmic devices, or other medical applications as described herein.

[0146] According to some embodiments of the invention, at least two types of PVOH are used to prepare the elastomeric matrix. In some embodiments, the difference between the types of PVOH is one or more of the degree of hydrolysis and degree of polymerization. In some embodiments, a potential advantage of combining at least two types of PVOH is that it allows manipulation of the mechanical properties (e.g., tensile strength and / or elastic modulus) of the matrix over time under humid conditions. Additionally or alternatively, in some embodiments, a potential advantage of combining at least two types of PVOH is that it allows manipulation of the time required for the elastomeric matrix to degrade under humid conditions.

[0147] In some embodiments, the first type of PVOH used to prepare the elastomer matrix is ​​characterized by a degree of complete hydrolysis (DH) ranging from 97% to 100%.

[0148] In some embodiments, the second type of PVOH used to prepare the elastomer matrix is ​​characterized by a degree of partial hydrolysis (DH) of less than 95%, for example, from 80% to 93%. In some embodiments, the degree of partial hydrolysis of the PVOH is less than 90%.

[0149] Those skilled in the art should understand that the percentages mentioned above are average percentages, and that the degree of hydrolysis in each type of PVOH is distributed around and within the figures mentioned above.

[0150] The degree of polymerization (DP) of a polymer is estimated by dividing the polymer’s molecular weight by the molecular weight of the monomer unit.

[0151] In some embodiments, the first type of PVOH used to prepare the elastomer matrix is ​​characterized by the degree of polymerization of long chains comprising chains having a molecular weight of more than 2,500 units and / or more than 100 kg.

[0152] In some embodiments, the second type of PVOH used to prepare the elastomer matrix is ​​characterized by the degree of polymerization of shorter chains, which include, for example, chains having less than 1,500 units or less, or 1,000 units or less.

[0153] Those skilled in the art should understand that the percentages mentioned above are average percentages, and that in each type of PVOH, the degree of polymerization is distributed around and within the numbers mentioned above.

[0154] In some implementations, the molecular weight scales with the chain length, but the scaling depends in part on the degree of hydrolysis, because not all repeating units are identical unless the degree of hydrolysis is 100%, and the molecular weight of the hydrolyzed unit differs from that of the unhydrolyzed unit. For example, for fully hydrolyzed PVOH: chain length ≌ 3.8 + 22.3 MW [kg], while for partially hydrolyzed PVOH: chain length ≌ 3.6 + 20.6 MW [kg].

[0155] In some embodiments of the invention, the PVOH used to prepare the elastomer matrix provided herein is also characterized by a degree of polymerization ranging from 500 to 5000. In some embodiments, the PVOH is a mixture of different degrees of polymerization; for example, it may contain a PVOH with a high molecular weight (e.g., a chain length of 3000 or more monomers) and a PVOH with a low molecular weight (e.g., a chain length of 1000 or fewer monomers).

[0156] In some embodiments, the elastomeric matrix provided herein is a biodegradable matrix. In some embodiments, the elastomeric matrix is ​​stable in a 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 a liquid (water, body fluid). In some embodiments, the elastomeric matrix provided herein is bioerodible, i.e., the amount of polymer bulk in the matrix is ​​reduced due to physical processes such as dissolution and / or chemical processes that occur when the matrix comes into contact with body tissues and / or body fluids. In some embodiments, the body fluid is tears.

[0157] In some implementations, the amount of different types of PVOH in the elastomer matrix is ​​related to the time required for the elastomer matrix to degrade. For example, when the ratio between fully hydrolyzed PVOH and partially hydrolyzed PVOH increases, the time required for the matrix to completely dissolve under humid conditions also increases.

[0158] Now for reference Figure 1 , Figure 1 The diagram illustrates exemplary degradation characteristics of three different elastomeric matrix compositions according to some embodiments of the invention as they evolve over time under humid conditions. The diagram shows the degradation characteristics of the three matrices, which differ from each other only in the amount and type of PVOH contained in their compositions.

[0159] The X-axis represents time. Substrates with diverse compositions can exhibit behaviors qualitatively similar to those illustrated in the figure. One possible difference between the behaviors of different substrates is the duration of their transition from one stage to another.

[0160] The Y-axis is the phase axis. The listed values ​​(elastic solid, gel, mucus, and degraded) are a qualitative description of the matrix. These points are measurements of compressive modulus, presented on a logarithmic scale.

[0161] The upper line (dashed line) illustrates the characteristics of the first elastomer matrix, in which all PVOH is completely hydrolyzed and has long chains. The middle line (short dashed line) illustrates the characteristics of the second elastomer matrix, in which approximately half of the PVOH is completely hydrolyzed and has long chains, and the remainder is partially hydrolyzed. The lower line (long dashed line) illustrates the characteristics of the third elastomer matrix, in which approximately two-thirds of the PVOH is partially hydrolyzed and has short chains, and the remainder of the PVOH is completely hydrolyzed.

[0162] The upper line shows that the first matrix primarily remains elastic and may acquire some gel-like properties after 4 hours in the liquid. In some embodiments, these gelling properties continue further, as illustrated by the gently downward slope of the line towards 24 hours. It should be noted that some elastomeric matrices containing only fully hydrolyzed long chains (not shown) do not show any signs of gelling after 48 hours, a week, or even three months.

[0163] The center line (dashed line) illustrates the transformation of the second matrix from an elastomeric state to a gel state after approximately one and a half hours under humid conditions. In the gel phase, the matrix retains its shape as it does in the elastomeric phase but becomes more flexible, which can be represented by a lower tensile modulus of elasticity and / or compressive modulus of elasticity. In some embodiments, the gel phase can be characterized by a smaller elongation at break and / or a smaller tensile force than the matrix in the elastomeric phase.

[0164] When kept under humid conditions for approximately 4 hours, the second matrix transforms into a viscous phase. In the viscous phase, the matrix can exhibit catarrhal consistency, which can manifest as complete collapse under even slight compressive force and / or rupture under even slight tension.

[0165] The figure shows that the third matrix (lowest line) undergoes the same phase transition at different times: the transition from the elastomeric phase to the gel phase occurs more rapidly than in any of the other matrices, and the transition to the viscous phase occurs before a similar transition occurs in the second matrix. However, the third matrix also enters a complete degradation phase, in which the matrix exhibits no measurable compressibility. Therefore, Figure 1 The figure illustrates an elastomeric matrix composition having long-chain fully hydrolyzed PVOH and short-chain and / or partially hydrolyzed PVOH in some embodiments—the higher the amount of short-chain partially hydrolyzed PVOH, the faster the degradation process under humid conditions.

[0166] It should be noted that the transitions between multiple phases are not necessarily abrupt, and the matrix can be in many intermediate phases, such as from elastomer to gel or from gel to viscous. It should also be noted that not all matrices undergo all phases. While it is preferred that each elastomer matrix be in the elastomer phase at least under dry conditions, not all matrices undergo the gel phase, and not all matrices undergo the viscous phase. It is assumed that all matrices will completely degrade, although this is not confirmed by tracking each matrix in the laboratory for a sufficiently long period. Such details as what exact phase the matrix undergoes and for what time period can depend, for example, on the exact type of PVOH used, the total amount of PVOH (e.g., as part of the total dry material in the matrix), and the other components of the composition and their amounts (e.g., plasticizers).

[0167] Now for reference Figure 2 , Figure 2 The diagram illustrates the degradation of some matrices during wet and dry cycles according to some embodiments of the invention. Degradation is represented in the diagram as a change in matrix mass. This change in mass may be accompanied by other changes (e.g., changes in mechanical properties and / or chemical composition).

[0168] The first stage of the cycle, which may be called the encapsulation stage, begins with the production of the substrate and continues until the end of its shelf life, provided the substrate remains under dry conditions. In some implementations, the encapsulation stage can last for 3 months, 6 months, 1 year, 2 years, or even 3 years or longer.

[0169] During the encapsulation stage, as illustrated in the figure, each substrate retains its respective mass. All three substrates mentioned in the figure begin with the same initial mass and maintain the same mass throughout the first stage. Therefore, the lines representing them are indistinguishable from each other. In some substrates not illustrated in the figure according to embodiments of the invention, some mass loss may occur during the first stage, but in most embodiments, such a change is no greater than 25%.

[0170] In some implementations, other properties of the matrix do not change, or only nominally change, during the first stage. These properties may include, for example, shape, size, chemical composition, and mechanical properties.

[0171] The second phase of the cycle, which may be referred to as the moist phase, continues as long as the substrate remains moist. This can last, for example, from about 5 minutes to 1 hour, 1 day, 1 week, 1 month, or even 3 months. In the case of the substrate used for medical applications, the behavior of the second phase can refer to the behavior of the substrate upon contact with bodily fluids.

[0172] The three substrates behaved differently during the wet phase.

[0173] In the first type of matrix, the mass change is indicated by dashed lines, and the mass does not change significantly during the wetting phase. However, the chemical composition of the matrix can change significantly. For example, the organic elastomer that constitutes part of the matrix can be replaced by a liquid (e.g., water or body fluid) that wets the matrix.

[0174] First-class substrates tend to retain their shape and size after being moistened, but their mechanical properties can change; for example, they can become softer and more flexible than before they were moistened.

[0175] In some embodiments, the PVOH in the first type of matrix is ​​primarily long-chain and fully hydrolyzed (although it may include two or more types of fully hydrolyzed long-chain PVOH). In some embodiments, some PVOH in the first type of matrix may have shorter lengths and / or lower degrees of hydrolysis, but these should preferably be in small amounts, such as 10% or less of the total PVOH content.

[0176] While still in the wet phase, the degradation behavior of the second type of matrix is ​​shown as a solid line in the figure. The second type of matrix loses a significant portion of its weight during the wet phase, but retains most of its weight regardless of the duration of the wet phase. The chemical composition of such a matrix can be altered by replacing the plasticizer with water during wetting (similar to the compositional changes that occur with the first type of matrix), and some of its PVOH can be lost to dissolve or disperse in the liquid. The mechanical properties of the second type of matrix change during the wet phase, and the matrix becomes softer and more flexible. In some embodiments, the second type of matrix loses some of its dimensions during the wet phase but remains intact.

[0177] The chemical composition of the second type of matrix comprises a substantial portion (e.g., at least 50%) of long-chain, highly hydrolyzed PVOH, with the remainder of the PVOH (e.g., no more than 50%) having short chains and / or partial hydrolysis. It should be noted that the transition between the first and second type matrix compositions is not abrupt, and whether a particular composition of different types of PVOH will result in a first or second type matrix depends on the specific type of PVOH used, as well as the type and amount of plasticizer.

[0178] While still in the wet phase, the degradation behavior of the third type of matrix is ​​shown by dashed lines in the figure. When the third type of matrix remains under wet conditions for a sufficiently long time, it loses almost all of its mass, and also loses its size and shape, to the point that it becomes shapeless and slippery if not removed from the water soon. The chemical composition of such a matrix can be altered by the loss of plasticizers and PVOH. The mechanical properties of the third type of matrix change significantly during the wet phase, and the matrix can completely dissolve during this period.

[0179] The chemical composition of the third type of matrix primarily consists of short-chain and / or partially hydrolyzed PVOH, with only a small amount of PVOH (e.g., less than 40%) having long chains and / or complete hydrolysis. It should be noted that the required compositional change from the second type of matrix to the third type of matrix is ​​not the same for all compositions of the second type of matrix, and whether a particular composition of different types of PVOH will result in a second or third type of matrix depends on the specific type of PVOH used and the plasticizer used and its amount.

[0180] The third phase of the cycle, which may be referred to as the drying phase, begins when the matrix is ​​removed from the liquid and continues as long as the dry conditions are maintained. In cases where the matrix is ​​used for medical applications, the behavior of the third phase can refer to the behavior of the matrix after the drainage of bodily fluids or drying (e.g., after bleeding, sweating, or tearing has stopped or significantly decreased).

[0181] During the drying stage, the first type of substrate can lose a significant portion of its mass (e.g., up to 70%), primarily due to water evaporation or release. It can retain its shape and may reduce in size. Rewetting allows the dried substrate to at least partially regain its shape and size. Flexibility and suppleness are lost during drying but can be partially recovered through rewetting.

[0182] The second type of substrate undergoes a similar process during the drying phase, but may lose a larger portion of its mass (e.g., up to 85%). Changes in size and shape will be similar to those occurring in the first type of substrate, but to a greater extent. In some embodiments, the second type of substrate does not regain its flexibility and suppleness upon rewetting.

[0183] The lifespan of the third type of substrate is insufficient to reach the drying stage, as it may dissolve during the moistening stage. If the environment of the third type of substrate becomes dry before a significant portion of the substrate's mass dissolves, some recovery of shape and size can be achieved by re-moistening.

[0184] In some embodiments, such as for medical applications, desired combinations of PVOH types within the elastomeric matrix can be designed to achieve a product that retains its geometry under dry conditions (meaning prior to placement in the body). Retaining form under dry conditions potentially increases the shelf life of the matrix, whether used as part of an ophthalmic device or any other medical device. In some embodiments, maintaining form under dry conditions is important because the user needs to manipulate the ophthalmic device to properly position it within the patient's body, for example, on the surface of the eye in the case of an ophthalmic device. Therefore, in some embodiments, such as for ophthalmic devices, combinations of PVOH types within the elastomeric matrix provide a matrix that retains its geometry and mechanical properties under dry conditions.

[0185] In some implementations, the critical value for the combination of PVOH types is based on the following:

[0186] .

[0187] According to some preferred embodiments, the matrix has the following PVOH composition:

[0188] .

[0189] It should be noted that the right column covers embodiments in which PVOH is completely hydrolyzed, embodiments in which PVOH is partially hydrolyzed, or embodiments in which PVOH is a mixture of completely hydrolyzed PVOH and partially hydrolyzed PVOH.

[0190] Unbound by theory, the degradation behavior of various matrices according to embodiments of the present invention can be influenced by physical crosslinking, which can be, for example, influenced by different types of PVOH, their relative amounts, the total amount of PVOH relative to the plasticizer or other components of the matrix, the plasticizer contained in the composition, and the amount of each plasticizer. Additionally or alternatively, the degradation behavior of the matrix can be influenced by chemical crosslinking (e.g., by boric acid), for example, when chemical crosslinking is not mild enough and interferes with the desired properties of the matrix.

[0191] Exemplary amounts of components in an exemplary elastomer matrix composition

[0192] In some implementations, the exemplary elastomer matrix comprises one or more of the following components:

[0193] 1. Water comprising approximately 5% wt to approximately 50% wt of the substrate;

[0194] 2. PVOH + plasticizer comprising approximately 35% wt to approximately 95% wt of the matrix; wherein:

[0195] —i. PVOH is PVOH + plasticizer ranging from about 5% wt to about 33% wt;

[0196] —ii. The weight of the plasticizer is at least twice the weight of the PVOH;

[0197] 3. Other ingredients, ranging from about 0%wt to about 30%wt of the total weight of PVOH + plasticizer + other ingredients.

[0198] In some implementations, other components may include, for example, active pharmaceutical ingredients (APIs), buffers, etc.

[0199] Exemplary mechanical properties

[0200] In some implementations, the elastomeric matrix provided herein can substantially alter its mechanical properties, such as rheological properties, elongation at break, tensile strength, yield strength, elongation at yield, modulus of elasticity, etc., when exposed to humid conditions.

[0201] When “dry conditions” are mentioned herein, it should be understood to refer to conditions in which the matrix of the present invention is exposed to air at room temperature in an open or closed container and is not immersed in a liquid, and in particular not in an aqueous liquid. When “wet conditions” are mentioned herein, it should be understood to refer to conditions in which the matrix of the present invention is in direct contact with a liquid (immersed in the liquid or after immersion in the liquid and before the liquid evaporates or is wiped away).

[0202] In some embodiments, the liquid is a naturally occurring bodily fluid (including, but not limited to, blood, saliva, tears, excrement, body tissue, tissue fluid), an aqueous solution (e.g., an aqueous solution of at least one plasticizer), a buffer solution, or any combination thereof. In some embodiments, the liquid is a naturally occurring fluid or a fluid that mimics a naturally occurring fluid, such as artificial tears. In some embodiments, the simulated tear is based on an aqueous solution containing about 0.67% sodium chloride, about 0.2% sodium bicarbonate, and about 0.008% calcium chloride.

[0203] In some embodiments, the elastomeric matrix provided herein is characterized by an elongation at break of at least 50%, 100%, 200%, 300%, 400%, 500%, 700%, at least 800%, at least 900%, or at least 1000% under dry conditions. In some embodiments, the elongation at break of the matrix is ​​at least 100% under wet conditions (immersion in a liquid or after immersion in a liquid).

[0204] Surprisingly, in some embodiments of the invention where the water content is relatively low, the elongation at break is surprisingly high. Therefore, according to some embodiments of the invention, elastomer matrices having a water content of 30% wt or less, 25% wt or less, or 20% wt or less exhibit relatively high elongation at break of 50% or more, 100% or more, and even 300% or more, or 500% or more under dry conditions.

[0205] In some embodiments, the elastomer matrix provided herein is characterized under dry conditions by tensile strength in the ranges of 0.01 MPa to 1 MPa, 0.01 MPa to 2 MPa, 0.01 MPa to 3 MPa, 0.01 MPa to 4 MPa, or 0.01 MPa to 10 MPa. The modulus of elasticity (Young's modulus) varies within a similar range.

[0206] The table below (Table 2) summarizes some mechanical properties measured under dry conditions using a matrix with the same composition except for the type of PVOH.

[0207] Table 2

[0208]

[0209] These examples illustrate how increasing the amount of short-chain partially hydrolyzed PVOH can reduce elastic modulus, tensile strength, and elongation at break. In these examples, the differences between PVOH with the same degree of hydrolysis (88%) and slightly different chain lengths (750 and 630) are reflected in modest changes in mechanical properties.

[0210] The mechanical measurements presented in this article were performed using a computer-controlled Mark 10 model F105 tensile / compression test frame equipped with a 10N or 100N force sensor, which features a standard handle and head. Software: "IntelliMESUR".

[0211] Wet measurements were performed in simulated tear fluid (STF) with a pH adjusted to ~7.2.

[0212] Tensile measurements were performed using a "dog bone" model. Dog bone dimensions: total length 6 cm, handle width 2 cm, neck width 0.8 cm, thickness 0.5 mm–3.5 mm. Measurement speed 40 mm / min.

[0213] Tensile measurements of the wet sample were performed after immersing the "dog bone" sample in 5 ml of STF. After a specified time, the dog bone was removed from the liquid, mounted on the handle, and measured immediately.

[0214] Pressure measurements were performed using 12.7 mm flat-head and cylindrical samples. Sample dimensions: 4 mm diameter, 2.5 mm–3.0 mm height. Measurement speed: 20 mm / min.

[0215] A set of individual samples are immersed separately in small containers, and each sample is measured after a specified time. The samples are pressed into the liquid and are not touched or moved before measurement.

[0216] An exemplary elastomer matrix (whose dry material contains 20% PVOH (all 28-99), 20% polyethylene glycol and 60% glycerol) 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%.

[0217] Exemplary plasticizers

[0218] As used herein, the term "plasticizer" refers to a wide range of substances that, together with PVOH, impart a broad range of mechanical properties to the elastomeric matrix provided herein. Without being bound by any particular theory, it is assumed that PVOH and at least one plasticizer interact to form a hydrogen-bonded network that allows the matrix to exhibit shape stability and elasticity under both wet and dry conditions. The hydrogen-bonded network may include plasticizer molecules linked to two (or more) PVOH residues.

[0219] In some embodiments of the present invention, the plasticizer is an organic material, i.e., a substance containing carbon atoms in various forms thereof.

[0220] According to embodiments of the present invention, at least one of the plasticizers is characterized by exhibiting at least two hydrogen bond forming functional groups, namely 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.

[0221] According to some embodiments of the invention, the plasticizer exhibits more than two H-bonded functional groups, or more than three, four, five, six, seven, or eight H-bonded functional groups. In some embodiments, the plasticizer contains more than one H-bonded functional group.

[0222] 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 where the elastomer matrix comprises at least two plasticizers, the matrix may comprise at least one plasticizer, which is an oligomer characterized by a molar mass greater than 1,000 g / mol. In some embodiments, the oligomer is characterized by a molar mass in the range of 1,000-2000 g / mol.

[0223] According to some embodiments of the invention, plasticizers are characterized by forming non-rigid crosslinking bridges with other elements of the matrix, such as PVOH. In this context, plasticizers are characterized by exhibiting at least one or at least two rotatable bonds in their structure, excluding bonds that link hydroxyl groups to the molecule. In some embodiments, plasticizers are characterized by exhibiting at least one bond with a variable dihedral angle. A dihedral angle is the angle between two sets of three atoms in a half-plane, the two sets of three atoms sharing two common atoms. In some embodiments, the dihedral angle is defined between two sets of three non-hydrogen atoms in a half-plane, the two sets of three non-hydrogen atoms sharing two common non-hydrogen atoms. For example, ethylene glycol exhibits a variable dihedral angle defined by two sets of three atoms, each set of three atoms sharing one oxygen atom and two carbon atoms common to both sets of non-hydrogen atoms.

[0224] In some embodiments, the plasticizer is biocompatible, meaning that the plasticizer does not cause intolerable local or systemic effects in the recipient / user. In some embodiments, the plasticizer is ophthalmologically compatible (acceptable), meaning that it is biocompatible and, in particular, does not cause intolerable ophthalmic effects in the recipient / user.

[0225] In some embodiments, the plasticizers interact and form a hydrogen-bonded network that allows the matrix to exhibit shape stability and elasticity under both wet and dry conditions. The hydrogen-bonded network may include plasticizer molecules linked to two (or more) PVOH residues.

[0226] In some embodiments of the present invention, the plasticizer is an organic material, i.e., a substance containing carbon atoms in various forms thereof.

[0227] According to embodiments of the present invention, at least one of the plasticizers is characterized by exhibiting at least two hydrogen bond forming functional groups, namely 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.

[0228] According to some embodiments of the invention, the plasticizer exhibits more than two H-bonded functional groups, or more than three, four, five, six, seven, or eight H-bonded functional groups. In some embodiments, the plasticizer contains more than one H-bonded functional group.

[0229] 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 where the elastomer matrix comprises at least two plasticizers, the matrix may comprise at least one plasticizer, which is an oligomer characterized by a molar mass greater than 1,000 g / mol. In some embodiments, the oligomer is characterized by a molar mass in the range of 1,000-2000 g / mol.

[0230] According to some embodiments of the invention, plasticizers are characterized by forming non-rigid crosslinking bridges with other elements of the matrix, such as PVOH. In this context, plasticizers are characterized by exhibiting at least one or at least two rotatable bonds in their structure, excluding bonds that link hydroxyl groups to the molecule. In some embodiments, plasticizers are characterized by exhibiting at least one bond with a variable dihedral angle. A dihedral angle is the angle between two sets of three atoms in a half-plane, the two sets of three atoms sharing two common atoms. In some embodiments, the dihedral angle is defined between two sets of three non-hydrogen atoms in a half-plane, the two sets of three non-hydrogen atoms sharing two common non-hydrogen atoms. For example, ethylene glycol exhibits a variable dihedral angle defined by two sets of three atoms, each set of three atoms sharing one oxygen atom and two carbon atoms common to both sets of non-hydrogen atoms.

[0231] In some embodiments, the plasticizer is biocompatible, meaning that the plasticizer does not cause intolerable local or systemic effects in the recipient / user. In some embodiments, the plasticizer is ophthalmologically compatible (acceptable), meaning that it is biocompatible and, in particular, does not cause intolerable ophthalmic effects in the recipient / user.

[0232] In the context of this 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 should be noted that when a specific characteristic of a plasticizer is referred to herein, it is meant to be understood as referring to a single plasticizer or individually to each of more than one plasticizer.

[0233] According to some embodiments of the invention, when the matrix contains more than one plasticizer, one plasticizer is characterized by a viscosity at least five times higher than that of another plasticizer. In some embodiments, at least one plasticizer is characterized by a viscosity of at least 1000 cp, and another plasticizer is characterized by a viscosity of less than 200 cp. Alternatively, one plasticizer has a viscosity of 500 cp or higher, and another plasticizer has a viscosity of 50 cp or lower. For example, in one exemplary matrix, one plasticizer is glycerol, exhibiting a viscosity of about 1400 cp, and the other plasticizer is polyethylene glycol, exhibiting a viscosity of about 100 cp. In another example, one plasticizer is glycerol, and the other plasticizer is propylene glycol, exhibiting a viscosity of about 40 cP. It should be noted that when a specific characteristic of a plasticizer is mentioned in this document, it means that it is considered to refer to a single plasticizer, some plasticizers in a group of plasticizers, or each of more than one plasticizer individually.

[0234] According to some embodiments of the invention, when the matrix contains more than one plasticizer, one plasticizer is characterized by a viscosity at least five times higher than that of another plasticizer. In some embodiments, at least one plasticizer is characterized by a viscosity of at least 1000 cp, and another plasticizer is characterized by a viscosity of less than 200 cp. Alternatively, one plasticizer has a viscosity of 500 cp or higher, and another plasticizer has a viscosity of 50 cp or lower. For example, in one exemplary matrix, one plasticizer is glycerol, exhibiting a viscosity of about 1400 cp, and the other plasticizer is polyethylene glycol, exhibiting a viscosity of about 100 cp. In another example, one plasticizer is glycerol, and the other plasticizer is propylene glycol, exhibiting a viscosity of about 40 cP. All viscosities are for liquid plasticizers at 20°C.

[0235] According to some implementation schemes, all plasticizers are liquid at room temperature.

[0236] In some embodiments, one or more plasticizers constitute at least 30% wt, 40% wt, 50% wt, 60% wt, 70% wt, or 80% wt of the total weight of the matrix. In some embodiments, the plasticizer constitutes any subrange between 30% wt and 80% wt of the weight of the matrix.

[0237] 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, glycerides (e.g., triacetin), polybasic organic acids (e.g., oxalic acid, maleic acid, citric acid, etc.), polyamines (e.g., spermine, spermidine, diethylenetriamine, triethylenetetramine, tri(2-aminoethyl)amine, polyethyleneimine (PEI; polyaziridinium, etc.)), trypan blue, alkyl glucosyl polyethers, aliphatic polyether sugars (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.

[0238] In some implementations, the plasticizer is an ophthalmic lubricant, emollient, or demulcent, as described by the FDA in 21 CFR 349.12. In this document, the terms lubricant and demulcent are used interchangeably.

[0239] Examples of lubricants that can be used as plasticizers include dextran, gelatin, povidone, hyaluronic acid or pharmaceutically acceptable salts thereof, polyols, cellulose and cellulose derivatives.

[0240] Examples of polyols include glycerol, polyethylene glycol (e.g., PEG 300 or PEG 400), propylene glycol, and polysorbates (e.g., polysorbate 70).

[0241] Examples of cellulose derivatives include sodium carboxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose (HPMC).

[0242] Therefore, according to some embodiments of the invention, the plasticizer is an ophthalmic soothing agent selected from the group consisting of cellulose derivatives, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hemicellulose, dextran, gelatin, liquid polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, povidone, and any combination thereof. While in some embodiments, the ophthalmic soothing agent may be considered an active pharmaceutical ingredient, whenever a pharmaceutical product or ophthalmic device is described in this disclosure and claims as comprising both an API and an ophthalmic soothing agent, the ophthalmic soothing agent, such as each of the following ophthalmic soothing agents, is not considered an API: PVOH, dextran, gelatin, povidone, hyaluronic acid or a pharmaceutically acceptable salt thereof, glycerin, polyethylene glycol (e.g., PEG 300 or PEG 400), propylene glycol, polysorbate (e.g., polysorbate 70), sodium carboxymethyl cellulose, hydroxyethyl cellulose, methylcellulose, and hydroxypropyl methylcellulose (HPMC).

[0243] In some embodiments, the matrix comprises glycerol as a single plasticizer. In some embodiments, the matrix comprises propylene glycol as a single plasticizer. In some embodiments, the matrix comprises both glycerol and propylene glycol as plasticizers. In some embodiments, the matrix comprises glycerol and propylene glycol, each individually or in mixtures with PEG, as plasticizers. In some embodiments, the matrix comprises glycerol and propylene glycol, each individually or in mixtures with PEG, as plasticizers. In some embodiments, the amounts of PEG and PVOH are substantially the same.

[0244] Exemplary compositions of elastomer matrices

[0245] The present invention also provides a composition of an elastomeric matrix, said elastomeric matrix composition being immersed in a liquid and / or combined with one or more other elastomeric matrices, each matrix as disclosed herein. In some embodiments, medical devices, for example for eluting drugs, may comprise such a matrix combination. In some embodiments, the medical device may be an ophthalmic device, a dental device, or a medical device used with other tissues.

[0246] In some embodiments, the medical device comprises two matrices as described herein, the two matrices differing from each other in their composition. For example, each of the two matrices may include different types of PVOH. In some embodiments, the two matrices may differ in the mass ratio between PVOH and the matrix. In some embodiments, the two matrices may differ in the type of PVOH they each contain, and in some embodiments, the two matrices may differ in the mass ratio between the two types of PVOH. In some embodiments, the two matrices differ in more than one of the following aspects: the mass ratio of PVOH to the matrix, the type of PVOH, and the mass ratio between the types of PVOH.

[0247] In some embodiments, the elastomeric matrix composition comprises two or more matrices, each with a different PVOH composition. For example, the two compositions may differ in the weight percentage of PVOH in the matrix, the different types of PVOH contained in the matrix, and / or the weight percentage of each PVOH type relative to the total PVOH in the matrix. In some embodiments, the elastomeric matrix composition may comprise two or more matrices, each with different mechanical properties under dry conditions. In some embodiments, each of the elastomeric matrices degrades at a different rate under wet conditions and / or develops one or more different mechanical properties over time. In some embodiments, the two matrices are in contact across a contact surface, which may be open or closed.

[0248] refer to Figure 3 , Figure 3 A simplified schematic cross-sectional view of a medical device 200 according to some embodiments of the present invention is shown. In some embodiments, the medical device 200 is configured to reside on the ocular surface below the eyelid. In some ophthalmic embodiments, the device 200 has an anterior surface (e.g., 202) adjacent to the eyelid when worn on the eye and a posterior surface 201 adjacent to the ocular surface (e.g., adjacent to the sclera) when worn on the eye.

[0249] In some embodiments, contours 202, 204, 206, and 208 illustrate the front surface of the device 200 at different times, such as when the device 200 degrades while residing on the eye, starting from contour 202 and ending at contour 208. In some embodiments, contour 208 defines the core 210 of the device 200.

[0250] In some embodiments, device 200 includes different portions that degrade at different rates. In some embodiments, core 210 comprises a material that degrades more slowly than other portions of the device (or does not degrade within the eye). In some embodiments, the different portions of device 200 contain matrices of different compositions. In one example, the slower-degrading portion of the device (e.g., core portion 210) is made of a matrix with more PVOH than other portions, or in another example, the slower-degrading portion has the same amount of PVOH as other portions, but more of that PVOH is completely hydrolyzed. In some embodiments, core 210 differs from other portions of device 200 in other aspects of composition, such as different amounts and types of PVOH. In some embodiments, core 210 contacts other portions of the device across an open, dome-shaped contact surface 211.

[0251] Now for reference Figures 4a-4b , Figures 4a-4b A simplified schematic cross-sectional view of a medical device 300 according to some embodiments of the present invention is shown. In some embodiments, the medical device 300 may be an ophthalmic device. In some embodiments, the medical device 300 may be an oral device. Hereinafter, the device 300 is referred to as an ophthalmic device configured to reside between the surface of the eye and the eyelid.

[0252] In some embodiments, device 300 includes different components 302 and 304 with different degradation times. Components 302 and 304 are shown as spanning contact surface 311. While device 200 illustrates a device in which both the front and rear surfaces change profile due to degradation under humid conditions, in device 300, only the rear surface 306 changes profile. In some embodiments, this is because the two components of device 300, namely the rear component 304 and the front component 302, are made of different matrices, each with corresponding degradation properties. Therefore, in some embodiments, the front component 302 changes almost nothing, while the rear component 304 degrades completely, causing the profile of the rear surface 306 to change from... Figure 4a The outline depicted in the middle (where the rear surface is shown as flat) changes to Figure 4b The outline depicted in the figure (where the rear surface is shown as engaging with contact surface 311).

[0253] Now for reference Figure 5 , Figure 6 , Figure 7 , Figure 8 , Figure 9 and Figure 10 These show simplified schematic cross-sectional views of portions of an ophthalmic device according to some embodiments of the present invention. Figures 5 to 10The ophthalmic devices illustrated in the schematic diagram provide examples of the richness of drug release profiles achievable with medical devices comprising two or more matrices as described herein, and more generally, provide examples of the richness of drug release profiles achievable through embodiments of the present invention.

[0254] According to some implementation plans, in Figures 5-8 In the image, the shaded areas indicate the presence of therapeutic ingredients.

[0255] Now for reference Figure 5 and Figure 8 In some embodiments, the second layers 602 and 902 contain therapeutic ingredients. In some embodiments, layers 602 and / or 902 are configured to at least periodically contact the inner surface of the eyelid and / or form at least a portion of the anterior surface. In some embodiments, layers 602 and / or 902 have a smooth outer surface and / or include a lubricating material.

[0256] exist Figure 5 In this embodiment, the therapeutic agent is shown dispersed in layer 602, which spans an open contact surface 611 in contact with layer 604, while... Figure 8 In this embodiment, the therapeutic agent is shown dispersed only in one or more discrete regions 904 within layer 902. The discrete regions 904, also referred to herein as pellets, contact layer 902 across a closed elliptical contact surface 911. Layers 604 and 906 do not contain the therapeutic component. In some embodiments, the discrete regions 904 are made of an elastomeric matrix with degradation properties different from those of the layer 902 that carries them. Therefore, layer 902 can degrade first to release the pellets 904, which then gradually degrade after release. This arrangement can result in delayed release of the therapeutic agent, which is released only after layer 902 has degraded, and then slowly as the pellets 904 degrade.

[0257] Now for reference Figure 6 and Figure 9 They respectively show the same as Figure 5 and Figure 8 The implementation scheme is similar to that of the previous one, but the therapeutic agent is dispersed in the rear part of the described ophthalmic device instead of the front part.

[0258] Now for reference Figure 7 and Figure 10 In some embodiments depicted therein, the therapeutic agent is dispersed throughout both the front components 804 and 1104 and the rear components 802 and 1102. In some embodiments, Figure 7 Each component is made of a different matrix, thus releasing the therapeutic agent at different rates. Figure 10In this process, pellets 1106 may be made of a matrix that is different from the matrix surrounding them and optionally different from the matrix used to manufacture another component.

[0259] In some embodiments, the compositions of the present invention comprise at least two elastomeric matrices as disclosed herein, which may be similar or different in composition, structure, and properties. In some embodiments, a formulation may be cast into a mold and allowed to dry to provide an elastomer, and another solution may be cast over said elastomer to provide a bilayer elastomer composition of matrices. In some embodiments, more than one type (or several types) of microelastomers may be mixed with a formulation that provides another type of elastomer upon settling, thus providing a "raisin cake" composition of one or more microelastomer samples (e.g., as an example) within a "dough" of another elastomer as the formulation settles. Figure 8 , Figure 9 and Figure 10 (As shown in the diagram).

[0260] Now for reference Figures 11a-11b , Figures 11a-11b A simplified schematic cross-sectional view of an apparatus on the surface of an eye according to some embodiments of the present invention is shown.

[0261] For simplicity, the device 1100 is illustrated as having a rectangular cross-section; however, in some embodiments, the device 1100 has a shape having one or more features of the device described elsewhere in this document (e.g., a shape including the curvature of the rear and / or front surfaces of the device).

[0262] In some embodiments, the device 1100 includes a layer 1102 comprising therapeutic material particles 1104. In some embodiments, the material particles 1104 include one or more features of microparticles and / or nanoparticles.

[0263] In some embodiments, the material particles 1104 are devices having retaining portions. In some embodiments, the device 1100 includes 1-10 particles 1104, for example, each particle having a retaining portion.

[0264] In some embodiments, the other materials of layer 1102 are rapidly soluble and / or degradable and / or erodible. In some embodiments, erosion exposes and allows the dispersion of particles 1104, for example, as... Figures 11a to 11b The transition between them is shown. In some implementations, such as alternatives Figure 11b As illustrated, the particles are dispersed within the eyelid and held below the eyelid. For example, holding means that the eye tissue holds the particles 1104 below the eyelid.

[0265] In some embodiments, particle 1104 comprises therapeutic material. Optionally, in some embodiments, particle 1104 comprises a mucosal adhesive material. Potentially, once the particle is released from layer 1102, it adheres to the ocular surface 1106 if it comes into contact with it (e.g., during movement of one or more of the eyelids, eyeball, and tear film). In some embodiments, the particle adheres to one or more mucosal surfaces, such as the eyeball and / or eyelids. In some embodiments, the particle then (e.g., within a duration of about 10 minutes, about 1 hour, about 12 hours, about 1 day, about 3 days, or a shorter or longer duration) degrades to release the therapeutic material into the ocular tissue.

[0266] Optionally, in some embodiments, the device includes one or more additional layers (e.g., in addition to layer 1102). For example, in some embodiments, device 1100 includes an adhesive film layer 1108.

[0267] In some embodiments, a treatment material layer 1102 comprising particles is incorporated into one or more of the equipment embodiments described in this document. Features include, for example, covering and / or protruding from the treatment material layer 1102.

[0268] In some embodiments, the compositions of the present invention comprise a solution containing at least one plasticizer, wherein at least one elastomer 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, wherein the at least one elastomer matrix is ​​immersed in the fluid.

[0269] In some embodiments, the composition is stored under dry conditions before use.

[0270] While the elastomeric matrices presented herein can be formulated to suit desired properties, some applications require matrices to exhibit unique properties. This necessitates the addition of another type of polymer, which is not any type of PVOH but is typically generated from hydrogen-formed monomers. This type of elastomeric matrix is ​​referred to herein as a composite matrix.

[0271] Generally, composite materials are products of the bonding between two different chemical entities. The bonding between these entities can be through covalent bonds, non-covalent bonds, ionic bonds, or other types of bonds. The resulting properties sometimes represent a simple or complex weighted average of the individual properties of each component, and sometimes yield products with properties very different from those of the two original components.

[0272] In the context of this invention, it has been found that by adding one or more polymers that are not of any type of PVOH, new materials with a wide variety of properties can be obtained while maintaining the essential properties of the elastomeric matrix provided herein, namely, low polymer content, softness, and shape retention under different dry and wet conditions.

[0273] The addition of non-PVOH polymers may be used, for example, to further modify one or more of the following: stability under dry and / or wet conditions, biodegradability, rheological properties, bioadhesion, compatibility with the active material, release profile of the active material, and imprinting of the active material.

[0274] In some embodiments, the composite elastomer matrix is ​​prepared by blending one or more types of PVOH with a non-PVOH polymer capable of hydrogen bonding with the 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.

[0275] Those skilled in the art will understand that covalent or non-covalent interactions can be used to link two polymers, and composite materials having one or more types of PVOH can be produced using other polymers and various types of molecular linkages (e.g., ions, complexes, etc.). Other polymers that are not PVOH can be selected from a variety of polymers, including naturally occurring polymers and macromolecules, synthetic polymers, and the like. For example, but not limited to, polymers that are not PVOH hydrogen-bonded monomers include polyacrylic acid, polyvinylpyrrolidone, cellulose, chitin, glycogen, starch, gellan gum, dextran, inulin, pectin, arabinoxylan, and any mixtures thereof.

[0276] According to some embodiments of the invention, the mass content of non-PVOH polymers in the elastomer matrix provided herein is less than the sum of the mass contents of all types of PVOH. In some embodiments, the mass ratio between PVOH (one or more types of PVOH) and non-PVOH polymers is in the range of about 100:1 to 2:1. Some exemplary embodiments of the composite matrix are provided in the Examples section below.

[0277] Exemplary medical equipment / ophthalmic equipment

[0278] The present invention also includes aspects of medical devices (e.g., ophthalmic devices / eye devices) that can be used to treat pathologies and diseases, wherein the device comprises or is composed of the elastomeric matrix provided herein. In some embodiments, the device can be used topically, in a body cavity, etc. In some embodiments, the device can be injected into a body site or tissue.

[0279] In the context of ophthalmic devices, according to some embodiments of the invention, the matrix comprises or is composed of ophthalmologically acceptable components. For example, any component permitted or approved by any regulatory agency for ophthalmic use may be referred to as an ophthalmologically acceptable component. In some embodiments, all plasticizers are ophthalmic soothing agents. While in some embodiments, ophthalmic soothing agents may be considered active pharmaceutical ingredients, whenever a pharmaceutical product or ophthalmic device is described in this disclosure and claims as comprising both an API and an ophthalmic soothing agent, the ophthalmic soothing agent, such as each of the following ophthalmic soothing agents, is not considered an API: PVOH, dextran, gelatin, povidone, hyaluronic acid or a pharmaceutically acceptable salt thereof, glycerin, polyethylene glycol (e.g., PEG 300 or PEG 400), propylene glycol, polysorbate (e.g., polysorbate 70), sodium carboxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose (HPMC).

[0280] In some embodiments, the elastomeric matrix provided herein is particularly useful for chelating and / or releasing active pharmaceutical ingredients (APIs) because it is non-reactive, stable, and benign. In some embodiments, ophthalmic devices comprising the elastomeric matrix provided herein are configured for drug delivery, both for bolus injection and for sustained-release protocols. Therefore, according to some embodiments, the matrix contains at least one active pharmaceutical ingredient (API) therein or thereon. Optionally, the active pharmaceutical ingredient (API) is selected for treating ophthalmic symptoms, diseases, or disorders. Optionally, the active pharmaceutical ingredient (API) is selected for treating oral symptoms, diseases, or disorders (see below).

[0281] In some embodiments, the ophthalmic devices described herein are typically sized and shaped to be positioned on the outer surface of the eye, wherein at least a portion of the ophthalmic device is positioned below an eyelid in a manner that does not contact or interfere with the cornea. In some embodiments, the ophthalmic devices provided herein are configured to be positioned on the surface of the eye, at least partially below the upper or lower eyelid and outside the cornea of ​​the eye, for delivering at least one active pharmaceutical ingredient (API) to the eye for a sustained extended period of time, such as an extended period of time between 5 minutes and 24 hours, optionally exceeding 24 hours.

[0282] In some embodiments, the elastomeric matrix provided herein is characterized by a porous microstructure that allows liquid to be trapped therein. In some embodiments, the liquid may be, for example, a solution or colloid containing an active pharmaceutical ingredient (API), and the liquid may be dispersed in the matrix and / or trapped in the pores of the matrix. Thus, in some embodiments, the apparatus includes at least one active pharmaceutical ingredient (API) dispersed, chelated, or impregnated within the elastomeric matrix provided herein.

[0283] In some implementations, the active pharmaceutical ingredient (API) may include, for example, small molecules, macromolecules, cells, or tissues.

[0284] In some embodiments, the active pharmaceutical ingredient (API) is in liquid form. In some embodiments, the active pharmaceutical ingredient (API) is in solid form. In some embodiments, the active pharmaceutical ingredient (API) is soluble in water, soluble in organic solvents, or amphiphilic.

[0285] In some implementations, the active pharmaceutical ingredient (API) is encapsulated or microencapsulated, or is in the form of microparticles or nanoparticles.

[0286] In the context of this invention, the active pharmaceutical ingredient (API) is, but is not limited to, analgesics, antacids, anxiolytics, antiarrhythmics, antibacterial agents, antibiotics, anticoagulants, thrombolytics, anticonvulsants, antidepressants, antiemetics, antifungals, antihistamines, antihypertensives, anti-inflammatory agents, antitumor agents, antipsychotics, antipyretics, antiviral agents, barbiturates, bronchodilators, beta-blockers, corticosteroids, cryotherapy agents, cytotoxic agents, decongestants, diuretics, expectorants, hormones, hypoglycemic agents, immunosuppressants, laxatives, muscle relaxants, sedatives, sex hormones, hypnotics, tranquilizers, vitamins, and any combination thereof.

[0287] In some embodiments, the active pharmaceutical ingredient (API) is an ophthalmic active pharmaceutical ingredient (API). In some embodiments, the ophthalmic active pharmaceutical ingredient (API) is a lubricant, an anti-angiogenic agent, a mydriatic agent, an anesthetic, an anti-infective agent, an anti-inflammatory agent, an antihistamine, a glaucoma treatment agent, a surgical agent, a diagnostic agent, or any combination thereof.

[0288] While in some embodiments ophthalmic soothing agents may be considered as active pharmaceutical ingredients, whenever a pharmaceutical product or ophthalmic device is described in this disclosure and claims as comprising both an API and an ophthalmic soothing agent, the ophthalmic soothing agent, such as each of the following ophthalmic soothing agents, is not considered an API: PVOH, dextran, gelatin, povidone, hyaluronic acid or a pharmaceutically acceptable salt thereof, glycerin, polyethylene glycol (e.g., PEG 300 or PEG 400), propylene glycol, polysorbate (e.g., polysorbate 70), sodium carboxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose (HPMC).

[0289] In some implementations, the active pharmaceutical ingredient (API) may include, but is not limited to, bimatoprost, travoprost, latanoprost, tafluprost, NSAIDs, steroids, antihistamines, carbonic anhydrase inhibitors (CAI), dzodamine, cyclosporine, antibiotics, doxycycline, tetracycline, azithromycin, fatty acids, long-chain fatty acids, fatty alcohols, cetyl alcohol, stearyl alcohol, non-permeable steroids, steroid free acids, lipids, ketorolac, silicone oil, olopatadine, prostaglandins, prostaglandin analogs, prostaglandins, small molecule integrin antagonists, rituximab, clotiprenor and fluocinolone, or combinations thereof.

[0290] In some embodiments, the active pharmaceutical ingredient (API) may include a prostaglandin analogue. In some embodiments, the prostaglandin analogue may include at least one of bimatoprost, latanoprost, travoprost, and tafluprost. In some embodiments, the active pharmaceutical ingredient (API) may be used to lower intraocular pressure. In some embodiments, the active pharmaceutical ingredient (API) may be used to treat dry eye syndrome. In some embodiments, the active pharmaceutical ingredient (API) may include at least one of cyclosporine, steroids, clotiprenorphine, fluorometholone, non-permeable steroids, steroid free acids, nonsteroidal anti-inflammatory drugs, ketorolac, small molecule integrin antagonists, ristatin, doxycycline, azithromycin, lipids, fatty alcohols, cetyl alcohol, stearyl alcohol, fatty acids, long-chain fatty acids, oils, or silicone oils. In some embodiments, the active pharmaceutical ingredient (API) may include a steroid. The steroid may include at least one of clotiprenorphine or fluorometholone.

[0291] In some embodiments, when preparing an ophthalmic device comprising an elastomeric matrix according to some embodiments of the invention, the formulation is prepared according to the preparation procedure provided below. In short, a liquid formulation that can be used to prepare the final device is obtained. An active pharmaceutical ingredient (API) can be mixed into the liquid formulation, resulting in a matrix and device comprising the active pharmaceutical ingredient (API). Hydrophilic active pharmaceutical ingredients (APIs) readily dissolve in the formulation, while hydrophobic active pharmaceutical ingredients (APIs) can be suspended (e.g., as colloids) in the formulation.

[0292] The amount of active pharmaceutical ingredient (API) in the matrix depends on the API and the treatment regimen. The nature and requirements of the matrix allow the matrix to include up to 30% of its non-aqueous components as the active pharmaceutical ingredient (API), for example, from about 5% to about 25%, optionally from about 3% to about 27%, or any percentage of its non-aqueous components as the active pharmaceutical ingredient (API) between 0% and 30%.

[0293] In some implementations, the matrix of the device also contains at least one ophthalmologically acceptable carrier / supplement / adjuvant / additive / non-pharmaceutical agent.

[0294] In some implementations, the drug release profile depends on the active pharmaceutical ingredient (API) and the regimen. Those skilled in the art will understand the means and techniques currently available for controlling the sustained release of drugs from a variety of devices and under various conditions, such as encapsulation of the active pharmaceutical ingredient (API), the addition of materials that alter the interaction between the agent and the matrix, and others.

[0295] In some embodiments, the active pharmaceutical ingredient (API) is released from the matrix when the matrix is ​​in the presence of a liquid such as water, saline, simulated tears, saliva, blood, or any bodily fluid. When referring to "the presence of a liquid," it should be understood to relate to conditions in which the matrix of the present invention is exposed to, partially or completely immersed in, a liquid.

[0296] When “the presence of liquid” is mentioned, it should be understood to refer to conditions in which the matrix of the present invention is exposed to liquid, or partially or completely immersed in liquid.

[0297] In some embodiments, the active pharmaceutical ingredient (API) is retained within an elastomeric matrix under dry conditions. In some embodiments, the active pharmaceutical ingredient (API) is retained within the matrix during storage. In some embodiments, the active pharmaceutical ingredient (API) is retained within the matrix under dry conditions for at least six months.

[0298] Exemplary treatment methods

[0299] In some embodiments, the elastomeric matrix of the present invention can be used for the administration of an active pharmaceutical ingredient (API) to cells, tissues, or membranes. The present invention also provides a method for administering at least one active pharmaceutical ingredient (API) to cells or tissues / membranes by contacting the cells or tissues / membranes with a therapeutically effective amount of the active pharmaceutical ingredient (API) present in the elastomeric matrix disclosed herein. In some embodiments, the tissue is selected from ocular tissue, oral tissue, dental tissue, orthodontic tissue, muscle tissue, mucosal tissue, dermatological tissue, connective tissue, cardiac tissue, and any combination thereof.

[0300] As used herein, the phrase "therapeuticly effective amount" describes the amount of an active pharmaceutical ingredient (API) administered that will, to some extent, alleviate one or more of the symptoms of the medical condition being treated. Therefore, any amount can be therapeutically effective, depending on the condition being treated, the effectiveness of the active pharmaceutical ingredient (API), the patient's body type, etc. In the context of embodiments of the invention, the phrase "therapeuticly effective amount" describes the amount of an active pharmaceutical ingredient (API) administered and / or re-administered that will, to some extent, alleviate one or more of the symptoms of the condition being treated. In some embodiments, relief can be achieved at a level harmful to target cells or microorganisms and causing disruption to the life cycle of the target cells or microorganisms. In some embodiments, relief can be achieved at a level that is pharmaceutically effective in inducing a therapeutic effect on the patient, such as an effective amount of a muscle relaxant, analgesic, and / or antibiotic.

[0301] In the context of embodiments of the present invention, a therapeutically effective amount may refer to the amount of an active pharmaceutical ingredient (API) as a whole or to one or more active pharmaceutical ingredients (APIs) releasably chelated and / or contained in a matrix. The efficacy of any active pharmaceutical ingredient (API) can be determined by several methods known in the art.

[0302] According to another aspect of the embodiments of the invention, any of the matrices described herein are suitable for treating a subject diagnosed with a medical condition that can be treated by chelating (or containing in) and controllably releasing from the matrix at least one active pharmaceutical ingredient (API).

[0303] According to another aspect of embodiments of the invention, any of the elastomeric matrices described herein is provided for use as a drug delivery medium. In some embodiments, the drug is used to treat a subject diagnosed with a medical condition that can be treated by at least one of the drugs chelated in (or contained in) and controllably released from the matrix.

[0304] In any of the methods and uses described herein, the matrix can be used as part of a medical device for medical purposes.

[0305] Exemplary preparation method

[0306] The present invention also provides a method for preparing an elastomer matrix as disclosed herein, wherein the method comprises the following steps:

[0307] Option 1: Prepare separate solutions, each containing a different type of PVOH. Mix portions of the separate solutions according to the desired ratio.

[0308] Option 2: Two or more types of PVOH are dissolved in water to form a solution.

[0309] -Optionally heat the solution (Option 1 or Option 2)

[0310] - The plasticizer is mixed into the solution to form a mixture;

[0311] -Optional heating of the mixture;

[0312] Add the mixture to the mold;

[0313] - Allow the mixture to solidify in the mold, thereby forming the elastomeric matrix of the present invention.

[0314] In some embodiments, preparing a PVOH solution may include preparing separate solutions, each containing a different type of PVOH; and partially mixing the separate solutions in amounts selected to achieve a desired ratio between the different types of PVOH. Preparing each separate solution may include stirring the PVOH with water while heating.

[0315] In some embodiments, the PVOH solution can be prepared by dissolving two or more types of PVOH, each by its respective weight, in water such that the ratio of the two types of PVOH in the solution is as desired. Dissolution preferably includes heating and mixing.

[0316] In some implementations, the mixture has less than 20% wt PVOH.

[0317] In some implementations, the plasticizer accounts for 30% wt or more of the mixture.

[0318] In some embodiments of the method for preparing the matrix of the present invention, the optional heating, as well as the heating applied for preparing the PVOH solution, should reach a temperature in the range of 60°C to 100°C.

[0319] In another embodiment of the method, the mixture is added to the mold, for example, by allowing the mixture to cool while mixing and then at room temperature. In some embodiments of the method, the addition of the mixture to the mold is carried out in an open manner, such as in an open flask or mold. In some embodiments, the elastomeric matrix is ​​poured into the mold. In some embodiments, the elastomeric matrix is ​​pumped into the mold.

[0320] In some embodiments of this method, preferably, at least one active pharmaceutical ingredient (API) is added to the solution while the solution is at approximately room temperature so as not to promote a reaction between the active pharmaceutical ingredient (API) and other components in the solution. In some embodiments, this also allows the use of heat-sensitive active pharmaceutical ingredients (APIs). In some embodiments, the API is added as is. In some embodiments, the API is dissolved or dispersed in a suitable liquid. Which liquid is suitable may depend on the API. Examples of suitable liquids include water and organic solvents such as glycerol and / or propylene glycol.

[0321] In some implementations, the API is not heated at any stage of the method, and an elastomeric matrix or ophthalmic device containing an elastomeric matrix is ​​obtained without heating the API.

[0322] In some embodiments of the method, the elastomeric matrix formed in step (f) is immersed in a solution containing at least one plasticizer or water or an aqueous solution or solvent for, for example, for 5 minutes.

[0323] As used herein, when referring to a quantity or value, the term “about” means “in”. Within 10%.

[0324] The terms “comprises”, “comprising”, “includes”, “including”, “has”, “having”, and their cognates mean “including but not limited to”.

[0325] The term "consisting of" means "including and limited to".

[0326] The term "consisting essentially of" means that a composition, method, or structure may include additional components, steps, and / or portions, provided that such additional components, steps, and / or portions do not substantially alter the essential and novel properties of the claimed composition, method, or structure.

[0327] As used herein, the phrases “substantially devoid of” and / or “essentially devoid of” in the context of a substance mean a composition that contains no such substance or contains less than about 5%, 1%, 0.5%, or 0.1% of such substance by weight or volume of the composition. Alternatively, the phrases “substantially devoid of” and / or “essentially devoid of” in the context of a process, method, property, or characteristic mean a process, composition, structure, or article that completely lacks a certain process / method step, or a certain property or characteristic, or a process / method in which a certain process / method step is affected by less than about 5%, 1%, 0.5%, or 0.1% compared to a given standard process / method, or a property or characteristic characterized by less than about 5%, 1%, 0.5%, or 0.1% compared to a given standard.

[0328] When applied to the original, desired, or provided properties of an object or composition, the term “substantially retained” as used herein means that the properties are not altered by more than 20%, 10%, or 5% in the processed object or composition.

[0329] The term “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any implementation described as “exemplary” is not necessarily to be construed as preferred or advantageous over other implementations, and / or excludes features incorporated from other implementations.

[0330] The terms “optionally” or “optionally” are used herein to mean “provided in some embodiments but not in others.” Any particular embodiment of the invention may include more than one “optional” feature, unless such features contradict each other.

[0331] As used herein, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural indicators. For example, the terms “a compound” or “at least one compound” can include more than one compound, including mixtures thereof.

[0332] Throughout this application, embodiments of the invention may be presented with reference to a scope format. It should be understood that the scope format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the invention. Therefore, the scope description should be considered to have specifically disclosed all possible sub-scopes and individual numerical values ​​within those scopes. For example, a scope such as 1 to 6 should be considered to have specifically disclosed sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc.; and individual numbers within those scopes such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the scope.

[0333] Unless the context clearly indicates otherwise, whenever a range of numbers is indicated herein (e.g., “10-15”, “10 to 15”, or any pair of numbers connected by such other range indications), it is intended to include any number (fraction or integer) within the indicated range limit, including the range limit. The phrases “range / ranging / ranges between the first and second indicating numbers” and “range from the first indicating number to, up to, until, through (or another such range indication term) the second indicating number” are used interchangeably herein and are intended to include the first and second indicating numbers, as well as all fractions and integers between the first and second indicating numbers.

[0334] Unless otherwise indicated, the figures used herein and any ranges of figures based thereon are approximations within reasonable measurement precision and rounding errors as understood by those skilled in the art.

[0335] As used herein, the terms “process” and “method” refer to the manner, means, techniques and procedures used to accomplish a given task, including but not limited to those manner, means, techniques and procedures known to practitioners in the fields of chemistry, materials, mechanics, computing and digital, or those manner, means, techniques and procedures that are readily developed by practitioners in the fields of chemistry, materials, mechanics, computing and digital.

[0336] It should be understood that certain features of the invention described in the context of a single embodiment for clarity are also provided in combination in that single embodiment. Conversely, many features of the invention described in the context of a single embodiment for brevity are also provided individually or in any suitable sub-combination or appropriately in any other described embodiment of the invention. Certain features described in the context of multiple embodiments are not considered essential features of those embodiments unless the embodiment does not function without those elements.

[0337] The various embodiments and aspects of the invention described above and claimed in the claims section below are experimentally supported in the following examples.

[0338] Example

[0339] The following embodiments are now mentioned, which, together with the foregoing description, illustrate some implementations of the invention in a non-limiting manner.

[0340] Exemplary elastomer matrix

[0341] Example 1

[0342] Preparation of elastomer matrix

[0343] The preparation of the elastomer matrix according to an embodiment of the present invention can begin with the preparation of a PVOH solution.

[0344] In short, add 420 ml of purified water to a 500 ml round-bottom flask equipped with a top stirrer. Place the flask under a heating hood and add 80 g of PVOH in batches while stirring and heating until all the PVOH is dissolved. Optionally, the PVOH may comprise two or more types of PVOH in the desired mass ratio. See Table 7 for exemplary mass ratios between exemplary different types of PVOH.

[0345] Stir and heat the PVOH solution for another 1-2 hours, and then cool the solution to room temperature while stirring.

[0346] Add the plasticizer and 80 g of PVOH solution to a 500 ml glass beaker to obtain a mixture according to Table 3 (based on dry matter). Optionally, add purified water to dilute the concentration of the solute. Heat the mixture with magnetic stirring until completely dissolved, then turn off the heating and allow the mixture to cool.

[0347] Table 3 presents some exemplary formulations for preparing exemplary elastomer matrices as provided herein. These values ​​represent mass content as a percentage of the total weight of non-aqueous components.

[0348] Table 3

[0349]

[0350] Example 2

[0351] Comparative study

[0352] To investigate the criticality of the mass ratio between PVOH and plasticizer, 20 g of PVOH was mixed with 36 g of glycerol in a 500 ml glass beaker, and water was added to obtain a 20% wt PVOH solution. It should be noted that this formulation for producing the matrix is ​​characterized by a 36:20, or 1:1.8, mass ratio of plasticizer to PVOH, which is beyond the scope of this invention. The mixture was heated until completely dissolved. Heating was then turned off, and the solution was allowed to cool.

[0353] Compared with a comparable matrix in which the mass ratio of plasticizer to PVOH is 2:1, the resulting elastomer matrix exhibits poor stability under both dry and wet conditions.

[0354] Another comparative example was prepared using 35% wt of high molecular weight PVOH, 11% wt of polyethylene glycol, 27% wt of glycerol, and 27% wt of propylene glycol according to the procedure described above.

[0355] This formulation produces a substance that exhibits more than 20% expansion in water and does not retain its shape under dry conditions.

[0356] Example 3

[0357] Equipment preparation

[0358] Pour a solution of each of the formulations specified in Table 5 into the corresponding mold (open or closed) and allow it to dry. Optionally, use a coating machine to produce a film of the desired thickness. Allow the film to dry.

[0359] Example 4

[0360] Composite elastomer matrix

[0361] To prepare the composite elastomer matrix, according to some embodiments of the invention, a formulation according to Table 3 is prepared, and 10 grams of this formulation is mixed with a non-PVOH polymer to achieve the polyvinyl alcohol to non-PVOH polymer ratio according to Table 4 below. The mixture is stirred until completely dissolved and further processed to produce an apparatus (e.g., a membrane).

[0362] Table 4

[0363]

[0364] Exemplary elastomer matrix containing two or more types of PVOH

[0365] Example 5

[0366] Preparation of elastomer matrix

[0367] The preparation of the elastomer matrix according to embodiments of the present invention can begin with the preparation of a PVOH solution containing two types of PVOH. Optionally, two (or more) types of PVOH are mixed together with water, as described below. Alternatively, two separate PVOH mixtures are prepared, and then the two separate PVOH mixtures are combined according to the desired ratio between the two types of PVOH and the PVOH concentration in the mixture. Optionally, one PVOH is prepared as a solution, and the other is added as is, for example, with a plasticizer.

[0368] In short, add 420 ml of purified water to a 500 ml round-bottom flask equipped with a top stirrer. Place the flask under a heating hood and, while stirring and heating, add 80 g of PVOH in batches (e.g., 40 g of type I PVOH and 40 g of type II PVOH) until all the PVOH dissolves.

[0369] Stir and heat the PVOH solution for another 1-2 hours, and then cool the solution to room temperature while stirring.

[0370] Add the plasticizer and 80 g of PVOH solution to a 500 ml glass beaker to obtain a mixture according to Table 5 (based on dry matter). Optionally, add purified water to dilute the concentration of the solute. Heat the mixture with magnetic stirring until completely dissolved, then turn off the heating and allow the mixture to cool.

[0371] Table 5 presents some exemplary formulations for preparing the exemplary elastomer matrices provided herein. The values ​​in rows 1, 7, 8, and 9 represent mass content as a percentage of the total weight of the non-aqueous components. In Table 1, the total amount of PVOH is provided in row 1. This amount can be allocated among two or more types of PVOH, for example, as depicted in rows 2 through 6, which show the percentage of each type of PVOH in the total amount of PVOH shown in row 1. In some embodiments, one type may be long-chain, highly hydrolyzed PVOH, and the other type may be short-chain, partially hydrolyzed PVOH. The ratio between them may be, for example, between 25% and 75% long-chain, fully hydrolyzed PVOH and the remainder short-chain, partially hydrolyzed PVOH. The inventors were surprised to find that while the short-chain partially hydrolyzed PVOH alone resulted in a very low-quality matrix (e.g., such a matrix may swell anisotropically when immersed in water, and its volume may increase by more than 100%), replacing as little as a quarter of the short-chain partially hydrolyzed PVOH with long-chain fully hydrolyzed PVOH was sufficient to provide a satisfactory matrix.

[0372] Many types of commercially available PVOH exist, and in the following examples, in addition to Sigma Aldrich 8.21039 used as the PVOH for synthesis, Merck's Emprove was used. ® The product line includes PVOH. The average molecular weight, chain length, and degree of hydrolysis of the products used are provided in Table 1 above.

[0373] LCFH1 and LCFH2 are two different types of long-chain, fully hydrolyzed PVOH derived from the table above. Similarly, SCPH1 and SCPH2 are two different types of short-chain, partially hydrolyzed PVOH derived from the table above.

[0374]

[0375] Example 6

[0376] Equipment preparation

[0377] Pour a solution of each of the formulations specified in Table 5 or Table 7 into the corresponding mold (open or closed) and allow it to dry. Optionally, use a coating machine to produce a film of the desired thickness. Allow the film to dry.

[0378] Example 7

[0379] Mechanical properties

[0380] compression modulus

[0381] The compressive modulus of an elastomer (or any other sample) is the slope of the elastic portion of a stress-strain diagram measured when the elastomer is compressed. The following shows the variation of the compressive modulus of some elastomer matrices according to some embodiments of the invention with composition and immersion time in STF (simulated tear fluid). The only difference between the first six matrices is the type of PVOH used in the formulation and their relative amounts. The seventh formulation differs from the first six formulations further in the total amount of PVOH and various plasticizers.

[0382]

[0383] As can be seen in the table above, the compressive modulus decreases during immersion in the STF across all matrices. At any given time, as some LCFH PVOH is replaced by SCPH PVOH, matrices with different compositions differ from each other in terms of compressive modulus, with matrices containing more SCPH PVOH exhibiting lower compressive modulus. When different portions of the LCFH PVOH are replaced by SCFH PVOH, at any given time, there is no significant trend in the differences between the matrices' compressive moduli, and these differences are within the estimated error (i.e., the differences are not significant).

[0384] In some implementations, changes in compressive modulus are an indicator of matrix degradation. Therefore, the results summarized in the table above regarding some of the matrices in which some LCFH PVOH were replaced by SCPH PVOH indicate that the varying amounts of the two types of PVOH determine the degradation rate of these matrices.

[0385] The table above also shows that compressive modulus is insufficient as a measure of degradation for the other matrices listed in the table. As will be seen in the table below, compressive strength is a suitable mechanical property for demonstrating matrix degradation for these embodiments.

[0386] Compressive strength

[0387] Compressive strength is the pressure at which the sample fractures. In a stress-strain diagram, compressive strength is shown as a sharp drop. The table below shows the compressive strength results extracted from the same diagram, and the compressive modulus values ​​presented in the table above have been extracted from that diagram. Measurements were taken using a 10N probe. When the diagram shows no sharp drop, the table indicates "maximum load," meaning that a 10N load is insufficient to cause the matrix to fracture through compression.

[0388]

[0389] As can be seen in the table, of all the compositions tested, only those in which some LCFH PVOH was replaced by SCFH PVOH fractured under a 10N load. Within the fractured matrix, the more LCFH PVOH present, the longer the matrix remained in the STF for fracture.

[0390] In some implementations, changes in compressive strength are an indicator of matrix degradation. Therefore, the results summarized in the table above regarding matrices where some LCFH PVOH was replaced by SCFH PVOH indicate that the varying amounts of the two types of PVOH determine the degradation rate of these matrices.

[0391] The table above also shows that changes in compressive strength (at least when measured with a 10N load) are insufficient as a measure of degradation for the other matrices in the table. As shown in the previous table, for those embodiments, compressive modulus is a suitable mechanical property for demonstrating matrix degradation.

[0392] expansion

[0393] The swelling of four matrices according to embodiments of the invention was measured by measuring the thickness (i.e., height) and diameter of the disc-shaped matrices before immersion in STF and after different immersion time periods. These four matrices have formulations similar to the first four formulations shown in the preceding table. The matrices were imaged, and the images were processed to estimate the thickness and diameter. The results detailed in the table below show that after immersion in STF for 15 minutes (or less), all matrices swelled by no more than 50% ± 5%.

[0394]

[0395] In some implementations, the maximum swelling observed in the matrix was: 21% at 2 minutes; 40% at 5 minutes; 21% at 10 minutes; 55% at 15 minutes; and 75% at 30 minutes; all values ​​are ±5%.

[0396] Simulated tear fluid (STF)

[0397] The following simulated tear (STF) composition is used: 6.76 g NaCl; 2.05 g sodium bicarbonate; 0.08 g dehydrated calcium chloride; 1.7 mL acetic acid (10%) in 1 liter of purified water.

[0398] Example 8

[0399] Clinical results

[0400] Each participant was given an ophthalmic device for 3 to 6 hours. The device contained equal amounts of long-chain fully hydrolyzed PVOH and short-chain partially hydrolyzed PVOH and contained no active pharmaceutical ingredients (APIs) other than ophthalmic soothing agents (PVOH, glycerin, propylene glycol, and PEG 400). The participants were 29 healthy individuals (aged 18 to 60 years). Participants reported that the device was virtually undetectable, likely due to the degradative nature of the matrix, which allowed the device to adapt to the wearer's individual eye anatomy. With the device in place, there was no loss of distance vision, and slit-lamp biomicroscopy, including fluorescein corneal staining, performed after removal of the device showed no significant difference compared to the same tests performed before application.

[0401] When removed from the eye, the device was softer than before it was inserted. Some devices were removed as debris. Some devices were dried and weighed after removal from the eye. They were found to weigh approximately 70% less than the devices before they were inserted.

[0402] Dry eye syndrome

[0403] The first in human history

[0404] Nearly 40 healthy subjects used the ophthalmic device according to the invention for a sustained period of 6 hours. All reported that the device was easy to use and virtually imperceptible, likely due to the degradable nature of the matrix, which allows the device to adapt to the wearer's individual eye anatomy. No serious adverse events were observed during the study. A small number of participants experienced mild discomfort or tearing in the first few minutes after application of the device, which subsequently resolved spontaneously (within 15 minutes).

[0405] According to the Visual Analogue Scale (VAS) questionnaire, wear and tear on the device over time was largely imperceptible, and no discomfort was reported at the end of the treatment before the device was removed. The device was deemed safe to use.

[0406] During treatment, reports included increased intraocular moisture, improved sensation (easier eyelid movement), eye relaxation, and improved or clearer vision, which may be related to tear film stabilization. Some subjects who reported some degree of eye dryness at baseline experienced improvement in their dryness symptoms. Some subjects applied the device independently, and most subjects easily removed it on their own.

[0407] When removed from the eye, the device was softer than before it was inserted. Some devices were removed as debris. Some devices were dried and weighed after removal from the eye. They were found to weigh approximately 70% less than the devices before they were inserted.

[0408] 5-day trial

[0409] Ten patients with mild to moderate dry eye participated in a clinical trial in which each patient had an ophthalmic device according to an embodiment of the invention inserted under the lower eyelids of both eyes; the ophthalmic device consisted essentially of water, PVOH and a plasticizer, once daily for five consecutive days.

[0410] All participants were trained to apply the device independently. All participants reported that the device was easy to use and virtually imperceptible, likely due to the biodegradable nature of the matrix, which allows the device to adapt to the wearer's individual eye anatomy. No serious adverse events were observed during the study. A small number of participants experienced mild discomfort or tearing within the first few minutes after application, which subsequently resolved spontaneously within 15 minutes of application. No serious adverse events were observed throughout the 5-day study. Wear and tear on the device was largely imperceptible over time, from at least 15 minutes of daily treatment until removal, according to the Visual Analogue Scale (VAS) questionnaire. The device was found to be safe to use.

[0411] When removed from the eye, the device was softer than before it was inserted. Some devices were removed as debris. Some devices were dried and weighed after removal from the eye. They were found to weigh approximately 70% less than the devices before they were inserted.

[0412] Presbyopia

[0413] A total of 18 subjects aged 45–61 years diagnosed with presbyopia were enrolled in the study. All subjects completed the study as planned. After insertion of a device containing 200 micrograms of pilocarpine under the lower eyelid of one eye, the mean pupil diameter decreased compared to the untreated eye, with the mean minimum pupil diameter observed in the treated eye 1 hour after insertion. The mean pupil diameter in the treated eye increased over time until 8 hours after insertion. At 2 hours after insertion, monocular near visual acuity measured using the Jaeger near vision chart decreased to J1 in all subjects except one subject with J1+. The BCDVA remained at 6 / 6 throughout the study.

[0414] All participants reported that the device was easy to use and virtually imperceptible, likely due to the degradable nature of the matrix, which allows the device to adapt to the wearer's individual ocular anatomy. No serious adverse events were observed during the study. Some subjects reported mild discomfort for up to 5 minutes after insertion. All subjects reported that the device was easy to use and virtually imperceptible. IOP remained within the normal range during the study. No clinically significant changes in slit-lamp biomicroscopy were observed between baseline and endpoint.

[0415] Although the invention has been described in conjunction with its specific embodiments, it will be apparent to those skilled in the art that many changes, modifications, and variations will be apparent. Therefore, it is intended to include all such changes, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0416] The applicant intends that all publications, patents, and patent applications mentioned in this specification be incorporated herein by reference in their entirety, as if each individual publication, patent, or patent application were specifically and individually indicated when cited, and would be incorporated herein by reference. Furthermore, any reference or designation of any reference in this application should not be construed as an admission that such reference is available as prior art to the invention. The use of section headings should not be construed as necessarily limiting. Additionally, any priority documents of this application are incorporated herein by reference in their entirety.

Claims

1. An elastomer matrix comprising: a. Polyvinyl alcohol (PVOH); b. One or more organic plasticizers; each organic plasticizer being characterized by exhibiting at least two hydrogen-bonding functional groups; wherein the mass ratio of the one or more organic plasticizers to the PVOH is at least 2:1 and less than 20:1; and c. Water, wherein the water constitutes less than 50% wt% of the total mass of the elastomer matrix; The PVOH mentioned therein includes two or more types of PVOH that differ from each other in one or both of the degree of hydrolysis (HD) and chain length.

2. The elastomer matrix of claim 1, wherein the PVOH comprises two or more types of PVOH that differ from each other in degree of hydrolysis (HD).

3. The elastomer matrix according to claim 1 or claim 2, wherein the two types of PVOH differ in chain length by at least 1000 and have similar degrees of hydrolysis, both between 97% and 100%.

4. The elastomeric matrix according to any one of claims 1-3, wherein the first type of the two or more types has a degree of hydrolysis from 97% to 100%.

5. The elastomeric matrix according to any one of claims 1-4, wherein the second type of the two or more types has a degree of hydrolysis of less than 93%.

6. The elastomeric matrix according to any one of claims 1-5, wherein the second type of the two or more types has a degree of hydrolysis from 80% to 93%.

7. The elastomeric matrix according to any one of claims 1-6, wherein the first type of the two or more types has a chain with more than 2,500 units.

8. The elastomeric matrix according to any one of claims 1-7, wherein the second type of the two or more types has a chain with fewer than 1,500 units.

9. The elastomeric matrix according to any one of claims 1-8, wherein the relationship between the first type of PVOH and the second type of PVOH in the two or more types is from 3:1 to 1:

3.

10. The elastomeric matrix according to any one of claims 1-9, wherein the first type of the two or more types has chains with more than 2,500 units and a degree of hydrolysis of 97% to 100%, and the second type of the two or more types has chains with less than 1,000 units and a degree of hydrolysis of 80% to 93%.

11. The elastomer matrix according to claim 5, wherein the second type of PVOH accounts for more than 50% of the PVOH.

12. The elastomeric matrix according to any one of claims 1-11, wherein the mass content of the combination of said PVOH and said one or more organic plasticizers is at least 70% wt of the total weight of the matrix excluding said water.

13. The elastomeric matrix according to any one of claims 1-12, wherein the elastomeric matrix is ​​used as a medical device.

14. The elastomeric matrix according to any one of claims 1-13, further comprising a pharmaceutically active agent.

15. An ophthalmic device comprising an elastomeric matrix according to any one of claims 1-14.

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