Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• APIs active pharmaceutical ingredients
• topical delivery of APIs to the eye is commonly limited by a number of factors, including low residence time, poor penetration and delivery to target tissue, and physiological barriers to delivery. These limiting factors are particularly significant for diseases affecting the posterior segment of the eye, and for this reason it is common to resort to other routes of administration, e.g., intraocular (intravitreal) injection and systemic administration, to deliver APIs to the posterior segment of the eye.
• intravitreal injection is invasive and requires highly specialized conditions including performance by an ophthalmologist in an operating room. Moreover, intravitreal injection carries attendant risks of infection and, in the case of intravitreal inserts, displacement.
• systemic administration e.g., intravenous injection
• BBB blood-brain barrier
• BBB blood-brain barrier
• systemic administration may require unacceptably high dosages of API in order to achieve efficacious drug levels within the eye.
• Microemulsions are thermodynamically stable and isotropic formulations composed of a polar phase (e.g., water), a non-polar phase (e.g., oil), surfactant, and co-surfactant. Unlike nanoemulsions, microemulsions form without the need for input energy; they form essentially spontaneously. Certain microemulsions, characterized by their clarity, stability, and the possibility of sterilization, represent candidate topical delivery platforms for APIs directed to the eye.
• the eye is divided into two anatomical compartments, called the anterior chamber and the posterior chamber.
• the smaller anterior chamber includes all structures including and anterior to the lens, e.g., the cornea, aqueous humor, iris, and the lens.
• the much larger posterior segment includes all remaining structures, i.e., all structures posterior to the lens. These structures include, inter alia, the vitreous humor, retina, retinal blood vessels, macula, choroid, part of the sclera, and optic nerve.
• microemulsions and microemulsion formulations which useful as pharmaceutical carriers.
• the microemulsions and microemulsion formulations may be used for topical delivery of active pharmaceutical ingredients, particularly lipophilic APIs, to any tissue. It has been found, for example, that microemulsions and microemulsions and microemulsions
• microemulsions and microemulsion formulations of the invention are suitable for delivering therapeutically meaningful amounts of certain APIs to internal structures of the eye.
• the microemulsions and microemulsion formulations of the invention are suitable for topical administration to the eye, for example in the form of eyedrops.
• topical delivery of microemulsion formulations according to the invention is effective to treat even diseases of the posterior segment of the eye.
• An aspect of the invention is a pharmaceutical carrier suitable for topical administration to the eye, comprising:
• an oil-in-water microemulsion comprising
• a pair of surfactants selected from the group consisting of two polysorbates, a polysorbate and propylene glycol, a polysorbate and glycerol, a polysorbate and triacetin (1,2,3-triacetoxypropane), cremophor EL (polyethoxylated castor oil) and triacetin (1,2,3- triacetoxypropane), and cremophor EL (polyethoxylated castor oil) and propylene glycol; and
• the water represents 50 to about 95 percent (w/w) of the pharmaceutical carrier; the oil and surfactants represent substantially all of the remainder of the water
• An aspect of the invention is a method of making the pharmaceutical carrier of the invention. The method comprises the steps of combining the oil and the pair of surfactants, to yield an oil/surfactant mixture; and combining the oil/surfactant mixture with the water.
• An aspect of the invention is a pharmaceutical composition, comprising a lipophilic active pharmaceutical ingredient (API) and the pharmaceutical carrier of the invention, wherein the pharmaceutical composition is formulated for topical administration to the eye.
• API active pharmaceutical ingredient
• An aspect of the invention is a method of making the pharmaceutical composition of the invention.
• the method comprises the steps of combining the oil, the pair of surfactants, and the lipophilic active pharmaceutical ingredient (API), to yield an oil/surfactant/API mixture; and combining the oil/surfactant/API mixture with the water.
• API lipophilic active pharmaceutical ingredient
• An aspect of the invention is method of treating a disease of the posterior segment of the eye.
• the method comprises the step of topically administering to an eye of a subject in need thereof a composition comprising:
• an oil-in-water microemulsion comprising
• a pair of surfactants selected from the group consisting of two polysorbates, a polysorbate and propylene glycol, a polysorbate and glycerol, a polysorbate and triacetin (1,2,3-triacetoxypropane), cremophor EL (polyethoxylated castor oil) and triacetin (1,2,3- triacetoxypropane), and cremophor EL (polyethoxylated castor oil) and propylene glycol;
• the API represents about 0.01 to about 5 percent (w/v) of the composition
• the water represents 50 to about 95 percent (w/w) of the composition
• oil and surfactants represent substantially all of the remainder of the oil and surfactants
• the ratio of percent (w/w) total surfactant to percent (w/w) oil is at least about 10:1;
• composition is formulated for topical administration to the eye.
• the API is represented by
• the disease of the posterior segment of the eye is characterized by inflammation, neovascularization, vascular leakage, fibrosis, or any combination thereof.
• the disease of the posterior segment of the eye is selected from the group consisting of: age-related macular degeneration, diabetic retinopathy, posterior uveitis, retinal edema, macular edema, and retinal vein occlusion.
• the disease of the posterior segment of the eye is age-related macular degeneration.
• the disease of the posterior segment of the eye is diabetic retinopathy.
• An aspect of the invention is pharmaceutical composition, comprising an effective amount, for treating a disease of the posterior segment of the eye, of a compound represented by
• the pharmaceutical composition is formulated for topical administration to the eye.
• the pharmaceutical composition is formulated as eyedrops.
• FIG. 1 is a pair of photographic images of a single series of twenty clear glass vials containing various formulations of water, oil, and surfactant; and a map representing the formulations in the vials.
• the vial at the left of the upper photo corresponds to map position Al, and successive vials to the right correspond to map positions A2, A3, etc.
• the vial at the left of the lower photo corresponds to map position Bl, and successive vials to the right correspond to map positions B2, B3, etc.
• Vial Al contains (i) 500 ⁇ , of oil phase comprised of 90 percent 3: 1 Cremophor EL propylene glycol surfactant/co-surfactant mixture / 10 percent isopropyl myristate, and (ii) 500 water.
• Vial A2 comprises (i) 475 ⁇ of the same oil phase, and (ii) 525 water. This successive dilution continues until reaching vial B10, which comprises (i) 25 ⁇ of the same oil phase, and (ii) 975 ⁇ water. Clear formulations represent microemulsions.
• FIG. 2 is a representative pseudoternary phase diagram with 100 percent water, 100 percent oil, and 100 percent total surfactant at the apices labeled Water, Oil, and Surfactant, respectively.
• the area enclosed by heavier lines represents potential oil-in-water microemulsion space (water > 50 percent).
• Each symbol represents a data point for actual combinations of different water/oil/total surfactant combinations tested in the Examples. (Microemulsions correspond to only a subset of these points.)
• FIG. 3 is a graph depicting quantification of MSH-1001 in rabbit aqueous humor measured 1 hour after topical administration to the eye.
• X axis shows percent (w/v) of drug in individual emulsion formulations.
• ED-007 to ED-017 are microemulsions;
• ED-002 is a nanoemulsion.
• AH aqueous humor;
• IPM isopropyl myristate.
• FIG. 4 is a whisker plot graph depicting microemulsion size distribution. Higher and lower extremes represent the d90 and dlO droplet sizes, respectively.
• FIG. 5 is a whisker plot graph depicting microemulsion size distribution. Higher and lower extremes represent the d90 and dlO droplet sizes, respectively. Data is shown in pairs for values measured on Day 1 and Day 14 for each microemulsion.
• FIG. 6 is whisker plot graph depicting microemulsion size distribution for
• FIG. 7 is a pair of bar graphs depicting concentrations of fenobrate and fenofibric acid in retina (left panel) and retinal pigment epithelium (RPE) (right panel) of rabbits, as measured by LC/MS, following QID x 5 days eye drop administration to eyes of fenofibrate formulated as 0.5% fenofibrate in the indicated microemulsions (MEM0043 and
• FIG. 8 is a bar graph depicting lesion size measured in rats where choroidal neovascularization was induced by laser. Rats were treated QID for 19 consecutive days with either vehicle alone or fenofibrate formulated as 3% fenofibrate in nanoemulsion (NEM-001) or 0.5% fenofibrate in microemulsion (MEM-0043). *** p ⁇ 0.001 compared to vehicle. DETAILED DESCRIPTION
• microemulsion formulations particularly well suited for use in topical administration of lipophilic drugs, including, in particular, for ophthalmic use.
• the microemulsion formulations are clear, stable, well tolerated, and capable of delivering therapeutically effective amounts of active pharmaceutical ingredients to target sites, including sites within the eye.
• the microemulsion formulations of the invention are capable of delivering therapeutically effective amounts of active pharmaceutical ingredients to the posterior segment of the eye following topical administration to the eye.
• An aspect of the invention is a pharmaceutical carrier suitable for topical administration to the eye, comprising:
• an oil-in-water microemulsion comprising
• an oil selected from the group consisting of isopropyl myristate, isopropyl palmitate, medium chain triglycerides, and any combination thereof;
• a pair of surfactants selected from the group consisting of two polysorbates, a polysorbate and propylene glycol, a polysorbate and glycerol, a polysorbate and triacetin (1,2,3-triacetoxypropane), cremophor EL (polyethoxylated castor oil) and triacetin (1,2,3- triacetoxypropane), and cremophor EL (polyethoxylated castor oil) and propylene glycol; and
• the water represents 50 to about 95 percent (w/w) of the pharmaceutical carrier; the oil and surfactants represent substantially all of the remainder of the water
• the ratio of percent (w/w) total surfactant to percent (w/w) oil is at least about 10: 1.
• an "oil-in-water microemulsion” is a microemulsion comprised of at least 50 percent (w/w) water, at least one organic chemical that is normally at least substantially immiscible in water (i.e., an oil), and at least two surfactants (sometimes referred to as surfactant and co-surfactant).
• the dispersed oil phase is dispersed as droplets in the continuous (water) phase, where the droplets typically have a mean diameter of less than about 300 nm, e.g., about 5 nm to about 200 nm.
• a microemulsion characteristically has a clear or translucent appearance on visual inspection because the droplets are too small to scatter light of visible wavelengths.
• Microemulsions typically have viscosities lower than liquid crystals, e.g., about 10-400 mPa-s.
• MCT medium chain triglyceride
• fatty acids examples include Myglyol® 810 or 812 (triesters of glycerol, capric acid, and caprylic acid; Sasol Germany GmbH, Witten, Germany) and oils obtained by hydrolysis, fractionation, and esterification of coconut oil.
• Myglyol® 810 or 812 triesters of glycerol, capric acid, and caprylic acid; Sasol Germany GmbH, Witten, Germany
• oils obtained by hydrolysis, fractionation, and esterification of coconut oil.
• BB A et al. (1982) Am J Clin Nutr 36:293.
• MCTs are more water-soluble than long-chain triglycerides, yet they accommodate large amounts of lipophilic drugs.
• surfactant takes its usual meaning, and a “pair of surfactants” refers to two surfactants or, equivalently, a surfactant and a co-surfactant.
• the two surfactants can be present in the same or different amounts.
• polysorbate refers generally to a polyoxyethylene derivative of sorbitan fatty acid ester. Common commercial preparations of polysorbates are sold under the name Tween®, Alkest, or Canarcel. In the nomenclature of
• polysorbates the numeric designation following polysorbate (or Tween®) refers to the lipophilic group.
• polysorbate 20 is a monolaurate ester
• polysorbate 80 is a monooleate ester.
• Cremophor® EL (BASF SE), is a version of polyethoxylated castor oil, the major component of which is glycerol polyethylene glycol ricinoleate. Additional components include free polyethylene glycols and ethoxylated glycerol. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil. The product has been given CAS number 61791-12-6.
• the water represents 50 percent (w/w) of the pharmaceutical carrier.
• the water represents at least about 55 percent (w/w) of the pharmaceutical carrier.
• the water represents at least about 60 percent (w/w) of the pharmaceutical carrier.
• the water represents at least about 65 percent (w/w) of the pharmaceutical carrier.
• the water represents at least about 70 percent (w/w) of the pharmaceutical carrier. In one embodiment, the water represents at least about 75 percent (w/w) of the pharmaceutical carrier.
• the water represents at least about 80 percent (w/w) of the pharmaceutical carrier.
• the water represents at least about 85 percent (w/w) of the pharmaceutical carrier.
• the water represents at least about 90 percent (w/w) of the pharmaceutical carrier.
• w/w as used herein means ratio of weight of component (in grams) to weight of solution (in grams), where weight of solution refers to the total weight of the oil, water, and surfactant.
• 1 percent (w/w) isopropyl myristate denotes 1 g isopropyl myristate per 100 g total weight.
• w/v means ratio of weight (in grams) to volume (in mL), where volume refers to the final volume.
• 1 percent (w/v) isopropyl myristate denotes 1 g isopropyl myristate per 100 mL final volume.
• the term “about” means that particular numerical value plus or minus 5% of that particular value.
• the term “about 1 percent (w/w)” can be understood to embrace a range of values from 0.95 to 1.05 percent (w/w).
• the term “about 10: 1” can be understood to embrace a range of values from 9.5: 1 to 10.5:1.
• the term "at least about 10:1" in one embodiment means from about 10: 1 to about 20: 1.
• the term "at least about 10: 1" means from about 10: 1 to about 11 : 1; from about 10: 1 to about 12: 1; from about 10: 1 to about 13: 1; from about 10: 1 to about 14: 1; and from about 10: 1 to about 15: 1.
• the term "at least about 10: 1" means about 10: 1.
• the oil is isopropyl myristate.
• the oil is isopropyl palmitate.
• the oil is medium chain triglycerides.
• the pair of surfactants is two polysorbates.
• the pair of surfactants is polysorbate 20 and polysorbate 80.
• the pair of surfactants is a polysorbate and propylene glycol. In one embodiment, the pair of surfactants is a polysorbate and glycerol. In one embodiment, the pair of surfactants is a polysorbate and triacetin (1,2,3- triacetoxypropane) .
• the pair of surfactants is cremophor EL (polyethoxylated castor oil) and triacetin (1,2,3-triacetoxypropane).
• the pair of surfactants is cremophor EL (polyethoxylated castor oil) and propylene glycol.
• An aspect of the invention is a method of making the pharmaceutical carrier just described above, i.e., a method of making the pharmaceutical carrier of the invention.
• the method includes the steps of combining the oil and the pair of surfactants, to yield an oil/surfactant mixture; and combining the oil/surfactant mixture with the water.
• the combined components will form a microemulsion essentially spontaneously. That is, thorough mixing alone, for example by rocking or gentle vortexing, sufficient to bring all components into contact, should suffice to form the microemulsion.
• Preferred microemulsions are optically clear and homogeneous to visual inspection, and thermodynamically stable.
• the method of making the pharmaceutical carrier optionally can include the further step of sterilizing the formed pharmaceutical carrier, for example by sterile filtering or autoclaving for 20 min at 121 °C.
• the method of making the pharmaceutical carrier optionally can include the further step of sizing the droplets.
• An aspect of the invention is a pharmaceutical composition, comprising a lipophilic active pharmaceutical ingredient (API) and the pharmaceutical carrier of the invention, wherein the pharmaceutical composition is formulated for topical administration to the eye.
• API active pharmaceutical ingredient
• the API can be any lipophilic API.
• lipophilic means substantially more soluble in lipid, oil, or fat than in water at room temperature.
• lipophilic further means having a solubility in water at room temperature of less than or equal to 30 mg/mL.
• lipophilic further means having a solubility in water at room temperature of less than or equal to 10 mg/mL.
• lipophilic further means having a solubility in water at room temperature of less than or equal to 1 mg/mL.
• lipophilic further means having a solubility in water at room temperature of less than or equal to 0.5 mg/mL.
• the term “lipophilic” further means having a solubility in water at room temperature of less than or equal to 0.2 mg/mL. In one embodiment, the term “lipophilic” further means having a solubility in water at room temperature of less than or equal to 0.1 mg/mL. In one embodiment, the term “lipophilic” further means negligibly soluble in water at room temperature.
• the lipophilic API is selected from the group consisting of antiinflammatory agents, anti-infective agents, anti-allergic agents, antihistamines,
• antiproliferative agents antiproliferative agents, anti-angiogenic agents, anti-oxidants, antihypertensive agents, neuroprotective agents, cell receptor agonists, cell receptor antagonists, immunomodulating agents, immunosuppressive agents, intraocular pressure lowering agents, a2-adrenergic receptor agonists, ⁇ -adrenergic receptor antagonists, carbonic anhydrase inhibitors, cholinesterase inhibitor miotics, prostaglandins, prostaglandin receptor agonists, mast cell degranulation inhibitors (mast cell stabilizers), thromboxane A2 mimetics, protein kinase inhibitors, prostaglandin F derivatives, prostaglandin F 2a receptor antagonists,
• cyclooxygenase-2 inhibitors cyclooxygenase-2 inhibitors, muscarinic agents, and any combination thereof.
• the lipophilic API is selected from the group consisting of adaprolol maleate, cyclosporine A, fenofibrate, fenofibric acid, indomethacin, miconazole, pilocarpine, piroxicam, and A 8 -THC.
• the lipophilic API is fenofibrate
• the lipophilic API is fenofibric acid.
• the lipophilic API is an API that is useful for the treatment of a disease of anterior segment of the eye.
• a “disease of the anterior segment of the eye” refers to any disease of the anterior segment of the eye.
• diseases of the anterior segment of the eye include, without limitation, cataract, corneal neovascularization, dry eye (keratoconjunctivitis sicca), Fuchs' dystrophy, glaucoma, keratitis (including herpes keratitis), and keratoconus.
• a disease of the anterior segment of the eye specifically excludes diseases of the lens, e.g., cataract.
• a disease of the anterior segment of the eye is glaucoma.
• the API is an API that is useful for the treatment of a disease of the posterior segment of the eye.
• anterior segment of the eye takes its usual meaning and refers to that part of the eye bounded anteriorly by the lens and anterior hyaloid membrane, and extending to the back of the eye. It is much larger than the anterior segment and includes the vitreous humor, retina, retinal blood vessels, macula, choroid, and optic nerve.
• a "disease of the posterior segment of the eye” refers to any disease of the posterior segment of the eye. Of particular interest are inflammatory, autoimmune, vascular, and certain infectious diseases of the posterior segment of the eye. Diseases of the posterior segment of the eye specifically include, without limitation, age-related macular
• AMD diabetic retinopathy
• posterior uveitis retinal edema
• macular edema retinal vein occlusion
• AMD specifically includes both dry AMD and wet AMD.
• the disease of the posterior segment of the eye is characterized by inflammation, neovascularization, vascular leakage, fibrosis, or any combination thereof.
• the disease of the posterior segment of the eye is selected from the group consisting of: age-related macular degeneration, diabetic retinopathy, posterior uveitis, retinal edema, macular edema, and retinal vein occlusion.
• Topical administration refers to localized administering to a surface of a tissue.
• Topical administration to the eye refers to localized administering to a surface of an eye, for example, to any exterior aspect of the eye normally accessible between the eyelids.
• Topical administration to the eye generally may be achieved, for example, with drops, irrigants, ointments, or sprays.
• the pharmaceutical composition of the invention is formulated as eyedrops.
• the composition may be presented in a rigid bottle fitted with a combination screw-cap/bulb pipette dropper cap.
• the composition is presented in a squeeze bottle fitted with a tip constructed and arranged to serve as a dropper and a removable cap to cover the tip.
• the eyedrops are dispensed as 30 microliter to 300 microliter single drops.
• An aspect of the invention is method of making the pharmaceutical composition just described.
• the method includes the steps of combining the oil, the pair of surfactants, and the lipophilic active pharmaceutical ingredient (API), to yield an oil/surfactant/API mixture; and combining the oil/surfactant/API mixture with the water.
• API lipophilic active pharmaceutical ingredient
• a "therapeutically effective amount” is any amount that is sufficient to achieve a desired therapeutic result.
• a therapeutically effective amount for treating a disease of the posterior segment of the eye is an amount sufficient to treat a disease of the posterior segment of the eye.
• a therapeutically effective amount of a given API for a given disease to be treated can be determined based on existing clinical experience using the API to treat the disease, or through reasonable amounts of experimentation performed in vitro and/or in vivo in animals and/or in human subjects.
• the therapeutic amount of the API should be selected so as not to prevent formation of a microemulsion.
• the API will be present in an amount less than or equal to about 5 percent (w/v) of the pharmaceutical composition.
• the amount of API may be selected from 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7,
• An aspect of the invention is a method of treating a disease of the posterior segment of the eye.
• the method includes the step of
• composition comprising
• an oil-in-water microemulsion comprising
• an oil selected from the group consisting of isopropyl myristate, isopropyl palmitate, medium chain triglycerides, and any combination thereof;
• a pair of surfactants selected from the group consisting of two polysorbates, a polysorbate and propylene glycol, a polysorbate and glycerol, a polysorbate and triacetin (1,2,3-triacetoxypropane), cremophor EL (polyethoxylated castor oil) and triacetin (1,2,3- triacetoxypropane), and cremophor EL (polyethoxylated castor oil) and propylene glycol;
• the API represents about 0.01 to about 5 percent (w/v) of the composition
• the water represents 50 to about 95 percent (w/w) of the composition
• oil and surfactants represent substantially all of the remainder of the oil and surfactants
• composition comprising: the ratio of percent (w/w) total surfactant to percent (w/w) oil is at least about 10:1;
• composition is formulated for topical administration to the eye.
• treat refers to slowing the progression of, halting the progression of, reversing the progression of, or resolving a disease or condition in a subject. In one embodiment, “treat” or “treating” further refer to preventing a disease or condition in a subject.
• a "subject" refers to a mammal. In one embodiment, a subject is a human.
• the subject can administer the composition to itself, or a caregiver can administer the composition to the eye of the subject.
• the administering is administering once a day. In one embodiment, the administering is administering more than once a day. In various embodiments, the administering is administering 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, or 12 times a day. In one embodiment, the administering is administering one time to six times a day.
• the administering involves topically administering a single drop of the composition to the eye to be treated.
• Such single-drop administration can include administration 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, or 12 times a day.
• the lipophilic API is selected from the group consisting of adaprolol maleate, cyclosporine A, fenofibrate, fenofibric acid, indomethacin, miconazole, pilocarpine, piroxicam, and A 8 -THC.
• the lipophilic API is fenofibrate
• the lipophilic API is fenofibric acid.
• the lipophilic API is l-acetyl-5-hydroxyanthracene-9,10-dione, represented by
• the disease of the posterior segment of the eye is characterized by inflammation, neovascularization, vascular leakage, fibrosis, or any combination thereof.
• the disease of the posterior segment of the eye is selected from the group consisting of: age-related macular degeneration, diabetic retinopathy, posterior uveitis, retinal edema, macular edema, and retinal vein occlusion.
• the disease of the posterior segment of the eye is age-related macular degeneration.
• the disease of the posterior segment of the eye is dry age-related macular degeneration.
• the disease of the posterior segment of the eye is wet age-related macular degeneration.
• the disease of the posterior segment of the eye is diabetic retinopathy.
• An aspect of the invention is a pharmaceutical composition, comprising an effective amount, for treating a disease of the posterior segment of the eye, of a compound represented by
• the pharmaceutical carrier the invention, wherein the pharmaceutical composition is formulated for topical administration to the eye.
• the pharmaceutical composition is formulated as eyedrops. It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention.
• oil-in- water microemulsion formulations comprised of (i) oils selected from isopropyl myristate, isopropyl palmitate, and medium chain triglyceride, and (ii) pairs of surfactants selected from Tween® 20, Tween® 80, polypropylene glycol, glycerol, triacetin, and Cremophor® EL were identified.
• each microemulsion was characterized for stability.
• microemulsions have been tested for ocular tolerability in mice.
• microemulsions have been used in combination with up to 5 percent (w/v) CLT-005.
• FIG. 1 presents representative results from part of one single combination of oil, surfactants, and water.
• FIG. 2 presents a representative pseudoternary phase diagram generated in accordance with this systematic study.
• Each filled circle on the plot represents a microemulsion.
• Each unfilled triangle on the plot represents a clear mixture that is not a microemulsion, e.g., a liquid crystal.
• Each unfilled circle on the plot represents a cloudy mixture.
• Tables 1 - 26 present representative formulations of microemulsions comprised of isopropyl myristate and pairs of surfactants selected from Tween® 20 (“T20”), Tween® 80 (“T80”), polypropylene glycol (“P”), glycerol (“G”), triacetin (“TriAc”), and Cremophor® EL (“CEL”). Numerical values are given as percent (w/w). "Surfactant” represents the percent (w/w) of total surfactant in each formulation.
• Tables 27 - 45 present representative formulations of microemulsions comprised of isopropyl palmitate and pairs of surfactants selected from Tween® 20 (“T20”), Tween® 80 (“T80”), polypropylene glycol (“P”), and glycerol (“G”). Numerical values are given as percent (w/w). "Surfactant” represents the percent (w/w) of total surfactant in each formulation.
• MEMO 170-MEMO 175 were unstable.
• Tables 46 - 68 present representative formulations of microemulsions comprised of medium chain triglyceride (“MCT”) and pairs of surfactants selected from Tween® 20 (“T20”), Tween® 80 (“T80”), polypropylene glycol (“P”), glycerol (“G”), triacetin
• TriAc TriAc
• Cremophor® EL Cremophor® EL

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