Enhanced artificial tear formulations

Abstract

Provided herein are low salt ophthalmic pharmaceutical composition and methods of use thereof, for example, in the treatment of dry eye syndrome.

Description

[0001] ENHANCED ARTIFICIAL TEAR FORMULATIONS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 554,661, filed February 16, 2024; the disclosures of which are hereby incorporated by reference in their entirety.

[0004] BACKGROUND OF THE INVENTION

[0005] Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles. (Craig et al, Ocul Surf. 2017; 15(3):276- 83). An estimated 25 million Americans are reported to have DED, making DED one of the most common reasons patients seek care with their eye care professional. (Behrens et al., Cornea. 2006;25(8):900-7; and Stapleton et al., Epidemiology Report. Ocul Surf. 2017; 15(3):334-65).

[0006] Mechanistically, DED is recognized as a disturbance of the lacrimal functional unit, an integrated system comprised of the ocular surface (cornea, conjunctiva, accessory lacrimal glands, and Meibomian glands), the main lacrimal glands, and the sensory and interconnecting innervation. (Stem et al., Cornea. 1998; 17(6): 584-9). The diagnosis and classification (i.e., mild / moderate / severe) of DED is achieved by assessing both clinical signs (ocular surface epithelial damage [corneal and conjunctival staining]), tear volume (Schirmer score), tear film stability (tear break-up time [TBUT]), and patient-reported symptoms (questionnaires such as the Ocular Surface Disease Index© [OSDI] and Eye Dryness Score - Visual Analog Scale). (Wolffsohn et al., Ocul Surf. 2017; 15(3):539-74).

[0007] The normal tear film is a relatively stable, thin film (i.e., 0.1-0.2 micron) composed of a superficial lipid layer and an aqueous layer intermixed with a mucus gel layer, which is partially adherent to the corneal and conjunctival surface epithelium. The tear film is important for lubrication, protection, and nourishment of the ocular surface and serves as the primary refractive surface of the eyes visual system. Dry eye disease is a complex disease characterized by a dysfunction of 1 or more components of the tear film, leading to the loss of tear film stability, a hyperosmolar shift in the tear film osmotic balance, and / or an inadequate amount of fluid on the ocular surface. This is characterized by rapid break-up of the tear film and numerous symptoms, including burning / stinging, foreign body sensation, blurred vision, and photophobia.

[0008] Dry eye disease is often brought about or exacerbated by a variety of adverse environmental conditions, including prolonged computer use (visual display terminal syndrome), excessive wind or air conditioning, and overheated or dry air. Most patients with DED are initially managed with artificial tears. Environmental modifications, lid compresses and scrubs, and the addition of essential fatty acids to the diet are often recommended as well. With advancing severity of DED, treatment options, if needed, can include topical cyclosporine or other anti-inflammatory medications, as well as surgical options ranging from insertion of punctal plugs to tarsorraphy of the eyelids. (Jones et al., Ocul Surf. 2017; 15(3):575-628).

[0009] The present application relates to compositions and methods to supplement and enhance the native tear film of the eye, e.g., the native lipid layer of the tear film. The compositions and methods disclosed herein provide inter alia relief of hyperosmotic stress and other conditions associated with dry eye syndrome.

[0010] Previous methods of supplementing and enhancing the lipid layer of the tear film have been addressed by a variety of approaches, including using a substantial amount of lipid (e.g., 1-5%) and / or building an emulsion system that readily separates. However, such methods suffer multiple disadvantages, including a requirement for shaking of the composition prior to instillation, reduced clarity of the composition upon instillation, variability of the total volume of lipid delivered to the eye, and problems with tolerability vis- a-vis aqueous eye drops.

[0011] Typical symptoms of keratoconjunctivitis or dry eye include feelings of dryness, burning, and a sandy-gritty eye sensation that can worsen during the day. Symptoms may also be described as itchy, scratchy, stingy or tired eyes. Other symptoms include pain, redness, a pulling sensation, and pressure behind the eye. The damage to the eye surface resulting from dry eye increases discomfort and sensitivity to bright light and both eyes usually are affected. Because blinking coats the eye with tears, symptoms are worsened by activities in which the rate of blinking is reduced due to prolonged use of the eyes. These activities include prolonged reading, computer usage, driving or watching television. Symptoms increase in windy, dusty or smoky areas, in dry environments, high altitudes including airplanes, on days with low humidity, and in areas where an air conditioner, fan, or heater, is being used. Symptoms are less severe during cool, rainy, or foggy weather, and in humid places. Most people who have dry eyes experience mild irritation with no long-term effects. However, if the condition is left untreated or becomes severe, it can produce complications that can cause eye damage, resulting in impaired vision or possibly in the loss of vision.

[0012] Having dry eyes for a prolonged period of time can lead to tiny abrasions on the surface of the eyes. In advanced cases, the epithelium undergoes pathologic changes, namely squamous metaplasia and loss of goblet cells sometimes due to activation of T cells acting against those cells.. Some severe cases result in thickening of the corneal surface, corneal erosion, punctate keratopathy, epithelial defects, corneal ulceration, corneal neovascularization, corneal scarring, corneal thinning, and even corneal perforation. An abnormality of any one of the three layers of tears which produces an unstable tear film, may result in symptoms of keratitis sicca.

[0013] Keratoconjunctivitis sicca is usually due to inadequate tear production. The aqueous tear layer is affected, resulting in aqueous tear deficiency or lacrimal hyposecretion. The lacrimal gland does not produce sufficient tears to keep the entire conjunctiva and cornea covered by a complete layer. This usually occurs in people who are otherwise healthy. Increased age is associated with decreased tearing. This is the most common type found in postmenopausal women. Causes include idiopathic, congenital alacrima, xerophthalmia, lacrimal gland ablation, and sensory denervation. In rare cases, it may be a symptom of collagen vascular diseases, including rheumatoid arthritis, Wegener's granulomatosis, and systemic lupus erythematosus. Sjogren's syndrome and autoimmune diseases associated with Sjogren's syndrome are also conditions associated with aqueous tear deficiency. Drugs such as isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, oral contraceptives, antihistamines, nasal decongestants, beta-blockers, phenothiazines, atropine, and pain relieving opiates such as morphine can cause or worsen this condition. Infiltration of the lacrimal glands by sarcoidosis or tumors, or postradiation fibrosis of the lacrimal glands can also cause this condition. Keratoconjunctivitis sicca can also be caused by abnormal tear composition resulting in rapid evaporation or premature destruction of the tears. When caused by rapid evaporation, it is termed evaporative dry eyes. In this condition, although the tear gland produces a sufficient amount of tears, the rate of evaporation of the tears is too rapid. There is a loss of water from the tears that results in tears that are too "salty" or hypertonic. As a result, the entire conjunctiva and cornea cannot be kept covered with a complete layer of tears during certain activities or in certain environments.

[0014] The present invention provides improved compositions for treating dry eye.

[0015] SUMMARY OF THE INVENTION

[0016] In a first aspect, there is provided a low salt ophthalmic pharmaceutical composition which includes a polymer lubricant, a salt-sensitive viscosity modulating polymer, one or more tonicity agents, sodium hyaluronate, and trehalose.

[0017] In another aspect, there is provided a low salt ophthalmic pharmaceutical composition including: 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); levocamitine at a concentration of about 0.25% (w / w); potassium chloride at a concentration of about 0.03% (w / w); calcium chloride dihydrate at a concentration of about 0.006% (w / w); 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); carboxymethylcellulose sodium at a concentration of about 0.5% (w / w); glycerin at a concentration of about 0.9% (w / w); NaOH; and water.

[0018] In another aspect, there is provided a method for treating dry eye syndrome. The method includes administering to a subject in need of treatment of dry eye syndrome a low salt ophthalmic pharmaceutical composition as described herein, thereby treating the dry eye syndrome.

[0019] The formulation described in Table 5 includes the concentrations of actives and / or excipients as disclosed above which can be in concentrations which vary from what is stated above. The variation may be such that the amounts are “about” what is stated above so long as that amount would be found bioequivalent by a regulatory agency such as the FDA or the EMEA.

[0020] The formulation is preferably non-preserved (not containing Purite®). However, in other embodiments, the formulation is preserved and is the same as that in Table 5 except that it contains Purite® at a concentration of about 0.1% (w / v). The formulation may be packaged in a unit dose form.

[0021] In other embodiments, the formulation is preferably non-preserved (not containing Purite®) and is used in combination with a preservative-free, multidose bottle.

[0022] In some embodiments, the present invention is directed to a low salt ophthalmic pharmaceutical composition comprising a polymer lubricant, a salt-sensitive viscosity modulating polymer, one or more tonicity agents, trehalose, and a hyaluronate.

[0023] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said hyaluronate is sodium hyaluronate.

[0024] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the one or more tonicity agents are selected from carnitine, glycerin, erythritol and trehalose.

[0025] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said composition comprises carnitine, glycerin, erythritol and trehalose.

[0026] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said polymer lubricant is carboxymethylcellulose sodium present at a concentration of about 0.5% (w / w).

[0027] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising a compatible solute, wherein said compatible solute is levocarnitine.

[0028] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments comprising erythritol at a concentration of about 0.25% (w / w) and levocamitine at a concentration of about 0.25% (w / w).

[0029] In some embodiments, the present invention is directed to the 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).

[0030] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said sodium hyaluronate is present at a concentration of about 0.1% (w / w).

[0031] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said composition is preservative free.

[0032] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments further comprising a buffer.

[0033] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said buffer is boric acid present at a concentration of about 0.5% (w / w).

[0034] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising sodium borate decahydrate.

[0035] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising sodium citrate dihydrate.

[0036] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising potassium chloride. In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising calcium chloride dehydrate.

[0037] In some embodiments, the present invention is directed to the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising a pH adjustment agent, wherein said pH adjustment agent is NaOH, and wherein said pharmaceutical composition has a pH of about 7.3.

[0038] In other embodiments, the present invention is directed to the combination of a low salt ophthalmic pharmaceutical composition according, wherein said 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); calcium chloride dihydrate at a concentration of about 0.006% (w / w); 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); carboxymethylcellulose sodium at a concentration of about 0.5% (w / w); glycerin at a concentration of about 0.9% (w / w); NaOH; and water; and a bottle designed to reliable dispense sterile, non-pre served, liquid.

[0039] In some embodiments, the present invention is directed to methods for treating dry eye syndrome comprising a method of administering to a subject in need of treatment of dry eye syndrome a low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments.

[0040] In some embodiments, the present invention is directed to methods for treating dry eye syndrome comprising a method of using a preservative-free bottle to administer to a subject in need of treatment of dry eye syndrome said a low salt ophthalmic pharmaceutical composition comprising any combination of the above embodiments; thereby treating said dry eye syndrome.

[0041] BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Fig. 1 depicts the study design of a Ph l / II clinical study to evaluate the safety and efficacy of patients treated with Formulation 1 and Formulation 2. Fig. 2 depicts the observed change from baseline of current symptom severity total score with LS Mean and 95% CI (ITT Population) after patients were treated with Formulation 1 and Formulation 2. As shown, Formulation 1 demonstrated similar levels of efficacy to Formulation 2 at each of the evaluated time points.

[0043] Fig. 3 depicts the observed change from baseline of ocular surface disease index with LS Mean and 95% CI (ITT Population) after patients were treated with Formulation 1 and Formulation 2. As shown, Formulation 1 demonstrated similar levels of efficacy to Formulation 2 up to day 30, and then higher levels of efficacy between days 30 thru 90.

[0044] Fig. 4 depicts the observed change from baseline of ocular staining with LS Mean and 95% CI (ITT Population) after patients were treated with Formulation 1 and OM-3 in a retrospective, non-head-to-head, comparative study. As shown Formulation 1 demonstrated positive trends across all patient visits relative to OM-3.

[0045] Fig. 5 depicts the observed change from baseline of ocular surface disease index with LS Mean and 95% CI (ITT Population) after patients were treated with Formulation 1 and OM-3 in a retrospective, non-head-to-head, comparative study. As shown Formulation 1 demonstrated positive trends across all patient visits relative to OM-3.

[0046] Fig. 6 depicts the study design of a patient experience clinical study to evaluate the symptom relief, product tolerability, and the patient experience of dry eye patients treated with Formulation 1.

[0047] Fig. 7 depicts change from baseline in Ocular Disease Severity Index (OSDI) score at Day 30 for the 40 intent to treat (ITT) patients that were evaluated in the patient experience clinical trial. As shown, a statistically significant reduction in OSDI score was observed.

[0048] Fig. 8 depicts change from baseline in Ocular Disease Severity Index (OSDI) score at Day 30 for the 34 per protocol (PP) patients that were evaluated in the patient experience clinical trial. As shown, a statistically significant reduction in OSDI score was observed.

[0049] Fig. 9 depicts change from baseline in total Current Symptom Survey (CSS) score within 5 minutes score at Day 30 for the 40 intent to treat (ITT) patients that were evaluated in the patient experience clinical trial. As shown, a statistically significant reduction in CSS score was observed. Fig. 10 depicts change from baseline in total Current Symptom Survey (CSS) score within 5 minutes score at Day 30 for the 34 per protocol (PP) patients that were evaluated in the patient experience clinical trial. As shown, a statistically significant reduction in CSS score was observed.

[0050] Fig. 11 depicts change from baseline in Patient Eye Drop Experience (PEDE) scores at Day 30 within 5 minutes for the 40 intent to treat (ITT) patients that were evaluated in the patient experience clinical trial. As shown, a statistically significant reduction in PEDE score at 5 minutes was observed.

[0051] Fig. 12 depicts change from baseline in Patient Eye Drop Experience (PEDE) scores at Day 30 within 30 minutes for the 40 intent to treat (ITT) patients that were evaluated in the patient experience clinical trial. As shown, a statistically significant reduction in PEDE score at 30 minutes was observed.

[0052] Fig. 13 depicts change from baseline in Patient Eye Drop Experience (PEDE) scores at Day 30 within 24 hours for the 40 intent to treat (ITT) patients that were evaluated in the patient experience clinical trial. As shown, a statistically significant reduction in PEDE score at 24 hours was observed.

[0053] Fig. 14 depicts change from baseline in Patient Eye Drop Experience (PEDE) scores at Day 30 at day 5 for the 40 intent to treat (ITT) patients that were evaluated in the patient experience clinical trial. As shown, a statistically significant reduction in PEDE score at day 5 was observed.

[0054] DETAILED DESCRIPTION OF THE INVENTION

[0055] Over the years, a variety of ophthalmic artificial tear formulations have been developed to treat dry eye.

[0056] The inventors had sought innovative solutions to advance the art of artificial tears by developing a unique formulation that combined the beneficial elements of multiple artificial tear formulations into a single artificial tear formulation.

[0057] The result was the formulation described in Table 5, which for the first time, incorporated the osmoprotectant properties of erythritol, levocarnitine, and glycerol from Refresh Optive eye drops, the combination of carboxymethyl cellulose (CMC) and hyaluronic acid (HA) from Optive Fusion eye drops, and the addition of trehalose from Optive Mega3 eye drops, into a unique low salt / low osmolarity, lipid free, preservative-free formulation.

[0058] Inclusion of the combination of an organic solute component (carnitine), and one or more polyols (erythritol), and glycerol, provides a number of advantages. Carnitine components have unique properties in multiple roles, for example serving as an osmoprotectant, serving as an energy source for ocular cells, serving as an antioxidant, promoting wound healing, serving as a protein chaperone, and aiding in neuroprotection. On account of it being an amino acid, and thus being much larger in size compared to a polyol, carnitine is able to function as a long-acting intracellular compatible solute and protein stabilizer, which provides beneficial properties when used in lower concentrations of less than 1%. Erythritol also serves as an effective tonicity / osmotic agent which due to its larger size, relative to glycerol, tends to accumulate in the cells more slowly than glycerol and thus enables it to remain within the cells for prolonged periods of time relative to glycerol, when used topically on the eye. Inclusion of glycerol helps to provide more acute relief due to its lower residence time compared to erythritol. Thus, the combination of all three provides full spectrum osmoprotection.

[0059] Inclusion of the combination of carboxymethyl cellulose (CMC) and hyaluronic acid (HA) results in an observed greater than additive increase in viscosity over the inclusion of either alone, which decreases shearing and maintains the tears’ ability to coat the eye while at the same time providing improved distribution of the tears onto the cornea during blinking.

[0060] Inclusion of trehalose was intended to provide a protective mechanism for reducing the level of expression of pro-inflammatory cytokines in response to hyperosmotic conditions that are typically prevalent in dry eye patients.

[0061] In addition, the present inventors had also sought ways of further reducing the osmolarity of the formulation with the intention of not contributing to the hyperosmotic condition already present on the surface of a patient’s dry eye. Numerous means of implementing this goal were considered. However, in the end, the inventors had chosen to reduce the boric acid concentration down to 0.5% in addition to reducing the potassium chloride concentration down to 0.03%. That specific low combination of boric acid and potassium chloride had never been utilized in a commercial eye drop formulation. The inventors had chosen a lipid free formulation for a variety of reasons, but most notably due to the challenges the inclusion of lipids can present to developing a preservative free-formulation, including but not limited to disrupting the free-flow from preservative-free bottles. Thus, by developing a lipid-free formulation, the inventors were able to combine for the first time, a high-performance artificial eye drop that could be utilized in combination with a preservative-free, multi-dose bottle.

[0062] As demonstrated herein, the new formulation performed similarly to a competing commercial formulation despite not containing a highly hydrophilic artificial polymer (e.g., PEG400) and despite not containing hydroxypropyl guar which was unexpected. In general, the new formulation was comparable to the competing commercial formulation in some metrics, and had exceeded performance in some other metrics as described more particularly in Example 1.

[0063] In addition, a retrospective analysis comparing the performance end points of the new formulation with OPTIVE MEGA3 demonstrated positive trends suggesting the new formulation may exceed the performance of OPTIVE MEGA3 across all of the metrics compared within the analysis.

[0064] Lastly, the new formulation also demonstrated patients had experienced significant dry eye symptom reduction over the course of a second clinical trial including improvements in the observed severity disease index (OSDI) score at Day 30, improvements in total current symptom scores (CSS) within 5 minutes, improvements in dry eye symptoms observed as early as 30 secs, as well as favorable patient eye drop experience (PEDE) scores observed at Day 30. Importantly, no adverse events were reported throughout the trial.

[0065] Overall, the novel combination of osmoprotectants (1-carnitine and erythritol), humectants / lubricants (glycerin and carboxymethylcellulose), trehalose, and sodium hyaluronate had significantly increased the clinical usefulness of this product to a broader range of dry eye patients than other dry eye formulations not containing such a combination of excipients.

[0066] The rationale for developing a low-salt formulation was to ensure the artificial tear eye drop did not contribute to the hyperosmolarity of a patient’s dry eye. Corneal surface cells respond to osmotic forces by regulating salt and water transport in an effort to maintain a constant cell volume. In conditions of chronic hypertonicity, for example, such as exist in dry eye disease, transport mechanisms for uptake of compatible solutes, including various amino acids and polyols, are up-regulated. In one embodiment of the present invention, ophthalmic compositions, for example, artificial tears, containing a compatible solute component are formulated to have a tonicity higher or in excess of isotonicity, advantageously in a tonicity range of about 300 or about 310 to about 600 or about 1000 mOsmols / kg. Without wishing to limit the invention to any particular theory of operation, it is believed that, under such conditions, both immediate and long-term mechanisms to accumulate compatible solutes in cells are stimulated, allowing enhanced uptake and retention compared to cellular activity under isotonic or hypotonic conditions. Once the compatible solute component is accumulated by the cells, the cells have enhanced protection from ongoing hypertonic insult, for example, caused by dry eye syndrome and / or one or more other conditions / diseases. Results of this enhanced protection include improved cellular metabolism and survival for a period of hours to days following application of an ophthalmic composition of the present invention.

[0067] In the normal lacrimal system, tear production, tear drainage, and tear evaporation is balanced in order to provide a moist, lubricated ocular surface. Typical values for tear osmolarity range from 290 to 310 mOsmols / kg in normal individuals, and these may change throughout the day or in response to changing environmental conditions. In the normal individual, neural feedback from the ocular surface to the lacrimal glands controls tear production in order to maintain a stable ocular surface fluid. It has been proposed that tear film tonicity is one of the principal stimuli for this regulatory feedback. In dry eye disease, dysfunction of the production apparatus (the various glands), the drainage system, the neural signaling mechanism, or the ocular surface itself leads to an inadequate tear film, ocular surface compromise, and subjective discomfort.

[0068] On the cellular level, dry eye disease is usually characterized by a chronically hypertonic extracellular (tear film) environment. Published reports of the tonicity of the tear film of dry eye patients gives a range of 300 to 500 mOsmols / kg, with most values between 320 and 400 mOsmols / kg. Under these conditions, cells will tend to lose water and / or gain salts, and may undergo cell volume changes. Hypertonicity has been shown to alter cellular metabolic processes, reduce the functioning of enzymatic processes, and lead to apoptosis and cell death.

[0069] As a defense against hypertonic challenge, corneal cells have been demonstrated to up-regulate transport mechanisms for non-ionic solutes such as amino acids and polyols, and accumulate these solutes intracellularly in order to maintain cell volume without changing electrolyte balance. Under these conditions, cellular metabolism is less affected than with volume and electrolyte changes, and such compounds are referred to as 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 to be osmoprotectants since they may allow cell metabolism or enhance cell survival under hypertonic conditions that would otherwise be restricting.

[0070] Cells accumulate certain compatible solutes by biosynthesis within the cell and others by increased trans-membrane transport from the extracellular fluid (in this case the tear fluid). In both cases, specific synthetic or transport proteins are involved in this process. Experimental evidence indicates that these proteins are activated in the presence of hypertonic conditions, and that transcription and translation events to produce these proteins are up-regulated by hypertonic conditions. Conversely, experimental evidence indicates that corneal and other cells will expel compatible solutes when exposed to hypotonic conditions, or when moving from a hypertonic to an isotonic environment.

[0071] In dry eye disease, corneal surface cells are exposed to a hypertonic environment, and are stimulated to accumulate osmoprotectant substances as they are available. The addition of an iso- or hypo-tonic artificial tear to the ocular surface provides relief from symptoms due to enhanced lubrication, but tends to down-regulate mechanisms in these cells for accumulation of osmoprotectants. This may result in further vulnerability to osmotic insult in the minutes to hours following drop use as the tear film returns to its hypertonic dry eye state.

[0072] Current FDA guidance stipulates that "an ophthalmic solution should have an osmotic equivalence between 0.8 and 1.0 percent sodium chloride to comply with labeling claims of 'isotonic solution' ." This is equivalent to a range from 274 to 342 mOsm / kg. Further, FDA guidelines state that "two to 5 percent sodium chloride ophthalmic preparations are hypertonic and are acceptable OTC products when labeled as 'hypertonic solutions' ." This range equates to 684 to 1711 mOsm / kg. For the purposes of the present invention, a "supratonic" solution is defined to have an osmolality intermediate between these two ranges, or approximately 300 or 310 to about 600 or about 800 or about 1000 mOsmols / kg, equivalent to about 0.9 to about 1.8 percent sodium chloride (1.8% is the maximum FDA guidance for topical ophthalmic solutions not labeled as hypertonic).

[0073] The present invention takes these concepts into account by formulating an artificial tear at supra-tonic levels more compatible with the existing hypertonic state of the dry eye ocular surface. In addition to being formulated in the supra-tonic range (about 300 or about 310 to about 600 or about 1000 mOsmols / kg total tonicity), the present compositions contain one or more organic compatible solute agents as described herein. The combination of supratonicity and inclusion of one or more compatible solutes in the present compositions serve to both stimulate or maintain uptake of these protective substances into the corneal surface cells, and to provide abundant supplies of these materials or substances.

[0074] I. Definitions

[0075] The term “about” in the context of a numerical value refers, absent an express indication otherwise, to the nominal amount that is ± 10% thereof.

[0076] The terms “clear,” “clarity” and the like in the context of ophthalmic pharmaceutical compositions refer to absorbance and / or light scattering (e.g., opacity, pearlesence, and the like) which are sufficiently low such that the ophthalmic pharmaceutical composition appears substantially free of haziness, mistiness or cloudiness to the naked human eye. A clear ophthalmic pharmaceutical composition does not include emulsions that visibly separate into a hydrophobic portion and a hydrophilic portion.

[0077] The terms “compatible solute,” “osmolytes” and the like in the context of ophthalmic pharmaceutical compositions refers to substances that are taken into the cell and act to counterbalance the osmotic pressure found outside the cell. Without wishing to be bound by any theory, it is believed that compatible solutes have osmoprotective properties which may protect the surface cells of the eye from osmotic stress. It is further believed that the incorporation of compatible solutes increases the clinical usefulness of the composition disclosed herein to contemplate a broader range of subject suffering from dry eye syndrome compared to previous emulsion systems which target lipid deficiency per se or meibomian gland dysfunction.

[0078] The terms “dry eye,” “dry eye syndrome,” “keratitis sicca,” “xerophthalmia,” “keratoconjunctivits sicca,” and the like refer in the customary sense to a condition or spectrum of conditions wherein the eye is unable to maintain a healthy tear layer (i.e., tear film) sufficient to coat the eye. Dry eye syndrome is more prevalent with age, as subjects typically produce fewer tears with age.

[0079] As used herein, the term “effective amount” or “effective dose” refers in the customary sense to an amount which is sufficient to bring about a desired result. Accordingly, a therapeutically effective amount employed in a treatment is a sufficient amount to reduce the extent, undesirable clinical manifestation, of both, of a disease, disorder or condition.

[0080] “Formulation,” “composition,” and “preparation” as used herein are equivalent terms referring to a composition of matter suitable for pharmaceutical use (i.e., producing a therapeutic effect as well as possessing acceptable pharmacokinetic and toxicological properties).

[0081] The term “low salt” as used herein in the context of a ophthalmic pharmaceutical composition refers to a salt content which is sufficiently low so as to provide a stabilized submicron emulsion within the ophthalmic pharmaceutical composition. Salt content can be measured by a variety of methods known in the art, e.g., measurement of ionic strength. Accordingly, the term “low salt ophthalmic pharmaceutical composition” refers to a pharmaceutical composition for use in the eye having sufficiently low salt content that a submicro emulsion which includes a surfactant and a therapeutic lipid is stable therein.

[0082] The term “polymer lubricant” refers to a polymeric agent able coat the ocular surface (i.e., demulcent) and provide lubrication to the eye. Exemplary polymer lubricants useful in the composition and methods disclosed herein include any of a variety of cellulose derivatives, e.g., hydroxymethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like, polyvinyl pyrrolidone, polyvinyl alcohol, and the like, and mixtures thereof.

[0083] The term “hyaluronic acid” as used herein refers to any grade that can be formulated for topical use. Preferably, hyaluronic acid is in the form of sodium hyaluronate. In some embodiments, the hyaluronic acid has an intrinsic viscosity of about 0.5 m.sup.3 / kg to about 4.0 m.sup.3 / kg, more preferably about 1.1 m.sup.3 / kg to about 2.0 m.sup.3 / kg, or also more preferably about 2.5 m.sup.3 / kg to about 4.0 m.sup.3 / kg. Some embodiments may have an intrinsic viscosity of about 2.2 m.sup.3 / kg to about 2.6 m.sup.3 / kg, and some embodiments may have an intrinsic viscosity of about 1.1 m.sup.3 / kg to about 3.0 m.sup.3 / kg. In some preferred embodiments, the hyaluronic acid has an average molecular weight from about 2.0 to about 2.6 million Daltons. In some other preferred embodiments, the hyaluronic acid has an intrinsic viscosity from about 1.1 m.sup.3 / kg to about 2.0 m.sup.3 / kg. In some other preferred embodiments, the hyaluronic acid has an average molecular weight from about 0.5 to about 1.2 million Dalton.

[0084] The term “levocamitine” and “carnitine” as used herein refers to L-carnitine, and components of carnitine, for example, carnitine itself, isomers / stereo-isomers thereof, salts thereof, derivatives thereof and the like and mixtures thereof. L-carnitine is an organic compatible solute, and is well-established as necessary for various parts of fatty acid metabolism, so it has a significant role in the metabolism of liver and muscle cells. Carnitine may also serve as an energy source for many types of cells, including ocular cells. Carnitine components may have unique properties in multiple roles, for example as osmoprotectants, in fatty acid metabolism, as an antioxidant, in promoting wound healing, as a protein chaperone, and in neuroprotection.

[0085] The term “erythritol” as used herein refers to a 4-carbon polyol and serves as an effective tonicity / osmotic agent.

[0086] The term “trehalose” as used herein refers to a natural alpha-linked disaccharide formed by an a, a- 1,1 -glucoside bond between two a-glucose units.

[0087] The term “prevent” as used herein refers to a decrease in the occurrence of dermatological symptoms (e.g., urticardial wheals) in a patient. The prevention may be complete (i.e., no detectable symptoms) or partial, so that fewer symptoms are observed than would likely occur absent treatment.

[0088] As used herein, the terms “prevent” and “treat” are not intended to be absolute terms. Treatment can refer to any delay in onset, e.g., reduction in the frequency or severity of symptoms, amelioration of symptoms, improvement in patient comfort, reduction in symptoms of dry eye, and the like. The effect of treatment can be compared to an individual or pool of individuals not receiving a given treatment, or to the same patient before, or after cessation of, treatment.

[0089] The terms “salt- sensitive viscosity modulating polymer,” “salt-sensitive polymer” and the like refer to polymeric agents useful to maintain a stable sub-micron emulsion under low salt conditions within a low salt ophthalmic pharmaceutical composition disclosed herein, and which in turn destabilize, upon an increase in salt content, the sub-micron emulsion. The term “destabilize” in this context refers to a change in the sub-micron emulsion such that therapeutic lipid is released from the sub-micron emulsion. Accordingly, the terms “salt-sensitive” and the like in this context refer to a change in one or more properties of a compound (e.g., conformation, extent of hydration, effective charge due to ion screening, viscosity and the like) in response to a change in salt concentration. Exemplary salt-sensitive viscosity modulating polymers include polymers of acrylic acid which are crosslinked with poly alkenyl ethers or di vinyl glycol. A preferred salt-sensitive viscosity modulating polymer includes crosslinked copolymers of acrylic acid and C10-C30 alkyl acrylate, commonly referred to as Pemulen™ TR-2 (Lubrizol Corporation, Wickliffe, OH).

[0090] The term “sorbitan ester” in the context of surfactants refers in the customary sense to a class of polyethylene glycol (i.e., PEG) derivatives of sorbitan which are further esterified with fatty acids, as known in the art.

[0091] The term “surfactant” refers in the customary sense to compounds able to lower the surface tension of liquid, the interfacial tension between two liquids, or the surface tension between a liquid and a solid.

[0092] Unless indicated otherwise, the term “tear” as used herein refers in the customary sense to the basal tears of the mammalian eye which function to continuously bathe and nourish the cornea. Other types of tear include reflex tears resulting e.g., from irritation of the eye by foreign particles or lacrimator compounds, and psychic tears resulting, e.g., from strong emotional stress, anguish, or physical pain.

[0093] The terms “tear film,” “precorneal film” and like refer in the customary sense to the multilayered coating of the normal eye which includes an innermost mucous layer, a middle aqueous layer, and an outermost lipid layer. The innermost mucous layer contains proteins, e.g., mucin produced by the goblet cells of the conjunctiva, and facilitates even spreading of the overlying middle aqueous layer, e.g., by providing a hydrophilic layer coating the cornea. The middle aqueous layer is produced by the lacrimal glands and includes water, proteins and salt as known in the art. The outermost lipid layer contains oils produced by the meibomian glands and coats the middle aqueous layer, providing a hydrophobic barrier that envelopes tears and prevents outflow, e.g., to the cheek. Importantly, the outermost lipid layer decreases evaporation of the middle aqueous layer.

[0094] The term “therapeutic lipid” refers to a pharmaceutically acceptable amphiphilic or hydrophobic agent which acts to supplement and / or enhance the naturally occurring oils 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 symptoms of dry eye syndrome can result from insufficient production of naturally occurring oils produced by the meibomian glands. Accordingly, it is further believed that supplement and / or enhancement by a therapeutic lipid described herein is beneficial to the treatment of dry eye syndrome. The term “therapeutically effective amount” as used herein refers to that amount of the composition or agent in a composition sufficient to ameliorate one or more aspects of the disorder.

[0095] Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5- fold, or more effect over a control.

[0096] The term “tonicity agent” as used herein refers in the customary sense to a compound which can modulate the effective osmotic pressure within a cell. For example, for comfort during administration or instillation, the tonicity of pharmaceutical dosage forms can be adjusted by a tonicity agent. Exemplary tonicity agents include dextrose, glycerin, mannitol, KC1, and NaCl. Tonicity agents can provide additional benefit, including e.g., function as a humectant or lubricant.

[0097] The term “treatment” as used herein refers to an approach (e.g., a procedure or regimen) for obtaining beneficial or desired results, including clinical results. “Treating,” “palliating,” or “ameliorating” a disease, disorder or condition means that the extent, undesirable clinical manifestations, or both, of a disease, disorder or condition are lessened and / or the time course of the progression is slowed (i.e., lengthened in time), as compared to not treating the disease, disorder or condition. For purposes of the methods disclosed herein, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms (e.g., symptoms of dry eye syndrome), diminishment of extent of disorder, stabilized (i.e., not worsening) state of disorder, delay or slowing of disorder progression, amelioration or palliation of the disorder, and remission (whether partial or total), whether detectable or undetectable.

[0098] “Treating” and “treatment” as used herein may include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.

[0099] The phrase “multidose, preservative-free,” or “MDPF” as used herein is meant to refer to formulations that do no contain a preservative, yet are stable enough to safely permit multidose administration.

[0100] The phrase “multidose, preservative-free bottle,” or “MDPF bottle” as used herein is meant to refer to a bottle that is amenable to multidose administration while at the same time being designed to maintain the sterility of the liquid contained within the bottle, such as an artificial eye drop formulation described herein. One example of such a bottle is the FDA approved, MDPF bottle used with RESTASIS MULTIDOSE 0.05% (see Figure 3 of Marx & Birkoff, Drug Development & Delivery, 17(7):40-44 (2017), in which the bottle incorporates (i) a dual-overcap cap design, which features both a vented cap and a non-vented cap as described in U.S. Patent No. 10,806,628 (see description in the “Disclosure”, Figures 1 thru 6, and as well as in the claims), (ii) a container with a dispensing tip; (iii) a unidirectional valve, which may optionally include a filter, the unidirectional valve being configured to allow the therapeutic agent contained within the container to pass through to the dispensing tip, but prevents re-entry of the therapeutic agent and / or other fluids or contaminants into the container, such the Novelia valve available from Rexam and the valve system of the Ophthalmic Squeeze Dispenser available from Aptar Pharma, for example (elements (ii) and

[0101] (iii) are described in U.S. Patent Nos. 8,292,129; 8,561,859; 9,669,974 and 9,676,525); and

[0102] (iv) a therapeutic, sterile liquid such as an artificial eye drop formulation described herein; each of these references are hereby incorporated by reference herein specifically, and in their entirety.

[0103] IL Methods of Use

[0104] In another aspect, there is provided a method for treating dry eye syndrome. The method includes administering to a subject in need of treatment of dry eye syndrome a therapeutically effective amount of a low salt ophthalmic pharmaceutical composition as disclosed herein, thereby treating dry eye syndrome in the subject. In one embodiment, the low salt ophthalmic pharmaceutical composition includes a polymer lubricant, a salt-sensitive viscosity modulating polymer, one or more tonicity agents, sodium hyaluronate, and trehalose.

[0105] The formulation is preferably non-preserved (not containing Purite®). However, in other embodiments, the formulation is preserved and is the same as that in Table 5 except that it contains Purite® at a concentration of about 0.1% (w / v). The formulation may be packaged in a unit dose form.

[0106] In other embodiments, the formulation is preferably non-preserved (not containing Purite®) and is used in combination with a preservative-free, multidose bottle.

[0107] In some embodiments, the present invention is directed to a method for administering a low salt ophthalmic pharmaceutical composition comprising a polymer lubricant, a saltsensitive viscosity modulating polymer, one or more tonicity agents, trehalose, and a hyaluronate.

[0108] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said hyaluronate is sodium hyaluronate.

[0109] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein the one or more tonicity agents are selected from carnitine, glycerin, erythritol and trehalose.

[0110] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said composition comprises carnitine, glycerin, erythritol and trehalose.

[0111] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said polymer lubricant is carboxymethylcellulose sodium present at a concentration of about 0.5% (w / w).

[0112] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising a compatible solute, wherein said compatible solute is levocarnitine. In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments comprising erythritol at a concentration of about 0.25% (w / w) and levocarnitine at a concentration of about 0.25% (w / w).

[0113] In some embodiments, the present invention is directed to a method for administering the 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).

[0114] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said sodium hyaluronate is present at a concentration of about 0.1% (w / w).

[0115] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said composition is preservative free.

[0116] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments further comprising a buffer.

[0117] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, wherein said buffer is boric acid present at a concentration of about 0.5% (w / w).

[0118] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising sodium borate decahydrate.

[0119] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising sodium citrate dihydrate. In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising potassium chloride.

[0120] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising calcium chloride dehydrate.

[0121] In some embodiments, the present invention is directed to a method for administering the low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments, further comprising a pH adjustment agent, wherein said pH adjustment agent is NaOH, and wherein said pharmaceutical composition has a pH of about 7.3.

[0122] In other embodiments, the present invention is directed to a method for administering the combination of a low salt ophthalmic pharmaceutical composition according, wherein said 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); calcium chloride dihydrate at a concentration of about 0.006% (w / w); 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); carboxymethylcellulose sodium at a concentration of about 0.5% (w / w); glycerin at a concentration of about 0.9% (w / w); NaOH; and water; and a bottle designed to reliable dispense sterile, non-preserved, liquid.

[0123] In some embodiments, the present invention is directed to methods for treating dry eye syndrome comprising a method of administering to a subject in need of treatment of dry eye syndrome a low salt ophthalmic pharmaceutical composition according to any combination of the above embodiments.

[0124] In some embodiments, the present invention is directed to methods for treating dry eye syndrome comprising a method of using a preservative-free bottle to administer to a subject in need of treatment of dry eye syndrome said a low salt ophthalmic pharmaceutical composition comprising any combination of the above embodiments; thereby treating said dry eye syndrome. III. Examples

[0125] Example 1 - Development of a Novel, Low Salt Ophthalmic Composition

[0126] The inventors had sought innovative solutions to advance the art of artificial tears by developing a unique formulation that combined the beneficial elements of multiple artificial tear formulations into a single artificial tear formulation.

[0127] The result was the formulation described in Table 1, which for the first time, incorporated the osmoprotectant properties of erythritol, levocarnitine, and glycerol from Refresh Optive eye drops, the combination of carboxymethyl cellulose (CMC) and hyaluronic acid (HA) from Optive Fusion eye drops, and the addition of trehalose from Optive Mega3 eye drops, into a unique low salt / low osmolarity, lipid free, preservative-free formulation.

[0128] Two versions of this formulation were developed and have been referred to herein as Formulation 1 and Formulation 3.

[0129] Both formulations were subjected to human clinical trials as described in the examples that follow.

[0130] Example 2 - Clinical Study - A Multicenter, Single-masked, Randomized Study to Compare the Efficacy and Safety of a New Artificial Tear Formulation 1 with Formulation 2 for 90 Days in Participants with Dry Eye Disease (DED)

[0131] The objective of the study was to evaluate the efficacy and safety of Formulation 1 in subjects with signs and symptoms of DED compared with Formulation 2.

[0132] Methodology

[0133] This was a multicenter, single-masked, randomized, 2-arm, parallel-group study comparing the efficacy and safety of a Formulation 1 with Formulation 2 (see Error! Reference source not found.IG. 1). The study was designed to compare the relative relief of symptoms of DED between the formulations as well as to characterize the effect on ocular surface staining. The study population consisted of adult male and female subjects with objective and subjective evidence of DED. To be able to show a reduction in DED symptoms and in ocular surface staining at Day 90, the inclusion criteria were selected to include subjects with clinically significant ocular surface staining and symptoms of DED at Screening (Day -7) and Day 1 (baseline) visits. These subjects were anticipated to have a clinically treatable condition with sufficient room for improvement.

[0134] All study subjects who qualified received REFRESH PLUS® for approximately 7 days during a run-in period prior to the Day 1 (baseline) visit. Subjects were instructed to instill 1 to 2 drops of the run-in medication in each eye, 3 times per day for 7 days. Subjects who still met eligibility criteria at the Day 1 (baseline) visit were randomized in a 1 : 1 ratio to use Formulation 1 or Formulation 2, with central stratification by Day 1 (baseline) total ocular staining score of the study eye (mild / moderate = score of 6 to 25 versus severe = score of 26 to 43). Subjects were instructed to instill 1 to 2 drops of their assigned study intervention (investigational eye drops) in each eye, 3 times per day for approximately 90 days. The primary efficacy measure was total ocular staining and the primary analysis timepoint was at Day 90.

[0135] Number of Subjects (Planned and Enrolled)

[0136] Approximately 400 subjects (200 subjects in each treatment group) were to be enrolled at approximately 28 sites in the US in order for 340 subjects (170 subjects in each treatment group) to complete the study through Day 90, assuming an approximate 15% dropout rate Subjects who prematurely discontinued from the study were not to be replaced.

[0137] Treatment Regimen

[0138] Following the 7-day run-in period, during which all subjects received REFRESH PLUS®, subjects were randomized in a 1 : 1 ratio to receive either Formulation 1 or Formulation 2 for 90 days. For all study drugs, including the run-in medication, subjects were instructed to instill 1 to 2 drops in each eye, 3 times per day. As this was a single-masked study, Formulation 1 and Formulation 2 were each supplied in identical outer cartons (kits). Study formulation information is summarized in Table 1.

[0139] Per protocol, subjects were instructed to instill 1 to 2 drops of study drug in each eye, 3 times per day. To ensure treatment compliance, subjects completed a study eye drop usage questionnaire at each follow-up visit. A total of 399 subjects received study drug at least once and were included in the Safety population (199 subjects in the Formulation 2 group and 200 subjects in the Formulation 1 group).

[0140] The mean (SD) study duration was 87.0 (12.19) days in the Formulation 2 group and 82.8 (22.69) days in the Formulation 1 group. A total of 97 (48.7%) subjects in the Formulation 2 group and 88 (44.0%) subjects in the Formulation 1 group received study treatment for at least 90 days.

[0141] No treatment interruptions due to COVID-19 were reported.

[0142] Table 1 - Test Formulations

[0143] Diagnosis and Main Criteria for Eligibility

[0144] Adult male and female subjects with objective and subjective evidence of DED. To be able to show a reduction in DED symptoms and in ocular surface staining at Day 90, the inclusion criteria were selected to include subjects with clinically significant ocular surface staining and symptoms of DED at the Screening (Day -7) and Day 1 (baseline) visits. These subjects were anticipated to have a clinically treatable condition with sufficient room for improvement.

[0145] In the Safety population, the most common (> 10% of subjects overall) ophthalmic medical and surgical histories reported by preferred term (PT) were dry eye (100.0%), cataract (24.8%), myopia (15.5%), intraocular lens implant (12.5%), astigmatism and cataract nuclear (11.3% each), and presbyopia (10.5%)

[0146] In the Safety population, 29 (7.3%) subjects received concomitant other ophthalmological medications (Formulation 2: 16 [8.0%] subjects; Formulation 1 : 13 [6.5%] subjects). The most common (> 1.0% of subjects in either treatment group) concomitant other ophthalmological medications were cyclosporin.

[0147] Patient Demographics

[0148] A total of 638 subjects were screened at 23 sites in the US. Of those, 400 subjects were randomized at 21 sites (200 subjects in the Formulation 2 group and 200 subjects in the Formulation 1 group) (See Table 2). The ITT population included all 400 randomized subjects.

[0149] Demographic characteristics were balanced between Formulation 2 and Formulation 1 treatment groups (see Table 2). Overall, the mean (SD) age of subjects was 58.4 (13.76) years. The majority of subjects were female (323 [80.8%] subjects), were white (304 [76.0%] subjects) and were not Hispanic or Latino (335 [83.8%] subjects). Table 2. Demographics (ITT Population)

[0150] Formulation 2 Formulation 1AU Subjects

[0151] (N = 200) (N = 200)(N = 400)

[0152] Age (years)

[0153] Mean (SD) 57.5 (13.95) 59.3 (13.55) 58.4 (13.76)

[0154] Median 59.0 61.0 60.0

[0155] Minimum, maximum 19, 90 18, 83 18, 90

[0156] Sex, n (%)

[0157] Male 34 (17.0) 43 (21.5) 77 (19.2)

[0158] Female 166 (83.0) 157 (78.5) 323 (80.8)

[0159] Race, n (%)

[0160] White 147 (73.5) 157 (78.5) 304 (76.0)

[0161] Black or African American 49 (24.5) 30 (15.0) 79 (19.8)

[0162] Asian 4 (2.0) 12 (6.0) 16 (4.0)

[0163] Multiple30 (0.0) 1 (0.5) 1 (0.2)

[0164] Ethnicity, n (%)

[0165] Hispanic or Latino 32 (16.0) 33 (16.5) 65 (16.2)

[0166] Not Hispanic or Latino 168 (84.0) 167 (83.5) 335 (83.8)

[0167] ITT = intent-to-treat; SD = standard deviation a. Subjects who reported multiple races were only included in the multiple category.

[0168] Note: Age was relative to informed consent date.

[0169] In the ITT population overall, 378 (94.5%) subjects completed the study and 22 (5.5%) subjects discontinued from the study. The most common reason for study discontinuation in both treatment groups was withdrawal by subject (5 [2.5%] subjects in the Formulation 2 group and 7 [3.5%] subjects in the Formulation 1 group). Three (1.5%) subjects in the Formulation 1 group discontinued from the study due to an AE. Of those, only 1 subject was discontinued due to an AE that was treatment emergent.

[0170] Table 3. Disposition of Subjects (ITT Population) n (%)

[0171] Formulation 2 Formulation 1 All Subjects

[0172] Disposition Status (N = 200) (N = 200) (N = 400)

[0173] Number of subjects randomized 200 (100.0) 200 (100.0) 400 (100.0)

[0174] Number of subjects treated 199 (99.5) 200 (100.0) 399 (99.8)

[0175] Number of subjects who completed study 192 (96.0) 186 (93.0) 378 (94.5)

[0176] Number of subjects who discontinued from study 8 (4.0) 14 (7.0) 22 (5.5)

[0177] Reason for discontinuation

[0178] Adverse event 0 (0.0) 3 (1.5) 3 (0.8)

[0179] Withdrawal by subject 5 (2.5) 7 (3.5) 12 (3.0)

[0180] Lost to Follow-up 0 (0.0) 2 (1.0) 2 (0.5)

[0181] Protocol deviation 2 (1.0) 1 (0.5) 3 (0.8)

[0182] Other11 (0.5) 1 (0.5) 2 (0.5)

[0183] ITT = intent-to-treat; MD = multidose a. 'Other' reasons included randomization error (subject in the Formulation 2 group) and subject moving out of state (subject in the Formulation 1 group). Note: Denominator of 'All Subjects' column is the total number of subjects treated as a member of either treatment group. Total is not additive across interventions.

[0184] A subject was considered to have completed the study if he / she completed all study visits, including the last scheduled procedure shown in the study Schedule of Assessments. A total of 5 subjects (1.3%) in the Safety population were impacted by coronavirus disease 2019 (COVID-19). Of those, 3 (0.8%) subjects reported AEs related to COVID-19 infection, including 1 subject who had a non-treatm ent-emergent serious adverse event (SAE) of COVID-19 that led to study discontinuation. In addition, several assessments or procedures were impacted, with each affecting < 2 subjects

[0185] Data Sets Analyzed

[0186] Table 4. Data Sets Analyzed

[0187] Population Definition N

[0188] ITT All randomized subjects 400

[0189] PP All randomized subjects who had no protocol deviations affecting the 395 primary analysis

[0190] Safely All treated subjects who received / took > 1 administration of study 399 intervention

[0191] ITT = intent-to-treat; PP = per-protocol

[0192] Note: The PP population consisted of subjects who contributed data to the PP analysis after implementing the data exclusion algorithm. Five subjects' data were excluded at all visits; 4 subjects' data were excluded at 1 visit.

[0193] Efficacy and Safety Measurements

[0194] Efficacy assessments included corneal staining, conjunctival staining, Schirmer test (with anesthesia), OSDI score, TBUT, and self-assessed questionnaires / surveys. The following efficacy endpoints were collected during the study:

[0195] Primary Efficacy Endpoint

[0196] • Change from baseline in total staining score at Day 90

[0197] Secondary Efficacy Endpoint

[0198] • Change from baseline in Current Symptom Survey (composite of all symptoms) at Day 90

[0199] Other Efficacy Endpoints

[0200] • Change from baseline in corneal staining score

[0201] • Change from baseline in conjunctival staining score

[0202] • Change from baseline in total staining score other than Day 90

[0203] • Change from baseline in Current Symptom Survey (composite of all symptoms) other than Day 90

[0204] • Change from baseline in individual symptom scores from Current Symptom Survey

[0205] • Change from baseline in Schirmer test

[0206] • Change from baseline in TBUT

[0207] • Change from baseline in Functional Vision Questionnaire, 5-Minute Blurry Vision, and Ocular Discomfort Questionnaire

[0208] • Change from baseline in OSDI Study Eye Drop Experience and Tolerability Questionnaire

[0209] Corneal and conjunctival staining was assessed using the modified National Eye Institute grading scheme. Total staining score was defined as the sum of corneal and conjunctival staining scores.

[0210] Current Symptom Survey assessed the following symptoms using a visual analogue scale (VAS) from 0 (no symptom) to 100 (maximum severity): burning, dryness, irritation, grittiness / foreign body sensation, blurry / fluctuating vision, and overall ocular pain / discomfort.

[0211] The OSDI questionnaire was designed to capture a range of ocular surface symptoms, including symptoms related to dry eye, their severity, and their impact on the subject's ability to function. Symptoms were evaluated on a scale from 0 (no disease) to 100 (maximum severity of disease), where the OSDI score was calculated as (sum of scores) x 25 I (number of questions answered).

[0212] Questionnaires related to functional vision, 5-minute blurry vision and ocular discomfort, and study eye drop experience and tolerability were evaluated using VAS from 0 to 100.

[0213] The following safety evaluations were performed during the study: monitoring of adverse events (AEs), slit lamp biomicroscopy, currently corrected distance visual acuity, best corrected distance visual acuity (BCDVA), and intraocular pressure (IOP) (subjects with glaucoma or ocular hypertension [OHT] only).

[0214] Statistical Methods:

[0215] Based on the assumption of noninferiority test for a between-group difference (i.e., the noninferiority margin) of 2.3 units in mean change from baseline in total staining at Day 90 (primary efficacy variable) with no inherent treatment difference with common standard deviation (SD) of 6.01, 170 subjects would be required in each intervention to detect the above intervention difference with a power of 90% or greater at the 1 -sided 2.5% significance level. Assuming a 15% dropout rate, 200 subjects were to be randomized to each treatment group with a total of 400 subjects.

[0216] The primary efficacy analysis was performed on the intent-to treat (ITT) population using mixed-effects model repeated measures (MMRM) method. The difference and the 95% confidence interval (CI) were constructed with the least squares (LS) means from the MMRM model with treatment, visit, visit-by-treatment interaction, baseline total staining stratum, and baseline total staining stratum -by-vi sit interaction as the fixed effects. Sensitivity analyses were performed for the primary efficacy endpoint using the per-protocol (PP) population, applying the primary efficacy analytical approach. Additional details are provided in the PP data exclusion algorithm.

[0217] The secondary efficacy variable was analyzed with the same model as described for the primary efficacy analysis.

[0218] Safety analyses were performed based on the Safety population. Continuous variables were summarized by number of subjects with observed values (n), mean, SD, median, 1st and 3rd quartiles, minimum, and maximum. Categorical variables were summarized by number of subjects with observed values or events and percentages based on the specified population. Adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 24.0.

[0219] Efficacy:

[0220] Conclusions for primary and secondary endpoints are as follows:

[0221] • Formulation 1 was noninferior to Formulation 2 in reducing total staining at Day 90 based on the noninferiority margin of 2.3 as measured by change from baseline and the upper limit of the 95% CI (LS mean difference of 1.1 [95% CI: 0.01, 2.27]). However, the lower limit of the 95% CI was above 0, indicating that the Formulation 1 was not as effective as Formulation 2 in the ITT population.

[0222] • In the PP population, the LS mean difference in total staining score at Day 90 for the Formulation 1 versus Formulation 2 group comparison was 1.3 (95% CI: 0.13, 2.41), indicating that the Formulation 1 was inferior to Formulation 2.

[0223] • In both ITT and PP populations, both treatment groups showed significant within-group improvements in total staining score at Day 90 compared to baseline.

[0224] • With respect to the secondary endpoint, both treatment groups similarly reduced the current severity total score at Day 90, with an LS mean (SE) change from baseline of -138.5 (11.46) for the Formulation 2 group and -136.5 (11.62) for the Formulation 1 group (LS mean difference of 2.1 [95% CL -30.03, 34.14] in the ITT population).

[0225] Conclusions for other efficacy endpoints are as follows (ITT population): • In both treatment groups, significant within-group improvements in mean change from baseline in corneal and conjunctival staining scores were observed at all follow-up visits from Days 7 through 90.

[0226] • Both treatment groups showed significant within-group improvements in change from baseline of total staining score from Days 7 through 60. The LS mean difference for the Formulation 1 versus Formulation 2 group comparison 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.

[0227] • The Formulation 1 was comparable to Formulation 2 in reducing current symptom severity total score over time. The LS mean difference for the Formulation 1 versus Formulation 2 group comparison 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.

[0228] • The Formulation 1 was comparable to Formulation 2 in reducing current symptom severity individual symptom scores (i.e., burning, dryness, irritation, grittiness / foreign body sensation, blurry / fluctuating vision, overall ocular pain / discomfort) over time.

[0229] • No significant within-group improvements in mean change from baseline in Schirmer test values were observed in either treatment group over time.

[0230] • Significant within-group improvements in mean change from baseline in TBUT were observed at all follow-up visits from Day 7 and onwards for the Formulation 2 group and from Day 30 and onwards for the Formulation 1 group.

[0231] • In general, Formulation 1 performed numerically better than Formulation 2 from Day 7 and onwards with respect to functional vision questionnaire (composite score), though both treatment groups showed significant within-group improvements compared to baseline at all follow-up visits. At Day 90, the mean (SD) change from baseline in composite score based on combined vision tasks was 16.3 (24.61) for the Formulation 2 group and 18.9 (23.41) for the Formulation 1 group. At Day 90, the mean (SD) change from baseline in general vision was 15.6 (29.86) for the Formulation 2 group and 17.9 (29.89) for the Formulation 1 group.

[0232] • The Formulation 1 formulation was comparable to Formulation 2 in terms of reducing blurry vision and improving ocular discomfort after eye drop instillation on Days 1 and 90. At 5 minutes post dose on Day 90, the mean (SD) change from baseline in blurry vision was 15.0 (24.28) for the Formulation 2 group and 12.1 (22.69) for the Formulation 1 group. At 5 minutes post dose on Day 90, the mean

[0233] (SD) change from baseline in ocular discomfort was 13.4 (21.32) for the Formulation 2 group and 14.6 (25.95) for the Formulation 1 group.

[0234] • Both treatment groups showed significant within-group improvements in change from baseline in OSDI score from Days 7 through 90. At Day 90, the LS mean

[0235] (SE) change from baseline was 17.7 (1.57) for the Formulation 2 group and -20.6 (1.59) for the Formulation ' group (LS mean difference of -2.9 [95% CI: -7.34, 1.47]).

[0236] • The average response to each of the 6 questions on the Study Eye Drop Experience and Tolerability was generally comparable between the treatment groups at all follow-up visits (i.e., continued relief, long-lasting relief [effectiveness], immediate relief, stickiness, buming / stinging, and soothing).

[0237] Safety:

[0238] The safety conclusions from this study are as follows:

[0239] • Overall, at least 1 treatment-emergent AE (TEAE) was reported for 21 (10.6%) subjects in the Formulation 2 group and 31 (15.5%) subjects in the Formulation 1 group.

[0240] • The most commonly reported TEAEs (> 1.0% of subjects) by preferred term were conjunctival hemorrhage, vitreous floaters, eye irritation, punctate keratitis, and hordeolum in the Formulation 1 group and conjunctival edema and headache in the Formulation 2 group. No TEAEs occurred in > 1% of subjects by preferred term in either treatment group.

[0241] • No deaths were reported in the study.

[0242] • One (0.5%) subject in the Formulation 2 group had 2 treatment emergent serious adverse events (pneumonia and acute respiratory failure) that were not considered related to study treatment.

[0243] • Treatment-related TEAEs were reported for 2 (1.0%) subjects in the Formulation 2 group and 4 (2.0%) subjects in the Formulation 1 group. All treatment-related TEAEs were in the system organ class of eye disorders. Except for 1 subject in the Formulation 1 group who had a treatment related TEAE of moderate eye irritation, all treatment-related TEAEs were mild in severity.

[0244] • One (0.5%) subject in the Formulation 1 group had a TEAE of dry eye that led to study discontinuation; the event was mild in severity and was not considered related to study treatment.

[0245] • The majority of subjects in both treatment groups had "no change" from baseline in currently corrected distance visual acuity and in BCDVA at Day 90.

[0246] • Clinically significant biomicroscopy findings included erythema of eyelid and conjunctival hyperemia (1 subject each in the Formulation 2 group) and hordeolum (1 subject in the Formulation 1 group).

[0247] • For subjects in the Formulation 2 group with glaucoma or OHT, the mean change from baseline in IOP in the study eye ranged from -0.4 to +1.0 mmHg on Days 7, 30, and 60. No subjects in the Formulation 1 group had glaucoma or OHT

[0248] Conclusions

[0249] Formulation 1 was noninferior to Formulation 2 in reducing total staining at Day 90 based on the noninferiority margin as measured by change from baseline and the upper limit of the 95% CI. However, the lower limit of the 95% CI was above 0, indicating that the Formulation 1 formulation was not as effective as Formulation 2. For other efficacy endpoints, including the secondary endpoint of change from baseline in Current Symptom Survey at Day 90, the Formulation 1 formulation was generally comparable to Formulation 2.

[0250] The overall safety results indicated that Formulation 1 was safe and well-tolerated, and the safety profile of Formulation 1 was generally similar to that of Formulation 2.

[0251] Example 2 - Cross-Clinical Study Comparison of Formulation 1 to OPTIVE MEGA3

[0252] In view of the favorable results observed from the multicenter, single-masked, randomized, 2-arm, parallel-group human study comparing the safety and efficacy of Formulation 1 and Formulation 2 (see Example 5), an end-point analysis comparing the key data points of Formulation 1 from that trial with the key data points from a separate human clinical trial that evaluated the formulation of OPTIVE MEGA3 (“OM-3”). Patients in the OM-3 clinical trial were treated similarly to the way patients were treated in the human clinical trial described in Example 5 in terms of patient selection, treatment regimen, and analyses.

[0253] Specifically, both ocular staining and ocular surface disease index analyses were performed on patients at baseline, at day 7, at day 30, at day 60, and at day 90.

[0254] As shown in Figure 4, Formulation 1 demonstrated a higher mean change in ocular staining from baseline at each time point when compared to OM-3.

[0255] As shown in Figure 5, Formulation 1 demonstrated a higher mean change in ocular disease severity index from baseline at each time point when compared to OM-3.

[0256] Although this retrospective analysis was not a head-to-head study, the data clearly demonstrated positive trends with Formulation 1 exceeding the performance of OPTIVE MEGA3 across all of the metrics compared in this analysis.

[0257] Example 3 - Reformulation

[0258] As demonstrated by the results disclosed in Example 5, Formulation 1 had demonstrated clinical benefits in a pivotal, human clinical trial. Although Formulation 1 did not demonstrate noninferiority on the stringent, ocular staining endpoint compared with Formulation 2, it had nonetheless achieved numerically better results than Formulation 2 in the Ocular Surface Disease Index (OSDI) which is typically the primary endpoint for a consumer artificial eye drop study. As described in Example 5, Formulation 1 had also met or exceeded the efficacy of Formulation 2 in several secondary measures as well. In addition, Formulation 1 had also achieved positive trends when compared to OPTIVE MEGA3 as shown in FIG. 4 and FIG. 5 and described in Example 6.

[0259] In an effort to further refine and enhance the efficacy of Formulation 1, the formulation was further reformulated to reduce the overall level of osmolarity by reducing the potassium chloride concentration as shown in Table 5. This new formulation is described as Formulation 3.

[0260] Table 5. - New Formulation

[0261] An additional human clinical trial was performed in order to obtain patient experience data for this new formulation on patient symptom relief and product tolerability. Such patient reported outcomes are widely recognized as important measures for clinicians and patients and may be useful for further guiding prescribing and purchasing decisions.

[0262] Example 4 - Clinical Study - A Multicenter, Single-masked, Randomized Study to Compare the Efficacy and Safety of a New Artificial Tear Formulation 1 with Formulation 2 for 90 Days in Participants with Dry Eye Disease (DED) Formulation 1, a novel over-the-counter ophthalmic solution for the treatment, of dry eye containing trehalose and sodium hyaluronate was developed. The study objective was to describe the effect of Formulation 1 on patient symptom relief, product tolerability, and the patient eye drop experience.

[0263] This single arm, single center, open label study utilized the validated Ocular Surface Disease Index (OSDI) and other visual analog scales (VAS) to assess symptom relief and evaluate the patient experience. The OSDI is a validated patient-reported outcome (PRO) tool consisting of a 12-item questionnaire evaluating a patient's dry eye symptom severity using a 5-point scale. The purpose of the OSDI is to capture a range of ocular surface symptoms, including symptoms related to dry eye, their severity, and their impact on the participant's ability to function, scaled into a 0 (no disease) to 100 (maximum severity of disease) score. The Patient Eye Drop Experience (PEDE) Survey evaluated the short- and long-term subjective eye drop experience in relief and tolerability with the study eye drops using a VAS (0 to 100). The Current Symptom Survey (CSS) evaluated the subjective onset of action of the eye drop as it pertains to symptom relief using a VAS (0 to 100).

[0264] The study endpoints were as follows:

[0265] Primary endpoint:

[0266] • Change from baseline in OSDI Score at Day 30

[0267] Secondary endpoints:

[0268] • PEDE scores at Day 30

[0269] • Change from baseline in symptom scores within 5 minutes post-administration of Formulation 3

[0270] Exploratory endpoints:

[0271] • PEDE scores at Day 14

[0272] • Change from baseline in OSDI score at Day 14

[0273] Inclusion Criteria:

[0274] • Participant must be > 18 years of age

[0275] • Written informed consent and written documentation, in accordance with the relevant country and local privacy requirements, had been obtained prior to any study procedures

[0276] • Had used artificial tears for dry eyes within the past year

[0277] • Females of childbearing potential, with a negative pregnancy test result at Screening; these patients must have been currently using a reliable form of birth control and have agreed to use a reliable form of birth control for the duration of the study

[0278] • OSDI score of > 18 and < 65 (based upon a 0 to 100 scale) at Screening and Baseline Visits

[0279] • Three consecutive tear break-up time (TBUT) tests < 10 seconds in at least 1 eye at Screening Visit • Grade 1 to 4 (modified NEI Grid, score range = 0 to 5) staining in at least 1 area of the cornea (5 areas examined) or conjunctiva (6 areas examined) that was related to dry eye in at least 1 eye at both at Screening and Baseline Visits

[0280] • Was able / agreed to continue to wear existing current spectacle correction during the study period (if applicable)

[0281] • Currently corrected distance visual acuity of at least 20 / 32 Snellen equivalent in each eye using the 3-meter LogMar chart, with existing spectacle correction (if necessary) at Screening Visit

[0282] • If using any form of topical ophthalmic cyclosporine (i.e., RESTASIS®), lifitegrast 5% ophthalmic solution (Xiidra®), participants must be using the drops for > 90 days prior to the Screening Visit and plan to continue without change for the duration of the study

[0283] • Intraocular pressure (IOP) < 21 mmHg in both eyes at Screening Visit for patients with primary open-angle glaucoma or ocular hypertension (OHT). Patients with primary open-angle glaucoma or OHT were included provided they were on stable monotherapy bilaterally with IOP controlled (< 21 mmHg) in both eyes. Any topical lOP-lowering medications must have had a start date of > 3 months prior to Screening Visit date and dosage that was not expected to change during the study

[0284] • Was able to follow study instructions and was likely to complete all required visits

[0285] Data Sources:

[0286] The OSDI is a validated patient-reported outcome (PRO) tool consisting of a 12-item questionnaire evaluating a patient's dry eye symptom severity using a 5-point scale. The purpose of this assessment is to capture a range of ocular surface symptoms, including symptoms related to dry eye, their severity, and their impact on the participant's ability to function, scaled into a 0 (no disease) to 100 (maximum severity of disease) score. Participants completed the OSDI at Screening Visit, Baseline Visit, Day 14, and Day 30 / Early exit.

[0287] The Patient Eye Drop Experience Survey evaluates the short- and long-term subjective eye drop experience in relief and tolerability with the study eye drops using a visual analog scale (VAS). All participants completed the PEDE survey at Day 14 and Day 30 / Early exit. Participants were instructed to mark a vertical line on the anchored VAS that best described their agreement with the statements within the questionnaire. Lumanity then converted the participant's response to a numerical value (0 to 100). This is an overall evaluation, not per eye.

[0288] The Current Symptom Survey evaluates the subjective onset of action of the eye drop as it pertains to relief and tolerability using a VAS. All participants completed the CSS at Day 1. The survey was administered at TO (pre-dosing), T30s, Timin, T3min and T5min post-dosing. Participants were instructed to mark a vertical line on the anchored VAS that best described their agreement with the statements within the questionnaire. Lumanity then converted the participant's response to a numerical value (0 to 100). This is an overall evaluation, not per eye.

[0289] The Study Product Usage Questionnaire evaluates the product usage and compliance of study drug. All participants completed the Study Product Usage Questionnaire at Day 14 and Day 30 / Early exit.

[0290] Screening and Enrollment:

[0291] Forty-two (42) individuals were screened for the this human clinical study. Of the 42 participants who were screened, 40 participants (95.2%) were treated with Formulation 1. Of the 40 participants who were treated, 38 (95.0%) completed the study (i.e. Baseline to Day 30). Two participants (5.0%) discontinued the study after their Day 14 visits. Of the 38 participants who completed the study, four (10.5%) participants were deemed protocol deviations following data entry and analysis given their baseline OSDI scores were outside the 18 to 65 inclusion range. In summary, the intend on-to treat (ITT) population includes all 40 participants who were treated with Formulation 1 at any point during the trial while the per-protocol (PP) population includes 34 participants after excluding those who were deemed protocol deviations and those who discontinued treatment.

[0292] Patient Demographics:

[0293] ITT (Intent to Treat) Population:

[0294] Participant ages ranged from 18 to 74 years old. The average age of participants was 37.7 years old (standard deviation [SD]): 15.8). Female participants made up 60% (n=24 of 40) of the sample. The majority of participants (n=38 of 40, 95.0%) identified as White and Hispanic / Latino. The majority of participants (n=27 of 40, 67.5%) had a baseline OSDI score of Severe (33-100). Four participants (n=4 of 40, 10.0%) had a baseline OSDI score outside of the 18 to 65 inclusion criteria - one participant (n=l of 40, 2.5%) had a baseline OSDI score less than 18 while three participants (n=3 of 40, 7.5%) had a baseline OSDI score greater than 65. These four participants are excluded from the PP population.

[0295] PP (Per-Protocol) Population:

[0296] Participant ages ranged from 18 to 74 years old. The average age of participants was 37.8 years old (SD: 15.2). Female participants made up over half (n=21 of 34, 61.8%) of the sample. The majority of participants (n=32 of 34, 94.1%) identified as White and Hispanic / Latino. The majority of participants (n=24 of 34, 70.6%) had a baseline OSDI score of Severe (33-100).

[0297] Study Product Usage Questionnaire

[0298] The Study Product Usage Questionnaire evaluated the product usage and compliance of study drug (Formulation 1). All participants completed the Study Product Usage Questionnaire at Day 14 and Day 30 / Early Exit. The majority of participants selected “N / A” for use of RESTASIS or intraocular pressure-lowering therapy drops in the past four hours at baseline in the PP population (n=28 of 34, 82.4%). On average, participants in the PP population reported administering the eye drops 2.3 times a day (SD: 0.7) at Day 14 and 2.8 times a day (SD: 1.5) at Day 30.

[0299] Results:

[0300] Mean OSDI score from baseline to Day 30 decreased by 8.0 points (SD: 17.0) in the intent-to-treat (ITT) population and by 6.8 points (SD: 15.0) in the per-protocol (PP) population (see FIG. 7 & FIG. 8). A paired t-test was conducted between baseline and Day 30 mean OSDI scores and change in mean OSDI score was found to be statistically significant (p < 0.05) in both the ITT and PP population.

[0301] Mean total CSS score decreased within 5 minutes in both the ITT and PP population; participants experienced the greatest change in mean total CSS score at 5 minutes post-dose (ITT: -13.6 [SD: 15.4], PP: -10.1 [SD: 10.6]) (see FIG. 9 & FIG. 10). A paired t-test was conducted on mean total CSS scores between TO and subsequent timepoints (T30s, T1 min, T3 min, and T5 min) and change in mean total CSS score from baseline to all subsequent timepoints were statistically significant (p < 0.05) in both the ITT and PP population.

[0302] Mean PEDE scores at Day 30 ranged from 75.8 (Stinging / buming SD: 36.8, Stickiness SD: 31.2) to 86.0 (SD: 20.0) in the ITT population and from 76.4 (SD: 36.7) to 85.7 (SD: 21.0) in the PP population. In the ITT population, mean PEDE scores at Day 30 ranged from 75.8 (SD: 36.8) to 84.3 (SD: 20.3) for the 5-minute recall period questions, 75.8 (SD: 31.2) to 86.0 (SD: 20.0) for the 30-minute recall period questions, 84.7 (SD: 19.1) to 85.1 (SD: 20.7) for the 24-hour recall period questions, and 81.6 (SD: 22.6) to 84.1 (SD: 22.0) for the 5-day recall period questions. In the PP population, mean PEDE scores at Day 30 ranged from 76.4 (SD: 36.7) to 84.1 (SD: 21.1) for the 5-minute recall period questions, 78.6 (SD: 30.8) to 85.7 (SD: 21.0) for the 30-minute recall period questions, 84.4 (SD: 20.0) to 84.5 (SD: 21.5) for the 24-hour recall period questions, and 82.0 (SD: 22.6) to 83.8 (SD: 23.2) for the 5-day recall period questions (see FIG. 11, 12, 13, & 14).

[0303] • From baseline to 5 minutes, participants’ scores on the CSS decreased on all items, demonstrating improvement of symptoms over time.

[0304] • Participants experienced a significant change in mean score from baseline at all timepoints (30s, Imin, 3min, and 5min) on Item 3 (Eye dryness).

[0305] • At Day 30, participants’ scores on the PEDE survey generally skewed toward 100 (Strongly Agree), demonstrating a trend toward agreement with statements about short- and long-term relief and tolerability with the study eye drops.

[0306] • Participants’ PEDE score at Day 30 was greatest on Item 9 (Continued comfort to eye dryness after 30 minutes) and lowest on Item 1 (Stinging / burning within 5 minutes) and Item 7 (Stickiness after 30 minutes)

[0307] Mean PEDE scores at Day 14 ranged from 62.7 (SD: 41.8) to 82.4 (SD: 20.1) in the ITT population and from 57.1 (SD: 42.9) to 81.2 (SD: 21.3) in the PP population. In the ITT population, mean PEDE scores at Day 14 ranged from 62.7 (SD: 41.8) to 76.9 (SD: 25.3) for the 5-minute recall period questions, 74.7 (SD: 30.5) to 82.1 (SD: 20.5) for the 30-minute recall period questions, 77.8 (SD: 24.6) to 82.4 (SD: 20.1) for the 24-hour recall period questions, and 77.9 (SD: 19.0) to 78.6 (SD: 21.5) for the 5-day recall period questions. In the PP population, mean PEDE scores at Day 14 ranged from 57.1 (SD: 42.9) to 75.0 (SD: 26.3) for the 5-minute recall period questions, 75.4 (SD: 31.1) to 81.2 (SD: 21.3) for the 30-minute recall period questions, 75.5 (SD: 25.3) to 80.5 (SD: 20.7) for the 24-hour recall period questions, and 76.3 (SD: 19.2) to 76.5 (SD: 22.2) for the 5-day recall period questions.

[0308] Mean OSDI score from baseline to Day 14 decreased by 7.7 points (SD: 16.7) in the ITT population and by 8.1 points (SD: 15.9) in the PP population. A paired t-test was conducted between baseline and Day 14 mean OSDI scores and change in mean OSDI score was found to be statistically significant (p < 0.05) in both the ITT and PP population.

[0309] Conclusion: Overall, the survey data collected as a part of this human clinical trial demonstrated participants treated with Formulation 3 experienced symptom reduction over the course of the trial including improvements in the OSDI score at Day 30, improvements in total current symptom scores (CSS) within 5 minutes, improvements in dry eye symptoms observed as early as 30 secs, favorable patient eye drop experience (PEDE) scores observed at Day 30. In addition, no adverse events reported throughout the trial.

Claims

WHAT IS CLAIMED IS:

1. A low salt ophthalmic pharmaceutical composition comprising a polymer lubricant, a salt-sensitive viscosity modulating polymer, one or more tonicity agents, trehalose, and a hyaluronate.

2. The low salt ophthalmic pharmaceutical composition according to Claim 1, wherein said hyaluronate is sodium hyaluronate.

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

4. The low salt ophthalmic pharmaceutical composition according to Claim 3, wherein said composition comprises carnitine, glycerin, erythritol and trehalose.

5. The low salt ophthalmic pharmaceutical composition according to Claim 4, wherein said polymer lubricant is carboxymethylcellulose sodium present at a concentration of about 0.5% (w / w).

6. The low salt ophthalmic pharmaceutical composition according to Claim 4, further comprising a compatible solute, wherein said compatible solute is levocarnitine.

7. The low salt ophthalmic pharmaceutical composition according to Claim 6 comprising erythritol at a concentration of about 0.25% (w / w) and levocamitine 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 said 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 said composition is preservative free.

11. The low salt ophthalmic pharmaceutical composition according to Claim 10 further comprising a buffer.

12. The low salt ophthalmic pharmaceutical composition according to Claim 11, wherein said 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, further comprising sodium borate decahydrate.

14. The low salt ophthalmic pharmaceutical composition according to Claim 13, further comprising sodium citrate dihydrate.

15. The low salt ophthalmic pharmaceutical composition according to Claim 14, further comprising potassium chloride.

16. The low salt ophthalmic pharmaceutical composition according to Claim 15, further comprising calcium chloride dehydrate.

17. The low salt ophthalmic pharmaceutical composition according to Claim 16, further comprising a pH adjustment agent, wherein said pH adjustment agent is NaOH, and wherein said pharmaceutical composition has a pH of about 7.3.

18. A low salt ophthalmic pharmaceutical composition 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); levocamitine at a concentration of about 0.25% (w / w); potassium chloride at a concentration of about 0.03% (w / w); calcium chloride dihydrate at a concentration of about 0.006% (w / w); 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); carboxymethylcellulose sodium at a concentration of about 0.5% (w / w); glycerin at a concentration of about 0.9% (w / w);NaOH; and water.

19. Combination of a low salt ophthalmic pharmaceutical composition according to Claim 18, and a multidose, preservative free bottle, to reliably dispense said low salt ophthalmic pharmaceutical composition liquid, wherein said composition is sterile and preservative free.

20. A method for treating dry eye syndrome comprising using the combination according to Claim 19 to administer to a subject in need of treatment of dry eye syndrome said a low salt ophthalmic pharmaceutical composition; thereby treating said dry eye syndrome.