Ophthalmic suspension vehicles and related methods of pharmaceutical ingredient delivery

Abstract

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

Description

[Technical field]

[0001] The present disclosure provides ophthalmic suspension vehicles for the delivery of ophthalmic treatments to the eye over an extended period of time. In particular, the ophthalmic suspension vehicles described herein provide for the extended delivery of pharmaceutical ingredients to the eye over an extended period of time. [Background technology]

[0002] Extended release of therapeutic agents to the eye has been attempted over the past 25 years. This has been attempted with both ophthalmic drug formulations and devices for drug delivery to provide release of active therapeutic ingredients or drugs with a resultant effect on the eye. Unfortunately, to date, consistent delivery to the eye over time with pharmaceutical formulations has not been achieved, as ophthalmic formulations, and their vehicles, remain on the eye only for a maximum of 5 to 30 minutes. Thus, an ideal delivery vehicle for active drugs with the requirement to remain on the eye for extended periods of time beyond 30 minutes is not possible. Such shortcomings are based in part on the fact that the tear film, which is produced by the secretions of different glands in the eye during normal blinking, drives the drug ingredients and vehicle (medium) out of the eye. The largest portion of the tear film is the tear fluid, which is produced primarily by the lacrimal glands activated by blinking (blinking). The outer tear film layer is a lipid layer that is primarily excreted from the meibomian glands located in the eyelids during blinking. The lipid layer provides a protective layer on top of the tear film designed to reduce evaporation of the aqueous solution of the tear film. Thinning the lipid layer increases the evaporation of the aqueous layer, resulting in dry eye at the corneal surface during blinking. The rate of tear film evaporation in such patients with dry eye increases by 30% to 38% at relative humidities below 50%. This is in addition to the measured loss of the aqueous layer through the punta. These collective secretions from the lacrimal and meibomian glands, along with the eyelids that provide the wiper effect from normal blinking, provide a normal, long-lasting, and stable ocular tear film. While normal component production involves continuous repair and replacement of the tear film, loss of vital components due to dysfunction or lack of secretions leads to instability of the tear film, rapid loss of tear film structure, and dry eye. Dry eye problems due to tear film dysfunction result in vehicles and drugs not staying on the eye for long periods of time in their action.

[0003] Normal tears maintain the correct balance of lipid, water, and mucin components during blinking to form a stable and protective tear film. During blinking, the tear film thins due to evaporation, and lipid molecules from the outer layer begin to migrate through the aqueous layer toward the mucin layer. The aqueous portion of the tears also exchanges on the eye at a rate of about 16% by volume per minute, where the lipid layer exchanges on the eye at a rate of about 2% per minute. Contamination of the mucin layer with the lipid layer increases the surface tension of the tear film, eventually causing the tears to rupture (break down) and bead up on the surface of the cornea, forming a dry patch. Subsequent blinks usually repair this rupture by removing lipid contaminants from the mucin layer and restoring the normal aqueous layer. However, repeated ruptures cause loss of the mucin layer, which shows staining when observed with fluorescein.

[0004] U.S. Patent Nos. 5,371,108, 5,278,151 and U.S. Patent Application Publication No. 2016 / 03389952 to Korb teach methods or formulations for making emulsions or gels containing oils and waxes to form a tear film on the ocular surface to increase the residence time of the oil. However, wax-containing gels have not been manufactured and marketed because of the difficulty of homogenizing the wax in a way that does not induce visual blurring beyond the tolerance of most consumers. In particular, high pressure steam sterilization (autoclaving) to sterilize wax-containing formulations results in an increase in particle size, which causes irritation and blurred vision. Gels are semi-solid formulations with high viscosity. In contrast, the present disclosure relates to metastable emulsions that behave as flowable liquids at room temperature. Emulsions behave as liquids and as such do not exhibit a static internal structure or have a high viscosity. Korb also utilizes preservatives at levels known to be toxic to corneal cells upon administration and does not disclose vehicles that exhibit extended residence times.

[0005] Many ophthalmic formulations and compositions for use focus on the use of zeta potential, as described in WO2016209555, WO2015057847, WO2011098578, WO2011084509, WO03053405, US2012328702, US2012225834, and U.S. Patent Nos. 7,060,285, 9,827,191, 8,298,569, 7,893,040, 7,834,172, and 10,137,083, which are incorporated by reference herein for their teachings of the use of zeta potential.

[0006] The tear film layer can be used as a base agent to deliver small concentrations of pharmaceutical ingredients into the eye, which is a challenge for the industry. See Patel et al. 2013, “Ocular drug delivery systems: An overview” World J. Pharmacol 2(2) 47-64. Acceptable carriers for pharmaceutical ingredients need to mimic the properties and osmolality of the natural tear film and remain in the eye for extended periods of time. The above products increase the bioavailability of active pharmaceutical ingredients ("API") to corneal epithelial cells, which has long been a desirable route for ocular drugs. Summary of the Invention

[0007] Disclosed herein is an ophthalmic suspension comprising an ophthalmic suspension vehicle useful for delivering at least one pharmaceutical component to the ocular surface of the eye. The ophthalmic suspension allows for enhanced bioavailability by delivering at least one pharmaceutical component to the ocular surface of the eye. The residence time of the ophthalmic suspension on the eye allows for improved delivery of the at least one pharmaceutical component to the eye for an extended period of time, thereby resulting in increased contact time of the at least one pharmaceutical component to the eye. The residence time of the ophthalmic suspension on the eye also allows for the utilization of lower levels of the pharmaceutical component while achieving the required therapeutic effect with reduced undesirable side effects.

[0008] Also provided is a method for delivering at least one pharmaceutical ingredient to a patient in need of treatment, comprising administering to an eye of the patient an ophthalmic suspension provided herein. [Brief description of the drawings]

[0009] [Figure 1] FIG. 1 shows a close-up of the tear film identifying different regions. A normal tear film is 3-6 microns thick. The figure shows the lipid layer, lipid / aqueous interface, aqueous layer, aqueous / mucin interface, mucin layer, and cornea. Two insets show close-ups of the lipid / aqueous interface and the aqueous / mucin interface. The third inset shows the thinning of layers and interfaces associated with dry eye. In particular, the third inset shows the thinning of (i) the aqueous layer, (ii) the unbound mucin layer, and (iii) the bound mucin layer bound to the surface of corneal epithelial cells. Methods for evaluating the tear film are further provided in U.S. Patent Application Serial No. 16 / 708120 (U.S. Patent Publication No. 2020 / 0179281), the entire contents of which are incorporated herein by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Although the following terms are believed to be well understood to those of ordinary skill in the art, the following definitions are provided to facilitate description of the presently disclosed subject matter.

[0011] The term "pharmaceutical ingredient" as used herein means a substance used in a finished pharmaceutical product (FPP) that is intended to provide pharmacological activity or to have a direct effect in the diagnosis, cure, mitigation, treatment or prevention of a disease or disorder, or to have a direct effect in the restoration, correction or modification of a physiological function in human beings.

[0012] As used herein, the terms "about" and / or "approximately" may be used with numerical values ​​and / or ranges. The term "about" is understood to mean a value close to the recited value. Alternatively, depending on the context, the term "about" may mean ±1 / 2 standard deviation, ±1 standard deviation, or ±2 standard deviations. Furthermore, the phrases "less than about [value]" or "greater than about [value]" should be understood in light of the definition of the term "about" provided herein. The terms "about" and "approximately" may be used interchangeably. Throughout this specification, numerical ranges are provided for specific quantities.

[0013] As used herein, the verb "comprise" and its conjugations as used in the specification and claims are used in an open-ended sense meaning that the items following the word are included but not excluding items not specifically mentioned.

[0014] As used herein, the word "comprise" or variations such as "comprises" or "comprising" are understood to imply the inclusion of a recited element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The disclosure may "comprise," "consist of," or "consist essentially of" the steps, elements, and / or agents recited in the claims, as appropriate.

[0015] It should be further noted that the claims are drafted to exclude any optional elements. Accordingly, this statement is intended to serve as an antecedent basis for using exclusive terminology such as "solely," "only," and the like in connection with reciting claim elements or using a "negative" limitation.

[0016] As used herein, the term "wt %" means the amount based on the ophthalmic suspension vehicle, unless otherwise specified.

[0017] As used herein, the term "wax ester" refers to an ester of a fatty acid and a fatty alcohol and may include a number of compounds with various carbon chain lengths. The wax esters provided herein may include long carbon chains. The wax esters provided herein may be present in solid particles that exhibit a melting point of about 60°C to about 100°C. The wax esters provided herein may be natural beeswax. Natural beeswax is also commercially available as Cera Alba or Cera Flava (white or yellow beeswax). The use of natural beeswax may include hydrocarbons as a component. During the preparation of one embodiment of the emulsion of the present disclosure, the wax esters may undergo hydrolysis to generate additional acids and / or alcohols as part of the process. 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 (vehicle component) provided herein.

[0019] The term "residence time" as used herein refers to the time (e.g., minutes or hours) that an ophthalmic suspension vehicle remains on the eye from a single application when assessing the level or amount of lipid layer thickness from the baseline of the eye.The lipid layer thickness can be measured by interferometry instrumentation to measure the residence time on the eye.

[0020] As used herein, the term "persistence" refers to an increase in residence time observed over a period of time compared to untreated eyes.

[0021] As used herein, the term "stability" 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 that shown in FIG.

[0023] As used herein, the term "dry eye" refers to an ocular condition in which the tear film is unable to perform its lubricating function and may be caused by a lack of important components to 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 pharmaceutical ingredient to the ocular surface over an extended period of time.

[0025] As used herein, the terms "light mineral oil" and "light mineral oil" may be used interchangeably and refer to low viscosity mineral oils as defined by the NF or USP formulas.

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

[0027] Unless otherwise defined, 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. The ophthalmic suspensions provided herein include an ophthalmic suspension vehicle and at least one pharmaceutical ingredient added to provide extended delivery of an active drug upon delivery to a patient's eye.

[0029] The ophthalmic suspension vehicle comprises an aqueous phase and an oil phase. The aqueous phase can comprise water and one or more wax esters, at least one anionic polar surfactant, at least one nonionic surfactant, at least one salt and at least one phosphate. The water used in the ophthalmic suspension vehicle provided herein can be purified water or ion-exchanged water. The oil phase can comprise at least one mineral oil, and optionally at least one wax ester. Thus, the at least one wax ester can be present in the aqueous phase, the oil phase, or both the aqueous phase and the oil phase. According to certain embodiments, the at least one wax ester is in either the aqueous phase or the oil phase.

[0030] The ophthalmic suspension provided herein comprises at least one pharmaceutical component. The ophthalmic suspension provides delivery of at least one pharmaceutical component such that the at least one pharmaceutical component is maintained in the ophthalmic suspension vehicle and in therapeutic contact with the eye for at least 2 hours after administration to the eye. According to one embodiment, the at least one pharmaceutical component is soluble in the aqueous phase. According to another aspect, the at least one pharmaceutical component is soluble in the 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. Oils derived from animals, plant seeds, and nuts are similar to fats and are primarily glycerides or fatty acids, and therefore contain a significant number of acid and / or ester groups that make the oil polar. Examples of these oils are safflower oil, corn oil, canola oil, whale oil, and seal oil, or chemically similar oils. Additional oils provided herein include vegetable oils such as castor oil, almond oil, myrrh oil, corn oil, peanut oil, canola oil, safflower oil, kola nut oil, light olive oil, bay leaf oil, or other generally recognized as safe (GRAS) oils that are listed as suitable for ophthalmic formulations. Alternatively, the oil may be an oil suitable for forming liposomes. According to one embodiment, the oil is a straight chain hydrocarbon oil having 10 to 150 carbon atoms, and more preferably, the oil is a saturated n-alkane or isoalkane hydrocarbon having 10 to 26 carbon atoms. Unsaturated alkene hydrocarbons can be used, but are less chemically stable.

[0032] According to one embodiment, the oil present in the ophthalmic suspension vehicle provided herein is a mineral oil. According to one embodiment, the oil provided herein is a light mineral oil. According to one embodiment, the oil provided herein is a 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 different viscosities. According to a particular embodiment, the light mineral oil has a viscosity of about 3.0 mm at 40° C. 2 s ‐1 from about 34.4 mm 2 s ‐1 According to a particular embodiment, the heavy mineral oil has a kinematic viscosity of about 34.5 mm at 40° C. 2 s ‐1 From about 150 mm 2 s ‐1According to yet another embodiment, the light mineral oil has a kinematic viscosity of about 28 mm at 40° C. 2 s ‐1 From about 30 mm 2 s ‐1 According to yet another embodiment, the heavy mineral oil has a kinematic viscosity of about 65 mm at 40° C. 2 s ‐1 From about 71 mm 2 s ‐1 The kinematic viscosity of

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

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

[0036] According to one embodiment, the oil present in the ophthalmic suspension vehicle provided herein comprises a mixture of two or more oils of different weights. According to such an embodiment, the oil is a mixture of at least one light oil and at least one heavy oil. According to a particular embodiment, the oil is a mixture of mineral oils commercially available under the trademarks Drakeol® 15 (light mineral oil) and Drakeol® 35 (white heavy mineral oil). According to one embodiment, the light mineral oil can be present in an amount of about 0.5% to about 1.5% by weight. According to one embodiment, the light mineral oil can be present in an amount of about 0.6% to about 1.4% by weight. According to one embodiment, the light mineral oil can be present in an amount of about 0.7% to about 1.3% by weight. According to one embodiment, the light mineral oil can be present in an amount of about 0.8% to about 1.2% by weight.

[0037] According to one embodiment, the heavy mineral oil can be present in an amount of about 2.7% to about 6.5% by weight. According to one embodiment, the heavy mineral oil can be present in an amount of about 2.9% to about 6.3% by weight. According to one embodiment, the heavy mineral oil can be present in an amount of about 3.1% to about 6.1% by weight. According to one embodiment, the heavy mineral oil can be present in an amount of about 3.3% to about 5.9% by weight. According to one embodiment, the heavy mineral oil can be present in an amount of about 3.5% to about 5.7% by weight. According to one embodiment, the heavy mineral oil can be present in an amount of about 3.7% to about 5.5% by weight. According to one embodiment, the heavy mineral oil can be present in an amount of about 4.05% 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. The role of wax ester and their hydrolysis products is believed to be, without being bound by any particular theory, to maintain the integrity of the stromal layer itself, to bind the mucin layer to the aqueous layer, and to bind the aqueous layer to the lipid layer. In addition, wax esters help to thicken the mucin, aqueous layer, and lipid layer itself. The binding process and subsequent homeostasis enabled by wax esters allows the layers of the tear film to stick together, thereby allowing the entire tear film to remain on the eye for an extended period of time and provide drug delivery of at least one pharmaceutical ingredient. The ophthalmic suspension vehicle provided herein passes through all layers of the tear film, including the stromal layer, which has not previously been incorporated with the product.

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

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

[0042] According to one embodiment, the at least one wax ester is beeswax. According to one embodiment, the beeswax is natural beeswax. The beeswax may be Cera Alba, Cera Flava, or a combination thereof. The beeswax may be USDA certified organic beeswax or conventional natural beeswax. According to one embodiment, the at least one wax ester is synthetic beeswax.

[0043] The ophthalmic suspension vehicle provided herein comprises wax ester particles.According to one embodiment, wax or wax ester particles can be mixed with at least one oil as provided herein.According to one embodiment, 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 provided herein exhibit a particle size that allows the particles to be retained on and in contact with the eye to allow delivery of at least one pharmaceutical ingredient. According to one embodiment, the wax ester particles provided herein form emulsion particles that are retained on 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 ophthalmic suspension vehicles to form a specific particle size range.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, allowing wax ester particles to degrade at different rates, with smaller wax ester particles and oil particles degrading quickly and larger wax ester particles degrading more slowly.As wax ester particles degrade, it is believed that oil and wax ester particles interact with the natural tear film to support a more stable barrier for the aqueous tear film that is prone to evaporation.

[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 no greater than about 30.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of no greater than about 25.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of no greater than about 24.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of no greater than about 23.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of no greater than about 22.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of no greater than about 21.0 microns. According to one embodiment, the wax ester particles exhibit an average particle size of no greater 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 no greater 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 not greater 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 not greater 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 not greater 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 not greater 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 not greater 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 not greater 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 not greater 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 not greater 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 for the dual purpose of stabilizing the vehicle and at least one pharmaceutical ingredient, and for spreading and maintaining the vehicle and pharmaceutical ingredient on the ocular surface after application to the eye. In one embodiment, the combination of surfactants can comprise a primary surfactant and a secondary surfactant. The at least one surfactant allows for the formation of an ophthalmic suspension vehicle that is stable during manufacture and storage, but desirably is meta stable when applied to the ocular surface. As an example, the at least one surfactant allows for phase separation of the components when applied to the ocular surface. The at least one surfactant provided herein is suitable for rapid differentiation when applied to the eye, which allows for the rapid formation of an unblurred film of oil on the ocular surface and the spreading of wax esters through each phase of the ophthalmic suspension vehicle.

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

[0049] According to one embodiment, the at least one surfactant comprises diphosphatidylglycerol, such as dimyristoylphosphatidylglycerol or commercially available 1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol sodium salt (DMPG). The surfactant can be lysophosphatidylcholine, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, or phosphatidylserine. In other embodiments, the surfactant comprises 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 may be one or more of phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), and its phosphorylated derivatives may be phosphoinositides (e.g., phosphatidylinositol-4-phosphate [PI4P] and phosphatidylinositol-4,5-bisphosphate, and dimyristoyl phosphatidylglycerol). According to one embodiment, the anionic surfactant is dimyristoyl phosphatidylglycerol. According to one embodiment, the surfactant is a mixture of two surfactants 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 dimyristoyl phosphatidylglycerol.

[0050] According to one embodiment, dimyristoyl phosphatidylglycerol may be present in the 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 the 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 the 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 the 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 and dibasic phosphate salts.

[0052] According to certain embodiments, the monobasic phosphate is a monosodium phosphate, such as NaH2PO4. According to one embodiment, the monobasic phosphate may be present in an amount of about 0.01% to about 0.05% by weight. According to one embodiment, the monobasic phosphate may be present in an amount of about 0.02% 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 certain embodiments, the dibasic phosphate is a disodium phosphate such as NaHPO (sodium hydrogen phosphate or sodium phosphate dibasic). According to one embodiment, the dibasic phosphate may be present in an amount of about 0.1% to about 0.5% by weight. According to one embodiment, the dibasic phosphate may be present in an amount of about 0.2% 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 can include at least one salt. According to one embodiment, the at least one salt is sodium chloride or other salt suitable for application to the eye. The at least one salt can be present in an amount of about 0.50% to about 0.75% by weight. According to another embodiment, the at least one salt can be present in an amount of about 0.55% to about 0.70% by weight. According to another embodiment, the at least one salt can be present in an amount of about 0.55% by weight. According to another embodiment, the at least one salt can 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 glycosylaminoglycan. Suitable glycosylaminoglycans include hyaluronic acid (HA), the corresponding sodium salt, sodium hyaluronate, or a combination thereof. According to one embodiment, the hyaluronic acid or sodium hyaluronate may be present in the ophthalmic suspension vehicle in an amount of about 0.06% to about 0.5% by weight. According to one embodiment, the hyaluronic acid or sodium hyaluronate may be present in the ophthalmic suspension vehicle in an amount of about 0.07% to about 0.4% by weight. According to one embodiment, the hyaluronic acid or sodium hyaluronate may be present in the ophthalmic suspension vehicle in an amount of about 0.08% to about 0.3% by weight. According to one embodiment, the hyaluronic acid or sodium hyaluronate may be present in the ophthalmic suspension vehicle in an amount of about 0.09% to about 0.2% by weight. According to one embodiment, hyaluronic acid or sodium hyaluronate may be present in the ophthalmic suspension vehicle in an amount of about 0.1% by weight.

[0056] According to one embodiment, the ophthalmic suspension vehicle provided herein may optionally include ethylenediaminetetraacetic acid (EDTA). According to one embodiment, the EDTA may be present in the ophthalmic suspension vehicle in an amount of about 0.007% to about 0.02% by weight. According to one embodiment, the EDTA may be present in the ophthalmic suspension vehicle in an amount of about 0.008% to about 0.015% by weight. According to one embodiment, the EDTA may 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 comprises at least one anti-inflammatory compound, such as inactivated brewer's yeast or adenosine diphosphate ribose.Currently, 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% to about 1.0% by weight.

[0058] According to one embodiment, the ophthalmic suspension vehicle provided herein may have an osmolarity that may be adjusted by the concentration of a salt such as NaCl. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolarity of at least about 245 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolarity of at least about 260 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolarity of about 245 mOsmol / kg to about 315 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolarity of about 245 mOsmol / kg to about 310 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolarity of about 255 mOsmol / kg to about 305 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of about 270 mOsmol / kg to about 300 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of about 275 mOsmol / kg to about 295 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of about 280 mOsmol / kg to about 290 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of about 282 mOsmol / kg to about 289 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of about 285 mOsmol / kg to about 287 mOsmol / kg. According to one embodiment, the ophthalmic suspension vehicle provided herein has an osmolality of about 286 mOsmol / kg.

[0059] According to one embodiment, the ophthalmic suspension vehicle provided herein has a pH of about 6.8-7.8. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH of about 6.9-7.7. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH of about 7.0-7.6. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH of about 7.0-7.4. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH between about 7.1-7.5. According to one embodiment, the ophthalmic suspension vehicle provided herein exhibits a pH of about 7.2-7.4. 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 adjuster such as HCl or citric acid or a base such as NaOH.

[0060] The viscosity of the ophthalmic suspension vehicles described herein may vary, but the viscosity allows for suitable droplet size for application to the eye. According to one embodiment, the viscosity of the ophthalmic suspension vehicles provided herein is between about 5 centipoise at 25°C and about 8 centipoise at 25°C. The viscosity of the ophthalmic suspension vehicles described herein can be measured using techniques well known to those skilled in the art. Non-limiting examples of methods for measuring viscosity include a falling ball viscometer, a viscosity cup, a consistometer (measuring flow up a slope), a capillary glass viscometer, or a rotational viscometer. Various instruments are commercially available (Cole-Palmer Instrument Co., Vernon Hills, IL,USA).

[0061] The ophthalmic suspension vehicle provided herein can be preservative-free. In some embodiments, the preservative-free ophthalmic suspension vehicle is delivered in a single-use package due to the risk of bacterial contamination associated with conventional multi-use applications. 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 that is mechanically actuated and utilizes a filter membrane (see PCT Publications WO 2017 / 074420 and WO 2017 / 132190 (Aptargroup, Inc.) and Nemera La Verpillier (France) multi-dose squeeze bottle (see PCT Publication WO2013 / 140069)), each of which is incorporated by reference with respect to such containers.

[0062] According to an alternative embodiment, the ophthalmic suspension medium provided herein may optionally include at least one preservative. The amount of preservative does not adversely affect the stability of the ophthalmic suspension vehicle, performance on the eye, or adversely affect the user. According to another embodiment, the ophthalmic suspension medium 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 either the aqueous or oil phase of the ophthalmic suspension vehicle. Suitable classes of pharmaceutical ingredients include antibiotics, antivirals, anti-inflammatory agents and antiglaucoma agents, as shown in part in Sections 5.3.1 and 5.3.2 of European Patent Application No. 0092453, published October 26, 1983, or PCT Publication No. WO 2015 / 05531, published April 23, 2015, page 5, lines 5-22, which are incorporated herein by reference. Other suitable pharmaceutical ingredients include adenosine diphosphate ribose, antazoline, apraclonidine, atropine, azelastine, bepotastine, ethamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, bromfenac, cardiolipin peroxidation inhibitors, carteolol, cetrimide, chloramphenicol, ciprofloxacin, cyclosporine, dexamethasone, Diclofenac, Dorzolamide, Emedastine, Epinastine, Epinastine, Flurbiprofen, Framycetin Sulfate, Gentamicin, Gramicidin, Hamamelis Water, Homatropine, Hyaluronic Acid, Ketotifen Fumarate, Lacritin / Lacritin Protein Fragment, Latanoprost, Levobunolol, Levofloxacin, Lodoxamide Droteprednol, Lymphocyte Function-Associated Antigen-1 (LFA-1) Antagonist, Modified 19kDa These include, but are not limited to, TNF receptors, moxifloxacin, naphazoline, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonists, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, reactive aldehyde species inhibitors, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thiomersal, timolol, tobramycin, trafluprost, travoprost, ketorolac trometamol, trometamol, xylometazoline, or any combination thereof.According to one embodiment, the at least one pharmaceutical ingredient suitable for delivery to the eye via the ophthalmic suspension vehicle is cannabidiol, tetrahydrocannabinol, or a combination thereof. Other pharmaceutical ingredients and combinations thereof, although not expressly listed, are considered to be available 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 hydroxylated esters, cholesterol esters, and high molecular weight isoprenoids. According to one embodiment, the at least one pharmaceutical ingredient is a stabilizer, surfactant, mucosal (e.g., HP Guar), preservative, pH adjuster, salt, buffer, glycerin, sugar, emollient, or 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 carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), polyacrylic acid (PAA), polyethylene glycol, (PEG) propylene glycol, 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 includes separately preparing a mixture of oils (e.g., heavy mineral oil and light mineral oil), 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 components 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 the ophthalmic suspension vehicle. The resulting ophthalmic suspension vehicle is autoclaved. Throughout this process, the ophthalmic suspension vehicle continues to be mixed.

[0066] According to one embodiment, a method for preparing an ophthalmic suspension vehicle includes separately preparing an oil phase (e.g., heavy mineral oil and light mineral oil) by heating to a temperature of about 63° C. to about 71° C. The step of preparing the oil phase can optionally include adding or introducing at least one wax ester to the oil phase, 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.).

[0067] According to one embodiment, the method for preparing an ophthalmic suspension vehicle includes separately preparing an aqueous phase, which 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 components, 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).

[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.According to such an embodiment, therefore, the individual oil and aqueous phases are not autoclaved separately before being combined.According to one embodiment, the resulting ophthalmic suspension vehicle is not autoclaved and sterilized, for example, by e-beam or gamma irradiation, or by alternative methods such as filtration.

[0069] According to an alternative embodiment, a method for preparing an ophthalmic suspension vehicle is provided. The alternative method includes preparing a wax dispersion by mixing or dissolving at least one wax ester (e.g., natural beeswax) with a surfactant and purified or ion-exchanged water. According to one embodiment, at least one wax ester can be mixed or dissolved such that the natural wax ester can be delivered in a controlled manner and results in increased residence time on the eye. According to one embodiment, preparing a wax dispersion includes dissolving one or more salts and one or more phosphates, such as monosodium phosphate and disodium phosphate, in purified or ion-exchanged water. According to one embodiment, preparing a wax dispersion includes heating one or more salts, phosphates, surfactants and wax esters and stirring the resulting dispersion liquid. According to one embodiment, the dispersion is heated to about 70°C to about 90°C. According to certain embodiments, wax ester particle dispersions can be prepared by homogenizing molten beeswax (~1.0%) in purified or distilled water with the addition of a salt, phosphate, Octoxynol-40 (~0.2%, 1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol sodium salt) at about 75°C. The high cloud point of Octoxynol-40 (>100°C) allows for emulsification efficiency at higher temperatures due to its reduced water solubility (effectively lowering the HLB value).

[0070] An alternative method includes preparing an oil-in-water emulsion. According to one embodiment, preparing the oil-in-water emulsion includes mixing mineral oils of different weights or viscosities as described herein and heating the mixture of mineral oils to a temperature of about 65° C. to about 75° C. According to one embodiment, preparing the oil-in-water emulsion includes introducing the heated mixture of mineral oils dropwise into purified water or ion-exchanged 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 involves autoclaving the wax dispersion and the oil-in-water emulsion separately, with the integrity of the emulsion being maintained during autoclaving.

[0072] Without being bound to a particular theory, it is believed that the mechanism responsible for irreversible aggregation of wax (wax breakout) under autoclave conditions involves the presence of a relatively high (near isotonic) salt concentration. This high ionic load is believed to significantly reduce the zeta potential of the wax ester particles, which removes an important stabilization mechanism when these dispersions are subjected to autoclave conditions.

[0073] Another method involves 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 may be stabilized by a surfactant in the oil phase that prevents agglomeration and droplet coalescence during cooling.

[0074] To maintain a storage stable vehicle, separate preparation and autoclaving of the wax ester particle dispersion and emulsion components can be performed, followed by a sterile blending step, to ensure product sterility according to an alternative method. The sterile blending step of the autoclaved beeswax dispersion and oil-in-water emulsion ensures that the desired final concentrations of mineral oil, beeswax, and other ingredients are present in the ophthalmic suspension vehicle. The oil-in-water emulsion is formulated with increased ingredient levels, while the beeswax ester particles are emulsified in water with added surfactants. The concentrations of the various ingredients in the two fractions (before autoclaving) can be adjusted to allow for a relatively wide variation in the final emulsion vehicle composition.

[0075] Example 1 Preparation of an ophthalmic suspension vehicle containing a pharmaceutical ingredient An exemplary ophthalmic suspension vehicle was prepared containing the ingredients shown in Table 1 below. [Table 1]

[0076] To prepare a 500 gram batch of eye drop suspension, a batch of NaCl, dimyristoyl phosphatidylglycerol (DPMG), NaH2PO4 and Na2HPO4 were dissolved in purified water in a beaker. Tween 80, DPMG, ADP-ribose and sodium hyaluronate were added to the aqueous solution and heated to 85°C (+ / -2°C) with continuous stirring. In a separate glass beaker, Drakeol® 15, Drakeol® 35 and wax esters were mixed and heated to 71°C (+ / -2°C) with continuous stirring for 10 minutes (+ / -20 seconds). The aqueous phase was homogenized for 30 seconds (+ / -5 seconds). With the homogenizer running, the oil phase was preheated to 71°C (+ / -2°C) and added dropwise to the aqueous phase at 85°C (+ / -2°C). After oil addition was complete, the homogenizer was run. The target homogenization speed was approximately 10,000 RPM (+ / - 400 RPM) and the target homogenization time was approximately 4 minutes (+ / - 20 seconds). The homogenization procedure was terminated and stirring continued until the suspension reached room temperature (approximately 4 hours). While stirring, pH and osmolality were checked and adjusted (target pH: 7.2-7.4; osmolality 240 mOsmol / kg-290 mOsmol / kg). While stirring, the vehicle mixture was dispensed using a syringe into an autoclavable bottle and loaded with a magnetic stir bar. The bottle and autoclave were closed for 35 minutes (+ / - 1 minute) and heated to 15 psi and 121°C with stirring. The ophthalmic suspension vehicle was allowed to cool to room temperature with stirring (approximately 6 hours).

[0077] Example 2 Ophthalmic pharmaceutical ingredients in suspension vehicles - performance in the eye A study was conducted to investigate the ocular performance of an ophthalmic suspension vehicle using the known anti-inflammatory drug ADP-ribose, shown in Table 1. The study yielded favorable results in terms of both suspension vehicle properties and ocular performance. Specifically, the study was conducted in patients with low levels of lipid layer thickness (LLT) and reduced tear film, based on day-ahead and day-1 screening. Interferometry was used to measure the lipid layer thickness of the tear film at baseline. The baseline lipid layer thickness of these patients ranged from 25 nm to 70 nm, with a mean of 45 nm. A lipid layer thickness of less than 70 nm was considered deficient.

[0078] After baseline measurements were taken, subjects self-instilled one drop of the test eye drop suspension vehicle in Table 1 (Example 1) and one drop of a control solution into the contralateral eye. The control solution selected was a solution commercially available as Systane® Ultra PF (commercially available, preservative-free, non-greasy drops).

[0079] The primary objective was to assess the duration of eyes with increased lipid layer thickness, and the first challenge was to develop rigorous inclusion and exclusion criteria for patient recruitment to select subjects with chronically dry tear film due to evaporative dry eye (e.g., meibomian gland dysfunction or MGD) rather than partial blinking or a side effect of another drug or procedure. The study primarily sought subjects with baseline lipid layer thickness <55 nm and partial blink rate <50% in at least one eye, both measured using LipiView (Johnson and Johnson).

[0080] Once the inclusion criteria were established, a formal protocol had to be developed for clinicians and personnel to follow. In this document, each step of the patient assessment process was laid out in a checkbox format, from the initial patient assessment and on-the-day participation confirmation to the actual assessment and measurement process.

[0081] 1.Selection 2. Check for exclusions 3. Eye health check (evaluation will be at the discretion of the doctor) 4. Baseline LLT measurements 5. SPEED Pre-assessment (standardized patient assessment of dry eye), see Korb et al. Lid wiper epitheliopathy and dry eye symptoms. Eye Contact Lens. 2005 Jan;31(1):2-8; and Korb et al. The effect of two novel lubricant eye drops on tear film lipid layer thickness in subjects with dry eye symptoms. Optom Vis Sci. 2005 Jul;82(7):594-601, which are incorporated by reference for the research studies. 6. Instillation of test and control drugs Measurements at intervals of 7.5, 30, 60, 120, 180, and 240 minutes 8. SPEED Ex-post Evaluation

[0082] The eye drops were masked to patients but not to physicians or personnel. All study results were recorded on data records masked to patient identity.

[0083] Twelve patients completed the study over a two-week period. The results, as shown in Tables 2 and 3, show the raw mean lipid layer thickness readings of the 12 patients measured. The ophthalmic suspension vehicles in Table 1 showed a significant increase in lipid layer thickness at the 5 and 30 minute time points. Significant differences were noted between the ophthalmic suspension vehicles and the control drops at all measurement time points. The ophthalmic suspension vehicles maintained a mean lipid layer thickness of 72.5 (+ / -3.8) nm at the 4 hour mark compared to the control which was 61.8 (+ / -2.2) nm.

[0084] [Table 2]

[0085] [Table 3]

[0086] Based on the raw data of the paired eyes, differences appeared in the mean baseline lipid layer thickness of the test eye and the control eye.Thus, in addition to using lipid layer thickness at each time point as the key measure, the mean increase in lipid layer thickness from baseline was evaluated in patients who received both test and control drops.Table 4 shows the increase in lipid layer thickness obtained from the eye drop suspension vehicles listed in Table 1.Table 5 shows the increase in lipid layer thickness obtained from Systane® Ultra PF solution.

[0087] A clear separation of the test and control solutions at each time point is illustrated, with the lipid layer thickness of the ophthalmic suspension vehicle increasing by nearly 50% at the 4 hour mark. Thus, the decrease in lipid layer thickness is delayed well beyond the 4 hour mark before returning to baseline. If the dissolution rate remained linear, it is likely that a significant lipid layer thickness increase would continue well beyond 8 hours using only a single drop of ophthalmic suspension vehicle.

[0088] [Table 4]

[0089] [Table 5]

[0090] Two subjective questions were asked of patients immediately upon instillation in each eye. The first question asked patients to rate their initial comfort from 0 to 100. The second question asked them to report the duration of any visual blurring they noticed. With the ophthalmic suspension vehicle, the average patient had a comfort score of 85 out of 100 and slight visual blurring of 5.6 seconds. For the control drops, the average results were 92 out of 100 and 2.9 seconds. There was a difference between the test and control in both of these subjective indices, but the blurring lasted less than 3 seconds with the ophthalmic suspension vehicle, while the initial comfort score was 7 out of 100.

[0091] With the ophthalmic suspension vehicle, most patients reported no blurring, but the longest duration of blurring was 30 seconds (1 test eye, 1 control eye). Patient comfort scores were similar, ranging from 45 to 100 in the test eye and 50 to 100 in the control eye. Based on thousands of hours of in-house testing, comfort and blurring are similar to the control solution.

[0092] The self-administered SPEED Dry Eye Symptom Questionnaire was incorporated into the study. A score of 8 or higher indicated the presence of dry eye. Patient response was a mean SPEED score of 13.58 at the start of the study, before any drops were administered.

[0093] Four hours after instillation, patients were re-examined using the SPEED. The mean result of the post-hoc evaluation was a score of 10.5, with no patients reporting an increase in score and five patients reporting a score below 8. The evaluation did not distinguish between symptoms in both eyes. Because the experiment was performed on paired eyes, it was difficult to distinguish between the effects of the ophthalmic suspension vehicle and the control drop. The SPEED evaluation was intended to measure symptoms over a period of weeks or months, so the immediate results may not accurately reflect the patient's symptoms. Finally, time of day was an uncontrolled variable in this study and may have influenced the symptoms reported by the patients.

[0094] In summary, this study demonstrated a significant increase in on-eye duration of the suspension vehicle compared to the control group at a 4-hour interval in a physician-administered arm-length test. Notably, the eye drop was shown to increase tear film thickness by approximately 50% at the 4-hour time point in a controlled ocular patient evaluation, demonstrating that eye drop suspensions can be used as drug delivery vehicles for chronic ocular administration.

[0095] As the wax acid ester particles dissolve, without being bound by any particular theory, it is believed that the oil bound to the wax acid ester particles is released into the tear film and migrates to the surface, continually replenishing the patient's diminished evaporative lipid barrier. Different sized particles dissolve at different rates. In effect, the widespread distribution of oil-bound wax acid ester particles creates a controlled release mechanism that delivers lipids to the tear film upon blinking as the wax ester particles dissolve. It is believed that the wax ester acts as a mechanism to slow the flow of the lipid layer through puncta during normal tear turnover.

[0096] Example 3 particle size To provide the desired pharmaceutical delivery properties, the oil and wax ester portions of the ophthalmic vehicle are retained in the ocular environment for extended periods of time, and the particle size of the wax esters is preferably maintained to increase a long-lasting lipid layer on the eye over extended periods of time.

[0097] Particle size was determined using a Microtrac Sync 3R Flow device. Particle size analysis was performed using approximately 6.0 mL samples of the ophthalmic vehicle of Example 1. Samples were stored in plastic bottles until testing. Each bottle was shaken 10 times prior to testing. The entire cap was then removed and approximately 2 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 2 drops (0.060 g) of sample were injected into a 200 mL ion-exchanged water circulating chamber and testing was initiated.

[0098] Results for mineral oil alone showed that loss of added mineral oil did not exceed 30 minutes, as observed with the competitive Systane® Balance. Results are summarized in Table 6.

[0099] The processing parameters labeled "Homogenizer" in Table 6 refer to processing with the homogenizer alone, ranging from about 10k to about 18k rpm, for about 4 to about 8 minutes. The other processing parameters refer to the pressure of the microfluidizer system used to assess homogeneity. This additional processing was added after the initial homogenization and resulted in a reduction in particle size, but at the expense of reduced clinical performance (mean increase above baseline). More specifically, based on particle size analysis performed on several test formulas, the homogenizer-only process resulted in an average particle size in the range of 2 to 20 microns, while samples further processed with the microfluidizer resulted in an average particle size of ≦1 micron. Actual measurements of the formulations determined a significant range of particle size and distribution. Specifically, formulations with an average particle size of about 1 micron did not remain in the eye, while the best performing formulations had an average particle size in the range of 5 to 20 microns under the conditions measured.

[0100] [Table 6]

[0101] Example 4 Zeta potential and ion mobility analysis Zeta potential tests were performed to evaluate the particle performance and stability of various eye drop vehicles for eye drop droplets marketed as Systane Balance. Zeta potential indicates the degree of electrostatic repulsion between similarly charged particles in a dispersion. Generally, a high negative zeta potential correlates with stability (e.g., the dispersion resists aggregation). For eye drops, applicants have demonstrated that a higher negative potential translates directly into a longer residence time of the eye drop vehicle on the eye.

[0102] To evaluate particle velocities generated by an electric field, ion mobility studies were performed on the same ophthalmic vehicle and Systane® Balance eye drops.

[0103] The contents of the eye drop vehicles tested (Samples A-F) are shown in Table 7. For Sample A, beeswax was added to the water phase and homogenized at 10,000 RPM for 2 minutes. For Sample B, beeswax was added to the water phase and homogenized at 20,000 RPM for 8 minutes. For Samples C and D, beeswax was added to the water phase and homogenized at 18,000 RPM for 8 minutes. For Samples E and F, the oil and water phases were separated, beeswax was added to the oil phase and homogenized at 18,000 RPM for 8 minutes and then tested. Systane® Balance eye drops contained propylene glycol (0.6%) as the primary lubricant, as well as various inactive ingredients including boric acid, dimyristoyl phosphatidylglycerol, disodium edetate, hydroxypropyl guar, mineral oil, polyoxyl 40 stearate, POLYQUAD® (polyquaternium-1) 0.001% preservative, sorbitan tristearate, sorbitol, and purified water, as well as hydrochloric acid and / or sodium hydroxide for pH adjustment.

[0104] The results of the zeta potential and ion mobility tests are shown in Table 8.

[0105] [Table 7]

[0106] [Table 8]

[0107] Ophthalmic vehicles A-F all exhibited a zeta potential of about -75 to about -95 and an ion mobility of about -6 to about -7.5. These results demonstrate that the ophthalmic vehicles provided herein provide significant stabilization of large particles as well as sustained thickening of the tear film, unlike those of Systane® Balance eye drops, which exhibited significantly different zeta potentials and ion mobilities.

[0108] Example 5 Ophthalmic vehicles compared with commercially available artificial tears A study was conducted to examine the on-eye performance of the eye drop vehicles listed in Table 1 in comparison to various commercially available artificial tear products (HyloCare®, Tears Again, Cationorm®, Hylovision®, Thealoz®, EvoTears®, TheraTears®, Systane® Complete, Systane® Balance, Soothe® XP, Retaine® MGD, and Refresh Optive® Advanced).

[0109] The lipid layer thickness measurements of the commercial products were performed up to 60 minutes. The measurement time of the ophthalmic vehicle was 120 minutes or more. The study was open-label, and Systane Ultra PF® was used as the control. A total of 93 observations (n=93) were performed among 12 commercial products. The results showed that in a 5-minute time interval, none of the products could increase the lipid layer thickness by 13 nm over the control, and the best commercial product showed an increase of 10 nm over the control in a 60-minute time interval.

[0110] On average, lipid layer thickness increased by 21 nm over the control over the 5 minute time interval and continued to increase to 24.7 nm at 60 minutes (n=78). Aggregate data are summarized in Tables 9 and 10.

[0111] [Table 9]

[0112] [Table 10]

[0113] In total, the eye drop vehicle showed a five-fold (5x) improvement in immediate lipid layer thickness increase over 78 cumulative observations compared to 93 cumulative observations for the 12 commercial products. This gap in lipid layer thickness increase was eleven-fold (11x) at the 60 minute mark, with the eye drop vehicle showing a 23 nm increase from baseline compared to the control, while the commercial products only showed a 2 nm increase from baseline compared to the control.

[0114] It should be understood that the above description is merely representative of exemplary embodiments and examples. For the convenience of the reader, the above description has focused on a limited number of representative examples of all possible embodiments that teach the principles of the present disclosure. The specification does not attempt to exhaustively list all possible variations or combinations of these variations that are described. If alternative embodiments are not presented for a particular part of the disclosure, or even if alternative embodiments that are not further described for a part may be available, this is not considered a disclaimer of those alternative embodiments. Those skilled in the art will understand that many of the embodiments that are not described involve differences in technology and materials, rather than differences in the application of the principles of the disclosure. Thus, the present disclosure is not intended to be limited to less than the scope and equivalents set forth in the following claims.

[0115] Although the present disclosure has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, but not to limit, the scope of the invention. Other aspects, advantages, and modifications are within the scope of the following claims.

[0116] General Description of Disclosure The following numbered statements provide a general description of the disclosure and are not intended to limit the scope of the appended claims.

[0117] Description 1. An ophthalmic suspension vehicle is provided that includes a wax dispersion that includes at least one wax ester, an anionic polar surfactant, and water, and an oil-in-water emulsion that includes at least one oil and water. The wax ester exhibits an average particle size of at least about 5.0 microns using a Microtrack Particle Analyzer procedure for determining particle size.

[0118] Description 2. The present disclosure provides an ophthalmic emulsion vehicle according to description 1.

[0119] Statement 3. The present disclosure provides an ophthalmic suspension vehicle according to any one of statements 1 to 2, wherein the ophthalmic suspension vehicle has an osmolality of about 245 mOsmol / kg to about 315 mOsmol / kg.

[0120] Statement 4. The present disclosure provides an ophthalmic suspension vehicle according to any one of statements 1 to 3, wherein the ophthalmic suspension vehicle is formulated as a free flowing emulsified vehicle at about 30°C.

[0121] Statement 5. The present disclosure provides an ophthalmic suspension medium according to any one of statements 1 to 4, wherein the wax ester is present in a concentration of about 0.8% to about 1.2% by weight.

[0122] Statement 6. The present disclosure provides the eye drop suspension vehicle of any of statements 1 to 5, wherein the wax ester is natural beeswax.

[0123] Statement 7. The present disclosure provides an ophthalmic suspension vehicle according to any one of statements 1 to 6, wherein the ophthalmic suspension vehicle exhibits a negative zeta potential of about -60 mV to about -110 mV.

[0124] Statement 8. The present disclosure provides an ophthalmic suspension vehicle according to any one of statements 1 to 7, wherein the ophthalmic suspension vehicle exhibits an ion mobility of about -5.9 (μms) / (V / cm) to about -7.4 (μms) / (V / cm).

[0125] Statement 9. The present disclosure provides an ophthalmic suspension vehicle according to any one of statements 1 to 8, wherein the oil is a mixture of light and heavy mineral oils.

[0126] Description 10. The present specification relates to a method for manufacturing a light mineral oil having a viscosity of about 3.0 mm at 40° C. 2 s ‐1 from about 34.4 mm 2 s ‐1 and the heavy mineral oil has a kinematic viscosity of about 34.5 mm at 40° C. 2 s ‐1 From about 150 mm 2 s ‐1 The present invention provides an ophthalmic suspension vehicle according to any one of claims 1 to 9, which exhibits a kinetic viscosity of

[0127] Statement 11. The present disclosure provides an ophthalmic suspension vehicle of any of statements 1 to 10, further comprising an anionic polar surfactant comprising a mixture of a polysorbate nonionic surfactant at a concentration of about 0.35 to about 0.45% by weight and an anionic polar dimyristoyl phosphatidylglycerol at a concentration of about 0.35 to about 0.55% by weight.

[0128] Description 12. The present disclosure provides an ophthalmic suspension vehicle according to any one of descriptions 1 to 11, packaged in a sterile multi-use or sterile single-use container.

[0129] Statement 13. The present disclosure provides an ophthalmic suspension vehicle of any of statements 1-12 packaged in a multi-dose non-preserved (MDNP) container or a container that includes at least one preservative.

[0130] Statement 14. The present disclosure provides an ophthalmic suspension vehicle of any of statements 1 to 13, wherein the ophthalmic suspension vehicle increases the lipid layer thickness by at least 20 nanometers 5 minutes after administration.

[0131] Statement 15. The present disclosure provides an ophthalmic suspension vehicle of any of statements 1 to 14, wherein the ophthalmic suspension vehicle increases the lipid layer thickness by at least 20 nanometers 4 hours after administration.

[0132] Description 16. A method for increasing lipid layer thickness is provided, comprising administering to the eye of a patient in need of treatment any of the ophthalmic suspension vehicles described in descriptions 1 to 15.

[0133] Statement 17. The present disclosure provides a method of increasing lipid layer thickness of statement 16, wherein the lipid layer thickness is increased by at least 20 nm within 5 minutes after administration.

[0134] Description 18. The present disclosure provides a method for increasing the thickness of a lipid layer according to any of descriptions 16 to 17, wherein the lipid layer thickness is increased by at least 20 nm 4 hours after administration.

[0135] Description 19. The present disclosure provides a method of lubricating an eye, comprising administering to an eye of a patient in need of treatment any of the ophthalmic suspension vehicles of descriptions 1-15.

[0136] Description 20. The present disclosure provides a method for relieving symptoms of dry eye, comprising administering to the eye of a patient in need of treatment any of the ophthalmic suspension vehicles of descriptions 1-15.

[0137] Description 21. An ophthalmic suspension vehicle is provided that includes (a) water, (b) at least one oil, (c) a surfactant, and (d) a wax dispersion that includes 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 with the mucin layer, the aqueous layer, and the lipid layer of a subject's eye and acts to maintain or enhance the integrity of the stromal layer between the mucin layer and the aqueous layer, and the stromal layer between the aqueous layer and the lipid layer.

[0138] Statement 22. The present disclosure provides an ophthalmic suspension vehicle of 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.

[0139] Description 23. The present disclosure provides an ophthalmic suspension vehicle according to descriptions 21-22, in which binding and homeostasis by the wax, wax ester or hydrolysis product allows the mucin layer, aqueous layer, and lipid layer of the tear film to interact with each other, allowing the tear film to be maintained on the eye for an extended period of time (e.g., at least 2 hours).

[0140] Description 24. An ophthalmic suspension vehicle is provided that exhibits a zeta potential of about -60 mV to about -110 mV.

[0141] Description 25. An ophthalmic suspension vehicle is provided which upon contact with the eye separates into an oil phase and an aqueous phase and forms a meta stable emulsion that provides lubrication to the eye for about 2 to about 12 hours.

[0142] Item 26. There is provided a method for relieving symptoms of dry eye, comprising the step of contacting an eye with an ophthalmic suspension vehicle according to any one of items 21 to 25.

[0143] Statement 27. The present disclosure provides a method of relieving dry eye symptoms of 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 with unprotected corneal cells.

[0144] Statement 28. The present disclosure provides a method for relieving dry eye symptoms according to any of statements 26 to 27, wherein the wax ester of the ophthalmic suspension vehicle is natural beeswax or synthetic beeswax.

[0145] Statement 29. The present disclosure provides a method for relieving dry eye symptoms of any of statements 26-28, wherein the oil is a mixture of lighter and heavier mineral oils.

[0146] Description 30. The present disclosure provides a method for relieving dry eye symptoms of any of descriptions 26 to 29, wherein the oil is present in a concentration of about 1.0% to about 5% by weight.

[0147] Description 31. The present disclosure provides a method for relieving a symptom of dry eye according to any of descriptions 26 to 30, wherein the surfactant is a mixture of two or more surfactants.

[0148] Statement 32. The present disclosure provides a method of relieving a symptom of dry eye of any of statements 26 to 31, wherein (i) the oil is a mixture of lighter and heavier oils and is present in a concentration of about 1.0 to about 5.5% by weight, (ii) the surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 to about 0.45% by weight and dimyristoyl phosphatidylglycerol at a concentration of about 0.3 to about 0.5% by weight, (iii) the wax ester is natural or synthetic beeswax present at a concentration of about 0.5 to about 1.0% by weight, and the ophthalmic suspension suspension vehicle has an osmolality of about 245 to about 310 mOsmol / kg.

[0149] Description 33. The present disclosure provides a method for relieving dry eye symptoms of any of descriptions 26 to 32, wherein the ophthalmic suspension vehicle is packaged in a sterile multi-use or sterile single-use container.

[0150] Statement 34. The present disclosure provides a method for relieving dry eye symptoms of any of statements 26-33, wherein the ophthalmic suspension vehicle is packaged in a multi-dose non-preserved (MDNP) container or a container containing at least one preservative.

[0151] Statement 35. The present disclosure provides a method for preparing an ophthalmic suspension vehicle comprising the steps of: (a) preparing a wax ester and a surfactant in a purified or deionized water vehicle; (b) preparing an oil-in-water emulsion comprising an oil in the purified or deionized water vehicle; (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 suspension vehicle.

[0152] Statement 36. The present disclosure provides a method for preparing an ophthalmic suspension vehicle of statement 35, which provides lubrication on the eye for at least about 2 hours.

[0153] Description 37. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any one of descriptions 35-36, which provides lubrication to the eye for at least about 12 hours.

[0154] Statement 38. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any of statements 35 to 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.

[0155] Description 39. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any one of descriptions 35 to 38, wherein the wax ester is natural beeswax.

[0156] Description 40. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any one of descriptions 35 to 39, wherein the beeswax is synthetic beeswax.

[0157] Description 41. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any of descriptions 35 to 40, wherein the oil is a mixture of a lighter oil and a heavier oil.

[0158] Description 42. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any one of descriptions 35 to 41, wherein the surfactant is a mixture of two or more surfactants.

[0159] Statement 43. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any of statements 35 to 42, wherein (i) the oil is a mixture of light and heavy oils and is present at a concentration of about 1.0 to about 5.5% by weight, (ii) the surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 to about 0.45% by weight and dimyristoyl phosphatidylglycerol at a concentration of about 0.3 to about 0.5% by weight, and (iii) the wax ester is natural or synthetic beeswax present at a concentration of about 0.25 to about 1.0% by weight, and the ophthalmic suspension vehicle has an osmolality of about 245 to about 310 mOsmol / kg.

[0160] Description 44. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any one of descriptions 35 to 43, comprising packaging the ophthalmic suspension vehicle in a sterile multi-use container or a sterile single-use container.

[0161] Statement 45. The present disclosure provides a method of preparing an ophthalmic suspension vehicle of any of statements 35-44, wherein the ophthalmic suspension vehicle is packaged in a multi-dose non-preserved (MDNP) container or a container containing at least one preservative.

[0162] Description 46. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any one of descriptions 35 to 44, comprising packaging the ophthalmic suspension vehicle in a container containing a preservative.

[0163] Description 47. The present disclosure provides a method for preparing an ophthalmic suspension vehicle of any of descriptions 35 to 46, wherein the wax ester acts to increase the thickness of the mucin layer, the aqueous layer, the lipid layer, or a combination thereof.

[0164] Description 48. The present disclosure provides a method for preparing an ophthalmic suspension vehicle according to any of descriptions 35-47, wherein the binding and homeostasis enabled by the wax esters allows the mucin layer, the aqueous layer, and the lipid layer of the tear film to interact with each other and the tear film to remain on the eye for at least 2 hours.

[0165] Statement 49. The present disclosure provides a method for delivering at least one pharmaceutical ingredient to a patient in need of treatment, 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 combining with at least one pharmaceutical ingredient.

[0166] Statement 50. The present disclosure provides a method of delivering at least one medicinal ingredient to a patient in need of the treatment of any of statements 49, wherein the medicinal ingredient is water soluble.

[0167] Description 51. The present disclosure provides a method for delivering at least one medicinal ingredient to a patient in need of the treatment of any of descriptions 49-50, wherein the medicinal ingredient is oil-soluble.

[0168] Description 52. The present disclosure provides a method for delivering at least one medicinal ingredient to a patient in need of the treatment of any of descriptions 49-51, wherein the at least one medicinal ingredient is an antibiotic, an antiviral, an anti-inflammatory or an anti-glaucoma agent.

[0169] Description 53. The present disclosure provides a method for delivering at least one pharmaceutical ingredient to a patient in need of the treatment of any of descriptions 49 to 52, wherein the at least one pharmaceutical ingredient is selected from the group consisting of adenosine diphosphate ribose, antazoline, apraclonidine, apraclonidine, atropine, azelastine, bepotastine, ethamethasone, betaxolol, betaxolol, bimatoprost, brimonidine, brinzolamide, bromfenac, bromfenac, cardiolipin peroxidation inhibitors, carteolol, cetrimide, chloramphenicol ... Muphenicol, ciprofloxacin, cyclosporine, dexamethasone, diclofenac, dorzolamide, emedastine, epinastine, flurbiprofen, framycetin sulfate, gentamicin, gramicidin, witch hazel water, homatropine, hyaluronic acid, ketotifen fumarate, lacritin / lacritin protein fragment, latanoprost, levobunolol, levofloxacin, lodoxamide droteprednol, lymphocyte function-associated antigen 1 (LFA-1) antagonist, modified 19 kDa TNF receptors, moxifloxacin, naphazoline, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonists, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, reactive aldehyde species inhibitors, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thiomersal, timolol, tobramycin, trafluprost, travoprost, ketorolac trometamol, trometamol, xylometazoline, or any combination thereof.

[0170] Description 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; ii) an oil phase comprising at least one mineral oil, and optionally at least one wax ester; Including, At least one pharmaceutical ingredient remains in the ophthalmic suspension vehicle and in therapeutic contact with the eye for at least two hours after administration to the eye.

[0171] Statement 55. The present disclosure provides an ophthalmic suspension vehicle for delivering at least one medicinal ingredient to a patient in need of the treatment of any of statements 54, wherein the at least one medicinal ingredient is water-soluble or oil-soluble.

[0172] Description 56. The present disclosure provides an ophthalmic suspension vehicle for delivering at least one medicinal ingredient to a patient in need of the treatment of descriptions 54-55, wherein the at least one medicinal ingredient is an antibiotic, an antiviral, an anti-inflammatory or an anti-glaucoma agent.

[0173] Description 57. The present disclosure relates to a method for treating a pulmonary artery disease, the method comprising administering to a patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition comprising administering to the patient a pharmaceutical composition xamethasone, diclofenac, dorzolamide, emedastine, epinastine, epinastine, flurbiprofen, framycetin sulfate, gentamicin, gramicidin, witch hazel water, homatropine, hyaluronic acid, ketotifen fumarate, lacritin / lacritin protein fragment, latanoprost, levobunolol, levofloxacin, lodoxamide droteprednol, lymphocyte function-associated antigen 1 (LFA-1) antagonist, modified 19 kDa 57. An ophthalmic suspension vehicle for delivery of at least one pharmaceutical ingredient according to claims 54 to 56, selected from the group consisting of TNF receptors, moxifloxacin, naphazoline, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonists, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, reactive aldehyde species inhibitors, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thiomersal, timolol, tobramycin, trafluprost, travoprost, ketorolac trometamol, trometamol, xylometazoline, or any combination thereof.

[0174] Description 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: In the patient's eyes, 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; ii) an oil phase comprising at least one mineral oil, and optionally at least one wax ester; an ophthalmic suspension vehicle comprising b) at least one pharmaceutical ingredient, at least one pharmaceutical ingredient that remains in therapeutic contact with the eye for at least two hours after administration to the eye, within the ophthalmic vehicle; The method includes administering an ophthalmic suspension comprising:

[0175] Statement 59. The present disclosure provides a method for delivering at least one pharmaceutical ingredient of statement 58, wherein the at least one pharmaceutical ingredient is maintained in an ophthalmic vehicle in therapeutic contact with the eye for up to six hours after administration to the eye.

[0176] Statement 60. The present disclosure provides a method for delivering at least one pharmaceutical ingredient of statements 58-59, wherein the at least one pharmaceutical ingredient is maintained within the ophthalmic suspension vehicle and in therapeutic contact with the eye for at least 6 hours after administration to the eye.

[0177] Statement 61. The present disclosure provides a method for delivering at least one pharmaceutical ingredient of 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% by weight and an anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 to about 0.55% by weight.

[0178] Statement 62. The present disclosure provides a method for delivering at least one pharmaceutical ingredient according to statements 58-61, wherein the oil phase comprises at least one oil comprising a mixture of light mineral oil and heavy mineral oil.

[0179] Item 63. The present disclosure provides a method for delivering at least one pharmaceutical ingredient of items 58 to 62, wherein the light mineral oil has a viscosity of about 3.0 mm at 40°C. 2 s ‐1 ~Approx. 34.4mm 2 s ‐1 The heavy mineral oil has a kinematic viscosity of about 34.5 mm at 40° C. 2 s ‐1 ~about 150mm 2 s ‐1 The kinematic viscosity of

[0180] Statement 64. The present disclosure provides a method for delivering at least one pharmaceutical ingredient of statements 58-63, wherein either the oil phase or the aqueous phase comprises at least one wax ester present in a concentration of about 0.8% to about 1.2% by weight.

[0181] Statement 65. The present disclosure provides a method for delivering at least one medicinal ingredient of statements 58-64, wherein the at least one wax ester is natural or synthetic beeswax.

[0182] Statement 66. The present disclosure provides a method for delivering at least one pharmaceutical ingredient according to statements 58-65, wherein the ophthalmic suspension exhibits an average particle size of at least about 2.0 microns to about 20.0 microns.

[0183] Statement 67. The present disclosure provides a method for delivering at least one pharmaceutical ingredient of statements 58-66, wherein the ophthalmic suspension exhibits a mean particle size distribution of about 5.0 microns to about 15.0 microns.

[0184] Statement 68. The present disclosure provides a method for delivering at least one pharmaceutical ingredient of statements 58-67, wherein the at least one pharmaceutical ingredient is soluble in the aqueous phase.

[0185] Statement 69. The present disclosure provides a method for delivering at least one pharmaceutical ingredient of statements 58 to 68, wherein the at least one pharmaceutical ingredient is soluble in the oil phase.

[0186] Statement 70. The present disclosure provides a method for delivering at least one pharmaceutical ingredient of statements 58-69, wherein the at least one pharmaceutical ingredient is selected from the group consisting of an antibiotic, an antiviral agent, an anti-inflammatory agent, an anti-allergic agent, an anti-glaucoma agent, a dry eye lubricant, and an ocular gland secretion enhancer.

[0187] Description 71. The present disclosure relates to a method for treating a pulmonary artery disease, the method comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition comprising administering to a patient a pharmaceutical composition Dolocannabinol, dexamethasone, diclofenac, dorzolamide, emedastine, epinastine, flurbiprofen, framycetin sulfate, gentamicin, gramicidin, witch hazel water, homatropine, hyaluronic acid, ketotifen fumarate, lacritin / lacritin protein fragment, latanoprost, levobunolol, levofloxacin, lodoxamide droteprednol, lymphocyte function-associated antigen 1 (LFA-1) antagonists, modified 19 kDa The present invention provides a method for delivering at least one pharmaceutical ingredient of claims 58 to 70, which is selected from the group consisting of TNF receptors, moxifloxacin, naphazoline, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonists, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, reactive aldehyde species inhibitors, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thiomersal, timolol, tobramycin, trafluprost, travoprost, ketorolac trometamol, trometamol, and xylometazoline.

[0188] Description 72. An ophthalmic suspension for delivering at least one pharmaceutical ingredient to a patient in need of treatment, 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; ii) an oil phase comprising at least one mineral oil, and optionally at least one wax ester; an ophthalmic suspension vehicle comprising b) at least one pharmaceutical ingredient; Including, The ophthalmic suspension vehicle has a mean particle size of at least about 2.0 microns.

[0189] Statement 73. The present disclosure provides the ophthalmic suspension of statement 72, wherein at least one pharmaceutical ingredient is soluble in the aqueous phase.

[0190] Description 74. The present disclosure provides an ophthalmic suspension according to descriptions 72-73, wherein at least one pharmaceutical ingredient is soluble in the oil phase.

[0191] Statement 75. The present disclosure provides the ophthalmic suspension of statements 72-74, wherein the at least one pharmaceutical ingredient is selected from the group consisting of an antibiotic, an antiviral agent, an anti-inflammatory agent, an anti-allergic agent, an anti-glaucoma agent, a dry eye lubricant, and an ocular gland secretion enhancer.

[0192] Statement 76. The present disclosure provides an ophthalmic suspension according to statements 72 to 75, having a negative zeta potential of about -60 mV to about -110 mV.

[0193] Description 77. An ophthalmic suspension vehicle for delivering at least one pharmaceutical ingredient to a patient in need thereof, comprising: a wax dispersion comprising natural beeswax particles, an anionic polar surfactant, and water; Sodium hyaluronate, an oil-in-water emulsion comprising oil and water; Optionally, at least one preservative selected from the group consisting of polyhexamethylene biguanide, stabilized oxychloro complexes, and polyquaternium-1; It consists of: Where: (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 to about 6.25 weight percent; (ii) the anionic polar surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 to about 0.45% by weight and anionic polar dimyristoylphosphatidylglycerol at a concentration of about 0.35 to about 0.50% by weight; (iii) 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; The vehicle of the ophthalmic suspension is (i) upon contact with the eye, it forms a metastable emulsion that separates into an oil phase and an aqueous phase; (ii) providing a residence time on the eye of at least 2 hours; (iii) formulated as a free-flowing liquid at room temperature; (iv) an osmolality of about 230 mOsmol / kg to about 260 mOsmol / kg; and (v) having a pH of about 6.5 to about 7.8.

[0194] Statement 78. The present disclosure provides the ophthalmic suspension vehicle of statement 77, wherein the beeswax is present in a concentration of about 1.0% by weight.

[0195] Description 79. The present disclosure provides an ophthalmic suspension vehicle according to descriptions 77-78, wherein the beeswax is Cera Alba or Cera Flava.

[0196] Description 80. The present disclosure provides an ophthalmic suspension vehicle according to any one of claims 77 to 79, packaged in a sterile, single-use container.

[0197] Description 81. The present disclosure provides an ophthalmic suspension vehicle of any one of descriptions 77 to 80 packaged in a sterile multi-dose container.

[0198] Description 82. The present disclosure provides a final pharmaceutical product comprising the ophthalmic suspension vehicle of description 77 and a predetermined amount of at least one pharmaceutical ingredient.

[0199] Statement 83. The present disclosure provides a final pharmaceutical product comprising an ophthalmic suspension vehicle according to statement 82, wherein the predetermined amount of at least one pharmaceutical ingredient is a therapeutically effective dose.

[0200] Statement 84. The present disclosure provides a final pharmaceutical product comprising an ophthalmic suspension vehicle according to statement 82, wherein the predetermined amount of at least one pharmaceutical ingredient is a sub-therapeutically effective dose.

Claims

1. 1. A method for delivering a predetermined amount of at least one pharmaceutical ingredient to a patient in need of treatment, the method comprising: 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; ii) an oil phase comprising at least one mineral oil, and optionally at least one wax ester; an ophthalmic suspension vehicle comprising: b) at least one pharmaceutical ingredient; and Including, The at least one pharmaceutical ingredient is maintained within an ophthalmic vehicle and is in therapeutic contact with the eye for at least two hours after administration to the eye.

2. 10. The method of claim 1, wherein the at least one pharmaceutical ingredient is maintained in an ophthalmic suspension vehicle and is in therapeutic contact with the eye for up to six hours after administration to the eye.

3. 10. The method of claim 1, 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.

4. 10. The method of claim 1, wherein the anionic polar surfactant comprises a mixture of a polysorbate nonionic surfactant at a concentration of about 0.35 to about 0.45% by weight and an anionic polar dimyristoyl phosphatidylglycerol at a concentration of about 0.35 to about 0.55% by weight.

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

6. The light mineral oil has a viscosity of about 3.0 mm at 40° C. 2 s ‐1 Approximately 34.4 mm 2 s ‐1 and the heavy mineral oil has a kinematic viscosity of about 34.5 mm at 40° C. 2 s ‐1 About 150 mm from 2 s ‐1 The method of claim 5, wherein the viscosity of the mixture is 100% or less.

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

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

9. 10. 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. 10. The method of claim 1, wherein the ophthalmic suspension exhibits a mean 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. 10. The method of claim 1, wherein the at least one pharmaceutical ingredient is selected from the group consisting of antibiotics, antivirals, anti-inflammatories, anti-allergy agents, anti-glaucoma agents, dry eye lubricants, and ocular gland secretion enhancers.

14. At least one pharmaceutical ingredient is adenosine diphosphate ribose, antazoline, apraclonidine, atropine, azelastine, bepotastine, ethamethasone, betaxolol, bimatoprost, brimonidine, brinzolamide, bromfenac, cardiolipin peroxidation inhibitors, carteolol, cetrimide, chloramphenicol, ciprofloxacin, cyclosporine, cannabidiol, tetrahydrocannabin ... Binol, dexamethasone, diclofenac, dorzolamide, emedastine, epinastine, epinastine, flurbiprofen, framycetin sulfate, gentamicin, gramicidin, witch hazel water, homatropine, hyaluronic acid, ketotifen fumarate, lacritin / lacritin protein fragment, latanoprost, levobunolol, levofloxacin, lodoxamide droteprednol, lymphocyte function-associated antigen 1 (LFA-1) antagonists, modified 19 kDa 2. The method of claim 1, wherein the agent is selected from the group consisting of TNF receptors, moxifloxacin, naphazoline, nedocromil maleate, nicotinic acetylcholine receptor (nAChR) agonists, ofloxacin, olopatadine, pegaptanib, perfluorohexyl octane, pheniramine, pilocarpine, pranoprofen, prednisolone, ranibizumab, reactive aldehyde species inhibitors, recombinant lubricin, rimexolone, sodium, tetracaine, tetrahydrozoline, thiomersal, timolol, tobramycin, trafluprost, travoprost, ketorolac trometamol, trometamol, N-[[2-(6-benzofuranylcarbonyl)-5,7-dichloro-1,2,3,4-tetrahydro-6-isoquinolinyl]carbonyl]-3-(methylsulfonyl)-L-phenylalanine, and xylometazoline.

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

16. The method of claim 1 , wherein the predetermined amount is a sub-therapeutically effective amount.

17. 1. An ophthalmic suspension for delivery to a patient in need thereof at least one pharmaceutical ingredient, 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; ii) an oil phase comprising at least one mineral oil, and optionally at least one wax ester; an ophthalmic suspension vehicle comprising: b) at least one pharmaceutical ingredient; and Including, An ophthalmic suspension, wherein the ophthalmic suspension exhibits an average particle size of at least about 2.0 microns.

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

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

20. 20. The ophthalmic suspension of claim 17, wherein the at least one pharmaceutical ingredient is selected from the group consisting of antibiotics, antivirals, anti-inflammatory agents, anti-allergy agents, anti-glaucoma agents, dry eye lubricants and ocular gland secretion enhancers.

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

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

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

24. 23. The ophthalmic suspension of claim 22, wherein the predetermined amount is a sub-therapeutically effective amount.

25. An ophthalmic suspension vehicle for delivering at least one pharmaceutical ingredient to a patient in need thereof, the ophthalmic suspension vehicle comprising: a wax dispersion comprising natural beeswax particles, an anionic polar surfactant, and water; Sodium hyaluronate, and oil-in-water emulsions comprising oil and water; Optionally, at least one preservative selected from the group consisting of polyhexamethylene biguanide, stabilized oxychloro complexes, and polyquaternium-1; where: (i) the oil is a mixture of a lighter molecular weight mineral oil and a heavier molecular weight mineral oil and is present at a concentration of about 4.0 to about 6.25 weight percent; and (ii) the anionic polar surfactant is a mixture of polysorbate 80 at a concentration of about 0.35 to about 0.45% by weight and anionic polar dimyristoyl phosphatidylglycerol at a concentration of about 0.35 to about 0.50% by weight; 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 comprises: (I) upon contact with the eye, it forms a metastable emulsion that separates into an oil phase and an aqueous phase; (II) providing a residence time on the eye of at least 2 hours; (III) formulated as a free-flowing liquid at room temperature; (IV) an osmolality of about 230 mOsmol / kg to about 260 mOsmol / kg; and (V) An ophthalmic suspension vehicle having a pH of about 6.5 to about 7.

8.

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

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

28. 27. The finished pharmaceutical product of claim 26, wherein the predetermined amount is a sub-therapeutically effective amount.

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