Ophthalmic suspension vehicles for drug ingredient delivery and related methods

Abstract

The present disclosure relates to ophthalmic suspension vehicles for delivering at least one pharmaceutical ingredient to a patient in need of treatment. The disclosure also provides methods of delivering at least one pharmaceutical ingredient to a patient in need of treatment.

Description

Technical Field

[0001] The present disclosure provides an ophthalmic suspension vehicle for providing sustained ocular therapy to the eye. In particular, the ophthalmic suspension vehicle described herein provides a sustained delivery of a drug ingredient to the eye for an extended period of time. Background Art

[0002] In the past 25 years, the lasting release of therapeutic drugs to the eyes has been attempted. This has been attempted with the aid of both ophthalmic pharmaceutical preparations and devices for drug delivery, so that active therapeutic ingredients or drugs with synthetic effects are released to the eyes. Unfortunately, since the ophthalmic preparations and their vehicles so far are only retained on the eyes for 5 minutes to a maximum of 30 minutes, the consistent delivery of drug preparations over time on the eyes has not yet been achieved. Therefore, it is impossible to require an ideal delivery vehicle for active drugs that are retained on the eyes for an extended time of more than 30 minutes. This shortcoming is partly based on the fact that the tear film produced by the secretions of the different glands of the eyes during normal blinking causes the drug components and vehicles to be discharged from the eyes. The largest part of the tear film is the aqueous liquid of the tears and is mainly produced by the tear glands activated by blinking. The outer tear film layer is a lipid layer, which is mainly secreted from the meibomian glands located in the eyelids during blinking. The lipid layer provides a protective layer on the top of the tear film, aiming to reduce the evaporation of the tear film aqueous liquid. The thinning of the lipid layer increases the evaporation of the aqueous layer, which leads to dry eyes on the corneal surface between blinks. The evaporation rate of the tear film in patients with such dry eyes increases by 30% to 38% at less than 50% relative humidity. This is in addition to the measured loss of the aqueous layer through the puncta. Secretions from the lacrimal and meibomian glands, coupled with these collections of eyelids that provide a wiper effect during normal blinking, provide a normal, long-lasting and stable tear film on the eye. While normal production of components continues to repair and replace the tear film, the loss of key components due to dysfunction or no secretion makes the tear film unstable and quickly leads to the loss of tear film structure, resulting in dry eyes. The dry eye problem caused by a dysfunctional tear film results in the inability of vehicles and drug actives to stay on the eye for a long time.

[0003] Normal tears with the correct balance of lipid, aqueous and mucin components combined during blinking form a stable and protective tear film. Between blinks, the tear film thins due to evaporation, and the lipid molecules of the outer layer begin to migrate through the aqueous layer toward the mucin layer. The aqueous portion of the tears is also exchanged on the eye at approximately 16% by volume per minute, while the lipid layer is exchanged on the eye at a rate of approximately 2% per minute. Contamination of the mucin layer by the lipid layer increases the surface tension of the tear film and eventually causes the tear film to rupture (rupture / break-up) and aggregate into beads on the corneal surface, forming dry spots. Subsequent blinks usually repair the rupture by removing lipid contaminants from the mucin layer and restoring the normal aqueous layer. However, repeated ruptures may result in loss of the mucin layer and show staining when observed using fluorescein.

[0004] U.S. Patent Nos. 5,371,108, 5,278,151 and U.S. Patent Publication No. 2016 / 03389952 issued to Korb teach a method or formulation for producing an emulsion or gel containing oil and wax to form a tear film on the surface of the eye to extend the residence time of the oil. However, wax-containing gels have not yet been produced and commercially sold because it is difficult to homogenize the wax in a manner that does not cause visual blur beyond what is acceptable to most consumers. Specifically, autoclaving wax-containing formulations results in increased particle size, which causes irritation and blurred vision. Gels are semisolid formulations with high viscosity. In contrast, the present disclosure relates to metastable emulsions that behave as flowing liquids at room temperature. Emulsions behave as liquids and therefore do not exhibit static internal structures or have high viscosity. Korb also utilizes preservatives at levels known to be toxic to corneal cells after application, and does not disclose a vehicle that will exhibit a persistent residence time.

[0005] Many ophthalmic formulations and compositions for use take note of the use of zeta potential and are disclosed in WO2016209555, WO 2015057847, WO 2011098578, WO 2011084509, WO 03053405, US2012328702, US2012225834, and U.S. Pat. Nos. 7,060,285, 9,827,191, 8,298,569, 7,893,040, 7,834,172, and 10,137,083, each of which is incorporated herein by reference for its teachings regarding the use of zeta potential.

[0006] The tear film can be used as a substrate for providing ocular delivery of small concentrations of drug ingredients, which is a challenge for the industry. See Patel et al. 2013, "Ocular drug delivery systems: An overview" World J. Pharmacol [World Pharmaceutical Association] 2 (2) 47-64. Acceptable drug ingredient carriers need to mimic the properties and osmotic pressure of the natural tear film and remain on the eye for an extended period of time. Such products will increase the bioavailability of active pharmaceutical ingredients ("API") to corneal epithelial cells, which is a desired long route for ocular drugs. Summary of the invention

[0007] Disclosed herein are ophthalmic suspensions comprising an ophthalmic suspension vehicle that can be used to deliver at least one pharmaceutical ingredient to the ocular surface of the eye. The ophthalmic suspension enables enhanced bioavailability by delivering at least one pharmaceutical ingredient to the ocular surface of the eye. The residence time of the ophthalmic suspension on the eye allows for extended and improved delivery of at least one pharmaceutical ingredient to the eye, thereby increasing the contact time of the at least one pharmaceutical ingredient on the eye. The residence time of the ophthalmic suspension on the eye also allows for the utilization of lower levels of the pharmaceutical ingredient while achieving the desired therapeutic effect while reducing any unwanted side effects.

[0008] Also provided is a method for delivering at least one pharmaceutical ingredient to a patient in need of treatment. The method comprises the step of administering to the patient's eye an ophthalmic suspension as provided herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 A magnified view of the tear film identifying different areas is shown. A normal tear film is 3-6 microns thick. The figure shows a lipid layer, a lipid / aqueous interface, an aqueous layer, an aqueous / mucin interface, a mucin layer, and a cornea. Two of the illustrations show magnified views of the lipid / aqueous interface and the aqueous / mucin interface. The third illustration shows thinning of layers and interfaces associated with dry eye. In particular, the third illustration shows thinning of (i) an aqueous layer, (ii) an unbound mucin layer, and (iii) a bound mucin layer bound to the surface of corneal epithelial cells. Methods for evaluating tear films are further provided in U.S. Serial No. 16 / 708,120 (U.S. Publication No. 2020 / 0179281), the entire contents of which are incorporated herein by reference. DETAILED DESCRIPTION

[0010] While the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[0011] As used herein, the term "pharmaceutical ingredient" refers to a substance used in a finished pharmaceutical product (FPP) that is intended to provide pharmacological activity or otherwise have a direct role in the diagnosis, cure, mitigation, treatment, or prevention of disease or disorder, or in restoring, correcting, or altering a physiological function in humans.

[0012] As used herein, the terms "about" and / or "approximately" can be used in conjunction with numerical values ​​and / or ranges. The term "about" is understood to mean those values ​​that are close to the recited values. Alternatively, depending on the context, the term "about" can mean ± half a standard deviation, ± one standard deviation, or ± two standard deviations. In addition, the phrase "less than about [value]" or "greater than about [value]" should be understood according to the definition of the term "about" provided herein. The terms "about" and "approximately" can be used interchangeably. Throughout this specification, numerical ranges are provided for certain quantities.

[0013] As used herein, the verb "comprise" and its conjugations as used in the specification and claims are used in their non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.

[0014] As used herein, the word "comprising" or variations such as "comprises / comprising" will be understood to imply the inclusion of the stated elements, integers, or steps, or groups of elements, integers, or steps, but not the exclusion of any other elements, integers, or steps, or groups of elements, integers, or steps. The present disclosure may appropriately "comprise / comprises," "consist of," or "consist essentially of," the steps, elements, and / or agents described in the claims.

[0015] It is further noted that the claims may be drafted to exclude any optional element. Thus, this statement is intended to serve as antecedent basis for use of exclusive terminology such as "solely," "only" and the like in connection with the recitation of claim elements or use of a "negative" limitation.

[0016] As used herein, the term "weight percent" refers to the amount based on the ophthalmic suspension vehicle unless otherwise indicated.

[0017] As used herein, the term "wax ester" refers to esters of fatty acids and fatty alcohols, and may include a variety of compounds with various carbon chain lengths. Wax esters provided herein may include long carbon chains. Wax esters provided herein may exist as solid particles that exhibit a melting point of about 60°C to about 100°C. Wax esters provided herein may be natural beeswax. Natural beeswax may also be commercially available as white beeswax (Cera Alba) or yellow beeswax (Cera Flava) (white or yellow beeswax). The use of natural beeswax may include hydrocarbons as a component. During the preparation of an embodiment of the emulsion of the present disclosure, as part of the method, wax esters may be hydrolyzed to form additional acids and / or alcohols. The terms "wax ester dispersion" and "wax dispersion" may be used interchangeably.

[0018] As used herein, the term "particle size" refers to the size of wax ester particles alone or in combination with one or more oils, phospholipids, surfactants, hyaluronic acid (HA), sodium hyaluronate, or any other ophthalmic suspension vehicle components provided herein.

[0019] As used herein, the term "residence time" refers to the time (e.g., minutes or hours) that an ophthalmic suspension vehicle remains on the eye after a single application when the level or amount of lipid layer thickness is evaluated from a baseline on the eye. The lipid layer thickness can be determined by an interferometric measurement instrument to measure the residence time on the eye.

[0020] As used herein, the term "persistent" refers to an increase in retention time observed over a period of time and demonstrated compared to an untreated eye.

[0021] As used herein, the term "stable" refers to the time that the tear film maintains its structure between blinks.

[0022] As used herein, the term "tear film" refers to the entire protective coating provided to the eye, including Figure 1 As shown in the figure.

[0023] As used herein, the term "dry eye" refers to a condition of the eye in which the tear film fails to perform its lubricating function and may be caused by a lack of key components that form a stable tear film.

[0024] As used herein, the term "dry delivery" refers to the use of the ophthalmic suspension vehicles provided herein to provide sustained release of at least one drug ingredient to the ocular surface over an extended period of time.

[0025] As used herein, the terms "light mineral oil" and "light mineral oil" are used interchangeably and refer to low viscosity mineral oils as defined in the NF or USP formularies.

[0026] As used herein, the terms "heavy mineral oil" and "heavy mineral oil" are used interchangeably and refer to high viscosity mineral oil variants that meet the requirements of the NF or USP monographs for mineral oils.

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0028] The present disclosure relates to ophthalmic suspensions and related methods.Ophthalmic suspensions provided herein comprise an ophthalmic suspension vehicle and at least one drug ingredient added to provide sustained delivery of an active drug upon delivery to the patient's eye.

[0029] The ophthalmic suspension vehicle comprises an aqueous phase and an oil phase. The aqueous phase may comprise water and one or more of: at least one wax ester, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt and at least one phosphate. The water utilized in the ophthalmic suspension vehicle provided herein may be purified water or deionized water. The oil phase may comprise at least one mineral oil and optionally at least one wax ester. Therefore, the at least one wax ester may be present in the aqueous phase, the oil phase, or both the aqueous phase and the oil phase. According to specific embodiments, at least one wax ester is in the aqueous phase or the oil phase.

[0030] The ophthalmic suspensions provided herein comprise at least one pharmaceutical ingredient. The ophthalmic suspensions provide for delivery of the at least one pharmaceutical ingredient such that the at least one pharmaceutical ingredient remains within the ophthalmic suspension vehicle and is in therapeutic contact with the eye for at least two hours after administration to the eye. According to one embodiment, the at least one pharmaceutical ingredient is soluble in an aqueous phase. According to another embodiment, the at least one pharmaceutical ingredient is soluble in an oil phase.

[0031] At least one oil present in the ophthalmic suspension vehicle provided herein can be derived from animals, plants, nuts or other suitable sources. The oil derived from animals, plant seeds and nuts is similar to fat, and is mainly glyceride or fatty acid, and therefore contains a large amount of acid and / or ester groups, so that oil has polarity. The example of these oils is safflower oil, corn oil, canola oil, whale oil and seal oil or chemically similar oil. As provided herein, other oil includes vegetable oil such as castor oil, almond oil, geranium oil, corn oil, peanut oil, canola oil, safflower oil, cola nut oil, light olive oil, bay leaf oil or other generally recognized safety (GRAS) oils suitable for eye preparations. Alternatively, oil can be the oil suitable for forming liposomes. According to one embodiment, oil is a straight chain hydrocarbon oil with 10 to 150 carbon atoms, and more preferably, oil is a saturated normal alkane or isoalkane with 10 to 26 carbon atoms. Unsaturated olefins can be used, but chemical stability is poor.

[0032] According to one embodiment, the oil present in the ophthalmic suspension vehicle provided herein is mineral oil. According to one embodiment, the oil as provided herein is light mineral oil. According to one embodiment, the oil as provided herein is heavy mineral oil.

[0033] According to one embodiment, the oil present in the ophthalmic suspension vehicle provided herein comprises a mixture of light mineral oil and heavy mineral oil, each having a different viscosity. According to a specific embodiment, the light mineral oil exhibits a viscosity of about 3.0 mm at 40°C. 2 s -1 to about 34.4mm 2 s -1 According to a specific embodiment, the heavy mineral oil exhibits a dynamic viscosity of about 34.5 mm at 40°C. 2 s -1 To about 150mm 2 s -1 According to yet another embodiment, the light mineral oil exhibits a dynamic viscosity of about 28 mm at 40°C. 2 s -1 To about 30mm 2 s -1 According to yet another embodiment, the heavy mineral oil exhibits a dynamic viscosity of about 65 mm at 40°C. 2 s -1 To about 71mm 2 s -1 The dynamic viscosity.

[0034] The amount of oil in the oil phase may vary within reasonable limits, however administration to the eye should not exceed 25 μL. According to one embodiment, the volume does not exceed 15 μL. According to one embodiment, the volume varies between about 1 μL and 10 μL. According to one embodiment, the volume varies between about 1 μL and 30 μL.

[0035] The total amount of the oil or combination of oils may be present in the ophthalmic suspension vehicle in an amount of at least about 0.1% by weight based on the total weight of the ophthalmic suspension vehicle. According to one embodiment, the oil or combination of oils is present in an amount of at least about 0.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount of at least about 1.0% by weight. According to one embodiment, the oil or combination of oils is present in an amount of at least about 1.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 12.5% ​​by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 10.0% by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 7.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 6.6% by weight. According to one embodiment, the oil or combination of oils is present in an amount of less than about 6.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 0.5% by weight and about 12.5% ​​by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 1.0% by weight and about 8.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 3.5% by weight and about 7.5% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 4.0% by weight and about 7.0% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 4.4% by weight and about 6.6% by weight. According to one embodiment, the oil or combination of oils is present in an amount between about 4.95% by weight and about 6.05% by weight.

[0036] According to embodiments, the oil present in the ophthalmic suspension vehicle provided herein comprises a mixture of two or more oils of different weights. According to such embodiments, the oil is a mixture of at least one light oil and at least one heavy oil. According to specific embodiments, the oil is obtained under the trade name 15 (light mineral oil) and According to one embodiment, the light mineral oil may be present in an amount of about 0.5% by weight to about 1.5% by weight. According to one embodiment, the light mineral oil may be present in an amount of about 0.6% by weight to about 1.4% by weight. According to one embodiment, the light mineral oil may be present in an amount of about 0.7% by weight to about 1.3% by weight. According to one embodiment, the light mineral oil may be present in an amount of about 0.8% by weight to about 1.2% by weight.

[0037] According to one embodiment, the heavy mineral oil may be present in an amount of about 2.7% by weight to about 6.5% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 2.9% by weight to about 6.3% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 3.1% by weight to about 6.1% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 3.3% by weight to about 5.9% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 3.5% by weight to about 5.7% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 3.7% by weight to about 5.5% by weight. According to one embodiment, the heavy mineral oil may be present in an amount of about 4.05% by weight to about 4.95% by weight.

[0038] According to one embodiment, the light mineral oil may be present in an amount of about 1.0% by weight, and the heavy mineral oil may be present in an amount of about 4.5% by weight.

[0039] The ophthalmic suspension vehicle provided herein comprises at least one wax ester. Although not bound by a particular theory, it is believed that the role of the wax ester and its hydrolyzate is to maintain the integrity of the interstitial layer itself, to bind the mucin layer to the aqueous layer and to bind the aqueous layer to the lipid layer. In addition, the wax ester is used to thicken the mucin, aqueous layer, and lipid layer itself. The binding process and subsequent steady state achieved by the wax ester allow the layers of the tear film to adhere to each other, thereby allowing the entire tear film to remain on the eye for an extended period of time and providing drug delivery of at least one drug ingredient. The ophthalmic suspension vehicle provided herein penetrates all layers of the tear film, including the interstitial layer that was not previously incorporated with the product.

[0040] According to one embodiment, the wax esters are insoluble, thereby providing an ophthalmic suspension that slowly dissolves in the presence of the wax esters secreted by the glands of the eye, thereby increasing the viscosity of the lipid layer. This has the effect of actually slowing down the turnover rate of the tear film through the puncta, as the higher viscosity liquid will flow more slowly than the unstable and low viscosity tear film of a dry eye patient.

[0041] According to one embodiment, at least one wax ester is present in the ophthalmic suspension vehicle in an amount of at least about 0.2% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.3% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.4% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.5% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.6% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.7% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.8% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 0.9% by weight. According to one embodiment, at least one wax ester is present in an amount of at least about 1.0% by weight. According to one embodiment, at least one wax ester is present in an amount of less than about 1.8% by weight. According to one embodiment, at least one wax ester is present in an amount of about 0.2% by weight to about 1.8% by weight. According to one embodiment, at least one wax ester is present in an amount of about 0.4% by weight to about 1.6% by weight. According to one embodiment, the at least one wax ester is present in an amount of about 0.6 wt % to about 1.4 wt %. According to one embodiment, the at least one wax ester is present in an amount of about 0.8 wt % to about 1.2 wt %. According to one embodiment, the at least one wax ester is present in an amount of about 1.0 wt %.

[0042] According to one embodiment, at least one wax ester is beeswax. According to one embodiment, the beeswax is natural beeswax. The beeswax can be white beeswax, yellow beeswax, or a combination thereof. The beeswax can be USDA certified organic beeswax or regular natural beeswax. According to one embodiment, at least one wax ester is synthetic beeswax.

[0043] The ophthalmic suspension vehicle provided herein comprises wax ester particles. According to one embodiment, the wax or wax ester particles can be mixed with at least one oil as provided herein. According to one embodiment, the wax or wax ester particles can be mixed with water and at least one oil as provided herein.

[0044] According to one embodiment, the wax ester particles as provided herein exhibit a particle size that allows the particles to remain on the eye and in contact with the eye to allow delivery of at least one pharmaceutical ingredient. According to one embodiment, the wax ester particles as provided herein form emulsion particles that are retained on the eye and in contact with the eye to allow delivery of at least one pharmaceutical ingredient.

[0045] According to one embodiment, wax ester particles can be emulsified in an ophthalmic suspension vehicle to form a series of specific particle sizes. The irregular shape and charge of the particles themselves allow wax ester particles to have more surface area to interact with oil as provided herein, and allow wax ester particles to decompose at a variable rate, wherein smaller wax ester particles and oil particles decompose quickly, and larger wax ester particles decompose more slowly. When wax ester particles decompose, it is believed that oil and wax ester particles interact with natural tear film to support a more stable barrier of an aqueous tear film that is easy to evaporate.

[0046] According to one embodiment, the wax ester particles exhibit an average particle size of at least about 2.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 3.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 4.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 5.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 30.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 25.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 24.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 23.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 22.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 21.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of less than about 20.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 2.0 microns but less than about 25.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 2.0 microns but less than about 20.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 2.0 microns but less than about 15.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 3.0 microns but less than about 24.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 4.0 microns but less than about 23.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 5.0 microns but less than about 22.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 6.0 microns but less than about 21.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 7.0 microns but less than about 20.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of at least about 10.0 microns but less than about 15.0 microns.

[0047] The ophthalmic suspension vehicle provided herein comprises at least one surfactant. According to one embodiment, the ophthalmic suspension vehicle comprises at least two or more surfactants. According to one embodiment, the ophthalmic suspension vehicle comprises a combination of surfactants, which is used to stabilize the vehicle and at least one drug ingredient and to spread the vehicle and drug ingredient and maintain the dual purpose on the ocular surface after being applied to the eyes. In one embodiment, the surfactant combination may include a primary surfactant and a secondary surfactant. At least one surfactant can form an ophthalmic suspension vehicle that is stable during manufacture and storage, but is expected to be metastable when applied to the ocular surface. As an example, when applied to the ocular surface, at least one surfactant allows the phase separation of components. At least one surfactant as provided herein is suitable for rapid differentiation when applied to the eyes, thereby quickly forming a non-fuzzy film of oil on the ocular surface, and wax esters are spread through each phase of the ophthalmic suspension vehicle.

[0048] According to one embodiment, at least one surfactant includes at least one polyoxyethylene sorbitan monooleate, such as polyoxyethylene-sorbitan-20 monooleate, which is commercially available as polysorbate 80 or Tween 80. According to one embodiment, polyoxyethylene sorbitan monooleate may be present in the ophthalmic suspension vehicle in an amount of about 0.1% by weight to about 0.7% by weight. According to one embodiment, polyoxyethylene sorbitan monooleate may be present in the ophthalmic suspension vehicle in an amount of about 0.2% by weight to about 0.6% by weight. According to one embodiment, polyoxyethylene sorbitan monooleate may be present in the ophthalmic suspension vehicle in an amount of about 0.3% by weight to about 0.6% by weight. According to one embodiment, polyoxyethylene sorbitan monooleate may be present in the ophthalmic suspension vehicle in an amount of about 0.4% by weight to about 0.6% by weight.

[0049] According to one embodiment, at least one surfactant includes diphosphatidylglycerol, such as commercially available dimyristoylphosphatidylglycerol or 1,2-dimyristoyl-sn-glycero-3-phosphatidylglycerol sodium salt (DMPG). The surfactant can be lysophosphatidylcholine, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, or phosphatidylserine. In other embodiments, the surfactant includes at least one anionic surfactant. According to one embodiment, the anionic surfactant can be one or more of anionic polar phospholipids, such as lysophosphatidylcholine, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, or phosphatidylserine. According to another embodiment, the anionic polar phospholipid can be one or more of the following: phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), and its phosphorylated derivative phosphoinositide (e.g., phosphatidylinositol-4-phosphate [PI4P] and phosphatidylinositol-4,5-bisphosphate), and dimyristoylphosphatidylglycerol. According to one embodiment, the anionic surfactant is dimyristoylphosphatidylglycerol. According to one embodiment, the surfactant is a mixture of two surfactants as provided herein. According to one embodiment, the surfactant is a combination of two anionic polar phospholipids. According to one embodiment, the anionic polar surfactant is a mixture of Tween 80 and anionic polar dimyristoylphosphatidylglycerol.

[0050] According to one embodiment, dimyristoyl phosphatidylglycerol may be present in an ophthalmic suspension vehicle in an amount of about 0.1% to about 0.7% by weight. According to one embodiment, dimyristoyl phosphatidylglycerol may be present in an ophthalmic suspension vehicle in an amount of about 0.2% to about 0.6% by weight. According to one embodiment, dimyristoyl phosphatidylglycerol may be present in an ophthalmic suspension vehicle in an amount of about 0.3% to about 0.6% by weight. According to one embodiment, dimyristoyl phosphatidylglycerol may be present in an ophthalmic suspension vehicle in an amount of about 0.4% to about 0.6% by weight.

[0051] According to one embodiment, the ophthalmic suspension vehicle provided herein comprises one or more phosphate salts. According to one embodiment, the ophthalmic suspension vehicle comprises both monobasic phosphate salts and dibasic phosphate salts.

[0052] According to a specific embodiment, the monobasic phosphate is monosodium phosphate (sodium dihydrogen phosphate), such as NaH2PO4. According to one embodiment, the monobasic phosphate may be present in an amount of about 0.01% by weight to about 0.05% by weight. According to one embodiment, the monobasic phosphate may be present in an amount of about 0.02% by weight to about 0.04% by weight. According to one embodiment, the monobasic phosphate may be present in an amount of about 0.03% by weight.

[0053] According to a specific embodiment, the dibasic phosphate is disodium phosphate (sodium hydrogen phosphate or disodium hydrogen phosphate), such as Na2HPO4. According to one embodiment, the dibasic phosphate may be present in an amount of about 0.1% by weight to about 0.5% by weight. According to one embodiment, the dibasic phosphate may be present in an amount of about 0.2% by weight to about 0.3% by weight. According to one embodiment, the dibasic phosphate may be present in an amount of about 0.25% by weight.

[0054] According to one embodiment, the ophthalmic suspension vehicle provided herein comprises at least one salt. According to one embodiment, at least one salt is sodium chloride or other salt suitable for ophthalmic administration. At least one salt may be present in an amount of about 0.50% by weight to about 0.75% by weight. According to another embodiment, at least one salt may be present in an amount of about 0.55% by weight to about 0.70% by weight. According to another embodiment, at least one salt may be present in an amount of about 0.55% by weight. According to another embodiment, at least one salt may be present in an amount of about 0.67% by weight.

[0055] According to one embodiment, the ophthalmic suspension vehicle provided herein may include at least one glycosaminoglycan. Suitable glycosaminoglycans include hyaluronic acid (HA), corresponding sodium salt sodium hyaluronate, or a combination thereof. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension vehicle in an amount of about 0.06% by weight to about 0.5% by weight. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension vehicle in an amount of about 0.07% by weight to about 0.4% by weight. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension vehicle in an amount of about 0.08% by weight to about 0.3% by weight. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension vehicle in an amount of about 0.09% by weight to about 0.2% by weight. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in an ophthalmic suspension vehicle in an amount of about 0.1% by weight.

[0056] According to one embodiment, the ophthalmic suspension vehicle provided herein optionally includes ethylenediaminetetraacetic acid (EDTA). According to one embodiment, EDTA can be present in the ophthalmic suspension vehicle in an amount of about 0.007% by weight to about 0.02% by weight. According to one embodiment, EDTA can be present in the ophthalmic suspension vehicle in an amount of about 0.008% by weight to about 0.015% by weight. According to one embodiment, EDTA can be present in the ophthalmic suspension vehicle in an amount of about 0.01% by weight.

[0057] According to one embodiment, in addition to one or more pharmaceutical ingredients, the ophthalmic suspension vehicle provided herein optionally further comprises at least one anti-inflammatory compound, such as inactivated brewer's yeast or adenosine diphosphate ribose. When present, the at least one anti-inflammatory compound does not affect the stability or ocular performance of the ophthalmic suspension vehicle. According to one embodiment, the anti-inflammatory compound may be present in the ophthalmic suspension vehicle in an amount of about 0.02% by weight to about 1.0% by weight.

[0058] According to one embodiment, the ophthalmic suspension vehicle provided herein can have an osmolality (osmolality), which can be adjusted by the concentration of salts such as NaCl. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of at least about 245mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of at least about 260mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of about 245mOsmol / kg to about 315mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of about 245mOsmol / kg to about 310mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of about 255mOsmol / kg to about 305mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmotic pressure molar concentration of about 270mOsmol / kg to about 300mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmotic pressure molar concentration of about 275mOsmol / kg to about 295mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmotic pressure molar concentration of about 280mOsmol / kg to about 290mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmotic pressure molar concentration of about 282mOsmol / kg to about 289mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmotic pressure molar concentration of about 285mOsmol / kg to about 287mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmotic pressure molar concentration of about 286mOsmol / kg.

[0059] According to one embodiment, the ophthalmic suspension vehicle provided herein has a pH between about 6.8 and 7.8. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH between about 6.9 and 7.7. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH between about 7.0 and 7.6. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH between about 7.0 and 7.4. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH between about 7.1 and 7.5. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH between about 7.2 and 7.4. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH of about 7.2. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH of about 7.3. The pH can be adjusted by adding a pH adjusting agent such as HCl or citric acid or a base such as NaOH.

[0060] The viscosity of the ophthalmic suspension vehicle described herein can vary, but will show a viscosity that allows appropriate drop sizes to be applied to eyes. According to one embodiment, the viscosity of the ophthalmic suspension vehicle provided herein shows a viscosity of about 5 centipoise at 25 ° C to about 8 centipoise at 25 ° C. The viscosity of the ophthalmic suspension vehicle described herein can be measured using technology well known to those skilled in the art. The non-limiting examples of the method for measuring viscosity include a falling ball viscometer, a viscosity cup, a consistency meter (measuring flow on an inclined plane), a capillary glass viscometer, or a rotational viscometer. Various instruments are commercially available (Cole-Palmer Instrument Co., Ltd., Vernon Hills, IL, USA).

[0061] The ophthalmic suspension vehicle provided herein may be preservative-free. In certain embodiments, due to the risk of bacterial contamination associated with conventional multiple use applications, the ophthalmic suspension vehicle without preservatives is delivered in a disposable package. In another embodiment, the ophthalmic suspension vehicle is delivered in a sterile multi-dose bottle. Examples include Aptar Pharma (Crystal Lake, IL, USA) multi-dose squeeze dispenser, which is mechanically operated and utilizes a filter membrane (see PCT Publication No. WO 2017 / 074420 and WO 2017 / 132190 (Aptar Group, Inc.); Nemera LaVerpillier (France) multi-dose squeeze bottle (see PCT Publication WO 2013 / 140069), each of which is incorporated by reference about such containers.

[0062] According to alternative embodiments, the ophthalmic suspension vehicle provided herein may optionally include at least one preservative. The amount of the preservative will not negatively affect the stability of the ophthalmic suspension vehicle, the performance on the eye, or adversely affect the user. According to alternative embodiments, the ophthalmic suspension vehicle provided herein may include at least one borate buffer.

[0063] Suitable pharmaceutical ingredients for delivery to the eye via the ophthalmic suspension vehicle provided herein include those that are soluble in the aqueous or oil phase of the ophthalmic suspension vehicle. Suitable classes of pharmaceutical ingredients include antibiotics, antivirals, anti-inflammatory agents, and anti-glaucoma agents, as partially shown in European Patent Application No. 0092 453, published on October 26, 1983, Sections 5.3.1 and 5.3.2, or PCT Publication No. WO 2015 / 05531, published on April 23, 2015, Page 5, Lines 5-22. Other suitable pharmaceutical ingredients include, but are not limited to, adenosine diphosphate ribose, antazoline, apraclonidine, atropine, azelastine, bepotastine, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, bromfenac, cardiolipin peroxidation inhibitors, carteolol, cetrimonium bromide, chloramphenicol, ciprofloxacin, cyclosporine, dexamethasone, diclofenac, dorzolamide, emedastine, epinastine, flurbiprofen, framycetin sulfate, gentamicin, gramicidin, witch hazel water, homatropine, hyaluronic acid, ketotifen fumarate, lacritin / tear protein fragments, latanoprost, levobunolol, levofloxacin, lodoxamide, loteprednol, lymphocyte function-associated antigen 1 (LFA-1) antagonist, modified 19-kDa TNF receptor, moxifloxacin, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonist, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, inhibitor of reactive aldehydes, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thimerosal, timolol, tobramycin, tafluprost, travoprost, ketorolac tromethamine, tromethamine, tebuconazole or any combination thereof. According to one embodiment, at least one pharmaceutical ingredient suitable for being delivered to eyes via an ophthalmic suspension vehicle is cannabidiol, tetrahydrocannabinol or a combination thereof. Other pharmaceutical ingredients and combinations thereof (although not explicitly named) should be considered to be useful for delivery with the ophthalmic suspension vehicle of the present disclosure.

[0064] According to one embodiment, the at least one pharmaceutical ingredient is a neutral lipid or oil, such as one or more triglycerides, partially hydrolyzed esters, cholesterol esters and high molecular weight isoprenoids. According to one embodiment, the at least one pharmaceutical ingredient is a stabilizer, a surfactant, a mucus mimetic (e.g., HP guar gum), a preservative, a pH regulator, a salt, a buffer, glycerol, a sugar, an emollient or a demulcent. According to one embodiment, the at least one pharmaceutical ingredient is a polymer of ethylene oxide, propylene oxide or butylene oxide. According to one embodiment, the at least one pharmaceutical ingredient is carboxymethyl cellulose (CMC), hydroxypropyl methylcellulose (HPMC), polyacrylic acid (PAA), polyethylene glycol (PEG), propylene glycol (PG) or polyvinyl alcohol (PVA).

[0065] A method for preparing an ophthalmic suspension vehicle is provided. According to one embodiment, the method for preparing an ophthalmic suspension vehicle comprises the following steps: preparing a mixture of oils (e.g., heavy mineral oil and light mineral oil) separately and adding a wax ester component such as beeswax, and heating the mixture to a temperature above the melting point of the wax ester (e.g., about 63°C to about 71°C). In a separate water / aqueous phase, salts, phosphates, surfactants, and any other water-soluble ingredients can be prepared and heated to about 85°C. The oil phase can then be slowly added to the water / aqueous phase, mixed, and homogenized to form an ophthalmic suspension vehicle. The resulting ophthalmic suspension vehicle is autoclaved. Throughout the process, the ophthalmic suspension vehicle is continuously mixed.

[0066] According to one embodiment, a method of preparing an ophthalmic suspension vehicle comprises the steps of separately preparing an oil phase (e.g., heavy mineral oil and light mineral oil) and heating to a temperature of about 63° C. to about 71° C. The step of preparing the oil phase may optionally include the steps of adding or introducing at least one wax ester to the oil phase and then heating the mixture to a temperature above the melting point of the wax ester (e.g., about 63° C. to about 71° C.).

[0067] According to one embodiment, the method of preparing an ophthalmic suspension vehicle includes a step of separately preparing an aqueous phase. The aqueous phase can be prepared by mixing at least one wax ester, at least one salt, at least one phosphate, at least one surfactant, and any other water-soluble ingredients, followed by heating the mixture to a temperature above the melting point of the wax ester (e.g., about 63° C. to about 71° C.).

[0068] According to one embodiment, the oil phase as provided herein can then be slowly added to the aqueous phase, mixed, and homogenized to form an ophthalmic suspension vehicle. The resulting ophthalmic suspension vehicle can then be autoclaved. Therefore, according to such an embodiment, the separate oil phase and aqueous phase are not autoclaved separately before combination. According to one embodiment, the resulting ophthalmic suspension vehicle is not autoclaved and is sterilized according to an alternative method such as, for example, electron beam or gamma irradiation, or filtration.

[0069] According to an alternative embodiment, a method for preparing an ophthalmic suspension vehicle is provided. The alternative method includes the step of preparing a wax dispersion by mixing or dissolving at least one wax ester (such as natural beeswax) with a surfactant and purified water or deionized water. According to one embodiment, the at least one wax ester can be mixed or dissolved in such a manner that the natural wax ester can be delivered in a controlled manner, resulting in an increased residence time on the eye. According to one embodiment, the step of preparing the wax dispersion includes dissolving one or more salts and one or more phosphates (such as monosodium phosphate and disodium phosphate) in purified water or deionized water. According to one embodiment, the step of preparing the wax dispersion includes heating the one or more salts, phosphates, surfactants and wax esters and stirring the resulting dispersion. According to one embodiment, the dispersion is heated to about 70°C to about 90°C. According to a particular embodiment, the wax ester particle dispersion can be prepared by homogenizing melted beeswax (about 1.0%) in purified or distilled water containing salts, phosphates and added Octoxynol-40 (about 0.2% 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol sodium salt (DMPG)) at about 75° C. The high cloud point (>100° C.) of Octoxynol-40 allows for emulsification efficiency at higher temperatures by reducing its water solubility (effective reduction of the HLB value).

[0070] An alternative method includes the steps of preparing an oil-in-water emulsion. According to one embodiment, the step of preparing the oil-in-water emulsion includes mixing mineral oils as described herein of different weights or viscosities, and heating the mixture of mineral oils to a temperature of about 65° C. to about 75° C. According to one embodiment, the step of preparing the oil-in-water emulsion includes introducing the heated mixture of mineral oils dropwise into purified water or deionized water, and homogenizing the water and mineral oil mixture to form the oil-in-water emulsion. The pH of the oil-in-water emulsion can be adjusted to a range of about 6.8 to about 7.8.

[0071] An alternative method includes the steps of separately autoclaving the wax dispersion and the oil-in-water emulsion. The integrity of the emulsion is maintained during autoclaving.

[0072] While not being bound by a particular theory, it is believed that the mechanism involved in the irreversible aggregation of wax (wax cracking) under autoclave conditions involves the presence of relatively high (nearly isotonic) salt concentrations. It is believed that this high ion loading significantly reduces the zeta potential of the wax ester particles, which eliminates an important stabilization mechanism when these dispersions are subjected to autoclave conditions.

[0073] An alternative method includes the step of aseptically blending an autoclaved beeswax dispersion and an oil-in-water emulsion to prepare an ophthalmic suspension vehicle as provided herein. According to one embodiment, the wax ester particles can be stabilized by a surfactant in the oil phase to prevent flocculation and droplet aggregation during cooling.

[0074] In order to maintain a storage-stable vehicle, according to an alternative method, the separate preparation and autoclaving of the wax ester particle dispersion and the emulsion component can be carried out, followed by an aseptic blending step to ensure that the product is sterile. The aseptic blending step of the autoclaved beeswax dispersion and the oil-in-water emulsion ensures that the mineral oil, beeswax and other components of the desired final concentration are present in the ophthalmic suspension vehicle. The oil-in-water emulsion is formulated with an increased component level, and the beeswax ester particles are emulsified in water with an added surfactant. The concentration of the various components in the two parts (before autoclaving) can be customized to allow for a relatively wide variation in the final emulsified vehicle composition. Example 1 Preparation of ophthalmic suspension vehicles containing drug ingredients

[0075] An exemplary ophthalmic suspension vehicle is prepared containing the components set forth in Table 1 below. Table 1

[0076] To prepare a 500 gram batch of ophthalmic suspension vehicle, dissolve NaCl, dimyristoylphosphatidylglycerol (DPMG), NaH2PO4, and Na2HPO4 in purified water in a beaker. Add Tween 80, DPMG, ADP-Ribose, and sodium hyaluronate to the aqueous solution and heat to 85°C (+ / - 2°C) with continuous stirring. In a separate glass beaker, 15. 35 and wax esters are mixed and heated to 71°C (+ / -2°C) for 10 minutes (+ / -20 seconds) under continuous stirring. The aqueous phase is homogenized for 30 seconds (+ / -5 seconds). The oil phase is preheated to 71°C (+ / -2°C) and added dropwise to the aqueous phase at 85°C (+ / -2°C) while the homogenizer is running. After the addition of the oil is complete, the homogenizer is run. The target homogenization speed is about 10,000RPM (+ / -400RPM) and the target homogenization time is about 4min (+ / -20 seconds). The homogenization procedure is terminated and stirring is continued until the vehicle reaches room temperature (approximately 4 hours). While stirring, the pH and osmolality are checked and adjusted (target pH: 7.2-7.4; osmolality is 240mOsmol / kg-290mOsmol / kg). While stirring, the vehicle mixture is dispensed into an autoclavable bottle using a syringe and a magnetic stirring bar is loaded. The bottle and autoclave were sealed for 35 minutes (+ / - 1 minute) and heated to 121°C / heated at 121°C and 15 psi while stirring. The ophthalmic suspension vehicle was allowed to cool to room temperature (approximately 6 hours) while stirring. Example 2 Ophthalmic drug ingredients in suspension vehicles - ocular performance

[0077] A study was conducted to evaluate the ocular performance of an ophthalmic suspension vehicle with a known anti-inflammatory agent ADP-Ribose as described in Table 1. Positive results were obtained in both the suspension vehicle characteristics and the ocular performance. In particular, patients who exhibited a reduction in tear film and a low lipid layer thickness (LLT) level were studied based on previous and day screening. The lipid layer thickness of the tear film at baseline was measured using interferometry. The baseline lipid layer thickness of these patients ranged from 25nm to 70nm, with an average of 45nm. A lipid layer thickness of less than 70nm was considered insufficient.

[0078] After baseline measurements were taken, a single test drop of the ophthalmic suspension vehicle of Table 1 (Example 1) and a single control drop were self-instilled into the contralateral eye. The control drops were selected as Ultra PF commercial solution (commercially available, preservative-free, lipid-free drops).

[0079] The primary objective was to evaluate the duration of dry eye on the eye as measured by an increase in lipid layer thickness, and the first challenge was to develop strict inclusion and exclusion criteria for patient recruitment to select subjects with a chronically dry tear film due to evaporative dry eye (e.g., meibomian gland dysfunction or MGD) and not with partial blinking or a side effect of another medication or procedure. Primarily, the study sought subjects with a baseline lipid layer thickness of less than 55 nm and a partial blink rate of less than 50% in at least one eye, both measured using LipiView (Johnson and Johnson).

[0080] Once the inclusion criteria are established, a formal protocol must be created for clinicians and staff to follow. In this document, each step of the patient evaluation process is listed in a checkbox format; from the initial patient evaluation and inclusion confirmation date to the actual evaluation and measurement process. 1. Confirmation of inclusion 2. Exclusion confirmation 3. Eye health examination (evaluation details to be determined by the physician) 4. Baseline LLT Reading 5. SPEED pre-assessment (Standardized patient evaluation of dry eyes), see Korb et al. Lid wiper epitheliopathy and dryeye symptoms. Eye Contact Lens. 2005 Jan;31(1):2-8; and Korb et al. The effect of two novel lubricanteye drops on tear film lipid layer thickness in subjects with dry eyesymptoms. Optom Vis Sci. 2005 Jul;82(7):594-601, each incorporated by reference with respect to such investigational tests. 6. Test and Control Drop Instillation 7.Measure at 5, 30, 60, 120, 180, and 240 minute intervals 8.SPEED post-evaluation

[0081] The drops were masked to the patients but not to the physicians and staff.All study results were recorded on a data record form, with the patient identity masked.

[0082] In two weeks, 12 patients completed the study. As shown in Tables 2 and 3, the results show the original average lipid layer thickness readings of 12 patients measured. The ophthalmic suspension vehicle of Table 1 shows a significant increase in lipid layer thickness at 5 minutes and 30 minutes. At all time points, there is a significant distinction between the ophthalmic suspension vehicle and the control drops. Compared with 61.8 (+ / - 2.2) nm of the control, the ophthalmic suspension vehicle maintains an average lipid layer thickness of 72.5 (+ / - 3.8) nm at the 4 hour mark. Table 2 Ophthalmic suspension vehicle with drug ingredients Time interval Lipid layer thickness (nm) Baseline 49.5 5 minutes 79.2 30 minutes 77.6 60 minutes 70.2 120 minutes 74.0 180 minutes 70.4 240 minutes 72.5 Table 3 Ultra

[0083] Based on the raw data from the fellow eye, the mean baseline lipid layer thickness in the test eye and the control eye differed. Therefore, in addition to using the lipid layer thickness at each time point as the key indicator, the mean increase in lipid layer thickness from baseline was also evaluated for patients using both the test and control drops. Table 4 provides the increase in lipid layer thickness obtained from the ophthalmic suspension vehicle as set forth in Table 1. Table 5 provides the increase in lipid layer thickness from the ophthalmic suspension vehicle as set forth in Table 1. The thickness of the lipid layer obtained with Ultra PF solution was increased.

[0084] Clear differentiation of the test and control drops at each time point was demonstrated, with the ophthalmic suspension vehicle showing a nearly 50% increase in lipid layer thickness at the 4 hour mark. Thus, the decrease in lipid layer thickness was delayed to return to baseline well beyond the 4 hour mark. If the degradation rate remained linear, significant lipid layer thickness increases would likely be seen well beyond 8 hours using only a single drop of the ophthalmic suspension vehicle. Table 4 Ophthalmic suspension vehicle with drug ingredients Table 5 Ultra

[0085] Immediately after each eye was instilled with drops, the patient was asked two subjective questions. The first question required the patient to score its initial comfort from 0-100. The second question was to report the duration of any blurred vision they noticed. For the ophthalmic suspension vehicle, it was noted that the average comfort rating of the patient was 85 points (out of 100 points) and the minimum blurred vision time was 5.6 seconds. For the control drops, the average result was 92 points (out of 100 points) and 2.9 seconds. Although these two subjective indicators between the test and the control were different, the blur time of the ophthalmic suspension vehicle was less than 3 seconds, and the initial comfort rating differed by 7 points (out of 100 points).

[0086] Most patients reported no clouding with the ophthalmic suspension vehicle, with the longest duration of clouding being 30 seconds (one in the test eye and one in the control eye). Patient comfort ratings were similar and ranged from 45 to 100 in the test eyes and 50 to 100 in the control eyes. Based on thousands of hours of in-house testing, comfort and clouding were similar to the control solution.

[0087] A self-administered SPEED dry eye symptom questionnaire was incorporated into this study. A score of 8 or higher indicates the presence of dry eye. At the beginning of the test, prior to drop instillation, patients responded with an average SPEED score of 13.58.

[0088] After 4 hours had passed after the drop instillation, the patients were retested using the SPEED. The average result of the post-evaluation was a score of 10.5, with no patients reporting an increase in the score and five patients reporting a score of less than 8. The evaluation did not differentiate symptoms between eyes. Because the experiments were performed in the fellow eye, it is difficult to delineate the effects of the ophthalmic suspension vehicle relative to the control drops. The SPEED evaluation is designed to measure symptoms over a period of weeks or months, so the immediate results may not accurately reflect the symptoms a patient has. Finally, the time of day was a variable that was not controlled in this study and may have had an impact on the symptoms reported by the patients.

[0089] In summary, this study demonstrated that in an independent (arms-length), physician-managed study, the on-eye duration of the suspension vehicle was demonstrated to be significantly increased relative to the control over a four-hour interval. In particular, in a controlled on-eye patient evaluation, the ophthalmic suspension demonstrated a nearly 50% increase in tear film thickness at the 4-hour mark, demonstrating that the ophthalmic suspension can be used as a vehicle for drug delivery for long-term on-eye activity.

[0090] While not being bound by a particular theory, as the wax ester particles dissolve, it is believed that the oil bound to the wax ester particles is released into the tear film and migrates to the surface, continuously replenishing the patient's weakened evaporative lipid barrier. Particles of different sizes dissolve at different rates. In fact, the widespread distribution of oil-bound wax ester particles creates a controlled release mechanism, delivering lipids to the tear film with each blink as the wax ester particles dissolve. Wax esters are believed to act as a mechanism to slow the drainage of the lipid layer through the puncta during the regular tear turnover process. Example 3 granularity

[0091] In order to provide the desired drug ingredient delivery characteristics, the oil and wax ester portions of the ophthalmic vehicle remain in the ocular environment for an extended period of time. The wax ester particle size is preferably maintained to provide a persistent lipid layer increase on the eye over time.

[0092] Particle size is determined using a Microtrac Sync 3R Flow device. A sample of about 6.0 mL of the ophthalmic vehicle of Example 1 was used for particle size analysis. The samples were stored in plastic bottles until testing. Before testing, each bottle was shaken 10 times. The entire cover was then removed and approximately two drops of sample were transferred to the Microtrac Sync 3R Flow device using a plastic pipette. The sample was loaded into the particle size analyzer. Approximately two drops (0.060 g) of sample were injected into a 200 mL deionized water circulation chamber and the test was started.

[0093] The results for mineral oil alone indicate that the loss of added mineral oil will not exceed 30 minutes, as in competitive products The results are summarized in Table 6.

[0094] The processing parameter marked as "homogenizer" in Table 6 refers to processing only by the homogenizer in the range of about 10k rpm to about 18k rpm for about 4 minutes to about 8 minutes. Other processing parameters refer to the pressure of the microfluidizer system used to evaluate uniformity. This additional processing is added after the initial homogenization and causes a reduction in particle size but reduces clinical performance (average increase over baseline). More specifically, based on the particle size analysis performed on several test formulations, the processing of the homogenizer alone produces an average particle size in the range of 2 microns to 20 microns, while the samples further processed with the microfluidizer produce an average particle size of ≤1 micron. The actual measurement of the formulation determines a significant range of particle size and distribution. Specifically, formulations with an average particle size of about 1 micron will not remain in the eye, while the best performing formulations have an average particle size in the range of 5 microns to 20 microns under the measurement conditions. Table 6 Example 4 Zeta potential and ion mobility analysis

[0095] Zeta potential testing was performed to evaluate the effects of various ophthalmic vehicles on Balance particle performance and stability of commercially available ophthalmic drops. Zeta potential indicates the degree of electrostatic repulsion between similarly charged particles in a dispersion. Typically, a high negative zeta potential is associated with stability (e.g., a dispersion will resist aggregation). In the ophthalmic context, the applicant has demonstrated that a higher negative potential directly translates into a longer residence time of an ophthalmic vehicle on the eye.

[0096] For the same ophthalmic vehicle and Balance Eye Drops was subjected to ion mobility testing to evaluate the particle velocity generated by the electric field.

[0097] The contents of the ophthalmic vehicles (Samples AF) tested are shown in Table 7. Sample A was homogenized at 10,000 RPM for two minutes with beeswax added to the water phase. Sample B was homogenized at 20,000 RPM for eight minutes with beeswax added to the water phase. Samples C and D were homogenized at 18,000 RPM for eight minutes with beeswax added to the water phase. Samples E and F were homogenized at 18,000 RPM for eight minutes with beeswax added to the oil phase and the oil and water phases were separated and tested. Balance eye drops contain propylene glycol (0.6%) lubricant as the main active ingredient and various inactive ingredients including boric acid, dimyristoyl phosphatidylglycerol, disodium EDTA, hydroxypropyl guar gum, mineral oil, polyoxyl 40 stearate, (Polyquaternium-1) 0.001% preservatives, sorbitan tristearate, sorbitol and purified water, and hydrochloric acid and / or sodium hydroxide to adjust pH.

[0098] The results of the zeta potential and ion mobility tests are provided in Table 8. Table 7 Table 8

[0099] Ophthalmic vehicles AF all exhibited zeta potentials of about -75 to about -95 and ion mobilities of about -6 to about -7.5. These results demonstrate that ophthalmic vehicles as provided herein provide substantial stabilization of large particles and sustained thickening of the tear film, unlike Balance eye drops, which exhibit distinctly different zeta potentials and ion mobilities.

[0100] Example 5 Comparison of ophthalmic vehicles and commercial artificial tears

[0101] A study was conducted to evaluate the ophthalmic vehicles described in Table 1 in comparison with different commercially available artificial tear products ( Tears Again, Complete, Balance, XP, MGD and Refresh Advanced) on-eye performance.

[0102] The lipid layer thickness of the commercial product was measured up to 60 minutes. The ophthalmic vehicle was measured up to 120 minutes and above. The test was open label and utilized Systane Ultra As a control. A total of 93 observations (n=93) were made in 12 commercially available products. The results showed that no product was able to increase the lipid layer thickness by more than 13 nm over the control at a 5-minute time interval, and the best performing commercial product showed a 10 nm increase over the control at a 60-minute time interval.

[0103] On average, there was an increase of 21 nm over the control at the 5 minute time interval, while the lipid layer thickness continued to increase to 24.7 nm at the 60 minute time point (n=78). The pooled data are summarized in Tables 9 and 10. Table 9 Ophthalmic Vehicles (n=78) Table 10 Commercial products (n=93)

[0104] Overall, the ophthalmic vehicle showed a five-fold (5×) improvement in immediate lipid layer thickness increase in 78 cumulative observations compared to 93 cumulative observations for the 12 commercially available products. At the 60 minute mark, this difference in lipid layer thickness increase was eleven-fold (11×), with the ophthalmic vehicle showing a 23 nm increase over baseline relative to the control compared to the commercial product which only showed a 2 nm increase over baseline relative to the control.

[0105] It should be understood that the above description represents only illustrative embodiments and examples. For the convenience of the reader, the above description focuses on a limited number of representative examples of all possible embodiments, examples of the principles of the present disclosure. This description does not attempt to exhaustively list all possible variations or even combinations of those variations described. Alternative embodiments may not be proposed for a specific portion of the present disclosure, or other alternative embodiments that may be available that are not described for a part should not be considered as a waiver of those alternative embodiments. Those of ordinary skill will understand that many embodiments in those undescribed embodiments relate to differences in technology and materials, rather than differences in the application of the principles of the present disclosure. Therefore, the present disclosure is not intended to be limited to less than the scope set forth in the following claims and equivalents.

[0106] It is to be understood that while the disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to be illustrative and not limiting of the scope. Other aspects, advantages and modifications are within the scope of the claims set forth below. General Statement of This Disclosure

[0107] The following numbered statements provide a general description of the disclosure and are not intended to limit the appended claims.

[0108] Statement 1. An ophthalmic suspension vehicle is provided comprising a wax dispersion comprising at least one wax ester, a cationic polar surfactant and water; and an oil-in-water emulsion comprising at least one oil and water. Using a Microtrac particle analyzer procedure to determine particle size, the wax ester exhibits an average particle size of at least about 5.0 microns.

[0109] Statement 2. The present disclosure provides an ophthalmic emulsion vehicle as described in Statement 1.

[0110] Statement 3. The present disclosure provides an ophthalmic suspension as described in any of Statements 1-2, wherein the ophthalmic suspension vehicle has an osmolality of about 245 mOsmol / kg to about 315 mOsmol / kg.

[0111] Statement 4. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-3, wherein the ophthalmic suspension vehicle is formulated as an emulsified suspension vehicle that is free flowing at about 30°C.

[0112] Statement 5. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-4, wherein the wax ester is present at a concentration of about 0.8 weight % to about 1.2 weight %.

[0113] Statement 6. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-5, wherein the wax ester is natural beeswax.

[0114] Statement 7. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-6, wherein the ophthalmic suspension vehicle exhibits a negative zeta potential of about -60 mV to about -110 mV.

[0115] Statement 8. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-7, wherein the ophthalmic suspension vehicle exhibits an ion mobility of about -5.9 (μms) / (V / cm) to about -7.4 (μms) / (V / cm).

[0116] Statement 9. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-8, wherein the oil is a mixture of light mineral oil and heavy mineral oil.

[0117] Statement 10. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-9, wherein the light mineral oil exhibits a viscosity of about 3.0 mm at 40°C. 2 s -1 to about 34.4mm 2 s -1 The heavy mineral oil exhibits a dynamic viscosity of about 34.5 mm at 40°C. 2 s -1 To about 150mm 2 s -1 The dynamic viscosity.

[0118] Statement 11. The present disclosure provides an ophthalmic suspension vehicle as described in any of Statements 1-10, further comprising an anionic polar surfactant, wherein the anionic polar surfactant includes a mixture of a polysorbate nonionic surfactant at a concentration of about 0.35 weight % to about 0.45 weight % and an anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 weight % to about 0.55 weight %.

[0119] Statement 12. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-11, which is packaged in a sterile multiple-use or sterile single-use container.

[0120] Statement 13. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-12, packaged in a multi-dose non-preserved (MDNP) container or a container comprising at least one preservative.

[0121] Statement 14. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-13, wherein the ophthalmic suspension vehicle increases the thickness of the lipid layer by at least 20 nanometers five minutes after administration.

[0122] Statement 15. The present disclosure provides an ophthalmic suspension vehicle as described in any one of Statements 1-14, wherein the ophthalmic suspension vehicle increases the thickness of the lipid layer by at least 20 nanometers four hours after administration.

[0123] Statement 16. A method of increasing lipid layer thickness is provided, and the method comprises the step of administering to an eye of a patient in need of treatment an ophthalmic suspension vehicle as described in any one of Statements 1-15.

[0124] Statement 17. The present disclosure provides a method of increasing lipid layer thickness as described in Statement 16, wherein the lipid layer thickness is increased by at least 20 nm within five minutes of administration.

[0125] Statement 18. The present disclosure provides a method of increasing lipid layer thickness as described in any of Statements 16-17, wherein the lipid layer thickness is increased by at least 20 nm four hours after administration.

[0126] Statement 19. The present disclosure provides a method of lubricating an eye, the method comprising administering to an eye of a patient in need of treatment the ophthalmic suspension vehicle of any one of Statements 1-15.

[0127] Statement 20. The present disclosure provides a method for alleviating symptoms of dry eye disease, the method comprising administering to an eye of a patient in need of treatment an ophthalmic suspension vehicle as described in any one of Statements 1-15.

[0128] Statement 21. An ophthalmic suspension vehicle is provided comprising a wax dispersion comprising (a) water; (b) at least one oil; (c) a surfactant; and (d) a wax or wax ester present at a concentration of about 0.5% to about 1.5% by weight. The wax or wax ester in the ophthalmic suspension vehicle binds to the mucin layer, the aqueous layer, and the lipid layer in the eye of a subject and functions to maintain or enhance the integrity of the interstitial layer between the mucin layer and the aqueous layer, and the interstitial layer between the aqueous layer and the lipid layer.

[0129] Statement 22. The present disclosure provides an ophthalmic suspension vehicle as described in Statement 21, wherein the wax or wax ester acts to increase the thickness of the mucin layer, the aqueous layer, the lipid layer, or a combination thereof.

[0130] Statement 23. The present disclosure provides an ophthalmic suspension vehicle as described in any of Statements 21-22, wherein the binding and stabilization achieved by the wax, wax ester or hydrolysate allows the mucin layer, aqueous layer and lipid layer of the tear film to interact with each other, thereby allowing the tear film to be retained on the eye for an extended period of time (e.g., at least two hours).

[0131] Statement 24. An ophthalmic suspension vehicle is provided which exhibits a zeta potential of about -60 mV to about -110 mV.

[0132] Statement 25. An ophthalmic suspension vehicle is provided which forms a metastable emulsion which separates into an oil phase and an aqueous phase upon contact with the eye and provides lubrication on the eye for about 2 hours to about 12 hours.

[0133] Statement 26. A method for alleviating symptoms of dry eye is provided, the method comprising the step of contacting the eye with an ophthalmic suspension vehicle as described in any one of Statements 21-25.

[0134] Statement 27. The present disclosure provides a method for alleviating symptoms of dry eye as described in Statement 26, wherein upon contact with the eye, the ophthalmic suspension vehicle interacts with: the lipid layer; the aqueous layer; the mucin layer; the interface between the lipid layer and the aqueous layer; and the interface between the aqueous layer and the mucin layer of the eye and unprotected corneal cells.

[0135] Statement 28. The present disclosure provides a method of alleviating symptoms of dry eye as described in any one of Statements 26-27, wherein the wax ester of the ophthalmic suspension vehicle is natural beeswax or synthetic beeswax.

[0136] Statement 29. The present disclosure provides a method of alleviating dry eye symptoms as described in any of Statements 26-28, wherein the oil is a mixture of a lighter mineral oil and a heavier mineral oil.

[0137] Statement 30. The present disclosure provides a method of alleviating dry eye symptoms as described in any of Statements 26-29, wherein the oil is present at a concentration of about 1.0 wt % to about 5 wt %.

[0138] Statement 31. The present disclosure provides a method of alleviating dry eye symptoms as described in any of Statements 26-30, wherein the surfactant is a mixture of two or more surfactants.

[0139] Statement 32. The present disclosure provides a method for relieving symptoms of dry eye as described in any of Statements 26-31, wherein (i) the oil is a mixture of a lighter oil and a heavier oil and is present at a concentration of about 1.0 weight % to about 5.5 weight %; (ii) the surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 weight % to about 0.45 weight % and dimyristoyl phosphatidylglycerol at a concentration of about 0.3 weight % to about 0.5 weight %; (iii) the wax ester is natural or synthetic beeswax, which is present at a concentration of about 0.5 weight % to about 1.0 weight %; and the ophthalmic suspension vehicle has a weight osmotic pressure molar concentration of about 245 mOsmol / kg to about 310 mOsmol / kg.

[0140] Statement 33. The present disclosure provides a method of alleviating dry eye symptoms as described in any one of Statements 26-32, wherein the ophthalmic suspension vehicle is packaged in a sterile multiple-use or sterile single-use container.

[0141] Statement 34. The present disclosure provides a method of alleviating dry eye symptoms as described in any of Statements 26-33, wherein the ophthalmic suspension vehicle is packaged in a multi-dose non-preserved (MDNP) container or a container comprising at least one preservative.

[0142] Statement 35. The present disclosure provides a method for preparing an ophthalmic suspension vehicle, the method comprising the steps of: (a) preparing a vehicle of a wax ester and a surfactant in purified water or deionized water; (b) preparing an oil-in-water emulsion comprising a vehicle of oil in purified water or deionized water; (c) separately autoclaving the beeswax dispersion and the oil-in-water emulsion; and (d) aseptically blending the autoclaved beeswax dispersion and the oil-in-water emulsion to prepare a metastable oil-in-water emulsion ophthalmic suspension vehicle.

[0143] Statement 36. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in Statement 35, wherein the ophthalmic solution provides lubrication on the eye for at least about 2 hours.

[0144] Statement 37. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in any of Statements 35-36, wherein the ophthalmic solution provides lubrication on the eye for at least about 12 hours.

[0145] Statement 38. The present disclosure provides a method for preparing an ophthalmic suspension vehicle as described in any of Statements 35-37, wherein upon contact with the eye, the ophthalmic suspension vehicle penetrates: the lipid layer; the aqueous layer; the mucin layer; the interface between the lipid layer and the aqueous layer; and the interface between the aqueous layer and the mucin layer of the eye and unprotected corneal cells.

[0146] Statement 39. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in any one of Statements 35-38, wherein the wax ester is natural beeswax.

[0147] Statement 40. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in any of Statements 35-39, wherein the beeswax is synthetic beeswax.

[0148] Statement 41. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in any of Statements 35-40, wherein the oil is a mixture of a lighter oil and a heavier oil.

[0149] Statement 42. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in any of Statements 35-41, wherein the surfactant is a mixture of two or more surfactants.

[0150] Statement 43. The present disclosure provides a method for preparing an ophthalmic suspension vehicle as described in any of Statements 35-42, wherein (i) the oil is a mixture of light oil and heavy oil and is present at a concentration of about 1.0 weight % to about 5.5 weight %; (ii) the surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 weight % to about 0.45 weight % and dimyristoylphosphatidylglycerol at a concentration of about 0.3 weight % to about 0.5 weight %; (iii) the wax ester is natural beeswax or synthetic beeswax, which is present at a concentration of about 0.25 weight % to about 1.0 weight %; and the ophthalmic suspension vehicle has a weight osmotic pressure molar concentration of about 245 mOsmol / kg to about 310 mOsmol / kg.

[0151] Statement 44. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in any of Statements 35-43, wherein the ophthalmic suspension vehicle is packaged in a sterile multiple-use or sterile single-use container.

[0152] Statement 45. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in any of Statements 35-44, wherein the ophthalmic suspension vehicle is packaged in a multi-dose non-preserved (MDNP) container or a container comprising at least one preservative.

[0153] Statement 46. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in any of Statements 35-44, wherein the ophthalmic suspension vehicle is packaged in a container containing a preservative.

[0154] Statement 47. The present disclosure provides a method of preparing an ophthalmic suspension vehicle as described in any of Statements 35-46, wherein the wax ester acts to increase the thickness of the mucin layer, the aqueous layer, the lipid layer, or a combination thereof.

[0155] Statement 48. The present disclosure provides a method for preparing an ophthalmic suspension vehicle as described in any of Statements 35-47, wherein the binding and stabilization achieved by the wax ester allows the mucin layer, aqueous layer, and lipid layer of the tear film to interact with each other, thereby allowing the tear film to be retained on the eye for at least two hours.

[0156] Statement 49. The present disclosure provides a method for delivering at least one pharmaceutical ingredient to a patient in need of treatment, the method comprising administering to an eye of the patient an ophthalmic suspension vehicle comprising at least one wax ester, an anionic polar surfactant, and water; and an oil-in-water emulsion comprising at least one oil and water, wherein the ophthalmic suspension vehicle exhibits an average particle size of at least about 2.0 microns. The ophthalmic suspension vehicle is suitable for combination with at least one pharmaceutical ingredient.

[0157] Statement 50. The present disclosure provides a method for delivering at least one pharmaceutical agent to a patient in need of treatment as described in Statement 49, wherein the pharmaceutical agent is water soluble.

[0158] Statement 51. The present disclosure provides a method for delivering at least one pharmaceutical ingredient to a patient in need of treatment as described in any of Statements 49-50, wherein the pharmaceutical ingredient is oil-soluble.

[0159] Statement 52. The present disclosure provides a method for delivering at least one pharmaceutical agent to a patient in need of treatment as described in any of Statements 49-51, wherein the at least one pharmaceutical agent is an antibiotic, an antiviral agent, an anti-inflammatory agent, or an anti-glaucoma agent.

[0160] Statement 53. The present disclosure provides a method for delivering at least one pharmaceutical ingredient to a patient in need of treatment as described in any of Statements 49-52, wherein the at least one pharmaceutical ingredient is selected from the group consisting of: adenosine diphosphate ribose, antazoline, apraclonidine, atropine, azelastine, bepotastine, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, bromfenac, cardiolipin peroxidation inhibitor, carteolol, cetrimonium bromide. , chloramphenicol, ciprofloxacin, cyclosporine, dexamethasone, diclofenac, dorzolamide, emedastine, epinastine, flurbiprofen, neomycin sulfate, gentamicin, gramicidin, witch hazel water, homatropine, hyaluronic acid, ketotifen fumarate, tear protein / tear protein fragment, latanoprost, levobunolol, levofloxacin, lodoxamide, loteprednol, lymphocyte function-associated antigen 1 (LFA-1) antagonist, modified 19-kDa TNF receptor, moxifloxacin, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonist, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, reactive aldehyde inhibitor, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thimerosal, timolol, tobramycin, tafluprost, travoprost, ketorolac tromethamine, tromethamine, tebuconazole, or any combination thereof.

[0161] Statement 54. The present disclosure provides an ophthalmic suspension vehicle for delivering at least one pharmaceutical ingredient to a patient in need of treatment, the ophthalmic suspension vehicle comprising: i) an aqueous phase comprising water and one or more components selected from the group consisting of at least one wax ester, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt, and at least one phosphate; and ii) an oily phase comprising at least one mineral oil and optionally at least one wax ester; wherein the at least one pharmaceutical ingredient remains within the ophthalmic vehicle and is in therapeutic contact with the eye for at least two hours following administration to the eye.

[0162] Statement 55. The present disclosure provides an ophthalmic suspension vehicle for delivering at least one pharmaceutical ingredient to a patient in need of treatment as described in Statement 54, wherein the at least one pharmaceutical ingredient is water-soluble or oil-soluble.

[0163] Statement 56. The present disclosure provides an ophthalmic suspension vehicle for delivering at least one pharmaceutical ingredient to a patient in need of treatment as described in any of Statements 54-55, wherein the at least one pharmaceutical ingredient is an antibiotic, an antiviral agent, an anti-inflammatory agent, or an anti-glaucoma agent.

[0164] Statement 57. The present disclosure provides an ophthalmic suspension vehicle for delivering at least one pharmaceutical ingredient as described in Statements 54-56, wherein the at least one pharmaceutical ingredient is selected from the group consisting of: adenosine diphosphate ribose, antazoline, apraclonidine, atropine, azelastine, bepotastine, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, bromfenac, cardiolipin peroxidation inhibitor, carteolol, cetrimide, chloramphenicol. , ciprofloxacin, cyclosporine, dexamethasone, diclofenac, dorzolamide, emedastine, epinastine, flurbiprofen, neomycin sulfate, gentamicin, gramicidin, witch hazel water, homatropine, hyaluronic acid, ketotifen fumarate, tear protein / tear protein fragment, latanoprost, levobunolol, levofloxacin, lodoxamide, loteprednol, lymphocyte function-associated antigen 1 (LFA-1) antagonist, modified 19-kDa TNF receptor, moxifloxacin, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonist, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, reactive aldehyde inhibitor, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thimerosal, timolol, tobramycin, tafluprost, travoprost, ketorolac tromethamine, tromethamine, tebuconazole, or any combination thereof.

[0165] Statement 58. The present disclosure provides a method for delivering a predetermined amount of at least one pharmaceutical ingredient to a patient in need of treatment, the method comprising the steps of: administering to the patient's eye an ophthalmic suspension comprising: a) an ophthalmic suspension vehicle comprising: i) an aqueous phase comprising water and one or more components selected from the group consisting of at least one wax ester, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt, and at least one phosphate; and ii) an oily phase comprising at least one mineral oil and optionally at least one wax ester; and b) at least one medicinal ingredient, wherein the at least one pharmaceutical ingredient remains within the ophthalmic vehicle and is in therapeutic contact with the eye for at least two hours following administration to the eye.

[0166] Statement 59. The present disclosure provides a method for delivering at least one pharmaceutical ingredient as described in Statement 58, wherein the at least one pharmaceutical ingredient is maintained within an ophthalmic suspension vehicle and is in therapeutic contact with the eye for up to six hours after administration to the eye.

[0167] Statement 60. The present disclosure provides a method for delivering at least one pharmaceutical ingredient as described in any of Statements 58-59, wherein the at least one pharmaceutical ingredient is maintained in an ophthalmic suspension vehicle and is in therapeutic contact with the eye for at least six hours after administration to the eye.

[0168] Statement 61. The present disclosure provides a method for delivering at least one pharmaceutical ingredient as described in Statements 58-60, wherein the anionic polar surfactant comprises a mixture of a polysorbate nonionic surfactant at a concentration of about 0.35 to about 0.45 weight percent and an anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 to about 0.55 weight percent.

[0169] Statement 62. The present disclosure provides methods for delivering at least one pharmaceutical ingredient as described in Statements 58-61, wherein the oil phase comprises at least one oil comprising a mixture of light mineral oil and heavy mineral oil.

[0170] Statement 63. The present disclosure provides a method for delivering at least one pharmaceutical ingredient as described in Statements 58-62, wherein the light mineral oil exhibits a viscosity of about 3.0 mm at 40°C. 2 s- 1 to about 34.4mm 2 s- 1The heavy mineral oil exhibits a dynamic viscosity of about 34.5 mm at 40°C. 2 s- 1 To about 150mm 2 s- 1 The dynamic viscosity.

[0171] Statement 64. The present disclosure provides a method for delivering at least one pharmaceutical agent as described in Statements 58-63, wherein the oil phase or the aqueous phase comprises at least one wax ester present in a concentration of about 0.8 weight % to about 1.2 weight %.

[0172] Statement 65. The present disclosure provides methods for delivering at least one pharmaceutical ingredient as described in Statements 58-64, wherein the at least one wax ester is natural or synthetic beeswax.

[0173] Statement 66. The present disclosure provides methods for delivering at least one pharmaceutical agent as described in Statements 58-65, wherein the ophthalmic suspension exhibits an average particle size of at least about 2.0 microns to about 20.0 microns.

[0174] Statement 67. The present disclosure provides a method for delivering at least one pharmaceutical agent as described in Statements 58-66, wherein the ophthalmic suspension exhibits an average particle size distribution of about 5.0 microns to about 15.0 microns.

[0175] Statement 68. The present disclosure provides methods for delivering at least one pharmaceutical ingredient as described in Statements 58-67, wherein the at least one pharmaceutical ingredient is soluble in an aqueous phase.

[0176] Statement 69. The present disclosure provides methods for delivering at least one pharmaceutical ingredient as described in Statements 58-68, wherein the at least one pharmaceutical ingredient is soluble in an oil phase.

[0177] Statement 70. The present disclosure provides a method for delivering at least one pharmaceutical ingredient as described in Statements 58 to 69, wherein the at least one pharmaceutical ingredient is selected from the group consisting of: antibiotics, antiviral agents, anti-inflammatory agents, anti-allergic agents, anti-glaucoma agents, dry eye lubricants, and ocular gland secretagogues.

[0178] Statement 71. The present disclosure provides a method for delivering at least one pharmaceutical ingredient as described in Statements 58-70, wherein the at least one pharmaceutical ingredient is selected from the group consisting of: adenosine diphosphate ribose, antazoline, apraclonidine, atropine, azelastine, bepotastine, betamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, bromfenac, cardiolipin peroxidation inhibitor, carteolol, cetrimonium bromide, chloramphenicol, ciprofloxacin, cyclopentolone ...acetylcholine, chloramphenicol, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine, acetylcholine Sporogen, cannabidiol, tetrahydrocannabinol, dexamethasone, diclofenac, dorzolamide, emedastine, epinastine, flurbiprofen, neomycin sulfate, gentamicin, gramicidin, witch hazel water, homatropine, hyaluronic acid, ketotifen fumarate, tear protein / tear protein fragment, latanoprost, levobunolol, levofloxacin, lodoxamide, loteprednol, lymphocyte function-associated antigen 1 (LFA-1) antagonist, modified 19-kDa TNF receptor, moxifloxacin, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonists, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, reactive aldehyde inhibitor, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thimerosal, timolol, tobramycin, tafluprost, travoprost, ketorolac tromethamine, tromethamine, and tebuconazole.

[0179] Statement 72. An ophthalmic suspension for delivering at least one pharmaceutical agent to a patient in need of treatment, said ophthalmic suspension comprising: a) an ophthalmic suspension vehicle comprising: i) an aqueous phase comprising water and one or more components selected from the group consisting of at least one wax ester, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt, and at least one phosphate; and ii) an oily phase comprising at least one mineral oil and optionally at least one wax ester; and b) at least one medicinal ingredient, wherein the ophthalmic vehicle exhibits an average particle size of at least about 2.0 microns.

[0180] Statement 73. The present disclosure provides an ophthalmic suspension as described in Statement 72, wherein said at least one drug ingredient is soluble in said aqueous phase.

[0181] Statement 74. The present disclosure provides an ophthalmic suspension as described in Statements 72-73, wherein the at least one drug ingredient is soluble in the oil phase.

[0182] Statement 75. The present disclosure provides an ophthalmic suspension as described in Statements 72-74, wherein the at least one pharmaceutical ingredient is selected from the group consisting of: antibiotics, antiviral agents, anti-inflammatory agents, anti-allergic agents, anti-glaucoma agents, dry eye lubricants, and ocular gland secretagogues.

[0183] Statement 76. The present disclosure provides an ophthalmic suspension as described in Statements 72-75, which has a negative zeta potential of about -60 mV to about -110 mV.

[0184] Statement 77. An ophthalmic suspension vehicle for delivering at least one pharmaceutical ingredient to a patient in need thereof, said ophthalmic suspension vehicle consisting of: a wax dispersion comprising natural beeswax particles, an anionic polar surfactant and water; Sodium hyaluronate; and Oil-in-water emulsions comprising oil and water; and Optionally, at least one preservative selected from the group consisting of polyhexamethylene biguanide, a stable oxychloro complex and polyquaternium-1, in: (i) the oil is a mixture of a lighter molecular weight mineral oil and a heavier molecular weight mineral oil and is present in a concentration of about 4.0 weight percent to about 6.25 weight percent; (ii) the anionic polar surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 wt % to about 0.45 wt % and anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 wt % to about 0.50 wt %; and (iii) the natural beeswax particles are solid up to about 60°C and are present in a concentration of about 0.50% to about 1.25% by weight; and The ophthalmic suspension vehicle is: (i) forms a metastable emulsion which separates into an oily and aqueous phase upon contact with the eye; (ii) provides a residence time on the eye of at least two hours; (iii) formulated to be a free-flowing liquid at room temperature; (iv) having an osmolarity of about 230 mOsmol / kg to about 260 mOsmol / kg; and (v) has a pH of about 6.5 to about 7.8.

[0185] Statement 78. The present disclosure provides an ophthalmic suspension vehicle as described in Statement 77, wherein the beeswax is present at a concentration of about 1.0 weight %.

[0186] Statement 79. The present disclosure provides an ophthalmic suspension vehicle as described in Statements 77-78, wherein the beeswax is white beeswax or yellow beeswax.

[0187] Statement 80. The present disclosure provides an ophthalmic suspension vehicle as described in Statements 77-79, which is packaged in a sterile single-use container.

[0188] Statement 81. The present disclosure provides an ophthalmic suspension vehicle as described in Statements 77-80, which is packaged in a sterile multi-dose container.

[0189] Statement 82. The present disclosure provides a finished pharmaceutical product comprising an ophthalmic suspension vehicle as described in Statement 77 and a predetermined amount of at least one pharmaceutical ingredient.

[0190] Statement 83. The present disclosure provides a finished pharmaceutical product comprising an ophthalmic suspension vehicle as described in Statement 82, wherein the predetermined amount of the at least one pharmaceutical ingredient is a therapeutically effective dose.

[0191] Statement 84. The present disclosure provides a finished pharmaceutical product comprising an ophthalmic suspension vehicle as described in Statement 82, wherein the predetermined amount of the at least one drug ingredient is a subtherapeutically effective dose.

Claims

1. A method for delivering a predetermined amount of at least one pharmaceutical ingredient to a patient in need of treatment, the method comprising the steps of: administering to the patient's eye an ophthalmic suspension comprising: a) an ophthalmic suspension vehicle comprising: i) an aqueous phase comprising water and one or more components selected from the group consisting of at least one wax ester, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt, and at least one phosphate; and ii) an oily phase comprising at least one mineral oil and optionally at least one wax ester; and b) at least one medicinal ingredient, wherein the at least one pharmaceutical ingredient remains within the ophthalmic vehicle and is in therapeutic contact with the eye for at least two hours following administration to the eye.

2. The method of claim 1, wherein: The at least one pharmaceutical ingredient remains within the ophthalmic suspension vehicle and is in therapeutic contact with the eye for up to six hours following administration to the eye.

3. The method of claim 1, wherein: The at least one pharmaceutical ingredient remains within the ophthalmic suspension vehicle and is in therapeutic contact with the eye for at least six hours following administration to the eye.

4. The method of claim 1, wherein: The anionic polar surfactant includes a mixture of a polysorbate nonionic surfactant at a concentration of about 0.35 wt % to about 0.45 wt % and an anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 wt % to about 0.55 wt %.

5. The method of claim 1, wherein: The oil phase comprises at least one oil, and the oil comprises a mixture of light mineral oil and heavy mineral oil.

6. The method of claim 5, wherein: The light mineral oil exhibits a viscosity of about 3.0 mm at 40°C. 2 s -1 to about 34.4mm 2 s -1 The heavy mineral oil exhibits a dynamic viscosity of about 34.5 mm at 40°C. 2 s -1 To about 150mm 2 s -1 The viscosity of the dynamic viscosity.

7. The method of claim 1, wherein: The oil phase or the water phase comprises at least one wax ester present in a concentration of about 0.8 wt % to about 1.2 wt %.

8. The method of claim 7, wherein: The at least one wax ester is natural or synthetic beeswax.

9. The method of claim 1, wherein: The ophthalmic suspension exhibits an average particle size of at least about 2.0 microns to about 20.0 microns.

10. The method of claim 1, wherein: The ophthalmic suspension exhibits an average particle size distribution of about 5.0 microns to about 15.0 microns.

11. The method of claim 1, wherein: The at least one pharmaceutical ingredient is soluble in the aqueous phase.

12. The method of claim 1, wherein: The at least one pharmaceutical ingredient is soluble in the oil phase.

13. The method of claim 1, wherein: The at least one pharmaceutical ingredient is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anti-allergic agents, anti-glaucoma agents, dry eye lubricants, and ocular gland secretagogues.

14. The method of claim 1, wherein: The at least one pharmaceutical ingredient is selected from the group consisting of adenosine diphosphate ribose, antazoline, apraclonidine, apraclonidine, atropine, azelastine, bepotastine, betamethasone, betaxolol, betaxolol, bimatoprost, brimonidine, brinzolamide, bromfenac, bromfenac, cardiolipin peroxidation inhibitor, carteolol, cetrimonium bromide, chloramphenicol, ciprofloxacin, cyclosporine, cannabidiol, tetrahydrocannabinol, dimethoate ... Dexamethasone, diclofenac, dorzolamide, emedastine, epinastine, epinastine, flurbiprofen, neomycin sulfate, gentamicin, gramicidin, witch hazel water, homatropine, hyaluronic acid, ketotifen fumarate, tear protein / tear protein fragment, latanoprost, levobunolol, levofloxacin, lodoxamide, loteprednol, lymphocyte function-associated antigen 1 (LFA-1) antagonist, modified 19-kDa TNF receptor, moxifloxacin, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonists, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, reactive aldehyde inhibitor, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thimerosal, timolol, tobramycin, tafluprost, travoprost, ketorolac tromethamine, tromethamine, N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolyl]carbonyl]-3-(methylsulfonyl)-L-phenylalanine, and tibazaline.

15. The method of claim 1, wherein: The predetermined amount is a therapeutically effective dose.

16. The method of claim 1, wherein: The predetermined amount is a subtherapeutically effective dose.

17. An ophthalmic suspension for delivering at least one pharmaceutical ingredient to a patient in need thereof, the ophthalmic suspension comprising: a) an ophthalmic suspension vehicle comprising: i) an aqueous phase comprising water and one or more components selected from the group consisting of wax esters, anionic polar surfactants, nonionic surfactants, salts and phosphates; and ii) an oily phase comprising at least one mineral oil and optionally at least one wax ester; and b) at least one medicinal ingredient, wherein the ophthalmic suspension exhibits an average particle size of at least about 2.0 microns.

18. The ophthalmic suspension according to claim 17, wherein The at least one pharmaceutical ingredient is soluble in the aqueous phase.

19. The ophthalmic suspension according to claim 17, wherein The at least one pharmaceutical ingredient is soluble in the oil phase.

20. The ophthalmic suspension according to claim 17, wherein The at least one pharmaceutical ingredient is selected from the group consisting of antibiotics, antiviral agents, anti-inflammatory agents, anti-allergic agents, anti-glaucoma agents, dry eye lubricants, and ocular gland secretagogues.

21. The ophthalmic suspension of claim 18 having a negative zeta potential of about -60 mV to about -110 mV.

22. The ophthalmic suspension of claim 17, wherein: The at least one pharmaceutical ingredient is in a predetermined amount.

23. The ophthalmic suspension of claim 22, wherein The predetermined amount is a therapeutically effective dose.

24. The ophthalmic suspension of claim 22, wherein: The predetermined amount is a subtherapeutically effective dose.

25. An ophthalmic suspension vehicle for delivering at least one pharmaceutical ingredient to a patient in need thereof, the ophthalmic suspension vehicle consisting of: a wax dispersion comprising natural beeswax particles, an anionic polar surfactant and water; Sodium hyaluronate; as well as Oil-in-water emulsions comprising oil and water; and Optionally, at least one preservative selected from the group consisting of: Polyhexamethylene biguanide, stabilized oxychloro complex and polyquaternium-1, wherein: (i) the oil is a mixture of a lighter molecular weight mineral oil and a heavier molecular weight mineral oil and is present in a concentration of about 4.0 weight percent to about 6.25 weight percent; (ii) the anionic polar surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 wt % to about 0.45 wt % and anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 wt % to about 0.50 wt %; and (iii) the natural beeswax particles are solid up to about 60°C and are present in a concentration of about 0.50% to about 1.25% by weight; and The ophthalmic suspension vehicle is: (i) forms a metastable emulsion which separates into an oily and aqueous phase upon contact with the eye; (ii) provides a residence time on the eye of at least two hours; (iii) formulated to be a free-flowing liquid at room temperature; (iv) has an osmolarity of about 230 mOsmol / kg to about 260 mOsmol / kg; and (v) has a pH of about 6.5 to about 7.

8.

26. A finished pharmaceutical product comprising the ophthalmic suspension vehicle of claim 25 and a predetermined amount of at least one pharmaceutical ingredient.

27. The finished pharmaceutical product of claim 26, wherein: The predetermined amount is a therapeutically effective dose.

28. The finished pharmaceutical product of claim 26, wherein: The predetermined amount is a subtherapeutically effective dose.

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