Biodegradable elastomer matrix, compositions containing the same, methods for preparing the same, and uses thereof

Abstract

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

Description

Technical Field

[0001] [Related Applications] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 462,269, filed Apr. 27, 2023, and U.S. Provisional Patent Application No. 63 / 463,034, filed Apr. 30, 2023. The entire disclosure of this U.S. application is incorporated herein by reference.

[0002] The present invention, in some embodiments thereof, relates to polyvinyl alcohol (PVOH)-based elastomeric matrices and their use, and more specifically, but not limited to, degradable PVOH-based elastomeric matrices and their use.

Background Art

[0003] U.S. Patent No. 4,874,562 discloses a method of molding polyvinyl alcohol contact lenses.

[0004] U.S. Patent No. 4,663,358 discloses a porous transparent hydrated gel prepared from a poly(vinyl alcohol) solution in a mixed solvent consisting of water and a water-miscible organic solvent.

[0005] U.S. Patent No. 10,513,588 discloses a water-soluble polyvinyl alcohol film containing a plasticizer blend.

[0006] International Publication No. 2022 / 016268 discloses a biocompatible polyvinyl alcohol (PVA) matrix composed of a blend of PVAs with different degrees of hydrolysis.

[0007] U.S. Patent Application Publication No. 2022 / 0168142 discloses an implantable bioerodible insert for delivering a pharmaceutical active ingredient to the eye. This invention also relates to a method of treatment using such an insert and a method of manufacturing such an insert.

[0008] U.S. Patent Application Publication No. 2017 / 0226298 discloses a water-soluble film comprising a polyvinyl alcohol (PVOH) resin blend and optionally one or more additional components such as plasticizers, fillers, surfactants, and other additives. [Overview of the Initiative]

[0009] The following is a non-exclusive list containing some examples of embodiments of the present invention. The present invention also includes embodiments that contain fewer features than all features in one example, and embodiments that use features from multiple examples (whether or not they are expressly described below).

[0010] Example 1: An elastomer matrix, a. Polyvinyl alcohol (PVOH) and b. One or more organic plasticizers, wherein the ratio of the total mass of the one or more organic plasticizers to the PVOH is at least 2:1, c. Water and, Includes, An elastomer matrix comprising at least two types of PVOH that differ from each other in either degree of hydrolysis (HD) or chain length.

[0011] Example 2. The elastomer matrix according to Example 1, wherein the PVOH comprises at least two types of PVOH having different degrees of hydrolysis (HD).

[0012] Example 3. An elastomer matrix according to Example 1 or 2, wherein two types of PVOH differ by at least 1,000 in chain length and both have similar degrees of hydrolysis of 97% to 100%.

[0013] Example 4. An elastomer matrix according to any one of Examples 1 to 3, wherein the first of at least two of the above types has a degree of hydrolysis of 97% to 100%.

[0014] Example 5. An elastomer matrix according to any one of Examples 1 to 4, wherein the second of the two types described above has a degree of hydrolysis of less than 93%.

[0015] Example 6. An elastomer matrix according to any one of Examples 1 to 5, wherein the second of the two types described above has a degree of hydrolysis of 80% to 93%.

[0016] Example 7. An elastomer matrix according to any one of Examples 1 to 6, wherein the first of at least two of the above types has a chain length of more than 2,500 units.

[0017] Example 8. An elastomer matrix according to any one of Examples 1 to 7, wherein the second of the two types described above has a chain length of less than 1,500 units.

[0018] Example 9. An elastomer matrix according to any one of Examples 1 to 8, wherein the relationship between the first type of PVOH and the second type of PVOH from the at least two types described above is approximately 3:1 to approximately 1:3.

[0019] Example 10. An elastomer matrix according to any one of Examples 1 to 9, wherein the first of the at least two types described above has a chain length of more than 2,500 units and a degree of hydrolysis of 97% to 100%, and the second of the at least two types described above has a chain length of less than 1,000 units and a degree of hydrolysis of 80% to 93%.

[0020] Example 11. The elastomer matrix described in Example 3, wherein the second type of PVOH described above accounts for more than 50% of the PVOH described above.

[0021] Example 12. An elastomer matrix according to any one of Examples 1 to 11, wherein at least two of the above-mentioned PVOHs determine the time required for the degradation of the elastomer matrix.

[0022] Example 13. The elastomer matrix described in Example 12, wherein the above decomposition includes a change in mechanical properties under wet conditions.

[0023] Example 14. The elastomeric matrix according to Example 12, wherein the decomposition includes a change in shape under wet conditions.

[0024] Example 15. The elastomeric matrix according to any one of Examples 1 to 14, wherein the at least two types of PVOH determine the temporal change in the mechanical properties of the elastomeric matrix under wet conditions.

[0025] Example 16. The ophthalmic device according to any one of Examples 1 to 15, wherein the total mass content ratio of the PVOH and the one or more organic plasticizers is at least 70 wt% of the total weight of the matrix excluding the water.

[0026] Example 17. The elastomeric matrix according to any one of Examples 1 to 16, wherein the elastomeric matrix is used as an ophthalmic device.

[0027] Example 18. The elastomeric matrix according to any one of Examples 1 to 17, wherein the ratio of the total mass of the one or more organic plasticizers to the PVOH is less than 20:1.

[0028] Example 19. The elastomeric matrix according to any one of Examples 1 to 18, which is characterized by substantially isotropic swelling and shrinkage.

[0029] Example 20. The elastomeric matrix according to any one of Examples 1 to 19, wherein the elastomeric matrix swells less than 50% by volume under wet conditions.

[0030] Example 21. The elastomeric matrix according to any one of Examples 1 to 20, wherein the one or more organic plasticizers are independently selected from the group consisting of polyols, polybasic organic acids, polyamines, alkyl glucoses, aliphatic polyalkylene glycols, ethanolamines, sugars, oligosaccharides, amino acids, polyphenols, tromethamine, urea, tannic acid, and any salts and / or combinations thereof.

[0031] 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, polyglycol, poloxamer, and copolymers thereof, as well as glycerol and its esters.

[0032] 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 salts thereof.

[0033] Example 24. The elastomer matrix according to Example 21, wherein the polyamine is selected from the group consisting of spermine, spermidine, diethylenetriamine, triethylenetetramine, tris(2-aminoethyl)amine, polyethyleneimine, and any salts thereof.

[0034] 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, polyglycol, poloxamer, and polysorbate.

[0035] Example 26. The elastomer matrix according to Example 21, wherein the aliphatic polyalkylene glycol is polyethylene glycol.

[0036] Example 27. The elastomer matrix according to Examples 24-25, wherein the mass content of the PVOH is substantially equal to the mass content of the aliphatic polyalkylene glycol.

[0037] 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.

[0038] Example 29. An elastomer matrix according to any one of Examples 1 to 28, wherein the water described above accounts for less than 50 wt% of the total mass content of the matrix.

[0039] Example 30. An elastomer matrix according to any one of Examples 1 to 29, wherein the mass content of the above PVOH is less than 25 wt% of the total weight of the non-aqueous components of the matrix.

[0040] Example 31. An elastomer matrix according to any one of Examples 1 to 30, wherein the mass content of the above PVOH is less than one-third of the total weight of the above one or more organic plasticizers.

[0041] Example 32. An elastomer matrix according to any one of Examples 1 to 31, substantially free from covalent crosslinking.

[0042] Example 33. An elastomer matrix according to any one of Examples 1 to 32, further comprising a pharmaceutically active substance.

[0043] Example 34. An ophthalmic device containing the elastomer matrix described in Example 1.

[0044] Example 35. The ophthalmic device according to Example 34, wherein the elastomer matrix consists of ophthalmologically acceptable components.

[0045] Example 36. An ophthalmic device as described in Example 34 or Example 35, wherein the device weighs 3 mg to 50 mg.

[0046] Example 37. An ophthalmic device according to any one of Examples 34 to 36, wherein the elastomer matrix contains a pharmaceutically active substance.

[0047] Example 38. An ophthalmic device according to any one of Examples 34 to 37, wherein the ophthalmic device described above is configured to be placed on the surface of the eye.

[0048] Example 39. The ophthalmic device according to Example 38, wherein the surface is at least partially below the upper eyelid, at least one of the lower eyelids, and outside the cornea of ​​the eye.

[0049] Example 40. An ophthalmic device according to any one of Examples 34 to 39, wherein the ophthalmic device is configured to deliver at least one pharmaceutically active substance to the eye over a long period of time from 5 minutes to 24 hours.

[0050] Example 41. A medical device comprising two types of elastomer matrices as described in Example 1, wherein the two matrices are a. The ratio between the mass content of PVOH contained in the matrix and the mass content of the matrix. b. The ratio between the mass content of PVOH contained in the matrix and the total mass content of one or more plasticizers. c. Types of PVOH, and d. Mass ratio between types of PVOH, A medical device that differs from each other in one or more of the following ways.

[0051] Example 42. The medical device according to Example 41, wherein two types of matrices are in contact via a contact surface.

[0052] Example 43. The medical device described in Example 42, wherein the contact surface is a closed surface.

[0053] Example 44. A medical device according to any one of Examples 41-43, wherein two types of matrices decompose at different rates under wet conditions.

[0054] Example 45. A medical device according to any one of Examples 41-44, wherein two types of matrices exhibit different mechanical properties under dry conditions.

[0055] Example 46. Elastomer matrix, a. Poly(vinyl alcohol) (PVOH), b. One or more organic plasticizers, wherein the ratio of the total mass of the one or more organic plasticizers to the PVOH is at least 2:1, c. Water and, Includes, The above PVOH includes only PVOH with a chain length of less than 2,000 units or less than 1,000 units, and a degree of hydrolysis of less than 90%. An elastomer matrix in which the above-mentioned water constitutes less than 10% or less than 5% of the matrix.

[0056] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which the invention relates. Similar or equivalent methods and materials may be used in carrying out or testing embodiments of the invention, but exemplary methods and / or materials are described below. In case of any conflict, the patent specification containing the definitions shall prevail. Furthermore, the materials, methods and examples are illustrative and not necessarily intended to be limiting.

[0057] Several embodiments of the present invention are described herein only as examples, with reference to the accompanying drawings. It is emphasized hereby that the details shown are illustrative and for illustrative purposes only, as the drawings are referred to in detail. In this regard, the description made in conjunction with the drawings will make it clear to those skilled in the art how embodiments of the present invention may be carried out. [Brief explanation of the drawing]

[0058] [Figure 1] This graph shows exemplary degradation characteristics of three different elastomer matrix compositions, as they change over time under wet conditions, according to several embodiments of the present invention. [Figure 2] This graph shows the decomposition of several matrices during wet and dry cycles according to several embodiments of the present invention. [Figure 3] This is a simplified schematic cross-sectional view of a medical device according to several embodiments of the present invention. [Figure 4] This is a simplified schematic cross-sectional view of a medical device according to several embodiments of the present invention. [Figure 5] This is a simplified schematic cross-sectional view of some ophthalmic devices according to several embodiments of the present invention. [Figure 6] This is a simplified schematic cross-sectional view of some ophthalmic devices according to several embodiments of the present invention. [Figure 7] This is a simplified schematic cross-sectional view of some ophthalmic devices according to several embodiments of the present invention. [Figure 8] This is a simplified schematic cross-sectional view of some ophthalmic devices according to several embodiments of the present invention. [Figure 9] This is a simplified schematic cross-sectional view of some ophthalmic devices according to several embodiments of the present invention. [Figure 10] This is a simplified schematic cross-sectional view of some ophthalmic devices according to several embodiments of the present invention. [Figure 11] This is a simplified schematic cross-sectional view of a device on the eye surface according to several embodiments of the present invention. [Modes for carrying out the invention]

[0059] In some embodiments, the present invention relates to polyvinyl alcohol (PVOH)-based elastomer matrices and their uses, and more specifically, to degradable, biodegradable, or bioerodible PVOH-based elastomer matrices, without limitation. In this specification, the terms “biodegradable” and “bioerodible” (and their variations such as “biodegradability” and “bioerodibility”) are used without distinction. For example, a matrix may be considered biodegradable if it is mechanically eroded within the body, regardless of whether any of its components are chemically broken down.

[0060] overview One aspect of several embodiments of the present invention relates to an elastomer matrix (hereinafter simply referred to as "matrix" or "matrices / matrixes") comprising one or more PVOHs to achieve a matrix having determined and / or desired mechanical properties. In some embodiments, the elastomer matrix is ​​PVOH-based in the sense that PVOH is the sole or primary film-forming polymer in the matrix.

[0061] In some embodiments, the matrix is ​​designed to dissolve and / or decompose under wet conditions according to predetermined timeline requirements. In some embodiments, the decomposition 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 various types of PVOH contained in the composition and their relative masses, or by the mass portion of the total PVOH provided by each type.

[0062] In some embodiments, when “wetting conditions” is referred to, it should be understood to relate to conditions in which the matrix of the present invention is in direct contact with a liquid (immersed in a liquid, or after immersion in a 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, and interstitial 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 naturally occurring or simulates a naturally occurring fluid such as artificial tears. In some embodiments, the artificial tears are based on an aqueous solution containing about 0.67% sodium chloride, about 0.2% sodium bicarbonate, and about 0.008% calcium chloride. In some embodiments, “wetting conditions” refers to the conditions under which the matrix is ​​placed on human mucosal tissue, e.g., cheek tissue or the ocular surface.

[0063] In some embodiments, the term matrix degradation is defined as a change in the properties of the matrix over time under wet conditions, and “degradability” is defined as the tendency or rate of degradation.

[0064] In some embodiments, changes in properties may include, for example, changes or losses in the mass of one or more of the matrix components or the entire matrix. For example, a plasticizer detaching from an ophthalmic device may be replaced by water, but in some embodiments, PVOH itself may detach from the ophthalmic device, and therefore the device may lose weight. Alternatively or additionally, changes may include changes in the mechanical properties, shape, and / or size of the matrix. Alternatively or additionally, decomposition may be expressed as dissolution, breakage, tearing, and / or collapse of the matrix. Generally, decomposition may result from the breaking of bonds between 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, decomposition allows for the flushing out of the body of the ophthalmic device, or the elastomer matrix contained in the ophthalmic device. For example, when used in an ophthalmic device, decomposition of the matrix may allow tears to flush out the matrix debris from the eye.

[0065] In some embodiments, the type of decomposition, such as a change from a soft solid to slime, dissolution, mass loss, or change in tearability, may depend on the type of PVOH contained in the matrix. For example, we have found that some matrices containing long-chain complete hydrolysis (LCFH) PVOH and short-chain partial hydrolysis (SCPH) PVOH tend to become “slimy” when immersed in simulated tears (STF). In such embodiments, increased sliminess may be accompanied by a decrease in compressive modulus over time under STF. In some embodiments, some matrices containing LCFH PVOH and long-chain partial hydrolysis (LCPH) PVOH tend to become more readily soluble in STF, meaning they can dissolve in a clear solution in cold water. In some embodiments, some matrices containing LCFH PVOH and short-chain complete hydrolysis (SCFH) PVOH tend to tear more easily the longer they are immersed in STF. In some embodiments, increased susceptibility of such a matrix to tearing may be accompanied by a decrease in compressive strength over time under STF conditions.

[0066] See also the exemplary mechanical properties in Example 7 below.

[0067] In some embodiments, degradation may eliminate the need to remove the matrix from the body. For example, the degradation products may be naturally excreted from the body, for example, by tears (if the matrix is ​​used in the eye) or by urine (if the matrix is ​​used in the bladder). In the case of ophthalmic devices, ophthalmic devices made from a degradable matrix may remain in the eye for a certain period of time and then naturally detach from the eye without the need for active removal. For example, the device may completely dissolve and detach from the eye with tears, or it may break down into small pieces so that it can be excreted from the eye as any other foreign body.

[0068] In some embodiments, slight pressure on a biodegradable matrix (e.g., used as an ophthalmic device) can immediately alter the morphology or integrity of the matrix, allowing the ophthalmic device to be spontaneously ejected immediately after being pressed.

[0069] In some embodiments, disintegration allows the matrix to remain in the anatomical site of use by acquiring a comfortable shape and / or viscosity. For example, an ophthalmic device may acquire a shape that fits into the space between the conjunctiva and the tarsal conjunctiva, where it can remain without causing discomfort to the patient until it disintegrates and is expelled from the eye. In some embodiments, on its way out of the eye, the disintegrated device may encounter the cornea, causing temporary discomfort.

[0070] In some embodiments, the terms “dissolve” and “degrade” are interchangeable and refer to a process in which the elastomer matrix changes, for example, a process under wet conditions. The change may be, for example, a change from a solid state to a completely degraded state. The change may be, for example, a loss of mass. In some embodiments, a completely degraded state may be defined as, for example, a degraded state of the matrix when the matrix is ​​so broken down into particles of such small size that it is not visible to the naked eye, and / or, in a matrix used or applied to any tissue such as the eyelid, for example, when the matrix elastically changes shape and / or does not maintain a defined shape under certain external pressures, such as pressure on the matrix from the eyelid. The terms “shape” and “geometry” are interchangeable and refer to the form of the matrix.

[0071] In some embodiments, the matrix comprises a mixture of at least two types of PVOH. In some embodiments, the difference between the types of PVOH lies in one or more of the degree of hydrolysis and the chain length of the PVOH. In some embodiments, the greater the amount of highly hydrolyzed PVOH in the matrix, the longer it takes for the matrix to decompose completely. In some embodiments, the PVOH comprises at least two types of PVOH that differ from each other in one or both of the degree of hydrolysis (HD) and / or chain length. In some embodiments, each of the at least two types of PVOH accounts for at least 10% of the total amount of PVOH in the matrix. In some embodiments, the at least two types of PVOH include one type that has a long chain and is completely hydrolyzed, and one type that is at least one of the following: having a short chain and being partially hydrolyzed, having a long chain and being partially hydrolyzed, or having a short chain and being completely hydrolyzed. In some embodiments, the short chain consists of 200 to 2,000 monomer units, the long chain consists of 2,200 to 5,000 monomer units, the fully hydrolyzed PVOH has a degree of hydrolysis of 97% or more, and the partially hydrolyzed PVOH has a degree of hydrolysis of 95% or less.

[0072] In some embodiments, the number of PVOH types is three or more.

[0073] In some embodiments, two of the PVOH types differ in chain length by, for example, at least 1,000 or 1,500 units. In some such embodiments, two of the PVOH types have similar degrees of hydrolysis, for example, 97% to 100%.

[0074] In some embodiments, two of the PVOH types have different degrees of hydrolysis, for example, one having 97% or more DH and the other 93%, 90%, or less. In some such embodiments, the two PVOH types also have different chain lengths, for example, by at least 1,000 or 1,500 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, when two of the PVOH types differ in their degree of hydrolysis, the two PVOH types have similar lengths and differ from each other by, for example, less than 500 units.

[0075] In some embodiments, short-chain PVOH has an average chain length of about 200 to about 2,000 monomer units, and long-chain PVOH has an average chain length of about 2,200 to about 5,000 monomer units. In some embodiments, fully hydrolyzed PVOH has a degree of hydrolysis of 97% or more, and partially hydrolyzed PVOH has a degree of hydrolysis of 94% or less. In some embodiments, the short chain has a molecular weight of about 50 kg / mol to less than about 80 kg / mol, while the long chain has a molecular weight of about 50 kg / mol to greater than about 80 kg / mol.

[0076] In some embodiments, the matrix is ​​specifically designed to maintain its geometric shape / form under wet conditions before the decomposition process begins. The decomposition process may begin after 1 minute under wet conditions in some embodiments, and after several hours or within an intermediate time under wet conditions in other embodiments. Matrices that maintain their geometric shape can be shaped outside the body (e.g., the eye) and are known to retain the same shape for at least a certain period after contact with the body.

[0077] In some embodiments, the elastomer matrix comprises PVOH, one or more organic plasticizers, and optionally water. In some embodiments, the elastomer matrix is ​​characterized in that the ratio between the total mass of one or more plasticizers and the total mass of various types of PVOH is at least 2:1.

[0078] In other words, the total mass of plasticizer / the total mass of PVOH ≥ 2 / 1.

[0079] This ratio is referred to in this specification as the "combined mass ratio."

[0080] In some embodiments, the elastomer matrix contains at least two types of plasticizers.

[0081] In some embodiments, the matrix is ​​characterized by maintaining its geometric shape when in contact with a moist environment, for example, when in contact with the eye or other body tissue. In some embodiments, in addition to maintaining its geometric shape when in contact with a moist environment, the matrix optionally increases in volume. In some embodiments, the volume increase is 50% or less. In some embodiments, the swelling is uniform in all directions, so the volume changes, but the geometric shape is maintained. In some embodiments, the elastomer matrix is ​​characterized by substantially isotropic swelling when immersed in simulated tear solution at room temperature for 5, 10, or 15 minutes. In some embodiments, the elastomer matrix swells by less than 50% by volume when immersed in simulated tear solution at room temperature for 5, 10, or 15 minutes.

[0082] In some embodiments, the mechanical properties and / or degradability of the elastomer matrix depend on the types of PVOH used to form the matrix and their respective masses. For example, if the PVOH consists of mostly long-chain complete hydrolysis (LCFH) PVOH and a small amount of short-chain partial hydrolysis (SCPH) PVOH, the matrix degrades more slowly than if LCFH PVOH constitutes a small amount of PVOH in the matrix and SCPH PVOH constitutes the majority.

[0083] The following table (Table 1) provides examples of several commercially available types of PVOH. The list is taken from the Mowiol® brand, but similar materials are available from other sources. The PVOH type labeled "30k" in the following table (Table 1) is not from the Mowiol brand. All PVOH types used in the examples and measurements described herein were performed using PVOH or 30k PVOH sold under the Emprove® brand (Sigma Aldrich 8.21039).

[0084] [Table 1]

[0085] In some embodiments, the elastomer matrix is ​​used as a medical device. For example, the matrix may be used as an ophthalmic device or constitute part of an ophthalmic device. In some embodiments, the ophthalmic device may be configured to be positioned on the surface of the eye, preferably on the sclera, without optionally covering any portion of the cornea so as not to obstruct vision. In some embodiments, the options for positioning the ophthalmic device include one or more of the following: local (sclera, cornea), subconjunctival, conjunctiva, choroidal, intravitreous, anterior chamber, subretinal, or any other method of providing to the eye. In some embodiments, the medical device is applied to body parts other than the eye, e.g., on or inside body cavities (e.g., bladder, stomach), joints, etc. In some embodiments, the matrix may be applied to body parts by intramuscular injection. In some embodiments, a potential advantage of positioning on the sclera is that the sclera is potentially less sensitive (to pain, irritation, etc.) than the cornea, and therefore designing the matrix to contact only the sclera potentially results in a more user-friendly matrix. In some embodiments, depending on the composition of PVOH types contained in the elastomer matrix, complete decomposition occurs, for example, between 0.5 and 12 hours after contact with the eye; optionally between 0.5 and 24 hours; optionally between 0.5 and 48 hours; or optionally within a longer timeframe than 48 hours. In some embodiments, a potential advantage of controlling the decomposition time is that it allows the user to use the ophthalmic device at a convenient and / or selected time of day (e.g., while the user is sleeping, or to allow the device to operate within a desired time frame).

[0086] In some embodiments, the elastomer matrix is ​​characterized by a tensile strength of 10 MPa, 4 MPa, or less than 3 MPa, preferably less than 2 MPa, under dry conditions. Additionally or alternatively, the elastomer matrix is ​​characterized by an elasticity (also known as Young's modulus) of 0.01 MPa to 10 MPa, 4 MPa, or 3 MPa, preferably 0.01 MPa to 2 MPa, under dry conditions. Additionally or alternatively, the elastomer matrix is ​​characterized by an elongation at break of at least 50%, for example, 50% to 900% or 50% to 1,000%, under dry conditions. In some embodiments, a potential advantage of having a matrix characterized by the above mechanical properties is that it potentially reduces user discomfort and thereby potentially improves compliance.

[0087] Before describing in detail at least one embodiment of the present invention, it should be understood that the present invention is not necessarily limited in its application to the details of the arrangement and / or method of configurations and components described in the following description and / or shown in the drawings and / or described in the embodiments. Other embodiments of the present invention are possible, or it can be carried out or implemented in a variety of ways.

[0088] Exemplary basic composition of an exemplary elastomer matrix In some embodiments, for example, an exemplary elastomer matrix used as an ophthalmic device 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 ratio of total masses (i.e., the ratio of the total mass of one or more plasticizers to the total mass of various types of PVOH contained 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 in the matrix is ​​at least 70 wt% of the total weight of the matrix excluding the mass of water, i.e., the total mass of PVOH and plasticizers (may be more than one) is at least 70 wt%, at least 80 wt%, or at least 90 wt% of the mass of all non-aqueous components in the matrix.

[0089] In some embodiments, the mass ratio of plasticizer(s) to PVOH is less than 5:1, less than 10:1, less than 15:1, less than 20:1, or less than 30:1 (e.g., 5.6:1). In some embodiments, the mass ratio of plasticizer(s) to PVOH is in the range of 10 to 2:1 (10:1 to 2:1), or 30:1 to 3:1.

[0090] In some embodiments, the mass content of PVOH (all types combined) accounts for less than 33 wt% of the total weight of the non-aqueous components of the matrix. For example, in some embodiments, the mass content of PVOH accounts for 3 wt% to 10 wt%, 5 wt% to 15 wt%, less than 20 wt%, less than 25 wt%, or less than 30 wt% of the total weight of PVOH and plasticizer (non-aqueous components of the matrix).

[0091] The term “ratio of total masses,” as used herein, refers to the total amount of one or more components of a first type (e.g., one or more plasticizers) relative to the amount of one or more other components of the matrix (e.g., types of PVOH), where all amounts are expressed in units of mass (e.g., grams). The ratio of total masses is calculated by summing the masses of one or more components of the first type to obtain a first total mass, summing the masses of one or more components of a second type to obtain a second total mass, and dividing the first total mass by the second total mass.

[0092] As used herein, the term "total mass" refers to the sum of the amounts of multiple components, expressed in units of mass. Total mass is calculated by summing the masses of the components that make up the multiple components.

[0093] The term "elastomer matrix," as used herein, refers to a crosslinked polymer structural form that exhibits rubbery elasticity, is deformable under the influence of force, and can recover its original shape when the force is removed. In some embodiments, the crosslinking is purely physical, i.e., the matrix does not contain covalent crosslinks. The absence of covalent crosslinks may be expressed as water solubility in hot water. The exact temperature and amount of hot water required to dissolve a particular matrix may 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 same as the solubility of the less soluble of the above types of PVOH.

[0094] In some embodiments, elastomer matrices containing less than 33% by weight (wt%) of polyvinyl alcohol have the advantage of maintaining their elastomer matrix morphology under dry conditions, swelling by less than 50% by volume (or less than 15% along each of its three dimensions) under wet conditions, and substantially maintaining their geometric shape when transitioning from a dry to a wet state. It has been found that the use of at least two plasticizers is necessary to manipulate these properties.

[0095] In the context of some embodiments of the present invention, an elastomer matrix is ​​a form of physically crosslinked polymer structure capable of releasing one or more of its components (e.g., plasticizers and / or active pharmaceutical ingredients (APIs)) into water (or any humid environment) with or without a change in its mechanical properties, and for example, having an open-cell porous microstructure that can incorporate released substances sequestered and / or added within its interconnected voids. According to some embodiments of the present invention, the elastomer matrix is ​​a network of hydrogen-bonded polymers and plasticizers. According to some embodiments of the present invention, the elastomer matrix is ​​a network of hydrogen-bonded polymers, plasticizers and water. According to some embodiments of the present invention, the elastomer matrix is ​​a network of hydrogen-bonded polymers and plasticizers. According to some embodiments of the present invention, the elastomer matrix is ​​a network of hydrogen-bonded polymers, plasticizers and water. In some embodiments, the elastomer matrix provided herein is essentially free of covalent crosslinks. Being essentially free of covalent crosslinks may be expressed as being water-soluble in hot water. The amount and temperature of water required to dissolve the matrix depend on the size of the matrix and its formulation, including the specific types of PVOH contained within it. In some embodiments, the solubility of the matrix is ​​approximately the same as that of the least soluble of the PVOH types.

[0096] In some embodiments, the elastomer 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%. In some embodiments, the matrix is ​​characterized by a porosity of at least about 50%, 60%, 70%, 80%, or at least about 90%.

[0097] In some embodiments, the PVOH-based elastomer matrix is ​​free of chemical crosslinking agent residues and remains stable in terms of geometric shape and viscosity during immersion in an aqueous medium, at least in the initial stages in the aqueous medium, for example, for the first 1-2 minutes after insertion into the aqueous medium, or for longer periods, depending on the formulation, for example, up to several hours. In some embodiments, the elastomer matrix is ​​soft and elastic under dry and wet conditions.

[0098] In some embodiments, the viscosity of the elastomer matrix provided herein may be similar to that of a hydrogel; however, in contrast to hydrogels, the elastomer matrix provided herein has a low water content (less than 50 wt%), is stable under dry conditions, and does not require immersion in water to maintain its flexibility. In some embodiments, under wet conditions, the water content may reach 150% or less of the mass of non-PVOH components that the matrix had under dry conditions.

[0099] In some embodiments, the mechanical properties of the elastomer matrices provided herein are similar to those of rubber (elastomer) under dry and / or wet conditions (e.g., immersion in an aqueous medium).

[0100] Unless otherwise explicitly 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 itself provided herein and not to any solution in which the matrix may or may not be immersed.

[0101] In some embodiments, water is structurally fixed within the elastomer matrix, evaporates / leaches freely from the matrix, or is absent from the matrix. In some embodiments, the exact amount of water (fixed and / or free) varies depending on the properties of the components in the matrix and the conditions under which it is stored. In some embodiments, when referring to “non-aqueous” elements / components of the elastomer matrix provided herein, it is intended to refer to all components except water. In some embodiments, the mass content of “non-aqueous” elements should not be confused with the mass content of the matrix under dry conditions, which may include the mass of water.

[0102] When referring to “drying conditions,” it should be interpreted that the elastomer matrix provided herein is exposed to air at room temperature in an open or sealed container and is not immersed in a liquid, such as water or any other aqueous medium or liquid.

[0103] In some embodiments, in the context of ophthalmic devices, “dry conditions” refer to conditions contrary to those of contact lens storage. Contact lenses are generally made of hydrogel and must always be stored in an aqueous medium to maintain their shape and malleability. In stark contrast, the elastomer matrices provided herein do not need to be kept wet to maintain their shape and malleability, and their shape does not change when moving between wet and dry conditions (although their size may change).

[0104] Therefore, in some embodiments, when an elastomer matrix is ​​said to have less than a certain wt% of polyvinyl alcohol of the total weight of the non-aqueous components of the matrix, it means that the mass content of PVOH accounts for less than a certain wt% of the total mass content of the matrix, excluding any water that is structurally fixed within the matrix or freely leaches out of the matrix (if any).

[0105] In some embodiments, a relatively small amount of water in the matrix allows the matrix to have a longer shelf life and can be stored under dry conditions (i.e., not immersed in liquid), with excess water being unnecessary and undesirable. In some embodiments, assuming that only water evaporates from a wet elastomer matrix, the amount of water remaining after conventional drying is considered to form part of the matrix. In the context of the present invention, conventional drying is drying the outer surface of the matrix by exposing it to ambient air at room temperature and ambient humidity. In some embodiments, the room temperature can be in the range of 15°C to 30°C, and the relative humidity can be in the range of 30% to 75%. In some embodiments, the exact conventional drying time can vary depending on the specific content of the matrix, but is typically 24 hours to 4 days. In some embodiments, drying is accelerated by heating, for example, to about 60°C, and the drying time is shortened accordingly. In some embodiments, drying is delayed by drying the solution, for example, in a sealed mold and / or with cooling to, for example, about 10°C.

[0106] In some embodiments, the moisture content can be determined by the Karl Fischer method and the direct measurement of mass loss by drying, i.e., the LOD method, among several other methods. The Karl Fischer method was performed by volumetric analysis using Hydranal Composite 5 (Honeywell) as the titrant and a Karl Fischer instrument model Titrando 852 (Metrohm). Methanol was used as the solvent. The LOD test was performed at a temperature of 85°C on samples of 700 mg or more using the MX-50 moisture meter from A&D Company, Limited, Inc. in Japan.

[0107] According to these methods, which yield similar results for a given sample, in some embodiments of the present invention, the elastomer matrix contains less than about 50 wt% water. In some embodiments, the water content 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 elastomer matrix contains about 50 wt% to about 5 wt% water.

[0108] In some embodiments, the elastomer matrices provided herein, due to their unique composition, swell to less than 50% by volume under wet conditions while maintaining their shape. In some embodiments, the matrices swell to 40% by volume or less, or less than 35% by volume, or less than 20% by volume, or less than 15% by volume, or less than 10% by volume, or less than 5% by volume under wet conditions.

[0109] In this specification, in some embodiments, the matrix can be manufactured into a distinct 3D shape by casting, molding, cutting, or other means, and it should be noted that this shape remains essentially unchanged even when conditions change from dry to wet and vice versa. This property is referred to herein as shape retention. In other words, the total volume of a fragment of the matrix provided herein may change (swell or shrink) under changing wet conditions, but the overall shape of the fragment remains essentially the same without strain, compression, or deformation. Thus, in some embodiments, another feature of the elastomer matrix provided herein is substantially uniform size variability along all directions and orientations under changing wet conditions. Substantially uniform means that the size changes by the same amount ±20% along each direction. This feature may also be referred to herein as isotropic swelling and shrinkage. In some embodiments, the elastomer matrix is ​​characterized by substantially isotropic swelling when immersed in simulated tear solution at room temperature for 5, 10, or 15 minutes. In some embodiments, the elastomer matrix swells by less than 50% by volume when immersed in simulated tear solution at room temperature for 5, 10, or 15 minutes.

[0110] In some embodiments, the composition and preparation methods of elastomer matrices provided herein also determine the degree of crystallinity of the matrix. Degree of crystallinity (DoC) is the proportion of regularly occurring molecules in a polymer material, and for many known polymer materials, it is typically in the range of 10% to 80%. Higher values ​​can be achieved in materials with small molecules or polymer materials prepared and / or stored at temperatures just below their melting point. Most methods for evaluating crystallinity assume a mixture of perfectly crystalline and completely disordered regions, with the transition region expected to be a few percent. These methods include density measurements, differential scanning calorimetry (DSC), X-ray diffraction (XRD), infrared spectroscopy, and nuclear magnetic resonance (NMR).

[0111] In some embodiments, the elastomer matrix provided herein does not need to be cooled below room temperature, nor does it need to be heated above room temperature after solidification and drying. In some embodiments, the elastomer matrix contains a pharmaceutically active ingredient (API), and the API or any mixture or solution containing the API can be obtained without heating. In some embodiments, the crystallinity of the matrix is ​​less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, or less than 20%. In some embodiments, the matrix is ​​frozen at a temperature of -18°C or below, and after thawing at room temperature, its shape does not change. In some embodiments, a potential advantage is that the matrix can potentially be used with pharmaceutically active ingredients (APIs) that require deep freezing.

[0112] In some embodiments, the elastomer matrices provided herein are highly suitable for use as ophthalmic devices in ophthalmic applications, including applications where the matrix needs to be transparent and applications where such a requirement is not raised. For this reason, the elastomer matrices provided herein, according to some embodiments, are characterized by relatively low transparency. Transparency of a material refers to the optical clarity through which an object can be seen when viewed through a film / sheet made from the material. The transparency of an object made from the elastomer matrices provided herein can be measured by total transmittance, which is the ratio of transmitted light to incident light, taking into account influencing factors such as reflection, absorption, and dispersion. For example, to subtract absorption / dispersion and reflection, the total transmittance of a sample is the incident light (100%) minus absorption / dispersion (X%) and reflection (Y%); in other words, total transmittance = incident light - (absorption / dispersion + reflection). In some embodiments, opaque elastomer matrices may be preferred, for example, because they are easier to manufacture without compromising functionality, and further, they facilitate user manipulation, potentially allowing the user to better visualize the matrix. For example, an opaque elastomer matrix can be obtained by using PEG as a plasticizer and / or by manufacturing the matrix at room temperature.

[0113] According to some embodiments of the present invention, the elastomer matrix is ​​characterized by having a total transmittance (transparency) of less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, or less than 30% through an optical path length of 0.5 millimeters.

[0114] In some embodiments, the elastomer matrix provided herein further comprises at least one inorganic ion and / or a salt thereof, and / or at least one organic ion and / or a salt thereof.

[0115] In some embodiments, the elastomer matrix provided herein further comprises at least one buffer. In some embodiments, the buffer is tromethamine, phosphate, citrate, and any combination thereof.

[0116] In some embodiments, the elastomer matrix provided herein further comprises at least one surfactant. In some embodiments, the surfactant is selected from sorbitan esters (Span), sorbitan tristearate (Tween), poloxamers, Triton, Betain, and any combination thereof.

[0117] 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 substantially free absence of covalent crosslinks 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, including the specific types of PVOH contained in the matrix. In some embodiments, the solubility of the matrix is ​​approximately the same as the solubility of the least soluble of these PVOH types.

[0118] Exemplary degree of hydrolysis (DH), degree of polymerization (DP), decomposition time, and combinations thereof. The inventors have discovered remarkable effects by combining two types of PVOH having different degrees of hydrolysis for use in the elastomer matrix described herein. This effect may be beneficial for, for example, medical applications of the matrix, such as ophthalmic devices, or other medical applications described herein.

[0119] According to several embodiments of the present invention, at least two types of PVOH are used for the preparation of an elastomer matrix. In some embodiments, the difference between the types of PVOH is one or more of the degree of hydrolysis and the degree of polymerization. In some embodiments, a potential advantage of combining at least two types of PVOH is that it allows for the manipulation of the changes over time in the mechanical properties of the matrix (e.g., tensile strength and / or modulus) under wet conditions. Additionally or alternatively, in some embodiments, a potential advantage of combining at least two types of PVOH is that it allows for the manipulation of the time it takes for the elastomer matrix to decompose under wet conditions.

[0120] In some embodiments, the first type of PVOH used to prepare the elastomer matrix is ​​characterized by a degree of complete hydrolysis (DH) of 97% to 100%.

[0121] In some embodiments, the second type of PVOH used to prepare the elastomer matrix is ​​characterized by a partial hydrolysis degree (DH) of less than 95%, for example, 80% to 93%. In some embodiments, the partial hydrolysis degree of PVOH is less than 90%.

[0122] Those skilled in the art should understand that the above percentages are average percentages, and that the degree of hydrolysis in each type of PVOH is distributed around and within the above values.

[0123] The degree of polymerization (DP) of a polymer is estimated by dividing the polymer's molecular weight by the molecular weight of its monomer units.

[0124] In some embodiments, the first type of PVOH used to prepare the elastomer matrix is ​​characterized by a degree of polymerization that includes long chains having a chain length of more than 2,500 units and / or a molecular weight of more than 100 kg.

[0125] In some embodiments, the second type of PVOH used to prepare the elastomer matrix is ​​characterized by a degree of polymerization that includes shorter chains, for example, with chain lengths of 1,500 units or less or 1,000 units or less.

[0126] Those skilled in the art should understand that the above percentages are average percentages, and that the degree of polymerization in each type of PVOH is distributed around and within the above values.

[0127] In some embodiments, molecular weight corresponds to chain length, but unless the degree of hydrolysis is 100%, not all repeating units are the same, and the molecular weight of the hydrolyzed units differs from that of the unhydrolyzed units, so the correspondence partially depends on the degree of hydrolysis. For example, in the case of completely hydrolyzed PVOH: chain length ≈ 3.8 + 22.3 MW [kg], while in the case of partially hydrolyzed PVOH: chain length ≈ 3.6 + 20.6 MW [kg].

[0128] In some embodiments of the present invention, the PVOH used in the preparation of the elastomer matrix provided herein is further characterized by a degree of polymerization in the range of 500 to 5,000. In some embodiments, the PVOH is a mixture of different degrees of polymerization and may contain, for example, one PVOH with a high molecular weight (e.g., a chain length of 3,000 monomers or more) and one PVOH with a low molecular weight (e.g., a chain length of 1,000 monomers or less).

[0129] In some embodiments, the elastomer matrix provided herein is a biodegradable matrix. In some embodiments, the elastomer matrix is ​​stable in liquid for more than one month at room temperature. In some embodiments, the elastomer matrix is ​​at least partially and gradually dissolved and / or eroded upon contact with a liquid (water, body fluid). In some embodiments, the elastomer matrix provided herein is bioerosive, meaning that the amount of polymer bulk in the matrix is ​​reduced by either physical processes, such as dissolution and / or chemical processes, that occur when the matrix comes into contact with biological tissue and / or body fluid. In some embodiments, the body fluid is tear fluid.

[0130] In some embodiments, the amounts of different types of PVOH in the elastomer matrix correlate with the time it takes for the elastomer matrix to decompose. For example, as the ratio between fully hydrolyzed PVOH and partially hydrolyzed PVOH increases, the time required under wet conditions for the matrix to completely dissolve also increases.

[0131] Referring here to Figure 1, a graph is shown illustrating exemplary degradation characteristics of three different elastomer matrix compositions, as they change over time under wet conditions, according to several embodiments of the present invention. The graph shows the degradation characteristics of three matrices that differ from each other only in the amount and type of PVOH contained in their compositions.

[0132] The x-axis represents the time axis. Matrices with various compositions may exhibit qualitatively similar behavior to that shown in the graph. One difference that may exist between the behaviors of different matrices is the time interval over which the matrix transitions from one phase to another.

[0133] The Y-axis is the phase axis. The listed values ​​(elastomer solids, gels, slime, and decomposition) are qualitative descriptions of the matrix. The points are measured values ​​of compressive modulus, shown on a logarithmic scale.

[0134] The upper (dotted) line represents the properties of a first elastomer matrix where all PVOH is completely hydrolyzed and has long chains; the middle (short dashed) line represents the properties of a second elastomer matrix where approximately half of the PVOH is completely hydrolyzed and has long chains, with the remainder being partially hydrolyzed; and the lower (long dashed) line represents the properties of a third elastomer matrix where approximately two-thirds of the PVOH is partially hydrolyzed and has short chains, with the remaining PVOH being completely hydrolyzed.

[0135] The upper line indicates that the first matrix remains primarily elastomer and may acquire some gel-like properties after 4 hours in the liquid. In some embodiments, these gelling properties continue further, as indicated by the gentle downward slope of the line toward 24 hours. It should be noted that some elastomer matrices (not shown) containing only fully hydrolyzed long chains show no signs of gelling even after 48 hours, 1 week, or even 3 months.

[0136] The central (dashed) line indicates that the second matrix transitions from an elastomer state to a gel-like state after approximately 1.5 hours under wet conditions. In the gel-like phase, the matrix retains the shape it had in the elastomer phase but becomes much more flexible, which can be represented by lower tensile and / or compressive moduli. In some embodiments, the gel-like phase may be characterized by smaller elongation at break and / or lower tensile force than the matrix in the elastomer phase.

[0137] The second matrix, when held under moist conditions for approximately 4 hours, transitions to a slime phase. In the slime phase, the matrix may have a viscous consistency, which can be manifested by its complete collapse upon application of slight compressive force and / or breakage upon application of slight tensile force.

[0138] The third matrix (bottom line) is shown in the figure to go through the same phases at different times. The transition from the elastomer phase to the gel-like phase occurs faster than with each of the other matrices, and the transition to the slime phase occurs before a similar transition occurs in the second matrix. However, the third matrix also enters a completely decomposed phase, where the matrix does not exhibit measurable resistance to compression. Thus, Figure 1 shows that, in some embodiments, in elastomer matrix compositions having long-chain completely hydrolyzed PVOH and short-chain and / or partially hydrolyzed PVOH, the greater the amount of short-chain partially hydrolyzed PVOH, the faster the decomposition process under wet conditions.

[0139] It should be noted that transitions between phases do not always have clear boundaries, and the matrix can be in numerous intermediate phases, for example, from elastomer to gel-like, or from gel-like to slime. It should also be noted that not all matrices go through all phases. While it is preferable that each elastomer matrix be in the elastomer phase at least under dry conditions, not all matrices go through the gel-like phase, nor do all matrices go through the slime phase. It is assumed that all matrices undergo complete decomposition, but not all matrices have been tracked in the laboratory for a sufficient time to confirm this. Details of the exact phases that a matrix goes through and at what time intervals may 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 other components of the composition (e.g., plasticizers) and their amounts.

[0140] Referring now to Figure 2, graphs are shown illustrating the decomposition of several matrices during wet and dry cycles according to several embodiments of the present invention. The decomposition is shown in the graph as a change in the mass of the matrix. This change in mass may be accompanied by other changes (e.g., changes in mechanical properties and / or chemical composition).

[0141] The first stage of the cycle, which may be called the packaging stage, lasts from the production of the matrix until, as long as it is stored under dry conditions, perhaps until the end of its shelf life. In some embodiments, the packaging stage may last for 3 months, 6 months, 1 year, 2 years, or even 3 years or more.

[0142] During the packaging stage, each of the matrices shown in the graph retains its own mass. All three matrices mentioned in the graph begin with the same initial mass and remain at the same mass throughout the first stage. Therefore, the lines representing the three matrices are indistinguishable from one another. In some matrices according to some embodiments of the present invention (not shown in the graph), some mass loss may occur during the first stage, but in most embodiments, such change is less than 25%.

[0143] In some embodiments, other properties of the matrix remain unchanged or change only nominally during the first step. These properties may include, for example, shape, size, chemical composition, and mechanical properties.

[0144] The second stage of the cycle, which may be called the wetting stage, continues as long as the matrix remains under wet conditions. This can last, for example, from about 5 minutes to 1 hour, 1 day, 1 week, 1 month, or even 3 months. If the matrix is ​​used for medical purposes, the behavior in the second stage may represent the behavior of the matrix when in contact with bodily fluids.

[0145] During the wetting phase, the three types of matrices exhibit different behaviors.

[0146] In the first type of matrix, the mass change is shown by a dashed line, and the mass does not change much during the wetting phase. However, the chemical composition of the matrix can change substantially. For example, the organic elastomers that form part of the matrix can be replaced by the liquid (e.g., water or bodily fluids) that wets the matrix.

[0147] The first type of matrix tends to retain its shape and size after wetting, but its mechanical properties may change; for example, it may become softer and more flexible than before wetting.

[0148] In some embodiments, the PVOH in the first type of matrix is ​​mainly long-chain and completely hydrolyzed (however, it may contain at least two types of completely hydrolyzed long-chain PVOH). In some embodiments, some of the PVOH in the first type of matrix may have shorter chain lengths and / or a lower degree of hydrolysis, but these should preferably be in small amounts, e.g., 10% or less of the total PVOH content.

[0149] Still in the wetting phase, the decomposition behavior of the second type of matrix is ​​shown by the solid line in the figure. The second type of matrix loses a considerable portion of its weight during the wetting phase, but retains most of its weight, no matter how long the wetting phase lasts. The chemical composition of such a matrix may change due to wetting, as plasticizers are replaced by water (similar to the compositional changes that occur in the first type of matrix), and it may also lose some of its PVOH and dissolve or disperse in the liquid. The mechanical properties of the second type of matrix change during the wetting phase, and the matrix becomes softer and more flexible. In some embodiments, the second type of matrix loses some of its size during the wetting phase but retains its original shape.

[0150] The chemical composition of the second type of matrix contains a substantial portion (e.g., at least 50%) of long-chain, highly hydrolyzable PVOH, with the remainder of the PVOH (e.g., less than 50%) being short-chain and / or partially hydrolyzed. It should be noted that there is no clear boundary between the transition between the first and second type of matrix compositions, and the question of whether a particular composition of different types of PVOH results in the first or second type of matrix may depend on the specific type of PVOH used, as well as the type and amount of plasticizer.

[0151] Still in the wetting phase, the decomposition behavior of the third type of matrix is ​​shown by the dotted line in the figure. The third type of matrix loses almost all of its mass if left under wetting conditions for a sufficiently long time, and if not removed from water immediately, it loses so much size and shape that it becomes shapeless and slime-like. The chemical composition of such a matrix may change due to the loss of plasticizers and PVOH. The mechanical properties of the third type of matrix change dramatically during the wetting phase, and the matrix may completely dissolve during the wetting phase.

[0152] The chemical composition of the third type of matrix mainly consists of short-chain and / or partially hydrolyzed PVOH, with only a small amount (e.g., less than 40%) of PVOH being long-chain and / or fully hydrolyzed. It should be noted that the compositional changes required to transition from the second type of matrix to the third type of matrix are not the same for all compositions of the second type of matrix, and the question of whether a particular composition of different types of PVOH results in the second or third type of matrix may depend on the use of specific types of PVOH, as well as the plasticizers used and their amounts.

[0153] The third stage of the cycle, which may be called the drying stage, begins when the matrix is ​​removed from the liquid and continues as long as the drying conditions are maintained. If the matrix is ​​used for medical purposes, the behavior in the third stage may represent the behavior of the matrix after bodily fluids have been drained or after drying (e.g., after bleeding, sweating, or tear secretion has stopped or significantly decreased).

[0154] During the drying phase, the first type of matrix may lose a significant portion of its mass (e.g., up to 70%), primarily due to water evaporation or moisture release. Shape may be retained, while size may decrease. Re-wetting can restore at least partially the shape and size of the dried matrix. Flexibility and pliability are lost during drying but can be partially restored by re-wetting.

[0155] The second type of matrix undergoes a similar process during the drying stage, but may lose a larger portion of its mass (e.g., up to 85%). Changes in size and shape are similar to those that occur in the first type of matrix, but greater. In some embodiments, the second type of matrix does not regain flexibility and pliability upon re-wetting.

[0156] The third type of matrix may dissolve during the wetting stage and therefore does not exist for long enough time to reach the drying stage. If the environment of the third type of matrix dries before a significant portion of the matrix's mass dissolves, some recovery of its shape and size can be achieved by re-wetting.

[0157] In some embodiments, for example for medical applications, the required combination of types of PVOH in the elastomer matrix may be designed to achieve a product that retains its geometric shape under dry conditions (meaning before placement in the body). Retention of shape 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, retention of shape under dry conditions is important because the user needs to manipulate the ophthalmic device to properly position it in the patient's body, for example, on the surface of the eye in the case of an ophthalmic device. Therefore, in some embodiments, for example in the case of an ophthalmic device, the combination of types of PVOH in the elastomer matrix provides a matrix that retains its geometric shape and mechanical properties under dry conditions.

[0158] In some embodiments, the critical value for combinations of PVOH types is as follows: Total PVOH / (Total PVOH + Plasticizer) = approximately 5 wt% to approximately 33 wt%.

[0159] The matrix according to several preferred embodiments has the following PVOH composition.

[0160] [Table A]

[0161] 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.

[0162] While not bound by theory, the decomposition behavior of various matrices according to embodiments of the present invention may be influenced by physical crosslinking, which may be influenced, for example, by different types of PVOH, their relative amounts, the total amount of PVOH relative to plasticizers or other components of the matrix, the plasticizers contained in the composition, and the amount of each plasticizer. Additionally or alternatively, the decomposition behavior of the matrix may be influenced by chemical crosslinking (e.g., by boric acid), for example, if it is mild enough not to interfere with the desired properties of the matrix.

[0163] Exemplary amounts of components in an exemplary elastomer matrix composition In some embodiments, the exemplary elastomer matrix comprises one or more of the following components: 1. Approximately 5 wt% to 50 wt% water in the matrix; 2. Approximately 35 wt% to 95 wt% of the matrix consists of PVOH + plasticizer, where, i. PVOH is present in the PVOH + plasticizer at approximately 5 wt% to 33 wt%. ii. The weight of the plasticizer is at least twice the weight of the PVOH; 3. PVOH + plasticizer + other components in an amount of approximately 0 wt% to 30 wt% by weight.

[0164] In some embodiments, other components may include, for example, active pharmaceutical ingredients (APIs), buffers, and the like.

[0165] Outstanding mechanical properties In some embodiments, the elastomer matrices provided herein may substantially alter their mechanical properties, such as rheological properties, elongation at break, tensile strength, yield strength, yield elongation, and modulus, when exposed to wet conditions.

[0166] Where “dry conditions” refer to in this specification, it should be understood to mean conditions in which the matrix of the present invention is exposed to air at room temperature in an open or sealed container and is not immersed in a liquid, particularly an aqueous liquid. Where “wet conditions” refer to conditions in which the matrix of the present invention is in direct contact with a liquid (either immersed in a liquid, or after immersion in a liquid and before the liquid evaporates or is wiped away).

[0167] In some embodiments, the liquid is a naturally occurring bodily fluid (including, but not limited to, blood, saliva, tears, excrement, biological tissue, and interstitial fluid), an aqueous solution (e.g., of at least one plasticizer), a buffer solution, or any combination thereof. In some embodiments, the liquid is naturally occurring or a simulation of a naturally occurring liquid, such as artificial tears. In some embodiments, the artificial tears are based on an aqueous solution containing about 0.67% sodium chloride, about 0.2% sodium bicarbonate, and about 0.008% calcium chloride.

[0168] In some embodiments, the elastomer matrices provided herein are characterized by a breaking elongation of at least 50%, 100%, 200%, 300%, 400%, 500%, 700%, at least 800%, or at least 900%, or at least 1,000% under dry conditions. In some embodiments, the breaking elongation of the matrix is ​​at least 100% under wet conditions (immersed in a liquid or after immersion in a liquid).

[0169] Surprisingly, in some embodiments of the present invention with relatively low moisture content, remarkably high elongation at break was found. Accordingly, according to some embodiments of the present invention, elastomer matrices having moisture content of 30 wt% or less, 25 wt% or less, or 20 wt% or less exhibited relatively high elongation at break of 50% or more, 100% or more, and even 300% or more or 500% or more under dry conditions.

[0170] In some embodiments, the elastomer matrices provided herein are characterized by tensile strengths in the range of 0.01 MPa to 1 MPa, 2 MPa, 3 MPa, 4 MPa, or 10 MPa under dry conditions. The modulus of elasticity (Young's modulus) varies within a similar range.

[0171] The following table (Table 2) summarizes several mechanical properties measured under dry conditions using matrices with the same composition but different types of PVOH.

[0172] [Table 2]

[0173] These examples illustrate that increasing the amount of short-chain partially hydrolyzed PVOH can decrease the modulus of elasticity, tensile strength, and elongation at break. In these examples, differences between PVOH having the same degree of hydrolysis (88%) and slightly different chain lengths (750 and 630) were reflected in slight changes in mechanical properties.

[0174] The mechanical measurements described herein were performed using a computer-controlled Mark10 Model F105 tensile / compression test frame equipped with 10N or 100N force sensors with standard grips and heads. Software: IntelliMESUR.

[0175] Moisture measurements were performed in simulated tear fluid (STF) with a pH adjusted to approximately 7.2.

[0176] Tensile measurements were performed using a "dogbone" model. Dogbone dimensions: total length 6cm, grip width 2cm, neck width 0.8cm, thickness 0.5mm-3.5mm. Measurement speed 40mm / min.

[0177] Tensile measurements of wet samples were performed after immersing the "dogbone" sample in 5 ml of STF. After the specified time had elapsed, the dogbone was removed from the liquid, attached to the grip, and measured immediately.

[0178] Press measurements were performed using a 12.7 mm flat head and cylindrical samples. Sample dimensions: 4 mm in diameter, 2.5 mm to 3.0 mm in height. Measurement speed: 20 mm / min.

[0179] Each set of samples was immersed separately in a small container, and each was measured after a specified time. The samples were pressed in the liquid without being touched or moved until measurement.

[0180] An exemplary elastomer matrix, in which the dry material consisted of 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%.

[0181] Exemplary plasticizers The term "plasticizer," as used herein, refers to a broad range of substances that, together with PVOH, contribute to the mechanical properties of the elastomer matrix provided herein. While not bound by any particular theory, it is assumed that PVOH and at least one of the plasticizers interact to form a hydrogen bonding network, thereby enabling the matrix to exhibit dimensional stability and elasticity under wet and dry conditions. The hydrogen bonding network may include plasticizer molecules linked to two (or more) PVOH residues.

[0182] In some embodiments of the present invention, the plasticizer is an organic material, i.e., various forms of substance containing carbon atoms.

[0183] According to embodiments of the present invention, at least one of the plasticizers is characterized by having at least two hydrogen bond-forming functional groups, i.e., at least two H bond acceptors, at least two H bond donors, or at least one H bond acceptor and at least one H bond donor.

[0184] According to some embodiments of the present invention, the plasticizer comprises three or more H-bond forming functional groups, or four or more, five or more, six or more, seven or more, eight or more, or nine or more H-bond forming functional groups. In some embodiments, the plasticizer comprises multiple H-bond forming functional groups.

[0185] According to several embodiments, the plasticizer is characterized by a molar mass of less than 1,000 g / mol or less than 500 g / mol. In some embodiments in which the elastomer matrix comprises at least two plasticizers, the matrix may comprise at least one plasticizer that 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 g / mol to 2,000 g / mol.

[0186] According to several embodiments of the present invention, the plasticizer is characterized by forming non-rigid crosslinks with other elements of the matrix, such as PVOH. In this context, the plasticizer is characterized by not containing bonds that connect hydroxyl groups to the molecule and exhibiting at least one or at least two rotatable bonds in its structure. In some embodiments, the plasticizer is characterized by exhibiting at least one bond having a variable dihedral angle. A dihedral angle is the angle between half-planes passing through two sets of three atoms that share two atoms. In some embodiments, the dihedral angle is defined between half-planes passing through two sets of three non-hydrogen atoms that share two non-hydrogen atoms. For example, ethylene glycol exhibits one variable dihedral angle determined by two sets of three atoms, each having oxygen and two carbon atoms common to two sets of non-hydrogen atoms.

[0187] In some embodiments, the plasticizer is biocompatible, i.e., does not induce intolerable local or systemic effects in the recipient / user. In some embodiments, the plasticizer is ophthalmally compatible (acceptable), i.e., biocompatible, and in particular does not induce intolerable ophthalmic effects in the recipient / user.

[0188] In some embodiments, plasticizers(s) interact to form a hydrogen bond network, thereby enabling the matrix to exhibit dimensional stability and elasticity under both wet and dry conditions. The hydrogen bond network may include plasticizer molecules linked to two (or more) PVOH residues.

[0189] In some embodiments of the present invention, the plasticizer is an organic material, i.e., various forms of substance containing carbon atoms.

[0190] According to embodiments of the present invention, at least one of the plasticizers is characterized by having at least two hydrogen bond-forming functional groups, i.e., at least two H bond acceptors, at least two H bond donors, or at least one H bond acceptor and at least one H bond donor.

[0191] According to some embodiments of the present invention, the plasticizer comprises three or more H-bond forming functional groups, or four or more, five or more, six or more, seven or more, eight or more, or nine or more H-bond forming functional groups. In some embodiments, the plasticizer comprises multiple H-bond forming functional groups.

[0192] According to several embodiments, the plasticizer is characterized by a molar mass of less than 1,000 g / mol or less than 500 g / mol. In some embodiments in which the elastomer matrix comprises at least two plasticizers, the matrix may comprise at least one plasticizer that 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 g / mol to 2,000 g / mol.

[0193] According to several embodiments of the present invention, the plasticizer is characterized by forming non-rigid crosslinks with other elements of the matrix, such as PVOH. In this context, the plasticizer is characterized by not containing bonds that connect hydroxyl groups to the molecule and exhibiting at least one or at least two rotatable bonds in its structure. In some embodiments, the plasticizer is characterized by exhibiting at least one bond having a variable dihedral angle. A dihedral angle is the angle between half-planes passing through two sets of three atoms that share two atoms. In some embodiments, the dihedral angle is defined between half-planes passing through two sets of three non-hydrogen atoms that share two non-hydrogen atoms. For example, ethylene glycol exhibits one variable dihedral angle determined by two sets of three atoms, each having oxygen and two carbon atoms common to two sets of non-hydrogen atoms.

[0194] In some embodiments, the plasticizer is biocompatible, i.e., does not induce intolerable local or systemic effects in the recipient / user. In some embodiments, the plasticizer is ophthalmally compatible (acceptable), i.e., biocompatible, and in particular does not induce intolerable ophthalmic effects in the recipient / user.

[0195] In the context of the present invention, according to some embodiments, the elastomer matrix comprises one or more plasticizers, and in other embodiments, the elastomer matrix comprises at least two plasticizers. It should be noted that when specific characteristics of plasticizers are referred to herein, it is intended that they refer to a single plasticizer or each of the multiple plasticizers individually.

[0196] According to some embodiments of the present invention, when the matrix contains two or more plasticizers, one plasticizer is characterized by a viscosity at least five times higher than the viscosity of the other plasticizers. In some embodiments, at least one plasticizer is characterized by a viscosity of at least 1,000 cp, and the other plasticizers are characterized by a viscosity of less than 200 cp. Alternatively, one plasticizer has a viscosity of 500 cp or more, and the other plasticizers have a viscosity of 50 cp or less. For example, in one exemplary matrix, one plasticizer is glycerol and exhibits a viscosity of about 1,400 cp, and the other plasticizer is polyethylene glycol and exhibits a viscosity of about 100 cp. In another example, one plasticizer is glycerol and the other plasticizer is propylene glycol and exhibits a viscosity of about 40 cp. It should be noted that when specific characteristics of plasticizers are referred to herein, it is intended that each of a single plasticizer, several plasticizers, or multiple plasticizers is to be considered to refer to each individually.

[0197] According to several embodiments of the present invention, when the matrix contains two or more plasticizers, one plasticizer is characterized by a viscosity at least five times higher than the viscosity of the other plasticizers. In some embodiments, at least one of the plasticizers is characterized by a viscosity of at least 1,000 cp, and the other plasticizers are characterized by a viscosity of less than 200 cp. Alternatively, one plasticizer has a viscosity of 500 cp or more, and the other plasticizers have a viscosity of 50 cp or less. For example, in one exemplary matrix, one plasticizer is glycerol and exhibits a viscosity of about 1,400 cp, and the other plasticizer is polyethylene glycol and exhibits a viscosity of about 100 cp. In another example, one plasticizer is glycerol and the other plasticizer is propylene glycol and exhibits a viscosity of about 40 cp. All viscosities are for liquid plasticizers at 20°C.

[0198] According to some embodiments, all plasticizers are liquid at room temperature.

[0199] 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 plasticizers constitute 30 wt% to 80 wt% and any partial range between them of the weight of the matrix.

[0200] 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, glycerol esters (e.g., triacetin), polybasic organic acids (e.g., oxalic acid, maleic acid, citric acid, etc.), polyamines (e.g., spermine, spermidine, diethylenetriamine, triethylenetetramine, tris(2-aminoethyl)amine, polyethyleneimine (PEI; polyaziridine, etc.), trypan blue, alkyl gluceth, aliphatic polyether glycols (e.g., polyethylene glycol, polypropylene glycol, polysorbate 80), polyoxyethylene, ethanolamine, erythritol, tromethamine, urea, sugars, amino acids (e.g., glycine, aspartate / aspartic acid, etc.), polyphenols (e.g., tannic acid), and any combination thereof.

[0201] In some embodiments, the plasticizer is an ophthalmic lubricant, emollient, or viscous agent, as described by the FDA in 21 CFR 349.12. The terms lubricant and viscous agent are used interchangeably herein.

[0202] 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.

[0203] Examples of polyols include glycerol, polyethylene glycol (e.g., PEG 300 or PEG 400), propylene glycol, and polysorbate (e.g., polysorbate 70).

[0204] Examples of cellulose derivatives include sodium carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, and hydroxypropylmethylcellulose (HPMC).

[0205] Accordingly, according to some embodiments of the present invention, the plasticizer is an ophthalmic lubricant selected from the group consisting of cellulose derivatives, sodium carboxymethylcellulose, hydroxyethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, hemicellulose, dextran, gelatin, liquid polyol, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, povidone, and any combination thereof. In some embodiments, the ophthalmic lubricant may be considered a pharmaceutically active ingredient, but whenever a pharmaceutical product or ophthalmic device is described in this disclosure and claims as containing both an API and an ophthalmic lubricant, each of the following ophthalmic lubricants shall not be considered an API. PVOH, dextran, gelatin, povidone, hyaluronic acid or pharmaceutically acceptable salts thereof, glycerol, polyethylene glycol (e.g., PEG 300 or PEG 400), propylene glycol, polysorbate (e.g., polysorbate 70), sodium carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, and hydroxypropylmethylcellulose (HPMC).

[0206] 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 glycerol and propylene glycol as plasticizers. In some embodiments, the matrix comprises glycerol and propylene glycol individually, or a mixture thereof mixed with PEG, as plasticizers. In some embodiments, the matrix comprises glycerol and propylene glycol individually, or a mixture thereof mixed with PEG, as plasticizers. In some embodiments, the amounts of PEG and PVOH are substantially the same.

[0207] Exemplary elastomer matrix compositions: The present invention further provides compositions of elastomer matrices immersed in a liquid and / or combined with one or more additional elastomer matrices, each of which is disclosed herein. In some embodiments, medical devices, such as medical devices for eluting drugs, may include combinations of such matrices. In some embodiments, the medical devices may be ophthalmic devices, oral devices, or medical devices for use in other tissues.

[0208] In some embodiments, the medical device comprises two matrices described herein that differ from each other in their composition. For example, each of the two matrices may contain a different type 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 contained in each, 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 two or more of the mass ratio between PVOH and the matrix, the type of PVOH, and the mass ratio between the types of PVOH.

[0209] In some embodiments, the elastomer matrix composition comprises two or more matrices, each having a different PVOH composition. For example, the two compositions may differ in the weight percentage of PVOH in the matrices, the different types of PVOH contained in the matrices, and / or the weight percentage of each type of PVOH in the total PVOH of the matrices. In some embodiments, the elastomer matrix composition may comprise two or more matrices, each having distinct mechanical properties under dry conditions. In some embodiments, each elastomer matrix decomposes at a different rate and / or has different temporal changes of one or more mechanical properties under wet conditions. In some embodiments, the two matrices are in contact via a contact surface, which may be open or closed.

[0210] Referring to Figure 3, a simplified schematic cross-sectional view of a medical device 200 according to several embodiments of the present invention is shown. In some embodiments, the medical device 200 is configured to rest 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 in the eye, and a posterior surface 201 adjacent to the ocular surface (e.g., the sclera) when worn in the eye.

[0211] In some embodiments, contours 202, 204, 206, and 208 represent the front surface of device 200, starting with contour 202 and ending with contour 208, at different times, for example, when device 200 disintegrates while dwelling on the eye. In some embodiments, contour 208 defines the core 210 of device 200.

[0212] In some embodiments, the device 200 comprises different parts that decompose at different rates. Here, in some embodiments, the core 210 comprises a material that decomposes more slowly (or does not decompose in the eye) than the other parts of the device. In some embodiments, the different parts of the device 202 comprise matrices of different compositions. In one example, the slower-decomposing part of the device (e.g., the core part 210) is made of a matrix having more PVOH than the other parts, or in another example, the slower-decomposing part has the same amount of PVOH as the other parts, but more of its PVOH is completely hydrolyzed. In some embodiments, the core 210 differs from the other parts of the device 200 in other aspects of composition, e.g., different compositions of different amounts and types of PVOH. In some embodiments, the core 210 contacts the other parts of the device via an open, dome-shaped contact surface 211.

[0213] Referring here to Figures 4A and 4B, simplified schematic cross-sectional views of the medical device 300 according to several embodiments of the present invention are 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 will be referred to as an ophthalmic device configured to be located between the ocular surface and the eyelid.

[0214] In some embodiments, device 300 includes different parts 302 and 304 having different decomposition times. Parts 302 and 304 are shown to be in contact via a surface 311. Device 200 shows a device in which both the front and rear contours change upon decomposition under wet conditions, whereas in device 300, only the contour of the rear surface 306 changes. In some embodiments, this is because each of the two parts of device 300, namely the rear part 304 and the front part 302, is fabricated from a different matrix having its own decomposition characteristics. Thus, in some embodiments, the front part 302 hardly changes, but the rear part 304 decomposes completely, so the contour of the rear surface 306 changes from what is shown in Figure 4A (where the rear surface is shown as flat) to what is shown in Figure 4B (where the rear surface is shown to be bonded with the contact surface 311).

[0215] Referring here to Figures 5, 6, 7, 8, 9, and 10, simplified schematic cross-sectional views of parts of ophthalmic devices according to several embodiments of the present invention are shown. The ophthalmic devices schematically shown in Figures 5 to 10 provide examples of the richness of drug release profiles that can be achieved with medical devices comprising two or more matrices as described herein, more generally, the richness of drug release profiles enabled by embodiments of the present invention.

[0216] In Figures 5 to 8, shaded areas indicate the presence of therapeutic components (sometimes multiple) in several embodiments.

[0217] Referring here to Figures 5 and 8, in some embodiments, the second layers 602, 902 contain therapeutic components (there may be more). In some embodiments, layers 602 and / or 902 are configured to contact the inner surface of the eyelid at least periodically and / or form at least a portion of the front surface. In some embodiments, layers 602 and / or 902 have a smooth outer surface and / or contain a lubricating material.

[0218] In Figure 5, the therapeutic agent is shown dispersed throughout layer 602, in contact with layer 604 via an open contact surface 611, whereas in Figure 8, the therapeutic agent is shown dispersed only within one or more individual regions 904 within layer 902. These individual regions 904, also referred to herein as pellets, are in contact with layer 902 via a closed ellipsoidal contact surface 911. Layers 604 and 906 do not contain therapeutic components. In some embodiments, the individual regions 904 are fabricated from an elastomer matrix with different degradation properties than that of the layer 902 containing them. Thus, layer 902 may degrade first, releasing the pellets 904, which then degrade gradually after release. This arrangement can result in delayed release of the therapeutic agent, where it is not released until layer 902 degrades, and then slowly released as the pellets 904 degrade.

[0219] Referring now to Figures 6 and 9, these show embodiments similar to those in Figures 5 and 8, respectively, but the therapeutic agent is distributed in the posterior part of the depicted ophthalmic device, rather than the anterior part.

[0220] Referring now to Figures 7 and 10, in some embodiments depicted therein, the therapeutic agent is dispersed throughout both the front sections 804 and 1104 and the rear sections 802 and 1102. In some embodiments, each section of Figure 7 is made of a different matrix and therefore releases the therapeutic agent at a different rate. In Figure 10, pellets 1106 may be made of a different matrix than the matrix around them, and optionally may be made of a different matrix than the matrix that makes up the other sections.

[0221] In some embodiments, the compositions of the present invention comprise at least two elastomer matrices disclosed herein, which may be similar in composition, structure, and properties, or different. In some embodiments, one formulation may be poured into a mold and dried to obtain an elastomer, or another solution may be poured onto the elastomer to obtain a two-layer elastomer composition of matrices. In some embodiments, one (or more) types of microelastomers may be mixed with a formulation that settles to yield another type of elastomer, thereby yielding a "raisin cake" composition of one or more elastomer microsamples in a "dough" of another elastomer (as described, for example, in Figures 8, 9, and 10).

[0222] Referring now to Figures 11A and 11B, simplified schematic cross-sectional views of devices on the eye surface according to several embodiments of the present invention are shown.

[0223] For simplicity, the device 1100 is shown to have a rectangular cross-section, but in some embodiments, the device 1100 may have a shape having one or more features of the devices (may be more) described elsewhere in this specification (e.g., a shape including curvature of the rear and / or front surfaces of the device).

[0224] In some embodiments, the device 1100 includes a layer 1102 containing therapeutic material particles 1104, where the material particles 1104 include one or more features of microparticles and / or nanoparticles in some embodiments.

[0225] In some embodiments, the material particles 1104 are devices having a retaining portion. Here, in some embodiments, the device 1100 includes, for example, 1 to 10 particles 1104, each having a retaining portion.

[0226] Here, in some embodiments, other materials in layer 1102 are rapidly dissolvable and / or decomposable and / or erosive. Erosion, in some embodiments, exposes the particles 1104 and allows their dispersion, for example, as shown in the transition from A to B in Figure 11. In some embodiments, for example, instead of as shown in B in Figure 11, the particles are dispersed within the eyelid and remain under the eyelid, and the retaining portion, for example, means that the eye tissue retains the particles 1104 under the eyelid.

[0227] In some embodiments, the particles 1104 contain a therapeutic material. Optionally, in some embodiments, the particles 1104 contain a mucosal adhesive material. Potentially, when the particles are released from layer 1102, they adhere to the ocular surface 1106 if the particles come into contact with the ocular surface 1106 (e.g., under the movement of one or more of the eyelids, eyeballs, and tear film). In some embodiments, the particles adhere to one or more mucosal surfaces, including, for example, the eyeballs and / or eyelids. In some embodiments, the particles then decompose (e.g., over a period of about 10 minutes, or about 1 hour, or about 12 hours, or about 1 day, or about 3 days, or shorter, longer, or in between) to release the therapeutic material into the ocular tissue.

[0228] Optionally, in some embodiments, the device includes one or more additional layers (e.g., layer 1102). For example, in some embodiments, device 1100 includes a mucosal adhesion layer 1108.

[0229] In some embodiments, the therapeutic material layer 1102 containing particles is incorporated into one or more of the device embodiments described herein (e.g., including coating and / or access features to the therapeutic material layer 1102).

[0230] In some embodiments, the composition of the present invention comprises a solution containing at least one plasticizer, and immerses at least one elastomer matrix in the solution. In some embodiments, the composition of the present invention further comprises a fluid selected from water or an aqueous solution or solvent, and immerses the at least one elastomer matrix in the fluid.

[0231] In some embodiments, the composition is stored under dry conditions before use.

[0232] The elastomer matrices provided herein can be prepared to suit desired properties, but depending on the application, the matrix may need to exhibit unique properties and may require the addition of another type of polymer (or more), which is not any type of PVOH but is typically produced from hydrogen-forming monomers. This type of elastomer matrix is ​​referred to herein as a composite matrix.

[0233] Generally speaking, composite materials are the product of a bond between two different chemical entities. This bond can be covalent, non-covalent, ionic, or other types of bonding. The resulting properties may represent a simple or complex weighted average of the individual properties of each component, and the resulting product may have properties that are quite different from those of the two original components.

[0234] In the context of the present invention, it has been found that by adding one or more polymers other than any type of PVOH, it is possible to obtain novel materials with countless diverse properties while maintaining the basic properties of the elastomer matrix provided herein, namely low polymer content, flexibility, and shape retention under various dry and wet conditions.

[0235] The addition of non-PVOH polymers can be used to further improve one or more of the following: stability under dry and / or wet conditions, biodegradability, rheological properties, bioadhesion, compatibility with active substances, active substance release profile, and active substance imprinting.

[0236] In some embodiments, the composite elastomer matrix is ​​prepared by blending one or more PVOHs with a non-PVOH polymer capable of hydrogen bonding with the PVOHs. 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.

[0237] It is apparent to those skilled in the art that composite materials with one or more PVOHs can be prepared by using either covalent or non-covalent interactions to link two polymers, and by using additional polymers and various types of molecular linkages (e.g., ionic bonds, complexes, etc.). The additional polymer, which is not PVOH, can be selected from a variety of polymers, including naturally occurring polymers, macromolecules, synthetic polymers, etc. For example, but are not limited to, polymers of hydrogen bond-forming monomers that are not PVOHs include polyacrylic acid, polyvinylpyrrolidone, cellulose, chitin, glycogen, starch, gellan, dextran, inulin, pectin, arabinoxylan, and any mixture thereof.

[0238] According to some embodiments of the present invention, the mass content of non-PVOH polymers in the elastomer matrix provided herein is less than the mass content of PVOH combined. In some embodiments, the mass ratio of (one or more) PVOH to non-PVOH polymers is in the range of about 100:1 to 2:1. Several exemplary embodiments of the composite matrix are presented in the Examples section that follows.

[0239] Exemplary medical / ophthalmic devices The present invention further includes embodiments of medical devices (e.g., ophthalmic / eye devices) that can be used for the treatment of pathologies and diseases, the devices comprising or consisting of an elastomer matrix provided herein. In some embodiments, the devices may be used locally, such as in a body cavity. In some embodiments, the devices may be injected into a part or tissue of the body.

[0240] In the context of ophthalmic devices, according to some embodiments of the present invention, the matrix contains or consists of ophthalmologically acceptable components. For example, any component permitted or authorized for ophthalmic use by any regulatory authority may be referred to as an ophthalmologically acceptable component. In some embodiments, all plasticizers are ophthalmic lubricants. In some embodiments, ophthalmic lubricants may be considered pharmaceutically active ingredients, but whenever a pharmaceutical product or ophthalmic device is described in this disclosure and claims as containing both APIs and ophthalmic lubricants, each of the following ophthalmic lubricants shall not be considered an API: PVOH, dextran, gelatin, povidone, hyaluronic acid or a pharmaceutically acceptable salt thereof, glycerol, polyethylene glycol (e.g., PEG 300 or PEG 400), propylene glycol, polysorbate (e.g., polysorbate 70), sodium carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, and hydroxypropylmethylcellulose (HPMC).

[0241] In some embodiments, the elastomer matrices provided herein are non-reactive, stable, and benign, and are therefore particularly useful for sequestering and / or releasing pharmaceutically active ingredients (APIs). In some embodiments, ophthalmic devices comprising the elastomer matrices provided herein are configured for drug delivery for both bolus and sustained-release regimens. Accordingly, according to some embodiments, the matrix contains at least one pharmaceutically active ingredient (API) in or on it. Optionally, the pharmaceutically active ingredient (API) is selected to treat ophthalmic symptoms, diseases, or disorders. Optionally, the pharmaceutically active ingredient (API) is selected to treat oral symptoms, diseases, or disorders (see below).

[0242] In some embodiments, the ophthalmic devices described herein are generally sized and shaped to be positioned on the outer surface of the eye, and positioned beneath one eyelid in such a manner that at least a portion of the ophthalmic device does not contact or interfere with the cornea. In some embodiments, the ophthalmic devices provided herein are configured to deliver at least one pharmaceutically active ingredient (API) to the eye over a long period of time, for example, from 5 minutes to 24 hours (optionally more than 24 hours), on the surface of the eye, at least partially beneath the upper or lower eyelid, and outside the cornea of ​​the eye.

[0243] In some embodiments, the elastomer matrix provided herein features a porous microstructure that allows for the encapsulation of a liquid therein. In some embodiments, the liquid may be, for example, a solution or colloid containing a pharmaceutically active ingredient (API), which can be dispersed in the matrix and / or encapsulated in the pores of the matrix. Thus, in some embodiments, the device includes at least one pharmaceutically active ingredient (API) dispersed, isolated, and impregnated within the elastomer matrix provided herein.

[0244] In some embodiments, the active pharmaceutical ingredient (API) may include, for example, small molecules, polymers, cells, or tissues.

[0245] 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, or soluble in organic solvents, or amphiphilic.

[0246] In some embodiments, the active pharmaceutical ingredient (API) is encapsulated, microencapsulated, in the form of microparticles, or in the form of nanoparticles.

[0247] In the context of the present invention, active pharmaceutical ingredients (APIs) are, but are not limited to, analgesics, antacids, anxiolytics, antiarrhythmics, antibacterial agents, antibiotics, anticoagulants, thrombolytics, anticonvulsants, antidepressants, antiemetics, antifungals, antihistamines, antihypertensives, anti-inflammatory agents, anticancer agents, antipsychotics, antipyretics, antivirals, barbiturates, bronchodilators, beta-blockers, corticosteroids, cold medicines, cytotoxic agents, decongestants, diuretics, expectorants, hormones, hypoglycemic agents, immunosuppressants, laxatives, muscle relaxants, sedatives, sex hormones, hypnotics, tranquilizers, vitamins, and any combination thereof.

[0248] 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, angiogenesis inhibitor, mydriatic, anesthetic, anti-infective, anti-inflammatory, antihistamine, glaucoma treatment, surgical agent, diagnostic agent, or any combination thereof.

[0249] In some embodiments, ophthalmic lubricants may be considered pharmaceutically active ingredients, but whenever a pharmaceutical product or ophthalmic device is described in this disclosure and claims as containing both an API and an ophthalmic lubricant, each of the following ophthalmic lubricants shall not be considered an API: PVOH, dextran, gelatin, povidone, hyaluronic acid or a pharmaceutically acceptable salt thereof, glycerol, polyethylene glycol (e.g., PEG 300 or PEG 400), propylene glycol, polysorbate (e.g., polysorbate 70), sodium carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, and hydroxypropylmethylcellulose (HPMC).

[0250] In some embodiments, the active pharmaceutical ingredient (API) may include, but is not limited to, bimatoprost, travoprost, latanoprost, tafluprost, NSAIDs, steroids, antihistamines, carbonic anhydrase inhibitors (CAIs), dorzolamide, cyclosporine, antibiotics, doxycycline, tetracycline, azithromycin, fatty acids, long-chain fatty acids, fatty alcohols, cetyl alcohol, stearyl alcohol, non-penetrating steroids, free acids of steroids, lipids, ketrolac, silicone oil, olopatadine, prostaglandins, prostaglandin analogs, prostamide, small molecule integrin antagonists, lifiteglast, loteprednol, and fluorometholone, or combinations thereof.

[0251] In some embodiments, the active pharmaceutical ingredient (API) may include a prostaglandin analog. In some embodiments, the prostaglandin analog may include at least one of bimatoprost, latanoprost, travoprost, and tafluprost. In some embodiments, the active pharmaceutical ingredient (API) may be for lowering intraocular pressure. In some embodiments, the active pharmaceutical ingredient (API) may be for treating dry eye. In some embodiments, the active pharmaceutical ingredient (API) may include at least one of cyclosporine, steroids, loteprednol, fluorometholone, non-penetrating steroids, free acids of steroids, nonsteroidal anti-inflammatory agents, ketorolac, small molecule integrin antagonists, lifiteglast, 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 loteprednol or fluorometholone.

[0252] In some embodiments, when preparing an ophthalmic device containing an elastomer matrix according to some embodiments of the present invention, the formulation is prepared according to the preparation procedure shown below. Briefly, a liquid formulation is obtained, which can be used to prepare the final device. A pharmaceutically active ingredient (API) can be mixed with the liquid formulation to yield a matrix and device containing the API. Hydrophilic APIs dissolve readily in the formulation, while hydrophobic APIs can be suspended in the formulation (e.g., as colloids).

[0253] The amount of active pharmaceutical ingredients (APIs) in the matrix varies depending on the API and the treatment regimen. Depending on the properties and requirements of the matrix, up to 30% of the non-aqueous components in the matrix can be APIs (e.g., approximately 5% to 25%, optionally approximately 3% to 27%, or any percentage from 0% to 30%).

[0254] In some embodiments, the device matrix further comprises at least one ophthalmologically acceptable carrier / adjuvant / excipient / non-pharmaceutical.

[0255] In some embodiments, the drug release profile varies depending on the active pharmaceutical ingredient (API) and regimen. Those skilled in the art will understand that there are means and techniques available to control the sustained release of drugs from various devices under various conditions. Examples include encapsulation of the API and the addition of materials that alter the interaction between the active substance and the matrix.

[0256] 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 solution, tear dummy solution, saliva, blood, or any other bodily fluid. When referring to "the presence of a liquid," it should be understood that this refers to conditions in which the matrix of the present invention is partially or completely immersed in a liquid.

[0257] When referring to the "presence of liquid," it should be understood that this refers to conditions under which the matrix of the present invention is partially or completely immersed in a liquid.

[0258] In some embodiments, the active pharmaceutical ingredient (API) is maintained within the elastomer matrix under dry conditions. In some embodiments, the active pharmaceutical ingredient (API) is maintained within the matrix during storage. In some embodiments, the active pharmaceutical ingredient (API) is maintained within the matrix for at least six months under dry conditions.

[0259] Exemplary treatment methods In some embodiments, the elastomer matrix of the present invention can be used for the administration of a pharmaceutically active ingredient (API) to cells, tissues, or membranes. The present invention further provides a method for administering at least one pharmaceutically active ingredient (API) to cells or tissues / membranes, which is achieved by contacting the cells or tissues / membranes with a therapeutically effective amount of the pharmaceutically active ingredient (API) present in the elastomer matrix disclosed herein. In some embodiments, the tissue is selected from eye tissue, cheek tissue, tooth tissue, dentition tissue, muscle tissue, mucous membrane tissue, skin tissue, connective tissue, cardiac tissue, and any combination thereof.

[0260] As used herein, the term "therapeutic dose" refers to the amount of an active pharmaceutical ingredient (API) administered that alleviates to some extent one or more symptoms of the medical condition being treated. Therefore, any amount may be therapeutically effective depending on the medical condition being treated, the efficacy of the API, the patient's physique, etc. In the context of this embodiment, the term "therapeutic dose" refers to the amount of an active pharmaceutical ingredient (API) administered and / or re-administered that alleviates to some extent one or more symptoms of the medical condition being treated. In some embodiments, alleviation is achieved by being at a level harmful to target cells(s) or microorganisms(s), which may disrupt the life cycle of the target cells(s) or microorganisms(s). In some embodiments, alleviation may be achieved by being at a level pharmaceutically effective to induce a therapeutic effect in the patient (e.g., an effective dose of a muscle relaxant, analgesic, and / or antibiotic).

[0261] In the context of embodiments of the present invention, the therapeutically effective dose may refer to the entire active pharmaceutical ingredient (API), or to the amount of one or more active pharmaceutical ingredients (APIs) that are released and / or contained within the matrix. The efficacy of any active pharmaceutical ingredient (API) can be determined by several methodologies known in the art.

[0262] According to another embodiment of the present invention, any one of the matrices described herein is suitable for use in treating a subject diagnosed with a medical condition treatable by at least a pharmaceutically active ingredient (API) that is isolated (or contained within) the matrix and can be controlledly released from the matrix.

[0263] According to another embodiment of the present invention, the use of any of the elastomer matrices described herein as a delivery vehicle used as a drug is provided. In some embodiments, the drug is for treating a subject diagnosed with a medical condition treatable by at least one drug that is isolated (or contained in the matrix) and can be controlledly released from the matrix.

[0264] In any of the methods and uses described herein, the matrix can be used for medical purposes as part of a medical device.

[0265] Exemplary preparation method The present invention further provides a method for preparing an elastomer matrix disclosed herein, the method comprising the following steps: Option 1: Prepare individual solutions, each containing a different type of PVOH. Mix portions of these individual solutions according to the required ratio. Option 2: Dissolve at least two types of PVOH in water to form a solution. Optionally, heat the solution (either option 1 or option 2); Mixing plasticizers (sometimes multiple) into a solution to form a mixture; Optionally, heat the mixture; Add the mixture to the mold; The mixture is solidified in a mold to form the elastomer matrix of the present invention.

[0266] In some embodiments, preparing a PVOH solution may involve preparing individual solutions, each containing a different type of PVOH, and mixing selected amounts of portions of these individual solutions to achieve the required ratio between the different types of PVOH. Preparing each individual solution may involve stirring PVOH with water while heating.

[0267] In some embodiments, a PVOH solution can be prepared by dissolving at least two types of PVOH in water by weight such that the ratio of the two types of PVOH in the solution is as required. Dissolution preferably involves heating and mixing.

[0268] In some embodiments, the mixture contains less than 20 wt% PVOH.

[0269] In some embodiments, the plasticizer accounts for 30 wt% or more of the mixture.

[0270] In some embodiments of the method for preparing the matrix of the present invention, any heating, and the heating applied to prepare the PVOH solution, is carried out to a temperature in the range of 60°C to 100°C.

[0271] In further embodiments of the method, the addition of the mixture to the mold is carried out, for example, at room temperature after cooling the mixture while mixing. In some embodiments of the method, the addition of the mixture to the mold is carried out in an open manner, for example, in an open flask or in the mold. In some embodiments, the elastomer matrix is ​​poured into the mold. In some embodiments, the elastomer matrix is ​​pumped into the mold.

[0272] In some embodiments of the method, preferably, at least one active pharmaceutical ingredient (API) is added to the solution when the solution is at about room temperature so as not to promote the reaction between the active pharmaceutical ingredient (API) and other components in the solution. In some embodiments, this enables the use of heat-sensitive pharmaceutical active ingredients (API). 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 some suitable liquids include water and organic solvents such as glycerol and / or propylene glycol.

[0273] In some embodiments, the API is not heated at any stage of the method, and the elastomeric matrix or ophthalmic device containing it is obtained without heating the API.

[0274] 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 a solvent, for example, for 5 minutes.

[0275] As used herein with respect to an amount or a value, the term "about" means "within ±10%".

[0276] The terms "comprises", "comprising", "includes", "including", "has", "having" and their conjugations mean "including but not limited to".

[0277] The term "consisting of" means "including and limited to this".

[0278] The term "consisting essentially of" means that the composition, method, or structure may include additional components, steps, and / or parts, provided that these additional components, steps, and / or parts do not substantially alter the basic and novel features of the claimed composition, method, or structure.

[0279] As used herein, the expressions “substantially devoid of” and / or “essentially devoid of” in the context of a particular substance mean that the substance is not present at all, or that the substance is present in less than about 5 percent, 1 percent, 0.5 percent, or 0.1 percent of the total weight or total volume of the composition. Alternatively, the expressions “substantially devoid of” and / or “essentially devoid of” in the context of a process, method, property, or feature mean that a particular process / method step, or a process, composition, structure, or article is not present at all of a particular property or feature, or a process / method step in which a particular process / method step is performed at less than about 5 percent, 1 percent, 0.5 percent, or 0.1 percent compared to a given standard process / method, or a property or feature characterized by less than about 5 percent, 1 percent, 0.5 percent, or 0.1 percent of the property or feature compared to a given standard.

[0280] Where applied to the original properties, desired properties, or given properties of an object or composition, the term "substantially maintaining" as used herein means that the properties of the treated object or composition have not changed by more than 20%, 10%, or 5%.

[0281] The term “exemplary” is used herein to mean “serving as an example, illustration, or explanatory role.” Any embodiment described as “exemplary” should not necessarily be construed as being preferable or advantageous to other embodiments, and / or preclude the incorporation of features from other embodiments.

[0282] The terms “optionally” or “alternatively” are used herein to mean “provided in some embodiments and not in other embodiments.” Any particular embodiment of the present invention may include several “optional” features, provided that such features do not contradict each other.

[0283] As used herein, the singular forms "a," "an," and "the" refer to multiple subjects unless the context clearly indicates otherwise. For example, the terms "a compound" or "at least one compound" may refer to multiple compounds, including mixtures thereof.

[0284] Throughout this application, embodiments of the invention may be presented by reference to range form. It should be understood that the use of range form is merely for convenience and brevity and should not be interpreted as an inflexible limitation to the scope of the invention. Therefore, range descriptions should be considered to specifically disclose all possible subranges and individual numerical values ​​within that range. For example, a range description such as "1 to 6" should be considered to specifically disclose subranges such as "1 to 3," "1 to 4," "1 to 5," "2 to 4," "2 to 6," and "3 to 6," as well as individual numerical values ​​within that range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0285] Whenever a numerical range is indicated herein (for example, “10-15” (“10-15”, “from 10”), or any pair of numbers linked by any other such range indication), it is intended to include any numbers (fractional or integer) within the indicated range limit, including the range limit, unless the context clearly indicates otherwise. The expressions “range / ranging / ranges between” and “range from” the first indicator to the second indicator (“to”, “up to”, “until”, or “through”) (or any other such range-indicating terms) are used herein without distinction and are intended to include the first and second indicators and all fractional and integer numbers between them.

[0286] Unless otherwise specified, the numerical values ​​used herein and any numerical ranges derived therefrom are approximations within reasonable measurement and rounding tolerances as understood by those skilled in the art.

[0287] As used herein, the terms “process” and “method” refer to modes, means, techniques and procedures for accomplishing a given task, including, but not limited to, modes, means, techniques and procedures known to practitioners of chemistry, materials, mechanics, computation and digital technology, or readily developed from known modes, means, techniques and procedures.

[0288] For clarity, it is understood that certain features of the Invention described in the context of separate embodiments may also be presented in combination in a single embodiment. Conversely, various features of the Invention described in the context of a single embodiment for brevity may be presented separately, in any suitable partial combination, or appropriately in any other described embodiment of the Invention. Certain features described in the context of various embodiments are not considered essential features of those embodiments unless the embodiments would not function without those elements.

[0289] The various embodiments and aspects of the invention, which are precisely outlined above and claimed in the appended claims sections, are experimentally supported in the following examples.

Example

[0290] Here, along with the above description, refer to the following examples that non - restrictively illustrate some embodiments of the invention.

[0291] Representative elastomer matrix

[0292] Example 1 Preparation of elastomer matrix The preparation of the elastomer matrix according to an embodiment of the invention can start from the preparation of a PVOH solution.

[0293] Briefly stated, 420 ml of purified water was added to a 500 ml round - bottom flask equipped with an overhead stirrer. The flask was placed in a heating mantle, and 80 grams of PVOH was added little by little while stirring and heated until all the PVOH was dissolved. Optionally, the PVOH contained at least two types of PVOH in the required mass ratio between them. See Table 7 for exemplary mass ratios between exemplary different types of PVOH.

[0294] The PVOH solution was further stirred and heated for 1 to 2 hours, and then the solution was cooled to room temperature while stirring.

[0295] A plasticizer and 80 grams of the PVOH solution were added to a 500 ml glass beaker to obtain a mixture according to Table 3 (on a dry - matter basis). Optionally, purified water was added to dilute the concentration of the solute. The mixture was heated while stirring magnetically until completely dissolved, then the heating was stopped and the mixture was left to cool.

[0296] Table 3 shows several exemplary formulations for preparing the exemplary elastomer matrices provided herein. The values ​​represent the mass content as a percentage of the total weight of the non-aqueous component.

[0297] [Table 3]

[0298] Example 2 comparative study To study the importance of the mass ratio between PVOH and plasticizer, 20 grams of PVOH were mixed with 36 grams of glycerol in a 500 ml glass beaker, and water was added to obtain a 20 wt% PVOH solution. Note that, in this specification, this formulation for producing the matrix is ​​characterized by a mass content ratio of 36:20, i.e., 1:1.8, of plasticizer to PVOH, and is outside the scope of the present invention. The mixture was heated until completely dissolved. Heating was stopped, and the solution was allowed to stand and cool.

[0299] The resulting elastomer matrix exhibits inferior stability under both dry and wet conditions compared to a comparative matrix with a plasticizer-to-PVOH mass content ratio of 2:1.

[0300] Another comparative example was prepared using 35 wt% high molecular weight PVOH, 11 wt% polyethylene glycol, 27 wt% glycerol, and 27 wt% propylene glycol, following the procedure described above.

[0301] This formulation exhibited a swelling of over 20% in water, producing a substance that did not retain its shape under dry conditions.

[0302] Example 3 Device preparation Each solution of the various formulations specified in Table 5 was poured into the respective molds (open or closed) and left to dry. Optionally, a film of the desired thickness was prepared using a coating machine. The film was then left to dry.

[0303] Example 4 Composite elastomer matrix To prepare composite elastomer matrices according to several embodiments of the present invention, formulations were prepared according to Table 3, and 10 grams of the formulation were mixed with a non-PVOH polymer to achieve the ratio of polyvinyl alcohol to non-PVOH polymer according to Table 4 below. The mixture was stirred until completely dissolved and further processed to produce a device (e.g., a film).

[0304] [Table 4]

[0305] Example 5 Preparation of elastomer matrix Preparation of the elastomer matrix according to embodiments of the present invention may begin with the preparation of a PVOH solution containing two types of PVOH. Optionally, two (or more) types of PVOH are combined and mixed with water as described below. Alternatively, two separate mixtures of PVOH are prepared and then mixed together according to the required ratio between the two types of PVOH and the PVOH concentration in the mixture. Alternatively, one type of PVOH is prepared as a solution, and the other is added as is, for example, together with a plasticizer.

[0306] In short, 420 ml of purified water was added to a 500 ml round-bottom flask equipped with an overhead stirrer. The flask was placed on a heating mantle, and 80 grams of PVOH (for example, 40 grams of the first type of PVOH and 40 grams of the second type of PVOH) were added in small amounts while stirring and heating until all the PVOH was dissolved.

[0307] The PVOH solution was stirred and heated for a further 1 to 2 hours, and then cooled to room temperature while stirring.

[0308] The plasticizer and 80 grams of PVOH solution were added to a 500 ml glass beaker to obtain the mixture according to Table 5 (dry matter basis). Optionally, purified water was added to dilute the solute concentration. The mixture was heated with magnetic stirring until completely dissolved, then the heating was stopped and the mixture was allowed to cool.

[0309] Table 5 shows several exemplary formulations for preparing exemplary elastomer matrices provided herein. The values ​​in rows 1, 7, 8, and 9 represent the mass content (percent) of the non-aqueous components relative to the total weight. In Table 1, the total amount of PVOH is shown in row 1. This amount can be divided into at least two types of PVOH, as shown in rows 2 through 6, for example, showing the percentage of each type of PVOH relative to the total amount of PVOH shown in row 1. In some embodiments, one type may be a long-chain highly hydrolyzable PVOH and the other type may be a short-chain partially hydrolyzable PVOH. The ratio between them may be, for example, 25% to 75% long-chain complete hydrolysis and the remainder short-chain partial hydrolysis. The inventors were surprised to find that while short-chain partial hydrolysis PVOH alone yields a very low-quality matrix (for example, when immersed in water, such a matrix swells anisotropically, and its volume can increase by more than 100%), replacing just one-quarter of the short-chain partial hydrolysis PVOH with long-chain complete hydrolysis PVOH was sufficient to provide a satisfactory matrix.

[0310] There are many types of commercially available PVOH, and in the following examples, with the exception of Sigma Aldrich's 8.21039, which is a PVOH for synthesis, we used PVOH from Merck's Emprove® product line. The average molecular weight, chain length, and degree of hydrolysis of the products used are shown in Table 1 above.

[0311] LCFH1 and LCFH2 are two different types of long-chain completely hydrolyzed PVOH taken from the table above. Similarly, SCPH1 and SCPH2 are two different types of short-chain partially hydrolyzed PVOH taken from the table above.

[0312] [Table 5]

[0313] Example 6 Device preparation Each solution of the various formulations specified in Table 5 or Table 7 was poured into the respective pouring molds (open or closed) and allowed to dry. Optionally, a film of the desired thickness was prepared using a coating machine. The film was allowed to dry.

[0314] Example 7 Mechanical properties Compression modulus The compressive modulus of an elastomer (or any other sample) is the slope of the elastic portion of the stress-strain graph measured when the elastomer is compressed. The following table shows the compressive moduli of several elastomer matrices according to several embodiments of the present invention as a function of composition and immersion time in STF (simulated tears). 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 further from the first six in the total amount of PVOH and the variety of plasticizers.

[0315] [Table B]

[0316] As seen in the table above, the compressive modulus decreases in all matrices during immersion in STF. When a portion of LCFH PVOH is replaced with SCPH PVOH at any given time, matrices of different compositions differ from one another in their compressive modulus, with matrices containing more SCPH PVOH having a lower compressive modulus. When different portions of LCFH PVOH are replaced with SCPH PVOH, there is no clear trend in the differences in the compressive moduli of matrices at any given time, and the differences between them are within the estimation error (i.e., the differences are not significant).

[0317] In some embodiments, the change in compressive modulus is an indicator of matrix decomposition. Therefore, the results summarized in the table above for matrices in which some LCFH PVOH is replaced with SCPH PVOH show that different amounts of the two types of PVOH determine the decomposition rate of these matrices.

[0318] The table above also shows that compressive modulus is not a suitable measure of the decomposition of the other matrices in the table. As shown in the following table, in these embodiments, compressive strength is a suitable mechanical property to indicate the decomposition of the matrices.

[0319] Compressive strength Compressive strength is the pressure at which a sample breaks. In a stress-strain graph, it appears as a sharp drop in the graph. The table below shows the compressive strength results extracted from the same graph from which the compressive modulus values ​​shown in the table above were extracted. Measurements were performed using a 10N probe. If no sharp drop is observed in the graph, the table is labeled "Max Load," which means that a 10N load is not sufficient to break the matrix by compression.

[0320] [Table C]

[0321] As shown in the table, of all the compositions tested, only those in which some of the LCFH PVOH was replaced with SCFH PVOH fractured under a 10N load. In the fractured matrix, the higher the amount of LCFH PVOH, the longer the matrix should remain in the STF to fracture.

[0322] In some embodiments, changes in compressive strength are an indicator of matrix decomposition. Therefore, the results summarized in the table above for matrices in which some LCFH PVOH is replaced with SCFH PVOH indicate that different amounts of the two types of PVOH determine the decomposition rate of these matrices.

[0323] The table above also shows that the change in compressive strength (measured at least under a 10N load) is not a suitable measure of the decomposition of the other matrices in the table. As shown in the previous table, in these embodiments, the compressive modulus is a suitable mechanical property to indicate the decomposition of the matrices.

[0324] swelling The swelling of four matrices according to embodiments of the present invention, having formulations such as the first four formulations shown in the preceding table, was measured by measuring the thickness (i.e., height) and diameter of the disc-shaped matrices before immersion in STF and after different immersion periods. The matrices were imaged, and the images were processed to estimate the thickness and diameter. The results detailed in the table below show that all matrices swelled by 50% ± 5% or less after immersion in STF for 15 minutes (or less).

[0325] [Table D]

[0326] In some embodiments, the maximum swelling rates observed in the matrix were 21% at 2 minutes, 40% at 5 minutes, 52% at 10 minutes, 55% at 15 minutes, and 75% at 30 minutes. All figures are within ±5%.

[0327] Simulated tears (STF) The artificial tear solution (STF) has the following composition: 1 liter of purified water, 6.76 grams of NaCl, 2.05 grams of sodium bicarbonate, 0.08 grams of calcium chloride dihydrate, and 1.7 mL of 10% acetic acid.

[0328] Example 8 clinical results Each participant received an ophthalmic device containing equal amounts of long-chain fully hydrolyzed PVOH and short-chain partially hydrolyzed PVOH, without any active pharmaceutical ingredients (APIs) other than ophthalmic lubricants (PVOH, glycerol, propylene glycol, and PEG 400), for 3 to 6 hours. The participants were 29 healthy individuals (18 to 60 years old). Participants reported that the device was barely perceptible, likely due to the degradable properties of the matrix, which allowed the device to conform to the anatomical structure of the wearer's individual eye. The device remained in the eye, distance visual acuity was not impaired, and slit-lamp biomicroscopy, including fluorescein corneal staining, performed after removal of the device from the eye, showed no significant difference compared to the same examination performed before administration.

[0329] Upon removal from the eye, the device was softer than before insertion. Some of the device was removed from the eye as fragments. These fragments were dried and weighed after removal. Their weight was found to be approximately 70% lower than the weight of the device before insertion into the eye.

[0330] Dry eye disease Human first dose Approximately 40 healthy subjects experienced using the ophthalmic device according to the present invention for 6 hours. All reported that the device was easy to use and almost imperceptible, likely due to the decomposition properties of the matrix, which allowed the device to conform to the anatomical structure of the wearer's individual eye. No serious adverse events were observed during the trial. A small number of participants experienced mild discomfort or tearing in the first few minutes after application of the device, but this resolved spontaneously later (within 15 minutes).

[0331] According to the Visual Analog Scale (VAS) questionnaire, device wear over time was barely noticeable, and no discomfort was reported at the end of treatment before device removal. The device was found to be safe to use.

[0332] During treatment, there were reports of improved moisture in the treated eye, improved sensation (eyelids gliding more easily), eye laxity, and improved or clearer vision, possibly related to stabilization of the tear film. Some subjects who reported some degree of dryness in the eye at baseline experienced improvement in dryness symptoms. Some subjects applied the device independently, while most subjects removed the device easily on their own.

[0333] Upon removal from the eye, the device was softer than before insertion. Some of the device was removed from the eye as fragments. These fragments were dried and weighed after removal. Their weight was found to be approximately 70% lower than the weight of the device before insertion into the eye.

[0334] 5-day exam Ten patients with mild to moderate dry eye disease participated in a clinical trial in which each patient had an ophthalmic device comprising one embodiment of the present invention, consisting essentially of water, PVOH, and a plasticizer, inserted under the lower eyelids of both eyes once daily for five consecutive days.

[0335] All participants were trained to apply the device themselves. All participants reported that the device was easy to use and barely noticeable, likely due to the matrix's decomposition properties, which allowed the device to conform to the individual anatomical structure of the wearer's eye. No serious adverse events were observed during the trial. A small number of participants experienced mild discomfort or tearing in the first few minutes after applying the device, but this resolved spontaneously within 15 minutes of application. No serious adverse events were observed throughout the 5-day trial. According to the Visual Analog Scale (VAS) questionnaire, device wear over time was barely noticeable for at least 15 minutes from the start of each day's treatment until removal. The device was found to be safe to use.

[0336] Upon removal from the eye, the device was softer than before insertion. Some of the device was removed from the eye as fragments. These fragments were dried and weighed after removal. Their weight was found to be approximately 70% lower than the weight of the device before insertion into the eye.

[0337] presbyopia 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 according to one embodiment of the present invention containing 200 mcg of pilocarpine under the eyelid of one eye, the mean pupil diameter decreased compared to the untreated eye, and the mean minimum pupil diameter of the treated eye was observed 1 hour after insertion. The mean pupil diameter of the treated eye increased over time up to 8 hours after insertion. At 2 hours after insertion, monocular near visual acuity, measured using a Jaeger chart, decreased to J1 in all subjects except one who was J1+. BCDVA remained at 6 / 6 throughout the study.

[0338] All participants reported that the device was easy to use and barely perceptible, likely due to the matrix's decomposition properties, which allowed the device to conform to the individual anatomical structure of the wearer's eye. 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 barely perceptible. IOP remained within the normal range throughout the study. No clinically significant changes were observed between baseline and the endpoint on slit-lamp biomicroscopy.

[0339] While the present invention has been described with regard to its specific embodiments, many alternative, modified, and altered forms will be apparent to those skilled in the art. Therefore, it is intended to encompass all such alternative, modified, and altered forms that fall within the spirit and broad scope of the appended claims.

[0340] All publications, patents, and patent applications referenced herein constitute part of this specification by reference, as is specifically and individually indicated by each individual publication, patent, or patent application. Furthermore, any reference or specification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. Section headings, to the extent used, should not necessarily be construed as limitations. In addition, any(s) priority documents of this application constitute part of this specification by reference.

Claims

1. It is an elastomer matrix, a. Poly(vinyl alcohol) (PVOH) and b. One or more organic plasticizers, wherein the ratio of the total mass of the one or more organic plasticizers to the PVOH is at least 2:1, c. Water and, Includes, An elastomer matrix comprising at least two types of PVOH that differ from each other in terms of degree of hydrolysis (HD) and / or chain length.

2. The elastomer matrix according to claim 1, wherein the PVOH comprises at least two types of PVOH having different degrees of hydrolysis (HD).

3. The elastomer matrix according to claim 1 or 2, wherein the difference in chain length of the two types of PVOH is at least 1,000, and they have similar degrees of hydrolysis, with each degree of hydrolysis being 97% to 100%.

4. The elastomer matrix according to any one of claims 1 to 3, wherein the first of the at least two types has a degree of hydrolysis of 97% to 100%.

5. The elastomer matrix according to any one of claims 1 to 4, wherein the second of the at least two types has a degree of hydrolysis of less than 93%.

6. The elastomer matrix according to any one of claims 1 to 5, wherein the second of the at least two types has a degree of hydrolysis of 80% to 93%.

7. The elastomer matrix according to any one of claims 1 to 6, wherein the first of the at least two types has a chain length of more than 2,500 units.

8. The elastomer matrix according to any one of claims 1 to 7, wherein the second of the at least two types has a chain length of less than 1,500 units.

9. The elastomer matrix according to any one of claims 1 to 8, wherein the relationship between the first type of PVOH and the second type of PVOH among the at least two types is about 3:1 to about 1:

3.

10. The elastomer matrix according to any one of claims 1 to 9, wherein the first of the at least two types has a chain length of more than 2,500 units and a degree of hydrolysis of 97% to 100%, and the second of the at least two types has a chain length of less than 1,000 units and a degree of hydrolysis of 80% to 93%.

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

12. The elastomer matrix according to any one of claims 1 to 11, wherein the at least two types of PVOH determine the time required for the decomposition of the elastomer matrix.

13. The elastomer matrix according to claim 12, wherein the decomposition includes a change in mechanical properties under wet conditions.

14. The elastomer matrix according to claim 12, wherein the decomposition includes a change in shape under wet conditions.

15. The elastomer matrix according to any one of claims 1 to 14, wherein the at least two types of PVOH determine the temporal change in the mechanical properties of the elastomer matrix under wet conditions.

16. The elastomer matrix according to any one of claims 1 to 15, wherein the total mass content of the PVOH and the one or more organic plasticizers is at least 70 wt% of the total weight of the matrix excluding water.

17. The elastomer matrix according to any one of claims 1 to 16, wherein the elastomer matrix is ​​used as an ophthalmic device.

18. The elastomer matrix according to any one of claims 1 to 17, wherein the ratio of the total mass of one or more organic plasticizers to the PVOH is less than 20:

1.

19. An elastomer matrix according to any one of claims 1 to 18, characterized by substantially isotropic swelling and shrinkage.

20. The elastomer matrix according to any one of claims 1 to 19, wherein the elastomer matrix swells by less than 50% by volume under wet conditions.

21. The elastomer matrix according to any one of claims 1 to 20, wherein the one or more organic plasticizers are independently selected from the group consisting of polyols, polybasic organic acids, polyamines, alkyl gluceths, aliphatic polyalkylene glycols, ethanolamines, sugars, oligosaccharides, amino acids, polyphenols, tromethamine, urea, tannic acid, and any salts and / or combinations thereof.

22. The elastomer matrix according to claim 21, wherein the polyol is selected from the group consisting of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, propylene glycol, triacetin erythritol, polyglycol, poloxamer, and copolymers thereof, as well as glycerol and its esters.

23. The elastomer matrix according to claim 21, wherein the polybasic organic acid is selected from the group consisting of oxalic acid, maleic acid, citric acid, and any salts thereof.

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

25. The elastomer matrix according to claim 21, wherein the aliphatic polyalkylene glycol is selected from the group consisting of polyethylene glycol, polypropylene glycol, polyglycol, poloxamer, and polysorbate.

26. The elastomer matrix according to claim 21, wherein the aliphatic polyalkylene glycol is polyethylene glycol.

27. The elastomer matrix according to any one of claims 24 to 25, wherein the mass content of the PVOH is substantially equal to the mass content of the aliphatic polyalkylene glycol.

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

29. The elastomer matrix according to any one of claims 1 to 28, wherein the water accounts for less than 50 wt% of the total mass content of the matrix.

30. The elastomer matrix according to any one of claims 1 to 29, wherein the mass content of the PVOH is less than 25 wt% of the total weight of the non-aqueous components of the matrix.

31. The elastomer matrix according to any one of claims 1 to 30, wherein the mass content of the PVOH is less than one-third of the total weight of the one or more organic plasticizers.

32. An elastomer matrix according to any one of claims 1 to 31, which essentially does not contain covalent crosslinks.

33. An elastomer matrix according to any one of claims 1 to 32, further comprising a pharmaceutically active substance.

34. An ophthalmic device comprising the elastomer matrix described in claim 1.

35. The ophthalmic device according to claim 34, wherein the elastomer matrix consists of ophthalmologically acceptable components.

36. The ophthalmic device according to claim 34 or 35, wherein the device weighs 1 mg to 50 mg or 1 mg to 30 mg.

37. The ophthalmic device according to any one of claims 34 to 36, wherein the elastomer matrix contains a pharmaceutically active substance.

38. The ophthalmic device according to any one of claims 34 to 37, wherein the ophthalmic device is configured to be placed on the surface of the eye.

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

40. The ophthalmic device according to any one of claims 34 to 39, wherein the ophthalmic device is configured to deliver at least one pharmaceutically active substance to the eye over a long period of time from 5 minutes to 24 hours.

41. A medical device comprising two elastomer matrices according to claim 1, wherein the two matrices are a. The ratio between the mass content of PVOH contained in the matrix and the mass content of the matrix, b. The ratio between the mass content of PVOH contained in the matrix and the total mass content of one or more plasticizers, c. Types of PVOH, and d. Mass ratio between types of PVOH, A medical device that differs from each other in one or more respects.

42. The medical device according to claim 41, wherein the two matrices are in contact via a contact surface.

43. The medical device according to claim 42, wherein the contact surface is a closed surface.

44. The medical device according to any one of claims 41 to 43, wherein the two matrices decompose at different rates under wet conditions.

45. The medical device according to any one of claims 41 to 44, wherein the two matrices exhibit different mechanical properties under dry conditions.

46. It is an elastomer matrix, a. Poly(vinyl alcohol) (PVOH) and b. One or more organic plasticizers, wherein the ratio of the total mass of the one or more organic plasticizers to the PVOH is at least 2:1, c. Water and, Includes, The PVOH comprises only PVOH with a chain length of less than 2,000 units or less than 1,000 units and a degree of hydrolysis of less than 90%. An elastomer matrix in which the water constitutes less than 10% or less than 5% of the matrix.

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