Dissolvable polymeric ocular inserts and methods of use thereof

Abstract

Polymeric ocular inserts are provided that can be dissolvable when placed in the fornix of the eye. These inserts can comprise one or more polymers and a softening agent / plasticizer such that when inserted into the eye, the polymers and softening agent / plasticizer can absorb tears, dissolve, and slowly release a lubricant into the tear film to lubricate and protect the ocular surface for a prolonged duration. Increasing the residence time on the ocular surface to achieve more sustained relief can decrease the frequency of dosing and the patient burden typically associated with topical drop usage. These polymeric ocular inserts can also comprise one or more pharmaceutically active agents.

Description

[0001] This invention patent application is a divisional application of the invention patent application filed on May 1, 2020, with application number 202080032297.3 and invention title "Soluble Polymer Eye Insert and Method of Using Thereof".

[0002] The invention described herein was accomplished under a joint research agreement between Novartis Pharma AG and Alcon Inc. Technical Field

[0003] This disclosure generally relates to polymeric eye insert technology, and more specifically to soluble polymeric eye inserts that release lubricants and drugs into the eye (including, but not limited to, the anterior and posterior segments) over a longer period of time compared to topical drop formulations. Background Technology

[0004] Many ophthalmic formulations include compounds that provide lubrication and other desired properties. When these formulations are instilled into the eye, the properties of these compounds can prevent undesirable problems such as tissue damage caused by bioadhesion and friction, and can promote the natural healing and recovery of previously damaged tissue.

[0005] Adherence to topical ophthalmic formulations (such as liquids, ointments, gels, and sprays) is often poor, especially for the treatment of dry eyes, allergies, infections, and slowly progressive diseases (such as glaucoma), which require multiple daily applications to lubricate and deliver medication to the eye. Contact-applied aqueous formulations are typically characterized by their short retention time on the ocular surface, which may be less than 25 minutes after instillation. (Paugh et al., Optom Vis Sci., August 2008; 85(8):725-31). Typical ophthalmic aqueous formulations can be diluted or rinsed off the ocular surface within minutes, causing variations in usage or reducing the accuracy and precision of the dosage delivered to the eye. Therefore, there is a need to reduce the burden of treatment and improve adherence.

[0006] Ointments and gels, with their high viscosity and longer residence time in the eye compared to liquids, can provide more accurate application. However, they can interfere with the patient's vision and may require at least 2-3 applications per day. Discontinuation rates can be high due to these and other reasons. (Swanson M., *Journal of the American Optometrist Association*, 2011; 10:649-6.)

[0007] Inserts (both bio-erosive and non-bio-erosive) are also available and allow for less frequent application. (Pescina S et al., *Drug Dev Ind Pharm*, May 2017, 7:1-8; Karthikeyan MB et al., *Asian J. Pharmacol*, Oct–December 2008, 192-200). However, these inserts require complex and detailed preparation and may cause patient discomfort. An additional problem with non-bio-erosive inserts is that they must be removed after use. However, with proper use and adequate patient education, inserts can be an effective and safe treatment option for patients with dry eye.

[0008] Hydroxypropyl cellulose (HPC) ophthalmic inserts, such as LACRISERT® (Aton Pharmaceuticals Inc.), have been used in patients with dry eye. These inserts are translucent cellulose-based rods with a measured diameter of 1.27 mm and a length of 3.5 mm. Each insert contains 5 mg of hydroxypropyl cellulose and is free of preservatives or other ingredients. The medication is administered by placing a single insert under the lower fornix of the eye, below the base of the tarsal plate. These inserts are particularly suitable for patients who still have dry eye symptoms after a full trial of artificial tears. They are also suitable for patients with dry keratoconjunctivitis, exposure keratitis, decreased corneal sensitivity, and recurrent corneal erosion. Several studies have been conducted to evaluate the efficacy of HPC ophthalmic inserts. (Luchs J et al., Cornea, 2010, 29:1417-1427; Koffler B et al., Eye Contact Lenses) Lens, 2010, 36:170-176; McDonald M et al., Trans Am Ophthalmol. Soc., 2009, 107:214-221; Wander A and Koffler B., Oculus Surf., July 2009, 7(3):154-62.

[0009] However, using these types of inserts also presents challenges. For example, LACRISERT® inserts tend to dissolve slowly and may remain in the eye even after 15-20 hours. Due to their rod-like design, they are rigid and inflexible with edges. This slow dissolution characteristic, combined with the rod's rigidity and design, can lead to side effects, including blurred vision, foreign body sensation and / or discomfort, eye irritation or redness, hypersensitivity, photophobia, eyelid edema, and clumping or dryness of the adhesive material on the eyelashes. The most common side effect of these hydroxypropyl cellulose ophthalmic inserts is blurred vision due to prolonged retention of the insert. Therefore, additional approaches are needed to develop polymeric ophthalmic inserts that are comfortable and improve patient compliance. Summary of the Invention

[0010] This invention provides a polymeric eye insert comprising: one or more mucosal adhesive polymers biocompatible with the ocular surface and tear film of the eye; and wherein, after the polymeric eye insert is inserted into the fornix of the eye, an increase in the thickness of the tear film persists for at least 30 minutes following insertion. This invention also provides a method for treating an eye disease, the method comprising applying the polymeric eye insert according to embodiments of this disclosure to the fornix of the eye.

[0011] This invention is based in part on the discovery that commercially available ophthalmic inserts, such as LACRISERT® inserts, often dissolve slowly and remain in the eye even after 15-20 hours. This problem can be solved by using a polymeric ophthalmic insert according to embodiments of this disclosure, which is small enough to fit the fornix of the eye and is rapidly wetted, resulting in little or no irritation upon insertion, and is also large enough to allow dissolution within any timeframe of approximately 30-120 minutes to allow for the release of the lubricant and / or pharmaceutical active agent(s). The insert also has a thickness that is relatively comfortable for the user. A preferred thickness is between 50-250 micrometers, with a most preferred thickness between 70-150 micrometers. A target thickness of 90 micrometers is desired for the membrane to dissolve in less than 2 hours. Attached Figure Description

[0012] To provide a more complete understanding of this disclosure, reference is now made to the following description taken in conjunction with the accompanying drawings, in which:

[0013] Figure 1 The placement of a polymer eye insert according to an embodiment of this disclosure is depicted;

[0014] Figure 2A to Figure 2C The results for SYSTANE® ULTRA eye drops were described before administration (Figure 2A), immediately after administration (Figure 2B), and 5 minutes after administration (Figure 2C). Figure 2C Tear film measurements;

[0015] Figures 3A to 3C depict tear film measurements for GENTEAL® gel drops before administration (Figure 3A), immediately after administration (Figure 3B), and 5 minutes after administration (Figure 3C).

[0016] Figures 4A to 4E The description of PROVISC® injection before administration ( Figure 4A Immediately after administration ( Figure 4B ), 5 minutes after administration ( Figure 4C ), 10 minutes after administration ( Figure 4D ) and 20 minutes after administration ( Figure 4E Tear film measurements;

[0017] Figures 5A to 5I illustrate tear film measurements associated with insertion of a polymer eye insert according to an embodiment of this disclosure;

[0018] Figure 6A This reflects the average tear film measurement using the polymer eye insert according to embodiments of this disclosure;

[0019] Figure 6B This reflects tear film measurements in individual animals according to embodiments of this disclosure;

[0020] Figure 6C This reflects tear film measurements based on intraocular locations (including the base and top of the eye) and temporal and nasal measurements according to embodiments of this disclosure;

[0021] Figure 7A This reflects the dynamic change in tear film thickness relative to the polymer eye insert according to embodiments of this disclosure;

[0022] Figure 7B Tear film measurements reflecting the position (apex, nose, temple, top, and bottom) of the polymer eye insert according to embodiments of this disclosure;

[0023] Figure 8 This reflects the average GENTEAL® gel tear film measurement in the right and left eyes;

[0024] Figure 9 This reflects tear film thickness data based on time elapsed after drug administration; and

[0025] Figures 10A to 10C The illustrations depict the shapes and features of various polymer eye inserts according to embodiments of this disclosure.

[0026] Figure 11 The illustration shows the results of the main outcome measures (comfort assessment) for two embodiments (thick insert and thin insert) according to the present disclosure.

[0027] Figure 12 The illustration shows the results of a secondary outcome measure (visual blur) for two embodiments (thick insert and thin insert) according to the present disclosure.

[0028] Figure 13 The illustration shows the results of an evaluation of the dissolution of the polymer eye insert according to an embodiment of this disclosure;

[0029] Figure 14 The illustration shows the results of the minor outcome measure (NITBUT) for two embodiments (thick insert and thin insert) according to this disclosure;

[0030] Figure 15 The illustration shows the results of a secondary outcome measure (tear river height) according to two embodiments (thick insert and thin insert) of this disclosure;

[0031] Figure 16 The illustration shows the results of eye irritation problems according to two embodiments (thick insert and thin insert) of this disclosure;

[0032] Figure 17 The illustration shows the results of eye dryness problems according to two embodiments (thick insert and thin insert) of this disclosure;

[0033] Figure 18 The illustration shows the results of eye burning / tingling problems according to two embodiments (thick insert and thin insert) based on this disclosure;

[0034] Figure 19 The illustration shows the results of eye itching problems according to two embodiments (thick insert and thin insert) of this disclosure; Detailed Implementation

[0035] This application relates to the following aspects:

[0036] Item 1. A polymer eye insert, said insert comprising:

[0037] One or more biocompatible mucosal adhesive polymers for the ocular surface and tear film of the eye; and wherein, after the polymer eye insert is inserted into the fornix of the eye, the increase in the thickness of the tear film persists for at least 30 minutes after insertion.

[0038] Item 2. The polymeric eye insert as described in Item 1, wherein the one or more mucosal adhesive polymers are selected from the group consisting of: hyaluronic acid or a salt thereof, hydroxypropyl methylcellulose (HPMC), methylcellulose, tamarind seed polysaccharide (TSP), guar gum, hydroxypropyl guar gum (HP guar gum), stearin poloxamer, poly(galacturonic acid), sodium alginate, pectin, xanthan gum, xylo-glucan gum, chitosan, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carbomer, polyacrylic acid and / or combinations thereof.

[0039] Item 3. The polymeric eye insert as described in Item 1, wherein the one or more mucosal adhesive polymers are HP guar gum, hyaluronic acid, or sodium hyaluronate.

[0040] Item 4. The polymeric eye insert as described in Item 3, wherein the one or more mucosal adhesive polymers are present in an amount of about 50% to about 99% w / w, about 60% to about 95% w / w, about 70% to about 90% w / w, or about 80% to about 90% w / w of the polymeric eye insert.

[0041] Item 5. The polymer eye insert as described in Item 3 or 4, further comprising a plasticizer or softener.

[0042] Item 6. The polymer eye insert as described in Item 5, wherein the plasticizer or softener is selected from the group consisting of:

[0043] Polyethylene glycol (PEG), PEG derivatives, water, vitamin E, and triethyl citrate.

[0044] Item 7. The polymer eye insert as described in Item 5 or Item 6, wherein the plasticizer or softener is present in an amount of about 2% to about 30% w / w, about 5% to about 25% w / w, about 5% to about 20% w / w, or about 5% to about 15% w / w of the polymer eye insert.

[0045] Item 8. A polymeric eye insert as described in Item 6 or 7, wherein the plasticizer or softener is PEG.

[0046] Item 9. A polymeric eye insert as described in any of the preceding items, wherein the insert comprises approximately 40% HP guar gum, approximately 10% PVP, approximately 40% sodium hyaluronate, and approximately 10% PEG.

[0047] Item 10. The polymer eye insert as described in Item 1, further comprising 1-20

[0048] Item 11. The polymeric eye insert as described in Item 8, further comprising 20-100 ppm menthol.

[0049] Item 12. The polymer eye insert as described in Item 1, wherein the insert does not include additional pharmaceutically active agents.

[0050] Item 13. The polymeric ophthalmic insert as described in Item 1, wherein the insert comprises one or more pharmaceutically active agents.

[0051] Item 14. The polymeric ophthalmic insert as described in Item 11, wherein the one or more pharmaceutically active agents are selected from the group consisting of:

[0052] Atropine derivatives that are not nitric oxide donors, travoprost complex drugs containing nitric oxide, lubricants, steroids, antibiotics, nonsteroidal anti-inflammatory drugs, antihistamines, antiviral drugs, antibacterial drugs, vasoconstrictors, and prostaglandin analogs.

[0053] Item 15. The polymer eye insert as described in Item 1, wherein the thickness of the tear film does not return to its pre-insertion thickness until approximately two hours after insertion.

[0054] Item 16. The polymer eye insert as described in Item 1, wherein, after insertion into the fornix of the eye, the thickness of the tear film increases for at least two hours after insertion.

[0055] Item 17. A polymer eye insert as described in Item 1, wherein the insert is in the shape of a membrane, rod, sphere, ring, or irregular shape having a maximum size of 5-6 mm in any single dimension.

[0056] Item 18. The polymer eye insert as described in Item 17, wherein the insert has a circular shape, a diameter of about 5 mm, a thickness of 50-400 µm, and a water content of 1% to 50% w / w.

[0057] Item 19. A polymeric eye insert as described in Item 18, wherein the insert has a thickness of about 150-250 µm and a water content of 30% to 50% w / w.

[0058] Item 20. The polymer eye insert as described in Item 3, wherein the HP guar gum has a weight-average molecular weight of 2 to 4 million Daltons, and the sodium hyaluronate has a weight-average molecular weight of 0.1 to 2 million Daltons.

[0059] Item 21. A method for treating an eye disease, the method comprising applying a polymeric eye insert as described in any one of items 1 to 20 to the fornix of the eye.

[0060] Item 22. As described in Item 21, wherein,

[0061] The eye diseases mentioned consist of dry eye, red eyes, myopia, glaucoma, allergies, and inflammation.

[0062] This disclosure provides a polymeric eye insert comprising an ocular lubricant comprising one or more polymers. In embodiments of this disclosure, the polymeric eye insert may consist of hyaluronic acid, hydroxypropyl guar gum (HP guar gum), and plasticizers such as polyethylene glycol (PEG); however, as described herein, other polymers and plasticizers / softeners may be used without departing from this disclosure. The insert according to embodiments of this disclosure can be inserted into the lower eyelid (also known as the fornix) of the eye, and upon insertion, the insert can rapidly absorb and dissolve tears to release the ocular lubricant into the tear film for prolonged lubrication and protection of the ocular surface compared to previously known topical ocular compositions. According to embodiments of this disclosure, pharmaceutically active agents may also be incorporated into the polymeric eye insert. Insertion of the polymeric eye insert according to embodiments of this disclosure can alleviate dry eye symptoms and other eye conditions in patients.

[0063] Biomaterials used to form polymeric eye inserts according to embodiments of this disclosure may consist of one or more polymers biocompatible with the ocular surface and tear film. Polymers that may be used in polymeric eye inserts according to embodiments of this disclosure include, but are not limited to, hyaluronic acid (in acid or salt form), hydroxypropyl methylcellulose (HPMC), methylcellulose, tamarind seed polysaccharide (TSP), galactomannan; guar gum and its derivatives, such as hydroxypropyl guar gum (HP guar gum), stearin poloxamer, poly(galacturonic acid), sodium alginate, pectin, xanthan gum, xylo-glucan gum, chitosan, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, carbomer, polyacrylic acid, and / or combinations thereof.

[0064] Preferred biocompatible polymers are hyaluronic acid, guar gum and its derivatives, and / or combinations thereof. Hyaluronic acid is an unsulfated glycosaminoglycan composed of repeating disaccharide units of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA) linked together by alternating β-1,4 and β-1,3 glycosidic bonds. Hyaluronic acid is also known as hyaluronic acid, hyaluronic acid salt, or HA. As used herein, the term "hyaluronic acid" also includes hyaluronic acid in salt form, such as sodium hyaluronate. Preferred hyaluronic acid is sodium hyaluronate. The weight-average molecular weight of the hyaluronic acid used in the inserts of the present invention can vary, but is typically from 0.1 to 2.0 million Daltons. In one embodiment, the hyaluronic acid has a weight-average molecular weight of 0.5 to 1 million Daltons. In another embodiment, the hyaluronic acid has a weight-average molecular weight of 1.5 to 2.0 million Daltons.

[0065] The galactomannans of the present invention can be obtained from many sources. These sources include fenugreek gum, guar gum, locust bean gum, and tara gum. Furthermore, galactomannans can also be obtained via classical synthetic routes or through chemical modification of naturally occurring galactomannans. As used herein, the term "galactomannan" refers to a polysaccharide derived from the aforementioned natural gums or similar natural or synthetic gums, containing mannose or galactose portions or both as the main structural component. The preferred galactomannans of the present invention consist of a linear chain of (1-4)-β-D-mannopyranosyl units and α-D-galactopyranosyl units attached by (1-6) bonds. For preferred galactomannans, the ratio of D-galactose to D-mannose varies, but generally will be from about 1:2 to 1:4. A D-galactose:D-mannose ratio of about 1:2 is most preferred for galactomannans. Furthermore, other chemically modified variants of the polysaccharide are also included in the definition of "galactomannan". For example, the galactomannan of the present invention can be substituted with hydroxyethyl, hydroxypropyl, and carboxymethyl hydroxypropyl groups. When a soft gel is desired, nonionic variants of the galactomannan, such as those containing alkoxy and alkyl (C1-C6) groups (e.g., hydroxypropyl substitution), are particularly preferred. Substitution at the noncis-hydroxyl position is most preferred. An example of nonionic substitution of the galactomannan of the present invention is hydroxypropyl guar gum with a molar substitution degree of about 0.4. Galactomannan can also be anionicly substituted. Anionic substitution is particularly preferred when a highly responsive gel is required, and preferred galactomannans of the present invention are guar gum and hydroxypropyl guar gum. Hydroxypropyl guar gum is particularly preferred. In the inserts of the present invention, the weight-average molecular weight of hydroxypropyl guar gum can vary, but is typically 1 to 5 million Daltons. In one embodiment, hydroxypropyl guar gum has a weight-average molecular weight of 2 to 4 million Daltons. In another embodiment, hydroxypropyl guar gum has a weight-average molecular weight of 3 to 4 million Daltons.

[0066] The polymer used in the insert according to embodiments of this disclosure should be non-toxic and soluble in eye drops to ensure that the insert is ultimately removed from the eye within a 60-minute timeframe. It should be understood that the selected polymer(s) should be mucosal adhesive. It should also be understood that one or more polymers can be mixed according to embodiments of this disclosure. For example, in embodiments of this disclosure, hyaluronic acid (HA) can be mixed with tamarind seed polysaccharide (TSP) because TSP has been shown to increase the residence time of HA in the aggregate mixture, and the mixture has the desired membrane mechanical and lubricating properties. In other embodiments of this disclosure, as described further in detail below, hyaluronic acid can be combined with HP guar gum.

[0067] In some embodiments, one or more mucosal adhesive polymers are present in amounts of about 50% to about 99% w / w, about 60% to about 95% w / w, about 70% to about 90% w / w, or about 80% to about 90% w / w based on the dry weight of the polymeric eye insert. In specific embodiments, the mucosal adhesive polymer is present in amounts of about 75%, about 80%, about 85%, about 90%, or about 95% w / w based on the dry weight of the polymeric eye insert. The total dry weight or mass of the polymeric eye insert can range from about 1 mg to about 10 mg, or from about 2 mg to about 8 mg, and in specific embodiments, it can be from about 2.5 mg to about 5 mg.

[0068] In some embodiments disclosed herein, softeners and / or plasticizers may be added to one or more polymers to help create a softer, more malleable delivery system and also improve insertion comfort. Plasticizers can soften the material to provide a desired dissolution rate. It should be understood that softeners and / or plasticizers can be low or high molecular weight compounds, including but not limited to: polyethylene glycol (PEG) and its derivatives, water, vitamin E, and triethyl citrate.

[0069] In some embodiments, the plasticizer or softener is present in amounts of about 2% to about 30% w / w, about 5% to about 25% w / w, about 5% to about 20% w / w, or about 5% to about 15% w / w based on the dry weight of the polymer eye insert. In specific embodiments, the plasticizer or softener is present in amounts of about 5%, about 7%, about 10%, or 12% w / w, or about 15% w / w based on the dry weight of the polymer eye insert.

[0070] In some embodiments, the polymer eye insert may have a water content of about 1% to about 50% after hydration. In a particular embodiment, the polymer eye insert may have a water content of 30-40%.

[0071] Polymer eye inserts can have any size or shape suitable for application to the eye. Exemplary shapes include membranes, rods, spheres, or irregular shapes with a maximum size in any single dimension of 5-6 mm. Figures 10A to 10C Additional exemplary shapes are shown in the figure.

[0072] In some embodiments, the polymer eye insert has a thickness of about 50-400 µm, about 100-300 µm, about 150-250 µm, or about 200 µm.

[0073] In certain embodiments, the polymer eye insert has a thickness of about 150-250 µm and a water content of 30% to 50% w / w.

[0074] In some embodiments disclosed herein, the polymeric eye insert does not include additional pharmaceutically active agents. In other embodiments, the polymeric eye insert may include one or more additional pharmaceutically active agents. In some embodiments, one or more pharmaceutically active agents may be selected from the group consisting of: ocular lubricants, anti-redness agents such as alpha-2 adrenergic agonists (e.g., brimonidine, araclonidine, etc.), sympathomimetic amines such as tetrahydrozoline, naphazoline, TRPM8 agonists such as menthol, menthol analogs, steroidal and nonsteroidal anti-inflammatory drugs for relieving eye pain and inflammation, antibiotics, antihistamines such as olopatadine, antiviral drugs, antibiotics and antibacterial agents for infectious conjunctivitis, antimuscarinic agents such as atropine and its derivatives for the treatment of myopia, and glaucoma drug delivery systems such as prostaglandins and prostaglandin analogs (e.g., travoprost), or therapeutically suitable combinations thereof.

[0075] Polymer eye inserts according to embodiments of this disclosure can be manufactured using various processing techniques, including but not limited to compression molding and solution casting. Compression molding can be performed at temperatures and pressures that do not alter the material or cause significant side effects. For example, compression molding of partially hydrated polysaccharides can be performed at about 200-300 degrees Celsius using a compressive force of about 5,000-12,000 pounds for about 1-2 minutes. Solution or film casting can be performed using solvents and / or co-solvents that provide a homogeneous film with virtually no defects. The solvent can be removed by air drying or vacuum drying, thereby ensuring that there is no residual solvent in the insert material. For example, a 1% (w / v) aqueous solution of a polymer (or mixture) can be cast and then evaporated. The film can then be cut using an elliptical punch of the desired size and geometry. While compression molding and solution / film casting have been described, it should be understood that other processing techniques can be used without departing from this disclosure.

[0076] In one embodiment, the membrane casting method used was found to produce reproducible inserts and good structural integrity. In this embodiment, distilled water was placed in a 1 L conical flask, and then (multiple) polymers were added. The flask was placed in an ultrasonic generator and attached to an overhead mechanical stirrer. The mixture was ultrasonicated at 30°C and stirred for 60 minutes. The speed of the mechanical stirrer was adjusted to 700 rpm and stirred for 60 minutes. Stirring was stopped and plasticizers (PEG and / or PVP) were added to the flask. This mixture was stirred ultrasonically at 700 rpm at 30°C for 30 minutes until a homogeneous, clear solution was obtained. Then, mechanical stirring was stopped, and ultrasonication was continued for an additional 30 minutes to remove all air bubbles. The conical flask was then removed from the ultrasonic generator and left to stand at room temperature for 30 minutes. To prepare the membrane, approximately 150 g ± 2 g of the stock solution was filled into a Piper dish (150 mm in diameter × 15 mm in height). The stock solution was evaluated using different evaporation techniques. In the first experiment, a vacuum oven at 50°C was used. Piper dishes were placed in the oven, and the oven was evacuated using a vacuum pump. After 30 hours, the resulting films were yellow, and some of these films exhibited a curved surface. The experiment was repeated under the same vacuum conditions at 45°C, 40°C, and 35°C. All of these experimental conditions produced colored films or films with uneven weight distribution. It was also observed that the higher the temperature, the deeper and more intense the yellow color became. Preferred evaporation techniques involve evaporation at room temperature in a chamber equipped with a variable-speed exhaust pipe. During the evaporation process, the airflow, temperature, and humidity were measured. The techniques described above produce uniform evaporation and films with consistent thickness.

[0077] As previously mentioned, in vivo studies have shown that conventional topical ophthalmic lubricants remain in the eye for no more than approximately 25 minutes. However, combining one or more polymers with plasticizers / softeners, such as mixing HP guar gum and hyaluronic acid with a plasticizer (e.g., PEG), can provide tunable hydration and dissolution rates for flexible membranes, enabling comfortable insertion. While some embodiments of the invention are polymeric eye inserts comprising a mixture of hyaluronic acid, HP guar gum, and PEG, it should be understood that other mixtures may be used for polymeric eye inserts according to other embodiments of this disclosure. Figure 1 The placement of an eye insert on the surface of the eye according to an embodiment of the present invention is depicted.

[0078] The eye insert disclosed herein is a platform for delivering lubricants and other pharmaceutically active agents to treat ocular surface symptoms such as redness, itching, and dryness. In some embodiments, the polymeric eye insert can be used to prolong contact with the pharmaceutically active agent or prolong the delivery of the pharmaceutically active agent to the eye. Therefore, in some embodiments, this disclosure provides a method for prolonging drug delivery or prolonging contact with the pharmaceutically active agent to the eye by administering a polymeric eye insert comprising a pharmaceutically active agent to a patient in need of this.

[0079] In some embodiments, this disclosure provides a method for treating or alleviating signs and / or symptoms of dry eye disease (keratoconjunctivitis sicca), the method comprising administering a polymeric ophthalmic insert according to this disclosure to a patient in need of such treatment.

[0080] The following non-limiting embodiments are provided to illustrate embodiments of the present invention.

[0081] Example

[0082] Example 1

[0083] In the embodiments disclosed herein, hyaluronic acid-fluorescein (Creative PegWorks, Chapel Hill, North Carolina), sodium hyaluronate (Novozyme, Franklin Clinton, North Carolina), HP guar gum, HP guar gum-fluorescein, PEG 400, and water may be used to form polymeric eye inserts comprising HP guar gum and sodium hyaluronate; however, it should be understood that, without departing from this disclosure, more or fewer components from different batches and / or distributors may be used to form polymeric eye inserts.

[0084] To form this HP guar gum / sodium hyaluronate insert, approximately 100 mL of water was added to an Erlenmeyer flask that had been autoclaved for approximately 30 minutes. The water temperature was approximately 22°C. The HA component was labeled with fluorescein isothiocyanate (FITC) to track in vivo release. FITC-hyaluronic acid (approximately 102.2 mg) was then added to the water while stirring at approximately 23°C with an IKA® RetControl-Visc C hot plate / stirrer at a setpoint of 500 rpm (1 / min). Sodium hyaluronate (approximately 354.3 mg) was then added, followed by HP guar gum (454.1 mg) and PEG 400 (approximately 97.2 mg). Additional water (approximately 100 mL) was then added. The mixture was stirred at ambient temperature (approximately 22°C) at a stirring setpoint of 600 rpm (1 / min) for approximately 20 hours. The solution was then poured into sterile disposable polystyrene Petri dishes (VWR, 55 mm in diameter and 15 mm in height). The Petri dishes containing the solution were then placed in a Lindberg Blue M convection oven (Thermo Scientific) and heated to approximately 35 degrees Celsius, and then dried under high vacuum at approximately 23 degrees Celsius for approximately 1–2 days.

[0085] The polymer eye insert of this embodiment has the following composition: 102.2 mg (about 10%) FITC-hyaluronic acid / 354.3 mg (about 35%) sodium hyaluronate, 454.1 mg (about 45%) HP guar gum, and 97.2 mg (about 9%) PEG 400. A 6 mm diameter disc was then punched out for in vivo evaluation studies. While a method for forming the HP guar gum / hyaluronic acid insert according to embodiments of this disclosure has been described, it should be understood that other methods may be used to form these or similar polymer eye inserts without departing from this disclosure.

[0086] In vivo tolerability studies were conducted using single polymer eye inserts and New Zealand white rabbits. The polymer eye inserts used in this study consisted of 3–7 mm discs containing an HP guar gum / hyaluronic acid mixture using PEG as a plasticizer. The hyaluronic acid component was labeled with fluorescein isothiocyanate (FITC) to track in vivo release. This study revealed acceptable tolerability and comfort using a membrane with a diameter of 6 mm and a thickness of 200 µm. In vivo retention studies were also conducted using single membranes of the HP guar gum / hyaluronic acid / PEG mixture (using 5% FITC-hyaluronic acid). The membranes hydrated within the fornix of the eye but retained debris after two hours. However, this debris could be explained by the low-frequency and intermittent blinking associated with the rabbit subjects. The results of fluorescence measurements for these polymer eye inserts are shown in Table 1.

[0087] Table 1

[0088] Fluorescence of thin-film inserts at baseline levels ≥ 1.5X - time points

[0089]

[0090] All polymer ocular inserts exhibit excellent tolerance, with no physical reaction, expulsion, squinting, or scab formation. Once placed, the insert remains almost immobile in the eye until it dissolves. The insert dissolves during the first 30 minutes after insertion. After one hour, lubricant residue is visible on the corneal surface. After 6 hours, no residue remains. A 6 mm diameter has been determined to be the maximum diameter that can fit the fornix without invading the corneal-scleral limbus. At a 7 mm diameter, the insert crosses the limbus. However, inserts of other diameters may be used without departing from this disclosure.

[0091] Testing of polymer ocular inserts according to embodiments of this disclosure has been conducted using Spectralis HRA-OCT. This is a diagnostic device that integrates SD-OCT with cSLO fundus imaging. Anterior segment structures can be imaged via the front module provided by Spectralis. SD-OCT imaging is ideal because it does not require labeled test articles, provides both visual and quantitative characteristics, offers direct micrometer measurements of the tear film / polymer ocular insert, and allows for tear film height acquisition from all four quadrants of the eye within seconds. This image shows the accumulation of the polymer insert in the lower tear trough.

[0092] Example 2

[0093] Various polymer intercalations were prepared by membrane casting to evaluate polymer compatibility and thus prepare clear and / or fairly transparent intercalated films. The following polymer formulations were prepared and evaluated using different concentration ratios of each specified polymer: HA / PEG, HA / PVP / PEG, HA / PVP, HA / HP-guar gum / PEG, HP-guar gum / PVP / PEG, HA / HP-guar gum / PVP / PEG, HA / HP-guar gum / PAA / PEG, and HA / HP-guar gum / HPMC / PEG. The characterization methods for the intercalated films are described below.

[0094] 1. Morphology

[0095] The surface morphology of the inserted membrane was tested using a suitable microscope. The texture and transparency of the inserted membrane were investigated, and the observations were recorded. If the membrane surface was found to be clear and transparent, this should be noted. If undissolved particles or turbidity were observed, this should also be noted.

[0096] 2. Thickness uniformity

[0097] Four membranes were sampled, and their thickness was assessed by cutting insertion disks with a diameter of 6 mm. The thickness of the disks was measured. The disk cutting locations were randomly selected near the middle and edges of each membrane. A Mitutoyo digital caliper was used to measure the disk thickness. For each membrane, the mean and standard deviation of the 12 disks were calculated.

[0098] 3. Weight uniformity

[0099] To determine weight uniformity, four different membranes were selected, and twelve disks with a diameter of 6 mm were cut from them. The locations of the disk cuts were randomly selected on the original membranes. A high-accuracy Sartorius balance was used to determine the weight of each disk. For each membrane, the weight of each individual disk was measured, and the average weight of the twelve disks was determined. The standard deviation of the twelve data points was calculated and recorded.

[0100] 4. Moisture absorption percentage

[0101] For the moisture absorption percentage test, four circular membranes with a diameter of 150 mm were prepared. Four discs with a diameter of 20 mm were cut from each membrane. The four discs were placed in a chamber containing 100 ml of saturated aluminum chloride solution. The chamber was sealed for 72 hours. During this period, the surface of the discs remained clear. The discs were carefully removed from the chamber, and the weight of each disc was measured. The moisture absorption percentage of each disc was calculated using the following formula:

[0102] %MA = ((Final weight - Initial weight) / Initial weight) × 100

[0103] The average moisture absorption percentage of 12 discs cut from four different films was recorded.

[0104] 5. Percentage of water loss

[0105] The same membranes used to produce the moisture absorption percentage were used for the moisture loss percentage measurement. The four discs were placed in a desiccator containing anhydrous calcium chloride for 72 hours. The discs were then removed from the desiccator and their weight determined. The moisture loss percentage for each membrane was calculated using the following formula:

[0106] %ML = ((Initial weight - Final weight) / Final weight) × 100

[0107] The average water loss of 12 discs cut from four different membranes was recorded.

[0108] 6. Flexural strength

[0109] Prepare four large circular membranes with a diameter of 150 mm. From each membrane, prepare four square membranes with dimensions of 4 cm × 4 cm. The membrane strips are repeatedly folded in the same position until they tear or visibly crack. The number of times the membrane can be folded in the same position without tearing gives a value for folding endurance. Collect data and record the average results. Determine the average folding endurance of 16 square strips cut from the four different membranes.

[0110] 7. Dissolution time and solution pH value

[0111] Four 6 mm diameter discs were cut from a master circular membrane with a diameter of 150 mm. The membranes were placed in vials containing 2 ml of distilled water, and the time required for complete dissolution was recorded. The mean dissolution time and standard deviation for each group were recorded.

[0112] 8. Tensile strength, modulus, displacement, and elongation percentage

[0113] Four membrane strips measuring 4 cm × 2 cm were used for measurements at each data point. All membranes were inspected for bubbles and physical defects. During measurement, the membrane strips were held between two clamps, with a distance of 3 cm between the clamps. The unit load used was 5 kg. The strips were pulled through the top clamp at a rate of 10 cm / min. The average tensile strength, modulus, and elongation percentage were measured and reported. The formulations used to prepare the test membranes, along with the polymer composition and test data, are provided below. The results in Table 2 indicate that the presence of 5% PVP in the HA / PEG formulation improved the membrane's flexibility and elasticity. As shown in Table 3, the presence of 30% PVP and 30% HP guar gum also provided membranes with relatively good elasticity and flexibility. As shown in the data in Table 4, the presence of carbomer in the tested formulations led to membrane embrittlement. As shown in Table 5, 200 ppm menthol resulted in a faster dissolution rate and produced a hard film. Films with menthol < 200 ppm (e.g., 150 ppm) have similar modulus and elongation percentage to the same film without menthol.

[0114] Table 2 - HA / PVP and PEG combinations

[0115]

[0116] Table 3 - HA / HP-Guar Gum / PVP / PEG Combination

[0117]

[0118] Table 4 - HA / HP-Guar Gum / PAA / PEG Combinations

[0119]

[0120] Table 5 - HA / HP guar gum / PEG combinations with 200 PPM menthol

[0121]

[0122] Characterization of HA / HP guar gum / PEG membranes

[0123] Based on data from various membrane compositions, a preferred polymer composition was determined to be 45.4% hyaluronic acid (HA), 45.4% hydroxypropyl guar gum (HP guar gum), and 9.2% polyethylene glycol (PEG 400) (referred to as Formulation 2 below). This membrane was prepared as follows:

[0124] Table 6 - HA / HP Guar Gum / PEG Combinations

[0125]

[0126] In a 1 L conical flask, pour 750 ml of distilled water into the flask, then add hyaluronic acid (5.107 g). Place the flask in an ultrasonic generator and attach it to a raised mechanical stirrer. Stir and sonicate the mixture at 700 rpm for 30 minutes (± 10 minutes) at 25°C to 35°C until a homogeneous, clear solution is obtained. Then add hydroxypropyl guar gum (5.107 g) to the flask. Return the flask to the ultrasonic generator and attach it to the raised mechanical stirrer. Stir and sonicate the mixture at 700 rpm for 120 minutes (± 10 minutes) at 38°C to 42°C until a homogeneous, clear solution is obtained. Add the plasticizer polyethylene glycol-400 (1.035 g) to the flask. The mixture was stirred and sonicated at 700 rpm for 30 minutes (± 10 minutes) at 40°C to 45°C until a homogeneous, clear solution was obtained. The mixture was then sonicated at 40°C to 45°C without stirring for an additional 30 minutes (± 10 minutes) until a homogeneous, clear solution (free of bubbles) was obtained. The flask was allowed to stand at room temperature for 30 minutes (± 10 minutes). After proper mixing, the casting solution (150 g ± 2 g) was poured into clean Piper dishes (150 mm × 15 mm). The Piper dishes were dried at room temperature for 60 h (± 5 h) in an evaporation chamber equipped with an exhaust fan. After drying, the discs were cut into 9 cm × 9 cm slices and kept in an airtight bag for 24 h (± 3 h) at controlled humidity (< 50%) and temperature (23°C to 26°C) levels for further characterization studies.

[0127] Table 7 – Average weight measurement of Formula 2

[0128]

[0129] Table 8 - Measurement of moisture absorption rate of Formula 2

[0130]

[0131] Table 9 – Measurement of Moisture Loss in Formula 2

[0132]

[0133] Table 10 – Flexural endurance measurement of Formula 2

[0134]

[0135] Table 11 - Dissolution time and pH measurement of Formula 2

[0136]

[0137] Table 12 - Measurement of tensile strength, modulus and elongation percentage of formulation 2

[0138]

[0139] Example 3

[0140] HRA-OCT can be used to directly measure tear film thickness. HRA-OCT imaging is used to measure tear film thickness after insert insertion, and this indirectly indicates the effect of lubricant delivery (i.e., increased tear film thickness indicates lubricant and / or drug delivery). After insertion, the insert is expected to slowly dissolve and release the lubricant and / or drug. The general method used is described below using New Zealand rabbits. In this procedure, inserts using 45.4% hydroxypropyl guar gum (HP guar gum) and 9.2% polyethylene glycol (PEG 400) were evaluated in rabbits using HRA-OCT. On day 1, a single insert was placed in the central inferior fornix of the right eye using forceps or other suitable devices. On day 3, the treatment was repeated, with the insert applied to the left eye. The study treatment design is summarized in Table 13.

[0141] Table 13 - Exemplary Study Design

[0142]

[0143] If necessary, optical coherence tomography (OCT) scans of the animals can be performed at different time points for up to 3 hours. The OCT imaging and image analysis methods for rabbits are as follows:

[0144] 1. The lights in the imaging room are dimmed to facilitate imaging.

[0145] 2. Gently brush the area under the eye you want to focus on with a cotton swab to induce a natural blinking response.

[0146] 3. Capture a horizontal image centered on the corneal apex.

[0147] 4. Gently brush under the eyes again with a cotton swab to induce a natural blinking response.

[0148] 5. Capture a vertical image centered on the corneal apex.

[0149] 6. Record medication information and image numbers.

[0150] 7. Identify 3 points on each image for analysis (horizontal: nose, apex of eye, temporal region; vertical: top of eye, apex, bottom of eye).

[0151] 8. Use the measurement tools on the Bioptogen to determine the tear film thickness at each analysis point and record the measurements.

[0152] The treatment groups and imaging schedules for the test animals are presented in Tables 14 and 15 below.

[0153] Table 14 – Treatment Group

[0154]

[0155] Table 15 – Composition like a timetable

[0156]

[0157] Figure 9Tear film thickness data from the tests are presented. LACRISERT® was used as a control in this test. In this in vivo study, no significant issues related to safety or tolerability were observed in either LACRISERT® or the test product containing HP guar gum / HA / PEG. In this in vivo test, the test product was exposed to two different post-dosing regimens. In one case, BSS was added every 15 minutes after insertion to attempt and accelerate the dissolution of the insert. In the second case, a single BSS was administered after insert insertion. LACRISERT® was simply inserted according to the instructions for human eyes. OCT measurements showed an increase in tear film thickness in both cases. The addition of BSS accelerated the dissolution of the insert, manifested as a rapid increase in tear film thickness around 5 minutes, reaching a maximum tear film thickness of 50 micrometers after 15 minutes. In contrast, a single instillation after insertion showed a tear film thickness extension within 90 minutes, followed by a decrease to baseline within 2 hours. During this timeframe, LACRISERT® had no significant effect on tear film thickness and remained solid after 3 hours. In this experiment, the HA / HPG / PEG insert test article completely dissolved after 2 hours.

[0158] Example 4 – Inserts with pharmaceutical active agents

[0159] As described above, the inserts of the present invention may include one or more pharmaceutically active agents. An insert membrane prepared using the antimuscarinic atropine is provided below.

[0160] Preparation using atropine eye inserts

[0161] 40% Hyaluronic Acid (HA): 40% Hydroxypropyl Guar Gum (HP): 10% Polyethylene Glycol (PEG 400): 10% Polyvinylpyrrolidone: 500 ppm Atropine

[0162] Table 17 - Atropine Insert Formulation

[0163]

[0164] program:

[0165] To prepare a 350 g insert formulation, the following quantities are required: HA (2.1 g): HP-Guar Gum (2.1 g): PEG-400 (0.525 g): PVP (0.525 g): Atropine (0.175 g) in 350 ml distilled water. In a 1 L Erlenmeyer flask, mix 350 ml of distilled water with 2.1 g of hyaluronic acid and 0.525 g of polyvinylpyrrolidone. Attach the flask to a high-mounted mechanical stirrer and stir the mixture at 600 RPM for 30 minutes at 35°C. Then add 2.1 g of hydroxypropyl guar gum. The mixture is then stirred at 38°C for 120 minutes until a homogeneous and clear solution is obtained. The plasticizer PEG-400 (0.525 g) and atropine (0.175 g) are then added to the flask, and the mixture is stirred at 700 RPM for an additional 30 minutes. The mixture is then cooled for 30 minutes. At this stage, the solution is ready for membrane casting.

[0166] Membrane casting:

[0167] Pour 150 g ± 2 g of the solution into a clean Piper dish (150 mm × 15 mm). Dry the Piper dish in a drying chamber at room temperature for 30 h. The resulting film was clear and showed no crystallization or abnormal visual appearance.

[0168] Preparation of eye inserts using povidone-iodine

[0169] In another example, the broad-spectrum bactericide povidone-iodine was used with the insert. This insert had the following formulation: 40% hyaluronic acid (HA), 40% hydroxypropyl guar gum (HP), 10% polyethylene glycol (PEG 400), 10% polyvinylpyrrolidone, and 500 ppm PVP-I by total mass.

[0170] program:

[0171] Procedure for preparing a 350 g batch formulation (0.015 g / mL concentration) in a 1 L Erlenmeyer flask. In 350 mL of distilled water, add HA (2.1 g): HP-Guar Gum (2.1 g): PEG-400 (0.525 g): PVP (0.525 g): PVP-I (0.175 g). In a 1 L Erlenmeyer flask, add 350 mL of distilled water, hyaluronic acid (2.1 g), and polyvinylpyrrolidone (0.525 g). Place the flask in an ultrasonic bath and attach it to a raised mechanical stirrer. Stir and sonicate the mixture simultaneously at 600 RPM and a temperature between 25°C and 35°C for 30 min (± 10 min) until a homogeneous, clear solution is obtained. Then add hydroxypropyl guar gum (2.1 g). Stir the contents of the flask at 600 RPM at a temperature between 38°C and 41°C for 120 minutes (± 10 minutes) until a homogeneous, clear solution is obtained. Then, add polyethylene glycol-400 (0.525 g) and PVP-I (0.175 g) to the flask. Stir the mixture for an additional 45 minutes. Pour 150 gm ± 2 g of the solution into clean Piper dishes (150 mm × 15 mm). Dry the Piper dishes in a ventilated chamber at room temperature for 30 hours (± 1 hour). Calculate 500 ppm of PVP-I based on the total mass (including water).

[0172] Example 5

[0173] Tear film measurements of the polymer eye insert according to embodiments of this disclosure were also compared with those of SYSTANE® ULTRA eye drops, GENTEAL® gel eye drops, and PROVISC® injection.

[0174] Figure 2A to Figure 2C The effects of SYSTANE® ULTRA eye drops on the patient before administration (Figure 2A), immediately after administration (Figure 2B), and 5 minutes after administration (Figure 2C) were described. Figure 2C Tear film measurements. Figures 2A to 29. Figure 2C This reflects the measured tear film thickness as 22 µm before drug administration, 60 µm immediately after drug administration, and 19 µm 5 minutes after drug administration.

[0175] Figures 3A to 3C depict tear film measurements of GENTEAL® gel eye drops before administration (Figure 3A), immediately after administration (Figure 3B), and 5 minutes after administration (Figure 3C). Figures 3A to 3C reflect the measured tear film size as 20 µm before administration, 31 µm immediately after administration, and 19 µm 5 minutes after administration.

[0176] Figures 4A to 4E The description of PROVISC® injection before administration ( Figure 4A Immediately after administration ( Figure 4B ), 5 minutes after administration ( Figure 4C ), 10 minutes after administration ( Figure 4D ) and 20 minutes after administration ( Figure 4E Tear film measurements. Figures 4A to 4E The results reflect the measured tear film thickness as follows: 19 µm before drug administration, 194 µm immediately after drug administration, 114 µm 5 minutes after drug administration, 61 µm 10 minutes after drug administration, and 16 µm 20 minutes after drug administration.

[0177] Figure 2A to Figure 2C Figures 3A to 3C and 4A to Figure 4E Each tear film measurement described herein reflects an immediate increase in tear film thickness after administration, but within any timeframe of 5 to 20 minutes after administration, the thickness returns to a similar level as measured before administration.

[0178] Conversely, Figures 5A through 5I reflect tear film measurements associated with the insertion of the polymer eye insert according to embodiments of this disclosure. These measurements reflect tear film thicknesses of 14 µm before administration (Figure 5A), 20 µm at 15 minutes after administration (Figure 5B), 81 µm at 30 minutes after administration (Figure 5C), 45 µm at 45 minutes after administration (Figure 5D), 43 µm at 1 hour after administration (Figure 5E), 37 µm at 1 hour and 15 minutes after administration (Figure 5F), 33 µm at 1 hour and 30 minutes after administration (Figure 5G), 22 µm at 1 hour and 45 minutes after administration (Figure 5H), and 18 µm at 2 hours after administration (Figure 5I). Therefore, in this embodiment of the disclosure, the tear film thickness does not return to its pre-administration thickness until approximately 2 hours after administration.

[0179] Additional tear film measurements were performed on New Zealand white rabbits. Each rabbit received a single polymer eye insert. Three horizontal and three vertical images were obtained at each time point. Three points along each line were measured and magnified to 800% to determine the depth of the tear film / test artifact.

[0180] Figure 6A This reflects the average tear film measurement using the polymer eye insert according to embodiments of this disclosure. Three rabbits were tested, and each rabbit blinked three times before image capture. In the tests on each rabbit, the insert diameter (6 mm) remained constant, and the insert weight ranged from 2.6 mg to 2.9 mg. Figure 6B This reflects tear film measurements of individual animals. Figure 6C It reflects tear film measurements based on intraocular locations including the fundus and top of the eye, as well as measurements of the temporal and nasal regions.

[0181] Further testing on New Zealand white rabbits measured the dynamic changes in tear film thickness associated with the polymer eye insert according to embodiments of this disclosure. Figure 7A The insert diameter is maintained at 6 mm. For the left eye (OS), the insert weight ranges from 3.2 mg to 3.8 mg, and for the right eye, the insert weight ranges from 2.2 mm to 2.6 mm. Figure 7B It reflects tear film measurements by location (apex, nose, temporal, top, and bottom).

[0182] This test also included similar measurements of GENTEAL® gel administered at a dose of 80 µL, or approximately 76.3 mg, into the central inferior fornix of the eye. Figure 8 This reflects the average GENTEAL® gel tear film measurements for the right and left eyes.

[0183] The results were analyzed after measurements were taken of both the polymer eye insert and the GENTEAL® gel according to embodiments of this disclosure. Table 18 below reflects the number of animals with a mean of 30 µm or greater from six readings.

[0184] Table 18

[0185]

[0186] This test confirms that changes in tear film thickness can be effectively monitored using Spectralis HRA + OCT. In most animals, the insert began to dissolve 15 minutes after administration. In most animals administered the polymer eye insert according to embodiments of this disclosure, tear film thickness increased significantly at least 30 minutes after administration. It should be understood that the position of the polymer eye insert (initial placement and movement after blinking) can produce variations in data, particularly at early time points; however, IR imaging and OCT can help distinguish the effects of insert position. It should also be understood that the weight of the insert may affect the length of retention. Furthermore, it should be recognized that intrinsic differences between animals can affect the results. For example, one animal experienced the longest duration of tear film thickness increase, regardless of insert size; however, larger inserts retained for approximately 45 minutes. It is also noted that aqueous solutions caused almost no change in tear film thickness.

[0187] As reflected in the foregoing research, the polymeric ophthalmic insert according to embodiments of this disclosure can take the form of a soluble membrane composed of a hydrophilic polymer with high mucosal adhesion and H-bonding properties. The membrane may contain one or more naturally derived polysaccharides or synthetic polymers that are biocompatible and well-tolerated by the eye. The soluble membrane may have a thin-film design that allows for easy and comfortable insertion into the fornix of the eye, as the membrane should be small enough to fit the fornix with little or no irritation upon insertion, but large enough to allow dissolution to occur over a longer period. This soluble membrane can rapidly hydrate to form a soluble gel and release the lubricant and / or pharmaceutically active agent over a short timeframe (e.g., the first 5-10 minutes after insertion). Compared to topical drop application, this slow, pulsating flow of lubricant maximizes adhesion and residence time on the ocular surface. By delivering the lubricant slowly to the tear film and ocular surface, retention time on the eye can be increased.

[0188] Insertion of the soluble membrane according to embodiments of this disclosure does not cause visual impairment after a few minutes. It should be understood that the soluble membrane can retain lubricant for approximately two hours or longer; however, embodiments of this disclosure may exist in which it can retain lubricant for approximately 30-60 minutes. Therefore, the soluble membrane or polymeric eye insert according to embodiments of this disclosure can provide advantages including, but not limited to: rapid dissolution to reduce blurring, membrane design to enhance wetting dynamics and ocular tolerance, improved insertion comfort, and reduced foreign body sensation. Furthermore, tolerance and lubricant delivery can be improved compared to other local delivery systems or inserts.

[0189] While embodiments of this disclosure have been described as being used as lubricants and / or pharmaceutical active agents to treat dry eye, it should be understood that polymeric ophthalmic inserts according to embodiments of this disclosure are also advantageous for delivering pharmaceutical active agents in ophthalmic treatment of other eye diseases. A non-exhaustive list of such diseases includes high intraocular pressure, glaucoma, glaucomatous retinopathy, optic neuropathy, macular degeneration, diabetic retinopathy, choroidal neovascularization, proliferative vitreoretinopathy, ocular trauma and infection, and myopia.

[0190] While some embodiments have been described as membranes, it should be understood that the polymer eye inserts according to embodiments of this disclosure can take various shapes, including but not limited to membranes, rods, and spheres. In embodiments of this disclosure, circular membranes with diameters from about 0.5 mm to 10 mm can be used. In other embodiments, circular membranes with diameters of 4-7 mm are particularly preferred. In some embodiments, a variety of other membrane shapes can be used, such as... Figures 10A to 10C Those shown.

[0191] Regardless of its shape, the polymer eye insert according to embodiments of this disclosure should be small enough to fit the fornix of the eye and be rapidly wetted, resulting in little or no irritation upon insertion. The insert should also be large enough to allow dissolution within any timeframe of approximately 30-120 minutes to allow for the release of the lubricant and / or pharmaceutically active agent(s). The insert should also have a thickness that is relatively comfortable for the user. A preferred thickness is between 50-250 micrometers, with a most preferred thickness between 70-150 micrometers. A target thickness of 90 micrometers is desired for the film to dissolve in less than 2 hours.

[0192] Example 6

[0193] Monkey tolerance study

[0194] Based on the pharmacological and anatomical relevance of monkey eyes and subsequent tolerability assessment in rabbits, male crab-eating macaques from China (natural protein) were selected for this study. Monkey eyes blink at a frequency similar to that of humans. Tolerance to the ocular test product was clinically observed at 15, 30, 45, 60, 120, 180, and 240 minutes post-administration. Special attention was paid to tear film retention and tolerability. Gross examination included tearing, redness, swelling, and blinking. At 24 hours post-administration, animals in groups 1 and 2 were mildly sedated, and the treated eyes were thoroughly examined for the presence of a tear film. If any tear film was detected, it should be noted during clinical observation, and any remaining tear film should be removed. If abnormalities persisted beyond the final observation time point, additional clinical observation was required. A veterinarian was notified immediately of any unexpected clinical signs. Animals were restrained manually, chemically (ketamine or alternatives, such as Telazol according to veterinary guidelines if necessary), or mechanically (chair). Administration was performed using a mild sedative. Observe animals in a mildly sedated or conscious state. Administer the test product to mildly sedated animals (ketamine 5–15 mg / kg, IM or an alternative [e.g., Telazol 5–10 mg / kg, IM]). Administration is considered complete once administration is to one eye. Once mild sedation has occurred, use forceps or other suitable device to place a single insert of the test product in the central inferior fornix of the left eye of all animals.

[0195] The eye inserts were composed of 40% HP guar gum / 40% HA / 10% PVP / 10% PEG and labeled TA1 and TA2. TA1 had a diameter of 6 mm and a thickness of 86 micrometers (standard deviation 8.4 micrometers). TA2 had a diameter of 6 mm and a thickness of 108 micrometers (standard deviation 8.3 micrometers). SYSTANE ULTRA® was used as a control.

[0196] Observations and Conclusions

[0197] After administration at T = 0, the thinner TA1 inserts were difficult to place and tended to fold upon contact with moisture in the tissue, but once placed, they flattened without much trouble. The thicker film TA2 did not fold and was easy to insert and flattened immediately in the tissue. Both groups TA1 and TA2 showed mild to moderate tearing after insertion (no tearing was observed in animals receiving the drops). No signs of irritation, redness, eye rubbing, or other squinting were observed within three hours. At 24 hours, no residual insert material was found in any animal, and all treated eyes appeared acceptable, without redness, swelling, or any other signs of irritation, compared to SYSTANE ULTRA® topical drops.

[0198] Example 7 – Human Study of Lubricated Polymer Eye Inserts

[0199] To evaluate the biocompatibility, safety, and tolerability of the polymeric eye inserts, a study using a randomized, crossover design was conducted in human participants. During a single study day, each participant received a total of three treatments: two polymeric eye inserts and one eye lubricating drop. Only one eye was treated, with the untreated contralateral eye serving as a control.

[0200] Research Design:

[0201] Ten participants (5 women and 5 men) were enrolled in the study. The mean age of the participants was 35.5 years (median age 33 years, ranging from 23 to 61 years).

[0202] The results of the study are measured as follows:

[0203] The primary outcome variable was the subjective assessment of eye comfort.

[0204] Secondary outcome variables: subjective assessment of visual blur, rate of dissolution of polymer eye insert, researcher treatment assessment, and non-invasive tear film breakup time (NITBUT).

[0205] The study was conducted as follows: The study day lasted approximately 9 hours and included screening and eligibility checks, insertion of the first treatment (polymer eye insert or eye lubricating drops) into one eye, assessment, and eye rinsing approximately 2 hours after insertion. After a minimum 1-hour wait, the second treatment was administered to the other eye (the previously unused eye), and the procedure was repeated. A minimum 1-hour wait was required before the final treatment, followed by a repetition of the procedure. For each treatment, ocular comfort and visual acuity assessments were performed: before insertion, and at 5, 15, 30, 60, 90, and 105 minutes after insertion to assess treatment tolerability. Tear film assessments were performed at 5, 60, 90, and 105 minutes after insertion. Ocular safety measurements were taken during screening and after each treatment. At the end of the study day, participants were asked to indicate their treatment preferences.

[0206] Research materials:

[0207] Two different polymer eye inserts are as follows:

[0208] Table 19

[0209]

[0210] An eye lubricating drop (Systane) was used as a control treatment. The components of the eye lubricating drop are as follows:

[0211]

[0212] This study consisted of one study day. During the study day, participants were required to attend five scheduled visits.

[0213] Visit 1 screening and eligibility assessment (0.75 hours)

[0214] Insertion, assessment, and removal during visit 2 and treatment 1 (2.0 hours)

[0215] Insertion, assessment, and removal during visit 3 and treatment 2 (2.0 hours)

[0216] Visit 4, Treatment 3: Insertion, assessment, and removal (2.0 hours)

[0217] Visit 5 study exit (0.25 hours).

[0218] Apply a one-hour flushing period between the second and third visits, and between the third and fourth visits.

[0219] The procedures for each visit are summarized in Table 20.

[0220] Table 20 – Research Visits and Procedures

[0221]

[0222] Research findings:

[0223] Key outcome variable – comfort rating

[0224] At each time point (before insertion, and 5, 15, 30, 60, 90, and 105 minutes after insertion), participants were asked the following question: "How would you rate the comfort of your eyes?"

[0225] Participants responded using a scale from 0 to 100, where 0 represented “very poor comfort” and 100 represented “very comfortable”. Figure 11 The results are provided above.

[0226] like Figure 11 As observed, there were statistically significant differences between the insert and the drops at the 5-minute and 15-minute time points, with the drops showing a statistically significantly higher comfort rating. Regarding comfort ratings, the two inserts performed similarly; however, a statistically significant difference emerged at the 60-minute time point, with the thicker insert showing a higher comfort rating (90 vs 95, p = 0.04).

[0227] Secondary outcome variables

[0228] The results for the secondary outcome variables are as follows:

[0229] Blurred vision – At each time point (before insertion, and 5, 15, 30, 60, 90, and 105 minutes after insertion), participants were asked the question: “How would you rate the visual blur in your eyes?” Participants responded using a scale of 0 to 100, where 0 represents “extremely blurry, unable to see clearly” and 100 represents “not blurry at all”. Figure 12 The results are provided above.

[0230] As in Figure 12 As observed, compared to drops, both inserts resulted in statistically significantly lower ratings of visual blur at time points of 5, 15, and 30 minutes (p < 0.01 or p = 0.01). Furthermore, at the 60-minute time point, the thicker insert resulted in a statistically significant reduction in ratings of visual blur (93 vs 100, p = 0.01), however, there was no statistically significant difference between the thicker and thinner inserts at 60 minutes (88 vs 93, p = 0.28).

[0231] Clinician insertion ease – Researchers assessed the ease of insertion of polymer eye inserts during insertion using a scale of 0 to 4 in 0.5 steps, where 0 represents “very easy” and 4 represents “very difficult”.

[0232] The results are as follows: thin insert - 1.3 ± 0.5, thick insert - 1.6 ± 0.5. The results indicate that there is no statistically significant difference in the ease of insertion between the two inserts. Furthermore, even with minimal training, the insert is relatively easy to place in the eye.

[0233] Polymer eye insert dissolution rate – The degree of dissolution of the polymer eye insert was assessed at each time point. At each time point (at insertion, and 45, 60, 75, 90, and 105 minutes after insertion), researchers assessed the degree of dissolution of the polymer eye insert. Solubility was graded using a scale of 0 to 6, where 0 represents “no dissolution” and 6 represents “complete dissolution”.

[0234] Figure 13 The results are shown, indicating that approximately 90% of the lubricating solids dissolve between 60 and 90 minutes. Furthermore, the data show no statistically significant difference in the solubility grades of the two inserts.

[0235] NITBUT – Assessment of noninvasive tear film breakup time (NITBUT) is performed at insertion and at 60, 90, and 105 minutes post-insertion. Figure 14 The results are presented in the document.

[0236] Figure 14 The figure shows that at the insertion time points, there were statistically significant differences between the treated and control eyes for both inserts, with the NITBUT of the treated eyes being greater than that of the control eyes (thick insert: 18.52 vs 8.12, p = 0.01; thin insert: 17.26 vs 7.93, p < 0.01). At the 60-minute and 90-minute time points, there were also statistically significant differences between the treated and control eyes for the thick insert (60 minutes: 14.47 vs 5.89, p = 0.02; 90 minutes: 10.36 vs 5.77, p = 0.02).

[0237] Tear River – Researchers assessed the tear film river height at time points during treatment and at 60, 90, and 105 minutes post-insertion. Figure 15 The results are presented in the document.

[0238] Other variables

[0239] Eye irritation – At each time point (before insertion, and 5, 15, 30, 60, 90, and 105 minutes after insertion), participants were asked, “How would you rate the eye irritation you experienced?” Participants responded using a scale of 0 to 100, where 0 represented “intense eye irritation” and 100 represented “no eye irritation at all.”

[0240] Figure 16 The results are shown in [the image / document]. For example, in [the image / document]... Figure 16 As observed, at the 5-minute time point, there were statistically significant differences between the treated and control eyes for both inserts, with the treated eyes showing significantly lower ocular stimulation ratings (thick insert: 71 vs 100, p = 0.01; thin insert: 67 vs 99, p = 0.02). There were no statistically significant differences in ocular stimulation ratings between the two inserts.

[0241] Eye dryness – At each time point (before insertion, and 5, 15, 30, 60, 90, and 105 minutes after insertion), participants were asked, “How would you rate the dryness of your eyes?” Participants responded using a scale of 0 to 100, where 0 represents “very dry” and 100 represents “not dry at all.” Figure 17 The results are shown in the table. For any treatment, there was no statistically significant difference in dryness between the treated and control eyes. There were also no differences between the inserts.

[0242] Burning / Stinging – At each time point (before insertion, and 5, 15, 30, 60, 90, and 105 minutes after insertion), participants were asked, “How would you rate the burning / stinging sensation in your eyes?” Participants responded using a scale of 0 to 100, where 0 represented “intense burning / stinging” and 100 represented “no burning / stinging at all.” Figure 18 The results are presented in the table. For any treatment, there was no statistically significant difference between the treated and control eyes in terms of burning / tingling sensation. There were also no differences between the inserts.

[0243] Itching – At each time point (before insertion, and 5, 15, 30, 60, 90, and 105 minutes after insertion), participants were asked, “How would you rate the itching sensation in your eyes?” Participants responded using a scale of 0 to 100, where 0 represented “intense itching” and 100 represented “no itching at all.” Figure 19 The results are presented in the table. As seen in the results, there was no statistically significant difference in itching between the treated and control eyes for any treatment. There was also no difference between the inserts.

[0244] High-contrast visual acuity – Researchers evaluated high-contrast, high-brightness visual acuity at screening and during treatment visits, at insertion time, and at 60 and 105 minutes post-insertion. At insertion time and 60 minutes, there were statistically significant differences between the treated and control eyes, with participants exhibiting significant visual impairment. (Insertion: Thick insert: 0.05 vs -0.11, p < 0.01; Thin insert: 0.07 vs -0.10, p = 0.01) (60 minutes: Thick insert: -0.06 vs -0.1, p = 0.03; -0.07 vs -0.10, p = 0.02). The difference in visual acuity at 60 minutes was approximately two letters, which may not be considered clinically significant. By the end of the treatment visit, visual acuity had returned to normal. There were no statistically significant differences in visual acuity between inserts.

[0245] Eye health – The Efron scale (0–4) is used to assess congestion (redness) and neovascularization of the eyeball and limbus, with 0 indicating normal and 4 indicating severe. There are no clinically relevant differences for any of the eye health measures.

[0246] Results Summary

[0247] The primary clinical outcome was subjective comfort and tolerability. Participants tolerated the insert, and for all patients, there were no negative impacts on ocular health during and after wear.

[0248] There were no statistically significant differences between SYSTANE ULTRA and the insert in terms of burning, stinging, itching, or dryness among participants.

[0249] The insert will not have a negative impact on eye health.

[0250] In vivo rabbit and clinical comfort study data suggest that this device could be a valuable platform for delivering ocular lubricants and other topical ocular medications.

[0251] Although this disclosure and its advantages have been described in detail, it should be understood that various changes, substitutions, and modifications may be made herein without departing from the spirit and scope of this disclosure as defined by the appended claims. Furthermore, the scope of this application is not intended to be limited to the specific embodiments of the processes, machines, manufactures, compositions of matter, means, methods, and steps described in the specification. As will be readily understood by those skilled in the art from the disclosure, according to embodiments of this disclosure, existing or to be developed processes, machines, manufactures, compositions of matter, means, methods, or steps that perform substantially the same functions or achieve substantially the same results as the corresponding embodiments described herein can be used. Therefore, the appended claims are intended to include such processes, machines, manufactures, compositions of matter, means, methods, or steps within their scope. All publications, patent applications, and patents referenced in this specification are incorporated herein by reference in their entirety.

Claims

1. A polymer eye insert, the insert comprising: One or more biocompatible mucoadhesive polymers and plasticizers or softeners for the ocular surface and tear film of the eye, wherein the one or more mucoadhesive polymers are hydroxypropyl guar gum (HP guar gum), hyaluronic acid, or sodium hyaluronate, wherein the one or more mucoadhesive polymers are present in an amount of 80% to 90% w / w of the polymer eye insert; and wherein, after the polymer eye insert is inserted into the fornix of the eye, the increase in the thickness of the tear film persists for at least 30 minutes after insertion.

2. The polymer eye insert as claimed in claim 1, wherein, The plasticizer or softener is selected from the group consisting of polyethylene glycol (PEG), water, vitamin E, and triethyl citrate.

3. The polymer eye insert as claimed in claim 2, wherein, The plasticizer or softener is present in amounts of 2% to 30% w / w, 5% to 25% w / w, 5% to 20% w / w, or 5% to 15% w / w in the polymer eye insert.

4. The polymer eye insert as described in claim 2 or 3, wherein, The plasticizer or softener is PEG.

5. The polymer eye insert as claimed in any one of claims 1-4, wherein, The insert consists of approximately 40% w / w HP guar gum, approximately 10% w / w PVP, approximately 40% w / w sodium hyaluronate, and approximately 10% w / w PEG.

6. The polymer eye insert of claim 1, further comprising 1-200 ppm menthol.

7. The polymer eye insert of claim 4, further comprising 20-100 ppm menthol.

8. The polymer eye insert as claimed in claim 1, wherein, The insert does not contain any additional pharmaceutical active agent.

9. The polymer eye insert as claimed in claim 1, wherein, The insert includes one or more pharmaceutically active agents.

10. The polymer eye insert of claim 9, wherein, The one or more pharmaceutically active agents are selected from the group consisting of: atropine derivatives that are not nitric oxide donors, travoprost complex drugs having nitric oxide, lubricants, steroids, antibiotics, nonsteroidal anti-inflammatory drugs, antihistamines, antiviral drugs, antibacterial drugs, vasoconstrictors, and prostaglandin analogs.

11. The polymer eye insert as claimed in claim 1, wherein, The thickness of the tear film did not return to its pre-insertion thickness until approximately two hours after insertion.

12. The polymer eye insert as claimed in claim 1, wherein, After insertion into the fornix of the eye, the thickness of the tear film increases for at least two hours after insertion.

13. The polymer eye insert of claim 1, wherein, The insert shape is a membrane, rod, sphere, ring, or irregular shape with a maximum size of 5-6 mm in any single dimension.

14. The polymer eye insert of claim 13, wherein, The insert has a circular shape, a diameter of about 5 mm, a thickness of 50-400 µm, and a water content of 1% to 50% w / w.

15. The polymer eye insert of claim 14, wherein, The insert has a thickness of approximately 150-250 µm and a water content of 30% to 50% w / w.

16. The polymer eye insert of claim 1, wherein, The HP guar gum has a weight-average molecular weight of 2 to 4 million Daltons, and the sodium hyaluronate has a weight-average molecular weight of 0.1 to 2 million Daltons.

17. The polymer eye insert of any one of claims 1 to 16, for a method of treating an eye disease, comprising applying the polymer eye insert to the fornix of the eye.

18. The polymer eye insert of claim 17, wherein, The eye diseases mentioned are selected from the group including: dry eye, red eyes, myopia, glaucoma, eye allergies, and eye inflammation.

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