Enhanced artificial tear formulations

Abstract

Provided herein are low-salt ophthalmic pharmaceutical compositions and methods of use thereof, e.g., for the treatment of dry eye syndrome.

Description

[0001] Cross-reference to related applications This application claims the benefit of U.S. Provisional Application Serial No. 63 / 554,661, filed February 16, 2024, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0002] Dry eye syndrome (DED) is a multifactorial ocular surface disorder characterized by loss of tear film homeostasis and accompanying ocular symptoms, with tear film instability and high osmolar concentration, ocular surface inflammation and damage, and neurosensory abnormalities playing etiological roles (Craig et al., Ocul Surf. 2017; 15(3):276-83). An estimated 25 million Americans are reported to have DED, making it one of the most common reasons patients seek care from eye care professionals (Behrens et al., Cornea. 2006;25(8):900-7; and Stapleton et al., Epidemiology Report. OculSurf. 2017; 15(3):334-65).

[0003] Mechanistically, DED is considered a disorder of the lacrimal gland functional unit, which is a whole system consisting of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and meibomian glands), the main lacrimal gland, and sensory and interconnected nerve innervation. (Stern et al., Cornea. 1998; 17(6): 584-9). The diagnosis and classification of DED (i.e., mild / moderate / severe) is achieved by assessing clinical signs (ocular surface epithelial damage [corneal and conjunctival staining]), tear volume (Schirmer score), tear film stability (tear breakup time [TBUT]), and patient-reported symptoms (questionnaires, such as the Ocular Surface Disease Index© [OSDI] and Dry Eye Score-Visual Analogue Scale). (Wolffsohn et al., Ocul Surf. 2017; 15(3):539-74).

[0004] A normal tear film is a relatively stable thin film (i.e., 0.1 to 0.2 micrometers) composed of a surface lipid layer and an aqueous layer mixed with a mucogel layer, partially adhering to the corneal and conjunctival epithelium. The tear film is important for the lubrication, protection, and nutrition of the ocular surface and serves as the primary refractive surface of the eye's visual system. Dry eye syndrome is a complex disease characterized by dysfunction of one or more components of the tear film, leading to loss of tear film stability, a shift in tear film osmotic balance towards a hyperosmolar concentration, and / or insufficient fluid volume on the ocular surface. Dry eye syndrome is characterized by rapid tear film breakup and numerous symptoms, including burning / stirring, foreign body sensation, blurred vision, and photophobia.

[0005] Dry eye syndrome is often caused or exacerbated by a variety of adverse environmental conditions, including prolonged computer use (Visual Display Terminal Syndrome), excessive airflow or air conditioning, and hot or dry air. Most patients with DED initially manage it with artificial tears. Environmental improvements, eyelid dressings and cleaning, and the addition of essential fatty acids to the diet are also generally recommended. As the severity of DED progresses, treatment options may include topical cyclosporine or other anti-inflammatory medications, as well as surgical options ranging from punctal plug insertion to eyelid margin sutures, if necessary. (Jones et al., Ocul Surf. 2017; 15(3):575-628).

[0006] This application relates to compositions and methods for supplementing and enhancing the eye's natural tear film (e.g., the natural lipid layer of the tear film). The compositions and methods disclosed herein particularly provide relief from hyperosmolar stress and other symptoms associated with dry eye syndrome.

[0007] Previous approaches to supplementing and enhancing the lipid layer of the tear film have been addressed through various methods, including the use of large amounts of lipids (e.g., 1%–5%) and / or the construction of easily separable emulsion systems. However, such methods have several drawbacks, including the need to shake the composition before instillation, reduced transparency of the composition after instillation, variability in the total volume of lipids delivered to the eye, and tolerability issues relative to aqueous eye drops.

[0008] Typical symptoms of keratoconjunctivitis or dry eye include dryness, burning, and a gritty feeling in the eyes that may worsen during the day. Symptoms can also be described as itchy, tingling, stinging, or tired eyes. Other symptoms include pain, redness, pulling, and pressure behind the eyes. Damage to the ocular surface caused by dry eye increases discomfort and sensitivity to bright light, and usually both eyes are affected.

[0009] Because blinking covers the eyes with tears, activities that reduce blinking rate due to prolonged eye strain can worsen symptoms. These activities include prolonged reading, computer use, driving, or watching television. Symptoms tend to increase in windy, dusty, or smoky areas, in dry environments, at high altitudes (including on airplanes), on days with low humidity, and in areas where air conditioning, fans, or heaters are used. Symptoms are less severe during cool, rainy, or foggy weather, and in humid places. Most people with dry eye experience mild irritation without long-term effects. However, if the condition is left untreated or becomes severe, it can lead to complications that damage the eyes, resulting in impaired vision or even vision loss.

[0010] Prolonged dry eye can lead to microscopic abrasions on the surface of the eye. In advanced cases, the epithelium undergoes pathological changes, namely squamous metaplasia and loss of goblet cells, sometimes due to activation of T cells that act on these cells. Some severe cases result in thickening of the corneal surface, corneal erosion, punctate keratosis, epithelial damage, corneal ulceration, corneal neovascularization, corneal scarring, corneal thinning, and even corneal perforation. Abnormalities in any of the three layers of the tear film that produce an unstable tear film can contribute to the symptoms of dry keratitis.

[0011] Dry keratoconjunctivitis is usually caused by insufficient tear production. The aqueous tear film is affected, leading to a lack of aqueous tears or insufficient tear secretion. The lacrimal glands cannot produce enough tears to keep the entire conjunctiva and cornea completely covered by the intact layer. This usually occurs in otherwise healthy individuals. Age-related decreases in tear production are associated with this condition. This is the most common type in postmenopausal women. Causes include idiopathic, congenital antear, xerophthalmia, lacrimal gland ablation, and sensory denervation. In rare cases, it can be a symptom of collagen vascular diseases, including rheumatoid arthritis, Wegener's granulomatosis, and systemic lupus erythematosus. Sjögren's syndrome and related autoimmune diseases are also conditions associated with a lack of aqueous tears. Medications such as isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, oral contraceptives, antihistamines, nasal decongestants, beta-blockers, phenothiazines, atropine, and analgesic opioids (such as morphine) can cause or worsen this condition. Lacrimal gland infiltration caused by sarcoidosis or tumors, or post-radiation fibrosis of the lacrimal gland, can also cause this condition.

[0012] Dry eye can also be caused by abnormal tear composition, leading to rapid tear evaporation or premature tear destruction. When dry eye is caused by rapid evaporation, it is also called evaporative dry eye. In this condition, although the lacrimal glands produce a sufficient amount of tears, the rate of tear evaporation is too fast. The loss of moisture in the tears results in excessively high tear "salt" or a state of hypertonicity. Therefore, during certain activities or in certain environments, the entire conjunctiva and cornea cannot remain completely covered by a tear film.

[0013] The present invention provides an improved composition for treating dry eye syndrome. Summary of the Invention

[0014] In a first aspect, a low-salt ophthalmic pharmaceutical composition is provided, comprising a polymeric lubricant, a salt-sensitive viscosity-modifying polymer, one or more tension agents, sodium hyaluronate, and trehalose.

[0015] In another aspect, a low-salt ophthalmic pharmaceutical composition is provided, comprising: sodium hyaluronate at a concentration of about 0.1% (w / w); trehalose at a concentration of about 1.5% (w / w); erythritol at a concentration of about 0.25% (w / w); levocarnitine at a concentration of about 0.25% (w / w); potassium chloride at a concentration of about 0.03% (w / w); and sodium erythritol at a concentration of about 0.006% (w / w). The following are the ingredients: calcium chloride dihydrate (w / w); magnesium chloride hexahydrate (w / w) at a concentration of about 0.006%; boric acid (w / w) at a concentration of about 0.5%; sodium borate decahydrate (w / w) at a concentration of about 0.20%; sodium citrate dihydrate (w / w) at a concentration of about 0.10%; sodium carboxymethyl cellulose (w / w) at a concentration of about 0.5%; glycerol (w / w) at a concentration of about 0.9%; NaOH; and water.

[0016] In another aspect, a method for treating dry eye syndrome is provided. The method comprises administering a low-salt ophthalmic pharmaceutical composition, as described herein, to a subject requiring treatment for dry eye syndrome, thereby treating the dry eye syndrome.

[0017] The formulations described in Table 5 contain concentrations of the active substance and / or excipients as disclosed above, which may differ from the concentrations described above. Such differences may result in the amount being “about” the amount described above, provided that the amount is deemed bioequivalent by a regulatory agency (such as the FDA or EMEA).

[0018] This formulation is preferably preservative-free (purite-free). ® However, in other embodiments, the formulation contains a preservative, and in addition to containing Purite at a concentration of about 0.1% (w / v). ® Except for the formulations listed in Table 5, this formulation can be packaged into unit dosage forms.

[0019] In other embodiments, the formulation is preferably preservative-free (purite-free). ® It can be used in combination with preservative-free multi-dose bottles.

[0020] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition comprising a polymeric lubricant, a salt-sensitive viscosity-modifying polymer, one or more tension agents, trehalose, and hyaluronic acid salt.

[0021] In some embodiments, the present invention relates to low-salt ophthalmic pharmaceutical compositions according to any combination of the above embodiments, wherein the hyaluronic acid salt is sodium hyaluronate.

[0022] In some embodiments, the present invention relates to low-salt ophthalmic pharmaceutical compositions according to any combination of the above embodiments, wherein the one or more tension agents are selected from carnitine, glycerin, erythritol and trehalose.

[0023] In some embodiments, the present invention relates to low-salt ophthalmic pharmaceutical compositions according to any combination of the above embodiments, wherein the compositions comprise carnitine, glycerin, erythritol and trehalose.

[0024] In some embodiments, the present invention relates to low-salt ophthalmic pharmaceutical compositions according to any combination of the above embodiments, wherein the polymeric lubricant is sodium carboxymethyl cellulose present at a concentration of about 0.5% (w / w).

[0025] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition of any combination according to the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising a compatible solute, wherein the compatible solute is levocarnitine.

[0026] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition comprising, in any combination of the above embodiments, erythritol at a concentration of about 0.25% (w / w) and levocarnitine at a concentration of about 0.25% (w / w).

[0027] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein glycerin is present at a concentration of about 0.9% (w / w).

[0028] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the sodium hyaluronate is present at a concentration of about 0.1% (w / w).

[0029] In some embodiments, the present invention relates to low-salt ophthalmic pharmaceutical compositions according to any combination of the above embodiments, wherein the compositions are preservative-free.

[0030] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition of any combination according to the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising a buffer.

[0031] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the buffer is boric acid present at a concentration of about 0.5% (w / w).

[0032] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising sodium borate decahydrate.

[0033] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition of any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising sodium citrate dihydrate.

[0034] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising potassium chloride.

[0035] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition of any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising dehydrated calcium chloride.

[0036] In some embodiments, the present invention relates to a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising a pH adjuster, wherein the pH adjuster is NaOH, and wherein the pharmaceutical composition has a pH of about 7.3.

[0037] In other embodiments, the present invention relates to a combination of a low-salt ophthalmic pharmaceutical composition and a vial, wherein the low-salt ophthalmic pharmaceutical composition comprises: sodium hyaluronate at a concentration of about 0.1% (w / w); trehalose at a concentration of about 1.5% (w / w); erythritol at a concentration of about 0.25% (w / w); levocarnitine at a concentration of about 0.25% (w / w); potassium chloride at a concentration of about 0.03% (w / w); and sodium chloride at a concentration of about 0.006% (w / w). Calcium dihydrate; magnesium chloride hexahydrate at a concentration of about 0.006% (w / w); boric acid at a concentration of about 0.5% (w / w); sodium borate decahydrate at a concentration of about 0.20% (w / w); sodium citrate dihydrate at a concentration of about 0.10% (w / w); sodium carboxymethyl cellulose at a concentration of about 0.5% (w / w); glycerol at a concentration of about 0.9% (w / w); NaOH; and water; this bottle is designed to reliably dispense sterile, preservative-free liquids.

[0038] In some embodiments, the present invention relates to a method for treating dry eye syndrome, the method comprising administering to a subject requiring treatment for dry eye syndrome a low-salt ophthalmic pharmaceutical composition of any combination according to the above embodiments.

[0039] In some embodiments, the present invention relates to a method for treating dry eye syndrome, the method comprising administering the low-salt ophthalmic pharmaceutical composition comprising any combination of the embodiments described above to a subject requiring treatment for dry eye syndrome using a preservative-free bottle; thereby treating the dry eye syndrome. Attached Figure Description

[0040] Figure 1The study design for a Phase 1 / II clinical trial evaluating the safety and efficacy of formulations 1 and 2 in patients was described.

[0041] Figure 2 The changes in total current symptom severity score relative to baseline, as well as the mean LS and 95% CI (ITT population), were depicted after treatment with formulations 1 and 2. As shown in the figure, formulation 1 demonstrated a similar level of efficacy to formulation 2 at each of the multiple evaluation time points.

[0042] Figure 3 The changes in ocular surface disease index relative to baseline, mean LS, and 95% CI (ITT population) observed after treatment with formulations 1 and 2 are depicted. As shown in the figure, formulation 1 exhibited similar efficacy levels to formulation 2 up to day 30, followed by an improvement in efficacy levels from day 30 to day 90.

[0043] Figure 4 The changes in ocular staining relative to baseline, along with the mean LS and 95% CI (ITT population), were observed in a retrospective, non-head-to-head comparative study after patients were treated with formulation 1 and OM-3. As shown in the figure, formulation 1 showed a positive trend relative to OM-3 at all patient visits.

[0044] Figure 5 This study depicts the changes in ocular surface disease index (OSI) relative to baseline, as well as the mean LS and 95% CI (ITT population), observed after treatment with formulation 1 and OM-3 in a retrospective, non-head-to-head comparative study. As shown in the figure, formulation 1 showed a positive trend relative to OM-3 across all patient visits.

[0045] Figure 6 The study design for a clinical study evaluating symptom relief, product tolerability, and patient experience in patients with dry eye syndrome treated with formulation 1 is described.

[0046] Figure 7 The changes in Ocular Disease Severity Index (OSDI) scores relative to baseline at day 30 were depicted in 40 patients evaluated in the Patient Experience Clinical Trial (ITT). As shown in the figure, a statistically significant decrease in OSDI scores was observed.

[0047] Figure 8 The changes in Ocular Disease Severity Index (OSDI) scores relative to baseline at day 30 were depicted in 34 protocol-compliant (PP) patients evaluated in the Patient Experience Clinical Trial. As shown in the figure, a statistically significant decrease in OSDI scores was observed.

[0048] Figure 9The changes in Total Current Symptom Survey (CSS) scores relative to baseline over 5 minutes on day 30 were depicted in 40 patients evaluated in the Patient Experience Clinical Trial for Intention to Treat (ITT). As shown in the figure, a statistically significant decrease in CSS scores was observed.

[0049] Figure 10 The study depicted the change in Total Current Symptom Survey (CSS) scores relative to baseline over 5 minutes on day 30 in 34 protocol-compliant (PP) patients evaluated in the Patient Experience Clinical Trial. As shown in the figure, a statistically significant decrease in CSS scores was observed.

[0050] Figure 11 The changes in Patient Eye Drop Experience (PEDE) scores relative to baseline over 5 minutes at day 30 in 40 patients evaluated in the Patient Experience Clinical Trial (ITT) were depicted. As shown in the figure, a statistically significant decrease in PEDE scores was observed at 5 minutes.

[0051] Figure 12 The changes in Patient Eye Drop Experience (PEDE) scores relative to baseline over 30 minutes at day 30 in 40 patients evaluated in the Patient Experience Clinical Trial (ITT) were depicted. As shown in the figure, a statistically significant decrease in PEDE scores was observed at 30 minutes.

[0052] Figure 13 The changes in Patient Eye Drop Experience (PEDE) scores relative to baseline over 24 hours at day 30 in 40 patients evaluated in the Patient Experience Clinical Trial (ITT) were depicted. As shown in the figure, a statistically significant decrease in PEDE scores was observed at 24 hours.

[0053] Figure 14 The changes in Patient Eye Drop Experience (PEDE) scores relative to baseline at day 5 in 40 patients evaluated in the Patient Experience Clinical Trial (ITT) were depicted on day 30. As shown in the figure, a statistically significant decrease in PEDE scores was observed at day 5. Detailed Implementation

[0054] Over the years, a variety of ophthalmic artificial tears have been developed to treat dry eye syndrome.

[0055] The inventors seek innovative solutions to advance the field of artificial tears by developing unique formulations that combine beneficial components of various artificial tear formulations into a single artificial tear formulation.

[0056] The result is the formulation described in Table 5, which for the first time combines the osmotic protective properties of a combination of erythritol, L-carnitine, and glycerin from Refresh Optive eye drops, carboxymethyl cellulose (CMC) and hyaluronic acid (HA) from Opve Fusion eye drops, and trehalose additive from Opve Mega3 eye drops into a unique low-salt / low-osmolarity, lipid-free, and preservative-free formulation.

[0057] The inclusion of an organic solute component (carnitine) and a combination of one or more polyols (erythritol) and glycerol offers numerous advantages. The carnitine component possesses unique properties in a variety of actions, such as acting as a permeation protectant, an energy source for ocular cells, an antioxidant, promoting wound healing, acting as a protein molecular chaperone, and aiding in neuroprotection. Because carnitine is an amino acid, it is much larger than polyols, thus enabling it to act as a long-acting intracellularly compatible solute and protein stabilizer, providing beneficial properties when used at lower concentrations of less than 1%. Erythritol also acts as a potent tonic / permeabilizer; due to its larger size relative to glycerol, erythritol tends to accumulate in cells more slowly than glycerol, thus allowing for a longer intracellular retention time compared to glycerol when applied topically to the eye. The inclusion of glycerol contributes to faster relief due to its shorter residence time compared to erythritol. Therefore, the combination of all three provides full-spectrum permeation protection.

[0058] The combined inclusion of carboxymethyl cellulose (CMC) and hyaluronic acid (HA) resulted in an observed increase in viscosity greater than the cumulative increase from the inclusion of either one alone. This reduced shear and maintained the tear film’s ability to cover the eye, while providing improved tear film distribution on the cornea during blinking.

[0059] The inclusion of trehalose aims to provide a protective mechanism for reducing the expression levels of pro-inflammatory cytokines in response to hyperosmolarity, a condition commonly found in patients with dry eye.

[0060] Furthermore, the inventors sought ways to further reduce the osmolar concentration of the formulation without affecting the hyperosmolarity already present on the surface of the patient's dry eye. Many means of achieving this goal were considered. However, ultimately, in addition to reducing the potassium chloride concentration to 0.03%, the inventors also chose to reduce the boric acid concentration to 0.5%. This specific low combination of boric acid and potassium chloride has never been used in commercial eye drop formulations.

[0061] The inventors chose lipid-free formulations for a variety of reasons, but most notably because the inclusion of lipids can pose challenges to the development of preservative-free formulations, including but not limited to interference with the free flow from preservative-free vials. Therefore, by developing lipid-free formulations, the inventors were able, for the first time, to formulate high-performance artificial eye drops that can be used in combination with preservative-free multi-dose vials.

[0062] As demonstrated herein, although the novel formulation does not contain highly hydrophilic synthetic polymers (e.g., PEG400) and, unexpectedly, does not contain hydroxypropyl guar gum, its performance is similar to that of competing commercial formulations. Typically, the novel formulation is comparable to competing commercial formulations on some metrics and outperforms them on others, as described more specifically in Example 1.

[0063] Furthermore, retrospective analysis comparing the performance endpoints of the new formulation with OPTIVE MEGA3 showed that, among all metrics compared in the analysis, the new formulation outperformed OPTIVE MEGA3.

[0064] Finally, the new formulation also demonstrated that patients experienced significant reductions in dry eye symptoms during the second clinical trial, including improvements in the Severity Disease Index (OSDI) score observed on day 30, improvements in the Total Current Symptom Score (CSS) within 5 minutes, improvements in dry eye symptoms observed as early as 30 seconds, and a good Patient Drops Experience (PEDE) score observed on day 30. Importantly, no adverse events were reported throughout the trial.

[0065] Overall, the novel combination of penetrant protectants (1-carnitine and erythritol), humectants / lubricants (glycerin and carboxymethyl cellulose), trehalose, and sodium hyaluronate significantly increases the clinical usefulness of this product for a wider range of dry eye patients compared to other dry eye formulations without excipients.

[0066] The fundamental principle behind developing low-salt formulations is to ensure that artificial tear eye drops do not result in high osmolar concentrations that cause dry eye in patients. Corneal surface cells respond to osmotic pressure by regulating the transport of salt and water in an effort to maintain a constant cell volume. Under prolonged high-tension conditions, such as those present in dry eye, transport mechanisms for absorbing compatible solutes (including various amino acids and polyols) are upregulated. In one embodiment of the invention, an ophthalmic composition (e.g., artificial tears) containing a compatible solute component is formulated to have a tension higher than or exceeding isotonicity, advantageously in the tension range of about 300 mOsmol / kg or about 310 mOsmol / kg to about 600 mOsmol / kg or about 1000 mOsmol / kg. It is not intended to limit the invention to any particular operational theory; it is believed that under such conditions, both the immediate and long-term mechanisms of compatible solute accumulation in cells are stimulated, allowing for enhanced absorption and retention compared to cellular activity under isotonic or low-tension conditions. Once the compatible solute components accumulate in the cells, the cells' protective capacity against persistent high-tension damage is enhanced, for example, high-tension damage caused by dry eye syndrome and / or one or more other conditions / diseases. This enhanced protection results in improved cell metabolism and survival over several hours to several days after application of the ophthalmic composition of the present invention.

[0067] In the normal tear system, tear production, tear drainage, and tear evaporation are balanced to provide a moist, lubricated ocular surface. Typical values ​​for tear osmolality in normal individuals range from 290 mOsmol / kg to 310 mOsmol / kg, and these values ​​can vary throughout the day or in response to changing environmental conditions. In normal individuals, neural feedback from the ocular surface to the lacrimal glands controls tear production to maintain ocular surface fluid stability. Tear film tension has been proposed as one of several major stimuli in this regulatory feedback. In dry eye, dysfunction of the producing organs (various glands), drainage system, neural signaling mechanisms, or the ocular surface itself leads to insufficient tear film, ocular surface damage, and subjective discomfort.

[0068] At the cellular level, dry eye is typically characterized by a chronically high-tension extracellular (tear film) environment. Publicly reported tear film tension in dry eye patients ranges from 300 mOsmol / kg to 500 mOsmol / kg, with most values ​​falling between 320 mOsmol / kg and 400 mOsmol / kg. Under these conditions, cells tend to lose water and / or gain salt, and may undergo changes in cell volume. High tension has been shown to alter cellular metabolic processes, reduce enzymatic processes, and lead to apoptosis and cell death.

[0069] As a defense against the challenges of high tension, corneal cells have demonstrated the ability to upregulate the transport mechanisms of nonionic solutes, such as amino acids and polyols, and to accumulate these solutes intracellularly to maintain cell volume without altering electrolyte balance. Under these conditions, cellular metabolism has less impact than changes in volume and electrolytes, and such compounds are termed compatible solutes. Compatible solutes include, but are not limited to, the amino acids betaine (trimethylglycine), taurine, glycine, and proline, and the polyols glycerol, erythritol, xylitol, sorbitol, and mannitol. Compatible solutes are also considered osmotic protectants because they can allow cellular metabolism or enhance cell survival under high tension conditions that would otherwise limit cell viability.

[0070] Cells accumulate certain compatible solutes through intracellular biosynthesis and other compatible solutes through increased transmembrane transport from extracellular fluid (in this case, tear fluid). In both cases, the process involves specific synthetic or transporting proteins. Experimental evidence suggests that these proteins are activated under high-stress conditions, and the transcriptional and translational events that produce these proteins are upregulated under high-stress conditions. Conversely, experimental evidence suggests that when exposed to low-stress conditions, or when moving from a high-stress environment to an isostress environment, the cornea and other cells expel compatible solutes.

[0071] In dry eye, corneal surface cells are exposed to a high-tension environment and are stimulated to accumulate penetrating protective substances when available. The addition of isotonic or hypotonic artificial tears to the ocular surface provides symptom relief due to enhanced lubrication, but tends to downregulate the mechanism by which penetrating protective substances accumulate in these cells. This may result in increased susceptibility to penetrating damage for several minutes to hours after drop application, as the tear film reverts to its high-tension dry eye state.

[0072] Current FDA guidance states that "ophthalmic solutions should have an osmotic equivalent of 0.8% to 1.0% chloride to meet the labeling requirements for 'isotonic solutions'." This corresponds to a range of 274 mOsm / kg to 342 mOsm / kg. Furthermore, FDA guidance states that "ophthalmic preparations containing 2% to 5% chloride are hypertonic and are acceptable OTC products when labeled as 'hypertonic solutions'." This range equals 684 mOsm / kg to 1711 mOsm / kg. For the purposes of this invention, a "hypertonic" solution is defined as having an osmolality between these two ranges, or approximately 300 mOsmol / kg or 310 mOsmol / kg to approximately 600 mOsmol / kg or approximately 800 mOsmol / kg or approximately 1000 mOsmol / kg, equivalent to approximately 0.9% to approximately 1.8% chloride (1.8% is the maximum FDA guidance for topical ophthalmic solutions not labeled as hypertonic).

[0073] This invention addresses these concepts by formulating artificial tears with hypertonic levels more compatible with the hypertonic state of the ocular surface in dry eye conditions. In addition to being formulated within the hypertonic range (total tension from about 300 mOsmol / kg or about 310 mOsmol / kg to about 600 mOsmol / kg or about 1000 mOsmol / kg), the compositions of this invention also contain one or more organically compatible solute agents as described herein. In the compositions of this invention, the hypertonicity and the combination of incorporating one or more compatible solutes serve to stimulate or maintain the absorption of these protective substances into the corneal surface cells and to provide an adequate supply of these materials or substances.

[0074] I. Definition In the context of numerical values, unless otherwise explicitly indicated, the term “about” refers to ±10% of the nominal quantity.

[0075] In the context of ophthalmic pharmaceutical compositions, the terms "transparent," "transparency," etc., refer to sufficiently low absorbance and / or light scattering (e.g., opacity, pearlescent properties, etc.) such that the ophthalmic pharmaceutical composition does not appear substantially hazy, foggy, or cloudy to the naked eye. Transparent ophthalmic pharmaceutical compositions do not contain emulsions that are clearly separated into hydrophobic and hydrophilic portions.

[0076] In the context of ophthalmic pharmaceutical compositions, the terms "compatible solute," "permeate," etc., refer to substances that are absorbed into cells and serve to counteract the osmotic pressure present outside the cells. Without wishing to be bound by any theory, it is believed that compatible solutes possess osmotic protective properties, which can protect the surface cells of the eye from osmotic stress. It is also believed that the inclusion of compatible solutes increases the clinical usefulness of the compositions disclosed herein, compared to previous emulsion systems targeting lipid deficiency itself or meibomian gland dysfunction, to consider a wider range of subjects with dry eye syndrome.

[0077] The terms "dry eye syndrome," "dry eye syndrome," "keratitis sicca," "dry eye disease," and "keratoconjunctivitis sicca," in their conventional sense, refer to conditions or a spectrum of conditions in which the eye is unable to maintain a healthy tear film (i.e., a layer of tears) sufficient to cover the eye. Dry eye syndrome becomes more common with age because individuals typically produce fewer tears as they age.

[0078] As used herein, the term "effective amount" or "effective dose" in its conventional sense refers to an amount sufficient to produce the desired result. Therefore, the therapeutically effective amount used in treatment is an amount sufficient to reduce the degree of disease, symptom or condition, undesirable clinical manifestations, or both.

[0079] As used herein, “formulation,” “composition,” and “preparation” are equivalent terms referring to a composition of substances intended for pharmaceutical use (i.e., to produce a therapeutic effect and to have acceptable pharmacokinetic and toxicological properties).

[0080] In the context of ophthalmic pharmaceutical compositions, as used herein, the term "low-salt" refers to a salt content low enough to provide a stable submicron emulsion within the ophthalmic pharmaceutical composition. Salt content can be measured by a variety of methods known in the art, such as measurements of ionic strength. Therefore, the term "low-salt ophthalmic pharmaceutical composition" refers to a pharmaceutical composition for use in the eye having a sufficiently low salt content such that a submicron emulsion containing surfactants and therapeutic lipids is stable therein.

[0081] The term "polymer lubricant" refers to a polymeric agent capable of covering the ocular surface (i.e., a soothing agent) and providing lubrication to the eye. Exemplary polymeric lubricants that can be used in the compositions and methods disclosed herein include any of a variety of cellulose derivatives (e.g., hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, etc.), polyvinylpyrrolidone, polyvinyl alcohol, and mixtures thereof.

[0082] As used herein, the term "hyaluronic acid" refers to any grade that can be formulated for topical application. Preferably, hyaluronic acid is in the form of sodium hyaluronate. In some embodiments, the hyaluronic acid has a content of about 0.5 mg / L. 3 / kg to approximately 4.0m 3 / kg, more preferably about 1.1m 3 / kg to approximately 2.0m 3 / kg, or more preferably about 2.5m 3 / kg to approximately 4.0m 3 The intrinsic viscosity is approximately 2.2 m / kg. Some implementations can have an intrinsic viscosity of approximately 2.2 m / kg. 3 / kg to approximately 2.6m 3 The intrinsic viscosity is approximately 1.1 m / kg, and some implementations can have an intrinsic viscosity of approximately 1.1 m / kg. 3 / kg to approximately 3.0m 3 The intrinsic viscosity is approximately 1.1 m³ / kg. In some preferred embodiments, the hyaluronic acid has an average molecular weight of about 2 million Daltons to about 2.6 million Daltons. In some other preferred embodiments, the hyaluronic acid has an intrinsic viscosity of approximately 1.1 m³ / kg. 3 / kg to approximately 2.0m 3 The intrinsic viscosity is approximately 500,000 Daltons to approximately 1,200,000 Daltons. In some other preferred embodiments, the hyaluronic acid has an average molecular weight of approximately 500,000 Daltons to approximately 1,200,000 Daltons.

[0083] As used herein, the terms “L-carnitine” and “carnitine” refer to L-carnitine and its components, such as carnitine itself, its isomers / stereoisomers, its salts, its derivatives, and mixtures thereof. L-carnitine is an organically compatible solute and has been identified as essential for various parts of fatty acid metabolism, thus playing a vital role in the metabolism of liver and muscle cells. Carnitine can also serve as an energy source for many cell types, including eye cells. Carnitine components can exhibit unique properties in a variety of roles, such as acting as an osmotic protectant, in fatty acid metabolism, as an antioxidant, in promoting wound healing, as a protein chaperone, and in neuroprotection.

[0084] As used in this article, the term "erythritol" refers to a 4-carbon polyol and is used as an effective tensioning / penetrating agent.

[0085] As used herein, the term "trehalose" refers to a naturally occurring α-linked disaccharide formed by an α,α-1,1-glucosidic bond between two α-glucose units.

[0086] As used in this article, the term "prevention" refers to reducing the occurrence of dermatological symptoms (e.g., urticarial rubella) in patients. Prevention can be complete (i.e., no detectable symptoms) or partial, resulting in fewer observed symptoms than would be possible without treatment.

[0087] As used herein, the terms “prevention” and “treatment” are not intended to be absolute terms. Treatment can refer to any delay in the onset of symptoms, such as a reduction in the frequency or severity of symptoms, improvement in symptoms, improvement in patient comfort, reduction in dry eye symptoms, etc. The effectiveness of treatment can be compared with individuals or a database of individuals who did not receive the given treatment, or with the same patient before or after treatment was discontinued.

[0088] The terms "salt-sensitive viscosity-modifying polymer," "salt-sensitive polymer," etc., refer to polymeric agents that can be used to maintain the stability of submicron emulsions inherently under low-salt conditions in the low-salt ophthalmic pharmaceutical compositions disclosed herein, and which subsequently destabilize the submicron emulsions upon increasing salt content. In the context of this document, the term "destabilization" refers to a change in the submicron emulsion that results in the release of therapeutic lipids from the submicron emulsion. Therefore, in the context of this document, the term "salt-sensitive," etc., refers to a change in one or more properties of a compound (e.g., conformation, degree of hydration, effective charge due to ion shielding, viscosity, etc.) in response to changes in salt concentration. Exemplary salt-sensitive viscosity-modifying polymers include acrylic polymers crosslinked with polyolefin ethers or divinyl glycol. Preferred salt-sensitive viscosity-modifying polymers include crosslinked copolymers of acrylic acid and C10-C30 alkyl esters of acrylic acid, commonly referred to as Pemulen. ™TR-2 (Lubrizol Corporation, Wickliffe, OH).

[0089] In the context of surfactants, the term "sorbitol ester" generally refers to a class of polyethylene glycol (i.e., PEG) derivatives of sorbitol that have been further esterified with fatty acids, as is known in the art.

[0090] The term "surfactant" in its conventional sense refers to a compound that can reduce the surface tension of a liquid, the interfacial tension between two liquids, or the surface tension between a liquid and a solid.

[0091] Unless otherwise stated, as used herein, the term "tears" generally refers to the basal tear fluid of the mammalian eye, which functions to continuously soak and nourish the cornea. Other types of tears include, for example, reflex tears produced by stimulation of the eye by foreign particles or lachrymatory compounds, and psychogenic tears produced, for example, by intense emotional stress, pain, or physical pain.

[0092] The terms "tear film," "epidermal membrane," etc., conventionally refer to the multi-layered covering of a normal eye, comprising an innermost mucus layer, a middle aqueous layer, and an outermost lipid layer. The innermost mucus layer contains proteins, such as mucin produced by goblet cells of the conjunctiva, and facilitates the uniform diffusion of the overlying middle aqueous layer, for example, by providing a hydrophilic layer covering the cornea. The middle aqueous layer is produced by the lacrimal glands and contains water, proteins, and salts as known in the art. The outermost lipid layer contains oil produced by the meibomian glands and covers the middle aqueous layer, providing a hydrophobic barrier that encapsulates the tear fluid and prevents outflow (e.g., onto the cheeks). Importantly, the outermost lipid layer reduces evaporation from the middle aqueous layer.

[0093] The term "therapeutic lipid" refers to a pharmaceutically acceptable amphiphilic or hydrophobic agent used to supplement and / or enhance the naturally occurring oil produced by the meibomian glands, which form the outermost lipid layer of the tear film. In some embodiments, the therapeutic lipid is a hydrophobic agent. Without wishing to be bound by any theory, it is believed that the symptoms of dry eye syndrome can be caused by insufficient production of the naturally occurring oil from the meibomian glands. Therefore, it is further considered that supplementation and / or enhancement by the therapeutic lipids described herein is beneficial for the treatment of dry eye syndrome.

[0094] As used herein, the term "therapeutic effective amount" refers to an amount of composition or a pharmaceutical agent in a composition sufficient to improve one or more aspects of a condition.

[0095] Therapeutic efficacy can also be expressed as an increase or decrease in "multiples". For example, an effective therapeutic dose can have an effect that is at least 1.2 times, 1.5 times, 2 times, 5 times or more than that of the control.

[0096] As used herein, the term "tonist" in its conventional sense refers to a compound that can regulate the effective osmotic pressure within cells. For example, the tonicity of a pharmaceutical dosage form can be regulated by a tonicist for comfort during administration or infusion. Exemplary tonics include dextran, glycerol, mannitol, KCl, and NaCl. Tonics can provide additional beneficial effects, including, for example, acting as humectants or lubricants.

[0097] As used herein, the term “treatment” refers to a method (e.g., procedure or protocol) used to obtain a favorable or desired outcome (including clinical outcomes). “Treatment,” “parole,” or “improvement” of a disease, symptom, or condition means a reduction (i.e., prolongation) in the time course of the severity, undesirable clinical manifestations, or both of the disease, symptom, or condition compared to an untreated disease, symptom, or condition. For the purposes of the methods disclosed herein, favorable or desired clinical outcomes include, but are not limited to, reduction or improvement of one or more detectable or undetectable symptoms (e.g., symptoms of dry eye syndrome), reduction in the severity of symptoms, stabilization of the condition (i.e., no worsening), delay or slowing of the progression of symptoms, improvement or parole of symptoms, and remission (whether partial or complete).

[0098] As used herein, “treatment” can include preventative treatment. Treatment methods include administering a therapeutically effective amount of an active agent to a subject. Administration may consist of a single administration or may include a series of administrations. The length of treatment depends on a variety of factors, such as the severity of the condition, the patient’s age, the concentration of the active agent, the activity of the composition used in the treatment, or a combination thereof. It should also be understood that the effective dose of a pharmaceutical agent used for treatment or prevention may be increased or decreased during a particular treatment or prevention regimen. Changes in dose can be obtained and known by standard diagnostic assays known in the art. In some cases, prolonged administration may be required. For example, the composition may be administered to the subject in an amount and for a duration sufficient to treat the patient.

[0099] As used in this article, the phrase "multi-dose, preservative-free" or "MDPF" means a formulation that is preservative-free but stable enough to allow for safe administration of multiple doses.

[0100] As used herein, the phrase "multi-dose, preservative-free bottle" or "MDPF bottle" refers to a bottle suitable for multiple-dose administration while being designed to maintain the sterility of the liquid contained within (such as the artificial eye drops described herein). An example of such a bottle is the FDA-approved MDPF bottle used with RESTASIS MULTIDOSE 0.05% (see Marx & Birkoff, Drug Development & Delivery, 17(7):40-44 (2017)). Figure 3 The bottle includes (i) a double-cap design, characterized by a ventilated cap and a non-ventilated cap as described in U.S. Patent No. 10,806,628 (see “Disclosure”). Figures 1 to 6 (ii) a container having a dispensing dropper; (iii) a one-way valve, which may optionally include a filter, configured to allow therapeutic agents contained in the container to reach the dispensing dropper, but to prevent the therapeutic agent and / or other fluids or contaminants from re-entering the container, such as the Novelia valve from Rexam and the valve system of an ophthalmic squeeze dispenser from Aptar Pharma (components (ii) and (iii) are described in U.S. Patent Nos. 8,292,129, 8,561,859, 9,669,974, and 9,676,525); and (iv) a therapeutic sterile liquid, such as the artificial eye drop formulation described herein; each of these references is hereby expressly incorporated herein by reference in its entirety.

[0101] II. Instructions for Use In another aspect, a method for treating dry eye syndrome is provided. The method comprises administering a therapeutically effective amount of a low-salt ophthalmic pharmaceutical composition, as disclosed herein, to a subject requiring treatment for dry eye syndrome, thereby treating the subject's dry eye syndrome. In one embodiment, the low-salt ophthalmic pharmaceutical composition comprises a polymeric lubricant, a salt-sensitive viscosity-modifying polymer, one or more tension agents, sodium hyaluronate, and trehalose.

[0102] This formulation is preferably preservative-free (purite-free). ® However, in other embodiments, the formulation contains a preservative, and in addition to containing Purite at a concentration of about 0.1% (w / v). ® Except for the formulations listed in Table 5, this formulation can be packaged into unit dosage forms.

[0103] In other embodiments, the formulation is preferably preservative-free (purite-free). ® It can be used in combination with preservative-free multi-dose bottles.

[0104] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition comprising a polymeric lubricant, a salt-sensitive viscosity-modifying polymer, one or more tension agents, trehalose, and hyaluronic acid salt.

[0105] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the hyaluronic acid salt is sodium hyaluronate.

[0106] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein one or more tension agents are selected from carnitine, glycerin, erythritol and trehalose.

[0107] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the composition comprises carnitine, glycerin, erythritol and trehalose.

[0108] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the polymeric lubricant is sodium carboxymethyl cellulose present at a concentration of about 0.5% (w / w).

[0109] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising a compatible solute, wherein the compatible solute is levocarnitine.

[0110] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition comprising erythritol at a concentration of about 0.25% (w / w) and levocarnitine at a concentration of about 0.25% (w / w).

[0111] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein glycerin is present at a concentration of about 0.9% (w / w).

[0112] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the sodium hyaluronate is present at a concentration of about 0.1% (w / w).

[0113] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the composition is preservative-free.

[0114] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising a buffer.

[0115] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the buffer is boric acid present at a concentration of about 0.5% (w / w).

[0116] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising sodium borate decahydrate.

[0117] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising sodium citrate dihydrate.

[0118] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising potassium chloride.

[0119] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising dehydrated calcium chloride.

[0120] In some embodiments, the present invention relates to a method for administering a low-salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, the low-salt ophthalmic pharmaceutical composition further comprising a pH adjuster, wherein the pH adjuster is NaOH, and wherein the pharmaceutical composition has a pH of about 7.3.

[0121] In other embodiments, the present invention relates to a method for administering a combination of a low-salt ophthalmic pharmaceutical composition and a vial, wherein the low-salt ophthalmic pharmaceutical composition comprises: sodium hyaluronate at a concentration of about 0.1% (w / w); trehalose at a concentration of about 1.5% (w / w); erythritol at a concentration of about 0.25% (w / w); levocarnitine at a concentration of about 0.25% (w / w); potassium chloride at a concentration of about 0.03% (w / w); and [unclear - possibly a concentration of 0.006% (w / w)]. The solution contains: calcium chloride dihydrate (approximately 0.006% w / w); magnesium chloride hexahydrate (approximately 0.5% w / w); boric acid (approximately 0.5% w / w); sodium borate decahydrate (approximately 0.20% w / w); sodium citrate dihydrate (approximately 0.10% w / w); sodium carboxymethyl cellulose (approximately 0.5% w / w); glycerol (approximately 0.9% w / w); NaOH; and water. The bottle is designed to reliably dispense sterile, preservative-free liquids.

[0122] In some embodiments, the present invention relates to a method for treating dry eye syndrome, the method comprising administering to a subject requiring treatment for dry eye syndrome a low-salt ophthalmic pharmaceutical composition of any combination according to the above embodiments.

[0123] In some embodiments, the present invention relates to a method for treating dry eye syndrome, the method comprising administering the low-salt ophthalmic pharmaceutical composition comprising any combination of the embodiments described above to a subject requiring treatment for dry eye syndrome using a preservative-free bottle; thereby treating the dry eye syndrome.

[0124] III. Examples Example 1 - Development of a Novel Low-Salt Ophthalmic Composition The inventors seek innovative solutions to advance the field of artificial tears by developing unique formulations that combine beneficial components of various artificial tear formulations into a single artificial tear formulation.

[0125] The result is the formulation described in Table 1, which for the first time combines the osmotic protective properties of a combination of erythritol, L-carnitine, and glycerin from Refresh Optive eye drops, carboxymethyl cellulose (CMC) and hyaluronic acid (HA) from Opve Fusion eye drops, and trehalose additive from Opve Mega3 eye drops into a unique low-salt / low-osmolarity, lipid-free, and preservative-free formulation.

[0126] Two forms of this formulation were developed, referred to herein as Formulation 1 and Formulation 3.

[0127] As described in the following examples, two formulations were subjected to human clinical trials.

[0128] Example 2 - Clinical Study - A multicenter, single-mask, randomized study comparing the efficacy and safety of novel artificial tear formulations 1 and 2 in participants with dry eye syndrome (DED) over 90 days. The aim of this study was to evaluate the efficacy and safety of formulation 1 compared to formulation 2 in subjects with signs and symptoms of DED.

[0129] Methodology This is a multicenter, single-masked, randomized, dual-group, parallel-group study comparing the efficacy and safety of formulation 1 and formulation 2 (see [link]). Figure 1 This study was designed to compare the relative relief of DED symptoms between formulations, and to characterize the effect on ocular surface staining.

[0130] The study population consisted of adult male and female participants with objective and subjective evidence of DED. To demonstrate a reduction in DED symptoms and ocular surface staining at day 90, inclusion criteria were used to include participants with clinically significant ocular surface staining and DED symptoms at the screening (day -7) and day 1 (baseline) visits. These participants were expected to have clinically treatable conditions with sufficient potential for improvement.

[0131] All eligible study participants received REFRESH PLUS during the introductory period prior to the Day 1 (baseline) visit. ® The treatment lasted approximately 7 days. Participants were instructed to instill 1 to 2 drops of the instillation drug into each eye three times daily for 7 days. Participants who still met the eligibility criteria at the Day 1 (baseline) visit were randomly assigned in a 1:1 ratio to receive either formulation 1 or formulation 2, stratified centrally according to the total ocular staining score of the study eye on Day 1 (baseline) (mild / moderate = 6 to 25 points, relative to severe = 26 to 43 points). Participants were instructed to instill 1 to 2 drops of the designated study intervention (investigation eye drops) into each eye three times daily for approximately 90 days. The primary efficacy endpoint was total ocular staining, and the primary time point for analysis was day 90.

[0132] Number of participants (planning and enrollment) Approximately 400 participants were enrolled at about 28 centers in the United States (200 participants in each treatment group) to ensure that 340 participants (170 participants in each treatment group) completed the study up to day 90, assuming an exit rate of approximately 15%, and participants who prematurely discontinued the study were not replaced.

[0133] Treatment plan During the 7-day induction period (during which all subjects received REFRESH PLUS) ® Following this, subjects were randomly assigned in a 1:1 ratio to receive either Formulation 1 or Formulation 2 for 90 days. For all study drugs, including the delivery drug, subjects were instructed to instill 1 to 2 drops into each eye three times daily. As this was a single-mask study, Formulation 1 and Formulation 2 were each provided in the same outer carton (kit). Study drug information is summarized in Table 1.

[0134] According to the protocol, participants were instructed to instill 1 to 2 drops of the study drug into each eye three times daily. To ensure treatment adherence, participants completed a study eye drop usage questionnaire at each follow-up visit.

[0135] A total of 399 subjects received the study drug at least once and were included in the safety population (199 subjects in formulation 2 and 200 subjects in formulation 1).

[0136] The mean (SD) study duration was 87.0 (12.19) days in formulation 2 and 82.8 (22.69) days in formulation 1. A total of 97 (48.7%) subjects in formulation 2 and 88 (44.0%) subjects in formulation 1 received study treatment for at least 90 days.

[0137] No treatment interruptions due to COVID-19 were reported. Key criteria for diagnosis and qualification Adult male and female participants with objective and subjective evidence of DED. To demonstrate a reduction in DED symptoms and ocular surface staining at day 90, inclusion criteria were used to include participants with clinically significant ocular surface staining and DED symptoms at the screening (day -7) and day 1 (baseline) visits. These participants were expected to have clinically treatable conditions with sufficient potential for improvement.

[0138] In the safety cohort, the most common ophthalmic medical and surgical histories reported by preferred term (PT) (overall >10% of subjects) were dry eye (100.0%), cataract (24.8%), myopia (15.5%), intraocular lens implantation (12.5%), astigmatism and nuclear cataract (11.3% each), and hyperopia (10.5%). In the safety cohort, 29 subjects (7.3%) received concomitant other ophthalmic medications (Formulation 2: 16 subjects [8.0%]; Formulation 1: 13 subjects [6.5%]). The most common concomitant other ophthalmic medication (>1.0% of subjects in either treatment group) was cyclosporine.

[0139] Patient Demographics A total of 638 participants were screened at 23 centers in the United States. Of these, 400 participants were randomized at 21 centers (200 participants in formulation 2 and 200 participants in formulation 1) (see Table 2). The ITT cohort includes all 400 randomized participants.

[0140] Demographic characteristics were balanced between the Formulation 2 treatment group and the Formulation 1 treatment group (see Table 2). Overall, the mean (SD) age of the participants was 58.4 (13.76) years. The majority of participants were female (323 [80.8%]), white (304 [76.0%]), and neither Hispanic nor Latino (335 [83.8%]). In the overall ITT population, 378 (94.5%) participants completed the study, and 22 (5.5%) discontinued it. The most common reason for discontinuation in both treatment groups was participant withdrawal (5 [2.5%] participants in Formulation 2 and 7 [3.5%] participants in Formulation 1). Three (1.5%) participants in Formulation 1 discontinued the study due to adverse events (AEs). Of these, only one participant discontinued due to an AE that occurred during treatment. In the safety cohort, a total of 5 participants (1.3%) were affected by COVID-19. Of these, 3 participants (0.8%) reported COVID-19-related adverse events (AEs), including one participant who experienced a non-treatment-related serious adverse event (SAE) of COVID-19 that led to study discontinuation. In addition, several assessments or procedures were affected, each affecting ≤2 participants. Datasets to be analyzed Efficacy and safety measurements Efficacy assessments included corneal staining, conjunctival staining, ink application test (under anesthesia), OSDI score, TBUT, and self-assessment questionnaires / surveys. The following efficacy endpoints were collected during the study: Primary efficacy endpoint • Change in total staining score relative to baseline on day 90 Secondary efficacy endpoint • Change in current symptoms (combined symptoms) relative to baseline on day 90. Other efficacy endpoints • Change in corneal staining score relative to baseline • Change in conjunctival staining score relative to baseline • Changes in total staining score relative to baseline, except for day 90 • Changes in current symptom survey (combination of all symptoms) relative to baseline, except for day 90. • Changes in individual symptom scores relative to baseline from the current symptom survey • Change in ink application test relative to baseline • Change of TBUT relative to baseline • Changes in Functional Visual Acuity Questionnaire, 5-Minute Blurred Vision Questionnaire, and Eye Discomfort Questionnaire relative to baseline • OSDI change relative to baseline • Study on eye drop experience and tolerance questionnaire The revised National Eye Institute (NEI) grading scheme was used to assess corneal and conjunctival staining. The total staining score was defined as the sum of the corneal and conjunctival staining scores.

[0141] The current symptom survey uses the Visual Analogue Scale (VAS) from 0 (asymptomatic) to 100 (maximum severity) to assess the following symptoms: burning, dryness, irritation, gritty / foreign body sensation, blurred / fluctuating vision, and overall eye pain / discomfort.

[0142] The OSDI questionnaire was designed to capture a range of ocular surface symptoms, including those associated with dry eye, their severity, and their impact on the subject's functional abilities. Symptoms were assessed on a scale from 0 (no disease) to 100 (maximum severity of disease), with the OSDI score calculated as (sum of scores) × 25 / (number of questions answered).

[0143] The VAS (Visual Analogue Scale) on a scale of 0 to 100 was used to evaluate questionnaires involving functional visual acuity, 5-minute blurred vision, and eye discomfort, as well as to study the experience and tolerance of eye drops.

[0144] The following safety assessments were performed during the study: adverse event (AE) monitoring, slit-lamp biomicroscopy, current corrected distance visual acuity, best corrected distance visual acuity (BCDVA), and intraocular pressure (IOP) (only for subjects with glaucoma or ocular hypertension [OHT]).

[0145] Statistical methods : Based on the assumption that the inter-group difference in the mean change of total staining (the primary power variable) relative to baseline on day 90 (i.e., the non-inferiority margin) is 2.3 units, with no inherent treatment differences and a common standard deviation (SD) of 6.01, each intervention will require 170 subjects to detect the above intervention difference at a one-sided 2.5% significance level with 90% or greater power. Assuming a 15% dropout rate, 200 subjects will be randomly assigned to each treatment group, for a total of 400 subjects.

[0146] The primary power analysis for the intention-to-treat (ITT) population was performed using a mixed-effects repeated measures (MMRM) model. Differences and 95% confidence intervals (CIs) were constructed using the least squares (LS) means from the MMRM model, with treatment, visits, visits by treatment group, baseline total chromatogram, and baseline total chromatogram interactions by visit group as fixed effects.

[0147] Using a protocol-compliant (PP) population, sensitivity analysis of the primary efficacy endpoint was performed using principal efficacy analysis methods. Additional details are provided in the PP data exclusion algorithm.

[0148] Secondary efficacy variables were analyzed using the same models described for the primary efficacy analysis.

[0149] Safety analysis was conducted based on the safety population. Continuous variables were summarized by the number of subjects with observations (n), mean, SD, median, 1st and 3rd quartiles, minimum and maximum values. Categorical variables were summarized by the number of subjects with observations or events and percentages based on the specified population. Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0.

[0150] effect : The conclusions for the primary and secondary endpoints are as follows: • Based on a non-inferiority margin of 2.3, measured by change relative to baseline, and an upper limit of 95% CI, formulation 1 was non-inferior to formulation 2 in reducing total staining on day 90 (LS mean difference 1.1 [95% CI: 0.01, 2.27]). However, the lower limit of 95% CI was greater than 0, indicating that formulation 1 was less effective than formulation 2 in the ITT population.

[0151] • In the PP population, the mean LS difference in total staining score on day 90 between formulation 1 and formulation 2 was 1.3 (95% CI: 0.13, 2.41), indicating that formulation 1 was inferior to formulation 2.

[0152] • In both the ITT and PP groups, both treatment groups showed significant within-group improvement in total staining score at day 90 compared to baseline.

[0153] • Regarding secondary endpoints, both treatment groups showed similar reductions in current severity total score at day 90, with the mean LS (SE) change relative to baseline being -138.5 (11.46) in treatment group 2 and -136.5 (11.62) in treatment group 1 (mean LS difference in the ITT population was 2.1 [95% CI -30.03, 34.14]).

[0154] The conclusions for other efficacy endpoints are as follows (ITT population): • In both treatment groups, significant within-group improvements in the mean change of corneal and conjunctival staining scores relative to baseline were observed at all follow-up visits from day 7 to day 90.

[0155] • From day 7 to day 60, both treatment groups showed significant intragroup improvements in total staining scores relative to baseline. The mean difference in LS between treatment group 1 and treatment group was 0.8 (95% CI: 0.02, 1.66) on day 7, 0.2 (95% CI: -0.77, 1.16) on day 30, and 1.3 (95% CI: 0.28, 2.30) on day 60.

[0156] • Formulation 1 was comparable to formulation 2 in reducing the total score of current symptom severity over time. The mean difference in LS between formulation 1 and formulation 2 was -1.7 (95% CI: -28.31, 24.92) on day 7, 1.9 (95% CI: -27.41, 31.13) on day 30, and 5.0 (95% CI: -25.90, 35.99) on day 60.

[0157] • Formulation 1 was comparable to Formulation 2 in reducing individual symptom scores (i.e., burning, dryness, irritation, gritty / foreign body sensation, blurred / fluctuating vision, and overall eye pain / discomfort) over time in terms of reducing the severity of current symptoms.

[0158] • No significant intragroup improvement in the mean change of Schmol test values ​​relative to baseline was observed over time in either treatment group.

[0159] • For formulation 2, significant within-group improvements in the mean change of TBUT relative to baseline were observed at all follow-up visits, starting from day 7, and for formulation 1, starting from day 30.

[0160] • Generally, starting from day 7, formulation 1 was numerically superior to formulation 2 in terms of the functional visual acuity questionnaire (composite score), but both treatment groups showed significant intra-group improvement from baseline at all follow-up visits. At day 90, the mean (SD) change from baseline in the composite score based on the combined visual acuity task was 16.3 (24.61) for formulation 2 and 18.9 (23.41) for formulation 1. At day 90, the mean (SD) change from baseline in general visual acuity was 15.6 (29.86) for formulation 2 and 17.9 (29.89) for formulation 1.

[0161] • Following administration of the eye drops on days 1 and 90, formulation 1 was comparable to formulation 2 in reducing blurred vision and improving ocular discomfort. Five minutes after administration on day 90, the mean (SD) change in blurred vision relative to baseline was 15.0 (24.28) for formulation 2 and 12.1 (22.69) for formulation 1. Five minutes after administration on day 90, the mean (SD) change in ocular discomfort relative to baseline was 13.4 (21.32) for formulation 2 and 14.6 (25.95) for formulation 1.

[0162] • From day 7 to day 90, both treatment groups showed significant intragroup improvements in OSDI scores relative to baseline. On day 90, the mean change in LS (SE) relative to baseline was 17.7 (1.57) for formulation 2 and -20.6 (1.59) for formulation ' (mean difference in LS was -2.9 [95% CI: -7.34, 1.47]).

[0163] • Throughout all follow-up visits, the average response to each of the six questions on the study of eye drop experience and tolerability was generally comparable across the treatment groups (i.e., sustained relief, long-lasting relief [effectiveness], immediate relief, stickiness, burning / stirring, and soothing).

[0164] Security : The safety conclusions from this study are as follows: • Overall, at least one treatment-related adverse event (TEAE) was reported in 21 (10.6%) subjects in formulation 2 and 31 (15.5%) subjects in formulation 1.

[0165] • The most frequently reported TEAEs (≥1.0% of subjects) by preferred terminology were conjunctival hemorrhage, vitreous floaters, eye irritation, punctate keratitis, and styes in formulation 1, and conjunctival edema and headache in formulation 2. No TEAEs occurred in >1% of subjects in either treatment group by preferred terminology.

[0166] • No deaths were reported during the study.

[0167] • One (0.5%) subject in formulation group 2 experienced two treatment-related serious adverse events (pneumonia and acute respiratory failure), which were not considered to be related to the study treatment.

[0168] • Treatment-related TEAEs were reported in 2 subjects (1.0%) in formulation 2 and 4 subjects (2.0%) in formulation 1. All treatment-related TEAEs fell under the systemic organ category of ocular symptoms. Except for one subject in formulation 1 with a treatment-related TEAE of moderate ocular irritation, all treatment-related TEAEs were of mild severity.

[0169] • One (0.5%) subject in formulation 1 had a TEAE of dry eye that led to study discontinuation; the severity of the event was mild and was not considered to be related to the study treatment.

[0170] • Most subjects in both treatment groups showed no change in current corrected distance visual acuity and BCDVA relative to baseline on day 90.

[0171] • Clinically significant biomicroscopic findings included eyelid erythema and conjunctival hyperemia (1 subject in each of formulation 2) and a stye (1 subject in formulation 1).

[0172] • In the formulation 2 group, subjects with glaucoma or OHT had mean changes in IOP relative to baseline ranging from -0.4 mmHg to +1.0 mmHg on days 7, 30, and 60. No subjects in the formulation 1 group had glaucoma or OHT. in conclusion Based on the non-inferiority margin measured by change relative to baseline and the upper limit of the 95% CI, formulation 1 was non-inferior to formulation 2 in reducing total staining on day 90. However, the lower limit of the 95% CI was greater than 0, indicating that formulation 1 was less effective than formulation 2. For other efficacy endpoints, including the secondary endpoint of change in current symptom survey relative to baseline on day 90, formulation 1 was generally comparable to formulation 2.

[0173] Overall safety results indicate that formulation 1 is safe and well-tolerated, and the safety profile of formulation 1 is generally similar to that of formulation 2.

[0174] Example 2 - Crossover Clinical Study Comparison of Formulation 1 and OPTIVE MEGA3 Given the favorable results observed in the multicenter, single-masked, randomized, dual-group, parallel-group human studies comparing the safety and efficacy of formulations 1 and 2 (see Example 5), the endpoint analysis compared key data points from formulation 1 in the study with key data points from separate human clinical trials evaluating the OPTIVE MEGA3 (“OM-3”) formulation.

[0175] In terms of patient selection, treatment protocols, and analysis, patients in the OM-3 clinical trial were treated in a manner similar to that used in the human clinical trials described in Example 5.

[0176] Specifically, ocular staining and ocular surface disease index analysis were performed on patients at baseline, day 7, day 30, day 60, and day 90.

[0177] like Figure 4 As shown, formulation 1 exhibited a higher mean change in ocular staining relative to baseline at each time point compared to OM-3.

[0178] like Figure 5 As shown, compared with OM-3, formulation 1 exhibited a higher mean change in the ocular disease severity index relative to baseline at each time point.

[0179] Although this retrospective analysis was not a head-to-head study, the data clearly show that formulation 1 has a positive trend of outperforming OPTIVE MEGA3 in all metrics compared in this analysis.

[0180] Example 3 - Re-preparation As demonstrated by the results disclosed in Example 5, Formulation 1 has shown clinically beneficial effects in pivotal human clinical trials. While Formulation 1 did not demonstrate non-inferiority to Formulation 2 at stringent ocular staining endpoints, it still achieved numerically better results than Formulation 2 in terms of the Ocular Surface Disease Index (OSDI), which is typically the primary endpoint in studies of consumer artificial eye drops. As described in Example 5, Formulation 1 also met or exceeded the efficacy of Formulation 2 in several secondary measurements. Furthermore, as... Figure 4 and Figure 5 As shown in the figure and described in Example 6, Formulation 1 also achieved a positive trend compared to OPTIVE MEGA3.

[0181] To further improve and enhance the efficacy of Formulation 1, the formulation was further reformulated to reduce the overall level of osmolality by decreasing the potassium chloride concentration, as shown in Table 5. This new formulation is described as Formulation 3. Further human clinical trials will be conducted to obtain patient experience data on the new formulation's symptom relief and product tolerability. Such patient-reported outcomes are widely considered important indicators for clinicians and patients and can be used to further guide prescribing and purchasing decisions.

[0182] Example 4 - Clinical Study- A multicenter, single-mask, randomized study comparing the efficacy and safety of novel artificial tear formulations 1 and 2 in participants with dry eye syndrome (DED) over 90 days. Formulation 1 (a novel over-the-counter ophthalmic solution for the treatment of dry eye syndrome) containing trehalose and sodium hyaluronate was developed. The study aimed to characterize the effects of formulation 1 on patient symptom relief, product tolerability, and patient eye drop experience.

[0183] This single-group, single-center, open-label study utilized the validated Ocular Surface Disease Index (OSDI) and other Visual Analogue Scales (VAS) to assess symptom relief and evaluate patient experience. The OSDI is a validated patient-reported outcome (PRO) tool consisting of a 12-item questionnaire that assesses the severity of dry eye symptoms using a 5-point scale. The OSDI aims to capture a range of ocular surface symptoms, including those associated with dry eye, their severity, and their impact on participants' functional abilities. The OSDI ranges from 0 (no disease) to 100 (maximum severity disease). The Patient Eye Drop Experience (PEDE) survey used VAS (0 to 100) to evaluate short- and long-term subjective experiences with eye drop relief and tolerability of the eye drops. The Current Symptom Survey (CSS) used VAS (0 to 100) to evaluate the subjective onset time of eye drops associated with symptom relief.

[0184] The study endpoints are as follows: Primary endpoint : • Change in OSDI score relative to baseline on day 30 Secondary endpoint : • PEDE score on day 30 • Change in symptom score relative to baseline within 5 minutes after administration of formulation 3 Exploratory endpoint : • PEDE score on day 14 • Change in OSDI score relative to baseline on day 14 Inclusion criteria : • Participants must be 18 years of age or older. • Written informed consent and written records complying with relevant national and local privacy requirements have been obtained prior to any research procedure. • Have you used artificial tears for dry eye in the past year? • Women of childbearing age who have a negative pregnancy test result at screening; these patients must currently be using reliable contraception and agree to use reliable contraception during the study period. • At screening and baseline visits, the OSDI score should be ≥18 and ≤65 (based on a 0 to 100 scale). • During screening visits, at least three consecutive tear breakup time (TBUT) tests in one eye must show a result ≤10 seconds. • At screening and baseline visit, at least one region of the cornea (5 study areas) or conjunctiva (6 study areas) associated with dry eye disease in at least one eye of both eyes must have a grade 1 to 4 (revised NEI Grid, score range = 0 to 5) staining. • Able / agree to continue wearing current corrective lenses during the study period (if applicable) • Using a 3-meter LogMar chart, the current corrected distance visual acuity in each eye is at least 20 / 32 Snellen equivalent, and existing glasses correction is used during screening visits (if necessary). • If any form of topical ophthalmic cyclosporine (i.e., RESTASIS) is used ® ), Lifitegrast 5% ophthalmic solution (Xiidra) ® If so, participants must have used the drops for ≥90 days prior to the screening visit and plan to continue using them during the study without changing their regimen. • For patients with primary open-angle glaucoma or ocular hypertension (OHT), intraocular pressure (IOP) in both eyes must be ≤21 mmHg at the screening visit. Patients with primary open-angle glaucoma or OHT are included provided they are using bilateral stable monotherapy with controlled IOP (≤21 mmHg) in both eyes. Any topical IOP-lowering medication must have a start date ≥3 months prior to the screening visit date, and the expected dose must not change during the study period. • Able to follow research instructions and potentially complete all required visits. Data source : The OSDI is a validated patient-reported outcome (PRO) tool consisting of a 12-item questionnaire that assesses the severity of dry eye symptoms using a 5-point scale. The aim of this assessment is to capture a range of ocular surface symptoms, including those associated with dry eye, their severity, and their impact on participants' functional abilities, with scores ranging from 0 (no disease) to 100 (maximum severity of disease). Participants completed the OSDI at the screening visit, baseline visit, day 14, and day 30 / early exit.

[0185] The Patient Eye Drop Experience Survey used the Visual Analogue Scale (VAS) to evaluate short- and long-term subjective experiences with eye drops in terms of relief and tolerability of the study eye drops. All participants completed the PEDE survey on days 14 and 30 / early exit. Participants were instructed to mark a vertical line on an anchored VAS that best described their level of agreement with the statements in the questionnaire. Lumanity then converted the participants' responses into numerical values ​​(0 to 100). This was an overall assessment, not an assessment for each eye.

[0186] The current symptom survey used the VAS to evaluate the subjective onset time of the eye drops in relation to relief and tolerability. All participants completed the CSS on day 1. The survey was conducted at T0 (before administration), T30s after administration, T1min, T3min, and T5min. Participants were instructed to mark a vertical line on an anchored VAS that best described their level of agreement with the statements in the questionnaire. Lumanity then converted the participants' responses into numerical values ​​(0 to 100). This was an overall assessment, not an assessment for each eye.

[0187] The study product use questionnaire assessed the use and adherence to the study drug. All participants completed the study product use questionnaire on day 14 and day 30 / early exit.

[0188] Screening and inclusion : Forty-two (42) individuals were screened for this human clinical study. Of the 42 screened participants, 40 (95.2%) were treated with Formulation 1. Of the 40 participants treated, 38 (95.0%) completed the study (i.e., from baseline to day 30). Two participants (5.0%) discontinued the study after the day 14 visit. Of the 38 participants who completed the study, four (10.5%) were considered protocol deviations after data entry and analysis, given that their baseline OSDI scores were outside the inclusion range of 18 to 65. In summary, the intention-to-treat (ITT) group included all 40 participants treated with Formulation 1 at any point during the trial, while the protocol-following (PP) group included 34 participants after excluding those considered protocol deviations and those who discontinued treatment.

[0189] Patient Demographics : ITT (Intention Therapy) Group : Participants ranged in age from 18 to 74 years. The mean age of participants was 37.7 years (standard deviation [SD]: 15.8). Female participants comprised 60% of the sample (n=24 / 40). The majority of participants (n=38 / 40, 95.0%) were identified as White and Hispanic / Latino. The majority of participants (n=27 / 40, 67.5%) had a baseline OSDI score of severe (33–100). Four participants (n=4 / 40, 10.0%) had baseline OSDI scores outside the inclusion criterion of 18–65—one participant (n=1 / 40, 2.5%) had a baseline OSDI score less than 18, while three participants (n=3 / 40, 7.5%) had a baseline OSDI score greater than 65. These four participants were excluded from the PP group.

[0190] PP (Program Compliance) Group : The participants ranged in age from 18 to 74 years. The mean age of the participants was 37.8 years (SD: 15.2). More than half of the participants were female (n=21 / 34, 61.8%). The majority of participants (n=32 / 34, 94.1%) were identified as White and Hispanic / Latino. The majority of participants (n=24 / 34, 70.6%) had a baseline OSDI score of severe (33–100).

[0191] Research Product Usage Questionnaire The Study Product Use Questionnaire assessed product use and adherence to the study drug (formulation 1). All participants completed the Study Product Use Questionnaire on day 14 and day 30 / early withdrawal. In the PP group, the majority of participants selected “N / A” for use of either RESTASIS or intraocular pressure-lowering therapy drops within the past four hours at baseline (n=28 / 34, 82.4%). On average, participants in the PP group reported 2.3 daily doses of eye drops on day 14 (SD: 0.7) and 2.8 daily doses on day 30 (SD: 1.5).

[0192] result : The mean OSDI score from baseline to day 30 decreased by 8.0 points (SD: 17.0) in the intention-to-treat (ITT) group and by 6.8 points (SD: 15.0) in the protocol-following (PP) group (see [link to relevant documentation]). Figure 7 and Figure 8 Paired t-tests were performed between baseline and mean OSDI scores on day 30, and the changes in mean OSDI scores were statistically significant in both the ITT and PP populations (p < 0.05).

[0193] In both the ITT and PP groups, the mean total CSS score decreased within 5 minutes; the largest change in mean total CSS score was observed 5 minutes after administration (ITT: -13.6 [SD: 15.4], PP: -10.1 [SD: 10.6]) (see [link to relevant documentation]). Figure 9 and Figure 10 Paired t-tests were performed on the mean total CSS scores between TO and subsequent time points (T30s, T1min, T3min, and T5min), and the changes in mean total CSS scores from baseline to all subsequent time points were statistically significant in both the ITT and PP groups (p<0.05).

[0194] In the ITT group, the mean PEDE score on day 30 ranged from 75.8 (stinging / burning SD: 36.8, stickiness SD: 31.2) to 86.0 (SD: 20.0), while in the PP group, the mean PEDE score ranged from 76.4 (SD: 36.7) to 85.7 (SD: 21.0). In the ITT group, for the 5-minute recall question, the mean PEDE score on day 30 ranged from 75.8 (SD: 36.8) to 84.3 (SD: 20.3); for the 30-minute recall question, the range was 75.8 (SD: 31.2) to 86.0 (SD: 20.0); for the 24-hour recall question, the range was 84.7 (SD: 19.1) to 85.1 (SD: 20.7); and for the 5-day recall question, the range was 81.6 (SD: 22.6) to 84.1 (SD: 22.0). In the PP population, the mean PEDE scores on day 30 ranged from 76.4 (SD: 36.7) to 84.1 (SD: 21.1) for the 5-minute recall question, from 78.6 (SD: 30.8) to 85.7 (SD: 21.0) for the 30-minute recall question, from 84.4 (SD: 20.0) to 84.5 (SD: 21.5) for the 24-hour recall question, and from 82.0 (SD: 22.6) to 83.8 (SD: 23.2) for the 5-day recall question (see [link]). Figure 11 , Figure 12 , Figure 13 and Figure 14 ).

[0195] • From baseline to 5 minutes, participants’ CSS scores decreased across all items, indicating that symptoms improved over time.

[0196] • Participants experienced significant changes in their mean score relative to baseline at all time points (30 seconds, 1 minute, 3 minutes, and 5 minutes) in item 3 (dry eyes).

[0197] • By day 30, participants’ PEDE survey scores typically tended to be 100 (strong agreement), indicating a tendency to agree with statements regarding short-term and long-term relief and the tolerability of the study eye drops.

[0198] • On day 30, participants' PEDE scores were highest on item 9 (lasting relief of dry eyes after 30 minutes) and lowest on item 1 (stirring / burning sensation within 5 minutes) and item 7 (stickiness after 30 minutes). In the ITT cohort, the mean PEDE score on day 14 ranged from 62.7 (SD: 41.8) to 82.4 (SD: 20.1), while in the PP cohort, the mean PEDE score ranged from 57.1 (SD: 42.9) to 81.2 (SD: 21.3). Within the ITT cohort, the mean PEDE score on day 14 ranged from 62.7 (SD: 41.8) to 76.9 (SD: 25.3) for the 5-minute recall question, from 74.7 (SD: 30.5) to 82.1 (SD: 20.5) for the 30-minute recall question, from 77.8 (SD: 24.6) to 82.4 (SD: 20.1) for the 24-hour recall question, and from 77.9 (SD: 19.0) to 78.6 (SD: 21.5) for the 5-day recall question. In the PP group, the average PEDE score on day 14 ranged from 57.1 (SD: 42.9) to 75.0 (SD: 26.3) for the 5-minute recall question, from 75.4 (SD: 31.1) to 81.2 (SD: 21.3) for the 30-minute recall question, from 75.5 (SD: 25.3) to 80.5 (SD: 20.7) for the 24-hour recall question, and from 76.3 (SD: 19.2) to 76.5 (SD: 22.2) for the 5-day recall question.

[0199] The mean OSDI score from baseline to day 14 decreased by 7.7 points (SD: 16.7) in the ITT group and by 8.1 points (SD: 15.9) in the PP group. A paired t-test between the mean OSDI score at baseline and day 14 showed that the change in mean OSDI score was statistically significant in both the ITT and PP groups (p < 0.05).

[0200] in conclusion : Overall, survey data collected as part of this human clinical trial indicated that participants treated with formulation 3 experienced symptom reductions during the trial, including improvements in OSDI scores on day 30, improvements in total current symptom scores (CSS) within 5 minutes, improvements in dry eye symptoms observed as early as 30 seconds, and a good patient drop experience (PEDE) score observed on day 30. Furthermore, no adverse events were reported throughout the trial.

Claims

1. A low-salt ophthalmic pharmaceutical composition comprising a polymeric lubricant, a salt-sensitive viscosity-modifying polymer, one or more tension agents, trehalose, and hyaluronic acid salt.

2. The low-salt ophthalmic pharmaceutical composition according to claim 1, wherein the hyaluronic acid salt is sodium hyaluronate.

3. The low-salt ophthalmic pharmaceutical composition according to claim 2, wherein one or more tension agents are selected from carnitine, glycerin, erythritol and trehalose.

4. The low-salt ophthalmic pharmaceutical composition according to claim 3, wherein the composition comprises carnitine, glycerin, erythritol and trehalose.

5. The low-salt ophthalmic pharmaceutical composition according to claim 4, wherein the polymeric lubricant is sodium carboxymethyl cellulose present at a concentration of about 0.5% (w / w).

6. The low-salt ophthalmic pharmaceutical composition according to claim 4, wherein the low-salt ophthalmic pharmaceutical composition further comprises a compatible solute, wherein the compatible solute is levocarnitine.

7. The low-salt ophthalmic pharmaceutical composition according to claim 6, wherein the low-salt ophthalmic pharmaceutical composition comprises erythritol at a concentration of about 0.25% (w / w) and levocarnitine at a concentration of about 0.25% (w / w).

8. The low-salt ophthalmic pharmaceutical composition according to claim 7, wherein glycerin is present at a concentration of about 0.9% (w / w).

9. The low-salt ophthalmic pharmaceutical composition according to claim 8, wherein the sodium hyaluronate is present at a concentration of about 0.1% (w / w).

10. The low-salt ophthalmic pharmaceutical composition according to claim 1, wherein the composition is preservative-free.

11. The low-salt ophthalmic pharmaceutical composition according to claim 10, wherein the low-salt ophthalmic pharmaceutical composition further comprises a buffer.

12. The low-salt ophthalmic pharmaceutical composition of claim 11, wherein the buffer is boric acid present at a concentration of about 0.5% (w / w).

13. The low-salt ophthalmic pharmaceutical composition according to claim 12, wherein the low-salt ophthalmic pharmaceutical composition further comprises sodium borate decahydrate.

14. The low-salt ophthalmic pharmaceutical composition according to claim 13, wherein the low-salt ophthalmic pharmaceutical composition further comprises sodium citrate dihydrate.

15. The low-salt ophthalmic pharmaceutical composition according to claim 14, wherein the low-salt ophthalmic pharmaceutical composition further comprises potassium chloride.

16. The low-salt ophthalmic pharmaceutical composition according to claim 15, wherein the low-salt ophthalmic pharmaceutical composition further comprises dehydrated calcium chloride.

17. The low-salt ophthalmic pharmaceutical composition of claim 16, further comprising a pH adjuster, wherein the pH adjuster is NaOH, and wherein the pharmaceutical composition has a pH of about 7.

3.

18. A low-salt ophthalmic pharmaceutical composition, said low-salt ophthalmic pharmaceutical composition comprising: Sodium hyaluronate with a concentration of approximately 0.1% (w / w); Trehalose at a concentration of approximately 1.5% (w / w); Erythritol at a concentration of approximately 0.25% (w / w); Levocarnitine at a concentration of approximately 0.25% (w / w); Potassium chloride at a concentration of approximately 0.03% (w / w); Calcium chloride dihydrate at a concentration of approximately 0.006% (w / w); Magnesium chloride hexahydrate at a concentration of approximately 0.006% (w / w); Boric acid at a concentration of approximately 0.5% (w / w); Sodium borate decahydrate at a concentration of approximately 0.20% (w / w); Sodium citrate dihydrate at a concentration of approximately 0.10% (w / w); Sodium carboxymethyl cellulose at a concentration of approximately 0.5% (w / w); Glycerin at a concentration of approximately 0.9% (w / w); NaOH; and water.

19. A combination comprising the low-salt ophthalmic pharmaceutical composition of claim 18 and a multi-dose, preservative-free bottle for reliably dispensing the liquid of the low-salt ophthalmic pharmaceutical composition, wherein the composition is sterile and preservative-free.

20. A method for treating dry eye syndrome, the method comprising administering the low-salt ophthalmic pharmaceutical composition to a subject requiring treatment for dry eye syndrome using the combination according to claim 19; thereby treating the dry eye syndrome.

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