Micronized lipids

Abstract

To provide effective treatments for dry eye and effective delivery systems for those treatments. [Solution] A lipid particle composition is provided, characterized in that it comprises solid nonpolar lipid particles containing an active lipid agent, the solid nonpolar lipid particles having an average particle size of less than 50 microns and stably suspended in an aqueous buffer vehicle suitable for topical administration.

Description

Technical Field

[0001] The present invention relates to a drug delivery vehicle comprising micronized particles containing an active lipid agent, and particularly to micronized lipid particles containing ether lipids such as sn-1-O-eicosanyl-sn-2-palmitoyl-glycerol and its isomers.

Background Art

[0002] Dry eye syndrome is caused by a chronic deficiency of sufficient lubrication and moisture on the surface of the eye. The consequences of dry eye range from minor but constantly irritating to the eye, to severe inflammation, and even scarring of the front of the eye. Evaporative dry eye, the major form of dry eye, is associated with meibomian gland dysfunction, and deficiencies and instabilities in the tear lipid layer can lead to, among other sequelae, increased evaporation and instability of the tear film. Thus, evaporative dry eye, meibomian gland dysfunction, and the resulting instability of the tear film contribute to both insufficient lubrication and insufficient moisture on the ocular surface in dry eye. For a review, see Chadya et al., Meibomian gland disease: the role of gland dysfunction in dry eye disease, Ophthalmology.2017 Nov; 124(11 Suppl):S20-S26, which is incorporated herein by reference in its entirety.

[0003] In addition to being called dry eye syndrome, dry eye disease, or simply "dry eye," there are alternative medical terms used to describe dry eye. Keratoconjunctivitis sicca refers to dryness and inflammation of the cornea. Keratoconjunctivitis refers to dry eye that affects both the cornea and the conjunctiva.

[0004] Dry eye syndrome is one of the most common eye conditions worldwide and a major reason for visiting an ophthalmologist. In a review published in the Journal of Global Health, researchers reported that the prevalence of dry eye ranges from 5% to 50% in various populations around the world. Risk factors for dry eye syndrome include older age, female gender, and computer use. Symptoms of dry eye syndrome include burning, itching, eye pain, eye heaviness, eye fatigue, dryness, redness, photophobia, and blurred vision. Clinical signs of dry eye include decreased tear production as measured by the Schirmer tear test, defects in corneal epithelial integrity as measured by corneal vital staining (e.g., fluorescein), and particular instability of the tear film, including instability of the tear lipid layer as measured by a decreased tear film break time (TBUT).

[0005] Tears are composed of aqueous, mucinous, and lipid components. With each blink, the aqueous and lipid components mix closely together and self-sort into the aqueous layer and the lipid layer on the outside of the tear film. Within the lipid layer, polar and nonpolar lipids self-sort; polar lipids form a monolayer at the aqueous interface, while nonpolar lipids form a thick outer layer of the tear lipid layer that directly interacts with the air. The nonpolar outer layer of the tear film lipid layer (TFLL) can be 5 to 50 molecules thick. Having a sufficient and stable layer of tears on the surface of the eye is essential for keeping the eyes healthy and comfortable and for good vision. The tear film lubricates the surface of the eye and washes away dust, debris, and microorganisms that can damage the cornea and cause eye inflammation and infection. As mentioned above, a normal tear film is composed of three important components: oily components (lipids), aqueous components (aqueous humor), and mucinous components (mucin). Each component of tears plays an important role. For example, tear lipids help prevent the aqueous layer of the tear film from evaporating too quickly, thus increasing its lubricity, while mucins (soluble and cell-associated) help fix and spread tears to the living surface of the corneal epithelium. The aqueous component is the thickest layer of the pre-corneal tear film and contains various proteins, including immunoglobulins and lysozyme, which play a role in preventing microbial colonization. The tear film is described in Yanez-Soto et al., Interfacial phenomena and the ocular surface, Ocul Surf. 2014 Jul;12(3):178-201, which is incorporated herein by reference in its entirety.

[0006] Each tear component is produced by different glands on or near the eyeball. The oily component is produced by the meibomian glands in the eyelids, or by the Hardarian glands in species that have them (e.g., rabbits). The aqueous humor component is secreted from the lacrimal gland located on the inner side of the outer upper eyelid (in humans). Many vertebrates also have accessory lacrimal glands (e.g., the accessory lacrimal gland attached to the third eyelid in dogs). The soluble mucin component is produced by goblet cells in the conjunctiva that covers the white of the eye (sclera). If there is a problem with any of these sources of tear components, the tear film can become unstable, potentially leading to dry eye.

[0007] What is needed in this field of technology are effective treatments for dry eye and effective delivery systems for those treatments. [Overview of the Initiative]

[0008] The present invention relates to a drug delivery vehicle comprising micronized particles containing an active lipid agent, and more particularly to micronized lipid particles containing ether lipids such as sn-1-O-eicosanyl-sn-2-palmitoyl-glycerol and its isomers, analogs, and congeners, as both the drug delivery vehicle and the active lipid agent.

[0009] In some preferred embodiments, the present invention provides a drug delivery vehicle comprising crystalline and amorphous solid micronized lipid particles having an average particle size of less than 100 microns, wherein the particles contain an active drug, and the drug delivery vehicle is selected from the group consisting of therapeutic compositions, physiologically compatible carriers, and medical insertion devices.

[0010] In a first embodiment, the present invention provides a lipid particle composition comprising solid nonpolar lipid particles containing an active lipid agent, the solid nonpolar lipid particles having an average particle size of less than 50 microns and stably suspended in an aqueous buffer vehicle suitable for topical administration.

[0011] In some preferred embodiments, the solid nonpolar lipid particles have a melting point of less than 80°C. In some preferred embodiments, the solid nonpolar lipid particles have a melting point of 20 to 80°C. In some preferred embodiments, the solid nonpolar lipid particles have a melting point of 30 to 60°C. In some preferred embodiments, the solid nonpolar lipid particles have an average particle size of less than 20 microns. In some preferred embodiments, the solid nonpolar lipid particles have an average particle size of less than 10 microns.

[0012] In some preferred embodiments, the active lipid agent is a nonpolar ether lipid.

[0013] In some preferred embodiments, the solid nonpolar lipid particles comprise an active lipid agent selected from the group consisting of:

[0014]

Chemical formula

[0015] where R1 is unsubstituted C6-C30 alkyl or alkenyl; R2 is unsubstituted C5-C29 alkyl or alkenyl; and R3 is hydrogen (i.e., H);

[0016]

Chemical formula

[0017] where R1 is hydrogen (i.e., H); R2 is unsubstituted C5-C29 alkyl or alkenyl; and R3 is unsubstituted C6-C30 alkyl or alkenyl; and

[0018]

Chemical formula

[0019] where R1 is unsubstituted C6-C30 alkyl or alkenyl; R2 is unsubstituted C5-C29 alkyl or alkenyl; and R3 is hydrogen (i.e., H).

[0020] In some preferred embodiments, the solid nonpolar lipid particles comprise an active lipid agent selected from the group consisting of:

[0021]

Chemical formula

[0022] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29 alkyl or alkenyl;

[0023] [ka]

[0024] Here R1 is an unsubstituted C5-C29 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C6-C30 alkyl or alkenyl; and

[0025] [ka]

[0026] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29 alkyl or alkenyl.

[0027] In some preferred embodiments, the solid nonpolar lipid particles contain an active lipid agent selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG), sn-1-O-eicosanyl-2-palmitoyl-glycerol, sn-2-palmitoyl-3-O-eicosanyl-glycerol, 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), sn-1-O-eicosanyl-3-palmitoyl-glycerol, sn-1-palmitoyl-3-O-eicosanyl-glycerol, and mixtures thereof. In some preferred embodiments, the solid nonpolar lipid particles comprise an active lipid agent selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) and mixtures thereof.

[0028] In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 95% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 98% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 99% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0029] In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 50% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 50% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing 50% (mol%) or less of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and more than 50% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0030] In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 5% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 2% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 1% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0031] In some preferred embodiments, the solid nonpolar lipid particles further comprise one or more additional lipids selected from the group consisting of nonpolar mono-, di-, or tri-glycerides, wax esters including cholesterol esters, sterols, free fatty acids, and combinations thereof. In some preferred embodiments, the aqueous buffered vehicle comprises phosphate-buffered saline (PBS), 3% or less (w / w of the vehicle) of polysorbate 80, and 0.3% or less (w / w of the vehicle) of xanthan gum, having a pH of 6.5 to 8.0 and an osmotic pressure of 260 to 320 mOsm / L.

[0032] In some preferred embodiments, the suspended particles are stable against phase separation from the suspension for 6 months at room temperature. In some preferred embodiments, the suspended particles are chemically stable against <5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 6 months. In some preferred embodiments, the suspended particles are stable against phase separation from the suspension for 24 months at room temperature. In some preferred embodiments, the suspended particles are chemically stable against <5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 24 months.

[0033] In some preferred embodiments, the composition is sterile. In some preferred embodiments, the composition contains a preservative. In some preferred embodiments, the suspension does not contain a preservative. In some preferred embodiments, the aqueous buffered vehicle is an ophthalmologically acceptable carrier. In some preferred embodiments, the aqueous buffered vehicle further comprises agents selected from the group consisting of buffers, tonics, wetting agents, thickeners / viscosities, density modifiers and combinations thereof.

[0034] In some preferred embodiments, the active lipid agent in solid nonpolar lipid particles is released from the solid nonpolar lipid particles as individual molecules for a certain period after administration as eye drops. In some preferred embodiments, the individual molecules are released for a period of 1 to 24 hours. In some preferred embodiments, the suspension is supplied in a dropper dispenser.

[0035] In some preferred embodiments, the present invention provides a method for treating an ocular disease or disorder selected from the group consisting of evaporative dry eye, meibomian gland dysfunction and associated symptoms, clinical signs or conditions, an unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and associated symptoms or clinical signs, in an animal or human subject requiring such treatment, comprising topically administering a lipid particle composition such as the one described above, comprising an effective amount of an active lipid agent, to the eye of the subject. In some preferred embodiments, the subject requiring treatment has a tear film break time (TBUT) below the normal clinical range of a normal healthy population, for example, in the United States or another country. In some preferred embodiments, the method provides improvement in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, dryness of the eye, significant conjunctival or corneal staining, and Schirmer tear test (e.g., compared to a control or as reported by the patient).

[0036] In some preferred embodiments, the present invention provides lipid particle compositions for therapeutic use in animal or human subjects requiring such treatment for eye diseases or disorders selected from the group consisting of dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and related symptoms, clinical signs or conditions, unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and related symptoms or clinical signs. In some preferred embodiments, administration of the composition results in improvement (e.g., compared to a control or reported by the patient) in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, dryness of the eye, significant conjunctival or corneal staining, and Schirmer tear test.

[0037] In a second embodiment, the present invention provides a drug delivery vehicle comprising solid nonpolar lipid particles having an average particle size of less than 100 microns, preferably less than 50 microns, wherein the particles comprise an active agent other than the lipids forming the solid nonpolar lipid particles (the lipids in the particles, for example, the ether lipid described herein may be referred to as the first active agent, and the active agent as the second active agent).

[0038] In some preferred embodiments, the solid nonpolar lipid particles have a melting point of less than 80°C. In some preferred embodiments, the solid nonpolar lipid particles have a melting point of 20 to 80°C. In some preferred embodiments, the solid nonpolar lipid particles have a melting point of 30 to 60°C. In some preferred embodiments, the solid nonpolar lipid particles have an average particle size of less than 20 microns. In some preferred embodiments, the solid nonpolar lipid particles have an average particle size of less than 10 microns.

[0039] In another preferred embodiment, the solid nonpolar lipid particles include ether lipids selected from the group consisting of:

[0040] [ka]

[0041] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is an unsubstituted C5-C29 alkyl or alkenyl; and R3 is hydrogen (i.e., H);

[0042] [ka]

[0043] Here R1 is hydrogen (i.e., H); R2 is an unsubstituted C5-C29 alkyl or alkenyl; and R3 is an unsubstituted C6-C30 alkyl or alkenyl; and

[0044] [ka]

[0045] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is an unsubstituted C5-C29 alkyl or alkenyl; and R3 is hydrogen (i.e., H).

[0046] In some preferred embodiments, the solid nonpolar lipid particles include ether lipids selected from the group consisting of:

[0047] [ka]

[0048] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29 alkyl or alkenyl;

[0049] [ka]

[0050] Here R1 is an unsubstituted C5-C29 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C6-C30 alkyl or alkenyl; and

[0051] [ka]

[0052] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29 alkyl or alkenyl.

[0053] In some preferred embodiments, the solid nonpolar lipid particles include ether lipids selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG), sn-1-O-eicosanyl-2-palmitoyl-glycerol, sn-2-palmitoyl-3-O-eicosanyl-glycerol, 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), sn-1-O-eicosanyl-3-palmitoyl-glycerol, sn-1-palmitoyl-3-O-eicosanyl-glycerol, and mixtures thereof. In some preferred embodiments, the solid nonpolar lipid particles comprise ether lipids selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) and mixtures thereof.

[0054] In some preferred embodiments, mixtures of the ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), and these mixtures are characterized by containing more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 95% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 98% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 99% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0055] In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 5% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 2% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 1% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0056] In some preferred embodiments, the solid nonpolar lipid particles further comprise one or more additional lipids selected from the group consisting of nonpolar mono-, di-, or tri-glycerides, wax esters including cholesterol esters, sterols, free fatty acids, and combinations thereof.

[0057] In some preferred embodiments, the active agent is selected from the group consisting of over-the-counter (OTC) or prescription topical ophthalmic drugs, OTC or prescription topical ophthalmic drugs for the treatment of dry eye, NMDA antagonists, antibacterial agents, antihistamines, decongestants, anti-inflammatory agents, antiparasitic agents, myotics, sympathomimetic agents, anticholinergics, adrenergic agents, antiviral agents, topical anesthetics, antifungal agents, anti-amoebic agents, trichomonazoles, analgesics, mydriatics, antiglaucoma agents, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic agents used as adjuvants in surgery, chelating agents, anticancer agents, antihypertensive agents, muscle relaxants, diagnostic agents, adrenergic anesthetics, β-blockers, α2-agonists, cycloplengic, prostaglandins, and combinations thereof.

[0058] In some preferred embodiments, the solid nonpolar lipid particles are formulated as an aqueous suspension in a physiologically acceptable carrier. In some preferred embodiments, the liquid composition is a suspension of solid micronized lipid particles in water containing phosphate-buffered saline (PBS), 3% or less (w / w of vehicle) of polysorbate 80, and 0.3% or less (w / w of vehicle) of xanthan gum, having a pH of 6.5 to 8.0 and an osmotic pressure of 260 to 320 mOsm / L.

[0059] In some preferred embodiments, the suspension is stable against phase separation of solid nonpolar lipid particles in the suspension for 6 months at room temperature. In some preferred embodiments, the suspension is chemically stable against <5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 6 months. In some preferred embodiments, the suspension is stable against phase separation of solid nonpolar lipid particles in the suspension for 24 months at room temperature. In some preferred embodiments, the suspension is chemically stable against <5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 24 months.

[0060] In some preferred embodiments, the suspension is sterile. In some preferred embodiments, the suspension contains a preservative. In some preferred embodiments, the suspension does not contain a preservative. In some preferred embodiments, the physiologically acceptable carrier is an ophthalmologically acceptable carrier. In some preferred embodiments, the ophthalmologically acceptable carrier contains an agent selected from the group consisting of buffers, tonics, wetting agents, thickeners / viscosities, density modifiers and combinations thereof.

[0061] In some preferred embodiments, the active agent is released from solid nonpolar lipid particles as individual molecules of the active agent for a certain period after administration as eye drops. In some preferred embodiments, the individual molecules are released for a period of 1 to 24 hours.

[0062] In some preferred embodiments, the suspension is provided in a dropper dispenser.

[0063] In some preferred embodiments, the drug delivery vehicle is a medical implant. In some preferred embodiments, the medical implant is formed from a physiologically acceptable material. In some preferred embodiments, the physiologically acceptable material is a polymer. In some preferred embodiments, the physiologically acceptable material is selected from the group consisting of hydroxypropyl cellulose, hydrogels, polymethyl methacrylate, and silicone acrylate. In some preferred embodiments, the medical implant is selected from the group consisting of puncture plugs, contact lenses, and ophthalmic implants. In some preferred embodiments, the medical implant is rechargeable. In some preferred embodiments, the medical implant is single-use. In some preferred embodiments, the medical implant conforms to a mucosal surface. In some preferred embodiments, the mucosal surface is selected from the group consisting of the ocular mucosa, vaginal mucosa, nasal mucosa, oral-pharyngeal mucosa, oral mucosa, and rectal mucosa.

[0064] In some preferred embodiments, the present invention provides a method for delivering an active drug to a target requiring it, comprising topically administering a drug delivery vehicle as described above to the target. In some preferred embodiments, the drug delivery vehicle is administered to the mucosal surface of the target. In some preferred embodiments, the mucosal surface is selected from the group consisting of the ocular mucosa, vaginal mucosa, fallopian tube mucosa, respiratory mucosa, nasal mucosa, oral / pharyngeal mucosa, oral mucosa, rectal mucosa, digestive mucosa, and esophageal mucosa. In some preferred embodiments, the drug delivery vehicle is applied or implanted beneath the mucosal surface. In some preferred embodiments, the mucosal surface is the ocular mucosa, and the drug delivery vehicle is implanted or applied beneath the conjunctiva or Tenon's capsule. In some preferred embodiments, the drug delivery vehicle is applied to the ocular mucosa by a delivery route selected from the group consisting of retrobulbar, intracavitary, intravitreous, suprachoroidal, and subretinal delivery routes.

[0065] In some preferred embodiments, the present invention provides a method for treating an ocular disease or disorder selected from the group consisting of evaporative dry eye, meibomian gland dysfunction and associated symptoms, clinical signs or conditions, an unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and associated symptoms or clinical signs, in an animal or human subject requiring such treatment, comprising topically administering a drug delivery vehicle such as the one described above, comprising an effective amount of an active lipid agent, to the eye of the subject. In some preferred embodiments, the subject requiring treatment has a tear film break time (TBUT) below the normal clinical range of a normal healthy population, for example, in the United States or another country. In some preferred embodiments, the method provides improvement in one or more symptoms or measurements selected from the group consisting of TBUT, ocular comfort, ocular dryness, significant conjunctival or corneal staining, and Schirmer tear test (e.g., compared to a control or as reported by the patient).

[0066] In some preferred embodiments, the present invention provides a drug delivery vehicle for use in the treatment of eye diseases or disorders selected from the group consisting of dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and related symptoms, clinical signs or conditions, unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and related symptoms or clinical signs, in animals or human subjects requiring such treatment. In some preferred embodiments, administration of the composition results in improvement (e.g., compared to a control or reported by the patient) in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, dryness of the eye, significant conjunctival or corneal staining, and Schirmer tear test. In yet another preferred embodiment, the present invention provides lipid particle compositions or drug delivery vehicles as described above for use in the treatment of animals or human subjects requiring such treatment, which can be identified by a tear film break time (TBUT) below the clinically recognized normal range in their species or humans.

[0067] In a third embodiment, the present invention provides a lipid particle composition comprising an active lipid agent and solid nonpolar lipid particles having an average particle size of less than 50 microns.

[0068] In some preferred embodiments, the solid nonpolar lipid particles have a melting point of less than 80°C. In some preferred embodiments, the solid nonpolar lipid particles have a melting point of 20 to 80°C. In some preferred embodiments, the solid nonpolar lipid particles have a melting point of 30 to 60°C. In some preferred embodiments, the solid nonpolar lipid particles have an average particle size of less than 20 microns. In some preferred embodiments, the solid nonpolar lipid particles have an average particle size of less than 10 microns.

[0069] In some preferred embodiments, the active lipid agent is a nonpolar ether lipid.

[0070] In some preferred embodiments, the solid nonpolar lipid particles comprise an active lipid agent selected from the group consisting of:

[0071] [ka]

[0072] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is an unsubstituted C5-C29 alkyl or alkenyl; and R3 is hydrogen (i.e., H);

[0073] [ka]

[0074] Here R1 is hydrogen (i.e., H); R2 is an unsubstituted C5-C29 alkyl or alkenyl; and R3 is an unsubstituted C6-C30 alkyl or alkenyl; and

[0075] [ka]

[0076] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is an unsubstituted C5-C29 alkyl or alkenyl; and R3 is hydrogen (i.e., H).

[0077] In some preferred embodiments, the solid nonpolar lipid particles comprise an active lipid agent selected from the group consisting of:

[0078] [ka]

[0079] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29 alkyl or alkenyl;

[0080] [ka]

[0081] Here R1 is an unsubstituted C5-C29 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C6-C30 alkyl or alkenyl; and

[0082] [ka]

[0083] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29 alkyl or alkenyl.

[0084] In some preferred embodiments, the solid nonpolar lipid particles contain an active lipid agent selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG), sn-1-O-eicosanyl-2-palmitoyl-glycerol, sn-2-palmitoyl-3-O-eicosanyl-glycerol, 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), sn-1-O-eicosanyl-3-palmitoyl-glycerol, sn-1-palmitoyl-3-O-eicosanyl-glycerol, and mixtures thereof. In some preferred embodiments, the solid nonpolar lipid particles comprise an active lipid agent selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) and mixtures thereof.

[0085] In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 95% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 98% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 99% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0086] In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 5% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 2% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 1% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0087] In some preferred embodiments, the solid nonpolar lipid particles further comprise one or more additional lipids selected from the group consisting of nonpolar mono-, di-, or tri-glycerides, wax esters including cholesterol esters, sterols, free fatty acids, and combinations thereof.

[0088] In some preferred embodiments, the solid nonpolar lipid particles are formulated as a suspension.

[0089] In some preferred embodiments, solid nonpolar lipid particles are provided as medical implants. In some preferred embodiments, the medical implants are formed from a physiologically acceptable material. In some preferred embodiments, the physiologically acceptable material is a polymer. In some preferred embodiments, the physiologically acceptable material is selected from the group consisting of hydroxypropyl cellulose, hydrogels, polymethyl methacrylate, and silicone acrylate. In some preferred embodiments, the medical implants are selected from the group consisting of puncture plugs, contact lenses, and ophthalmic implants. In some preferred embodiments, the medical implants are rechargeable. In some preferred embodiments, the medical implants are single-use. In some preferred embodiments, the medical implants conform to mucosal surfaces. In some preferred embodiments, the mucosal surfaces are selected from the group consisting of ocular mucosal surfaces, vaginal mucosal surfaces, nasal mucosal surfaces, oral-pharyngeal mucosal surfaces, oral mucosal surfaces, and rectal mucosal surfaces.

[0090] In some preferred embodiments, the lipid particles may preferably contain a second active agent in addition to a first active agent (i.e., ether lipids). In some preferred embodiments, the active agent is selected from the group consisting of over-the-counter (OTC) or prescription topical ophthalmic drugs, OTC or prescription topical ophthalmic drugs for the treatment of dry eye, NMDA antagonists, antibacterial agents, antihistamines, decongestants, anti-inflammatory agents, antiparasitic agents, myotics, sympathomimetic agents, anticholinergics, adrenergic agents, antiviral agents, topical anesthetics, antifungal agents, anti-amoebic agents, trichomonazoles, analgesics, mydriatics, antiglaucoma agents, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic drugs used as surgical adjuvants, chelating agents, anticancer agents, antihypertensive agents, muscle relaxants, diagnostic agents, adrenergic anesthetics, β-blockers, α2-agonists, cycloplengic, prostaglandins, and combinations thereof.

[0091] In some preferred embodiments, the present invention provides a method for treating a mucosal-related disease or disorder, comprising administering such lipid particle composition to a subject in need thereof. In some preferred embodiments, the disease or disorder is an ocular disease or disorder selected from the group consisting of dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and associated symptoms, clinical signs or conditions, an unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and associated symptoms or clinical signs in an animal or human subject in need of such treatment. In some preferred embodiments, administration of the composition results in improvement (e.g., compared to a control or reported by the patient) in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, dryness of the eye, significant conjunctival or corneal staining, and Schirmer tear test.

[0092] In some preferred embodiments, the present invention provides the use of the above-described lipid particle composition for treating diseases or disorders of the mucous membrane in question. In some preferred embodiments, the disease or disorder is an ocular disease or disorder selected from the group consisting of dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and associated symptoms, clinical signs or conditions, an unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and associated symptoms or clinical signs in an animal or human subject requiring such treatment. In some preferred embodiments, administration of the composition results in improvement (e.g., compared to a control or reported by the patient) in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, dryness of the eye, significant conjunctival or corneal staining, and the Schirmer tear test. [Brief explanation of the drawing]

[0093] [Figure 1] This is a schematic diagram relating to the synthesis of lipids used in embodiments of the present invention. [Figure 2]This graph shows the particle size of the solid micronized lipid particles of the present invention (measured by dynamic light scattering). [Figure 3] This is a photograph of solid, finely powdered particles stably suspended in the presence of xanthan gum excipients at different concentrations. [Figure 4] This provides NMR (nuclear magnetic resonance) spectral analysis of the 1,3-EPRG and 1,2-EPRG isomer content (1.15 mol% 1,3-EPRG) of MCAL-201 after jet milling. [Figure 5] This paper provides NMR (nuclear magnetic resonance) spectral analysis of the 1,3-EPRG and 1,2-EPRG isomer content (0.0991 mol% 1,3-EPRG) of MCAL-201 after storing a solid, finely powdered MCAL-201 suspension at room temperature for 6 weeks. [Figure 6] This document provides a graph showing that administration of the micronized solid lipid particles of the present invention resulted in an extension of TBUT after a single administration in five healthy dogs. [Figure 7] This provides an exemplary structure that identifies the sn-numbering of the carbon atoms in the glycerol skeleton. [Modes for carrying out the invention]

[0094] [Definition] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, domesticated animals (cattle, pigs, etc.), companion animals (dogs, cats, etc.), and rodents (mice, rats, etc.).

[0095] The "administration" or "administration" of a substance, compound, or drug can be carried out using any of the various methods known to those skilled in the art. For example, a compound or drug can be administered topically, ophthalmologically, intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, sublingually, orally (by ingestion), nasally (by inhalation), intraspinously, intracerebrally, and percutaneously (e.g., by absorption through the skin canal). Specific routes of administration to the eye include topical administration to the ocular surface (cornea and / or conjunctiva), subconjunctival administration, sub-Tenon's capsule administration, retrobulbar administration, intracavitary administration, intravitreous administration, suprachoroidal administration, and subretinal administration. Compounds or drugs can also be appropriately introduced by rechargeable or biodegradable polymer devices, or other devices that provide sustained-release, sustained-release, or controlled release of the compound or drug, such as patches and pumps, or by formulations. The polymer material may be a solid, implantable material, or it may be designed to maintain prolonged contact with the ocular surface (see, for example, LACRISERT®, see bausch.com / ecp / our-products / rx-pharmaceuticals / rx-pharmaceuticals / lacrisert on the World Wide Web), or it may be formed or contained in a puncture plug that slowly releases the test substance (see, for example, ois.net / punctal-plugs-for-sustained-delivery / on the World Wide Web) or an O-ring inserted into the conjunctiva (see, for example, https: / / www.aao.org / eye-health / news / new-glaucoma-treatment-ring-shows-promise). Other embodiments relating to therapeutic constructs include, but are not limited to, topical application or injection into and / or around the eyeball of a material that forms a hydrogel whose polymerization is induced by changes in temperature, pH, or ionic composition. Administration can also be carried out, for example, once, multiple times, and / or over a longer period of time. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing the drug.For example, a physician who instructs a patient to self-administer a drug or to have another person administer a drug to them, and / or a physician who provides a patient with a prescription for a drug, is administering a drug to the patient.

[0096] An "active lipid agent" is a lipid that has a therapeutic effect on the mucosal surface. When solid crystalline or amorphous active lipid agents are micronized and suspended in a buffer whose tension, viscosity, and density are adjusted to support a stable suspension of the micronized solid active lipid agent, they can also act as a sustained-release delivery vehicle for monomeric molecules of the active lipid agent.

[0097] The “therapeutically effective amount” or “therapeutic dose” of a drug or medication refers to the amount of the drug or medication administered to a subject that will produce the intended therapeutic effect. Complete therapeutic effect is not necessarily achieved with a single dose, and may only occur after a series of doses. Therefore, a therapeutically effective amount can be administered once, multiple times, daily, weekly, or within other therapeutic timeframes. The exact effective amount required for a subject depends, for example, on the subject's size, health status and age, and the nature and severity of the condition being treated, such as dry eye and / or other eye disorders. Those skilled in the art can easily determine the effective amount for a given situation through routine experimentation.

[0098] In this specification, the term "shelf life" means the period from the date of manufacture of the product until the drug is administered.

[0099] To “treat” a condition or patient means to take measures to obtain a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, relief, improvement, or delay of progression of one or more symptoms associated with deficiencies of the mucosal surface, particularly lipid deficiencies, and neuronal disorders, including neurodegeneration and traumatic brain injury, as well as pain and discomfort. In certain embodiments, treatment may be preventive. Exemplary beneficial clinical outcomes are described herein.

[0100] As used herein, the term chemical formula includes information about the spatial arrangement of atoms and bonds in a chemical substance, but does not necessarily refer to exact isomers, analogs, or congeners.

[0101] "Alkyl" refers to a monovalent linear, branched, or cyclic saturated aliphatic hydrocarbon radical. Preferably, the alkyl group is a linear radical having 1 to 40 carbon atoms. More preferably, it is an alkyl radical having 5 to 31 carbon atoms, most preferably 15 to 23 carbon atoms. Typical alkyl radicals include pentyl, hexyl, tridecanyl, tetradecanyl, nonadecanyl, docosanyl, triacontanyl, and hentriacontanyl. Preferably, this term refers to an acyclic carbon or saturated acyclic carbon chain represented by the formula CnH2n+1 (where n is an integer from 1 to 31).

[0102] "Alkenyl" refers to a monovalent, linear, branched, or cyclic, unsaturated aliphatic hydrocarbon radical having one or more, preferably one, double bonds. Preferably, alkenyl radicals have 2 to 40 carbon atoms. More preferably, they are alkenyl radicals with 6 to 30 carbon atoms, and most preferably 15 to 23 carbon atoms. Typical alkenyl groups include hexenyl, tridecenyl, tetradecenyl, nonadecenyl, dococenyl, triacotenyl, and hentriacotenyl. Preferably, the term refers to an acyclic carbon chain containing a carbon-carbon double bond and represented by the formula CnH2n-1 (where n is an integer from 2 to 40). Preferably, the shape of the alkenyl bond is the cis or Z configuration, which is commonly found in cell membrane lipids.

[0103] "Alkylene" refers to a divalent, linear, branched, or cyclic saturated aliphatic hydrocarbon radical. Preferably, the alkylene group has 1 to 12 carbon atoms. The term refers to an acyclic carbon or saturated acyclic carbon chain represented by the formula CnH2n-2 (where n is an integer from 1 to 12). More preferably, a lower alkylene, such as methylene, has 1 to 7 carbon atoms, most preferably 1 to 4 carbon atoms.

[0104] As used herein, the term “aliphatic” means linear or branched alkyl, alkenyl, or alkynyl. It is understood that embodiments of alkenyl or alkynyl require at least two carbon atoms in the aliphatic chain. Aliphatic groups typically contain 1 (or 2) to 30 carbon atoms, for example, 1 (or 2) to 20 carbon atoms.

[0105] Where used herein, the notation for carbon atoms may have the given integer and any intervening integer. For example, the number of carbon atoms in a (C1-C4)-alkyl group is 1, 2, 3, or 4. It should be understood that these designations refer to the total number of atoms in the appropriate group.

[0106] In this specification, “pharmaceutically acceptable salt” or “salt” is used to refer to the drug or compound according to this disclosure, which is a therapeutically active, non-toxic base and an acid salt form of the compound. Acid addition salt forms of compounds that exist in free form as a base can be obtained by treating the free base form with an inorganic acid, for example, a suitable acid such as a hydrohalogen acid such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid; or an organic acid, for example, acetic acid, hydroxyacetic acid, propionic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.

[0107] [Detailed explanation] The present invention relates to a drug delivery vehicle comprising micronized crystals or amorphous solids containing an active lipid agent, and more particularly to crystalline or amorphous solid micronized lipid particles containing ether lipids such as sn-1-O-eicosanyl-sn-2-palmitoyl-glycerol and its isomers.

[0108] This disclosure is intended to show that one or more of the aforementioned aspects and embodiments may be combined with each other and / or with any of the embodiments or features provided below.

[0109] Mucous membranes possess epithelial components with unique surface chemical properties, and the outermost layer of cells has topographic features on the nano- to micron scale in the form of microvilli and microprojections. These topographic features are thought to interact with the membrane in close relation to the cellular components and contribute to the relative stability of the membrane. In diseased states of the ocular surface, these surface topographic features are known to change, and such changes may contribute to the instability of the membrane. Fluid membranes, including but not limited to those associated with tears, saliva, gastrointestinal capsules, eyelids, ocular surface and periorbital tissues, the respiratory tract (nasal cavity, trachea, bronchi, and alveoli) and cervical-vaginal secretions, and the membranes associated with the rest of the female reproductive tract, cover the cellular elements of the mucous membranes of all vertebrate species. Tatematsu et al., Bone Marrow Transplant.2012 Mar;47(3):416-25. doi: 10.1038 / bmt.2011.89.Epub 2011 May 16.

[0110] The secretions covering mucous membranes are secreted from various sources and have components that can be broadly classified into three categories: a glycosaminoglycan (or mucus) layer, an aqueous component containing soluble species such as proteins, sugars, salts, and osmotic solutes, and, in the case of tears, a lipid-containing component. The mucosal membrane originates from cells embedded in the mucosa (or cells proximal to the mucosa) or glandular structures. Water forms the basis of lubrication in the human body, especially at the interface of water with lipids, waxes, and oils, but in pathological conditions it may not be able to provide sufficient lubrication without additives. The importance of biolubrication becomes apparent with age and disease, especially in situations that affect the secretion and composition of bodily fluids. Lack of biolubrication can impair proper speech, chewing, and swallowing, cause excessive friction and wear on the surfaces of articular cartilage in the hips and knees, lead to vaginal dryness, and cause dry and inflamed eyes. The act of blinking, which occurs an average of 28,800 times a day, is considered to be the most frequently used interaction of frictional surfaces. The average blinking time can be measured and may be limited by the integrity of the tear film and tear lipid layer. Insufficient biolubrication of the ocular surface and eyelids increases blinking frequency, leading to greater friction and inflammation. If this persists, it can lead to the inflammation underlying dry eye. Clinical improvement in ocular surface biolubrication can be measured by longer blink intervals, slower blinking, reduced blinking frequency per minute, hour, and day, improved patient comfort, and longer tear film break time (TBUT). Biolubrication is a combination of structure, lipid layer, and glycosylation of adsorbent protein membranes, and provides important clues for designing effective therapeutic agents to restore biolubrication in patients with insufficient biolubrication. Veeregowda et al.2012;7(8):e42600. doi: 10.1371 / journal.pone.0042600.Epub 2012 Aug 15.

[0111] As a non-limiting example, a widely accepted model of the tear film covering the surface of the eye consists of three main components: an outer lipid layer derived from glands lining the eyelid margin (meibomian glands or chalazion glands, and secretions from the Haderian glands in species with Haderian glands, including rabbits); an aqueous layer secreted from the lacrimal and accessory lacrimal glands (a mixture of soluble proteins, lipids, and mucin); and a mucin layer derived from goblet cells associated with conjunctival and corneal epithelial cells, and mucin arising from the epithelial cells themselves.

[0112] Mucinous components form a layer immediately adjacent to cellular elements on the ocular surface, such as the corneal epithelium, and are thought to be somewhat associated with the glycocalyx of the outermost epithelial cells, as well as being mixed in with the more concentrated aqueous component. Mucinous components are thought to be important for maintaining tear film stability by influencing the surface tension of the cell-aqueous layer interface. The aqueous layer is the largest component of the tear film and contains various solutes that maintain the pH, osmotic pressure, and eye health of the tear film. Immunoglobulins, lysozyme, transferrin, antimicrobial peptides, and other components help control the body's burden and reduce the risk of infection. Mucin is also present in this layer. Furthermore, growth factors, cytokines, and other cell-activating factors are also contained in the aqueous layer. The polar lipids of the tear lipid layer cover the aqueous layer with a monolayer of lipid molecules that have charged head groups. The nonpolar lipid layer outside the tear film is the outermost layer of the tear film and is in direct contact with the air. This nonpolar lipid layer provides lubrication and stability to the entire tear film, as clinically measured as tear film break time, and reduces the evaporation rate of the aqueous component of the tear film.

[0113] Many diseases and conditions are associated with mucosal dryness or dysfunction. These include, but are not limited to, dry eyes, dry mouth, vaginal dryness, and diseases involving defects / dysregulation of the respiratory membrane coating. What is needed are safe, effective, and flexible means to treat mucosal dryness and dysfunction, as well as therapies aimed at improving the performance of non-disease mucosa.

[0114] A broad challenge in developing effective therapeutic agents is the formulation and delivery of hydrophobic molecules to obtain therapeutic benefits from the mucosal surface, as well as the delivery of therapeutic agents that must traverse an intact mucosal surface to obtain therapeutic benefits from tissues / structures lying deeper. The novelty and practicality of the inventions described herein lies in the integration of highly hydrophobic molecules as low-temperature crystalline and amorphous lipids and waxes, or as molecules embedded in low-melting-point crystalline and amorphous solid lipids and waxes, which can be suspended as microparticles for topical application from biocompatible aqueous formulations where the lipids are intrinsically insoluble, or dissolved within formulations, and / or integrated into devices for the controlled release of therapeutically beneficial compounds from low-melting-point crystalline and amorphous solids or waxes. Furthermore, these low-temperature crystalline and amorphous solid lipids and waxes are intended to provide means for the controlled delivery of hydrophilic or amphiphilic compounds trapped within the low-temperature crystalline and amorphous solids and waxes. For example, in the case of a drug delivery vehicle containing micronized solid particles containing an active lipid agent, particularly for the treatment of dry eye including inflammatory dry eye and / or evaporative dry eye, a second active ophthalmic agent such as cyclosporine or Xiidra and micronized lipid particles containing ether lipids such as sn-1-O-eicosanyl-sn-2-palmitoyl-glycerol and its isomers. Micronized crystalline or amorphous solid lipid particles containing ether lipids such as sn-1-O-eicosanyl-sn-2-palmitoyl-glycerol can be prepared by spray-drying a 40 mg / mL solution of ether lipid in chloroform in a vacuum chamber. This results in micronized amorphous solid lipid particles less than 10 microns in size. Adding a second active agent (e.g., cyclosporine, Xiidra, or any of the second active agents described below) to the chloroform solution for spray-drying yields spray-dried micronized lipid particles containing both therapeutic amounts of ether lipid and the second active agent. Alternatively, a solid suspension of nano-sized particles of a second active agent in amorphous 1,2-EPRG can be formed by spray-drying a solution of 1,2-EPRG containing the suspended nanoparticles of the second active agent in chloroform or another suitable solvent.

[0115] In certain contexts, the drug delivery vehicles described herein can be used to treat patients suffering from mucosal disorders. The drug delivery vehicles of the present invention further find use when delivery of active lipid agents or lipophilic drugs to mucosa is desired as the route of administration. Thus, the present invention provides drug delivery vehicles useful for the delivery of active lipid components or other lipophilic drugs to the mucosa of interest. The present invention is not limited to a specific mucosal surface. In some preferred embodiments, the mucosal surface is the ocular mucosa, vaginal mucosa, fallopian tube mucosa, respiratory mucosa, nasal mucosa, oral / pharyngeal mucosa, oral mucosa, rectal mucosa, digestive mucosa, or esophageal mucosa. The present invention is not limited to a specific delivery route. In some preferred embodiments, the delivery route consists of topical administration. In some embodiments, when the target organ is the eye, preferred delivery routes include topical eye drops in addition to subconjunctival, sub-Tenon's capsule, retrobulbar, intracavitary, intravitreous, suprachoroidal, and subretinal delivery routes.

[0116] In some preferred embodiments, the drug delivery vehicle of the present invention comprises crystalline and amorphous solid micronized lipid particles. In some preferred embodiments, the micronized lipid particles have an average size of less than 100 microns. In some more preferred embodiments, the crystalline and amorphous solid micronized lipid particles have an average size of less than 50 microns. In some even more preferred embodiments, the crystalline and amorphous solid micronized lipid particles have an average size of less than 20 microns. In some even more preferred embodiments, the crystalline and amorphous solid micronized lipid particles have an average size of less than 10 microns. In some preferred embodiments, the crystalline and amorphous solid micronized lipid particles have an average size of 1 to 100, 1 to 50, or 1 to 10 microns. In some preferred embodiments, the particle size is measured by dynamic light scattering.

[0117] In some preferred embodiments, the micronized lipid particles of the present invention have a melting point of less than 80°C. In some even more preferred embodiments, the micronized lipid particles of the present invention have a melting point of less than 60°C. In some even more preferred embodiments, the micronized lipid particles of the present invention have a melting point of less than 50°C. In some other preferred embodiments, the solid micronized lipid particles have a melting point of 20 to 80°C.

[0118] It will be understood that the lipid composition of micronized lipid particles can be varied to provide a desired melting point. Therefore, in some preferred embodiments, the micronized lipid particles of the present invention comprise one or more carrier lipids, such as monoglycerides, diglycerides, ether ester glycerols, triglycerides, phospholipids, waxes, or sterols. In some embodiments, the lipids may include fatty acid moieties bonded to the glycerol backbone by either ester or ether bonds.

[0119] Various methods for preparing pulverized particles are known in the art. In some preferred embodiments, the pulverized particles are prepared by a jet mill. A suitable jet mill is available, for example, from Hosokawa Micron Powder Systems, Summit, NJ. The product to be supplied, for example, the lipid composition of the present invention, is fed into the grinding zone of the jet mill. Grinding air is injected tangentially into the jet mill through the Laval nozzle of the nozzle ring. This creates a spiral jet of air in the grinding zone. As a result of the spiral airflow, high pressure is generated inside the grinder, reaching an overpressure of 1 bar when operating without product. Since the built-in injector is filled with compressed air, the product is reliably transported into the machine against the overpressure inside the machine.

[0120] The supplied product circulates near the nozzle ring and is repeatedly interrupted by the air jet ejected from the nozzle. Grinding is the result of interparticle collisions caused by particles flowing at different speeds in the nozzle jet. The ground material is carried to the discharge port along with the air. The spiral flow performs a classification process, where only the fine (i.e., pulverized) particles are discharged, while the coarser particles remain in the grinder.

[0121] In some preferred embodiments, the pulverized particles are prepared by spray drying, in which a solution of a lipid composition containing or not containing the second active agent of the present invention is supplied through a nozzle into a vacuum chamber, and amorphous solid particles of 5-50 microns in size are obtained by evaporation of the solvent and sedimentation for recovery. One such spray drying apparatus is available from Buchi Instruments and is described at this URL: https: / / static1.buchi.com / sites / default / files / downloads / Spray_Drying_Encapsulation_Solutions_brochure_en_D_0.pdf?56fa5df1e4976c154c3b11af6a45ff69b22d63e3.

[0122] In some preferred embodiments, the micronized lipid particles contain an active lipid agent. The active lipid agent is a lipid molecule that provides therapeutic or preventive benefits or treats a disease or condition. Examples of active lipid agents used in the present invention include, but are not limited to, monoglycerides, diglycerides, triglycerides, ether ester glycerols, phospholipids, waxes, or sterols.

[0123] In some preferred embodiments, the active lipid agent is an ether lipid. Suitable ether lipids are described in detail in U.S. Patent No. 9,289,494, which is incorporated herein by reference in whole.

[0124] In some preferred embodiments, the active lipid agent is an sn-1,2-substituted glycerol, an sn-2,3-substituted glycerol, or a 1,2-substituted racemiglycerol (i.e., 1,2-rac-glycerol), preferably comprising a fatty acid moiety bonded to glycerol via an ether linkage. The stereospecific numbering sn- of the glycerol backbone carbons is shown in Figure 7 for 1,2-substituted ether lipids, where, for example, R1 is an alkyl or alkenyl bonded via an ether linkage, R2 is an alkyl or alkenyl bonded via an ester linkage, and R3 is -H. This sn-numbering of the glycerol backbone carbons applies to the structures shown herein.

[0125] In some embodiments, the active lipid agent is an ether lipid selected from the following:

[0126] [ka]

[0127] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl, preferably a C20 alkyl or alkenyl; R2 is an unsubstituted C5-C29 alkyl or alkenyl, preferably a C15 alkyl or alkenyl; and R3 is hydrogen (i.e., H);

[0128] [ka]

[0129] Here R1 is hydrogen (i.e., H); R2 is an unsubstituted C5-C29 alkyl or alkenyl, preferably a C15 alkyl or alkenyl; and R3 is an unsubstituted C6-C30 alkyl or alkenyl, preferably a C20 alkyl or alkenyl; and

[0130] [ka]

[0131] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl, preferably a C20 alkyl or alkenyl; R2 is an unsubstituted C5-C29 alkyl or alkenyl, preferably a C15 alkyl or alkenyl; and R3 is hydrogen (i.e., H).

[0132] In some preferred embodiments, the active lipid agent is an sn-1,3-substituted glycerol or a 1,3-substituted racemic glycerol (i.e., 1,3-rac-glycerol), preferably selected from a fatty acid moiety bonded to glycerol via an ether linkage:

[0133] [ka]

[0134] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl, preferably a C20 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29, preferably a C15 alkyl or alkenyl;

[0135] [ka]

[0136] Here R1 is an unsubstituted C5-C29 alkyl or alkenyl, preferably a C15 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C6-C30 alkyl or alkenyl, preferably a C20 alkyl or alkenyl; and

[0137] [ka]

[0138] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl, preferably a C20 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29 alkyl or alkenyl, preferably a C15 alkyl or alkenyl.

[0139] In some preferred embodiments, the active lipid agent is an ether ester glycerol lipid selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG), sn-1-O-eicosanyl-2-palmitoyl-glycerol, sn-2-palmitoyl-3-O-eicosanyl-glycerol, 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), sn-1-O-eicosanyl-3-palmitoyl-glycerol, sn-1-palmitoyl-3-O-eicosanyl-glycerol, and mixtures thereof. In some more preferred embodiments, the active lipid agent is an ether lipid selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) and mixtures thereof.

[0140] Therefore, in some preferred embodiments, the ether lipid is an ether ester glycerol, since one of the sn-positions of the lipid molecule of the present invention is an -OH group and the other of the two sn-positions has an ether-linked aliphatic chain and an ester-linked aliphatic chain. It will be understood that isomers are possible when the ether lipid contains two aliphatic chains. For example, if an alkyl or alkenyl ether is bonded to the sn-1 position of the glycerol skeleton of a diglyceride, the fatty acid bonded to the glycerol skeleton via an ester linkage can be located at either the sn-2 or sn-3 position of the glycerol skeleton. Similarly, if the fatty acid bonded to the glycerol skeleton via an ester linkage is located at the sn-1 position of the diglyceride, the alkyl or alkenyl ether bonded to the glycerol skeleton can be located at either the sn-2 or sn-3 position of the glycerol skeleton. In this regard, it will be apparent to those skilled in the art that when labeling diglyceride molecules, the sn-1 and sn-3 positions depend on the orientation of the molecule. For example, sn-1-O-eicosanyl-sn-2-palmitoyl-glycerol and sn-3-O-eicosanyl-sn-2-palmitoyl-glycerol are isomers.

[0141] When the active lipid agent is an ether ester glycerol, it will be further understood that the active lipid agent may also be a mixture of isomers of disubstituted glycerols, and that this mixture is characterized by the molar percentage of the mixture of ether ester glycerol isomers.

[0142] Therefore, in some preferred embodiments, mixtures of the ether ester lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), and mixtures thereof, are characterized by containing more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 95% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether ester lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 98% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether ester lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 99% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0143] In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 50% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 50% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing 50% (mol%) or less of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and more than 50% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0144] In some preferred embodiments, a mixture of the ether ester lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 5% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether ester lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 2% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers. In some preferred embodiments, a mixture of the ether ester lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) is characterized by containing more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 1% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[0145] The crystalline or amorphous solid micronized lipid particles of the present invention may contain other active agents, such as hydrophilic, amphiphilic, or lipophilic active agents. In some of these preferred embodiments, the active agent may be compounded with the carrier lipid, with the carrier lipid and the active lipid, or together with the active lipid.

[0146] Suitable active agents that are not active lipid agents include many different types of drug molecules. Suitable exemplary drug molecules are listed below. It will be recognized by those skilled in the art that whole molecules, isomers, and fragments of compounds known to be active represent compounds acceptable for inclusion.

[0147] Suitable active agents for inclusion in the drug delivery vehicle of the present invention include, but are not limited to, small molecule drugs, biological agents such as proteins, RNA and DNA-based therapeutics, and other molecules that have therapeutic or preventive benefits or are used to treat diseases or conditions. In some preferred embodiments, the agent is selected from agents that stabilize thin films covering mucosal surfaces, lubricants, agents that enhance the wetting of thin films covering mucosal surfaces (e.g., Pluronic), ophthalmic agents for the treatment of the ocular surface, ophthalmic agents for the treatment of periorbital tissues, ophthalmic agents for the treatment of posterior segment tissues and diseases, ophthalmic agents for the treatment of dry eye selected from corticosteroids, cyclosporine, Xiidra or other active ingredients of FDA-approved dry eye treatments, antibacterial agents, antiviral agents, polypeptide antibacterial agents, antifungal agents, buffers, vitamins or minerals, analgesics, anticoagulants, coagulants, anti-inflammatory agents, vasoconstrictors, vasodilators, diuretics, anticancer agents, nutrients, growth factors, neurotrophic agents, biofilm disruptors, agents that affect intraocular pressure by affecting aqueous humor drainage and / or production, neovascularization promoters, neovascularization inhibitors, extracellular matrix (ECM) agents, enzymes, enzyme inhibitors, polypeptides and combinations thereof.

[0148] In some embodiments, antimicrobial agents are incorporated into solid lipid particles. Suitable antimicrobial agents include loracalbef, cephalexin, cefadroxyl, cefixime, ceftibutene, cefprodil, cefpodoxime, cefradin, cefuroxime, cefaclor, neomycin / polymyxin / bacitracin dicloxacillin, nitrofurantoin, nitrofurantoin macrocrystal, nitrofurantoin / nitrofuran macro, dilithromycin, gemifloxacin, ampicillin, gatifloxacin, penicillin V potassium, ciprofloxacin, enoxacin, amoxicillin, amoxicillin / Potassium lavranate, clarithromycin, levofloxacin, moxifloxacin, azithromycin, sparfloxacin, cefdinir, ofloxacin, trovafloxacin, lomefloxacin, methenamine, erythromycin, norfloxacin, clindamycin / benzoyl peroxide, quinupristin / dalfopristin, doxycycline, amikacin sulfate, vancomycin, kanamycin, netylmycin, streptomycin, tobramycin sulfate, gentamicin sulfate, tetracycline, flamycin, minocycline Clin, demeclocycline nalidixate, trimethoprim, miconazole, colistimetinate, piperacillin sodium / tazobactam sodium, paromomycin, colistin / neomycin / hydrocortisone, amoebic agents, sulfisoxazole, pentamidine, sulfadiazine, clindamycin phosphate metronidazole, oxacillin sodium, naphicillin sodium, vancomycin hydrochloride, clindamycin, cefotaxime sodium, cotrimoxazole, ticarcillin disodium, piperacillin sodium , ticalcillin disodium / clavulanate potassium neomycin, daptomycin, cefazolin sodium, cefoxitin sodium, ceftizoxime sodium, penicillin G potassium and sodium, ceftriaxone sodium, ceftazidime, imipenem / cilastatin sodium, astreonam, cinoxacin, erythromycin / sulfisoxazole, cefotetan disodium, ampicillin sodium / sulbactam sodium, cefoperazone sodium, cefamandornaphate, gentamicin,Sulfisoxazole / phenazopyridine, tobramycin, lincomycin, neomycin / polymyxin B / gramicidin, clindamycin hydrochloride, lansoprazole / clarithromycin / amoxicillin, alatrofloxacin, linezolid, bismuth subsalicylate / metronidazole / tetracycline, erythromycin / benzoyl peroxide, mupirocin, fosfomycin, pentamidine isethionate, imipenem / cilastatin, troleandmycin, gatifloxacin, chloramphenicol, cycloserine, neomycin / polymyxin Kyxin B / hydrocortisone, ertapenem, meropenem, cephalosporin, fluconazole, cefepime, sulfamethoxazole, sulfamethoxazole / trimethoprim, neomycin / polymyxin B, penicillin-based antibiotics, rifampin / isoniazid, erythromycin estolate, erythromycin ethylsuccinate, erythromycin stearate, ampicillin trihydrate, ampicillin / probenecid, sulfasalazine, sulfanilamide, sulfacetoamide sodium, dapsone, doxycycline hypacrylate Trimethoprim / sulfonamides, methenamine mandelate, plasmazide, pyrimethamine, hydroxychloroquine, chloroquine phosphate, trichomonides, anthelmintics, atovaquone, bacitracin, bacitracin / polymyxin b, gentamicin, neomycin / polymyxin / dexameth, neomycin sulfate / dexameth, sulfacetamide / prednisolone, sulfacetamide / phenylephrine, tobramycin sulfate / dexameth, bismuth tribromophenate, silver ion compounds, silver nanoparticles, zero-valent silver, polyvalent silver, elemental silver, silver sulfadiazine and related compounds Examples include silver-containing compounds such as chlorhexidine, biofilm disruptors (gallium, tryptophan, imidazole derivatives, indole derivatives, emodin, phloretin, isolimonate, 7-epicruscyanone, casubenditerpene, carvacrol, kerelithrin, etc.), ellagic acid, tannic acid, ginkgolic acid, resveratrol, viniferin, diphenyl disulfide, S-phenyl-L-cysteine ​​sulfoxide, ajoene, brominated furanone, n-acylhomoserine lactone, skyramycin, sembranoid, calolactone, etc.This is not limited to these.

[0149] In some embodiments, antiviral agents are incorporated into solid lipid particles. Suitable antiviral agents include amantadine, acyclovir, foscarnet, indinavir, ribavirin, enfuvirtide, emtricitabine, lamivudine, abacavir fomivirsen sulfate, valacyclovir, tenofovir, cidofovir, atazanavir, amprenavir, delavirdin mesylate, famciclovir, adefovir, didanosine, efavirenz, trifluridine, inidinavir, lamivudine vidarabine, lopinavir / ritonavir, and Examples include, but are not limited to, ceciclovir, zanamivir, abacavir / lamivudine / zidovudine, lamivudine / zidovudine, nelfinavir, nelfinavir mesylate, nevirapine, ritonavir, saquinavir, saquinavir mesylate, rimantadine, stabudine, docosanol, zalcitabine, doxuridine, zidovudine, zidovudine / didanosine, valganciclovir, penciclovir, lamivudine, and oseltamivir.

[0150] In some embodiments, an antifungal agent is incorporated into solid lipid particles. Appropriate antifungal agents include, but are not limited to, amphotericin B, nystatin, nystatin / triamcinolone, itraconazole, ketoconazole, miconazole, sulconazole, clotrimazole, clotrimazole / betamethasone, enilconazole, econazole, oxiconazole, thioconazole, terconazole, butoconazole, thiabendazole, flucytosine, butenafine, cyclopirox haloprozine, naphthifine, tolnaftate, natamycin, undecylenic acid, mafenide, dapsone, clioquinol, clioquinol / hydrocortisone, potassium iodide, silver sulfadiazine, gentian violet, carvolfuxin, cylofungin, sertaconazole, voriconazole, fluconazole, terbinafine, caspofungin, other azole topical agents, and griseofulvin.

[0151] In some embodiments, a buffer is incorporated into solid lipid particles. Suitable buffers include, but are not limited to, maleic acid, phosphoric acid, glycine, chloroacetic acid, formic acid, benzoic acid, acetic acid, pyridine, piperazine, MES, bis-tris, carbonate, ACES, ADA MOPSO, P-piperazine, MES, bis-tris, carbonate, ACES, ADA MOPSO, PIPES, phosphoric acid, BES, MOPS, TES, HEPES, DIPSO, TAPSO, triethanolamine, HEPSO, tris, tricine, bicine, TAPS, borate, ammonia, CHES, ethanolamine, CAPSO, glycine, carbonate, CAPS, methylamine, piperidine, and phosphoric acid.

[0152] In some embodiments, vitamins or minerals are incorporated into solid lipid particles. Suitable vitamins and minerals include, but are not limited to, vitamin A, carotenoids, vitamin D, vitamin E, vitamin K, vitamin C / ascorbic acid, B1 / thiamine, B2 / riboflavin, B3 / niacin, B5 / pantothenic acid, B6 / pyridoxine, B12 / cobalamin, biotin, calcium, magnesium, phosphorus, sodium, chloride, potassium, boron, chromium, copper, iodine, iron, manganese, selenium, and zinc.

[0153] In some embodiments, analgesics are incorporated into solid lipid particles. Suitable analgesics include acetaminophen, anilelysine, acetylsalicylic acid, buprenorphine, butorphanol, fentanyl, fentanyl citrate, codeine, lofecoxib, hydrocodone, hydromorphone, hydromorphone hydrochloride, levorphanol, alfentanyl hydrochloride, meperidine, meperidine hydrochloride, methadone, morphine, nalbufine, opium, levometadil, sodium hyaluronate, sulfonate, morphine, opium, levometadil, sodium hyaluronate, Examples include, but are not limited to, sulfonates, morphine, opium, levometadil, sodium hyaluronate, sufentanil citrate, capsaicin, tramadol, leflunomide, oxycodone, oxymorphone, celecoxib, pentazocine, propoxifene, benzocaine, lidocaine, dezosin, clonidine, butarbital, phenobarbital, tetracaine, phenazopyridine, sulfamethoxazole / phenazopyridine, and sulfisoxazole / phenazopyridine.

[0154] In some embodiments, an anticoagulant is incorporated into solid lipid particles. Suitable anticoagulants include, but are not limited to, coumarin, 1,3-indanedione, anisindione, fondaparinux, heparin, repiridine, antithrombin, warfarin, enoxaparin, dipyridamole, dalteparin, ardeparin, nadroparin, and tinsaparin.

[0155] In some embodiments, the coagulant is incorporated into solid lipid particles. Suitable coagulants include, but are not limited to, factor I (fibrinogen), factor II (prothrombin), factor III (thromboplastin, tissue factor), factor IV (calcium), factor V (instability factor), factor VII (stabilization factor), factor VIII (antihemophilia globulin, antihemophilia globulin, antihemophilia factor A), factor IX (plasma thromboplastin component, Christmas factor, anti-epophilic factor B), factor X (Stuart factor, Prower factor, Stuart-Prower factor), factor XI (plasma thromboplastin precursor, anti-epophilic factor C), factor XII (Hegemann factor, surface factor, contact factor), and factor XIII (fibrin stabilizing factor, fibrin stabilizing enzyme, fibrinase).

[0156] In some embodiments, anti-inflammatory agents are incorporated into solid lipid particles. Suitable anti-inflammatory agents include NSAIDs such as diclofenac (Voltaren, Abitren, Alborane, Almiral, Arompin, Amfenax, Artlytes, Betaren, Brescin, Borabomin, Cataflam, Clofec, Clofen, Cordran, Crinflam, Diclomac, Diclocyan, Dixnar), Difenac, Ecofenac, Hizemin, Inflamac, Inflanac, Klotaren, Lidonin, Monoflam, Naboal, Oritaren, Remethan, Sa vismin, Silino, Staren, Tsudohmin, Voltarol, Voren, Voveran, and Vurdon), diflunisal (also known as Dolobid, Adomal, Diflonid, Diflunil, Dolisal, Dolobis, Dolocid, Donobid, Dopanone, Dorbid, Dugodol, Flovacil, Fruniget, Fluodonil, Flusar, Ilacen, Noaldol, Reuflos, and (also known as Unisal), etodolac (also known as Lodine), fenoprofen (also known as Nalfon, Fenoprex, Fenopron, Fepron, Nalgesic, and Progesic), flurbiprofen (also known as Ansaid and Ocuflur), ibuprofen (also known as Rufen, Motrin, Achesunpain, Advil, Nuprin, Dolgezik, Genpril, Hartran, Ibifon, Ibren, Ibmed, Ibuprin, Ibupro-600, Ibu Prome, Ibutab, Ibutex, Ifen, Medipren, Midor 200, Motrin-IB, Clampend, Profen, Loprofen, Trender, Araxan, Brofen, Alfam, Brufen, Algofen, Brufort, Amersol, Bruzon, Andran, Buburone, Anflagen, Butacortelone, Apsifen, Deflem, Artofen, Dolgit, Artril, Dolocyl, Bloom, Donjust, Bluton, Easifon,Ebufac, Emflam, Emodin, Fenbid, Fenspan, Focus, Ibosure, Ibufen, Ibufug, Ibugen, Ibumetin, Ibupirac, Imbun, Inabrin, Inflam, Irfen, Librofen, Limidon, Lopane, Mynosedin, Napacetin, Nobafon, Nobgen, Novogent, Novoprofen, Nurofen, Optifen, Paduden, Paxofen, Perofen, Proartinal, Pron (talgin, Q-Profen, Relcofen, Remofen, Roidenin, Seclodin, Tarein, Zofen), indomethacin (also known as Indameth, indosine, amno, antalgin, allumatin, argyrex, alterexin, altrexin, altrinovo, babylon, bonidone, buticine, cronoindoside, sidalgon, confortid, confortind, domesid, duramethacin, elemethacin, idicine, imbrilon, inasid, indacin, indesine, indocap, indoce Indoside, Indoflex, Indolag, Indomed, Indomie, Indomethacinam, Indomethicina, Indomethicina, Indomethine, Indovis, Indox, Indoz, Indorenin, Indiron, Infrazon, Inpan, Laujit, Liomete, Metacene, Methindon, Metoside, Mezoline, Mobilan, Novometacin, Pelargon, Liflox, Rheumacid, Rheumacin, Sarinac (also known as Servindomet, Toshisan, and Vonum), Ketoprofen (Orudis, Alrheumat, A (also known as lrheumun, Alrhumat, Aneol, Arcental, Dexal, Epatec, Fastum, Kedril, Kefenid, Keprofen, Ketofen, Ketonal, Ketosolan, Kevadon, Mero, Naxal, Oruvail, Profenid, Salient, Tofen, and Treosin), ketrolac (also known as Tradol), meclofenamic acid (also known as meclofen, mechromen, moven), mefenamic acid (also known as Ponstel, Alpain, Aprostal,Venostan, Bonabol, Koslan, Deisman, Deispen, Ecopan, Raisalgo, Manic, Mefak, Mefix, Parquemed, Pondex, Ponsfen, Ponstan, Ponstyl, Pontal, Ralgec, Youfenam), Nabumeton (also known as Relafen), Naproxen (also known as Naprosyn, Anaprox, Aleve, Apranax, Apronax, Arthrisil, Artrixen, Artroxen, Bonyl, Congex, Danaprox, Diocodal, Dysmenalg it, Femex, Flanax, Flexipen, Floginax, Gibixen, Headlon, Laraflex, Laser, Renialtil, Nafazole, Naxan, Nalixan, Napoton, Naprene, Naprelan, Naprilium, Naprius, Naprontag, Napplex, Napuxen, Naruma, Naxen, Nakid, Novonaprox, Nycoprene, Patsen, Prexan, Prodexin, Larsen, Loxen, Salicylon, Synalthrin, Synton, Sutney, Synflex, Tohexen, Bellador Vinsen, Xenar) , Oxaprozin (aka Daypro), Piroxicam (aka Feldene, Algidol, Antiflog, Arpyrox, Atidem, Bestocam, Butacinon, Desinflam, Dixonal, Doblexan, Dolonex, Fe line, Felrox, Fuldin, Indene, Infeld, Inflamene, Lampoflex, Larapam, Medoptil, Novopirocam, Osteral, Pilox, Piraldene, Piram, Pirax, Pirica m, Pirocam, Pirocaps, Piroxan, Piroxedol, Piroxim, Piton, Posidene, Pyroxy, Reucam, Rexicam, Riacen, Rosic, Sinalgico, Sotilen, Stopen, Zund (also known as en), Sulindac (Clinoril, Aflodac, Algocetil, Antribid, Arthridex, Arthrocine, Biflace, Citireuma, Crisundac, Imbaral, Lindak, Lyndak,Examples of steroid anti-inflammatory drugs include, but are not limited to, Mobilin (also known as Reumofil, Sudac, Sulene, Sulic, Sulindal, Suloril, and Sulreuma), Tolmetin (also known as Tolectin, Donison, Midocil, Reutol, and Safitex), Celecoxib (also known as Celebrex), Meloxicam (also known as Mobic), rofecoxib (also known as Vioxx), valdecoxib (also known as Bextra), aspirin (also known as Anacin, Ascriptin, Bayer, Bufferin, Ecotrin, and Excedrin), loteprednol etabonate, cortisone, prednisone, and dexamethasone.

[0157] In some embodiments, a vasoconstrictor is incorporated into solid lipid particles. Suitable vasoconstrictors include, but are not limited to, epinephrine (adrenaline, susphrine), phenylephrine hydrochloride (neosynephrine), oxymetazoline hydrochloride (afrine), norepinephrine (levofed), and caffeine.

[0158] In some embodiments, vasodilators are incorporated into solid lipid particles. Suitable vasodilators include bosentan (Tracleer), epoprostenol (Floran), treprostinil (Remodulin), cytaxentan, nifedipine (Adalat, Procardia), nicardipine (Cardene), verapamil (Karan, Covera-HS, Isobutin, Vereran), diltiazem (Dilacol XR, Diltia XT, Tiamate, Tiazac, Cardizem), izradipine (Dynacirc), nimodipine (Nimotop), and amlodipine (Norvasc). (Prendyl), Nisoldipine (Slur), Bepridil (Bascol), Hydralazine (Aprezolin), Minoxidil (Loniten), Isosorbide dinitrate (Dilatorate-SR, Isovid, Isonate, Isolvid, Isoldil, Isotrate, Sorbitrate), Isosorbide mononitrate (IMDUR), Prazosin (Minipress), Cilostazol (Pletal), Treprostinil (Remodulin), Cyclandelate, Isosuprine (Vasodilan), Nylidrine (Arli din), nitrates (Deponit, Minitran, Nitrovid, Nitrodisc, Nitrodul, Nitrol, transdermal nitro), benazepril (Rotensin), benazepril and hydrochlorothiazide (Rotensin HCT), captopril (Capoten), captopril and hydrochlorothiazide (Capozide), enalapril (Vasotec), enalapril and hydrochlorothiazide (Baseretic), hosinopril (Monopril), lisinopril (Prinvir, Zestril), lisinopril and hydrochlorothiazide (Prinopril) Examples include, but are not limited to, Pavavid (Zestretic), Moexipril (Univasc), Moexipril and hydrochlorothiazide (Uniretic), Perindopril (Aceon), Quinapril (Accupril), Quinapril and hydrochlorothiazide (Accuretic), Ramipril (Artes), Trandolapril (Mavic), and Papaverine (Cerespan, Genavid, Pavavid, Pavavid HP, Pavacells, Pavacot, Pavagen, Pavalin, Pavaced, Pavatin, Pavatim, Paveloran).

[0159] In some embodiments, diuretics are incorporated into solid lipid particles. Suitable diuretics include acetazolamide (Diamox), dichlorphenamide (Daranide), metazolamide (Neptazane), bendroflumethiazide (Naturetin), benzthiazide (Exna), chlorothiazide (Diuril), chlorthalidone (Hygroton), hydrochlorothiazide (Esidrix, HydroDiuril, Microzide), hydroflumethiazide (Diucardin), indapamide (Lozol), meticlothiazide (Enduron), metrazone (Zaroxolyn, Mykrox), and polythiazide. Examples include, but are not limited to, (Renese), kinetazone (Hydromox), trichlormethiazide (Naqua), bumetanide (Bumex), ethacrine (Edecrin), furosemide (Lasix), torsemide (Demadex), amiloride (Midamor), amiloride and hydrochlorothiazide (moduletic), spironolactone (aldactone), spironolactone and hydrochlorothiazide (aldactazide), triamterene (dilenium), and triamterene and hydrochlorothiazide (diazide, maxzide).

[0160] In some embodiments, anticancer drugs are incorporated into solid lipid particles. Suitable anticancer agents include aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anagrelide, anastrozole, arsenic trioxide, asparaginase bexarotene, bicalutamide, bleomycin, busulfan, carsterone, capecitabine, carboplatin, carmustine, celecoxib, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, darbepoetin α, daunorubicin, daunomycin, dexrazoxane, docetaxel, doxorubicin, epoetin α, estramustine, etoposide, etoposide phosphate, exemestane, filgrastim, floxuzinine, fludarabine, flutamide, fulvestrant, gemcitabine, and gemtuzumab. Ozogamicin, Goserelin acetate, Hydroxyurea, Ibritumomab, Tiuxetan, Idarubicin, Ifosfamide, Imatinib mesylate, Interferon α2a, Interferon α-2a, Interferon α-2b, Irinotecan, Leflunomide, Letrozole, Leucovorin, Lebamisol, Lomustine, Mechloretamine (Nitrogen Mustard), Megestrol acetate, Melphalan, Mercaptopurine, Mesna, Methotrexate, Methoxsalen, Mitomycin C, Mytotan, Mitoxantrone, Mycophenolate Mofetil, Nandrolone fenpropionate, Niltamide, Nofetumomab, Oprelbequin, Oxaliplatin, Paclita Examples include, but are not limited to, xerol, pamidronate, pegademase, pegapargase, pegfilgrastim, pentostatin, pipobromane, plicamycin, porfimer sodium, procarbazine, quinacrine, rasburicase, rituximab, salglamostim, streptozocin, tacrolimus, tamoxifen, temozolomide, teniposide, testactone, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, barbicin, vinblastine, vincristine, vinorelbine, and zoledronate.

[0161] In some embodiments, nutrients are incorporated into solid lipid particles. Suitable nutrients include epidermal growth factors including agrin, amphiregulin, artemin, cardiotrophin-1, and EGF; fibroblast growth factors (e.g., FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, and FGF-7); endothelial growth factors including LIF, CSF1, CSF2, CSF3, erythropoietin, and ECGF; and FGF- and ECGF-related growth factors (e.g., endothelial cell-stimulating angiogenic factor, tumor angiogenic factor, retinal growth factor (RDGF), vascular endothelial growth factor (VEGF), and breezia nervosa). Ovarian growth factors (BDGF-A and B), astrocyte growth factors (AGF1 and 2), ovarian growth factors, insulin-like growth factors (SSSR, fibroblast-stimulating factor (FSF), embryonic cancer growth factor (ECDGF), and other fragments); neurotrophic growth factors (e.g., nerve growth factor (NGF), neurolthurin, brain-derived neurotrophic factor (BDNF), neurotrophin 3, neurotrophin 4, and ciliary neurotrophic factor (CNTF)); glial growth factors (e.g., GGFI, GGFII, GGFIII, glial maturation factor) (GMF), and glial neurotrophic factor (GDNF); hepatocyte growth factors (e.g., hepatocyte growth factors including hepatopoetin A, hepatopoetin B, and HGF); prostate growth factors including prostate-derived growth factor (PGF); mammary growth factors including mammary growth factor 1 (MDGF1) and mammary tumor growth factor (MTGF); cardiac growth factors including non-myocytic growth factor (NMDGF); melanocyte growth factors including melanocyte-stimulating hormone (MSH) and melanoma growth-stimulating activity (MGSA); angiogenic factors (e.g., angio Genin, angiotropin, platelet-derived ECGF, VEGF, and pliotrophin; transforming growth factors including TGFα and TGFβ; TGF-like growth factors (e.g., TGFβ1, TGFβ2, TGFβ3, GDF1, CDGF, tumor-derived TGF-like factors, NDTGF, human epithelial transforming factor); regulatory peptides with growth factor-like properties (e.g., bombesin and bombesin-like peptides ranatensin and ritrin, angiotensin, endothelin, atrial natriuretic factor, vasoactive intestinal peptide, bradykinin);Platelet-derived growth factors such as PDGF-A, PDGF-B, and PDGF-AB; neuropeptides such as substance P, calcitonin gene regulatory peptide (CGRP), and neuropeptide Y; neurotransmitters and their analogues such as norepinephrine, acetylcholine, and carbachol; hedgehog, heregulin / neuregulin, IL-1, osteoclast-activating factor (OAF), lymphocyte-activating factor (LAF), hepatocyte-stimulating factor (HSF), B-cell-activating factor (BAF), tumor suppressor factor 2 (TIF2), keratinocyte-derived T cell growth factor (KDTCGF), IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, Examples of nutrients include, but are not limited to, IL-10, IL-11, stromal cell-derived cytokines (SCDC), IL-12, IL-13, IL-14, IL-15, insulin, IGF-1, IGF-2, and IGF-BP; interferons including INF-α, INF-β, and INF-γ; leptin, midkines, tumor necrosis factor (TNF-α and β), netrin, saposin, semaphorin, somatorem, somatropin, stem cell factors, VVGF, bone morphogenesis proteins (BMPs), adhesion molecules, other cytokines, heparin-binding growth factors, and tyrosine kinase receptor ligands. In some embodiments, the nutrients are peptides such as AcEEED, which is the N-terminal peptide of α-smooth muscle actin and has been shown to inhibit the contractile properties of myofibroblasts.

[0162] In some embodiments, the extracellular matrix (ECM) agent is incorporated into solid lipid particles. Suitable ECM agents include, but are not limited to, extracellular matrix proteins, reconstituted basement membrane-like complexes derived from eukaryotic cell lines, collagen, fibronectin, laminin, VCAM-1, vitronectin, and gelatin, native constructs of bacterial extracellular matrix, gel matrix, and polymer matrix, fragments of native constructs, and synthetic analogs. In some embodiments, the wound-healing agent is an integrin-binding sequence, exemplified by, but not limited to, RGD, EILDV, VCAM-1, and their recombinant or synthetic analogs, enzymes, enzyme inhibitors, and polypeptides.

[0163] In some embodiments, the enzyme is incorporated into solid lipid particles. Suitable enzyme preparations include, but are not limited to, exopeptidases and endopeptidases (also known as proteases and proteinases), serine proteases such as chymotrypsin, trypsin, elastase, and kallikrein, bacterial enzymes, cysteine ​​proteases such as papain, actinin, bromelain, cathepsin, cytoplasmic calpain, parasitic proteases, aspartate proteases, pepsin-series proteases such as pepsin and chymosin, lysosomal cathepsin D, renin, fungal proteases, viral proteases, retropepsin of the AIDS virus, metalloproteases (MMPs), collagenases, maggot enzymes, MMP1, MMP2, MMP8, MMP13, gelatinases, MMP2, MMP9, MMP3, MMP7, MMP10, MMP11, and MMP12.

[0164] In some embodiments, enzyme inhibitors are incorporated into solid lipid particles. Suitable enzyme inhibitors include, but are not limited to, NSAIDs, aspirin, captopril, thiophan, phosphoramidone, teprotide, protease and proteinase inhibitors, metalloproteinase inhibitors, and exopeptidase inhibitors.

[0165] In some embodiments, polypeptide antimicrobial agents are incorporated into solid lipid particles. Suitable polypeptide antimicrobial agents include, but are not limited to, α-defensins HNP1, 2, 3, and 4, and β-defensins HBD-1, HBD-2, HBD-3, and cathelicidine. Other suitable polypeptide antimicrobial agents include magainin (e.g., magainin I, magainin II, xenopsin, xenopsin precursor fragment, kerlein precursor fragment), magainin I and II analogs (e.g., PGLa, magainin A, magainin G, pexiganin, Z-12, pexiganin acetate, D35, MSI-78A, MG0 (K10E, K11E, F12W-magainin 2), MG2+ (K10E, F12W-magainin 2), MG4+ (F12W-magainin 2), MG6+ (f12W, E19Q-magainin 2 amide), MSI-238, reverse magainin II analogs (e.g., 53D, 87-ISM, A87-ISM), and Ala-magainin II. Amides (magainin II amide), cecropine P1, cecropine A, cecropine B, indolicidin, nisin, ranalexin, lactoferricin B, poly-L-lysine, cecropine A(1-8)-magainin II(1-12), cecropine A(1-8)-melittin(1-12), CA(1-13)-MA(1-13), CA(1-13)-ME(1-13), gramicidin, gramicidin A, gramicidin D, gramicidin S, aramethicin, protegrin, histatin, dermaceptin, lentiviral amphipathic peptide or analog, parasin I, lycotoxin I or II, globomycin, gramicidin S, surfactin, larinomycin, valinomycin, polymyxin B, PM2 ((+ / -) 1-(4-aminobutyl)-6-benzylindane), PM2c ((+ / -) -6-benzyl-1-(3-carboxypropyl)indane), PM3 ((+ / -)1-benzyl-6-(4-aminobutyl)indane), tachyplesin, buforin Examples of antimicrobial peptides include, but are not limited to, I or II, misgurin, melittin, PR-39, PR-26, 9-phenylnonylamine, paradaxin, Bac 5, Bac 7, ceratoxin, mdelin 1 and 5, bombin-like peptides, PGQ, cathelicidine, HD-5, Oabac5α, ChBac5, SMAP-29, Bac7.5, lactoferrin, granulylisin, thionine, hebein and nottin-like peptides, MPG1, 1bAMP, sunakinin, lipid transfer proteins, and plant defensins. Exemplary sequences of the above compounds are provided in Table 1. In some embodiments, the antimicrobial peptides are synthesized from L-amino acids, while in other embodiments, the peptides are synthesized from or contain D-amino acids.

[0166] In some embodiments, polypeptide agents are incorporated into solid lipid particles. Suitable polypeptide agents include, but are not limited to, antibodies and immunoglobulins and their fragments, single-chain antibodies, humanized antibodies, fibronectin, serotonin, PAF, PDEGF, TNFα, IL1, IL6, IGF, IGF-1, IGF-2, IL-1, PDGF, FGF, KGF, VEGF, bradykinin, prothymosin α, and thymosin α1.

[0167] The micronized lipid particles of the present invention are used in various drug delivery systems and devices.

[0168] In some preferred embodiments, the micronized lipid particles are provided in a liquid composition, most preferably in an aqueous suspension suitable for a mucosal surface. The term “liquid composition” according to the present invention means any water-containing liquid, solution, or suspension that can be applied to the body of a human or animal, comprising crystalline and amorphous solid low-melting-point micronized particles as described above, and optionally comprising active agents or active lipid agents as described in detail above. In some preferred embodiments, the liquid composition further comprises excipients, e.g., lipids, oils, lipophilic vitamins, lubricants, viscosity agents, acids, bases, antioxidants, stabilizers, synergists, colorants, thickeners, and—if required in particular—preservatives or surfactants and mixtures thereof.

[0169] Useful excipients can be added to low-melting-point suspended crystalline solids or amorphous solids in the atomization process and include, but are not limited to, glycerol, propylene glycol, polyethylene glycol, ethanol, acetone, ethyl acetate, isopropyl alcohol, pentylene glycol, liquid paraffin, and triglyceride oil. These excipients may be therapeutically beneficial or added to adjust the melting point of the low-melting-point suspended solid or the particle size of the atomized solids. Other excipients can be added to the aqueous component of the formulation as viscosity modifiers, stability enhancers, or therapeutically beneficial additives.

[0170] Useful antioxidants include, but are not limited to, vitamin E or vitamin E derivatives, ascorbic acid, sulfites, bisulfites, gallic acid esters, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), or acetylcysteine.

[0171] In some particularly preferred embodiments, the micronized crystalline or amorphous solid lipid particles are provided in an aqueous suspension of an ophthalmologically acceptable vehicle or carrier. Other components that may be included in the carrier component include, but are not limited to, buffering components, tonic components, preservative components, pH adjusters, viscosity-enhancing components commonly found in artificial tears, such as one or more electrolytes, and mixtures thereof. In one very useful embodiment, the carrier component comprises at least one of an effective amount of a buffering component, an effective amount of a tonic component, an effective amount of a viscosity component, an effective amount of a concentration component, an effective amount of a preservative component, and water.

[0172] These additional components are preferably ophthalmologically acceptable and can be selected from materials conventionally used in ophthalmic compositions, such as compositions used to treat eyes suffering from dry eye syndrome or other eye disorders, and artificial tear preparations.

[0173] The acceptable effective concentrations of these additional components in the composition of the present invention will be readily apparent to those skilled in the art.

[0174] The liquid composition may be administered alone or in combination with a buffer, such as phosphate-buffered saline, or a pharmaceutically acceptable substance including an inert carrier compound, glycerol, mineral oil, wax, or similar substance, to the ocular surface or other mucous membrane surface of the eye, as described herein.

[0175] The dosage of the above lipid compounds is optimized according to the formulation and delivery method, and the mode of administration is determined by conventional protocols to effectively treat human ocular disorders.

[0176] Liquid compositions containing micronized lipid particles can be used as vehicles for topical administration of therapeutic drugs. Suitable therapeutic drugs are as described above and include active compounds, including active lipid compounds. In particular, the liquid compositions of the present invention find use for delivering any desired therapeutic agent, or combination of therapeutic agents, including, but not limited to, active lipid agents, antibiotics, antivirals, antifungals, anticancer agents, antiglaucoma agents, anti-inflammatory agents, secretagogues that promote lacrimation, salivation, or the release of soluble mucin, and stimulate the expression of cell-associated mucins that promote the wettability and / or lubrication of mucosal surfaces, analgesics, immunomodulators, macromolecules, or mixtures thereof.

[0177] In some particularly preferred embodiments, therapeutic agents that may be included in the liquid composition of the present invention, which comprises micronized lipid particles in the liquid composition, include, but are not limited to, NMDA antagonists, antihistamines, antiparasitic drugs, myotics, sympathomimetics, anticholinergics, local anesthetics, amoebic stimulants, trichomonosidal drugs, mydriatics, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, and ophthalmic agents used in the treatment of dry eye (Xiidra, cyclosporine, Including but not limited to corticosteroids and steroids, ophthalmic drugs used as surgical adjuvants, chelating agents, anti-cancer drugs, diagnostic agents, adrenergic anesthetics, beta-blockers, alpha-2 agonists, cycloplengic, prostaglandins, ACE inhibitors, endogenous cytokines, drugs affecting the basement membrane, drugs affecting endothelial cell proliferation, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, analgesics, anesthetics, anti-allergic drugs, anti-inflammatory drugs, antihypertensive drugs, sedatives, antibacterial drugs, Antiviral drugs, antifungal drugs, antiparasitic drugs, antiinfective drugs, antitumor drugs, antimetabolites, angiogenesis inhibitors, tyrosine kinase inhibitors, aminoglycoside antibiotics such as gentamicin, kanamycin, neomycin, and vancomycin; amphenicol antibiotics such as chloramphenicol; cephalosporin antibiotics such as cefazolin HC1; penicillin antibiotics such as ampicillin, penicillin, carbenicillin, oxycillin, and methicillin; lincosamide antibiotics such as lincomycin; polypeptide antibiotics such as polymyxin and bacitracin; Tetracycline antibiotics such as tracycline; quinolone antibiotics such as cyproflaxin; sulfonamide antibiotics such as chloramine T; and sulfones such as sulfanilic acid as hydrophilic entities; antiviral agents such as acyclovir, ganciclovir, vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine, dexamethasone, cyproflaxin; water-soluble antibiotics such as acyclovir, ganciclovir, vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine; epinephrine; isofluphate;Water-soluble antibiotics such as Adriamycin, Bleomycin, Mitomycin, Alla-C, Actinomycin D, and Scopolamine; analgesics and anesthetics such as codeine, morphine, Keteroc, and naproxen, e.g., lidocaine; β-adrenergic blockers or β-adrenergic agonists such as ephydrine and epinephrine; aldose reductase inhibitors such as epalrestat, ponalrestat, sorbin, and torrestat; antiallergic agents such as cromolyn, beclomethasone, dexamethasone, and flunisolide; colchicine; anti-amebic agents such as chloroquine and chlortetracycline; antifungal agents such as amphotericin; anti-angiogenic compounds such as anecoltab acetate; Brimo This includes antiglaucoma agents such as nidin, acetozolamide, bimatoprost, timolol, and mebefnolol; antitumor agents such as memantine, α2 adrenergic receptor agonists, 2ME2, vinblastine, vincristine, and interferon; α, β, and γ antimetabolites such as folic acid analogs, purine analogs, and pyrimidine analogs; immunosuppressants such as azatiprone, cyclosporine, and mizoribine; mydriatics such as carbacol and atropine; protease inhibitors such as aprotinin, camostat, and gabexate; vasodilators such as bradykinin; and various growth factors such as epidermal growth factor, basic fibroblast growth factor, and nerve growth factor (including their derivatives and mixtures).

[0178] The effective amount of micronized lipid particles administered in the liquid composition is determined by standard methods and can be combined with buffers, such as phosphate-buffered saline, or pharmaceutically acceptable substances used in ophthalmic vehicles, including inert carrier compounds, glycerol, mineral oil, or similar substances. The dosage of micronized lipid particles is optimized according to the formulation and delivery method, and the mode of administration is determined by conventional protocols to effectively treat the relevant disorder or symptom in the subject, such as eye disorders or other mucosal disorders.

[0179] In some preferred embodiments, the liquid composition containing suspended micronized solid lipid particles is administered topically, for example, as eye drops. Therefore, in some preferred embodiments, the liquid composition containing micronized lipid particles is a stable suspension of lipids in a physiologically compatible carrier provided in a container, most preferably a dropper dispenser. Suitable dropper dispensers are known in the art and include those described in U.S. Patents 10,507,780; 10,507,132; 10,265,214; 9,999,540; 9,545,333; 7,846,140; 7,563,256; 7,527,613; 6,736,802; 5,810,794; 5,578,020 and 5,558,653, all of which are incorporated herein by reference in their entirety.

[0180] In a further embodiment, a liquid composition comprising a micronized liquid or solid lipid particles may be delivered to the ocular surface as a drop from any number of containers, including sterile single-use containers, blow-fill seal containers, and multi-purpose containers having a concentration of 250 to 35 mOsmol / L, comprising a stored or unstored micronized suspension of the micronized liquid or solid lipid particles in an aqueous component buffered to pH 5 to 8.

[0181] In some preferred embodiments, the liquid composition containing micronized lipid particles is a suspension of micronized crystalline or amorphous solid lipid particles. In some preferred embodiments, the liquid composition is PBS containing wetting agents and thickeners to maintain the micronized crystalline or amorphous solid lipid particles as a stable suspension in PBS with a pH of 5-8, an osmotic pressure of 250-350 mOsm / L, and a viscosity of 100 or less. In some preferred embodiments, the suspension may or may not contain a buffer and a preservative. In some preferred embodiments, the suspension contains a stabilizer.

[0182] In yet another preferred embodiment, the drug delivery vehicle is a medical insertion device. As used herein, a medical insertion device refers to a solid, three-dimensional structure that can be inserted into or onto the body of an object, such as an eye, vagina, recto-nose, or mouth. In some preferred embodiments, the medical insertion device is formed from micronized lipid particles that are formed in the three-dimensional structure of the device. In other preferred embodiments, the device is formed from a physiologically acceptable material. Suitable physiologically acceptable materials include metals, gels, polymers, and proteinaceous materials. In these embodiments, the device is coated or impregnated with micronized lipid particles.

[0183] In some preferred embodiments, the physiologically acceptable material is a physiologically acceptable polymer. In some preferred embodiments, the physiologically acceptable polymer is selected from the group consisting of hydroxypropyl cellulose, hydrogels, polymethyl methacrylate, and silicone acrylate. In some embodiments, bioacidic polymer films suitable for application to mucous membranes, such as poly(lactic acid / glycolic acid-PLGA) and poly(ε-caprolactone), are preferred. In other preferred embodiments, physiologically acceptable polymers include butyryl trihexyl citrate, di(2-ethylhexyl) phthalate, di-iso-nonyl-1,2-cyclohexane dicarboxylate, foamed PTFE, ethylene vinyl alcohol copolymer, hexamethylene diisocyanate, high-density PE, highly cross-linked PE, isophorone diisocyanate, low-density poly(ethylene), poly(amide), poly(acrylonitrile), poly(carbonate), poly(caprolactone diol), poly(D-lactic acid), poly(dimethylsiloxane), poly(dioxanone), poly(ethylene), and polyether ether keto The following are selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), polyester polymer alloy, polyethersulfone, poly(ethylene terephthalate), poly(glycolic acid), poly(hydroxyethyl methacrylate), poly(lactic acid-co-glycolic acid), poly(L-lactic acid), poly(methyl methacrylate), poly(methylpentene), poly(propylene), polysulfone, poly(tetrafluoroethylene), poly(vinyl alcohol), poly(vinyl chloride), poly(vinylidene fluoride), poly(vinylpyrrolidone), poly(styrene-β-isobutylene-β-styrene), and ultra-high molecular weight PE.

[0184] The medical implantation device of the present invention may be any shape or size that is suitable for insertion into a desired area of ​​the target body. In some preferred embodiments, the implant is in the shape of a sheet, rod, sphere, partial sphere, tube, cylinder, triangle, cone, etc. In some preferred embodiments, when the implant is positioned to contact the surface of the target eye, the implant may preferably be a puncture plug, a lens such as a contact lens, or an ophthalmic implant such as LACRISERT®. In some embodiments, the medical implantation device is rechargeable so that the micronized lipid particles of the present invention are replenished inside the device after use and the device can be reused. In other preferred embodiments, the device is a single-use device.

[0185] In several preferred embodiments, the drug delivery device of the present invention finds use for the delivery of active drugs to target mucosal surfaces. Exemplary mucosal surfaces include, but are not limited to, the ocular mucosa, vaginal mucosa, cervical mucosa, fallopian tube mucosa, respiratory mucosa, nasal mucosa, oral mucosa, rectal mucosa, digestive mucosa, and esophageal mucosa.

[0186] In some embodiments, the drug delivery vehicle is applied to or administered to a mucosal surface. In some preferred embodiments, the administration is topical. In yet other preferred embodiments, the administration is via retrobulbar, intracavitary, intravitreous, suprachoroidal, and subretinal pathways. In some embodiments, the drug delivery vehicle is applied to or implanted beneath a mucosal surface. In some preferred embodiments, the mucosal surface is the ocular mucosa, and the drug delivery vehicle is implanted or applied beneath the conjunctiva or Tenon's capsule.

[0187] In some preferred embodiments, the active agent is delivered into the target body via the mucosal surface.

[0188] In some preferred embodiments, the drug delivery vehicle of the present invention finds use in the treatment of various disorders, diseases, and conditions. In some preferred embodiments, the disorder, disease, or condition relates to the mucosal surface.

[0189] In some preferred embodiments, the present invention provides a method for treating ocular diseases or disorders selected from the group consisting of dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and associated symptoms, clinical signs or conditions, an unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and associated symptoms or clinical signs, in an animal or human subject requiring such treatment. In some preferred embodiments, the subject requiring treatment may be identified by a less-than-average tear film break time measurement. In some preferred embodiments, a therapeutically effective amount of an active agent formulated as micronized lipid particles is administered to the subject, preferably via the mucosal surface of the eye. In some preferred embodiments, the micronized crystalline or amorphous solid lipid particles are administered to the eye as a suspension in an ophthalmologically acceptable solution. In some preferred embodiments, the micronized crystalline or amorphous solid lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmologically acceptable solution with a shelf life of more than one day at room temperature. In some preferred embodiments, micronized crystalline or amorphous solid lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmologically acceptable solution with a shelf life of more than one week at room temperature. In some preferred embodiments, micronized crystalline or amorphous solid lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmologically acceptable solution with a shelf life of more than one month at room temperature. In some preferred embodiments, micronized crystalline or amorphous solid lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmologically acceptable solution with a shelf life of more than one year at room temperature.

[0190] In some preferred embodiments, the micronized lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmologically acceptable solution with a shelf life of more than one day at room temperature. In some preferred embodiments, the micronized lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmologically acceptable solution with a shelf life of more than one week at room temperature. In some preferred embodiments, the micronized lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmologically acceptable solution with a shelf life of more than one month at room temperature. In some preferred embodiments, the micronized lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmologically acceptable solution with a shelf life of more than one year at room temperature. In yet another preferred embodiment, the solid micronized lipid particles release an active lipid agent or other active agent to the tear film, including the tear lipid layer, over a long period of time. In yet another preferred embodiment, the solid micronized lipid particles release an active lipid agent or other active agent to the tear film, including the tear lipid layer, over a period of 12 to 24 hours after a single administration. In yet another preferred embodiment, solid micronized lipid particles release an active lipid agent or other active agent into the tear film, including the tear lipid layer, over a period of 12 to 24 hours after a single drop applied to the surface of the eyeball. In yet another preferred embodiment, solid micronized lipid particles release an active lipid agent or other active agent into the tear film, including the tear film lipid layer, over a period of 24 hours after a single drop with a volume of less than 50 microliters. In yet another preferred embodiment, the micronized lipid particles are embedded in or injected into an insertion device that can release the micronized lipid particles into the tear film, including the tear lipid layer, over a period of time. Such devices are exemplified by, but are not limited to, puncture plugs, contact lenses, hydroxypropyl cellulose inserts (e.g., LACRISERT®) or other similar devices.

[0191] In other preferred embodiments, the drug delivery device of the present invention finds use in the treatment of diseases or disorders associated with mucosal dysfunction, including dryness of the mouth, nose, or vagina; vaginal yeast infections; respiratory mucosal diseases; candidiasis; surfactant dysfunction; polypeptide antibacterial agents; herpes (caused by both HSV-1 and HSV-2); mucosal pemphigoid; oral lichen planus; Sjögren's syndrome; hirsutism leukoplakia; mucosal pemphigus vulgaris; and chronic aphthous stomatitis. In these embodiments, a therapeutically effective amount of the active agent formulated in micronized lipid particles is administered to the relevant mucosa.

[0192] The present invention is not limited in scope by the exemplary embodiments, which are intended only as examples of specific aspects of the invention. While specific methods for treating mucosal disorders using micronized lipid particles containing an active agent are described herein for the purpose of illustrating aspects in which the invention may be advantageously used, it will be understood that the invention is not limited thereto. For example, the methods and compositions of the present invention may be used to treat other mucosal conditions and disorders not described herein. Therefore, any modifications and alterations that may occur to those skilled in the art are considered to fall within the scope and spirit of the invention as defined in the appended claims. [Examples]

[0193] [Example 1: Synthesis of MCAL-201] 1-Eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG; referred to herein as MCAL-201) is manufactured using a process consisting of four separate chemical steps. The solid active pharmaceutical ingredient (DS) is further processed in a jet mill to produce 1-10 μm sized micronized solid particles suitable for suspension in a phosphate-buffered saline (PBS) vehicle containing polysorbate 80 and xanthan gum to stabilize the suspension of micronized particles.

[0194] MCAL-201 drug (DP) is supplied as a sterile, unprocessed aqueous suspension of jet-milled solid MCAL-201 in a white, single-use high-density polyethylene (HDPE) dropper vial for direct administration to the ocular surface as 35 μL eye drops.

[0195] MCAL-201 is 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and has the following structure:

[0196] [ka]

[0197] The general and physicochemical properties of MCAL-201 are as follows: The molecular weight of 1,2-EPRG is 611.05 g / mol Experimental formula: C 39 H 78 O4 Appearance: White powder Particle size: 1-10μm (after micronization) Moisture absorption: Low Chirality: Racemic Enantiomer excess: 0 Melting point: 57℃ Solubility: Insoluble in water. Soluble in chloroform (40 mg / mL) and castor oil (25 mg / mL).

[0198] In the manufacturing process, MCAL-201, the active pharmaceutical ingredient (API), is produced as a 1:1 racemic mixture of two enantiomers through a series of individual synthesis steps starting from a racemic solketal. The unit operation sequence is shown in Figure 1.

[0199] A 420-gram lot of MCAL-201 was manufactured. The Certificate of Analysis (CoA) indicates that the drug of MCAL201 is a 99:1 mixture of 1,2-EPRG and 1,3-EPRG. This lot was used in non-clinical trials, which are described in more detail herein. Following the synthesis described in Figure 1, MCAL-201 was further processed by jet pulverization or spray drying to obtain particulate matter size ranges of 1–10 microns, determined by dynamic light scattering (DLS) of the pulverized solid suspended in PBS (see Figure 2).

[0200] Solubilizing MCAL-201 in aqueous formulations for delivery as eye drops without micronization proved difficult due to MCAL-201's extreme insolubility in water. However, the preparation of a water-soluble cyclodextrin inclusion complex of MCAL-201 was used in non-clinical efficacy studies. Furthermore, a solution of MCAL-201 in castor oil, which can be emulsified into micron-sized liquid particles in an aqueous buffer, can be used for direct delivery of MCAL-201 to the tear lipid layer.

[0201] These cyclodextrin and emulsified castor oil formulations proved effective in animal models of dry eye. MCAL-201 lacked long-term chemical stability in the liquid solution phase due to an unacid level of palmitoyl acyl transfer from position 2 to the more thermodynamically stable position 3 of MCAL-201. The isomer stability of MCAL-201 in the solid phase was observed to be much higher than in solution. This led to the development of solid MCAL-201 delivery as a suspension of crystalline or amorphous micronized solid particles suspended in an aqueous formulation isotonic with tears. The crystalline MCAL-201 drug was suspended in phosphate-buffered saline (PBS), but could be suspended after micronization to 1-10 micron particles that could be stably suspended in PBS with the help of polysorbate 80 as a wetting agent and xanthan gum to adjust the density and viscosity of the drug.

[0202] [Example 2: Micronization of MCAL-201] MCAL-201 is a crystalline solid (mp57°C) with a low-density, fluid texture similar to powdered snow. Therefore, 50g of MCAL-201 active pharmaceutical ingredient fills a bottle designed to hold 500mL of a dense liquid or solid, such as powdered sugar. Two pulverization methods, spray drying and jet pulverization, appear to be suitable for MCAL-201.

[0203] [Spray drying method:] A solution of MCAL-201 in chloroform (3% w / w) was sprayed into a Buchi B-290 spray dryer in an inert gas stream to create an aerosol at an inlet temperature of 85 degrees Celsius over a 10-minute timeframe. This rate was chosen to ensure that the solid pulverized particles formed as amorphous solid particles, presumably at least 10 degrees below the crystalline melting point. Collection of the pulverized particles was carried out in a chamber with a cyclone stream from a pressurized inlet gas to an outlet vacuum pressure, after most of the solvent (chloroform) had evaporated and condensed separately. 50% of the injected MCAL-201 formed amorphous pulverized solid particles in the collection chamber. The average particle size was 8.6 microns, with a relatively tight particle size dispersion between 7 and 11 microns, as determined by dynamic light scattering. These particles were dried in vacuum until the residual chloroform was below the limit of quantification (gas chromatography).

[0204] Similarly, a solution of MCAL-201 in chloroform (3% w / w) containing cyclosporine (0.33% w / w) was sprayed into a Buchi B-290 spray dryer in an inert gas stream to create an aerosol at an inlet temperature of 85 degrees Celsius over a 10-minute timeframe. Collection of the pulverized particles was performed in a chamber with a cyclone stream from a pressurized inlet gas to an outlet vacuum pressure, after most of the solvent (chloroform) had evaporated and condensed separately. These particles were dried in vacuum until the residual chloroform was below the limit of quantification (gas chromatography).

[0205] [Jet pulverization method:] Crystalline solid MCAL-201 was fed into the grinding chamber of a spiral mill under a high-speed gas jet (e.g., supersonic) to induce high-energy interparticle collisions and fracture of MCAL-201 particles. These particles were constantly swept toward the center of the grinding chamber by a cyclone flow. Particles smaller than 10 microns were swept into the collection chamber by the cyclone flow. A considerable amount of MCAL-201 remained adhering to the chamber walls. Three lots of pulverized MCAL-201 with an average particle size of less than 10 microns were prepared. All had a particle size distribution of 1 to 15 microns, with the smallest particle size distribution being 1 to 10 microns. The average particle size of this lot was 3.56 microns and was carried over to the suspension development study described later.

[0206] [Example 4: Formulation of MCAL-201] MCAL-201 is a nonpolar ether lipid first identified in the secretions of rabbit Harderian's glands. It is a nonpolar lipid of the 1-O-ether, 2-ester glycerol (1,2-EPRG) class associated with the hyperstability of the tear lipid layer and long blink intervals (e.g., exceeding 20 minutes) observed in rabbits. MCAL-201 is chemically synthesized under cGMP conditions and used in humans.

[0207] MCAL-201 pharmaceutical (DP) is a milky white suspension of finely ground solid MCAL-201 particles. Each mL of the 0.1% suspension contains 1 mg of the active ingredient MCAL-201. The pharmaceutical can be formulated in 0.0001%, 0.001%, 0.01%, 0.1%, 0.3%, 1%, and 5% suspensions of finely ground solid MCAL-201. The pharmaceutical is aseptically filled into sterile HDPE bottles with a dropper tip and protective cap, each with a volume of 35 μL per drop. The pharmaceutical is either stored or unstored. The container closure system is separately sterilized by gamma irradiation before filling with DP.

[0208] Table 1 shows exemplary product batch compositions.

[0209] [Table 1]

[0210] MCAL-201 is formulated at the following concentrations: 0.0001%, 0.001%, 0.01%, 0.1%, 0.3%, and 1%. The finely ground MCAL-201 is mixed with polysorbate 80 as a wetting agent. The remaining excipients are weighed and dissolved in PBS to a target concentration of 260–320 mOsm / L. PBS containing 0.1–0.3% (w / v) xanthan gum as a viscosity and density modifier is added to the MCAL-201 / polysorbate 80 mixture while homogenizing to obtain a milky white suspension of solid MCAL-201 containing 0.001–10 (or TBD) mg / mL of the suspension agent. The pH is adjusted with 1N HCl or 1N NaOH to 6.5–7.2. The final polysorbate 80 concentration is 3% or less, and the final xanthan gum concentration is 0.1–0.3%. The suspension is analyzed for MCAL-201 content, MCAL-201 isomer content, particle size distribution, pH, denaturation, and osmotic pressure. The formulated stock solution is aseptically filled into 7.5 mL sterile HDPE bottles containing LDPE dropper tips and polypropylene cap closures. Table 2 shows the analytical specifications for the drug.

[0211] [Table 2]

[0212] Crystalline MCAL-201 is micronized into crystalline and amorphous solid particles of 1–10 microns (see Figure 2). Treatment of these particles with polysorbate 80 (0.3% w / w) as a wetting agent yields a suspension of the micronized particles in a mixture of xanthan gum (0.1–0.3% w / w, see Figure 3) in phosphate-buffered saline (PBS, pH 6–8, 260–320 mOsm / L), suitable for administration as a stable topical drop or injectable suspension. The physical stability of the micronized suspension against separation of the micronized solid particles by suspension, sedimentation, or aggregation has been demonstrated for over 6 months at room temperature. Recovery of the micronized solid particles from the formulation by centrifugation and washing with water demonstrates the chemical and isomeric stability of MCAL-201 to the micronization process (see Figure 4), and the isomeric stability of micronized MCAL-201 in the suspension formulation at room temperature for 6 weeks (see Figure 5).

[0213] [Example 3: Toxicity and Tolerability Test] A dose-ranging pharmacological and toxicity study of non-GLP topical intraocular administration of MCAL-201 was conducted in dogs with no prior medication history. The primary objective of the study was to evaluate the tolerability of topical intraocular administration of MCAL-201 in dogs, with a secondary objective of obtaining data supporting pharmacological activity in healthy dogs.

[0214] The effects of administering MCAL-201 at doses of 0.1, 0.5, 1, 3, and 10 mg / mL via bilateral 35 μL droplets (0.0035, 0.0175, 0.035, 0.105, and 0.35 mg / eye / day) were evaluated in Part I. The administration regimens are summarized in Section 3.

[0215] [Table 3]

[0216] The evaluated eye endpoints were summarized in Table 4. Scoring of the ocular surface and anterior segment was performed by a board-certified veterinary ophthalmologist using the SPOTS system. SPOTS was performed for each evaluation concentration. To measure TBUT, fluorescein was instilled into the eye, the eye was gently closed by hand and then gently opened, simulating a blink. The time interval in seconds from eye opening to the first sign of disruption of the uniform tear film indicated by the break in fluorescein was recorded. This procedure was repeated three times in both eyes, first in the right eye and then in the left eye. After administration of 10 mg / mL of MCAL-201 BID, SPOTS was also performed 48 hours after the last dose.

[0217] [Table 4]

[0218] The tolerability of MCAL-201 was good, and no ocular or systemic adverse events were observed at any of the evaluated times or concentrations (up to 10 mg / mL OU BID for 48 hours). MCAL-201 extended TBUT in five healthy adult dogs (Figure 6).

[0219] [Others] [1] A lipid particle composition comprising solid non-polar lipid particles containing an active lipid agent, the solid non-polar lipid particles having an average particle size of less than 50 microns and being stably suspended in an aqueous buffer vehicle suitable for topical administration. [2] The lipid particle composition according to [1], wherein the solid non-polar lipid particles have a melting point of less than 80°C. [3] The lipid particle composition according to [1], wherein the solid non-polar lipid particles have a melting point of 20 to 80°C. [4] The lipid particle composition according to [1], wherein the solid non-polar lipid particles have a melting point of 30 to 60°C. [5] The lipid particle composition according to any one of [1] to [4], wherein the solid non-polar lipid particles have an average particle size of less than 20 microns. The lipid particle composition according to any one of [1] to [5], wherein the solid nonpolar lipid particles have an average particle diameter of less than 10 microns. The lipid particle composition according to any one of [1] to [6], wherein the active lipid agent is a nonpolar ether lipid. [8] The lipid particle composition according to any one of [1] to [7], wherein the solid nonpolar lipid particles contain an active lipid agent selected from the group consisting of:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[10] The lipid particle composition according to any one of [1] to [9], characterized in that the solid nonpolar lipid particles contain an active lipid agent selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG), sn-1-O-eicosanyl-2-palmitoyl-glycerol, sn-2-palmitoyl-3-O-eicosanyl-glycerol, 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), sn-1-O-eicosanyl-3-palmitoyl-glycerol, sn-1-palmitoyl-3-O-eicosanyl-glycerol and mixtures thereof.

[11] The lipid particle composition according to

[10] , characterized in that the solid nonpolar lipid particles contain an active lipid agent selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) and mixtures thereof.

[12] The lipid particle composition according to

[11] , characterized in that a mixture of the ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 95% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[13] The lipid particle composition according to

[11] , characterized in that a mixture of the ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 98% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[14] The lipid particle composition according to

[11] , characterized in that a mixture of the ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 99% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[15] The lipid particle composition according to

[11] , wherein the mixture of ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomer and 5% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomer.

[16] The lipid particle composition according to

[11] , wherein the mixture of ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomer and 2% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomer.

[17] The lipid particle composition according to

[11] , wherein the mixture of ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomer and 1% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomer.

[18] The lipid particle composition according to any one of [1] to

[17] , wherein the solid nonpolar lipid particles further contain one or more additional lipids selected from the group consisting of nonpolar mono-, di- or tri-glycerides, wax esters containing cholesterol esters, sterols, free fatty acids and combinations thereof.

[19] The lipid particle composition according to any one of [1] to

[18] , characterized in that the aqueous buffer vehicle comprises phosphate-buffered saline (PBS), 3% or less (w / w of the vehicle) of polysorbate 80 and 0.3% or less (w / w of the vehicle) of xanthan gum, and has a pH of 6.5 to 8.0 and an osmotic pressure of 260 to 320 mOsm / L.

[20] The lipid particle composition according to any one of [1] to

[19] , characterized in that the suspended particles are stable at room temperature for 6 months with respect to phase separation from the suspension.

[21] The lipid particle composition according to

[20] , characterized in that the suspended particles are chemically stable against <5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 6 months.

[22] The lipid particle composition according to any one of [1] to

[19] , characterized in that the suspended particles are stable at room temperature for 24 months with respect to phase separation from the suspension.

[23] The lipid particle composition according to

[22] , characterized in that the suspended particles are chemically stable against <5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 24 months.

[24] A lipid particle composition according to any one of [1] to

[23] , characterized in that the composition is sterile.

[25] A lipid particle composition according to any one of [1] to

[24] , characterized in that the composition contains a preservative.

[26] The lipid particle composition according to any one of [1] to

[25] , characterized in that the suspension does not contain a preservative.

[27] The lipid particle composition according to any one of [1] to

[26] , characterized in that the aqueous buffer vehicle is an ophthalmologically acceptable carrier.

[28] The lipid particle composition according to any one of [1] to

[27] , characterized in that the aqueous buffer vehicle further comprises an agent selected from the group consisting of buffering agents, tonics, wetting agents, thickeners / viscosities, density modifiers and combinations thereof.

[29] The lipid particle composition according to any one of [1] to

[28] , characterized in that the active lipid agent in the solid nonpolar lipid particles is released from the solid nonpolar lipid particles as individual molecules for a certain period of time after being administered as eye drops.

[30] The lipid particle composition according to

[29] , characterized in that individual molecules are released over a period of 1 to 24 hours.

[31] The lipid particle composition according to any one of [1] to

[30] , characterized in that the suspension is provided by a dropper dispenser.

[32] A method for treating an eye disease or disorder selected from the group consisting of dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and associated symptoms, clinical signs or conditions, an unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and associated symptoms or clinical signs, in animals or human subjects requiring such treatment, A method comprising topically administering a lipid particle composition according to any one of [1] to

[31] , which contains an effective amount of an active lipid agent, to the eye of a subject.

[33] The method according to

[32] , characterized in that the subject requiring treatment has a tear film break time less than the normal clinical range of TBUT in a normal healthy population in the United States.

[34] A lipid particle composition according to any one of [1] to

[31] for use in the treatment of an eye disease or disorder selected from the group consisting of dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and associated symptoms, clinical signs or conditions, an unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and associated symptoms or clinical signs, in animals or human subjects requiring such treatment.

[35] A drug delivery vehicle comprising solid nonpolar lipid particles having an average particle size of less than 50 microns, wherein the particles contain an active agent other than the lipids that form the solid nonpolar lipid particles.

[36] The drug delivery vehicle according to

[35] , characterized in that the solid nonpolar lipid particles have a melting point of less than 80°C.

[37] The drug delivery vehicle according to

[35] , characterized in that the solid nonpolar lipid particles have a melting point of 20 to 80°C.

[38] The drug delivery vehicle according to

[35] , characterized in that the solid nonpolar lipid particles have a melting point of 30 to 60°C.

[39] The drug delivery vehicle according to any one of

[35] to

[38] , characterized in that the solid nonpolar lipid particles have an average particle size of less than 20 microns.

[40] The drug delivery vehicle according to any one of

[35] to

[39] , characterized in that the solid nonpolar lipid particles have an average particle size of less than 10 microns.

[41] The drug delivery vehicle according to any one of

[35] to

[40] , characterized in that the solid nonpolar lipid particles contain ether lipids selected from the group consisting of: [ka] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is an unsubstituted C5-C29 alkyl or alkenyl; and R3 is hydrogen (i.e., H); [ka] Here R1 is hydrogen (i.e., H); R2 is an unsubstituted C5-C29 alkyl or alkenyl; and R3 is an unsubstituted C6-C30 alkyl or alkenyl; and [ka] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is an unsubstituted C5-C29 alkyl or alkenyl; and R3 is hydrogen (i.e., H).

[42] The drug delivery vehicle according to any one of

[35] to

[41] , characterized in that the solid nonpolar lipid particles contain ether lipids selected from the group consisting of: [ka] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29 alkyl or alkenyl; [ka] Here R1 is an unsubstituted C5-C29 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C6-C30 alkyl or alkenyl; and [ka] Here R1 is an unsubstituted C6-C30 alkyl or alkenyl; R2 is hydrogen (i.e., H); and R3 is an unsubstituted C5-C29 alkyl or alkenyl.

[43] A drug delivery vehicle according to any one of

[35] to

[42] , characterized in that the solid nonpolar lipid particles include ether lipids selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG), sn-1-O-eicosanyl-2-palmitoyl-glycerol, sn-2-palmitoyl-3-O-eicosanyl-glycerol, 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), sn-1-O-eicosanyl-3-palmitoyl-glycerol, sn-1-palmitoyl-3-O-eicosanyl-glycerol and mixtures thereof.

[44] The drug delivery vehicle according to

[43] , characterized in that the solid nonpolar lipid particles contain ether lipids selected from the group consisting of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) and mixtures thereof.

[45] A drug delivery vehicle according to

[44] , characterized in that a mixture of the ether lipid isomer 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG), and a mixture thereof, contains more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 95% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[46] The drug delivery vehicle according to

[44] , characterized in that a mixture of the ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 98% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[47] The drug delivery vehicle according to

[44] , characterized in that a mixture of the ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers or more than 99% (mol%) of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[48] ​​A drug delivery vehicle according to

[44] , characterized in that a mixture of the ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 95% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 5% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[49] The drug delivery vehicle according to

[44] , characterized in that a mixture of the ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 98% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 2% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[50] A drug delivery vehicle according to

[44] , characterized in that a mixture of the ether lipid isomers 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) contains more than 99% (mol%) of 1-O-eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG) isomers and 1% (mol%) or less of 1-O-eicosanyl-3-palmitoyl-rac-glycerol (1,3-EPRG) isomers.

[51] The drug delivery vehicle according to any one of

[35] to

[50] , characterized in that the solid nonpolar lipid particles further comprise one or more additional lipids selected from the group consisting of nonpolar mono-, di-, or tri-glycerides, wax esters containing cholesterol esters, sterols, free fatty acids, and combinations thereof.

[52] A drug delivery vehicle according to any one of the claims

[35] to

[51] , wherein the active agent is selected from the group consisting of over-the-counter (OTC) or prescription topical ophthalmic drugs, OTC or prescription topical ophthalmic drugs for the treatment of dry eye, NMDA antagonists, antibacterial agents, antihistamines, decongestants, anti-inflammatory agents, antiparasitic agents, myotics, sympathomimetic agents, anticholinergics, adrenaline agents, antiviral agents, local anesthetics, antifungal agents, amoebic anthelmintics, trichomonazoles, analgesics, mydriatics, antiglaucoma agents, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic drugs used as adjuvants in surgery, chelating agents, anticancer agents, antihypertensive agents, muscle relaxants, diagnostic agents, adrenergic anesthetics, β-blockers, α2-agonists, cycloplengic, prostaglandins, and combinations thereof.

[53] The drug delivery vehicle according to any one of

[35] to

[52] , characterized in that the solid nonpolar lipid particles are formulated as an aqueous suspension in a physiologically acceptable carrier.

[54] The drug delivery vehicle according to

[53] , characterized in that the liquid composition is a suspension of solid micronized lipid particles in water containing phosphate-buffered saline (PBS), 3% or less (w / w of the vehicle) of polysorbate 80 and 0.3% or less (w / w of the vehicle) of xanthan gum, and has a pH of 6.5 to 8.0 and an osmotic pressure of 260 to 320 mOsm / L.

[55] The drug delivery vehicle according to any one of

[53] to

[54] , characterized in that the suspension is stable at room temperature for 6 months with respect to phase separation of solid nonpolar lipid particles in the suspension.

[56] The drug delivery vehicle according to

[55] , characterized in that the suspension is chemically stable against <5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 6 months.

[57] The drug delivery vehicle according to any one of

[53] to

[56] , characterized in that the suspension is stable at room temperature for 24 months with respect to phase separation of solid nonpolar lipid particles in the suspension.

[58] The drug delivery vehicle according to

[57] , characterized in that the suspension is chemically stable against <5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 24 months.

[59] The drug delivery vehicle according to any one of

[53] to

[58] , characterized in that the suspension is sterile.

[60] The drug delivery vehicle according to any one of

[53] to

[59] , characterized in that the suspension contains a preservative.

[61] The drug delivery vehicle according to any one of

[53] to

[59] , characterized in that the suspension does not contain a preservative.

[62] The drug delivery vehicle according to any one of

[53] to

[61] , characterized in that the physiologically acceptable carrier is an ophthalmologically acceptable carrier.

[63] The drug delivery vehicle according to

[62] , characterized in that the ophthalmologically acceptable carrier comprises a drug selected from the group consisting of buffers, tonics, wetting agents, thickeners / viscosities, density modifiers and combinations thereof.

[64] A drug delivery vehicle according to any one of

[53] to

[63] , characterized in that the active agent is released from the solid nonpolar lipid particles as individual molecules of the active agent for a certain period of time after being administered as eye drops.

[65] The drug delivery vehicle according to

[64] , characterized in that the individual molecules are released over a period of 1 to 24 hours.

[66] The drug delivery vehicle according to any one of

[53] to

[65] , characterized in that the suspension is provided by a dropper dispenser.

[67] The drug delivery vehicle according to any one of

[35] to

[52] , characterized in that the drug delivery vehicle is a medical insertion device.

[68] The drug delivery vehicle according to

[67] , characterized in that the medical insertion device is formed from a physiologically acceptable material.

[69] The drug delivery vehicle according to

[68] , characterized in that the physiologically acceptable material is a polymer.

[70] The drug delivery vehicle according to

[68] , characterized in that the physiologically acceptable material is selected from the group consisting of hydroxypropyl cellulose, hydrogel, polymethyl methacrylate, and silicone acrylate.

[71] The drug delivery vehicle according to any one of

[67] to

[70] , characterized in that the medical insertion device is selected from the group consisting of puncture plugs, contact lenses, and ophthalmic insertion devices.

[72] The drug delivery vehicle according to any one of

[67] to

[71] , characterized in that the medical insertion device is rechargeable.

[73] The drug delivery vehicle according to any one of

[67] to

[71] , characterized in that the medical insertion device is for single use.

[74] A drug delivery vehicle according to any one of

[67] to

[73] , characterized in that the medical insertion device is fitted to the mucosal surface.

[75] The drug delivery vehicle according to

[74] , characterized in that the mucosal surface is selected from the group consisting of the ocular mucosal surface, the vaginal mucosal surface, the nasal mucosal surface, the oral pharyngeal mucosal surface, the oral mucosal surface, and the rectal mucosal surface.

[76] A method for delivering an active agent to a target that requires it, A method comprising administering a drug delivery vehicle described in any one of items

[35] to

[75] locally to the subject.

[77] The method according to

[76] , characterized in that the drug delivery vehicle is administered to the mucosal surface of the target.

[78] The method according to any one of

[76] to

[77] , characterized in that the mucosal surface is selected from the group consisting of the ocular mucosa, vaginal mucosa, fallopian tube mucosa, respiratory system mucosa, nasal mucosa, oral pharyngeal mucosa, oral mucosa, rectal mucosa, digestive system mucosa, and esophageal mucosa.

[79] The method according to

[78] , characterized in that the drug delivery vehicle is applied or implanted under the mucosal surface.

[80] The method according to

[79] , characterized in that the mucosal surface is the ocular mucosa and the drug delivery vehicle is implanted or applied under the conjunctiva or Tenon's capsule.

[81] The method according to any one of

[79] to

[80] , characterized in that the drug delivery vehicle is applied to the surface of the ocular mucosa by a delivery route selected from the group consisting of retrobulbar, intracavitary, intravitreous, suprachoroidal and subretinal delivery routes.

[82] A method for treating an eye disease or disorder selected from the group consisting of dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and related symptoms or conditions, an unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and related symptoms or clinical signs, in an animal or human subject requiring such treatment, A method comprising topically administering a drug delivery vehicle according to any one of

[35] to

[75] , comprising an effective amount of an active lipid agent, to the eye of the subject.

[83] The method according to

[82] , characterized in that the subject requiring treatment has a tear film break time less than the normal clinical range of TBUT in a normal healthy population in the United States.

[84] A drug delivery vehicle according to any one of paragraphs

[35] to

[75] for use in the treatment of an eye disease or disorder selected from the group consisting of dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and related symptoms or conditions, an unstable tear film resulting in rapid tear evaporation, and keratoconjunctivitis sicca (dry eye) and related symptoms or clinical signs, in an animal or human subject requiring such treatment.

Claims

[Claim 1] A lipid particle composition, A lipid particle composition characterized by comprising solid nonpolar lipid particles containing an active lipid agent, wherein the solid nonpolar lipid particles have an average particle size of less than 50 microns and are stably suspended in an aqueous buffer vehicle suitable for topical administration.

Images