KR20240004849A - finely divided lipids - Google Patents

Abstract

The present invention relates to a drug delivery vehicle comprising finely divided particles comprising an active lipid agent, in particular sn -1-O-eicosanyl- sn -2-palmitoyl-glycerol ( sn -1-O-eicosanyl- sn It relates to finely divided lipid particles containing ether lipids such as -2-palmitoyl-glycerol).

Description

finely divided lipids

The present invention relates to a drug delivery vehicle comprising micronized particles comprising an active lipid agent, in particular sn -1-O-eicosanyl- sn -2-palmitoyl-glycerol ( sn -1-O-eicosanyl- sn -2-palmitoyl-glycerol) and isomers thereof.

Dry eye syndrome is caused by chronic lack of lubrication and moisture on the ocular surface. The consequences of dry eye can range from subtle but persistent eye irritation to severe inflammation and even scarring on the front of the eye. Evaporative dry eye, the main form of dry eye, is associated with meibomian gland dysfunction, where deficiency and instability of the tear film lipid layer lead to several sequelae, including increased tear evaporation and tear film instability. You can. Therefore, evaporative dry eye, meibomian gland dysfunction, and resulting tear film instability contribute to both lack of lubrication and hydration of the ocular surface in dry eye. Chadya et al., Meibomian gland disease: the role of gland dysfunction in dry eye disease, Ophthalmology. 2017 Nov; 124 (11 Suppl): S20-S26, the contents of which are incorporated herein by reference.

In addition to being called dry eye syndrome, dry eye disease, or simply “dry eye,” alternative medical terms to describe dry eye include: Keratitis refers to dryness and inflammation of the cornea. Keratoconjunctivitis sicca is dry eye that affects both the cornea and conjunctiva.

Dry eye is one of the most common eye diseases worldwide and the main 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 up to 50% in several study populations around the world. Risk factors for dry eye syndrome included older age, female sex, and computer use. Symptoms of dry eye include burning, itching, pain, heaviness in the eyes, eye strain, eye pain, dryness, redness, photophobia, and blurred vision. Clinical signs of dry eye include decreased tear production, as measured by the Schirmer tear test, and defects in the integrity of the corneal epithelium, as measured by biometric staining of the cornea (e.g., fluorescein). , especially tear film instability, including instability of the tear film lipid layer as measured by a decrease in tear film break-up time (TBUT).

Tears contain aqueous, mucin, and lipid components. Each time you blink, the aqueous and lipid components are intimately mixed and sorted into the inner aqueous and outer lipid layers of the tear film. Within the lipid layer, polar and nonpolar lipids self-sort, with the polar lipids forming a monolayer at the aqueous interface and the nonpolar lipids forming a thicker outer layer of the tear film lipid layer that directly faces the air. form The non-polar outer layer of the tear film lipid layer (TFLL) can be 5 to 50 molecules thick. An adequate and consistent tear layer on the surface of the eye is essential to keeping the eye healthy, comfortable, and able to see well. The tear film keeps the surface of the eye moist and flushes away dust, debris, and microorganisms that can damage the cornea and cause inflammation and/or infection in the eye. As previously mentioned, the normal tear film is composed of three important components: an oil (lipid) component, a water (aqueous) component, and a mucus-like (mucin) component. Each component of the tear film plays an important role. For example, tear lipids help prevent the aqueous layer of the tear film from evaporating too quickly and increase lubricity, while mucins (water-soluble and cell-associated) help anchor and spread tears across the living surface of the corneal epithelium. The aqueous component is the thickest layer of the precorneal tear film and contains various proteins, including lysozyme and immunoglobulins, which play a role in preventing microbial colonization. Regarding the tear film, see Yanez-Soto et al., Interfacial phenomena and the ocular surface, Ocul Surf. 2014 Jul;12(3):178-201, the contents of which are hereby incorporated by reference in their entirety.

Each component of tears is produced by various glands located in or near the eye. The oil component is produced by the meibomian glands in the eyelids, or by the harderian glands in species that have harderian glands (e.g., rabbits). The aqueous component is produced (in humans) by the lacrimal gland, located on the outside of the upper eyelid. Many vertebrate species also have accessory lacrimal glands (e.g., the accessory lacrimal glands associated with the third eyelid in dogs). Water-soluble mucin components are produced in the goblet cells of the conjunctiva, which covers the white of the eye (sclera). Problems with any of these sources of tear film components can cause tears to become unstable and dry eyes.

Effective treatments for dry eye and effective delivery systems for these treatments are needed.

SUMMARY OF THE INVENTION

The present invention relates to a drug delivery vehicle comprising finely divided particles comprising an active lipid agent, in particular sn -1-O-eicosanyl- sn -2-palmitoyl-glycerol ( sn -1-O-eicosanyl- sn -2-palmitoyl-glycerol) and its isomers, analogs and homologs.

In some preferred embodiments, the present invention provides a drug delivery vehicle comprising crystalline and amorphous solid finely divided lipid particles having an average particle size of less than 100 microns, the particles comprising an active agent, The drug delivery vehicle herein is selected from the group selected from therapeutic compositions, physiologically compatible carriers, and medical implantable devices.

In a first aspect, the invention provides a lipid particle composition comprising solid non-polar lipid particles comprising an active lipid agent, having an average particle size of less than 50 microns, stably suspended in a buffered aqueous vehicle suitable for topical administration. .

In some preferred embodiments, the solid non-polar lipid particles have a melting point below 80°C. In some preferred embodiments, the solid non-polar lipid particles have a melting point between 20 and 80°C. In some preferred embodiments, the solid non-polar lipid particles have a melting point between 30 and 60°C. In some preferred embodiments, the solid non-polar lipid particles have an average particle size of less than 20 microns. In some preferred embodiments, the solid non-polar lipid particles have an average particle size of less than 10 microns.

In some preferred embodiments, the active lipid agent is a non-polar ether lipid.

In some preferred embodiments, the solid non-polar lipid particles comprise an active lipid agent selected from the following group:

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₃ is hydrogen (ie H);

here,

R ₁ is hydrogen (ie H);

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₃ is hydrogen (i.e. H).

In some preferred embodiments, the solid non-polar lipid particles comprise an active lipid agent selected from the group:

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

here,

R ₁ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl.

In some preferred embodiments, the solid non-polar lipid particle is 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1-O-eicosanyl-2-palmitoyl- rac -glycerol, 1,2-EPRG), sn- 1-O-eicosanyl-2-palmitoyl-glycerol ( sn -1-O-eicosanyl-2-palmitoyl-glycerol), sn -2-palmitoyl-3-O-eicosanyl-glycerol ( sn -2-palmitoyl-3-O-eicosanyl-glycerol), 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1-O-eicosanyl-3-palmitoyl- rac -glycerol, 1,3- EPRG), sn -1-O-eicosanyl-3-palmitoyl-glycerol ( sn -1-O-eicosanyl-3-palmitoyl-glycerol), sn -1-palmitoyl-3-O-eicosanyl-glycerol ( sn -1-palmitoyl-3-O-eicosanyl-glycerol) and these It includes an active lipid agent selected from the group consisting of a mixture of. In some preferred embodiments, the solid non-polar lipid particles are 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl- rac -glycerol ( 1,3-EPRG) and mixtures thereof.

In some preferred embodiments, 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), the mixture comprises more than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl-3 -palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises more than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl-3 -palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises more than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl-3 It is characterized in that it contains more than 99% (mol%) of the -palmitoyl- rac -glycerol (1,3-EPRG) isomer.

In some preferred embodiments, 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), the mixture comprises more than 50% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 50% (mol%). In some preferred embodiments, 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), the mixture contains up to 50% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains more than 50% (mol%).

In some preferred embodiments, 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), the mixture comprises more than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 5% (mol%). In some preferred embodiments, 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), the mixture comprises more than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 2% (mol%). In some preferred embodiments, 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), the mixture comprises more than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 1% (mol%).

In some preferred embodiments, the solid non-polar lipid particles are non-polar mono-, di-, or tri-glycerides, wax esters, including cholesterol esters, sterols, free fatty acids and the like. It further includes one or more additional lipids selected from the group consisting of a combination of. In some preferred embodiments, the aqueous buffered vehicle is phosphate buffered saline (PBS), up to 3% (w/w of vehicle) polysorbate 80, and up to 0.3% (w/w) of xanthan gum. It has a pH of 6.5 to 8.0 and an osmotic pressure of 260 to 320 mOsm/L.

In some preferred embodiments, the suspended particles are stable to phase separation from suspension for 6 months at room temperature. In some preferred embodiments, the suspended particles are chemically stable with less than 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 to phase separation from the suspension for 24 months at room temperature. In some preferred embodiments, 1,2-EPRG is chemically stable with less than 5% isomerization to the isomer 1,3-EPRG during storage for 24 months at room temperature.

In some preferred embodiments, the composition is sterile. In some preferred embodiments, the composition includes a preservative. In some preferred embodiments, the composition contains no preservatives. In some preferred embodiments, the aqueous buffered vehicle is an ophthalmolgically acceptable carrier. In some preferred embodiments, the aqueous buffering vehicle contains a buffering agent, a tonicity agent, a wetting agent, a thickening agent and a viscosity agent, a density adjusting agent, and It further includes an agent selected from the group consisting of combinations thereof.

In some preferred embodiments, the active lipid agent within the solid non-polar lipid particle is released as individual molecules from the solid non-polar lipid particle over a period of time after administration as an ophthalmic drop. In some preferred embodiments, individual molecules are released over a period of 1 to 24 hours. In some preferred embodiments, the suspension is provided in a drop dispenser.

In some preferred embodiments, the present invention relates to evaporative dry eye, meibomian gland dysfunction and symptoms, clinical signs or conditions associated therewith, and unstable tear film in an animal or human subject in need of treatment for an eye disease or condition. Provided is a method of treating an eye disease or condition selected from the group consisting of rapid aqueous tear evaporation and keratoconjunctivitis sicca (dry eye) and symptoms or clinical signs associated therewith, comprising administering an effective amount of an active lipid agent. and topically administering to the eye of a subject a lipid particle composition as described above, comprising: In some preferred embodiments, the subject in need of treatment has a tear film breakup time (TBUT), e.g., relative to a normal healthy population in the United States or other countries. ) is shorter than the normal clinical range. In some preferred embodiments, the above methods provide an improvement in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, eye dryness, biostaining of the conjunctiva or cornea, and Schirmer tear testing (e.g., as reported in controls or patients). compared to what was provided).

In some preferred embodiments, the present invention relates to dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and symptoms, clinical signs or conditions related thereto, in an animal or human subject in need of treatment for a disease or condition of the eye. , for use in the treatment of diseases or diseases of the eye selected from the group consisting of rapid aqueous tear evaporation due to unstable tear film and keratoconjunctivitis sicca (dry eye) and symptoms or clinical signs related thereto, as described above. Provided is a use of a lipid particle composition. In some preferred embodiments, administration of the composition results in an improvement in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, eye dryness, biostaining of the conjunctiva or cornea, and Schirmer tear testing (e.g., in controls or patients). compared to reported).

In a second aspect, the present invention provides a drug delivery vehicle comprising solid non-polar lipid particles having an average particle size of less than 100 microns, preferably less than 50 microns, wherein the particles contain an active agent other than a lipid forming the solid non-polar lipid particles, which In the lipids within the particle, a second active agent may be referred to, for example, the ether lipids described herein may be referred to as a first active agent).

In some preferred embodiments, the solid non-polar lipid particles have a melting point below 80°C. In some preferred embodiments, the solid non-polar lipid particles have a melting point between 20 and 80°C. In some preferred embodiments, the solid non-polar lipid particles have a melting point between 30 and 60°C. In some preferred embodiments, the solid non-polar lipid particles have an average particle size of less than 20 microns. In some preferred embodiments, the solid non-polar lipid particles have an average particle size of less than 10 microns.

In another preferred embodiment, the solid non-polar lipid particle comprises an ether lipid selected from the following group:

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₃ is hydrogen (ie H);

here,

R ₁ is hydrogen (ie H);

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₃ is hydrogen (i.e. H).

In some preferred embodiments, the solid non-polar lipid particles comprise ether lipids selected from the group:

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

here,

R ₁ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl.

In some preferred embodiments, the solid non-polar lipid particles are 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG), sn -1-O-eicosanyl-2-palmitoyl-glycerol ( sn -1-O-eicosanyl-2-palmitoyl-glycerol), sn -2-palmitoyl-3-O-eicosanyl-glycerol ( sn -2-palmitoyl-3-O-eicosanyl-glycerol), 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1-O-eicosanyl-3-palmitoyl- rac -glycerol, 1,3- EPRG), sn -1-O-eicosanyl-3-palmitoyl-glycerol ( sn -1-O-eicosanyl-3-palmitoyl-glycerol), sn -1-palmitoyl-3-O-eicosanyl-glycerol ( sn -1-palmitoyl-3-O-eicosanyl-glycerol) and these It includes an ether lipid selected from the group consisting of a mixture of. In some preferred embodiments, the solid non-polar lipid particles are 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl- rac -glycerol ( 1,3-EPRG) and mixtures thereof.

In some preferred embodiments, 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), the mixture comprises more than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl-3 -palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises more than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl-3 -palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises more than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl-3 Characterized by comprising more than 99% (mole %) of the -palmitoyl- rac -glycerol (1,3-EPRG) isomer.

In some preferred embodiments, 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), the mixture comprises more than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 5% (mol%). In some preferred embodiments, 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), the mixture comprises more than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 2% (mol%). In some preferred embodiments, 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), the mixture comprises more than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 1% (mol%).

In some preferred embodiments, the solid non-polar lipid particles are non-polar mono-, di-, or tri-glycerides, wax esters, including cholesterol esters, sterols, free fatty acids and the like. It further includes one or more additional lipids selected from the group consisting of a combination of.

In some preferred embodiments, the active agent is an over the counter (OTC) or prescription topical ophthalmic, an OTC or prescription topical ophthalmic for the treatment of dry eye, an NMDA antagonist, an anti-bacterial agent. -bacterial, antihistamine, decongestant, anti-inflammatory, antiparasitic, miotics, sympathomimetic, anticholinergic, adrenaline Adrenergic, antiviral, local anesthetic, antifungal, amoebicidal, trichomonocidal, analgesic, mydriatic, antiglaucoma. Antiglaucoma drugs, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic agents used as adjuvants in surgery, chelating agents, antineoplastic agents (antineoplastic), antihypertensive, muscle relaxant, diagnostic, adrenergic anesthetic, beta blocker, alpha-2-agonist, It is selected from the group consisting of cycloplegics, prostaglandins, and combinations thereof.

In some preferred embodiments, the solid non-polar lipid particles are formulated in an aqueous suspension in a physiologically acceptable carrier. In some preferred embodiments, the liquid composition comprises phosphate buffered saline (PBS), water containing up to 3% (w/w of vehicle) polysorbate 80 and up to 0.3% (w/w of vehicle) xanthan gum. It is a suspension of solid finely divided lipid particles, with a pH of 6.5 to 8.0 and an osmotic pressure of 260 to 320 mOsm/L.

In some preferred embodiments, the suspension is stable to phase separation of the solid non-polar lipid particles within the suspension for 6 months at room temperature. In some preferred embodiments, the suspension is chemically stable with less than 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 to phase separation of the solid non-polar lipid particles within the suspension for 24 months at room temperature. In some preferred embodiments, the suspension is chemically stable with less than 5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 24 months.

In some preferred embodiments, the suspension is sterile. In some preferred embodiments, the suspension includes a preservative. In some preferred embodiments, the suspension contains no preservatives. In some preferred embodiments, the physiologically acceptable carrier is an ophthalmologically acceptable carrier. In some preferred embodiments, the ophthalmologically acceptable carrier consists of buffering agents, tonicity agents, wetting agents, thickening and viscosifying agents, density adjusting agents, and combinations thereof. It includes an agent selected from the group.

In some preferred embodiments, the active agent is released as individual molecules of the active agent from the solid non-polar lipid particles over a period of time after administration as an eye drop. In some preferred embodiments, individual molecules are released over a period of 1 to 24 hours.

In some preferred embodiments, the suspension is provided in a drop dispenser.

In some preferred embodiments, the drug delivery vehicle is a medical insert device. In some preferred embodiments, the medical implantable device 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, hydrogel, polymethyl methacrylate, and silicone acrylate. do. In some preferred embodiments, the medical implantable device is selected from the group consisting of punctal plugs, contact lenses, and ophthalmic inserts. In some preferred embodiments, the medical implantable device is rechargeable. In some preferred embodiments, the medical implantable device is single use. In some preferred embodiments, the medical implantable device is compatible with mucosal surfaces. In some preferred embodiments, the mucosal surface is ocular mucosal surface, vaginal mucosal surface, nasal mucosal surface, oropharyngeal mucosal surface, oral mucosal surface. It is selected from the group consisting of cavity mucosal surface and rectal mucosal surface.

In some preferred embodiments, the present invention provides a method of delivering an active agent to a subject in need thereof comprising topically administering to the subject a drug delivery vehicle as described above. In some preferred embodiments, the drug delivery vehicle is administered to the mucosal surface of the subject. In some preferred embodiments, the mucosal surface is an ocular mucosal surface, a vaginal mucosal surface, an oviduct mucosal surface, a respiratory system mucosal surface, a nasal mucosal surface, an oropharyngeal mucosal surface, an oral mucosal surface, a rectal mucosal surface. surface, digestive system mucosal surface, and esophageal mucosal surface. In some preferred embodiments, the drug delivery vehicle is applied or implanted beneath the mucosal surface. In some preferred embodiments, the mucosal surface is an ocular mucosal surface and the drug delivery vehicle is applied or implanted under the conjunctival or tenon's capsule. In some preferred embodiments, the drug delivery vehicle is administered by a delivery route selected from the group consisting of retrobulbar, intracameral, intravitreal, suprachoroidal, and subretinal delivery routes. Applied to the ocular mucosal surface.

In some preferred embodiments, the present invention provides, in an animal or human subject in need of treatment of an eye disease or condition, topically administering to the eye of the subject a drug delivery vehicle as described above comprising an effective amount of an active lipid agent. Evaporative dry eye, meibomian gland dysfunction and related symptoms, clinical signs or conditions, including rapid aqueous tear evaporation due to unstable tear film and keratoconjunctivitis sicca (dry eye) and related symptoms or clinical signs. It provides a method of treating an eye disease or disease selected from the group consisting of. In some preferred embodiments, the subject in need of treatment has a tear film break-up time that is greater than the normal clinical range of tear break-up time (TBUT) for a normal healthy population, e.g., in the United States or other countries. short. In some preferred embodiments, the above methods provide an improvement in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, eye dryness, biostaining of the conjunctiva or cornea, and Schirmer tear testing (e.g., as reported in controls or patients). compared to what was provided).

In some preferred embodiments, the present invention provides a drug delivery vehicle as described above in an animal or human subject in need of treatment of a disease or condition of the eye, such as dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and symptoms. Treating diseases or diseases of the eye selected from the group consisting of clinical signs or conditions related thereto, rapid aqueous tear evaporation due to unstable tear film and keratoconjunctivitis sicca (dry eye) and symptoms or clinical signs related thereto. It provides a purpose for using it. In some preferred embodiments, administration of the composition results in an improvement in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, eye dryness, biostaining of the conjunctiva or cornea, and Schirmer tear testing (e.g., in controls or patients). compared to reported).

In another preferred embodiment, the present invention provides the above-described drug delivery vehicle or lipid particle composition for use in treating an animal or human subject in need of treatment for a disease or condition of the eye, wherein the animal in need of treatment is said animal. This can be confirmed by a tear film break-up time (TBUT) below the clinically accepted normal range in the species or in humans.

In a third aspect, the present invention provides a lipid particle composition comprising solid non-polar lipid particles comprising an active lipid agent and having an average particle size of less than 50 microns.

In some preferred embodiments, the solid non-polar lipid particles have a melting point below 80°C. In some preferred embodiments, the solid non-polar lipid particles have a melting point between 20 and 80°C. In some preferred embodiments, the solid non-polar lipid particles have a melting point between 30 and 60°C. In some preferred embodiments, the solid non-polar lipid particles have an average particle size of less than 20 microns. In some preferred embodiments, the solid non-polar lipid particles have an average particle size of less than 10 microns.

In some preferred embodiments, the active lipid agent is a non-polar ether lipid.

In some preferred embodiments, the solid non-polar lipid particles comprise an active lipid agent selected from the group:

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₃ is hydrogen (ie H);

here,

R ₁ is hydrogen (ie H);

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₃ is hydrogen (i.e. H).

In some preferred embodiments, the solid non-polar lipid particles comprise an active lipid agent selected from the group:

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

here,

R ₁ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;

R ₂ is hydrogen (ie, H);

R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl.

In some preferred embodiments, the solid non-polar lipid particle is 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1-O-eicosanyl-2-palmitoyl- rac -glycerol, 1,2-EPRG), sn- 1-O-eicosanyl-2-palmitoyl-glycerol ( sn -1-O-eicosanyl-2-palmitoyl-glycerol), sn -2-palmitoyl-3-O-eicosanyl-glycerol ( sn -2-palmitoyl-3-O-eicosanyl-glycerol), 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1-O-eicosanyl-3-palmitoyl- rac -glycerol, 1,3- EPRG), sn -1-O-eicosanyl-3-palmitoyl-glycerol ( sn -1-O-eicosanyl-3-palmitoyl-glycerol), sn -1-palmitoyl-3-O-eicosanyl-glycerol ( sn -1-palmitoyl-3-O-eicosanyl-glycerol) and these It includes an active lipid agent selected from the group consisting of mixtures of. In some preferred embodiments, the solid non-polar lipid particles are 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl- rac -glycerol ( 1,3-EPRG) and mixtures thereof.

In some preferred embodiments, 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), the mixture comprises more than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl-3 -palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises more than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl-3 -palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises more than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl-3 It is characterized in that it contains more than 99% (mol%) of the -palmitoyl- rac -glycerol (1,3-EPRG) isomer.

In some preferred embodiments, 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), the mixture comprises more than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 5% (mol%). In some preferred embodiments, 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), the mixture comprises more than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 2% (mol%). In some preferred embodiments, 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), the mixture comprises more than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 1% (mol%).

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

In some preferred embodiments, the solid non-polar lipid particles are formulated as a suspension.

In some preferred embodiments, solid non-polar lipid particles are provided as medical implantable devices. In some preferred embodiments, the medical implantable device is formed from physiologically acceptable materials. 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 methacrylates and silicone acrylates. In some preferred embodiments, the medical implantable device is selected from the group consisting of punctum plugs, contact lenses, and ophthalmic inserts. In some preferred embodiments, the medical implantable device is rechargeable. In some preferred embodiments, the medical implantable device is disposable. In some preferred embodiments, the medical implantable device is compatible with mucosal surfaces. In some preferred embodiments, the mucosal surface is selected from the group consisting of ocular mucosal surface, vaginal mucosal surface, nasal mucosal surface, oropharyngeal mucosal surface, oral mucosal surface and rectal mucosal surface.

In some preferred embodiments, the lipid particles may comprise a second active agent, preferably in addition to the first active agent (i.e., an ether lipid). In some preferred embodiments, the active agent is an over-the-counter (OTC) or prescription topical ophthalmic medication, an OTC or prescription topical ophthalmic medication for the treatment of dry eye, an NMDA antagonist, an antibacterial agent, an antihistamine, a decongestant, an anti-inflammatory agent, an anti-parasitic agent, a miotic agent. , sympathomimetic agents, anticholinergics, adrenergic agents, antiviral agents, local anesthetics, antifungal agents, salamoeba agents, saltricomones, analgesics, mydriatics, antiglaucoma agents, carbonic anhydrase inhibitors, ophthalmic diagnostic agents, adjuvants in surgery. It is selected from the group consisting of ophthalmic agents, chelating agents, antineoplastic agents, antihypertensive agents, muscle relaxants, diagnostic agents, adrenergic anesthetics, beta blockers, alpha-2-agonists, paralytic agents, prostaglandins, and combinations thereof.

In some preferred embodiments, the present invention provides a method of treating a disease or condition associated with the mucous membrane comprising administering a lipid particle composition as described above to a subject in need thereof. In some preferred embodiments, in an animal or human subject in need of treatment for a disease or condition, the disease or condition includes dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and symptoms, clinical signs or conditions associated therewith, unstable A disease or condition of the eye selected from the group consisting of rapid aqueous tear evaporation due to tear film and keratoconjunctivitis sicca (dry eye) and symptoms or clinical signs associated therewith. In some preferred embodiments, administration of the composition results in an improvement in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, eye dryness, biostaining of the conjunctiva or cornea, and Schirmer tear testing (e.g., in controls or patients). compared to reported).

In some preferred embodiments, the present invention provides use of the above-described lipid particle composition for treating a disease or condition of the mucous membranes of a subject. In some preferred embodiments, in an animal or human subject in need of treatment for a disease or condition, the disease or condition includes dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and symptoms, clinical signs or conditions associated therewith, unstable A disease or condition of the eye selected from the group consisting of rapid aqueous tear evaporation due to tear film and keratoconjunctivitis sicca (dry eye) and symptoms or clinical signs associated therewith. In some preferred embodiments, administration of the composition results in an improvement in one or more symptoms or measurements selected from the group consisting of TBUT, eye comfort, eye dryness, biostaining of the conjunctiva or cornea, and Schirmer tear testing (e.g., in controls or patients). compared to reported).

1 is a schematic drawing for the synthesis of lipids used in embodiments of the present invention.
Figure 2 is a graph showing the particle size (analysis by dynamic light scattering) of solid finely divided lipid particles of the present invention.
Figure 3 is a photograph of solid finely divided particles stably suspended in the presence of different concentrations of xanthan gum excipient.
Figure 4 shows the results of NMR (nuclear magnetic resonance) spectrum analysis of the 1,3-EPRG and 1,2-EPRG isomer content (1.15 mol% 1,3-EPRG) of MCAL-201 after jet mill pulverization. .
Figure 5 shows NMR of the 1,3-EPRG and 1,2-EPRG isomer content (0.0991 mol% 1,3-EPRG) of MCAL-201 after storing the solid finely divided MCAL-201 suspension at room temperature for 6 weeks. This is the result of nuclear magnetic resonance (Nuclear Magnetic Resonance) spectrum analysis.
Figure 6 is a graph showing that TBUT was prolonged as a result of one-time administration of the finely divided solid lipid particles of the present invention to five healthy dogs.
Figure 7 shows an example structure for identifying the sn- serial number of the glycerol backbone.

Justice

“Patient,” “subject,” or “individual” are used interchangeably and refer to a human or non-human animal. This term includes mammals such as humans, primates, domestic animals (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

“Administering” or “administering” a substance, compound or agent to a subject can be accomplished using any of a variety of methods known to those skilled in the art. For example, the compound or agent can be administered topically, ophthalmically, intravenously, intraarterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, sublingually, orally (by injection), or (by inhalation). intranasally, intrathecally, intracerebrally (by absorption, eg, by absorption through a skin duct). Specific ocular routes of administration include topical administration to the ocular surface (cornea and/or conjunctiva), subconjunctival administration, sub-Tenon's capsule administration, retrobulbar administration, intracameral administration, intravitreal administration, suprachoroidal administration, and subretinal administration. (sub-retinal) administration. The compound or agent may suitably be introduced by rechargeable or biodegradable polymer devices or other devices, such as patches and pumps, or formulations that provide prolonged, slow, or controlled release of the compound or agent. Polymeric materials may be solid implantable materials or designed to remain in prolonged contact with the ocular surface (commercial examples include LACRISERT ^™ , bausch.com/ecp/our-products/rx-pharmaceuticals/rx-pharmaceuticals/lacrisert (see e.g., ois.net/punctal-plugs-for-sustained-delivery/), forming a punctal plug that slowly releases the test article (see, e.g., ois.net/punctal-plugs-for-sustained-delivery/), or an O-ring that is inserted into the conjunctival cavity. may be included. Other embodiments of the therapeutic construct are applied topically or injected intra- and/or peri-ocularly to form a hydrogel whose polymerization is triggered by changes in temperature, pH or ionic composition. Materials are illustrative, but not limited thereto. Administration may be performed, for example, once, multiple times and/or over one or more extended periods of time. In some aspects, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing medication. For example, as used herein, a physician who self-administers a drug to a patient, directs another person to administer a drug, and/or provides a prescription for a drug to a patient is administering a drug to the patient.

An “active lipid agent” is a lipid that has a therapeutic effect on mucosal surfaces. The solid crystalline or amorphous active lipid preparation is finely divided and, when suspended in a buffer of controlled tonicity, viscosity and density to aid in stable suspension of the finely divided solid active lipid preparation, releases the monomeric molecules of the active lipid preparation in a sustained manner. It can also act as a carrier for slow release.

A “therapeutically effective amount” or “therapeutically effective dose” of a drug or agent is the amount of the drug or agent that will produce the intended therapeutic effect when administered to a subject. The full therapeutic effect does not necessarily have to occur with a single administration, but may occur only after a series of administrations. Accordingly, a therapeutically effective amount may be administered once, in multiple doses, daily, weekly, or more than once during other treatment periods. The exact effective amount required by a subject will depend on the subject's size, health and age, and the nature and severity of the condition being treated, such as dry eye and/or other eye disease. An experienced operator can easily determine the effective dose for a given situation through routine experimentation.

As used herein, “shelf life” refers to the period from the date of product manufacture to administration of the drug.

“Treating” a condition or patient means taking steps to achieve beneficial or desired results, including clinical outcomes. Beneficial or desirable clinical outcomes include relief, improvement or progression of one or more symptoms associated with mucosal surface deficiencies, particularly lipid deficiencies, as well as neurological disorders, including neurodegeneration and traumatic brain injury, and pain and discomfort. Including, but not limited to, delays. In certain embodiments, treatment may be prophylactic. Exemplary beneficial clinical outcomes are described herein.

As used herein, the term chemical formula includes information about the spatial arrangement of atoms and bonds of a chemical substance, but does not necessarily imply exact isomers, analogs, and homologs; The term molecular formula refers to the number of atoms of each element in a compound.

“Alkyl” means a monovalent straight-chain, branched or cyclic saturated aliphatic hydrocarbon radical. Preferably, the alkyl group is a straight-chain radical having 1 to 40 carbon atoms. More preferably, it is an alkyl radical of 5 to 31 carbon atoms, most preferably of 15 to 23 carbon atoms. Common alkyl radicals are pentyl, hexyl, tridecanyl, tetradecanyl, nonadecanyl, docosanyl, triacontanyl, Hentri. Includes hentriacontanyl, etc. Preferably, the term refers to an acyclic carbon or a saturated acyclic carbon chain, represented by the formula C _n H _2n+1 , where n is an integer between 1 and 31.

“Alkenyl” means a monovalent, straight-chain, branched or cyclic, unsaturated aliphatic hydrocarbon radical having one or more, preferably one, double bond. Preferably, the alkenyl radical has 2 to 40 carbon atoms. More preferably, it is an alkenyl radical of 6 to 30 carbon atoms, most preferably of 15 to 23 carbon atoms. Common alkenyl groups are hexenyl, tridecenyl, tetradecenyl, nonadecenyl, docosenyl, triacontenyl, and hentriacontenyl. ), etc. Preferably, the term refers to an acyclic carbon chain containing carbon-to-carbon double bonds, represented by the formula C _n H _2n-1 , where n is an integer between 2 and 40. Preferably, the geometry of the alkenyl bond is the cis or Z-configuration commonly found in cell membrane lipids.

“Alkylene” means a divalent, straight-chain, branched or cyclic, saturated aliphatic hydrocarbon radical. Preferably, the alkylene group has 1 to 12 carbon atoms. This term refers to an acyclic carbon or a saturated acyclic carbon chain, represented by the formula C _n H _2n-2 , where n is an integer between 1 and 12. More preferably, it is a lower alkylene having 1 to 7 carbon atoms, and most preferably, it is a lower alkylene having 1 to 4 carbon atoms, such as methylene.

As used herein, the term “aliphatic” means straight-chain or branched alkyl, alkenyl, or alkynyl. Alkenyl or alkynyl embodiments are understood to require at least two carbon atoms in the aliphatic chain. An aliphatic group generally contains 1 (or 2) to 30 carbons, such as 1 (or 2) to 20 carbons.

As used herein, carbon atom designations may have any intermediate integer between the stated integer. For example, the (C ₁ -C ₄ )-alkyl group has 1, 2, 3 or 4 carbon atoms. It should be understood that these names refer to the total number of atoms in the appropriate group.

As used herein, “pharmaceutically acceptable salt” or “salt” is used herein to refer to preparations or compounds of the therapeutically active, non-toxic base and acid salt forms of the compound. The acid addition salt form of a compound found in its free form as a base is an acid addition salt form in which the free base form is reacted with an inorganic acid, for example a hydrohalic acid such as hydrochloric acid or hydrobromic acid. ), sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, such as acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic. ), fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid ( It can be obtained by treatment with an appropriate acid such as p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic, etc.

Detail explanation

The present invention relates to drug delivery vehicles comprising finely divided crystalline or amorphous solids comprising active lipid agents, particularly sn -1-O-eicosanyl- sn -2-palmitoyl-glycerol ( sn -1-O -eicosanyl- sn -2-palmitoyl-glycerol) and isomers thereof, comprising crystalline or amorphous solid finely divided lipid particles.

It is contemplated in this disclosure that any one or more of the above-described aspects and implementations may be combined with each other and/or with any of the implementations or features provided below.

Mucosa has an epithelial constituent with intrinsic surface chemistry, and the most superficial layer of cells has nano- to micron-scale topographic features in the form of microvilli and microplicae. These topographic features are closely associated with cellular components, interact with the thin fluid film, and may contribute to the relative stability of the thin film. It is known that these surface topographical features can be altered in diseased states of the ocular surface, and that these alterations can contribute to thin film instability. Thin films of fluid can be found in tears, saliva, gastrointestinal coating, eyelids, ocular surface and peri-ocular tissue, respiratory tract (nasal cavities, trachea, bronchi, bronchioles and alveoli). Fluid membranes, including, but not limited to, membranes associated with (alveoli) and cervico-vaginal secretions, and membranes associated with the rest of the female reproductive tract, contain cellular elements of the mucosa in all vertebrate species. covering. Tatematsu et al., Bone Marrow Transplant. 2012 Mar;47(3):416-25. doi: 10.1038/bmt.2011.89. Epub 2011 May 16.

Secretions covering the mucous membrane come from various sources and have three major components. glycosaminoglycan (or mucus) layer; an aqueous component containing soluble species such as proteins, sugars, salts and osmolytes; In the case of tears, components containing lipids. Mucosal membranes arise from cells or glandular structures embedded in the mucosa (or proximal portion of the mucosa). Water forms the basis of lubrication in the human body, especially at the lipid, wax and oil-water interface, but in diseased states it may not provide sufficient lubrication without additives. The importance of biolubrication becomes more evident under aging and disease, especially conditions that affect the secretion or composition of body fluids. A lack of biolubrication can interfere with proper speaking, chewing and swallowing, cause excessive friction and wear on the cartilage surfaces of hip and knee joints, cause vaginal dryness, and cause dry and irritated eyes. Blinking, an average of 28,800 times per day, may represent the most frequently used frictional surface interaction. The average time between eye blinks can be measured, which may be limited by the integrity of the tear film and tear film lipid layer. If there is insufficient biolubrication of the ocular surface and eyelids, blinking becomes more frequent and friction increases, causing irritation. Over time, this causes inflammation that causes dry eyes. Clinical improvements in ocular surface biolubrication can be measured by longer blink times, decreased blink rate, decreased number of blinks per minute, hour or day, improved patient comfort, and increased tear film break-up time (TBUT). Biolubrication occurs due to the combination of the structure of the adsorbed protein membrane, lipid layer, and glycosylation, and provides important clues for establishing effective treatments to restore biolubrication in patients lacking biolubrication. Veeregowda et al., PLoS One. 2012;7(8):e42600. doi: 10.1371/journal.pone.0042600. Epub 2012 Aug 15.

By way of non-limiting example, a well-known model of the tear film that coats the ocular surface is the tear film containing three major components; An external lipid layer derived from the glands lining the eyelid margins (secretions from the meibomian or tarsal glands, as well as the Harderian glands in species with Harderian glands, including rabbits); aqueous layer derived from the lacrimal or accessory lacrimal glands (mixed with soluble proteins, as well as lipids and mucins); and a mucin layer derived from goblet cells associated with conjunctival and corneal epithelial cells and mucin derived from the epithelial cells themselves.

The mucin component forms a layer immediately adjacent to the cellular elements of the ocular surface, such as the corneal epithelium, and is to some extent associated with the glycocalyx of the most superficial epithelial cells, as well as mixed into the thicker aqueous component. It is thought that Mucin components are believed to play an important role in maintaining the stability of the tear film by affecting the surface tension of the cell-aqueous layer interface. The aqueous layer is the largest component of the tear film and contains various solutes to maintain tear pH, osmotic pressure, and ocular health. Immunoglobulins, lysozyme, transferrin, antibacterial peptides and other components help control bioburden and reduce the risk of infection. Mucins may also be mixed in this layer. Additionally, growth factors, cytokines and other cell activating factors are found within the aqueous layer. The polar lipids of the tear film lipid layer coat the aqueous layer with a monolayer of lipid molecules with their charged head groups facing the aqueous layer. The outer tear film nonpolar lipid layer is the outermost layer of the tear film and is in direct contact with air. This nonpolar lipid layer provides lubricity and stability to the entire tear film with clinically measured tear breakup times and reduces the rate of evaporation of the aqueous component of the tear film.

Many diseases and conditions are associated with dryness or dysfunction of mucous membranes. Dry eye, dry mouth, vaginal dryness, and diseases associated with deficiencies/dysregulation of respiratory membrane coatings are examples, but are not limited to these. What is needed are safe, effective and flexible means of treating dry or dysfunctional mucosal diseases and treatments that improve the function of non-disease mucosa.

A broad challenge in developing effective therapeutics is the formulation and delivery of hydrophobic molecules for therapeutic benefit to the mucosal surface and the delivery of the therapeutic agent that must pass through an intact mucosal surface to provide therapeutic benefit to deeper tissues/structures. The novelty and practicality of the invention described herein lies in the incorporation of highly hydrophobic molecules into cold-melt crystalline and amorphous lipids and waxes or as embedded molecules in cold-melt crystalline and amorphous solid lipids and waxes, which can be suspended into small particles. or may be dissolved in formulations for topical application from biocompatible aqueous formulations in which the lipids are essentially insoluble and/or may be incorporated into devices for controlled release of therapeutically useful compounds from cold melt crystalline and amorphous solids or waxes. It is possible. Additionally, these cold melt crystalline and amorphous solid lipids and waxes are believed to provide a means of controlled delivery of hydrophilic or amphipathic compounds entrapped within the cold melt lipids and waxes. For example, for drug delivery vehicles comprising finely divided solid particles comprising an active lipid agent, cyclosporin or Xiidra, especially for the treatment of dry eye, including inflammatory and/or evaporative dry eye. ethers such as sn -1-O-eicosanyl- sn -2-palmitoyl-glycerol ( sn -1-O-eicosanyl- sn -2-palmitoyl-glycerol) and isomers thereof together with a second active ophthalmic agent such as ) It contains finely divided lipid particles containing lipids. Micronized crystalline or amorphous solid lipid particles containing ether lipids such as sn -1-O-eicosanyl- sn -2-palmitoyl-glycerol are prepared by dissolving them in a 40 mg/mL solution of the ether lipids in chloroform in a vacuum chamber. It can be manufactured by spray drying. The result is finely divided, amorphous solid lipid particles less than 10 microns. Addition of a second active agent (e.g., cyclosporine, Zydra, or one of the second active agents described below) to a chloroform solution for spray drying results in a spray-dried fine powder containing therapeutic amounts of both the ether lipid and the second active agent. lipid particles are generated. Alternatively, a solid suspension of nanosized particles of the second active agent in amorphous 1,2-EPRG can be prepared by spray drying a solution of 1,2-EPRG in chloroform or in a suitable solvent containing suspended nanosized particles of the second active agent. It can be formed by micronization.

In certain aspects, the drug delivery vehicles described herein can be used to treat patients suffering from mucosal diseases. The drug delivery vehicle of the present invention is more useful when the route of administration is to deliver an active lipid agent or lipophilic drug to the mucous membrane. As such, the present invention provides drug delivery vehicles useful for delivering active lipid components or other lipophilic drugs to the mucosa of a subject. The present invention is not limited to any particular mucosal surface. In some preferred embodiments, the mucosal surfaces are ocular mucosal surfaces, vaginal mucosal surfaces, fallopian tube mucosal surfaces, respiratory mucosal surfaces, nasal mucosal surfaces, oropharyngeal mucosal surfaces, oral mucosal surfaces, rectal mucosal surfaces, digestive mucosal surfaces, and esophageal mucosal surfaces. The present invention is not limited to any particular delivery route. In some preferred embodiments, the route of delivery includes topical administration. In some embodiments, when the target organ is the eye, preferred routes of delivery include subconjunctival, sub tenon's capsule, retrobulbar, intracameral, intravitreal, suprachoroidal, and sub-retinal delivery routes. Includes topical eye drops.

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

In some preferred embodiments, the finely divided lipid particles of the present invention have a melting point of less than 80°C. In some more preferred embodiments, the finely divided lipid particles of the present invention have a melting point of less than 60°C. In some even more preferred embodiments, the finely divided lipid particles of the present invention have a melting point of less than 50°C. In some other preferred embodiments, the solid finely divided lipid particles have a melting point between 20 and 80°C. In another preferred embodiment, the solid finely divided lipid particles have a melting point between 30 and 60°C.

It will be appreciated that the lipid composition of the finely divided lipid particles can be varied to provide a desired melting point. Accordingly, in some preferred embodiments, the finely divided lipid particles of the present invention include monoglycerides, diglycerides, ether ester glycerols, triglycerides, and phospholipids. , one or more carrier lipids such as wax or sterol. In some embodiments, the lipid may include a fatty acid moiety attached to the glycerol backbone by an ester or ether linkage.

A variety of methods for producing finely divided particles are known in the art. In some preferred embodiments, the finely divided particles are produced by jet milling. Suitable jet mills can be purchased, for example, from Hosokawa Micron Powder Systems, Summit, NJ. The feed product, for example the lipid composition of the invention, is fed to the grinding zone of a jet mill. Grinding air is injected tangentially into the jet mill through a Laval nozzle in the nozzle ring. This results in the formation of a spiral air jet in the grinding zone. The spiral flow of air creates high pressure in the mill, which can reach an overpressure of up to 1 bar when operated without product. The integrated injector is charged with compressed air, which allows the product to be delivered into the machine against the excess pressure present in the machine.

As the feed product circulates close to the nozzle ring, it is repeatedly intercepted by the air jet from the nozzle. Comminution is the result of particle-to-particle collisions caused by particles flowing at different velocities in a nozzle jet. The crushed material is delivered to the discharge along with air. The spiral flow sorts the particles, expelling only the fine (i.e. finely divided) particles and leaving the coarse particles in the mill.

In some preferred embodiments, the finely divided particles are prepared by spray drying a solution of the lipid composition with or without the second active agent of the invention by feeding it through a nozzle into a vacuum chamber, where the solvent evaporates to form a 5 to 50 micron particle. Amorphous solid particles of any size can be generated and collected by settling them. One such spray drying device is sold by Buchi instruments and is described at the following url: https://static1.buchi.com/sites/default/files/downloads/Spray_Drying_Encapsulation_Solutions_brochure_en_D_0.pdf?56fa5df1e4976c154c3b11af6a45ff69b22d63e3.

In some preferred embodiments, the finely divided lipid particles comprise an active lipid agent. Active lipid agents are lipid molecules that impart a therapeutic or prophylactic effect or treat a disease or condition. The active lipid agent used in the present invention includes monoglyceride, diglyceride, triglyceride, ether ester glycerol, phospholipid, wax or sterol. , but is not limited to this.

In some preferred embodiments, the active lipid agent is an ether lipid. Suitable ether lipids are described in detail in U.S. Pat. No. 9,289,494, which is hereby incorporated by reference in its entirety.

In some preferred embodiments, the active lipid agent is sn -1,2 substituted glycerol, sn -2,3 substituted glycerol, or 1,2 - substituted glycerol. It is a 1,2-substituted racemic glycerol (i.e., 1,2- rac -glycerol) and preferably contains a fatty acid moiety attached to glycerol through an ether bond. The stereospecific numbering of the glycerol main chain carbon, sn- , for 1,2-substituted ether lipids is shown in Figure 7, for example, R ₁ is alkyl or alkenyl attached through an ether bond, and R ₂ is It is alkyl or alkenyl attached through an ester bond, and R ₃ is -H. This sn- numbering of the glycerol main chain applies to the structures presented herein.

In some embodiments, the active lipid agent is an ether lipid selected from:

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl, preferably C ₂₀ alkyl or alkenyl;

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl, preferably C ₁₅ alkyl or alkenyl;

R ₃ is hydrogen (ie H);

here,

R ₁ is hydrogen (ie H);

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl, preferably C ₁₅ alkyl or alkenyl;

R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl, preferably C ₂₀ alkyl or alkenyl; and

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl, preferably C ₂₀ alkyl or alkenyl;

R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl, preferably C ₁₅ alkyl or alkenyl;

R ₃ is hydrogen (i.e. H).

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

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl, preferably C ₂₀ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl, preferably C ₁₅ alkyl or alkenyl;

here,

R ₁ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl, preferably C ₁₅ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl, preferably C ₂₀ alkyl or alkenyl; and

here,

R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl, preferably C ₂₀ alkyl or alkenyl;

R ₂ is hydrogen (ie H);

R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl, preferably C ₁₅ alkyl or alkenyl.

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

Accordingly, in some preferred embodiments, one of the sn- positions of the lipid molecule of the invention is an -OH donation, one of the two sn- positions has an ether-linked aliphatic chain and an ester-linked aliphatic chain, so that the ether lipid has It is an ester ether glycerol. It will be appreciated that when the ether lipid comprises two aliphatic chains, isomeric forms are possible. For example, when an alkyl or alkenyl is attached to the sn -1 position of the glycerol main chain of diglyceride, the fatty acid attached to the glycerol main chain through an ester bond may exist at either the sn -2 or sn -3 position. You can. Likewise, when the fatty acid attached to the glycerol main chain through an ester bond is present at the sn -1 position of the diglyceride, the alkyl or alkenyl ether attached to the glycerol main chain is at the sn -2 or sn -3 position of the glycerol main chain. It can exist in either location. In this regard, it will be clear to those skilled in the art that when labeling a diglyceride molecule, the sn -1 and sn -3 positions will vary depending 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.

It will be further understood that when the active lipid preparation is an ether ester glycerol, the active lipid preparation may be a mixture of isomeric forms of disubstituted glycerol, and the mixture may be characterized by a molar percentage of the ether ester glycerol isomers. .

Accordingly, in some preferred embodiments, the ether ester lipid isomers 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) and 1-O-eicosanyl-3-palmitoyl- rac -glycerol The mixture of (1,3-EPRG) comprises greater than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or It is characterized in that it comprises greater than 95% (mole %) of the sanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises greater than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl- Characterized by comprising more than 98% (molar percent) of the 3-palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises greater than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or 1-O-eicosanyl- Characterized by comprising more than 99% (molar percent) of the 3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.

In some preferred embodiments, 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), the mixture comprises more than 50% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer and 1-O-eicosanyl-3 -Palmitoyl- rac -glycerol (1,3-EPRG) isomer is characterized in that it contains less than 50% (mol%). In some preferred embodiments, 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), the mixture contains up to 50% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, and 1-O-eicosanyl-3 -palmitoyl- rac -glycerol (1,3-EPRG) isomer.

In some preferred embodiments, 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), the mixture comprises more than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, and 1-O-eicosanyl- It is characterized in that it contains 5% (mol%) or less of the 3-palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises more than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, and 1-O-eicosanyl- It is characterized in that it contains less than 2% (mol%) of the 3-palmitoyl- rac -glycerol (1,3-EPRG) isomer. In some preferred embodiments, 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), the mixture comprises more than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, and 1-O-eicosanyl- It is characterized in that it contains less than 1% (mol%) of the 3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.

The crystalline or amorphous solid finely divided lipid particles of the present invention may contain other active agents such as hydrophilic, amphipathic or lipophilic active agents. In some of these preferred embodiments, the active agent may be formulated with a carrier lipid, formulated with a carrier lipid and an active lipid, or formulated with an active lipid.

Suitable active agents that are not active lipid agents include many different types of drug molecules. Suitable exemplary drug molecules are described below. It will be appreciated by those skilled in the art that this refers to compounds that may include whole molecules of a compound known to have activity, isomers, as well as fragments thereof.

Active agents suitable for inclusion in the drug delivery vehicle of the present invention include small molecule drugs, biological agents such as proteins, RNA and DNA based therapeutics, and other molecules that have a therapeutic or prophylactic effect or are used in the treatment of a disease or condition. , but is not limited to this. In some preferred embodiments, the agent is an agent that stabilizes the thin film coating the mucosal surface, a lubricant, an agent that improves the wettability of the thin film coating the mucosal surface (e.g., pluronics), for the treatment of the ocular surface. Ophthalmic preparations for the treatment of dry eye selected from the group consisting of ophthalmic preparations for the treatment of peri-ocular tissues, ophthalmic preparations for the treatment of posterior ocular tissues and diseases, and corticosteroids. ophthalmic preparations, cyclosporine, Zydra, or other active ingredients in FDA-approved dry eye treatments, antibacterial agents, antiviral agents, polypeptide antimicrobial agents, antifungal agents, buffering agents, vitamins or minerals, analgesics, and anticoagulant agents. , coagulating agent, anti-inflammatory agent, vasoconstrictor agent, vasodilating agent, diuretic agent, anticancer agent, trophic agent, growth factor, nerve Neurotrophic agent, biofilm disrupting agent, agent that affects intraocular pressure by affecting drainage and/or production of aqueous, promoter of neovascularization agent , an inhibitor of neovascularization agent, an extracellular matrix (ECM) agent, an enzyme agent, an enzyme inhibiting agent, a polypeptide agent, and combinations thereof.

In some embodiments, the antimicrobial agent is incorporated into solid lipid particles. Suitable antibacterial agents include loracarbef, cephalexin, cefadroxil, cefixime, ceftibuten, cefprozil, cefpodoxime, Cephradine, cefuroxime, cefaclor, neomycin/polymyxin/bacitracin, dicloxacillin, nitrofurantoin , nitrofurantoin microcrystal, nitrofurantoin/nitrofuran mac, dirithromycin, Gemifloxacin, ampicillin, gatifloxacin , penicillin V potassium, ciprofloxacin, enoxacin, amoxicillin, amoxicillin/clavulanate potassium, clarithromycin, levofloxacin , moxifloxacin, azithromycin, sparfloxacin, cefdinir, ofloxacin, trovafloxacin, lomefloxacin ), methenamine, erythromycin, norfloxacin, clindamycin/benzoyl peroxide, quinupristin/dalfopristin, doxycycline , amikacin sulfate, vancomycin, kanamycin, netilmicin, streptomycin, tobramycin sulfate, gentamicin sulfate, tetra Tetracyclines, framycetin, minocycline, nalidixic acid, demeclocycline, trimethoprim, miconazole, colistimethate ( colistimethate, piperacillin sodium/tazobactam sodium, paromomycin, colistin/neomycin/hydrocortisone, antiamoebicides, Sulphigenus Sulfisoxazole, pentamidine, sulfadiazine, clindamycin phosphate, metronidazole, oxacillin sodium, nafcillin sodium, vancomycin hydrochloride hydrochloride), clindamycin, cefotaxime sodium, co-trimoxazole, ticarcillin disodium, piperacillin sodium, ticarcillin disodium/ Clavulanate potassium (ticarcillin disodium/clavulanate potassium), neomycin, daptomycin, cefazolin sodium, cefoxitin sodium, ceftizoxime sodium, Penicillin G potassium and sodium, ceftriaxone sodium, ceftazidime, imipenem/cilastatin sodium, aztreonam, cinoxacin (cinoxacin), erythromycin/sulfisoxazole, cefotetan disodium, ampicillin sodium/sulbactam sodium, cefoperazone sodium, cepha Cefamandole nafate, gentamicin, sulfioxazole/phenazopyridine, tobramycin, lincomycin, neomycin/polymyxin B/gramicidine (neomycin/polymyxin B/gramicidin), clindamycin hydrochloride, lansoprazole/clarithromycin/amoxicillin, alatrofloxacin, linezolid, bismuth subsalicil Bismuth subsalicylate/metronidazole/tetracycline, erythromycin/benzoyl peroxide, mupirocin, Fosfomycin, pentamidine isethionate isethionate), imipenem/cilastatin, troleandomycin, gatifloxacin, chloramphenicol, cycloserine, neomycin/polymyxin B/hydrocortisone (neomycin/ polymyxin B/hydrocortisone, ertapenem, meropenem, cephalosporins, fluconazole, cefepime, sulfamethoxazole, sulfamethoxazole/trimetho Prim (sulfamethoxazole/trimethoprim), neomycin/polymyxin B, penicillin, rifampin/isoniazid, erythromycin estolate, erythromycin ethylsuccinate, erythromycin stearate, ampicillin trihydrate, ampicillin/probenecid, sulfasalazine, sulfanilamide, sodium sulfacetamide ), dapsone, doxycycline hyclate, trimethoprim/sulfa, methenamine mandelate, plasmodicide, pyrimethamine, Hydroxychloroquine, chloroquine phosphate, trichomonocide, anthelmintic, atovaquone, bacitracin, bacitracin/polymyxin B), gentamycin, neomycin/polymyxin/dexameth, neomycin sulf/dexameth, sulfacetamide/prednisolone, sulfa Sulfacetamide/phenylephrine, tobramycin sulfate/dexameth, bismuth tribromophenate, silver ion compounds, silver nanoparticles nanoparticles, zerovalent silver, multivalent silver, elemental silver, and silver-containing compounds such as silver sulfadiazine and related compounds, chlorhexidine and biofilm-destroying agents such as gallium, tryptophan, imidazole derivative, indole derivative, emodine, phloretin, isolimonic acid. acid), 7-epiclusianone, casbane diterpene, carvacrol, chelerythrine, ellagic acid, tannic acid , ginkgoneolic acid, resveratrol, viniferin, diphenyl disulfide, S-phenyl-l-cysteine sulfoxide, Contains ajoene, brominated furanones, n-acyl homoserine lactones, skyllamycin, cembranoid, carolactone, etc. However, it is not limited to this.

In some embodiments, the antiviral agent is incorporated into solid lipid particles. Suitable antiviral agents include amantadine, acyclovir, foscarnet, indinavir, ribavirin, enfuvirtide, and emtricitabine. , lamivudine, abacavir sulfate, fomivirsen, valacyclovir, tenofovir, cidofovir, atazanavir, Amprenavir, delavirdine mesylate, famciclovir, adenofovir, didanosine, efavirenz, trifluridine , inidinavir, lamivudine, vidarabine, lopinavir/ritonavir, ganciclovir, zanamivir, abacavir/lamivudine /abacavir/lamivudine/zidovudine, lamivudine/zidovudine, nelfinavir, nelfinavir mesylate, nevirapine, ritonavir, Saquinavir, saquinavir mesylate, rimantadine, stavudine, docosanol, zalcitabine, idoxuridine, zidovudine ), zidovudine/didanosine, valganciclovir, penciclovir, lamivudine, and oseltamivir.

In some embodiments, the antifungal agent is incorporated into solid lipid particles. Suitable antifungal agents include amphotericin B, nystatin, nystatin/triamcinolone, itraconazole, ketoconazole, miconazole, and sulconazole. , clotrimazole, clotrimazole/betamethasone, enilconazole, econazole, oxiconazole, tioconazole, terraconazole ( terconazole, butoconazole, thiabendazole, flucytosine, butenafine, ciclopirox, haloprogin, naftifine, tolnaftate, natamycin, undecylenic acid, mafenide, dapsone, clioquinol, clioquinol/hydrocortisone, Potassium iodide, silver sulfadiazine, gentian violet, carbol-fuchsin, cilofungin, sertaconazole, voriconazole ( Includes, but is not limited to, voriconazole, fluconazole, terbinafine, caspofungin, other topical azole drugs, and griseofulvin.

In some embodiments, the buffering agent is incorporated into the solid lipid particles. In some embodiments, the present invention provides for the use and delivery of buffering agents. Suitable buffering agents include Maleic acid, Phosphoric acid, Glycine, Chloroacetic acid, Formic acid, Benzoic acid, Acetic acid, Pyridine. , Piperazine, MES, Bis-tris, Carbonate, ACES, ADA MOPSO, PIPES, Phosphoric acid, BES, MOPS, TES, HEPES, DIPSO, TAPSO, triethanolamine (Triethanolamine), HEPSO, Tris, Tricine, Bicine, TAPS, Borate, Ammonia, CHES, Ethanolamine, CAPSO, Glycine, Carbonate (Carbonate), CAPS, Methylamine, Piperidine, and Phosphoric acid, but are not limited thereto.

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

In some embodiments, the analgesic agent is incorporated into solid lipid particles. Suitable analgesics include acetaminophen, anilidine, acetylsalicylic acid, buprenorphine, butorphanol, fentanyl, fentanyl citrate, Codeine, rofecoxib, hydrocodone, hydromorphone, hydromorphone hydrochloride, levorphanol, alfentanil hydrochloride, meperidine (meperidine), meperidine hydrochloride, methadone, morphine, nalbuphine, opium, levomethadyl, hyaluronate sodium, water Fentanyl citrate, capsaicin, tramadol, leflunomide, oxycodone, oxymorphone, celecoxib, pentazocine, Propoxyphene, benzocaine, lidocaine, dezocine, clonidine, butalbital, phenobarbital, tetracaine, phenazopyridine. (phenazopyridine), sulfamethoxazole/phenazopyridine, and sulfisoxazole/phenazopyridine (sulfisoxazole/phenazopyridine), but are not limited thereto.

In some embodiments, the anticoagulant is incorporated into solid lipid particles. Suitable anticoagulants include coumarins, 1,3-indandione, anisindione, fondaparinux, heparin, lepirudin, and antithrompin ( Includes antithrombin, warfarin, enoxaparin, dipyridamole, dalteparin, ardeparin, nadroparin, and tinzaparin However, it is not limited to this.

In some embodiments, the coagulant is incorporated into the solid lipid particles. Suitable coagulants include Factor I (fibrinogen), Factor II (prothrombin), and Factor III (thromboplastin, tissue factor). tissue factor), Factor IV (calcium), Factor V (labile factor), Factor VII (stable factor), Factor VII (stable factor) Factor VIII (antihemophilic globulin, antihemophilic factor A), Factor IX (plasma thromboplastin component), Christmas factor, antihemophilic factor B (Factor IX (plasma thromboplastin component) , Christmas factor, antihemophilic factor B)), factor 10 (Stuart factor, Prower factor, Stuart-Prower factor) (Factor Factor XI (plasma thromboplastin antecedent, antihemophilic factor C)), Factor XII (Hageman factor, surface factor, contact factor) )), and Factor XIII (fibrin stabilizing factor, fibrin stabilizing enzyme, fibrinase).

In some embodiments, the anti-inflammatory agent is incorporated into solid lipid particles. Suitable anti-inflammatory agents include NSAIDs, such as diclofenac (Voltaren, Abitren, Allvoran, Almiral, Alonpin, Anfenax, Atrite ( Artrites, Betaren, Blesin, Bolabomin, Cataflam, Clofec, Clofen, Cordralan, Curinflam, Diclomax, Diclosian, Dicsnal, Difenac, Ecofenac, Hizemin, Inflamac, Inflanac, Klotaren, Lidonin, Monoflam, Naboal, Oritaren, Remethan, Savismin, Silino, Staren (Also known as Staren, Tsudohmin, Voltarol, Voren, Voveran, and Vurdon), diflunisal (Dolobid, Ado) Adomal, Diflonid, Diflunil, Dolisal, Dolobis, Dolocid, Donobid, Dopanone, Dor Dorbid, Dugodol, Flovacil, Fluniget, Fluodonil, Flustar, Ilacen, Noaldol, Loipl Also known as Reuflos, and Unisal), etodolac (also known as Lodine), fenoprofen (Nalfon, Fenoprex, Feno) (also known as Fenopron, Fepron, Nalgesic, and Progesic), flurbiprofen (also known as Ansaid and Ocuflur), Ibuprofen (Rufen, Motrin, Aches-N-Pain, Advil, Nuprin, Dolgesic, Genpril) , Haltran, Ibifon, Ibren, Ibumed, Ibuprin, Ibupro-600, Ibuprohm, Ibu-Tab (Ibu-Tab), Ibutex, Ifen, Medipren, Midol 200, Motrin-IB, Cramp End, Profen ( Profen, Ro-Profen, Trendar, Alaxan, Brofen, Alfam, Brufen, Algofen, Bruport (Brufort), Amersol, Bruzon, Andran, Buburone, Anflagen, Butacortelone, Apsifen, Diphlem (Deflem), Artofen, Dolgit, Artril, Dolocyl, Bloom, Donjust, Bluton, Easifon , Ebufac, Emflam, Emodin, Fenbid, Fenspan, Focus, Ibosure, Ibufen, Ibufug (Ibufug), Ibugen, Ibumetin, Ibupirac, Imbun, Inabrin, Inflam, Irfen, Librofen ), Limidon, Lopane, Mynosedin, Napacetin, Nobafon, Nobgen, Novogent, Novoprofen, Nurofen, Optifen, Paduden, Paxofen, Perofen, Proartinal, Prontalgin, Q- Profen, Relcofen, Remofen, Roidenin, Seclodin, Tarein, and Zofen), indomethacin ( Indameth, Indocin, Amuno, Antalgin, Areumatin, Argilex, Artherexin, Arthrexin , Artrinovo, Bavilon, Bonidon, Boutycin, Chrono-Indocid, Cidalgon, Confortid, Confort Confortind, Domecid, Durametacin, Elemetacin, Idicin, Imbrilon, Inacid, Indacin, Indecin, Indocap, Indocen, Indocid, Indoflex, Indolag, Indolar, Indomed, Indomie (Indomee), Indometacinum, Indometicina, Indometin, Indovis, Indox, Indozu, Indrenin, In Indylon, Inflazon, Inpan, Lauzit, Liometace, Metacen, Metindon, Metocid, Mezoline ( Mezolin, Mobilan, Novomethacin, Peralgon, Reflox, Rheumacid, Rheumacin, Salinac, Servindomet ), Toshisan, and Vonum), ketoprofen (Orudis, Alrheumat, Alrheumun, Alrhumat, Aneol (Aneol), Arcental, Dexal, Epatec, Fastum, Keduril, Kefenid, Keprofen, Ketofen ( Ketofen, Ketonal, Ketosolan, Kevadon, Mero, Naxal, Oruvail, Profenid, Salient, Tofen (also called Tofen, and Treosin), ketorolac (also called Toradol), meclofenamate (Meclofen, Meclomen) ), and Movens), mefenamic acid (Ponstel, Alpain, Aprostal, Benostan, Bonabol, Koslan) (Coslan), Dysman, Dyspen, Ecopan, Lysalgo, Manic, Mefac, Mefic, Mefix, Paque Also known as Parkemed, Pondex, Ponsfen, Ponstan, Ponstyl, Pontal, Ralgec, and Youfenam) , nabumetone (also known as Relafen), naproxen (Naprosyn, Anaprox, Aleve, Apranax, Apranax) Apronax, Arthrisil, Artrixen, Artroxen, Bonyl, Congex, Danaprox, Diocodal, Dysmenalgit ), Femex, Flanax, Flexipen, Floginax, Gibixen, Headlon, Laraflex, Laser, Leniartil, Nafasol, Naixan, Nalyxan, Napoton, Napren, Naprelan, Naprium, Naprius (Naprius), Naprontag, Naprux, Napxen, Narma, Naxen, Naxid, Novonaprox, Nicoprene ( Nycopren, Patxen, Prexan, Prodexin, Rahsen, Roxen, Saritilon, Sinartrin, Sinton, Sutoni ( Sutony, Synflex, Tohexen, Veradol, Vinsen, and Xenar), oxaprozin (also known as Daypro) ), piroxicam (Feldene, Algidol, Antiflog, Arpyrox, Atidem, Bestocam, Butacinon ), Desinflam, Dixonal, Doblexan, Dolonex, Feline, Felrox, Fuldin, Indene, Infeld (Infeld), Inflamene, Lampoflex, Larapam, Medoptil, Novopirocam, Osteral, Pilox, Pyralden ( Piraldene, Piram, Pirax, Piricam, Pirocam, Pirocaps, Piroxan, Piroxedol, Piroxim, Piton, Posidene, Pyroxy, Reucam, Rexicam, Riacen, Rosic, Sinalgico, Sotilen , Stopen, and Zunden), sulindac (Clinoril, Aflodac, Algocetil, Antribid, Atri) Arthridex, Arthrocine, Biflace, Citireuma, Clisundac, Imbaral, Lindak, Lyndak, Mobilin ), Reumofil, Sudac, Sulene, Sulic, Sulindal, Suloril, and Sulreuma), tolmetin (also called Tolectin, Donison, Midocil, Reutol, and Safitex), celecoxib (also called Celebrex), meloxicam (also called Mobic), rofecoxib (also called Vioxx), valdecoxib (also called Bextra), aspirin ( Anacin, Ascriptin, Bayer, Bufferin, Ecotrin, and Excedrin) and loteprednol etabonate, cortisone Includes, but is not limited to, steroidal anti-inflammatory agents, including cortisone, prednisone, and dexamethasone.

In some embodiments, the vasoconstrictor agent is incorporated into solid lipid particles. Suitable vasoconstrictors include epinephrine (Adrenaline, Sus-phrine), phenylephrine hydrochloride (Neo-Synephrine), oxymetazoline hydrochloride (Afrin), and norepinephrine (Levo). Including, but not limited to, Levophed and caffeine.

In some embodiments, the vasodilator is incorporated into solid lipid particles. Suitable vasodilators include bosentan (Tracleer), epoprostenol (Flolan), Treprostinil (Remodulin), and sitaxentan. (sitaxsentan), nifedipine (Adalat, Procardia), nicardipine (Cardene), verapamil (Calan, Corvera- HS (Covera-HS), Isoptin, Verelan), diltiazem (Dilacor XR, Diltia XT, Tiamate, Tiamate) Tiazac, Cardizem), isradipine (DynaCirc), nimodipine (Nimotop), amlodipine (Norvasc) ), felodipine (Plendil), nisoldipine (Sular), bepridil (Vascor), hydralazine (aprezoline) (Apresoline), minoxidil (Loniten), isosorbide dinitrate (Dilatrate-SR, Iso-Bid, Isonate) (Isonate), Isorbide, Isordil, Isotrate, Sorbitrate), isorbide mononitrate (IMDUR), prazosin ) (Minipress), cilostazol (Pletal), Treprostinil (Remodulin), cyclandelate, Isoxuprine ( isoxsuprine) (Vasodilan), nylidrin (Arlidin), nitrates (Deponit, Minitran, Nitro-Bid, Nitrodisc, Nitro-Dur, Nitrol, Transderm-Nitro, benazepril (Lotensin), benazepril, and Hydrogen Hydrochlorothiazide (Lotensin HCT), captopril (Capoten), captopril and hydrochlorothiazide (Capozide), enalapril (Vasotec), analapril and hydrochlorothiazide (Vaseretic), fosinopril (Monopril), lisinopril (Prinivil) ), Zestril), lisinopril and hydrochlorothiazide (Prinzide, Zestoretic), moexipril (Univasc), moexipril and hydrochlorothiazide (Prinzide, Zestoretic) Chlorothiazide (Uniretic), perindopril (Aceon), quinapril (Accupril), quinapril, and hydrochlorothiazide (Accuretic) )), ramipril (Altace), trandolapril (Mavik), papaverine (Cerespan, Genavid, Pavabid (Cerespan) Pavabid), Pavabid HP, Pavacels, Pavacot, Pavagen, Pavarine, Pavased, Pavatine, Pavacot (Pavatym), Paverolan), but is not limited thereto.

In some embodiments, the diuretic is incorporated into solid lipid particles. Suitable diuretics include acetazolamide (Diamox), dichlorphenamide (Daranide), methazolamide (Neptazane), and bendroflumethy. Bendroflumethiazide (Naturetin), benzthiazide (Exna), chlorothiazide (Diuril), chlorthalidone (Hygrotone) (Hygroton)), hydrochlorothiazide (Esidrix, HydroDiuril, Microzide), hydroflumethiazide (Diucardin), indapamide (Lozol), methyclothiazide (Enduron), metolazone (Zaroxolyn, Mykrox), Polythia polythiazide (Renese), quinethazone (Hydromox), trichlormethiazide (Naqua), bumetanide (part Bumex), ethacrynic acid (Edecrin), furosemide (Lasix), torsemide (Demadex), amyl Amiloride (Midamor), amiloride and hydrochlorothiazide (Moduretic), spironolactone (Aldactone), spironolactone and hydrochlorothiazide Zide (Aldactazide), triamterene (Dyrenium), triamterene and hydrochlorothiazide (Dyazide, Maxzide), It is not limited.

In some embodiments, the anti-cancer agent is incorporated into solid lipid particles. Suitable anticancer agents include aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anagrelide, Anastrozole, arsenic trioxide, asparaginase, bexarotene, bicalutamide, bleomycin, busulfan, callus Calusterone, capecitabine, carboplatin, carmustine, celecoxib, chlorambucil, cisplatin, cladribine , cyclophosphamide, cytarabine, dacarbazine, dactinomycin, darbepoetin alpha, daunorubicin, daunomycin , dexrazoxane, docetaxel, doxorubicin, epoetin alpha, estramustine, etoposide, etoposide phosphate, exemestane (exemestane), filgrastim, floxuridine, fludarabine, flutamide, fulvestrant, gemcitabine, gemtuzumab orzoga Gemtuzumab ozogamicin, goserelin acetate, hydroxyurea, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate ( imatinib mesylate, interferon alpha-2a, interferon alpha-2b, irinotecan, leflunomide, letrozole, leucovorin , levamisole, lomustine, meclorethamine (nitrogen mustard), megestrol acetate, melphalan, mercaptopurine , mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, mycophenolate mofetil, NAND Nandrolone phenpropionate, nilutamide, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, pamidronate, Pegada pegademase, pegaspargase, pegfilgrastim, pentostatin, pipobroman, plicamycin, porfimer sodium, Procarbazine, quinacrine, rasburicase rituximab, sargramostim, streptozocin, tacrolimus, tamoxifen, temo Temozolomide, teniposide, testolactone, thioguanine, thiotepa, topotecan, toremifene, tositumomab, tramide trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, and zoledronate ), but is not limited to this.

In some embodiments, nutritional agents are incorporated into solid lipid particles. Suitable nutritional agents 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 cell growth factors, including LIF, CSF-1, CSF-2, CSF-3, erythropoietin, and ECGF; FGF- and ECGF-related growth factors (e.g., endothelial cells that stimulate angiogenesis factor, tumor angiogenesis factor, retina-derived growth factor (RDGF), vascular endothelial growth factor (VEGF), brain- Insulin-like growth factors and fragments such as derived growth factors (BDGF-A and B), astroglial growth factors (AGF 1 and 2), omentum-derived growth factor, SSSR, fibroblast-stimulating factor (FSF), and embryonic carcinoma derived growth factor (ECDGF)); Neurotrophic growth factors (e.g., nerve growth factors (NGFs), neurturin, brain-derived neurotrophic factor (BDNF), neurotrophin-3, neurotrophin-4, and ciliary neurotrophic factor (CNTF)); glial growth factors (e.g., GGF-I, GGF-II, GGF-III, glial maturation factor (GMF), and glial-derived neurotrophic factor (GDNF)); liver growth factors (e.g., hepatocyte growth factors including hepatopoietin A, hepatopoietin B, and HGF); prostate growth factors, including prostate-derived growth factors (PGFs); mammary growth factors, including mammary-derived growth factor 1 (MDGF-1) and breast cancer-derived factor (MTGF); heart growth factors, including nonmyocyte-derived growth factor (NMDGF); melanocyte growth factors, including melanocyte stimulating hormone (MSH) and melanoma growth-stimulating activity (MGSA); angiogenic factors (e.g., angiogenin, angiotropin, platelet-derived ECGF, VEGF, and pleiotropin); transforming growth factors including TGF-α and TGF-β; TGF-like growth factors (e.g., TGF-beta1, TGF-beta2, TGF-beta3, GDF-1, CDGF, tumor-derived TGF-like factor, ND-TGF, and human epithelial cell transforming factor (human epithelial transforming factor)); Regulatory peptides with similar characteristics to growth factors (e.g. bombesin and the bombesin-like peptides ranatensin and litorin, angiotensin, endothelin, atrial atrial natriuretic factor, vasoactive intestinal peptide, and bradykinin); Platelet-derived growth factors including PDGF-A, PDGF-B, and PDGF-AB; neuropeptides (e.g., substance P, calcitonin gene-regulated peptide (CGRP), and neuropeptide Y); Neurotransmitters and their analogs, including 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 inhibitory factor 2 (TIF-2), keratinocyte-derived T-cell growth factor (KD-TCGF), IL -2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, stromal cell-derived cytokines Insulin-like growth factors including cytokine; SCDC), IL-12, IL-13, IL-14, IL-15, insulin, IGF-1, IGF-2, and IGF-BP; interferons, including INF-alpha, INF-beta, and INF-gamma; Leptin, midkine, tumor necrosis factor (TNF-alpha and beta), netrins, saposins, semaphorins, somatrem, somatropin (somatropin), stem cell factor, VVGF, bone morphogenetic proteins (BMPs), adhesion molecules, other cytokines, heparin-binding growth factor, and tyrosine kinase receptor ligands. It is not limited. In some embodiments, the nutrient is a peptide, such as AcEEED, which is an N-terminal peptide of alpha smooth muscle actin and has been shown to inhibit the contractile properties of myofibroblasts.

In some embodiments, an extracellular matrix agent (ECM agent) is incorporated into solid lipid particles. Suitable ECM preparations include extracellular matrix proteins, reconstituted basement membrane-like complexes derived from eukaryotic cell lines, collagen, fibronectin, laminin, VCAM-1, vitronectin and gelatin, and bacterial extracellular matrix. , native structures and synthetic analogs of gel matrices and polymeric matrices, but are not limited thereto. In some embodiments, the wound active agent would be integrin binding sequences, exemplified by RGD, EILDV, VCAM-1 and their recombinant or synthetic analogs, enzymes, enzyme inhibitors and polypeptides. It is not limited.

In some embodiments, the enzyme preparation is incorporated into solid lipid particles. Suitable enzyme preparations include, but are not limited to, exopeptidases and endopeptidases (also called proteases and proteinases), wherein exopeptidases and endopeptidases are serine Proteinases chymotrypsin, trypsin, elastase, kallikrein, bacterial enzymes, cysteine proteases papain, actinin, bromelain, protein cathepsins, cytosolic calpains, parasitic proteases, aspartic proteinases, pepsin family of pepsin and chymosin proteases, lysosomal cathepsins D, Renin, fungal proteases, viral proteases, AIDS virus retropepsin, metalloproteinases (MMPs), collagenase, Maggott enzyme, MMP1, MMP2, Including, but not limited to, MMP8, MMP13, gelatinases, MMP2, MMP9, MMP3, MMP7, MMP10, MMP11, and MMP12.

In some embodiments, the enzyme inhibitor is incorporated into solid lipid particles. Suitable enzyme inhibitors include NSAIDS, aspirin, captopril, thiorphan, phosphoramidon, teprotide, protease and proteinase inhibitors, and metalloproteins. Including, but not limited to, enzyme inhibitors and exopeptidase inhibitors.

In some embodiments, the polypeptide antimicrobial agent is incorporated into solid lipid particles. Suitable polypeptide antibacterial agents include, but are not limited to, alpha-defensins HNP 1, 2, 3, and 4 and beta-defensins HBD-1, HBD-2, HBD-3, and cathelicidins. Other suitable polypeptide antibacterial agents include magainin (e.g., magainin I, magainin II, xenopsin, xenopsin precursor fragment, caerulein precursor fragment), Magainin I and II analogs (e.g., PGLa, magainin A, magainin G, pexiganan, Z-12, pexigainin 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, reversed ) magainin II analogs (e.g., 53D, 87-ISM, and A87-ISM), Ala-magainin II amide, magainin II amide), cecropin P1, cecropin A, cecropin Lopin B, indolicidin, nisin, ranalexin, lactoferricin B, poly-L-lysine, cecropin A (1 -8)-Magaicin II (1-12), Cecropin 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, alamethicin, protegrin, histatin , dermaseptin, lentiviral amphipathic peptide or analogue, parasin I, lycotoxin I or II, globomycin, gramicidin S, sulpectin (surfactin), ralinomycin, 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 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, cathelicidin, HD-5, Oabac5 alpha, ChBac5, SMAP-29, Bac7.5, lactoferrin, granulysin, thionin, hevein and knottin-like peptides, MPG1, 1bAMP, snaking, lipid transport Includes proteins, and plant defensins. Exemplary sequences for the above compounds are shown in Table 1. In some embodiments, the antimicrobial peptide is synthesized from L-amino acids, while in other embodiments the antimicrobial peptide is synthesized from or includes D-amino acids.

In some embodiments, the polypeptide agent is incorporated into solid lipid particles. Suitable polypeptide preparations include antibodies and immunoglobulins and fragments thereof, single chain antibodies, humanized antibodies, fibronectin, serotonin, PAF, PDEGF, TNFa, IL1, IL6, IGF, IGF-1, IGF-2, IL-1, PDGF. , FGF, KGF, VEGF, bradykinin, prothymosin-alpha and thymosin-alpha 1.

The finely divided lipid particles of the present invention are used in a variety of drug delivery systems and devices.

In some preferred embodiments, the finely divided lipid particles are provided in a liquid composition, most preferably an aqueous suspension compatible with mucosal surfaces. The term "liquid composition" according to the present invention may be applied to the human or animal body and may optionally contain an active agent or an active lipid agent as detailed above, comprising crystalline and amorphous solid low melting point finely divided substances such as those described above. means any water-containing liquid, solution or suspension, including particles. In some preferred embodiments, the liquid composition may contain excipients, such as lipids, oils, lipophilic vitamins, lubricants, viscosifiers, acids, bases, antioxidants, stabilizers, synergists, colorants ( It further includes a coloring agent), a thickener - and, if necessary - in certain cases, a preservative or surfactant, and combinations thereof.

In the micronization process, useful excipients can be added to the low melting point suspended crystalline or amorphous solid. Useful excipients include glycerol, propylene glycol, polyethylene glycol, ethanol, acetone, ethyl acetate, isopropyl alcohol, pentylene glycol, liquid paraffin and Including, but not limited to, triglyceride oil. These added excipients may be therapeutically beneficial or may be added to control the melting point of the low melting point suspended solid or to control the finely divided particle size. Other excipients may be added to the aqueous component of the formulation as viscosity modifiers, stability enhancers, and therapeutically beneficial additives.

Useful antioxidants include vitamin E or vitamin E derivatives, ascorbic acid, sulphites, hydrogen sulphites, gallic acid esters, butyl hydroxyanisole (BHA), and butyl hydroxyanisole. Includes, but is not limited to, toluene (butyl hydroxytoluene (BHT)) or acetylcysteine (acetylcysteine).

In some particularly preferred embodiments, the finely divided crystalline or amorphous solid lipid particles are provided in an aqueous suspension in an ophthalmologically acceptable vehicle or carrier. Other components that may be included as carrier components include viscosity enhancing components commonly found in artificial tears, such as buffer components, tonicity components, preservative components, pH adjusters, one or more electrolytes, and mixtures thereof. , but is not limited to this. In one very useful embodiment, the carrier component includes at least one of the following: an effective amount of a buffering component; An effective amount of tonicity component; An effective amount of a viscosity component, an effective amount of a density component, an effective amount of a preservative component; and water.

These additional ingredients are preferably ophthalmologically acceptable and may be selected from materials commonly used in ophthalmic compositions, such as compositions used to treat eyes suffering from dry eye or other eye diseases, artificial tear formulations, etc. there is.

The acceptable effective concentrations for these additional ingredients within the compositions of the present invention will be readily apparent to those skilled in the art.

The liquid composition may be applied to the ocular surface of the eye or other mucosal surface as described herein, including a buffering solution, e.g., phosphate buffered saline or an inert carrier compound, glycerol, mineral oil, wax or similar material. It can be administered alone or in combination with pharmaceutically acceptable substances, including these.

The dosage of the lipid compound is optimized according to the formulation and delivery method, and the mode of administration of the lipid compound is determined according to a conventional protocol, which effectively treats human eye disease symptoms.

Liquid compositions comprising finely divided lipid particles can be utilized as a vehicle for topical administration of therapeutic agents. Suitable therapeutic agents are described above and include active compounds including active lipid compounds. In particular, the liquid compositions of the present invention can be used to deliver any desired therapeutic agent or combination of therapeutic agents, including active lipid agents, antibiotics, antiviral agents, antifungal agents, anticancer agents, Antiglaucoma agents, anti-inflammatory agents, secretagogues (activators of mucin-related cells that promote lacrimation, salivation, or release of soluble mucins, or promote wettability and/or lubricity of mucosal surfaces) Agents that promote expression include, but are not limited to, analgesics, immunomodulators, macro-molecules, or mixtures thereof.

In some particularly preferred embodiments, a therapeutic agent may be included in the liquid composition of the invention comprising finely divided lipid particles within the liquid composition, the therapeutic agent being Zydra, cyclosporine, corticosteroids and steroids, used as adjuvants in surgery. Ophthalmic agents, chelating agents, antineoplastic agents, diagnostic agents, adrenergic anesthetics, beta blockers, alpha-2-agonists, paralytics, prostaglandins, ACE-inhibitors, endogenous cytokines ( endogenous cytokines, agents affecting the basement membrane, agents affecting the growth of endothelial cells, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase Aldose reductase inhibitors, analgesics, anesthetics, anti-allergic agents, anti-inflammatory agents, antihypertensives, pressors, antibacterial agents, antiviral agents, antifungal agents, antiprotozoal agents, anti-infectives, antitumor agents. Agents, antimetabolites, antiangiogenic agents, tyrosine kinase inhibitors, antibiotics such as gentamycin, kanamycin, neomycin and vancomycin. aminoglycosides such as; amphenicols such as chloramphenicol; cephalosporins such as cefazolin HC1; Penicillins such as ampicillin, penicillin, carbenicillin, oxacillin, and methicillin; lincosamides such as lincomycin; polypeptide antibiotics such as polymyxin and bacitracin; tetracyclines such as tetracycline; quinolones such as ciproflaxin; Sulfonamides such as chloramine T; and sulfones such as sulfanilic acid, which are hydrophilic entities, and antiviral drugs such as acyclovir, ganciclovir, vidarabine, and azidotimi. azidothymidine, dideoxyinosine, dideoxycytosine, dexamethasone, ciproflaxin, water-soluble antibiotics such as acyclovir, ganciclovir ( ganciclovir, vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine; epinephrine; isoflurophate; Adriamycin; bleomycin; mitomycin; ara-C; actinomycin D; scopolamine; etc. and analgesics such as codeine, morphine, ketorolac, naproxen, etc., anesthetics such as lidocaine; beta-adrenergic blockers or beta-adrenergic agonists such as ephedrine, epinephrine, etc.; Aldose reductase inhibitors, such as epalrestat, ponalrestat, sorbinil, tolrestat; Antiallergic agents, such as cromolyn, beclomethasone, dexamethasone and flunisolide; colchicine; antiamebic agents, such as chloroquine and chlortetracycline; and antifungal agents such as amphotericin, anti-angiogenesis compounds such as anecortave acetate, anti-glaucoma agents such as brimonidine. ), acetazolamide, bimatoprost, Timolol, mebefunolol; memantine; alpha-2-adrenergic receptor agonist; 2ME2; Anti-neoplastics, such as vinblastine, vincristine, interferon; alpha, beta and gamma, antimetabolites such as folate analogs, purine analogs and pyrimidine analogs; immunosuppressants such as azathioprine, cyclosporine and mizoribine; Miotic agents such as carbachol, mydriatic agents such as atropine, protease inhibitors such as aprotinin, camostat, gabexate, Brady Vasodilators such as bradykinin and various intestinal factors such as epidermal growth factor, basic fibroblast growth factor, nerve growth factor, etc., including, but not limited to, derivatives thereof and combinations thereof. Ophthalmic preparations used to treat dry eye, NMDA antagonists, antihistamines, antiparasitics, miotics, sympathomimetics, anticholinergics, topical Includes local anesthetics, amoebicidals, trichomonocidals, mydriatics, carbonic anhydrase inhibitors, and ophthalmic diagnostic agents.

The effective amount of micronized lipid particles administered in liquid compositions is determined by routine methods and may be used in pharmaceutical formulations in ophthalmic vehicles, including buffered solutions such as phosphate buffered saline or inert carrier compounds, glycerol, mineral oil or the like. Can be combined with legally permitted substances. The dosage of the micronized lipid particles is optimized depending on the formulation and delivery method, and the mode of administration is determined by conventional protocols for effectively treating diseases or conditions in the subject, such as ocular diseases or other diseases associated with the mucous membrane.

In some preferred embodiments, the liquid composition comprising suspended finely divided solid lipid particles is administered topically, for example as eye drops. Accordingly, in some preferred embodiments, the liquid composition comprising finely divided lipid particles is a stable suspension in a physiologically compatible carrier provided in a container, most preferably a drop dispenser. Suitable drop dispensers are known in the art and include, but are not limited to, U.S. Patent Nos. 10,507,132; No. 10,265,214; No. 9,999,540; No. 9,545,333; No. 7,846,140; No. 7,563,256; No. 7,527,613; No. 6,736,802; No. 5,810,794; Nos. 5,578,020 and 5,558,653, the entire contents of which are hereby incorporated by reference.

In another embodiment, the liquid composition comprising the finely divided lipid or solid lipid particles is maintained at a concentration of 250-35 mOsmol/L in an aqueous component buffered to a pH between 5 and 8. It can be delivered to the ocular surface by drop in any number of containers, including sterile single-use containers, blow-fill seal containers, and multi-use containers, containing finely divided suspensions, either preservative or unpreserved. there is.

In some preferred embodiments, the liquid composition comprising finely divided lipid particles is a suspension of finely divided crystalline or amorphous solid lipid particles. In some preferred embodiments, the liquid composition is PBS containing wetting agents and thickening agents, wherein the finely divided crystalline or amorphous solid lipid particles are maintained in a stable suspension in PBS at a pH of 5-8, an osmolality of 250 to 350 mOsm/L, and a viscosity of 100 or less. do. In some preferred embodiments, the suspension comprises a buffer and may or may not contain a preservative. In some preferred embodiments, the suspension includes a stabilizing agent.

In another preferred embodiment, the drug delivery vehicle is a medical implantable device. The medical implantable device used herein refers to a solid, three-dimensional structure that can be inserted into or on the body of a subject, such as the eyes, vagina, rectum, nose, mouth, etc. In some preferred embodiments, the medical implantable device is formed from finely divided lipid particles that are formed into the three-dimensional structure of the device. In another preferred embodiment, the device is formed from physiologically acceptable materials. Suitable physiologically acceptable materials include metals, gels, polymers, proteinaceous materials, etc. In this embodiment, the device is coated or impregnated with finely divided lipid particles.

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, hydrogel, polymethyl methacrylate, and silicone acrylate. In some embodiments, bioerodible polymer films suitable for application to mucosal membranes include poly(lactic/glycolic acid-PLGA) and poly(ε-caprolactone). (ε-caprolactone)) is preferable. In another preferred embodiment, the physiologically acceptable polymer is butyryl-trihexyl-citrate, di(2-ethylhexyl)phthalate, di-iso -Nonyl-1,2-cyclohexanedicarboxylate (Di-iso-nonyl-1,2-cyclohexanedicarboxylate), Expanded PTFE, Ethylene vinyl alcohol copolymer, hexamethylene diisocyanate ( Hexamethylene diisocyanate, high density PE, highly crosslinked 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), polyether ether ketone, poly(ethylene glycol) ), poly(ethylene oxide), polyester polymer alloy, polyether sulfone, poly(ethylene terephthalate), poly(glycolic acid), poly(hydroxyethyl methacrylate), poly(lactic-co -Glycolic acid) (Poly(lactic-co-glycolic acid)), poly(L-lactic acid), poly(methyl methacrylate), poly(methylpentene), poly(propylene), polysulfone, poly(tetrafluoro) Ethylene), poly(vinyl alcohol), poly(vinyl chloride), poly(vinyliden fluoride), poly(vinylpyrrolidone), poly(styrene-b-isobutylene-b- styrene) and ultrahigh molecular weight polyethylene (Ultrahigh molecular weight PE).

The medical insertion device of the present invention may be of any shape or size suitable for insertion into a desired part of the subject's body. In some preferred embodiments, the insert is shaped like a sheet, rod, sphere, partial sphere, tube, cylinder, triangle, or cone. It has a shape such as (cone). In some preferred embodiments, when the insert is placed in contact with the subject's ocular surface, the insert may preferably be a lacrimal plug, a lens such as a contact lens, or an ophthalmic insert such as LACRISERT ^™ . In some embodiments, the medical implantable device is rechargeable so that the micronized lipid particles of the invention can be replenished after use and the device can be reused. In another preferred embodiment, the device is a disposable device.

In some preferred embodiments, the drug delivery device of the present invention is used to deliver an active agent to the mucosal surface of a subject's body. Exemplary mucosal surfaces include the ocular mucosal surface, vaginal mucosal surface, cervical mucosal surface, fallopian tube mucosal surface, respiratory mucosal surface, nasal mucosal surface, oropharyngeal mucosal surface, oral mucosal surface, rectal mucosal surface, digestive mucosal surface, and Including, but not limited to, the esophageal mucosal surface.

In some embodiments, the drug delivery vehicle is applied or administered to a mucosal surface. In some preferred embodiments, administration is topical. In another preferred embodiment, administration is by retro-ocular, intracameral, intravitreal, suprachoroidal and subretinal delivery routes. In some embodiments, the drug delivery vehicle is applied or implanted beneath the mucosal surface. In some preferred embodiments, the mucosal surface is an ocular mucosal surface and the drug delivery vehicle is implanted or applied under the conjunctiva or Tenon's capsule.

In some preferred embodiments, the active agent is delivered into the subject's body through a mucosal surface.

In some preferred embodiments, the drug delivery vehicles of the invention are used for the treatment of various diseases, disorders or conditions. In some preferred embodiments, the disease, disease or condition is associated with a mucosal surface.

In some preferred embodiments, the present invention provides, in an animal or human subject in need of treatment a disease or condition of the eye, dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and symptoms, clinical signs or conditions associated therewith; Provided is a method for treating an eye disease or condition selected from the group consisting of rapid aqueous tear evaporation due to unstable tear film and keratoconjunctivitis sicca (dry eye) and symptoms or clinical signs related thereto. In some preferred embodiments, subjects in need of treatment can be identified by measuring tear film breakup times that are less than average. In some preferred embodiments, a therapeutically effective amount of an active agent made of finely divided lipid particles is administered to the subject, preferably via the mucosal surface of the eye. In some preferred embodiments, the finely divided crystalline or amorphous solid lipid particles are administered to the eye as a suspension in an ophthalmologically acceptable solution. In some preferred embodiments, the finely divided 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 1 day at room temperature. In some preferred embodiments, the finely divided crystalline or amorphous solid lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmically acceptable solution with a shelf life of more than one week at room temperature. In some preferred embodiments, the finely divided crystalline or amorphous solid lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmically acceptable solution with a shelf life of more than 1 month at room temperature. In some preferred embodiments, the finely divided crystalline or amorphous solid lipid particles are administered to the eye as a chemically and physically stable suspension in an ophthalmically acceptable solution with a shelf life of more than one year 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 1 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 1 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 another preferred embodiment, the solid finely divided lipid particles release the active lipid agent or other active agent into the tear film comprising the tear film lipid layer over an extended period of time. In another preferred embodiment, the solid finely divided lipid particles release the active lipid agent or other active agent into the tear film comprising the tear film lipid layer over 12 to 24 hours after a single dose. In another preferred embodiment, the solid finely divided lipid particles release the active lipid agent or other active agent into the tear film comprising the tear film lipid layer over 12 to 24 hours after a single drop applied to the ocular surface. In another preferred embodiment, the solid finely divided lipid particles release the active lipid agent or other active agent into the tear film comprising the tear film lipid layer over 24 hours after a single drop of less than 50 microliters in volume. In another preferred embodiment, the finely divided lipid particles are embedded in or injected into an insertion device capable of releasing the finely divided lipid particles into the tear film comprising the tear lipid layer over an extended period of time. Such devices may include, but are not limited to, lacrimal plugs, contact lenses, hydroxycellulose inserts (e.g., LACRISERT ^™ ), or other similar devices.

In another preferred embodiment, the drug delivery device of the present invention is used to treat dryness of the mouth, nose or vagina, vaginal yeast infections, respiratory mucosal diseases, canker sores, surfactant dysfunction, polypeptide antibacterial agents. , herpes (caused by HSV-1 and HSV-2), mucous membrane pemphigoid, oral lichen planus, Sjogren's syndrome, hairy leukoplakia, vulgaris of the mucous membranes. It is used to treat diseases or disorders associated with mucosal dysfunction, including mucosal pemphigus vulgaris and chronic aphthous stomatitis. In these embodiments, a therapeutically effective amount of an active agent made of finely divided lipid particles is administered to the involved mucosa.

The invention should not be limited in scope by the exemplary embodiments, which are intended only as illustrations of specific aspects of the invention. Specific methods of treating mucosal diseases with finely divided lipid particles comprising active agents according to the invention have been described above for the purpose of illustrating the manner in which the invention may be advantageously used; however, it will be understood that the invention is not limited thereto. will be. For example, the methods and compositions of the present invention can be used to treat other mucosal conditions and diseases not listed. Accordingly, any and all variations and modifications that may occur to those skilled in the art should be considered within the scope and spirit of the invention as defined in the appended claims.

Example

Example 1 - MCAL-201 Synthesis

1-Eicosanyl-2-palmitoyl-rac-glycerol (1,2-EPRG, hereinafter referred to as MCAL-201) is a process consisting of 4 individual chemical steps. It was manufactured using. The solid drug substance (DS) is a finely divided solid with a size of 1-10 μm suitable for suspension in a phosphate-buffered saline (PBS) vehicle containing polysorbate 80 and xanthan gum to stabilize the suspension of finely divided particles. It is further processed by jet-milling into particles.

MCAL-201 drug product (DP) is a solid micronized (jet milled) dropper vial in a white, disposable high-density polyethylene (HDPE) dropper vial for direct administration to the ocular surface in 35 μL drops. ) MCAL-201 is supplied as a sterile, unpreserved aqueous suspension.

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

The general and physicochemical properties of MCAL-201 are as follows:

The molecular weight of 1,2-EPRG is 611.05 g/mol

Empirical formula: C ₃₉ H ₇₈ O ₄

Appearance: white powder

Particle size: 1-10 μm (after finely divided)

Hygroscopicity: low

Chirality: racemic

Enantiomeric excess: 0

Melting point: 57℃

Solubility: Insoluble in water. Soluble in chloroform (40 mg/mL) and castor oil (25 mg/mL).

Through a series of individual synthetic steps starting with the racemic solketal, the manufacturing process produces the active pharmaceutical ingredient (API), MCAL-201, which is a 1:1 racemic mixture of the two enantiomers. The unit operational sequences are as shown in Figure 1.

A 420 gram lot of MCAL-201 was prepared. According to the Certificate of Analysis (CoA), MCAL-201 raw drug substance is a 99:1 mixture of 1,2-EPRG and 1,3-EPRG. This lot was used in non-clinical studies described in further detail herein. After the synthesis described in Figure 1, MCAL-201 was synthesized to achieve microparticle sizes in the range of 1 to 10 microns, as measured by dynamic light scattering (DLS) of finely divided solids suspended in PBS. It is further processed by jet-milling or spray drying (see Figure 2).

Dissolving MCAL-201 in aqueous formulations for delivery as ophthalmic drops without micronization proved difficult due to MCAL-201's extreme insolubility in water. However, preparation of a water-soluble cyclodextrin inclusion complex of MCAL-201 was used in nonclinical efficacy studies. Additionally, MCAL-201 can be delivered directly to the tear film lipid layer using a solution of MCAL-201 in castor oil, which can be emulsified into micron-sized liquid particles in an aqueous buffer.

This cyclodextrin and emulsified castor oil formulation was found to be effective in an animal model of dry eye syndrome. Due to the unacceptable level of acyl transfer of the palmitoyl group from the 2-position to the thermodynamically more stable 3-position of MCAL-201, MCAL-201 lacked long-term chemical stability in liquid solution. The isomer stability of MCAL-201 in the solid phase was observed to be much greater than that in solution. This led to the development of the delivery of solid MCAL-201 as a suspension of crystalline or amorphous finely divided solid particles suspended in an aqueous formulation that is isotonic with tears. MCAL-201 crystalline drug substance floats in phosphate-buffered saline (PBS); however, MCAL-201 can be finely divided into 1-10 micron particles and then suspended, with polysorbate 80 as a wetting agent and the density of the drug product. It can be stably suspended in PBS with the help of xanthan gum to control viscosity.

Example 2 - Micronization of MCAL-201

MCAL-201 API is a crystalline solid (melting point 57°C) with a flocculent, low-density texture like powder snow. Therefore, 50 g of MCAL-201 drug substance is filled into a jar designed to hold 500 mL of a denser liquid or solid such as powdered sugar. Two micronization methods, spray drying and jet milling, appeared to be suitable for MCAL-201.

Spray drying method : MCAL-201 solution in chloroform (3% w/w) is sprayed into a Buchi B-290 spray dryer with an inert gas stream to produce an aerosol with an inlet temperature of 85 degrees for 10 minutes. Create. This rate is chosen to ensure a solid finely divided particle form, with amorphous solid particles presumably at least 10 degrees below the crystalline melting point. The collection of finely divided particles is placed in a chamber with a cyclonic flow from pressurized inlet gas to exit vacuum pressure after most of the solvent (chloroform) has evaporated and condensed separately. Fifty percent of the injected MCAL-201 formed amorphous finely divided solid particles in the collection chamber. As measured by dynamic light scattering, the average particle size was 8.6 microns, showing a relatively tight size distribution between 7 and 11 microns. These particles were dried under vacuum (gas chromatography) until the residual chloroform was below the limit of quantitation.

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 with an inert gas stream to generate aerosols with an inlet temperature of 85 degrees for 10 minutes. Create. After most of the solvent (chloroform) has evaporated and condensed separately, a collection of finely divided particles exists within the chamber with a cyclonic flow from the pressurized inlet gas to the outlet vacuum pressure. These particles were dried under vacuum (gas chromatography) until the residual chloroform was below the limit of quantitation.

Jet milling method : Crystalline solid MCAL-201 was fed into the grinding chamber of a spiral mill under high-velocity gas injection (e.g., supersonic) to induce high-energy particle-particle impact and fracture of MCAL-201 particles. . These particles are swept in a continuous cyclonic flow towards the center of the mill chamber. Particles smaller than 10 microns are swept into the collection chamber by the cyclonic gas flow. A significant amount of MCAL-201 is attached to the chamber wall. Three lots of finely divided MCAL-201 were produced with an average particle size of less than 10 microns. All had a size distribution between 1 and 15 microns, with the smallest particle distribution being between 1 and 10 microns. The average particle size of this lot was 3.56 microns and was transferred to the suspension development study mentioned below.

Example 3 - Formulation of MCAL-201

MCAL-201 is a non-polar ether lipid first identified in the secretions of the rabbit's Harderian gland. This is a non-polar molecule from the 1-O-ether, 2-ester glycerol (1,2-EPRG) series that is associated with the hyperstable tear film lipid layer and long interblink intervals (e.g., >20 min) observed in rabbits. It is lipid. MCAL-201 is chemically synthesized under cGMP conditions for use in humans.

MCAL-201 drug product (DP) is a milky white suspension of finely divided solid MCAL-201 particles. Each mL of 0.1% suspension contains 1 mg of MCAL-201 active ingredient. The finished drug product can be formulated as a suspension of 0.0001%, 0.001%, 0.01%, 0.1%, 0.3%, 1% and 5% finely divided solid MCAL-201. The finished drug product is aseptically filled into sterile HDPE bottles with protective caps and dropper tips delivering a volume of 35 μL per drop. Finished pharmaceutical products may or may not be preserved. The container closure system is separately sterilized by gamma irradiation before filling the drug product (DP).

An exemplary product batch configuration is provided in Table 1.

MCAL-201 is formulated in the following strengths: 0.0001%, 0.001%, 0.01%, 0.1%, 0.3%, and 1%. Finely divided MCAL-201 is mixed with polysorbate-80, a wetting agent. An appropriate amount of remaining excipient was weighed and dissolved in PBS at a target pressure of 260 to 320 mOsm/L. A milky white suspension of solid MCAL-201 containing 0.001 to 10 (or TBD) mg/mL of the suspended drug in PBS containing 0.1% to 0.3% (w/v) xanthan gum as a viscosity and density modifier. To obtain, homogenize and add to the MCAL-201/polysorbate 80 mixture. The pH is adjusted with 1N HCl or 1N NaOH to achieve a pH of 6.5 to 7.2. The final polysorbate 80 concentration is 3% or less, and the final xanthan gum concentration is 0.1 to 0.3%. The suspension is analyzed for MCAL-201 content, MCAL-201 isomer content, particle size distribution, pH, density and osmotic pressure. The formulated bulk material is aseptically filled into 7.5 mL sterile HDPE bottles containing LDPE dropper tips and polypropylene cap closures. Table 2 provides analytical specifications for the finished drug product.

Crystalline MCAL-201 was finely divided into 1 to 10 micron crystalline and amorphous solid particles (see Figure 2). These particles, when treated with the wetting agent polysorbate 80 (0.3% w/w), are stably suspended in phosphate-buffered saline (PBS, pH 6-8, 260), suitable for administration as a suspension for topical instillation or infusion. Provide a suspension of finely divided particles in a mixture of xanthan gum (0.1-0.3% w/w, see Figure 3) at -320 mOsm/L). The physical stability of finely divided suspensions with respect to separation of finely divided molecules due to floating, settling or agglomeration of finely divided solid particles was confirmed for at least 6 months at room temperature. The recovery of finely divided solid particles from the formulated drug by centrifugation and water washing is consistent with the chemical and isomeric stability of MCAL-201 for the micronization process (see Figure 4) and the micronized solid particles in suspension formulation for 6 weeks at room temperature. showed the isomer stability of MCAL-201 (Figure 5).

Example 4 - Toxicity and tolerability studies

Pharmacological and toxicological studies of MCAL-201 to explore non-GLP topical ocular dosage ranges were performed in naive dogs. The primary study objective was to evaluate the tolerability of topical ocular administration of MCAL-201 in dogs, with the secondary objective of obtaining data supporting pharmacological activity in healthy dogs.

Effects of vehicle and 0.1, 0.5, 1, 3, and 10 mg/mL MCAL-201 delivered bilaterally as 35 μL instillations once daily (QD) (0.0035, 0.0175, 0.035, 0.105, and 0.35 mg/eye/day). Evaluated in Part I. Dosing regimens are summarized in 3.

The ocular endpoints evaluated are summarized in Table 4. Scoring of the ocular surface and anterior region of the eye was performed by a board-certified veterinary ophthalmologist using the SPOTS system. SPOTS was performed for each concentration evaluated. To measure TBUT, fluorescein was injected into the eye and the eye was manually closed and gently opened to simulate blinking. The time interval between the first sign of disruption of the uniform tear film, indicated by the break of fluorescein, and the opening of the eye was recorded in seconds. The procedure was repeated three times on both eyes, first the right eye and then the left eye. After 10 mg/mL MCAL-201 was administered BID, SPOTS was also performed 48 hours after the last dose.

MCAL-201 was well tolerated and showed no ocular or systemic side effects at any time or concentration evaluated (up to 10 mg/mL OU BID for 48 hours). MCAL-201 extended TBUT in five healthy adult dogs (Figure 6).

Claims (84)

A lipid particle composition comprising solid non-polar lipid particles,
The solid non-polar lipid particles contain an active lipid agent, are stably suspended in a buffered aqueous vehicle suitable for topical administration, and have an average particle size of less than 50 microns, Lipid particle composition.
The lipid particle composition according to claim 1, wherein the solid non-polar lipid particles have a melting point of less than 80°C.
The lipid particle composition according to claim 1, wherein the solid non-polar lipid particles have a melting point of 20 to 80°C.
The lipid particle composition according to claim 1, wherein the solid non-polar lipid particles have a melting point of 30 to 60°C.
5. The lipid particle composition of any one of claims 1 to 4, wherein the solid non-polar lipid particles have an average particle size of less than 20 microns.
6. The lipid particle composition of any one of claims 1 to 5, wherein the solid non-polar lipid particles have an average particle size of less than 10 microns.
7. The lipid particle composition according to any one of claims 1 to 6, wherein the active lipid agent is a non-polar ether lipid.
The lipid particle composition according to any one of claims 1 to 7, wherein the solid non-polar lipid particle comprises an active lipid agent selected from the following group.

here,
R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;
R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;
R ₃ is hydrogen (ie H);

here,
R ₁ is hydrogen (ie H);
R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;
R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,
R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;
R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;
R ₃ is hydrogen (i.e. H).
The lipid particle composition according to any one of claims 1 to 8, wherein the solid non-polar lipid particle comprises an active lipid agent selected from the group of:

here,
R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;
R ₂ is hydrogen (ie, H);
R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

here,
R ₁ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;
R ₂ is hydrogen (ie, H);
R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,
R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;
R ₂ is hydrogen (ie, H);
R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl.
The method according to any one of claims 1 to 9, wherein the solid non-polar lipid particle is 1-O-eicosanyl-2-palmitoyl- rac -glycerol , 1,2-EPRG), sn -1-O-eicosanyl-2-palmitoyl-glycerol ( sn -1-O-eicosanyl-2-palmitoyl-glycerol), sn -2-palmitoyl-3-O-eico Sanyl-glycerol ( sn -2-palmitoyl-3-O-eicosanyl-glycerol), 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1-O-eicosanyl-3-palmitoyl- rac -glycerol, 1,3- EPRG), sn -1-O-eicosanyl-3-palmitoyl-glycerol ( sn -1-O-eicosanyl-3-palmitoyl-glycerol), sn -1-palmitoyl-3-O-eicosanyl-glycerol ( sn -1-palmitoyl-3-O-eicosanyl-glycerol) and these A lipid particle composition comprising an active lipid agent selected from the group consisting of a mixture of.
11. The method of claim 10, wherein the solid non-polar lipid particle is 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl- rac -glycerol. A lipid particle composition comprising an active lipid agent selected from the group consisting of (1,3-EPRG) and mixtures thereof.
12. The method of claim 11, wherein 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) mixture is
Contains greater than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or
A lipid particle composition, characterized in that it comprises greater than 95% (mol%) of the 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
12. The method of claim 11, wherein 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) mixture is
Contains greater than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or
A lipid particle composition, characterized in that it comprises greater than 98% (mol%) of the 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
12. The method of claim 11, wherein 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) mixture is
Contains greater than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or
A lipid particle composition, characterized in that it comprises greater than 99% (mol%) of the 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
12. The method of claim 11, wherein 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) mixture is
Containing greater than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer,
A lipid particle composition, characterized in that it contains less than 5% (mol%) of 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
12. The method of claim 11, wherein 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) mixture is
Containing greater than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer,
A lipid particle composition, characterized in that it contains less than 2% (mol%) of 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
12. The method of claim 11, wherein 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) mixture is
Containing greater than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer,
A lipid particle composition, characterized in that it contains less than 1% (mol%) of 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
18. The method of any one of claims 1 to 17, wherein the solid non-polar lipid particles are non-polar mono-, di-, or tri-glycerides, wax esters including cholesterol esters, sterols, A lipid particle composition further comprising one or more additional lipids selected from the group consisting of free fatty acids and combinations thereof.
According to any one of claims 1 to 18,
The aqueous buffered vehicle comprises phosphate buffered saline (PBS), up to 3% (w/w of vehicle) polysorbate 80, and up to 0.3% (w/w of vehicle) xanthan gum,
pH is 6.5 to 8.0,
A lipid particle composition having an osmotic pressure of 260 to 320 mOsm/L.
20. The lipid particle composition according to any one of claims 1 to 19, wherein the suspended particles are stable to phase separation from suspension for 6 months at room temperature.
The lipid particle composition of claim 20, wherein the suspended particles are chemically stable with less than 5% isomerization of 1,2-EPRG into the isomer 1,3-EPRG during storage at room temperature for 6 months. .
20. The lipid particle composition according to any one of claims 1 to 19, wherein the suspended particles are stable to phase separation from suspension for 24 months at room temperature.
The lipid particle composition of claim 22, wherein the suspended particles are chemically stable with less than 5% isomerization of 1,2-EPRG into the isomer 1,3-EPRG during storage at room temperature for 24 months. .
According to any one of claims 1 to 23,
The composition is a sterile lipid particle composition.
According to any one of claims 1 to 24,
A lipid particle composition, wherein the composition includes a preservative.
According to any one of claims 1 to 25,
The lipid particle composition, wherein the suspension is preservative-free.
According to any one of claims 1 to 26,
A lipid particle composition, wherein the aqueous buffered vehicle is an ophthalmologically acceptable carrier.
According to any one of claims 1 to 27,
The aqueous buffering vehicle consists of a buffering agent, a tonicity agent, a wetting agent, a thickening agent and a viscosity agent, a density adjusting agent, and combinations thereof. A lipid particle composition further comprising an agent selected from the group.
29. The lipid according to any one of claims 1 to 28, wherein the active lipid agent in the solid non-polar lipid particle is released as individual molecules from the solid non-polar lipid particle over a period of time after administration as an ophthalmic drop. Particle composition.
30. The lipid particle composition of claim 29, wherein the individual molecules are released over a period of 1 to 24 hours.
According to any one of claims 1 to 30,
The lipid particle composition, wherein the suspension is provided in a drop dispenser.
In an animal or human subject in need of treatment for an eye disease or disease, as a method for treating the same,
Topically administering to the eye of the subject the lipid particle composition of any one of claims 1 to 31 comprising an effective amount of an active lipid agent,
The above diseases or diseases of the eye include dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and symptoms, clinical signs or conditions related thereto, rapid aqueous tear evaporation due to unstable tear film, and keratoconjunctivitis sicca. ) (dry eye) and symptoms or clinical signs related thereto.
33. The method of claim 32, wherein the subject in need of treatment has a tear film breakup time that is shorter than the normal clinical range of TBUT for a normal healthy population in the United States.
Use of the lipid particle composition of any one of claims 1 to 31,
In animals or human subjects in need of treatment for eye disease or disease,
Dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and symptoms, clinical signs or conditions associated therewith, rapid aqueous tear evaporation due to unstable tear film, and keratoconjunctivitis sicca (dry eye) and the like. Use for treating diseases or diseases of the eye selected from the group consisting of related symptoms and clinical signs.
As a drug delivery vehicle,
comprising solid non-polar lipid particles having an average particle size of less than 50 microns,
A drug delivery vehicle, wherein the particles contain an active agent other than lipids that form solid non-polar lipid particles.
36. The drug delivery vehicle of claim 35, wherein the solid non-polar lipid particles have a melting point of less than 80°C.
36. The drug delivery vehicle of claim 35, wherein the solid non-polar lipid particles have a melting point of 20 to 80°C.
36. The drug delivery vehicle of claim 35, wherein the solid non-polar lipid particles have a melting point of 30 to 60°C.
39. The drug delivery vehicle of any one of claims 35-38, wherein the solid non-polar lipid particles have an average particle size of less than 20 microns.
40. The drug delivery vehicle of any one of claims 35-39, wherein the solid non-polar lipid particles have an average particle size of less than 10 microns.
41. The drug delivery vehicle of any one of claims 35 to 40, wherein the solid non-polar lipid particle comprises an ether lipid selected from the group of:

here,
R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;
R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;
R ₃ is hydrogen (ie H);

here,
R ₁ is hydrogen (ie H);
R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;
R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,
R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;
R ₂ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;
R ₃ is hydrogen (i.e. H).
42. The drug delivery vehicle of any one of claims 35 to 41, wherein the solid non-polar lipid particle comprises an ether lipid selected from the group of:

here,
R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;
R ₂ is hydrogen (ie H);
R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;

here,
R ₁ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl;
R ₂ is hydrogen (ie H);
R ₃ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl; and

here,
R ₁ is unsubstituted C ₆ to C ₃₀ alkyl or alkenyl;
R ₂ is hydrogen (ie H);
R ₃ is unsubstituted C ₅ to C ₂₉ alkyl or alkenyl.
43. The method of any one of claims 35 to 42, wherein the solid non-polar lipid particle is 1-O-eicosanyl-2-palmitoyl- rac -glycerol , 1,2-EPRG), sn -1-O-eicosanyl-2-palmitoyl-glycerol ( sn -1-O-eicosanyl-2-palmitoyl-glycerol), sn -2-palmitoyl-3-O-eico Sanyl-glycerol ( sn -2-palmitoyl-3-O-eicosanyl-glycerol), 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1-O-eicosanyl-3-palmitoyl- rac -glycerol, 1,3- EPRG), sn -1-O-eicosanyl-3-palmitoyl-glycerol ( sn -1-O-eicosanyl-3-palmitoyl-glycerol), sn -1-palmitoyl-3-O-eicosanyl-glycerol ( sn -1-palmitoyl-3-O-eicosanyl-glycerol) and these A drug delivery vehicle comprising an ether lipid selected from the group consisting of a mixture of.
44. The method of claim 43, wherein the solid non-polar lipid particle is 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) or 1-O-eicosanyl-3-palmitoyl- rac -glycerol. A drug delivery vehicle comprising an ether lipid selected from the group consisting of (1,3-EPRG) and mixtures thereof.
45. The method of claim 44, wherein 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 mixtures thereof.
Contains greater than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or
A drug delivery vehicle comprising greater than 95% (mol%) of 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
45. The method of claim 44, wherein 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) mixture is
Contains greater than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or
A drug delivery vehicle comprising greater than 98% (mol%) of 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
45. The method of claim 44, wherein 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) mixture is
Contains greater than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer, or
A drug delivery vehicle comprising greater than 99% (mol%) of 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
45. The method of claim 44, wherein 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) is a mixture of
Containing greater than 95% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer,
A drug delivery vehicle comprising less than 5% (mol%) of 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
45. The method of claim 44, wherein 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) mixture is
Containing greater than 98% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer,
A drug delivery vehicle comprising less than 2% (mol%) of 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
45. The method of claim 44, wherein 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) mixture is
Containing greater than 99% (mol%) of the 1-O-eicosanyl-2-palmitoyl- rac -glycerol (1,2-EPRG) isomer,
A drug delivery vehicle comprising less than 1% (mol%) of 1-O-eicosanyl-3-palmitoyl- rac -glycerol (1,3-EPRG) isomer.
According to any one of claims 35 to 50,
The solid non-polar lipid particles are a group consisting of non-polar mono-, di-, or tri-glycerides, wax esters including cholesterol esters, sterols, free fatty acids, and combinations thereof. A drug delivery vehicle further comprising one or more additional lipids selected from.
According to any one of claims 35 to 51,
The active agent may be an over the counter (OTC) or prescription topical ophthalmic, an over-the-counter or prescription topical ophthalmic for the treatment of dry eye, an NMDA antagonist, an anti-bacterial, or an antihistamine. ), decongestant, anti-inflammatory, antiparasitic, miotics, sympathomimetic, anticholinergic, adrenergic, antiviral ( antiviral, local anesthetic, antifungal, amoebicidal, trichomonocidal, analgesic, mydriatic, antiglaucoma drugs, carbonic anhydration Enzyme inhibitors (carbonic anhydrase inhibitors), ophthalmic diagnostic agents, ophthalmic agents used as adjuvants in surgery, chelating agents, antineoplastic agents, anti-inflammatory agents. Antihypertensive, muscle relaxant, diagnostic, adrenergic anesthetic, beta blocker, alpha-2-agonist, cycloplegic. ), a drug delivery vehicle selected from the group consisting of prostaglandins, and combinations thereof.
The method according to any one of claims 35 to 52,
A drug delivery vehicle, wherein the solid non-polar lipid particles are formulated as an aqueous suspension in a physiologically acceptable carrier.
According to clause 53,
The liquid composition comprises phosphate buffered saline (PBS) in water, solid micronized lipid particles containing up to 3% (w/w of vehicle) polysorbate 80 and up to 0.3% (w/w of vehicle) xanthan gum It is a suspension of solid micronized lipid particles,
pH is 6.5 to 8.0,
A drug delivery vehicle having an osmotic pressure of 260 to 320 mOsm/L.
55. The drug delivery vehicle of claim 53 or 54, wherein the suspension is stable against phase separation of solid non-polar lipid particles in the suspension for 6 months at room temperature.
The drug delivery vehicle of claim 55, wherein the suspension is chemically stable with less than 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 of any one of claims 53 to 56, wherein the suspension is stable against phase separation of solid non-polar lipid particles in the suspension for 24 months at room temperature.
The drug delivery vehicle of claim 57, wherein the suspension is chemically stable with less than 5% isomerization of 1,2-EPRG to the isomer 1,3-EPRG during storage at room temperature for 24 months.
According to any one of claims 53 to 58,
A drug delivery vehicle, wherein the suspension is sterile.
According to any one of claims 53 to 59,
A drug delivery vehicle, wherein the suspension contains a preservative.
According to any one of claims 53 to 59,
A drug delivery vehicle, wherein the suspension does not contain a preservative.
The method according to any one of claims 53 to 61,
A drug delivery vehicle, wherein the physiologically acceptable carrier is an ophthalmologically acceptable carrier.
The method of claim 62, wherein the ophthalmologically acceptable carrier is
Containing an agent selected from the group consisting of buffering agents, tonicity agents, wetting agents, thickeners and viscosifiers, density adjusting agents, and combinations thereof. , drug delivery vehicle.
The method according to any one of claims 53 to 63,
A drug delivery vehicle wherein the active agent is released as individual molecules of the active agent from the solid non-polar lipid particles over a period of time after administration as an eye drop.
65. The drug delivery vehicle of claim 64, wherein the individual molecules are released over a period of 1 to 24 hours.
The method according to any one of claims 53 to 65,
A drug delivery vehicle, wherein the suspension is provided in a drop dispenser.
53. The drug delivery vehicle according to any one of claims 35 to 52, wherein the drug delivery vehicle is a medical insert device.
68. The drug delivery vehicle of claim 67, wherein the medical implantable device is formed from a physiologically acceptable material.
69. The drug delivery vehicle of claim 68, wherein the physiologically acceptable material is a polymer.
The method of claim 68, wherein the physiologically acceptable material is selected from the group consisting of hydroxypropyl cellulose, hydrogel, polymethyl methacrylate, and silicone acrylate. The drug delivery vehicle of choice.
The method according to any one of claims 67 to 70,
The drug delivery vehicle of claim 1, wherein the medical implantable device is selected from the group consisting of a punctal plug, a contact lens, and an ophthalmic insert.
72. The drug delivery vehicle of any one of claims 67-71, wherein the medical implantable device is rechargeable.
72. The drug delivery vehicle of any one of claims 67-71, wherein the medical implantable device is single use.
74. The drug delivery vehicle of any one of claims 67-73, wherein the medical implantable device is compatible with a mucosal surface.
75. The method of claim 74, wherein the mucosal surface is ocular mucosal surface, vaginal mucosal surface, nasal mucosal surface, oropharyngeal mucosal surface, oral mucosal surface ( A drug delivery vehicle selected from the group consisting of oral cavity mucosal surface and rectal mucosal surface.
76. A method of delivering an active agent to a subject in need thereof comprising topically administering the drug delivery vehicle of any one of claims 35-75.
77. The method of claim 76, wherein the drug delivery vehicle is administered to the mucosal surface of the subject.
The method of claim 76 or 77, wherein the mucosal surface is
Ocular mucosal surface, vaginal mucosal surface, oviduct mucosal surface, respiratory system mucosal surface, nasal mucosal surface, oropharyngeal mucosal surface, oral mucosal surface, rectal mucosal surface, digestive system mucosal surface A method selected from the group consisting of surface) and esophageal mucosal surface.
79. The method of claim 78, wherein the drug delivery vehicle is applied or implanted below the mucosal surface.
80. The method of claim 79, wherein the mucosal surface is an ocular mucosal surface,
The method of claim 1, wherein the drug delivery vehicle is applied or implanted under the conjunctival or tenon's capsule.
81. The method of claim 79 or 80, wherein the drug delivery vehicle is
A method, wherein the method is applied to the ocular mucosal surface by a delivery route selected from the group consisting of retrobulbar, intracameral, intravitreal, suprachoroidal and subretinal delivery routes. .
In an animal or human subject in need of treatment for an eye disease or disease, as a method for treating the same,
Topically administering to the eye of the subject a drug delivery vehicle according to any one of claims 35 to 75 comprising an effective amount of an active lipid agent,
The above diseases or diseases of the eye include dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and symptoms or conditions related thereto, rapid aqueous tear evaporation due to unstable tear film, and keratoconjunctivitis sicca (dry eye). ) and symptoms or clinical signs related thereto.
83. The method of claim 82, wherein the subject in need of treatment has a tear film breakup time that is shorter than the normal clinical range of TBUT for a normal healthy population in the United States.
Use of the drug delivery vehicle of any one of claims 35 to 75,
In animals or human subjects in need of treatment for eye disease or disease,
Dry eye, inflammatory dry eye, evaporative dry eye, meibomian gland dysfunction and related symptoms or conditions, rapid aqueous tear evaporation due to unstable tear film, and keratoconjunctivitis sicca (dry eye) and related symptoms or conditions Use for treating a disease or disease of the eye selected from the group consisting of indications.