US 2014.0171490A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0171490 A1 Gross et al. (43) Pub. Date: Jun. 19, 2014

(54) METHOD AND DEVICE FOR OPHTHALMIC A613 L/4704 (2006.01) ADMINISTRATION OF ACTIVE A 6LX3/5377 (2006.01) PHARMACEUTICAL INGREDIENTS A613 L/433 (2006.01) A63/542 (2006.01) (71) Applicant: PHARMALIGHT INC., Wilmington, A63L/382 (2006.01) DE (US) A 6LX3/55.75 (2006.01) A619/00 (2006.01) (72) Inventors: Yossi Gross, Moshav Mazor (IL); Rafi A613 L/468 (2006.01) Herzog, Bat-Shlomo (IL); Steven B. (52) U.S. Cl. Koevary, Newton, MA (US) CPC ...... A61 K47746 (2013.01); A61 K31/4168 (2013.01); A61 K3I/498 (2013.01); A61 K (73) Assignee: PHARMALINGT INC., Wilmington, 31/496 (2013.01); A61K 3L/222 (2013.01); DE (US) A61 K3I/573 (2013.01); A61K47/48215 (2013.01); A61 K3I/575 (2013.01); A61 K (21) Appl. No.: 13/963,991 3 1/138 (2013.01); A61 K3I/4704 (2013.01): (22) Filed: Aug. 9, 2013 A6 IK3I/5377 (2013.01); A61 K3I/433 (2013.01); A61 K3I/542 (2013.01); A61 K Related U.S. Application Data 31/382 (2013.01); A61 K3I/55.75 (2013.01); A61 K9/0048 (2013.01) (62) Division of application No. 1 1/883,774, filed on Aug. USPC ... 514/44 R: 514/392: 514/249; 514/253.04; 6, 2007, now abandoned, filed as application No. PCT/ 514/548; 514/179; 514/182: 514/652: 514/312: IL2006/000145 on Feb. 6, 2006. 514/546; 514/236.2: 514/363; 514/226.5; (60) Provisional application No. 60/650,144, filed on Feb. 514/432: 514/622:514/530: 514/777 7, 2005, provisional application No. 60/742,870, filed on Dec. 7, 2005. (57) ABSTRACT (30) Foreign Application Priority Data Disclosed is the use of a mist of a pharmaceutical composition for ophthalmic delivery of a protein or peptide active phar Feb. 6, 2006 (IL) ...... PCTAIL2006/OOO145 maceutical ingredient, a related method of treatment and a device useful in implementing the use and method. Disclosed Publication Classification is also the use of a mist for ophthalmic delivery of a pharma ceutical composition including a highly irritating penetration (51) Int. Cl. enhancer and an ophthalmically acceptable carrier, a related A6 IK 47/46 (2006.01) method of treatment and a device useful in implementing the A6 IK3I/498 (2006.01) use and method. Disclosed is also a device for ophthalmic A6 IK3I/496 (2006.01) administration configured to direct a mist of a pharmaceutical A6 IK3I/222 (2006.01) composition to the eye only when the eye is open. Disclosed A 6LX3/573 (2006.01) is also a self-sterlizing device for ophthalmic administration. A6 IK 47/48 (2006.01) Disclosed is also a device and a method for increasing the A 6LX3/575 (2006.01) bioavailability of an ophthalmically administered API in a A6 IK3I/38 (2006.01) pharmaceutical composition.

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METHOD AND DEVICE FOR OPHTHALMC tion. Although much of an administered composition is ADMINISTRATION OF ACTIVE washed away, drains away and even leaks out along the face, PHARMACEUTICAL INGREDIENTS enough remains for a long enough time to be effective. The massive Volume of pharmaceutical composition washes away FIELD AND BACKGROUND OF THE the tear fluids and dilutes the concentration of the tear pro INVENTION teins. Further, the seemingly excessive amount of API ensures 0001. The present invention relates to the field of medicine that even if some API is bound to tear proteins or metabolized and more particularly, to methods and devices relating to by the proteins, enough API remains potent to exercise a ophthalmic administration of pharmaceutical compositions desired pharmaceutical effect. Thus, although seemingly including an active pharmaceutical ingredient (API) to a wasteful and difficult to accurately dose, eye drops in fact patient. provide a simple and effective route for ophthalmic adminis 0002. The bulb of the eye (bulbus oculi: eyeball) is con tration. tained in the cavity of the orbit, where it is protected from 0008. An additional mode of ophthalmic administration is injury. Associated with the eye are certain accessory structure by the use of a nebulizer that transforms a pharmaceutical Such as the muscles, fasciae, eyelids, conjunctiva, and lacri composition into a mist that is then contacted with exposed mal apparatus. Only the Surface of the anterior part of the eye, portions of the eye. Devices described as producing mists including the corneal epithelium and part of the episcleral effective for ophthalmic administration of pharmaceutical conjunctiva, are exposed to the environment. The mucosa of compositions include those described in U.S. Pat. Nos. 4,052, the conjunctiva provide a protective interface between the eye 985; 5,203,506; 5,893,515; 6,062,212, 6,530,370 and “Nano and accessory structures. The exposed anterior Surface is technology News from the University of Minnesota, Fall continuously washed by tear fluid. The nasolacrimal duct 2005, p. 7 Ophthalmic administration using a mist has the drains tears and other substances from the eye to be absorbed advantage of accurate dosing and economical use. That said, by a layer of mucosal membrane. the required device for Such administration is relatively com 0003. In the art, ophthalmic administration of a pharma plex (compared to an eye dropper). Further, as the Volumes of ceutical composition including an active pharmaceutical pharmaceutical composition actually delivered are relatively ingedient is known. Most commonly, ophthalmic administra small, the tear fluid effectively washes away such composi tion of a pharmaceutical composition is for ocular delivery tions as delivered. Further, as the rate of API delivery is via a corneal or scleral route. That said, systemic delivery of relatively small (in terms of molecules per unit time), the eye an API by ophthalmic administration of a pharmaceutical has sufficient time to bind to and metabolize administered composition via the conjunctival route (including the mucosa susceptible APIs. Devices for nebulizing pharmaceutical of the eyelids and nasolacrimal duct) is also known. compositions for ophthalmic administration to the eye are 0004 Ophthalmic administration of a pharmaceutical well known to one skilled in the art. composition is challenging for a number of reasons, see for discussion Burrows J. et al. Drug Deliv. Comp. Rep. 2002, 0009 Peptide and protein APIs are well-known in the field spring. As discussed below, the eye is a sensitive organ with of medicine. One of the challenges of using peptide and an easily damaged surface. There is rapid elimination of an protein APIs is administration. Like with any API, systemic applied composition due to lacrimation and drainage through administration by injection (whether intramuscular, Subcuta the nasolacrimal duct. APIs are neutralized by binding to, or neous or into the circulatory system) of a pharmaceutical metabolization by, tear proteins. composition including a peptide or protein API is unpleasant, 0005. There are many modes of ophthalmic administra especially for treatment of chronic medical condidtions that tion of pharmaceutical compositions. The most common require regular and repeated administration, for example the mode of ophthalmic administration is by instillation of drops treatment of diabetes mellitus with insulin. Further, many using an eye-dropper or other device, see for example U.S. peptide and proteins are potentially effective as APIs if deliv Pat. Nos. 5,152,435; 6,336,917; 6,386,394; 6,401,979; 6,447, ered to specific sites within the body, for example specific 476; 6,547,770; 6,610,036 and RE38,077. organs such as the brain or central nervous system, but sys 0006 Although technically simple, instillation of eye temic administration by injection is inefficient or ineffective. drops has many disadvantages. Receiving eye drops requires A peptide or protein API injected into the body is susceptible practice; it is unpleasant to open an eye widely while the drop to degradation by proteolytic enzymes found in the circula is instilled, for adults but especially for childre. Self-admin tion system. In order to ensure that a sufficient amount of istration is not simple and often not effective when a drop is peptide or protein arrives at a target organ or specific location innaccurately placed. Often a person will instill more than the in the body, a large amount of peptide or protein must be required number of drops, whether by accident or intent, and administered. Further, peptides and proteins cannot penetrate drops have a notoriously poorly defined Volume making accu the blood brain barrier, precluding the use of peptides and rate dosage virtually impossible (Lederer, C. M. Jr. et al. Am. proteins systemically administered via injection for treatment J. Opthalmol. 1986, 101(6), 691-694 reports between 25 and of the brain and central nervous system. 56 ul). Inadvertent contact of an eye dropper with the eye 0010. In the art, systemic administration of peptides and occurs, potentially damaging the eye and compromising Ste protein APIs via the conjunctiva using eye drops is known, see rility. Koevary, S. B. Curr: Drug. Metab 2003, 4(3) 213-222; Mor 0007 As noted above, much of an ophthalmically admin gan, R.V.J. Ocular Pharm. Ther: 1995, 11(4), 565-573 (Insu istered pharmaceutical composition is washed out or drained lin Saettone, M. F. et al. Int. J. Pharma. 1996, 142, 103-113 away, and much of the API is neutralized by the ocular pro (beta-blocking agents); Ke, T. L. et al. Inflammation 2000, tective mechanisms. Eye drops, by applying a seemingly 24(4), 371-384; Sasaki et al. J. Pharm Pharmacol 1994, wastefully large amount of pharmaceutical composition, 46(11), 871-875 (insulin): U.S. Pat. No. 5,182,258 (peptides overcome the challenges posed by ophthalmic administra and Small proteins up to 6 kDa) and references therein. US 2014/0171490 A1 Jun. 19, 2014

0.011 There are many advantages to systemic administra cal compositions, whether to increase the permeability of the tion via the conjunctiva of peptides and protein APIs relative conjunctiva, Sclera or cornea. Generally, effective penetration to systemic administration via injection, including ease of enhancers are irritants that cause severe ocular damage. In use, patient comfort, safety and simpler self-administation. Morgan, R. V.J. Ocular Pharm. Ther: 1995, 11(4),565-573 is However, as the conjunctival route is systemic, administered reported that saponin and Brij-99 are strongly irritation to the peptide and protein APIs are exposed to enzymatic degrada eye. In Saettone, M. F. et al. Int. J. Pharma. 1996, 142, tion and there exist locations in the body, Such as the nervous 103-113 is reported that saponin, escin, digitonin, BL-9, ben system and brain, which are not accessible to a systemically Zalkonium chloride and sodium deoxycholate are strongly administered peptide or protein API. irritating to the eye. In Furrer, P. et al. AAPS PharmSci 2002, 0012. As discussed above, instillation of eye drops is a 4(1), 1-5 is reported that saponin and Sodium fusidate are wasteful mode of ophthalmic administration, flooding the eye strongly irritating to the eye. with an excessive Volume of pharmaceutical composition and 0018. As a rsulet, less effective penetration enhancers are an excessive amount of API, but it is the wastefulness that used. However, the amount of such less effective penetration provides eye drops with particular efficacy. Thus, eye drops enhancers in an ophthalmic pharmaceutical composition have a disadvantage for use in the delivery of peptide and must be kep relatively low to prevent ocular damage and are protein APIs that are quite expensive. However, alternative conseuqnely of limied efficacy. In Morgan, R. V. J. Ocular modes of ophthalmic administration of a pharmaceutical Pharm. Ther: 1995, 11(4),565-573 is reported the use of 0.5% composition including a peptide or protein API are less Suit Brij-78 (polyoxyethylene(20) steryl ether) as a penetration able. For example, the use of a nebulizer to administer a enhancer in an ophthalmic pharmaceutical composition. In pharmaceutical composition including a peptide or protein Saettone, M. F. et al. Int. J Pharma. 1996, 142, 103-113 is API as a mist is expected to be ineffective. reported the use of 1% sodium ursodeoxycholate, 2% Brij78, 0013 The delivery of peptides and proteins, especially 1% sodium taurodeoxycholate, 2% sodium taurourSodeoxy larger peptide and protein APIs by mist cannot be expected to cholate, 0.5% Brij 35 and 0.5% EDTA as penetration enhanc Succeed. As is known, the activity of larger peptides and ers in ophthalmic pharmaceutical compositions. In Furrer, P. proteins is determined by a specific three-dimensional struc etal. AAPS PharmSci 2002, 4(1), 1-5 is reported the use of 1% ture. Modification of the structure causes the peptide or pro DMSO, 1% decamethonium bromide, 1% Tween 20, 1%Brij tein to lose activity or even change in activity. Whereas the 35, 1% EDTA, 1% sodium glycocholate and 1% sodium secondary structure of a peptide or protein is largely deter cholate as penetration enhancers in ophthalmic pharmaceuti mined by the amino acid sequence, tertiary structure is largely cal compositions. In Burgalassi, S. et al. Tox. Lett. 2001, 122. determined by the environment in which the peptide or pro 1-8 is reported that benzalkonium chloride and cetylpyri tein is found, especially salts and solvents. During nebuliza dinium chloride are less toxic to human corneal epithelial tion, a significant amount of energy is tran?ferred into a phar cells than Brij-78 but more toxic than EDTA, while poly maceutical composition. The energy is expected to heat each ethoxylated castor oil is less toxic than EDTA. individual mist particle to the extent that a peptide or protein 0019. There is a general lack of a method to allow the use held therein is denaturated. Further, the heat and the large of more effective penetration enhancers, (i.e., the use of more Surface are of the nebulized pharmaceutical composition effective but irritating penetration enhancers such as Saponin causes evaporation of Solvent molecules from the mist par or of higher amounts of less irritating penetration enhancers ticles, increasing the concentration of salts and additives in such as EDTA) for increasing the efficacy of ophthalmic the mist particles. This high concentration is expected to be of pharmaceutical compositions including an API. the extent that a peptide or protein held therein is denatured. 0020. In the field of medicine it is known that the treatment 0014 Further, as a class, peptide and protein APIs are of chronic conditions often necessitates administration of an more Susceptible to metabolization and binding than Small API repeatedly, often on a multiple daily basis. As API admin molecule APIs, so when applied more gradually and in lesser istration by a health-care professional is generally expensive amounts, as with a mist mode of delivery, the peptide or as a result of the cost of the health-care professional and the protein will be more quickly neutralized. As a result, the mist cost of transporting the health-care professional to the patient, mode is expected to be ineffective both for systemic delivery self-administration of an API is preferrd for a person who and for ocular delivery of a peptide or protein API. needs repeated administration of an API to treat a chronic 0.015 There is a lack of an effective and economical alter condition. The most convenient method of self-administra native to drops as a method of administration of peptide and tion of an API is using an orally administrable API, for protein APIs, for delivery in a pharmaceutically effective example using a pill or capsule, but many APIs are not orally form to a desired site within the body, especially to the central available. Other methods of administration may require an nervous system. expensive administration device, may provide inaccurate 0016 Topical administration of APIs, to surfaces such as dosing and may be unpleasant or inconvenient. For example, the skin, mucous membranes, conjunctiva, Sclera and cornea administration devices duch as insulin pumps or spring is well-known in the field of medicine. Generally, a pharma loaded syringes are expensive and complex. Eye drops, nose ceutical composition is formulated in Such a way that when drops and other transmucosal administration methods pro applied to a surface, the included API penetrates into or vide highly variable dosages both due to the variability in the through the Surface. To increase penetration of a topically amount of API-containing pharmaceutical composition and applied APIs, penetration enhancers are often added to topical to variability in amounts of API entering the body. Adminis pharmaceutical compositions. Penetration enhancers act by tration by injection, eye drops or inhalation is often unpleas various mechanisms to increase the permeability of a Surface ant, reducing patient quality of life and compliance. to an API. 0021. In the fild of medicine it is recognized that there is 0017. An exceptional challenge in the field of medicine is often a need for the administration of an API to a large group the use of penetration enhancers in ophthalmic pharmaceuti of people, for example for administration of vaccines or other US 2014/0171490 A1 Jun. 19, 2014

prophylactic APIs or for administration of APIs for the treat 0032. In embodiments of the present invention the deliv ment of epidemics, pandemics or endemic conditions. In Such ery is to part of an eye of the Subject, e.g., the Sclera, the optic high-throughput administration situations, it is necessary that nerve and/or the retina. the health-care professional actually administering the API 0033. In embodiments of the present invention the deliv spends as little time as possible per patient. At the same time, ery is to part of the nervous system of the Subject, e.g., the the issues of sterility and accurate dosage cannot be comprised. brain, the central nervous system, the cerebral cavity, the Known methods are insufficient. Many APIs are not suitable cerebrospinal fluid, or the spinal cord. for intramuscular administration using a transdermal spray 0034. According to the teachings of the present invention device. As noted above, many APIs cannot be orally admin there is also provided a method of treatment, comprising: a) istered and it is difficult to ensure that a varied population, for providing a pharmaceutical composition including an active example including the young, elderly or uneducated actually pharmaceutical ingredient and an ophthalmically acceptable takes the orally administered API. Injections require dispos carrier; b) generating a mist of the composition; and c) con able administration devices to ensure absolute sterility, tacting the mist with a posterior Surface of an eye of a subject require highly skilled health care professionals and are diffi in need thereofthereby depositing an effective amount of the cult to perform quickly due to ubiquitous needle phobia. Eye API on the posterior surface wherein the active ingredient is drops and inhalation devices are difficult to dose accurately selected from the group consisting of peptides and proteins. and often cause discomfort to Subjects, and sterility requires 0035. According to the teachings of the present invention disposable devices. there also is provided a method of delivering a composition, 0022. There is a general lack of a high-throughput admin comprising: a) providing a pharmaceutical composition istration method that provides accurate dosing, is quick, including a highly irritating penetration enhancer and an oph causes little discomfort to a patient including young, elderly thalmically acceptable carrier; b) generating a mist of the and frail and can be performed by a less-skilled health care composition; and c) contacting the mist with a posterior Sur professional. face of an eye of a subject in need thereof. 0023. It would be highly advantageous to have a method of 0036. In embodiments of the present invention a subject is administering peptide and protein APIs devoid of at least a human. Some of the disadvantages of the prior art. 0037. In embodiments of the present invention a subject is 0024. It is desirable to increase the bioavailibility of oph a non-human animal. thalmically administered APIs. A preferred method of 0038. In embodiments of the present invention the need is increasing bioavailability of topically administered APIs, Selected from the group consisting of curing a condition, coadministration of a penetration enhancers with the API, is treating a condition, preventing a condition, treating Symp not useful due to the ocular irritation caused by effective toms of a condition, curing symptoms of a condition, amelio penetration enhancers. There is a need for increasing the rating symptoms of a condition, treating effects of a condi bioavailability of ophthalmically administered APIs. It would tion, ameliorating effects of a condition, and preventing also be highly advantagous to have a method of ophthalmic results of a condition. Such conditions include, but are not administration of APIs employing penetration enhancers limited to conditions such as behavioral conditions, brain devoid of at least some of the disadvantages of the prior art. disorders, cancer, eye cancers, brain cancers, cerebral can 0025. It would also be highly advantageous to have a cers, nerve cancers, central nervous system disorders, chor method of high-throughput administration of APIs devoid of oidal neovascularization (e.g., associated with retinal or Sub retinal disorders. Such as, age-related mascular degeneration, at least some of the disadvantages of the prior art. presumed ocular histoplasmosis syndrome, myopic degen SUMMARY OF THE INVENTION eration, angioid streaks and ocular trauma), corneal neovas cularization (e.g., associated with trauma, chemical burns or 0026. The present invention successfully addresses at least corneal transplantation), glaucoma, infections, inflammatory Some of the shortcomings of prior art by providing diseases, inflammations, inflammatory diseases of the retina, 0027. According to the teachings of the present invention intravitreal neovascularization (e.g., associated with diabetic there is provided for the use of a mist of a pharmaceutical retinopathy, vein occlusion, sickle cell retinopathy, retinopa composition for ophthalmic delivery of an active pharmaceu thy of prematurity, retinal detachment, ocular ischemia and tical ingredient selected from the group consisting of proteins trauma), iris neovascularization (e.g., associated with dia and peptides to a subjec in need thereof. betic retinopathy, vein occlusion, ocular tumor and retinal detachment), macular edema, mental illnesses, neural condi 0028. According to the teachings of the present invention tions, neurological disorders, ocular diseases, ocular inflam there is also provided for the use of a mist of a pharmaceutical mation, optic disc neovas Vularization, optical nerve disor composition for ophthalmic delivery of an active pharmaceu ders, pannus posterior segment edema, postoperative ocular tical ingredient selected from the group consisting of proteins pain, proliferative vitreoretinopathy, prostaglandin forma and peptides to a subject in need thereof. tion, psychological conditions, psychoses and psychiatric 0029. According to the teachings of the present invention disorders, pterygium, retinoblastoma, retinal edema, retinal there is also provided for the use of a mist for ophthalmic degeneration, retinal revascularization (e.g., diabetic retin delivery of a pharmaceutical composition including a highly opathy, vein occlusion, sickle cell retinopathy, retinopathy of irritating penetration enhancer and an ophthalmically accept prematurity, retinal detachment, ocular ischemia and able carrier to a subject in need thereof. trauma), uveitis and vascular retinopathy. 0030. In embodiments of the present invention the deliv 0039. In embodiments of the present invention, the condi ery is systemic. tion is a condition Susceptible to an interaction of an active 0031. In embodiments of the present invention the deliv pharmaceutical ingredient with a part of an eye. Such as the ery is to the blood stream of the subject. cornea, retina, vitreos fluid, Sclera, lens. US 2014/0171490 A1 Jun. 19, 2014

0040. In embodiments of the present invention, the condi 2-one, dodecyl dimethyl amine oxides, EDTA and disodium tion is a condition Susceptible to an interaction of an active EDTA, ethyl caprate, ethyl caproate, ethyl caprylate, 2-ethyl pharmaceutical ingredient with a nerve. hexyl pelargonate, ethyl-2-hydroxypropanoate ethyl laurate, 0041. In embodiments of the present invention the condi ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl salicylate, tion is a condition susceptible to treatment with leptin or fusidic acid, fusidate fusidic acid derivatives, glycerol mono leptin homologues. laurate, hexyl laurate, glycocholate, glycocholic acid, gly 0042. In embodiments of the present invention the condi codeoxycholic acid, glycyrrhizic acid, 2-hydroxyoctanoic tion is a condition susceptible to treatment with antibodies or acid, 2-hydroxypropanoic acid, 2-hydroxypropionic acid, antibody homologues, such as IgG1. isethionates, isopropyl isostearate, isopropyl palmitate, guar 0043. In embodiments of the present invention the condi hydroxypropyltrimonium chloride, hexan-2,5-diol, khellin, tion is a condition Susceptible to treatment with an aptamer, lamepons, lauryl alcohol, lecithin, maypons, metal salts of e.g., an anti-VEGF aptamer. fatty acids, methy nicotinate, 2-methyl propan-2-ol. 1-me 0044. In embodiments of the present invention, the need thyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, methyl taurides, requires delivery of an active ingredient to the blood stream of miranol, nonionic Surface-active agents, octyl alcohol, the subject. octylphenoxy polyethoxyethanol, oleic thanolamide, pleyl 0045. In embodiments of the present invention, the need alcohol, pentan-2,4-diol, phenoxyethanol, phosphatidylcho requires delivery of an active ingredient part of an eye of the line, phosphine oxides, polyalkoxylated ether glycolates, Subject, e.g., the cornea, retina, vitreous fluid, Sclera, lens or poly(diallypiperidinium chloride), poly(dipropyldiallylam optic nerve. monium chloride), polyethylene glycol monolaurate, polyg 0046. In embodiments of the present invention, the need lycerol esters, polyoxyethylated castor oil (mild), polyoxy requires delivery of an active ingredient to a part of the ner ethylene, polyoxyethylene ethers of fatty acids such as Vous system of the Subject, e.g., the brain, the central nervous polyoxyethylene 4-, 9-,10-, and 23-lauryl ether, polyoxyeth system, the cerebral cavity, the cerebrospinal fluid, an optic ylene 10- and 20-cetyl ether, polyoxyethylene 10- and nerve, the retina and the spinal cord. 20-Stearyl ether, polyoxyethylene monolaurate, polyoxyeth 0047 According to the teachings of the present invention, ylene Sorbitans such as polyoxyethylene Sorbitan monolau there is also provided a device for ophthalmic administration rate, polyoxy:polyoxyethylene Stearate, polyoxypropylene of a pharmaceutical composition, comprising: a) a nebulizer; 15 Stearyl ether, poly(Vinyl pyridinium chloride), propan-1- b) a composition reservoir functionally associated with the ol, propan-2-ol, propylene glycol, propylene glycol dipelar nebulizer, and c) a pharmaceutical composition including an gonate, propylene glycol monolaurate, pyroglutamic acids, active pharmaceutical ingredient and an ophthalmically 2-pyrrolidone, pyruvic acids, Quaternium 5. Quaternium 18, acceptable carrier contained with the reservoic wherein the Quaternium 19, Quaternium 23, Quaternium 31, Quaternium active ingredient is selected from the group consisting of 40, Quaternium 57, quartenary amine salts, quaternized poly peptides and proteins. (dimethylaminoethylmethacrylate), quaternised poly (vinyl 0048. According to the teachings of the present invention alcohol), Sapamin hydrochloride, sodium cocaminopropi there is also provided a device for ophthalmic administration onate, sodium dioctyl Sulphonsuccinate, Sodium laurate, of a composition, comprising: a) a nebulizer; b) an composi Sodium lauryl ether Sulphate, Sodium lauryl Sulphate, sodium tion reservoir functionally associated with the nebulizer; and cholate, sodium glycocholate, glycocholate, sodium deoxy c) a pharmaceutical composition including a highly irritating cholate, Sodium taurocholate, sodium glycodeoxycholate, penetration enhancer and an ophthalmically acceptable car Sodium taurodeoxycholate, Sorbitan monooleate, Sorbitan monolaurate, Sugar esters, Sulphosuccinate, taurocholic acid, rier contained within the reservoir. taurodeoxycholic acid, tetrahydrofuran, tetrahydrofurfural 0049. In embodiments of the present invention, a compo sition including a peptide or protein API further comprises a alcohol, transcutol, triethanolamine dodecylbenzene Sulpho penetration enhancer. Suitable penetration enhancers nate, triethanolamine oleate, TWEEN 20, urazole, urea, uro include, but ar not limited to penetration enhancers selected sdeoxycholic acid, Saponin, Saponins and derivatives, esters, from the group consisting of acetone, acyl lactylates, acyl salts and mixtures thereof. peptides, acylsarcosinates, alcohols, alkanolamine salts of 0050. In embodiments of the present invention, a penetra fatty acids, alkylbenzene Sulphonates, alkyl ether Sulphates, tion enhancer is a penetration enhancer that is inherently alkyl Sulphates, allantoin, ammonium glycyrrhizide, anionic highly irritating Such as benzalkonium chloride, BL-9, Surface-active agents, 1-substituted azacycloheptan-2-ones, deoxycholic acid. digitonin, escin, fusidic acid, fusidate, benzyl benzoate, bezyl salicylate, bile salts, Brij 35, Brij fusidic acid derivatives, saponin, Saponins, sodium deoxy 78/35, butan-1,4-diol, butyl benzoate, butyl laurate, butyl cholate, acetone, acyl lactylates, acyl peptides, acylsarcosi myristate, butyl Stearate, cationic Surface-active agents, nates, alcohols, alkanolamine salts of fatty acids, alkylben cetylpyridium chloride (mild) chenodeoxycholic acid, cho Zene Sulphonates, alkyl ether Sulphates, alkyl Sulphates, late, cholic acid, citric acid, cocoamidopropylbetaine, deca allantoin, anionic Surface-active agents, 1-substituted azacy methonium, decamethonium bromide, decyl methyl sulfox cloheptan-2-ones, benzyl benzoate, benzyl salicylate, butan ide, decyl oleate, deoxycholic acid, dibutyl azelate, dibutyl 1,4-diol, butylbenzoate, butyl laurate, butyl myristate, butyl phthalate, dibenzyl sebacate, dibutyl sebacate, dibutyl suber Stearate, cationic Surface-active agents, citric acid, cocoami ate, dibuty Succinate, dicapryl adipate, didecyl phthalate, dopropylbetaine, decyl methyl sulfoxide, decyl oleate, dibu diethylene glycol, diethyl sebacate, diethyl-m-toluamide, tyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl seba di (2-hydroxypropyl) ether, diisopropyl adipate, diisopropyl cate, dibutyl Suberate, dibutyl Succinate, dicapryl adipate, sebacate, N,N-dimethyl acetamide, dimethyl azelate, N.N- didecyl phthalate, diethylene glycol, diethyl sebacate, dimethyl formamide, 1,5-dimethyl-2-pyrrolidone, dimethyl diethyl-m-toluamide, di(2-hydroxypropyl)ether, diisopropyl sebacate, dimethyl Sulphoxide, dioctyl adipate, dioctyl aze adipate, diisopropyl sebacate, N,N-dimethyl acetamide, dim late, dioctyl sebacate, 1.4 dioxane, 1-dodecylazacyloheptan ethyl azelate, N,N-dimethyl formamide, 1,5-dimethyl-2-pyr US 2014/0171490 A1 Jun. 19, 2014

rolidone, dimethyl sebacate, dioctyl adipate, dioctyl azelate, 0052. In embodiments of the present invention, the pen dioctyl sebacate, 1.4 dioxane, 1-dodecylazacyloheptan-2- etration enhancer comprises Saponin. one, dodecyl dimethyl amine oxides, ethyl caprate, ethyl 0053. In embodiments of the present invention, a compo caproate, ethyl caprylate, 2-ethyl-hexyl pelargonate, ethyl-2- sition further comprises an active pharmaceutical ingredient hydroxypropanoate, ethyl laurate, ethyl myristate, 1-ethyl-2- (API). Suitable APIs include but are not limited to alpha-2 pyrrolidone, ethyl salicylate, glycerol monolaurate, hexyl adrenergic agonists, analgesics, anesthetics, antibiotics (in laurate, 2-hydroxyoctanoic acid, 2-hydroxypropanoic acid, cluding agents having antimicrobial, antibacterial, antimy 2-hydroxypropionic acid, isethionates, isopropyl isostearate, cotic and/or antiprotozoal activity), antidepressants, antihis isopropyl palmitate, guar hydroxypropyltrimonium chloride, tamines, antipsychotics, antivascular agents, antiviral agents, hexan-2,5-diol, khellin lamepons, lauryl alcohol, lecithin, aptamers, artificial tears, beta-adrenergic blocking agents, maypons, metal salts offatty acids, methyl nicotinate, 2-me carbonic anhydrase inhibitors, catalytic antioxidants, chemo thyl propan-2-ol. 1-methyl-2-pyrrolidone, 5-methyl-2-pyr therapeutics, cholinesterase inhibitors, corticosteroids direct rolidone, methyl taurides, miranol, nonionic Surface-active acting miotics, hormones, light-activated drugs, non-steroi agents, octyl alcohol, octylphenoxy polyethoxyethanol, oleic dal anti-inflammatory drugs, ocular lubricants, ophthalmic ethanolamide, pleyl alcohol, pentan-2,4-diol, phenoxyetha decongestant agents, ophthalmic antiseptics, ophthalmic nol, phosphatidyl choline, phosphine oxides, polyalkoxy antifungals, peptides, prostaglandin analogs, proteins, cata lated ether glycollates, poly(diallylpiperidinium chloride), lytic antioxidants), sedatives, Steroid, stimulants, Sulfona poly(dipropyldiallylammonium chloride), polyethylene gly mides, vasoconstrictors and vasodilators. 0054. In embodiments of the present invention, the active col monolaurate, polyglycerol esters, poly(vinyl pyridinium ingredient is a peptides or proteins. Suitable peptides or pro chloride), propan-1-ol, propan-2-ol, propylene glycol, propy teins includde ACTH, angiotensin converting enzyme, lene glycol dipelargonate, propylene glycol monolaurate, bertilimumab, bevacizumab, calcitonin, concanavalin, pyroglutamic acids, 2-pyrrolidone, pyruvic acids, Quater dynorphin A, dynorphin B, enkephalins, endorphins, endot nium 5, Quaternium 18, Quaternium 19, Quaternium 23, helin-1, enzyme, glial cell-line derived neurotrophic factor Quaternium 31, Quaternium 40, Quaternium 57, quartenary (GDNF), glucagon, gonadotropin releasing hormone, growth amine salts, quaternised poly (dimethylaminoethylmethacry hormone rleasing hormone, hyaluronidase, ierdelimumab, late), quaternized poly (vinyl alcohol), Sapamin hydrochlo IgG1, insulin, leptin, lerdelimumab, leucin-enkephalin, luter ride, Sodium cocaminopropionate, sodium dioctyl Sulphon inizing hormone releasing hormone, lypressin, lysozyme, Succinate, sodium laruate, sodium lauryl ether Sulphate, metelimumab, methionin-enkephalin, monoclonal antibod Sodium lauryl Sulphate, Sorbitan monooleate, Sorbitan mono ies, alpha-neoendorphine, beta-neoendorphin, neurotrophic laurate, Sugar esters, Sulphosuccinate, tetrahydrofuran, tet factors, obestatin, oxytocin, peptide hormones, protein hor rahydrofurfural alcohol, transcutol, triethanolamine dodecyl mones, ranibizumab, ribonuclease, secretin, Somatostatin, benzene Sulphonate, triethanolamine oleate, urazole, urea, Somatotropin, thyrotrophin releasing hormone, Vasopressin, and derivatives, esters, salts and mixtures thereof. In embodi viral vectors and homologues thereof. In a preferred embodi ments of the present invention, Such an inherently highly ment of the present invention, the active ingredient is selected irritating penetration enhancer comprises at least 0.05%, at from the group consisting of leptin and and homologues least 0.1%, at least 0.2%, at least 0.5%, at least 1%, at least 2% thereof. In a preferred embodiment of the present invention, and even at least 3% by weight of the pharmaceutical com the active ingredient is selected from the group consisting of position. antibodies or antibody homologues. Such as IgG1. 0051. In embodiments of the present invention the pen 0055. In embodiments of the present invention, the pep etration enhancer is a penetration enhancer that is highly tide or protein active ingredient is a denaturizable active irritating at high concentrations such as ammonium glycyr ingredient. rhizide, Brij 35, Brij 78, Brij-98, cetylpyridium chloride, 0056. In embodiments of the present invention, the pep chenodeoxycholic acid, cholate, cholic acid, decametho tide or protein active ingredient has a molecular weight of nium, decamethonium bromide, dimethylsulphoxide, EDTA and disodium EDTA, glycocholate, glycocholic acid, gly greater than 1 kDa, greater than 1.5 kDa, greater than 3 kDa, codeoxycholic acid, glycyrrhizic acid, paraben, polyoxyeth greater than 5 kDa, greater than 10 kDa and even greater than ylene, polyoxyethylene ethers offatty acids Such as polyoxy 15 kDa. ethylene 4-, 9-,10-, and 23-lauryl ether, polyoxyethylene 10 0057. In embodiments of the present invention, a compo and 20-cetyl ether, polyoxyethylene 10- and 20-stearyl ether, sition further comprises a component selected from the group polyoxyethylated castor oil, polyoxyethylene monolaurate, consisting of bioadhesives, buffering agents, chelating polyoxyethylene Sorbitans such as polyoxyethylene Sorbitan agents, humectants, pH-adjusting agents, preservatives, solu monolaurate, polyoxy:polyoxyethylene Stearate, polyox bilizers, viscosity modifiers and vitamins. ypropylene 15 Stearyl ether, Sodium cholate, Sodium glyco 0.058 According to the teachings of the present invention cholate, sodium taurocholate, Sodium glycodeoxycholate, there is also provided a device for ophthalmic acministration Sodium taurodeoxycholate, Sodium ursodeoxycholate, tauro of a composition, comprising: a) a misting unit including i) a cholic acid, taurodeoxycholic acid, TWEEN 20, urosdeoxy nebulizer, configured to generate a mist from a composition; cholic acid, and derivatives, esters, salts and mixtures thereof and ii) a mist director, configured to direct mist generated by in a greater than accepted concentration. In embodiments of the nebulizer at an eye; b) an eye-state detector, configured to the present invention, Such a penetration enhancer that is detect if the eye is open or shut, and c) a Switch functionally highly irritating at high concentrations comprises at least associated with the misting unit and with the eye-state detec 0.05%, at least 0.1%, at least 0.2%, at least 0.5%, at least 1%, tor having at least two states, an “ON” state wherein a mist is at least 2%, at least 3% and even at least 4% by weight of the directed at the eye and an 'OFF' state wherein a mist is not pharmaceutical composition. directed at the eye. US 2014/0171490 A1 Jun. 19, 2014

0059. In embodiments of the present invention, the com 0076 According to the teachings of the present invention position is a pharmaceutical composition. there is also provided a method of treatment, comprising: a) 0060. In embodiments of the present invention the switch contacting a composition with a posterior section of an eye; b) sets to the “ON” state when the eye-state detector detects that shutting the eye with a respective eyelid; and c) vibrating the the eye is open. eyelid. 0061. In embodiments of the present invention the switch 0077. In embodiments of the present invention, the com sets to the “OFF state when the eye-state detector detects that position is a pharmaceutical composition. the eye is shut. 0078 in embodiments of the present invention, the con 0062. In embodiments of the present invention the nebu tacting comprisese instilling a drop of the composition in the lizer is deactivated when the switch is set to the 'OFF' state eye. and the nebulizer is activated when the Switch is set to the 0079. In embodiments of the present invention, the con “ON” State. tacting comprises spraying the composition in the eye. 0063. In embodiments of the present invention, misting 0080. In embodiments of the present invention, the con unit further comprises a blower (e.g., a fan or compressor) tacting comprises: i) generating a mist of the composition; functionally associated with the mist director, the blower and ii) contacting the mist with the cornea. being deactivated when the switch is set to the “OFF state I0081. In embodiments of the present invention, vibrating and the blower being activated when the switch is set to the the eyelid comprises contacting the eyelid with a vibrating “ON” State. physical component. 0064. In embodiments, the misting unit further comprises I0082 In embodiments of the present invention, the vibrat a valve functionally associated with the mist director, the ing comprises vibrating at ultrasonic frequencies. In embodi valve configured to close when the switch is set to the “OFF ments of the present invention, the vibrating comprises state and the valve configured to open when the Switch is set vibrating at Sonic frequencies. In embodiments of the present to the “ON” state. invention, the frequencies comprise frequencies of between 0065. In embodiments, the eye state detector is configured about 10 Hz, and 100 mHz. In embodiments of the present to detect light reflecting from the Surface of an anterior por invention, the frequencies comprise frequencies of no less tion of an open eye. than about 1 kHz, no less than about 10 kHz and even no less 0066. According to the teachings of the present invention than about 1 mHz. there is also provided a device for ophthalmic administ5ration of a pharmaceutical composition to an eye of a subject, com I0083. In embodiments of the present invention, the vibrat prising: a) a contact component with a contact surface, the ing is for at least 10 seconds, at least 30 seconds and even for contact Surface configured to contact a portion of the body of at least 60 seconds. the subject during the administration; and b) a reversibly I0084. According to the teachings of the present invention actuatable radiation-source, configured to irradiate the con there is also provided a device for increasing the bioavailabil tact surface with sterilizing radiation. ity of an ophthalmically administered API in a pharmaceuti 0067. In embodiments of the present invention the steril cal composition, comprising: a) an eyelid contact component, izing radiation comprises radiation selected from the group configured to physically contact an eyelid of an eye and consisting of microwave radiation, infrared radiation and maintain the eyelid in a shut position; and b) a vibration ultraviolet radiation. In embodiments of the present invention generator configured to generate vibrations (e.g., of ultra the sterilizing radiation is selected from the group consisting Sonic and/or Sonic frequencies) and transfer the vibrations to of coherent radiation and incoherent radiation. the eyelid contact component. 0068. In embodiments of the present invention, the contact I0085. In embodiments of the present invention, the device component and the radiation source are both integral ele further comprises a holder (e.g., a headband), configured to ments of a single unit of the device. hold the eyelid contact component (e.g., an eye patch) against 0069. In embodiments of the present invention, the single the eyelid. unit includes a power source (e.g., a battery, a fuel cell) I0086. In embodiments of the present invention, the vibra 0070. In embodiments of the present invention, the contact tion generator includes a piezoelectric crystal and/or a vibrat component is an integral element of a first unit of the device ing diaphragm. and the radiation source is an integral element of a second unit I0087. In embodiments of the present invention, the vibra of the device, wherein the first unit and the second unit are tion generator includes a liquid, an elastic material or the like physically distinct. In embodiments, the first unit includes a to effectively transfer vibrations to the eyelid. power source, preferably a rechargeable power source. 0071. In embodiments of the present invention, the second BRIEF DESCRIPTION OF THE DRAWINGS unit includes a recharger for the power source. I0088. The invention is herein described, by way of 0072. In embodiments of the present invention, the steril example only, with reference to the accompanying drawings. izing radiation is projected at the contact surface. With specific reference now to the drawings in detail, it is 0073. In embodiments of the present invention, the contact stressed that the particulars shown are by way of example and component acts as a wave guide to the sterilizing radiation. for purposes of illustrative discussion of the preferred 0.074. In embodiments, the radiation-source is user-actu embodiments of the present invention only, and are presented ated. In embodiments, the radiation-source is automatically in the cause of providing what is believed to be the most actuated. In embodiments, the radiation-source is autono useful and readily understood description of the principles mously actuated. and conceptual aspects of the invention. In this regard, no 0075. In embodiments, the device further comprises a fail attempt is made to show structural details of the invention in safe switch to prevent activation of the radiation source when more detail than is necessary for a fundamental understand the contact surface is in contact with the portion of the body. ing of the invention. The description taken with the drawings US 2014/0171490 A1 Jun. 19, 2014

making apparent to those skilled in the art how the several 0107 An additional aspect of the present invention relates forms of the invention may be embodied in practice. to the use of a mist of a pharmaceutical composition for I0089. In the drawings: ophthalmic administration of an API for selective delivery to 0090 FIGS. 1A-1H schematically depict an embodiment the nervous system and the eye. of a device of the present invention for administering a phar 0108. An additional aspect of the present invention relates maceutical composition, in accordance with the present to a device for ophthalmic administration comprising a nebu invention. lizer, a mist director to direct a generated mist at an eye, an 0091 FIGS. 2A-2E schematically depict an embodiment eye-state detector to detect if an eye is open or closed, and a of a device of the present invention with a cradle for admin switch associated with both the eye-state detector and the mist istering a pharmaceutical composition, in accordance with director to direct mist at the eye only when open. the present invention; 0109 An additional aspect of the present invention relates 0092 FIGS. 3A-3E schematically depict embodiments of to a device for ophthalmic administration that is self-steriliz computerized devices which may be used with a device of the ing. present invention in accordance with the present invention; 0110. An additional aspect of the present invention is a 0093 FIG. 4 is a flowchart of an embodiment of a method method and a device for increasing the availability of an of using an embodiment of a device of the present invention; ophthalmically administered API, whether systemic or local, 0094 FIG. 5 schematically depicts a self-sterilizing oph whether through the conjunctiva, Sclera, cornea or other thalmic delivery device of the present invention; route, by vibrating the eyelid subsequent to the ophthalmic 0095 FIGS. 6A-B schematically depicts an eyelid-vibrat administration. ing device of the present invention; 0111. The principles, uses and implementations of the 0096 FIGS. 7A-7C display comparative results of deliv teachings of the present invention may be better understood ery of a pharmaceutical composition including leptin to the with reference to the accompanying description, figures and retina and aqueous humor by instillation and as a mist; examples. Upon perusal of the description and figures present 0097 FIGS. 8A-8B display comparative results of deliv herein, one skilled in the artisable to implement the teachings ery of a pharmaceutical composition including leptin to the of the present invention without undue effort or experimen cerebrospinal fluid by instaillation and as a mist; tation. In the figures, like reference numerals refer to like 0098 FIGS. 9A-9B display results of duration of delivery parts throughout. of a pharmaceutical composition including leptinto the Sclera 0112 Befor explaining at least one embodiment of the as a mist; invention in detail, it is to be understood that the invention is 0099 FIGS. 10A-10C display comparative results of not limited in its application to the details set forth herein. The delivery of a pharmaceutical composition including leptin to invention can be implemented with other embodiments and the retina, Sclera and optic nerve by instillation and as a mist; can be practiced or carried out in various ways. It is also 0100 FIGS. 11A-11C display comparative results of understood that the phraseology and terminology employed delivery of a pharmaceutical composition including leptin to herein is for descriptive purpose and should not be regarded as the serum by instillation and as a mist; limiting. 0101 FIG. 12A is a reproduction of a photograph of a rat 0113 Generally, the nomenclature used herein and the into which eye a pharmaceutical composition including Sapo laboratory procedures utilized in the present invention nin was instilled; include techniques from the fields of medicine, biology, 0102 FIG. 12B is a reproduction of a photograph of a rat chemistry, material Sciences, pharmacology, and engineer into which eye a pharmaceutical composition including Sapo ing. Such techniques are thoroughly explained in the litera nin was administered as a mist; and ture 0103 FIG. 13 displays results of mouse IgG1 levels in the 0114. Unless otherwise defined, all technical and scien optic nerves of rats into which eye a pharmaceutical compo tific terms used herein have the same meaning as commonly sition including mouse IgG1 was administered as a mist. understood by one of ordinary skill in the art to which the invention belongs. In addition, the descriptions, materials, DESCRIPTION OF EMBODIMENTS OF THE methods and examples are illustrative only and not intended INVENTION to be limiting. Methods and materials similar or equivalent to 0104. The presewnt invention is related to the administra those described herein can be used in the practice or testing of tion of compositions, especially of pharmaceutical composi the present invention. tions including an API into the eye by nebulizing a composi 0.115. As used herein, the terms “comprising and “includ tion and then contacting the produced mist with an exposed ing’ or grammatical variants thereofare to be taken as speci anterior ophthalmic Surface. Such as the conjuncctiva, Sclera fying the stated features, integers, steps or components but do O CO8. not preclude the addition of one or more additional features, 0105. An aspect of the present invention relates to the use integers, steps, components or groups thereof. This term of a mist of a pharmaceutical composition for ophthalmic encompasses the terms “consisting of and "consisting essen administration of a peptide or protein active pharmaceutical tially of. ingredient, especially for delivery to the nervous system and 0116. The phrase “consisting essentially of or grammati the eye. cal variants thereof when used herein are to be taken as 010.6 An additional aspect of the present invention relates specifying the stated features, integers, steps or components to the use of a mist of a pharmaceutical composition for but do not preclude the addition of one or more additional ophthalmic administration including a highly irritating pen features, integers, steps, components or groups thereof but etration enhancer, whether inherently highly irritating or only if the additional features, integers, steps components or highly irritating at relatively high concentrations in a phar groups thereof do not materially alter the basic and novel maceutical composition. characteristics of the claimed composition, device or method. US 2014/0171490 A1 Jun. 19, 2014

0117 The term “method’ refers to manners, means, tech for ophthalmic administation of a pharmaceutical composi niques and procedures for accomplishing a given task includ tion, comprising: a) a nebulizer, a composition reservoir func ing, but not limited to, those manners, means, techniques and tionally associated with the nebulizer; and within the reser procedures either known to, or radily developed from known Voir a pharmaceutical composition including a peptide or manners, means, techniques and procedures by practitioners protein API and an ophthalmically acceptable carrier. of the relevant arts. Implementation of the methods of the 0.125. An aspect of the present invention relates to the use present invention involves performing or completing selected of a mist for ophthalmic delivery of a pharmaceutical com tasks or steps manually, automatically, or a combination position including a highly irritating penetration enhancer thereof. and an ophthalmically acceptable carrier (and preferably an 0118. Herein, the term “active pharmaceutical ingredient’ API) to a subject (human or non-human) in need thereof. In or API is understood to include a chemical, biological or embodiments, delivery is to the blood stream of the subject. In pharmaceutical entities including any natural or synthetic embodiments, delivery is selective to part of an eye (e.g., chemical or biological Substance that has a pharmaceutical Sclera, optic nerve and retina) or a part of the nervous system effect. Typical APIs include but are not limited to antibodies, (e.g., the brain, the central nervous system, the cerebral cav antigens, biological materials, chemical materials, drugs, ity, the cerebrospinal fluid, and the spinal cord). The teach enzymes, hormones, immunogenes, probes, tracers, nucleic ings of the present invention also provide a method of treat acids, peptides, proteins, selective toxins and toxins. ment where a pharmaceutical composition including a highly 0119 Herein, the term “peptide' or “protein' is under irritating penetration enhancer and an ophthalmically accept stood to include any polymer (dipeptide or greater) of amino able carrier (and preferably an API) is provided, the compo acids (R or L, natural or not-natural) linked through peptide sition nebulized; and the resulting mist contacted with a pos bonds. Thus, the terms include proteins, oligopeptides, pro terior surface of an eye of a subject in need thereof. The tein fragments, analogs, muteins, fusion proteins and the like. teachings of the present invention also provide a device for These terms also encompass amino acid polymers as ophthalmic administration of a pharmaceutical composition, described above that include additional moieties such as gly comprising: a) a nebulizer, a composition reservoir function coproteins, lipoproteins, phosphoproteins, metalloproteins, ally associated with the nebulizer; and within the reservoir a nucleoproteins, as well as other conjugated proteins. Herein, pharmaceutical composition including a highly irritating "peptide' refers to a polymer consisting of up to 40 amino penetration enhancer and an ophthalmically acceptable car acid residues whereas “protein refers to a polymer consist rier (and preferably an API). ing of more than 40 amino acid residues. 0.126 An aspect oftyhe present invention relates to the use 0120 Herein, the term “penetration enhancer is under of a mist for ophthalmic delivery of a pharmaceutical com stood to include an component of a composition that position for selective delivery to part of an eye (e.g., Sclera, increases the amount of absorption into the body of a sub optic nerve and retina) or a part of the nervous system (e.g., stance coadministered therewith. the brain, the central nervous system, the cerebral cavity, the 0121 Herein, the term “ophtbalmically acceptable car cerebrospinal fluid, and the spinal cord) of a Subject (human rier describes a carrier that does not cause significan irrita or non-human) in need thereof. The teachings of the present tion to the eye of an organism when applied in accordance invention also provide a method of treatment where a phar with the teachings of the present invention and does not maceutical composition including an API effective for treat abrogate the pharmacological activity and properties of an ing a part of the eye or a part of the nervous system and an API carried therewith. ophthalmically acceptable carrier, the composition nebu 0122. Herein, the term “nebulizer” is understood to mean lized; and the resulting mist contacted with a posterior Surface a device or a part of a device that converts a Substance, e.g., a of an eye of a subject in need thereof. The teachings of the Solid, gel, liquid, Solution, Suspension, ointment, pharmaceu present invention also provide a device for ophthalmic admin tical composition, into a mist. istration of a pharmaceutical composition, comprising: a) a 0123. Herein, the term “mist” refers to a cloud of particles nebulizer, a composition reservoir functionally associated having a mean partical diameter of less than about 20 with the nebulizer; and within the reservoir a pharmaceutical microns, less than about 10 microns, less than about 8 composition including an API effective for treating a part of microns, less than about 5 microns, less than about 3 micron the eye or a part of the nervous system and ophthalmically and even less than about 1 micron. acceptable carrier. 0.124. An aspect of the present invention relates to the use I0127. The teachings of the present invention are generally of a mist of a pharmaceutical composition for ophthalmic applied for or in the context of treating the need of a subject. delivery of a peptide or protein API to a subject (human or Typical needs include curing a condition, treating a condition, non-human) in need thereof. In embodiments, delivery is to preventing a condition, treating symptoms of a condition, the blood stream of the subject. In embodiments, delivery is curing symptoms of a condition, ameliorating symptoms of a selective to part of an eye (e.g., Sclera, optic nerve and retina) condition, treating effects of a condition, ameliorating effects or a part of the nervous system (e.g., the brain, the central of a condition, and preventing results of a condition. Typical nervous system, the cerebral cavity, the cerebrospinal fluid, conditions include but are not limited to behavioral condi and the spinal cord). The teachings of the present invention tions, brain disorders, cancer, eye cancers, brain cancers, also provide a method of treatment where a pharmaceutical cerebral cancers, nerve cancers, central nervous system dis composition including a peptide or protein API and an oph orders, choroidal neovascularization (Such as associated with thalmically acceptable carrier is provided, the composition retinal or Subretinal disorders, such as, age-related macular nebulized; and the resulting mist contacted with a posterior degeneration, presumed ocular histoplasmosis syndrome, surface of an eye of a subject in need thereofthereby depos myopic degeneration, angioid streaks and ocular trauma), iting an effective amount of the API on the posterior surface. corneal neovascularization (Such as associated with trauma, The teachings of the present invention also provide a device chemical burns or corneal transplantation), glaucoma, infec US 2014/0171490 A1 Jun. 19, 2014

tions, inflammatory diseases, inflammations, inflammatory mental section FIGS. 7A, 7C, 8A, 8B, 10A, 10B, 10C, but diseases of the retina, intravitreal neovascularization (such as delivering significantly less API to the serum and to the aque associated with diabetic retinopathy, vein occlusion, sickle ous humor than when administered by instillation, see cell retinopathy, retinopathy of prematurity, retinal detach Experimental section FIGS. 7B, 11A, 11C. ment, ocular ischemia or trauma), iris neoVacularization 0.138. It is important to note, that the experiments detailed (such as associated with diabetic retinopathy, vein occlusion, below on which the above conclusions and invention are ocular tumor or retinal detachment), macular edema, mental based, compare ophthalmic administration of a composition illnesses, neural conditions, neurological disorders, ocular as a mist to administration by instillation. These experiments diseases, ocular inflammation, optic disc neovascularization, indicate that delivery of an API to the retina, sclera and optic optical nerve disorders, pannus posterior segment edema, nerve by either method provides similar concentrations of postoperative ocular pain, proliferative vitreoretinopathy, API in the tissue. However, as in the experiments instillation prostaglandin formation, psychological conditions, psycho included forcibly shutting the eye of a subject rat for two ses and psychiatric disorders, pterygium, retinoblastoma, minutes, it is expected that in actual clinical use, administra retinal edema, retinal degeneration, retinal revascularization tion of a composition using a mist in accordance with the (such as associated with diabetic retinopathy, vein occlusion, teachings of the present invention will be more effective than sickle cell retinopathy, retinopathy of prematurity, retinal instillation of the same composition. detachment, ocularischemia or trauma), uveitis and vascular 0.139. In the art, the systemic delivery of small peptide or retinopathy. In embodiments of the present invention, condi protein APIs such as insulin is well established by instillation tions are conditions Susceptible to an interaction of an API of a pharmaceutical composition including the API. Instilla with a nerve and/or with part of an eye (e.g., cornea, retina, tion is considered the preferred method of ophthalmic admin vitreous fluid, Sclera, lens). istration as the large Volume of liquid instilled overcomes the 0128. In embodiments of the present invention, conditions ocular protective mechanisms. The evidence indicates that are conditions susceptible to treatment with leptin or leptin the API is washed to the conjunctiva and there absorbed homologues. through the mucosa. Once in the blood stream, such an API 0129. In embodiments of the present invention, conditions acts systemically and cannot reach certain organs, for are conditions susceptible to treatment with antibodies or example the central nervous system. Further, as many peptide antibody homologues, such as IgG1. and protein APIs have very subtle effects, systemic adminis 0130. In embodiments of the present invention, conditions tration may be contraindicated. are conditions Suceptible to treatment with aptamers, such as 0140. An aspect of the present invention relates to the use anti-VEGFaptamers such as EYE01. of a mist of a pharmaceutical composition for ophthalmic 0131. In embodiments of the present invention, the need delivery of a peptide or protein active pharmaceutical ingre requires delivery of an active ingredient to the blood stream dient, especially for delivery to the eye and nervous system. and/or part of an eye (e.g., cornea retina, vitreous fluid, Sclera, 0.141. The experimental data presented below demon lens) and/or part of the nervous system (e.g., brain, the central strates that the teachings of the present invention allow for nervous system, the cerebral cavity, the cerebrospinal fluid, advantageous ophthalmic delivery of peptides and proteins. an optic nerve, the retina and the spinal cord) of a Subject. 0.142 Embodiments of the teachings of the present inven 0132 Embodiments of the present invention are based on tion provide for the delivery of denaturable peptides and and supported by experiments performed and detailed below. protein APIs that do not lose an active tertiary or quaternary 0133. The experiments performed demonstrate that structure including APIs having a molecular weight of greater administration of a pharmaceutical composition including than 1 kDa, greater than 1.5 kDa, greater than 3 kDa, greater medium-sized proteins such as leptin or large sized proteins than 5 kDa, greater than 10 kDa and even greater than 15 kDa. such as the antibody leptin as a mist allows effective delivery 0.143 Embodiments of the teachings of the present inven of an API to the back of the eye (optic nerve), see Experimen tion provide for the delivery of peptide and protein APIs, tal Section FIGS. 10C and 13. systemically (e.g., to the blood stream) or selectively. 0134. The experiments performed demonstrate that an 0144. Embodiments of the teachings of the present inven API administered ophthalmically in a nebulized pharmaceu tion provide for the selective delivery of peptide and protein tical composition is transported from the posterior section of APIs, especially selective delivery to the eye (e.g., Sclera, the eye by a mechanism different than when administered by optic nerve and retina) and/or the nervous system (the brain, instillation, see Experimental section FIGS. 7B, 9A and 9B. the central nervous system, the cerebral cavity, the cere 0135 The experiments performed demonstrate that broSpinal fluid, and the spinal cord). administration of a pharmaceutical composition as a mist, but 0145 Administration of a peptide or protein API in accor not by instillation, allows delivery of an API to the cerebrospi dance with the teachings of the present invention is to a nal fluid (CSF), see Experimental section FIG. 8B. Subject (human or non-human) in need thereof. Typical needs 0136. The experiments performed demonstrate that include curing a condition, treating a condition, preventing a administration of a pharmaceutical composition as a mist in condition, treating symptoms of a condition, curing Symp accordance with embodiments of the present invention allows toms of a condition, ameliorating effects of a condition, and the use of otherwise irritant penetration enhancers, see preventing results of a condition. Typical conditions include, Experimental section FIGS. 12A and 12B. but are not limied to behavioral conditions, brain disorders, 0.137 The experiments performed demonstrate that cancer, eye cancers, brain cancers, cerebral cancers, nerve administration of a pharmaceutical composition including a cancers, central nervous system disorders, choroidal neovas penetration enhancer as a mist in accordance with embodi cularization (such as associated with retinal or Subretinal ments of the present invention is relatively selective, deliver disorders, such as, age-related macular degeneration, pre ing higher or comparable amounts of API to the retina, Sclera, Sumed ocular histoplasmosis syndrome, myopic degenera optic nerve and central nervous system (CNS), see Experi tion, angioid streaks and ocular trauma), corneal neovascu US 2014/0171490 A1 Jun. 19, 2014

larization (such as associated with trauma, chemical burns or posed (see Sasaki et al. Crit. Rev. Ther. Drug Carrier Syst. corneal transplantation), glaucoma, infections, inflammatory 1999, 16, 85-146) but is not generally used due to observa diseases, inflammations, inflammatory diseases of the retina, tions of irritation and corneal and conjunctival injury caused intravitreal neovascularization (such as associated with diae by known penetration enhancers, see Saettone et al. Int. J. betic retinopathy, vein occulsion, sickle cell retinopathy, ret Pharm. 1996, 142, 103-113 and Furrer et al. AAPS Pharm. inopathy of prematurity, retinal detachment, ocular ischemia Sci. 2002, 4(1), 1-5) or trauma), iris neovascularization (such as associated with 0150 Penetration enhancers can be classified as being diabetic retinopathy, vein occlusion, ocular tumor or retinal inherently highly irritating to the eye and as being mildly detachment), macular edema, mental illnesses, neural codi irritating to the eye. tions, neurological disorders, ocular diseases, ocular inflam 0151. Although inherently highly irritating penetration mation, optic disc neovascularization, optical nerve disor enhancers are expected to be more effective at enhancing the ders, pannus posterior segment edema, postoperative ocular penetration and consequently bioavailability of APIs in oph pain, proliferative vitreoretinopathy, prostaglandin forma thalmically administered pharmaceutical compositions. Such tion, psychological conditions, psychoses and psychiatric inherently highly irritating penetration enhancers are not used disorders, pterygium, retinoblastoma, retinal edema, retinal due to the danger of grievous injury and even blindness to a degeneration, retinal revascularization (such as assocciated Subject to to which Such compositions are applied. with diabetic retinopathy, vein occusion, sickle cell retinopa 0152. As a result, in the art it is known to use only mildly thy, retinopathy of prematurity, retinal detachment, ocular irritating penetration enhancers in ophthalmically adminis ischemia or trauma), uveitis and vascular retinopathy. tered pharmaceutical compositions. However, as mildly irri 0146 Peptide and protein APIs that are advantageously tating penetration enhancers do cause discomfort and may delivered in accordance with the teachings of the present damage the eye, the concentration of mildly irritating pen invention include but are not limited to ACTH, angiotensin etration enhancers in known ophthalmically pharmaceutical converting enzyme, bertilimumab, bevacizumab, calcitonin, compositions is limited to a relatively low and ineffective concanavalin, dynorphin A, dynorphin B, endothelin-1, level. enkephalins, endorphins, enzyme, glial cell-line derived neu 0153. An additional aspect of the present invention relates rotrophic factor (GDNF), glucagon, gonadotropin releasing to the use of a mist of a pharmaceutical composition for hormone, growth hormone releasing hormone, hyalu ophthalmic delivery of a including a highly irritating penetra ronidase, ierdelimumab, IgG1, insulin, leptin, lerdelimumab, tion enhancer, whether inherently highly irritating or highly leucine-enkephalin, luteinizing hormone releasing hormone, irritating at relatively high concentrations in a pharmaceutical lypressin, lysozyme, metelimurnab, methionine-enkephalin, composition. monoclonal antibodies, alpha-neoendorphin, beta-neoendor 0154 Inherently highly irritating penetration enhancers phin, neurotrophic factors, obestatin, oxytocin, peptide hor useful for implementing the teachings of the present inven mones, protein hormones, ranibizumab, ribonuclease, secre tion, for example as components of an embodiment of a tin, Somatostatin, Somatotropin, thyrotrophin releasing composition of the present invention include, but are not hormone, vasopressin, viral vectors and homologues thereof. limited to benzalkonium chloride, BL-9, deoxycholic acid, 0147 A preferred protein delivered in accordance with the digitonin, escin, fusidic acid, fusidate, fusidic acid deriva teachings of the present invention is leptin or leptin homo tives, Saponin, Saponins, sodium deoxycholate, acetone, acyl logues to treat conditions Susceptible to treatment with leptin lactylates, acyl peptides, acylsarcosinates, alcohols, alkano or leptinhomologues such as weight control (Zhang, Y. et al. lamine salts of fatty acids, alkylbenzene Sulphonates, alkyl Nature 1994, 372, 425-432), female sexual development and ether Sulphates, alkyl Sulphates, allantoin, anionic Surface hormonal imbalance, immune system disorders, bone devel active agents, 1-substituted azacycloheptan-2-ones, benzyl opment and retinal neuron preservation (Koeberle, PD et al. benzoate, benzyl salicylate, butan-1,4-diol, butylbenzoate, Vision Res. 1998,38, 1505-1515 and Schmeer, C. etal. Eur: J. butyl laurate, butyl myristate, butyl Stearate, cationic Surface Neurosci. 2002, 15, 637-643), for example during diabetic active agents, citric acid, cocoamidopropylbetaine, decyl retinopathy, macular degeneration, retinitis pigmentosa. methylsulfoxide, decyl oleate, dibutyl azelate, dibutyl phtha 0148. A preferred type of protein delivered in accordance late, dibenzyl sebacate, dibutyl sebacate, dibutyl suberate, with the teachings of the present invention are antibodies and dibutyl Succinate, dicapryl adipate, didecyl phthalate, dieth antibody homologues, especially IgG1 to treat conditions sus ylene glycol, diethyl sebacate, diethyl-m-toluamide, di(2-hy ceptible to treatment with antibody and antibody homo droxypropyl) ether, diisopropyl adipate, diisopropyl seba logues, for example to immunize populations or to inactivate cate, N,N-dimethyl acetamide, dimethyl azelate, N.N- factors, such as VEGF, that induce vascular leakage and dimethyl formamide, 1,5-dimethyl-2-pyrrolidone, dimethyl neovascularization in the retina in various diseases such as sebacate, dioctyl adipate, dioctyl azelate, dioctyl sebacate, wet age-related macular degeneration. Further, in the experi 1,4-dioxane, 1-dodecylazacyloheptan-2-one, dodecyl dim mental section it is demonstrated that IgG1 administered in ethylamine oxides, ethyl caprate, ethyl caproate, ethyl capry accordance with the teachings of the present invention accu late, 2-ethyl-hexyl pelargonate, ethyl-2-hydroxypropanoate, mulates in the optic nerve. Since the optic nerve is Surrounded ethyl laurate, ethyl myristate, 1-ethyl-2-pyrrolidone, ethyl by CSF and is directly connected to the brain, it is expected salicylate, glycerol monolaurate, hexyl laurate, 2-hydroxyoc that extremely large proteins such as antibodies such as IgG1 tanoic acid, 2-hydroxypropanoic acid, 2-hydroxypropionic are deliverable to the central nervous system using the teach acid, isethionates, isopropyl isostearate, isopropyl palmitate, ings of the present invention as demonstrated for leptin. guar hydroxypropyltrimonium chloride, hexan-2,5-diol. 0149 Penetration enhancers are materials that transiently khellin, lamepons, lauryl alcohol, lecithin, maypons, metal increase the permeability of the corneal epithelium or con salts of fatty acids, methyl nicotinate 2-methyl propan-2-ol. junctiva to facilitate API penetration therethrough. The use of 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, methyl known percutaneous penetration enhancers has been pro taurides, miranol, nonionic Surface-active agents, octyl alco US 2014/0171490 A1 Jun. 19, 2014 hol, octylphenoxy polyethoxyethanol, oleic ethanolamide, 0158 Embodiments of the teachings of the present inven pleyl alcohol, pentan-2,4-diol, phenoxyethanol, phosphatidyl tion provide for the selective delivery of APIs, especially choline, phosphine oxides, polyalkoxylated ether glycolates, selective delivery to the eye (e.g., Sclera, optic nerve and poly(diallylpiperidinium chloride), poly(dipropyldiallylam retina) and/or the nervous system (the brain, the central ner monium chloride), polyethylene glycol monolaurate, polyg Vous system, the cerebral cavity, the cerebrospinal fluids, and lycerol esters, poly(vinyl pyridinium chloride), propan-1-ol. the spinal cord). Administration of an API in accordance with propan-2-ol, propylene glycol, propylene glycol dipelargo the teachings of the present invention is to a Subject (human or nate, propylene glycol monolaurate, pyroglutamic acids, non-human) in need thereof. Typical needs include curing a 2-pyrrolidone, pyruvic acids, Quaternium 5. Quaternium 18, condition, treating a condition, preventing a condition, treat Quaternium 19, Quaternium 23, Quaternium 31, Quaternium ing symptoms of a condition, curing symptoms of a condi 40, Quaternium 57, quartenary amine salts, quaternised poly tion, ameliorating symptoms of a condition, treating effects (dimethylaminoethylmethacrylate), quaternised poly (vinyl of a condition, ameliorating effects of a condition, and pre alcohol), Sapamin hydrochloride, sodium cocaminopropi venting results of a condition. Typical conditions include, but onate, Sodium dioctyl Sulphonsuccinate, Sodium laurate, are not limited to, behavioral conditions, brain disorders, Sodium lauryl ether Sulphate, sodium lauryl Sulphate, Sorbitan cancer, eye cancers, brain cancers, cerebral cancers, nerve monooleate, Sorbitan monolaurate, Sugar esters, Sulphosuc cancers, central nervous system disorders, choroidal neovas cinate, tetrahydrofuran, tetrahydrofurfural alcohol, transcu cularization (such as associated with retinal or Subretinal tol, triethanolamine dodecyl benzene Sulphonate, triethano disorders, such as, age-related macular degernaetion, pre lamine oleate, urazole, urea and derivatives, esters, salts and Sumed ocular histoplasmosis syndrome, myopic degenera mixtures thereof. In embodiments of the present invention, an tion, angioid streaks and ocular trauma), corneal neovascu inherently highly irritating penetration enhancer comprises at larization (such as associated with trauma, chemical burns or least 0.05%, at least 0.1%, at least 0.2%, at least 0.5%, at least corneal transplantation), glaucoma, infections, inflammatory 1% and even at least 2% by weight of the pharmaceutical diseases, inflammations, inflammatory diseases of the retina, composition. intravitreal neovascularization (Such as associated with dia 0155. A preferred inherently highly irritating penetration betic retinopathy, vein occlusion, sickle cell retinopathy, ret enhancer useful for implementing the teachings of the present inopathy of prematurity, retinal detachment, ocular ischemia invention is Saponin. or trauma), iris neovascularization (such as associated with 0156 Penetration enhancers that are highly irritating at diabetic retinopathy, vein occlusion, ocular tumor or retinal high concentrations useful for implementing the teachings of detachment), macular edema, mental illnesses, neural condi the present invention, for example as components of an tions, neurological disorders, ocular diseases, ocular inflam embodiment of a composition of the present invention mation, optic disc neovascularization, optical nerve disor include, but are not limited to ammonium glycyrrhizide, Brij ders, pannus posterior segment edema, postoperative ocular 35, Brij 78, Brij-98, cetylpyridium chloride, chenodeoxy pain, proliferative vitreoretinopathy, prostaglandin forma cholic acid, cholate, cholic acid, decamethonium, decame tion, psychological conditions, psychoses and psychiatric thonium bromide, dimethylsulphoxide, EDTA and disodium disorders, pterygium, retinoblastoma, retinal edema, retinal EDTA, glycocholate, glycocholic acid, glycodeoxycholic degeneration, retinal revascularization (such as associated acid, glycyrrhizic acid, paraben, polyoxyethylene, polyoxy with diabetic retinopathy, vein occlusion, sickle cell retinopa ethylene ethers of fatty acids such as polyoxyethylene 4-, 9 thy, retinopathy of prematurity, retinal detachment, ocular 10-, and 23-lauryl ether, polyoxyethylene 10- and 20-cetyl ischemia or trauma), uveitis and vascular retinopathy. ether, polyoxyethylene 10- and 20-stearyl ether, polyoxy 0159. Non-peptide and protein APIs that are advanta ethylated castor oil, polyoxyethylene monolaurate, polyoxy geously delivered in accordance with the teachings of the ethylene Sorbitans Such as polyoxyethylene Sorbitan mono present invention include but are not limited to alpha-2 adr laurate, polyoxy:polyoxyethylene Stearate, energic agonists, analgesics, anesthetics, antibiotics, antide polyoxypropylene 15 Stearyl ether, Sodium cholate, sodium pressants, antihistamines, antipsychotics, antivascular glycocholate, sodium taurocholate, Sodium glycodeoxycho agents, antiviral agents, artificial tears, beta-adrenergic late, sodium taurodeoxycholate, sodium urSodeoxycholate, blocking agents, carbonic anhydrase inhibitors, catalytic anti taurocholic acid, taurodeoxycholic acid, TWEEN 20, uros oxidants, chemotherapeutics, cholinesterase inhibitors, cor deoxycholic acid, and derivatives, esters, salts and mixtures ticosteroids, direct acting miotics, hormones, light-activated thereof in a greater than accepted concentration. In embodi drugs, non-steroidal, anti-inflammatory drugs, ocular lubri ments of the present invention, an inherently highly irritating cants, ophthalmic decongestant agents, ophthalmic antisep penetration enhancer comprises at least 0.05%, at least 0.1%, tics, ophthalmic antifungals, peptides, prostaglandin analogs, at least 0.2%, at least 0.5%, at least 1%, at least 2%, at least proteins, catalytic antioxidants), sedatives, steroid, Stimu 3% and even at least 4% by weight of the pharmaceutical lants, Sulfonamides, vasoconstrictors. composition. 0160. In embodiments, a composition of the present 0157 Preferably, a composition of the present invention is invention includes an analgesic API. Suitable analgesics a pharmaceutical composition including an API. As noted include, but are not limited to, benzocaine, butamben picrate, above, in embodiments a composition of the present inven dibucaine, dimethisoquin, dyclonine, lidocaine, pramoxine, tion includes a peptide or protein API. In embodiments, a tetracaine, Salicylates and derivatives, esters, salts and mix composition of the present invention includes one or more tures thereof. non-peptide or protein APIs. In embodiments, a composition 0.161. In embodiments, a composition of the present of the present invention includes one or more non-peptide or invention inludes an anesthetic. Suitable anesthetics include, protein APIs in addition to a peptide or protein API. In but are not limited to, benzocaine, bupivacaine, butamben embodiments, a composition of the present invention is picrate, chlorprocaine, cocaine, dibucaine, dimethisoquin, devoid of a peptide or protein API. dyclonine, etidocaine, hexylcaine, ketamine, lidocaine, US 2014/0171490 A1 Jun. 19, 2014 mepivacaine, pramoxine, procaine, tetracaine, Salicylates and methylamitriptyline, dibenzepin, dimetacrine, dothiepin derivatives, ester, salts and mixtures thereof. doxepin, dulloxetine, etoperidone, femoxetine, fluacizine, flu 0162. In embodiments, a composition of the present oxetine, fluvoxamine, imipramine, imipramine-oxide, indal invention includes an aptamer. Suitable aptamers include pine, indeloxazine, iprindole, lofepramine, maprotiline, meli anti-VEGFaptamers such as EYE01. In embodiments of the tracen, metapramine, milnacipran, mitrazapine, nefazodone, invention, aptamers are encapsulated for controlled release, norclolipramine, nortripytyline, noxiptilin, opipramol. for example within microsphere. A description of anti-VEGF oxaflaZone, paroxetine, perlapine, pizotyline, prolintane, aptamers such as EYE01 and the encapsulation hereof in propizepine, protriptyline, quinupramine, reboxetine, microspheres is discussed in U.S. Patent Application 2005/ ritanserin, Sertraline, trimipramine, tianeptine, tandospirone, 0175708, incorporated by reference as if fully set forth traZadone, Venlafaxine, Zimeldine and derivatives, esters, herein. salts and mixtures thereof. 0163. In embodiments, a composition of of the present 0.165. In embodiments, a composition of of the present invention includes an antibiotic, including agents with anti invention includes an antihistamine. Suitable antihistamines microbial, antibacterial, antimycotic and/or antiprotozoal include, but are not limited to, chlorcyclizine, diphenhy activity. Suitable analgesics include, but are not limited to, dramine, mepyramine, methapyrilene, tripelennamine and amanfadine hydrochloride, amanfadine Sulfate, amikacin, derivatives, esters, salts and mixtures thereof. amikacin Sulfate, aminoglycosides, amoxicillin, amplicillin, 0166 In embodiments, a composition of of the present ansamycins, bacitracin, beta-lactams, butoconazole, candici invention includes an antipsychotic. Suitable antipsychotics din, capreomycin, carbenicillin, cephalexin, cephaloridine, include, but are not limited to, selective serotonin-reuptake cephalothin, cefazolin cephapirin, cephradine, cephaloglycin inhibitors, fluoxetine, fluvoxamine, Sertraline, escitalopram, chloramphenicols, chlorhexidine, chlorhexidine gluconate, citalopram, paroxetine, monoamine oxidase inhibitors, iso chlorhexidine hydrochloride, chloroxine, chlorquinaldol, carboxazid, phenelzine, tranylcypromine, conventional chlortetracycline, chlortetracycline hydrochloride, ciclo antipsychotics, haloperidol, molindone, thioridazine, atypi piroX olamine, ciprofloxacin, circulin, clindamycin, clinda cal antipsychotics, clozapine, olanzapine, risperidone, que mycin hydrochloride, clotrimazole, cloxacillin, demeclocy tiapine, sertindole, aripiprazole, Ziprasidone, and derivatives, cline, dicloSXacillin, diiodohydroxyquin, doxycycline, esters, salts and mixtures thereof. econazole, elubiol, ethambutol, ethambutol hydrochloride, 0167. In embodiments, a composition of of the present erythromycin, erythromycin estolate, erythomycin Stearate, invention includes a corticosteroid. Suitable corticosteroids farnesol, floxacillin, fluconazole, gentamicin, gentamicin include, but are not limited to, alclometasone dipropionate, Sulfate, gramicidin, griseofulvin, haloprogin, haloquinal, amcinafel, amcinafide, amcinonide, beclomethasone, hexachlorophene, iminocycline, iodochlorhydroxyquin, itra beclomethasone dipropionate, betamethsone, betamethasone conazole, kanamycin, kanamycin Sulfate, ketoconazole, lin benzoate, betamethasone dexamethasone-phosphate, comycin, lincomycin, lincomycin hydrochloride, mac betamethasonedipropionate, betamethasone Valerate, budes rolides, mafenide acetate, meclocycline, methacycline, onide, chloroprednisone, chlorprednisone acetate, clescino methacycline hydrochloride, methenamine, methenamine lone, clobetasol, clobetasol propionate, clobetasol Valerate, hippurate, methenamine mandelate, methicillin, metronida clobetasone, clobetaSone butyrate, clocortelone, cortisone, Zole, miconazole, miconazole hydrochloride, minocycline, cortodoxone, craposone butyrate, desonide, desocymetha minocycline hydrochloride, mupirocin, nafcillin, neomycin Sone, dexamethasone, desoxycorticosterone acetate, dichlor neomycin Sulfate, netilmicin, netilmicin Sulfate, nitrofura isone, diflorasone diacetate, difluorcortolone Valerate, Zone, norfloxacin nystatin, octopirox, oleandomycin, diflurosone diacetate, difharprednate, fluadrenolone, fluc orcephalosporins, oxacillin, oxiconazole, oxytetracycline, etonide, flucinolone acetonide, flucloronide, fluclorolone oxytetracycline hydrochloride, parachlorometa Xylenol, acetonide, flucortine butylesters, fludroxycortide, fludrocor paromomycin, paromomycin Sulfate, penicillins, penicillin tisone, flumethasone, flumethasone pivalate, flumethasone G. penicillin V, pentamidine, pentamidine hydrochloride, pivalate, flumisolide, fluocinolone, fluocinolone acetonide, phenethicillin, polymyxins, quinolones, streptomycin Sul fluocinonide, fluocortin butyl, fluocortolone, fluo fate, terbinafine, terconazole, tetracycline, tioconazole, rometholone, fluosinolone acetonide, fluperolone flupred tobramycin, tolnaftate, triclosan, trifampin, rifamycin, roli nidene acetate, fluprednisolone hydrocortamate, fluradre tetracycline, spectinomycin, spiramycin, streptomycin, Sul nolone, fluradrenolone acetonide, flurandrenolone, conazole, Sulfonamide, tetracyclines, tetracycline, tobramy fluticasone, halcinonide, halobetasol, hydrocortisone, hydro cin, tobramycin Sulfate, triclocarbon, triclosan, timethoprim cortisone acetate, hydrocortisone butyrate, hydrocortisone Sulfamethoxazole, tylosin, undecylenic acid, Vancomycin cyclopentylpropionate, hydrocortisone Valerate, hydroxyltri yrothricin and derivatives, esters, salts and mixtures thereof. amcinolone, medrysone, meprednisone, C.-methyl dexam 0164. In embodiments a composition of of the present ethasone, methylprednisolone, methylprednisolone acetate, invention includes an antidepressant. Suitable antidepres mometasone furoate, paramethasone, prednisolone, pred sants include, but are not limited to, C.-adrenoreceptorantago nisone, pregnenolone, progesterone, spironolactone, triamci nists, corticotropin-releasing factor antagonists, monoamine nolone, traiamcinolone acetonide and derivatives, esters, salts oxidase inhibitors, 5-HT-receptor agonist antagonists, and mixtures thereof. NK1-receptor antagonists, norepinephrinere-reuptake 0.168. In embodiments, a composition of of the present inhibitors, selective-serotonin-reuptake inhibitors, serotonin invention includes a hormone. Suitable hormones include, and-noradrenaline-reuptake inhibitors, tetracyclic antide but are not limited to, methyltestosterone, androsterone, pressant, tricyclic antidepressant, amitriptyline, adinazolam, androsterone acetate, androsterone propionate, androsterone amiltriptylinoxide, amoxapine, amineptine, butriptyline, benzoate, androsteronediol, androsteronediol-3-acetate, binedaline, biproprion hydrochloride, m-chloropiperzine, androsteronediol-17-acetate, androsteronediol 3-17-diac citalopram, clomipramine, demexiptiline, desipramine, des etate, androsteronediol-17-benzoate, androsteronedione, US 2014/0171490 A1 Jun. 19, 2014

androstenedione, androstenediol, dehydroepiandrosterone, acetazolamide, brinzolamide, dorzolamide, methazolamide, Sodium dehydroepiandrosterone Sulfate, dromostanolone, neptzane and unoprostone isopropyl. dromostanolone propionate, ethylestrenol, fluoxymesterone, 0.174. In embodiments, a composition of of the present nandrolone phenopropionate, nandrolone decanoate, nan invention includes a catalytic antioxidants. Suitable catalytic drolone furylpropionate, nandrolone cyclohexane-propi antioxidants include, but are not limited to, OT-551 and onate, nandrolone benzoate, nandrolone cyclohexanecar OT-730. boxylate, androsteronediol-3-acetate-1-7-benzoate, 0.175. In embodiments, a composition of of the present Oxandrolone, oxymetholone, stanozolol, testosterone, test invention includes a cholinesterase inhibitor. Suitable cho osterone decanoate, 4-dihydrotestosterone, 5a-dihydrotest linesterase inhibitors include, but are not limited to, echothio osterone, testolactone, 17a-methyl-19-nortestosterone, pate iodide. desogestrel, dydrogesterone, ethynodiol diacetate, medroX 0176). In embodiments, a composition of of the present yprogesterone, levonorgestrel, medroxyprogesterone invention includes a direct acting miotic. Suitable direct act acetate, hydroxyprogesterone caproate, norethindrone, nore ing miotics include, but are not limited to, carbachol and thindrone acetate, norethynodrel, allylestrenol, 19-nortest pilocarpine. osterone, lynoestrenol, quingestanol acetate, medrogestone, 0177. In embodiments, a composition of of the present norgestrienone, dimethisterone, ethisterone, cyproterone invention includes a light-activated drugs. Suitable light-ac acetate, chlormadinone acetate, megestrol acetate, norgesti tivated drugs include, but are not limited to, tin ethyletiopur mate, norgestrel, desogrestrel, trimegestone, gestodene, purin and verteporfin. nomegestrol acetate, progesterone, 5a-pregnan-3b.20a-diol 0178. In embodiments, a composition of of the present sulfate 5a-pregnan-3b.20b-diol sulfate, 5a-pregnan-3b-ol invention includes an ophthalmic decongestant agent. Suit 20-one, 16.5a-prenen-3b-ol-20-one, 4-pregnen-20b-ol-3- able ophthalmic decongestant agent include, but are not lim one-20-Sulfate, acetoxypregnenolone, anagestone acetate, ited to, iodoxamide tromethamine and tromethamine. cyproterone, dihydrogesterone, flurogestone acetate, gesta 0179. In embodiments, a composition of of the present dene, hydroxyprogesterone acetate, hydroxymethylprogest invention includes a prostaglandin analog. Suitable prostag erone, hydroxymethyl progesterone acetate, 3-ke landin analog include, but are not limited to, bimatoprost, todesogestrel, megestrol, melengestrol acetate, latanoprost, travoprost and unoprostone. norethisterone and derivatives, esters, salts and mixtures 0180. In embodiments, a composition of of the present thereof. invention includes a vasodilator. Suitable vasodilators 0169. In embodiments, a composition of of the present include, but are not limited to, isosorbide dinitrate and hes invention includes a non-steroidal anti-inflammatory drug. peridin. Suitable non-steroidal anti-inflammatory drugs include, but 0181. In embodiments, a composition of of the present are not limited to, acemaiacin, acetic acid derivatives, almi invention includes a vasoconstrictor. Suitable vasoconstric noprofen, amfenac, aspirin, azapropaZone, azelaic acid, tors include, but are not limited to, naphazoline and phenyle benorylate, benoxaprofen, carprofen, clindanac, CP-14.304, phrine. diclofenac, diflunisal, disalcid, felbinac, fenamates, fenbuf 0182 Specific APIs that preferably constitute part of a en, fenclofenac, fendosal, fenoprofen, fentiazac, feprazone, composition of the present invention include, but are not flufenamic, flurbiprofen, furofenac, ibuprofen, indometha limited to, Brimonidine tartrate, Dipivefrin HCl, Apracloni cin, indopropfen, isoxepac, isoxicam, ketoprofen, ketorolac, dine HCl, Dapiprazole, Dorzolamide, Timolol, Dorzolamide meclofenamic, mefenamic, miroprofen, naproxen, with Timolol, Unoprostone Isopropyl, Levobunolol, Betax nepafenac, niflumic, oxaprozin, oxepinac, oxicams, olol, Pilocarpine, Echothiphate Iodide, Latanoprost, Bimato oxyphenbutaZone, phenylbutaZone, piroXicam, pranoprofen, prost, Flurbiprofen Sodium, Prednisolone Acetate, Dexam propionic acid derivatives, pirprofen, pyrazoles, Safapryn, ethasone, Triamcinolone acetonide and Nepafenac. salicylates, Solprin, Sudoxicam, Sulindac, Suprofen, tenoxi cam, tiopinac, tiaprofen, tioxaprofen, tolfenamic acids, tol Brimonidine Tartrate metin, trilisate, trimethaZone, Zidometacin, Zomerpirac and 0183 Brimonidine tartrate (5-bromo-6-(2-imidazolidi derivatives, esters, salts and mixtures thereof. nylideneamino) quinoxaline L-tartrate) is an alpha-2 adren 0170 In embodiments, a composition of of the present ergic agonist known as an API for treating ocular hyperten invention includes an alpha-2 adrenergic agonist. Suitable sion in glaucoma Sufferers commercially available as an alpha-2 adrenergic agonists include, but are not limited to, instillable solution including 0.2% (2 mg/ml) or 0.15% (1.5 apraclonidine, brimonidine tartrate, dapiprazole and dipiv mg/ml) brimonidine tartrate as Aphagan R or Alphagan R. P. efrin. respectively, both of Allergan Inc (Irvine, Calif., USA). 0171 In embodiments, a composition of of the present 0184. In an embodiment of the present invention, a com invention includes a antivascular agent. Suitable antivascular position is provided comprising an ophthalmic carrier, a agents include, but are not limited to, anecortave acetate, highly irritant penetration enhancer (e.g., Saponin fusidate, pegaptainib and squalamine. aZone, bile acid salts such as glycholate and cholate) and brimonidine tartrate and is administered in accordance with 0172. In embodiments, a composition of of the present the teachings of the present invention. the coadministration of invention includes beta-adrenergic blocking agent. Suitable brimonidine tartrate and a highly irritant penetration beta-adrenergic blocking agents include, but are not limited enhancer generally allows for increased bioavailability and to, betaxolol, carteolol, levobunolol, metipranolol and more effective treatment of conditions for which treatment timolol maleate. with brimonidine tartrate is useful including glaucoma and 0173. In embodiments, a composition of of the present ocular hypertension. invention includes a carbonic anhydrase inhibitors. Suitable 0185. The coadministration of brimonidine tartrate and a carbonic anhydrase inhibitors include, but are not limited to, highly irritant penetration enhancer in accordance with the US 2014/0171490 A1 Jun. 19, 2014

teachings of the present invention generally increases the Sure within the eye is important in the treatment of conditions bioavailability of the brimonidine tartrate, allowing for Such as glaucoma and prior to or after laser Surgery on the eye. administration of a reduced dose of aPI. For example, a prior Apraclonidine HCl is commercially available in an instillable art course of treatment of ocular hypertension is one drop solution including 0.5% (5 mg/ml) Apraclonidine under the (approximately 39 microliter) of Alphagan R P per eye every tradename Iopidine(R) of Alcon USA (Fort Worth, Tex., USA). eight hours. In contrast, in embodiments of the present inven 0190. In an embodiment of the present invention, a com tion treatment of ocular hypertension includes administering position is provided comprising an ophthalmic carrier, a between about 1 microliter and about 39 microliters, prefer highly irritant penetration enhancer (e.g., Saponin, fusidate, ably between 1 microliters and about 20 microliters of a aZone, bile acid salts such as glycholate and cholate) and composition including 0.15% brimonidine tartrate and a Apraclonidine HCl and is administered in accordance with highly irritant penetration enhancer to each eye every eight the teachings of the present invention. The coadministration hours. The composition is administered is a mist using a of Apraclonidine HCl and a highly irritant penetration nebulizing device Such as a device of the present invention. enhancer in accordance with the teachings of of the present invention generally increases the bioavailability of the Apra Dipivefrin HCl clonidine HCl, allowing for administration of a reduced dose of API and more effective treatment of conditions for which 0186 Dipivefrin HCl ((+) 3, 4-dihydroxy-alpha-(methy treatment with Apraclonidine is useful, including short-term lamino)methylbenzyl alcohol 3,4-dipivalate hydrochloride) adjunctive therapy who require reduce intraocular pressure, is a prodrug formed by the diesterification of epinephrine and glaucoma and ocular hypertension. pivalic acid. The addition of the pivaloyl groups to the epi 0191 For example, a prior art course of treatment of high nephrine molecule enhances the molecules lipophilic charac intraocular pessure is one drop (approximately 39 microliter) ter increasing penetration into the anterior chamber of the ye of IopidineR per eye three times daily. In contrast, in embodi when topically applied. Dipivefin HCl is converted to epi ments of the present invention treatment of high intraocular nephrine inside the human eye by enzyme hydrolysis. The pressure includes administering between about 1 microliter liberated epinephrine, and adrenergic agonist, appears to and about 39 microliters, preferably between 1 microliters exert its action by decreasing water production and by and about 20 microliters of a composition including 0.5% enhancing aqueous outflow. Dipivefrin HCl is commercially Apraclonidine HCl and a highly irritant penetration enhancer available as an instillable solution including 0.1% (1 mg/ml) to each eye three times daily. The composition is administered dipivefrin HCl under the tradename PropineR of Alergan Inc is a mist using a nebulizing device Such as a device of the (Irvine, Calif., USA). present invention. 0187. In an embodiment of the present invention, a com position is provided comprising an ophthalmic carrier, a Dapiprazole highly irritant penetration enhancer (e.g., Saponin, fusidate, aZone, bile acid salts such as glycholate and cholate) and 0.192 Dapiprazole (5,6,7,8-tetrahydro-3-2-(4-o-toly-1- dipivefrin HCl and is administered in accordance with the piperazinyl)ethyl-s-triazolo 4.3-alpha pyridine) is an teachings of the present invention. The coadministration of alpha-adrenergic blocking agent having antimydriatic activ dipivefrin HCl and a high irritant penetration enhancer in ity that is used to reduce the pupil size. Dapiprazole hydro accordance with the teachings of the present invention gen chloride acts through blocking the alpha-adrenergic receptors erally increases the bioavailability of the diplivefrin HCl, in Smooth muscle, producing miosis through an effect on the allowing for administration of a reduced dose of API and dilator muscle of the iris. Dapiprazole does not have any more effective treatment of conditions for which treatment significant activity on ciliary muscle contraction and, there with diplivefrin HCl is useful, including glaucoma (especially fore does not induce a significant change in the anterior cham chronic open-angle glaucoma) and ocular hypertension. ber depth or the thickness of the lens. Dapiprazole is com 0188 For example, a prior art course of treatment of ocular mercially available in an instillable solution including 0.5% hypertension is one drop (approximately 39 microliter) of (5 mg/ml) Dapiprazole under the tradename Rev-Eyes(R) of PropineR per eye every twelve hours. In contrast, in embodi Bausch and Lomb (Rochester, N.Y., USA). ments of the present invention treatment of ocular hyperten 0193 In an embodiment of the rpesent invention, a com sion includes administering between about 1 microliter and position is provided comprising an ophthalmic carrier, a about 39 microliters, preferably between 1 microliters and highly irritant penetration enhancer (e.g., Saponin, fusidate, about 20 microliters of a composition including 0.1% dipiv aZone, bile acid salts such as glycholate and cholate) and efrin HCl and a highly irritant penetration enhancer to each Dapiprazole and is administered in accordance with the eye every twelve hours. the composition is administered is a teachings of the present invention. The coadministration of mist using a nebulizing device such as a device of the present Dapiprazole and a highly irritant penetration enhancer in invention. accordance with the teachings of the present invention gen erally increases the bioavailability of the Dapiprazole, allow Apraclonidine HCl ing for administration of a reduced dose of API and more effective treatment of conditions for which treatment with 0189 Apraclonidine HCl (2-(4-amino-2.7 dichlorophe Dapiprazole is useful, including reversal of diagnostic nyl)iminoimidazolidine monohydrochloride) is a relatively mydriasis. selective alpha-2-agonist vasoconstrictor. Apraclonidine acts 0194 For example, a prior art course of treatment to on adrenoceptors in the walls of blood vessels in the eye. This reverse diagnostic mydriasis includes application of two causes the blood vessels to narrow, restricting the flow of drops (approximately 39 microliter each) of Rev-Eyes(R fol blood threrethrough. Reduced blood flow leads to a decrease lowed after 5 minutes by an addional two drops to eacheye. In in the production of the aqueous humour decreasing the pres contrast, in embodiments of the present invention reversal of sure created within the eye by the fluid. Decreasing the pres diagnostic mydriasis includes administering between about 2 US 2014/0171490 A1 Jun. 19, 2014

microliter and about 80 microliters, preferably between 2 0200 For example, a prior art course of treatment to microliters and about 40 microliters of a composition includ reduce ocular hypertension includes application of one drop ing 0.5% Dapiprazole and a highly irritant penetration (approximately 39 microliters) of Timoptic(R) twice times enhancer to each eye a first time and after five minutes a daily to each eye. In contrast, in embodiments of the present second time. The composition is administered is a mist using invention to reduce oculawr hypertension includes adminis a nebulizing device Such as a device of the present invention. tering between about 1 microliter and about 40 microliters, preferably between 1 microliters and about 20 microliters of Dorzolamide a composition including 0.5% Timolol and a highly irritant penetration enhancer to each eye twice daily. The composi 0.195 Dorzolamide (4S-trans)-4-(ethylamino)-5,6-dihy tion is administered is a mist using a nebulizing device Such as dro-6-methyl-4H-thieno2,3-bithiopyran-2-sulfonamide a device of the present invention. 7,7-dioxide monohydrochloride) is a carbonic anhydrase Dorzolamide with Timolol inhibitor. Dorzolamide is commercially available in an instill 0201 Coadministration of Dorzolamide (4S-trans)-4- able solution including 2% Dorzolamide under the tradename (ethylamino)-5,6-dihydro-6-methyl-4H-thieno2,3-bithi Trusopter) of Merck and Co., Inc. (Whitehouse Station, N.J., opyran-2-sulfonamide 7,7-dioxide monohydrochloride), a USA). carbonic anhydrase inhibitor and timolol ((-)-1-(tert-buty 0196. In an embodiment of the present invention, a com lamino)-3-(4-morpholino-1,2,5-thiadiazol-3-yl)oxy-2-pro position is provided comprising an ophthalmic carrier, a panol maleate) a beta-blocker is known to be exceptionally highly irritant penetration enhancer (e.g., Saponin, fusidate, effective in treating open-angle glaucoma and ocular hyper qaZone, bile acid salts such as glycholate and cholate) and tension Dorzolamide HCl with Timolol Maleate is commer Dorzolamide and is administered in accordance with the cially available in an instillable solution including 2% Dor teachings of the present invention. The coadministration of Zolamide and 0.5% Timolol under the tradename Cosopter) of Dorzolamide and a highly irritant penetration enhancer in Merck and Co., Inc. (Whitehouse Station, N.J., USA). accordance with the teachings of the present invention gen 0202 In an embodiment of the present invention, a com erally increases the bioavailability of the Dorzolamide, allow position is provided comprising an ophthalmic carrier, a ing for administration of a reduced dose of API and more highly irritant penetration enhancer (e.g., Saponin, fusidate, effective treatment of conditions for which treatment with aZone, bile acid salts Seuch as glycholate and cholate), Dor Dorzolamide is useful, including glaucoma and ocular hyper Zolamide and Timolol and is administered in accordance with tension. the teachings of the present invention. The coadministration 0.197 For example, a prior art course of treatment to of Dorzolamide, Timolol and a highly irritant penetration reduce ocular hypertension includes application of one drops enhancer in accordance with the teachings of the present (approximately 39 microliters) of Trusopt(R) three times daily invention generally increases the bioavailability of the APIs, to each eye. In contrast, in embodiments of the present inven allowing for administration of a reduced dose and more effec tion to reduce ocular hypertension includes administering tive tr3eatment of conditions for which treatment with Dor between about 1 microliter and about 40 microliters, prefer Zolamide and Timolol is useful, including glaucoma and ocu ably between 1 microliters and about 20 microliters of a lar hypertension. composition including 2% Dorzolamide and a highly irritant 0203 For example, a prior art course of treatment to penetration enhancer to each eye three times daily. The com reduce ocular hypertension includes application of one drops position is administered is a mist using a nebulizing device (approximately 39 microliters) of Cosopt(R) twice times daily to each eye. In contrast, in embodiments of the present inven Such as a device of the present invention. tion to reduce ocular hypertension includes administering between about 1 microliter and about 40 microliters, prefer Timolol ably between 1 microliters and about 20 microliters of a 0198 Timolol ((-)-1-(tert-butylamino)-3-(4-mor composition including 2% Dorzolamide, 0.5% Timolol and a pholino-1,2,5-thiadiazol-3-yl)oxyl-2-propanol maleate) is a highly irritant penetration enhancer to each eye twice daily. non-selective beta-adrenergic receptor blocking agent known The composition is administered is a mist using a nebulizing to be exceptionally effective in reducing elevated as well as device Such as a device of the present invention. normal intraocular pressure, whether or not accompanied by glaucoma. Timolol Maleate is commercially available in an Unoprostone Isopropyl instillable solution including either 0.25% and 0.5% Timolol 0204 Unoprostone Isopropyl (isopropyl (+)-(Z)-7-(1R, under the tradename Timoptic(R) of Merck and Co., Inc. 2R, 3R,5S)-3,5-dihydroxy-2-(3-oxodecyl) cyclopentyl-5- (Whitehouse Station, N.J., USA). heptenoate) is the isopropyl ester of unoprostone, a 0199. In an embodiment of the present invention, a com PGF2alpha analog with a 13.14-dihydro-15-keto modifica position is provided comprising an ophthalmic carrier, a tion and a two-carbon extension of the aliphatic lower side highly irritant penetration enhancer (e.g., Saponin, fusidate, chain approved for teatment of open-angle extension of the aZone, bile acid salts such as glycholate and cholate) and aliphatic lower side chain approved for treatment of open Timolol and is administered in accordance with the teachings angle glaucoma or ocular hypertension. Unoprostone Isopro of the present invention. The coadministration of Timolol and pyl is commercially available in an instillable solution includ a highly irritant penetration enhancer in accordance with the ing 0.15% Unoprostone Isopropyl under the tradename teachings of the present invention generally increases the Rescula R) of CIBA Vision, A Novartis Company (Duluth, bioavailability of the API, allowing for administration of a Ga., USA). reduced dose and more effective treatment of conditions for 0205. In an embodiment of the present invention, a com which treatment with Timolol is useful, including ocular position is provided comprising an ophthalmic carrier, a hypertension. highly irritant penetration enhancer (e.g., Saponin, fusidate, US 2014/0171490 A1 Jun. 19, 2014

aZone, bile acid salts such as glycholate and cholate) and Betaxolol Unoprostone Isopropyl and is administered in accordance with the teachings of the present invention. The coadminis 0210 Betaxolol ((+)-1-p-2-(cyclopropylmethoxy)ethyl tration of Unoprostone Isopropyl and a highly irritant pen phenoxy-3-(isopropylamino)-2-propanol hydrochloride) is etration enhancer in accordance with the teachings of the a cardioselective (beta-1-adrenergic) receptor blocking present invention generally increases the bioavailability of agent, does not have significan membrane-stabilizing (local the Unoprostone Isopropyl, allowing for administration of a anesthetic) activity and is devoid of intrinsic sympathomi reduced dose of API and more effective treatment of condi metic action. Betaxolol tions for which treatment with Unoprostone Isopropyl is use 0211 Is approved for reducing elevated intraocular pres ful, including glaucoma and ocular hypertension. Sure, whether or not accompanied by glaucoma. Levobunolol is commercially available in an instillable Suspension includ 0206 For example, a prior art course of treatment to ing 0.25% Betaxolol under the tradename Betoptic S(R) of reduce ocular hypertension includes application of one drops alcon USA (Fort Worth, Tex., USA). (approximately 39 microliters) of Rescula R) twice daily to 0212. In an embodiment of the present invention, a com each eye. In contrast, in embodiments of the present invention position is provided comprising an ophthalmic carrier, a to reduce ocular hypertension includes administering highly irritant penetration enhancer (e.g., Saponin, flusidate, between about 1 microliter and about 40 microliters, prefer aZone, bile acid salts such as glycholate and cholate) and ably between 1 microliters and about 20 microliters of a Betaxolol and is administered in accordance with the teach composition including 0.15% Unoprostone Isopropyl and a ings of the present invention. the coadministration of Betax highly irritant penetration enhancer to each eye twice daily. olol and a highly irritant penetration enhancer in accordance the composition is administered is a mist using a nebulizing with the teachings of the present invention generally device Such as a device of the present invention. increases the bioavailability of the Betaxolol, allowing for administration of a reduced dose of API and more effective Levobunolol treatment of conditions for which treatment with Betaxolol is useful, including glaucoma and ocular hypertension. 0207 Levobunolol ((-)-5-[3-(tert-Butylamino)-2-hy 0213 For example, a prior art course of treatment to droxypropoxy-3, 4-dihydro-1 (2H)-naphthalenone hydro reduce ocular hypertension includes application of one drops chloride) is a noncardioselective beta-adrenoceptor blocking (approximately 39 microliters) of Betaxolol.R twice daily to agent, equipotent at both beta1 and beta2 receptors. each eye. In contrast, in embodiments of the presnet invention Levobunolol is greater than 60 times more potent than its to reduce ocular hypertension includes administering dextro isomer in its beta-blocking activity, yet equipotent in between about 1 microliter and about 40 microliters, prefer its potential for direct myocaridal depression. Levobunolol ably between 1 microliters and about 20 microliters of a HCl does not have significant local anesthetic (membrane composition including 0.25% Betaxolol and a highly irritant stabilizing) or intrinsic sympathomimetic activity. penetration enhancer to each eye twice daily. the composition Levobunolol HCl is approved for treatment of lowering is administered is a mist using a nebulizing device Such as a intraocular pressure and may be used in patients with chronic device of the present invention. open-angle glaucoma or ocular hypertension. Levobunolol is commercially available in an instillable solution including Pilocarpine 0.25% and 0.5% Levobunolol under the tradename Betagan LiquiflimR) of Allergan Inc (Irvine, Calif., USA). 0214) Pilocarpine (3S, 4R)-3-Ethyldihydro-4-(1-methyl 1H-imidazole-5-yl)methyl-2(3-H)-furanone) is a directact 0208. In an embodiment of the present invention, a com ing cholinergic (parasympathomimetic) agent causing pupil position is provided comprising an ophthalmic carrier, a lary constriction. By mimicking acetylcholine, pilocarpine highly irritant penetration enhancer (e.g., Saponin, fusidate, acts as a stimulant of the parasympathetic nervous system aZone, bile acid salts such as glycholate and cholate) and promoting the increases the outflow of fluid from the eye with Levobunolol and is administered in accordance with the a concomitant reduction of intraocular pressure. Pilocarpine teachings of the present invention. the coadministration of is approved for the treatment of primary open-angle glau Levobunolol and a highly irritant penetration enhancer in coma and also to lower intraocular pressure prior to Surgery accordance with the teachings of the present invention gen for acute angle-closure glaucoma. Pilocarpine is commer erally increases the bioavailability of the Levobunolol, allow cially available in an instillable suspension including 1%. 2% ing for administration of a reduced dose of API and more or 4% mg/mL. Pilocarpine under the tradename Pilagan Liq effective treatment of conditions for which treatment with uifilmR) of Allergan Inc (Irvine, Calif., USA). Levobunolol is useful, including glaucoma and ocular hyper 0215. In an embodiment of the present invention, a com tension. position is provided comprising an ophthalmic carrier, a 0209 For example, a prior art course of treatment to highly irritant penetration enhancer (e.g., Saponin, fusidate, reduce ocular hypertension includes application of one drops aZone, bile acid salts such as glycholate and cholate) and (approximately 39 microliters) of Betagan Liquifilm R twice Pilocarpine and is administered in accordance with the teach daily to each eye. In contrast, in embodiments of the present ings of the present invention. The coadministration of Pilo invention to reduce ocular hypertension includes administer carpine and a highly irritant penetration enhancer in accor ing between about 1 microliter and about 40 microliters, dance with the teachings of the present invention generally preferably between 1 microliters and about 20 microliters of increases the bioavailability of the Pilocarpine, allowing for a composition including 0.25% Levobunolol and a highly administration of a reduced dose of API and more efective irritant penetration enhancer to each eye twice daily. The treatment of conditions for which treatment with Pilocarpine composition is administered is a mist using a nebulizing is useful, including glaucoma, ocular hypertension and device Such as a device of the present invention. mydriasis. US 2014/0171490 A1 Jun. 19, 2014

0216 For example, a prior art course of treatment to mals and man Suggest that the main mechanism of action is reduce ocular hypertension includes application of two drops increased uveoscleral outflow. Latanoprost is approved for (approximately 39 microliters each) of Pilagan LiquifilmR) the treatment of elevated intraocular pressure in patients with 1% up to four times daily to each eye. In contrast, in embodi open-angle glaucoma or ocular hypertension. Latanoprost is ments of the present invention to reduce ocular hypertension commercially available in 0.005% instillable solutions under includes administering between about 1 microliter and about the tradename Xalatan(R) of Pfizer (New York, N.Y., USA). 80 microliters, preferably between 1 microliters and about 40 0221. In an embodiment of the present invention, a com microliters of a composition including 1% Pilocarpine and a position is provided comprising an ophthalmic carrier, a highly irritant penetration enhancer to each eye twice daily. highly irritant penetration enhancer (e.g., Saponin) fusidate, the composition is administered is a mist using a nebulizing aZone, bile acid salts such as glycholate and cholate) and device Such as a device of the present invention. Latanoprostandis administered in accordance with the teach ings of the present invention. The coadministration of Latano Echothiphate Iodide prost and a highly irritant penetration enhancer in accordance with the teachings of the present invention generally 0217 Echothiphate Iodide ((2-mercaptoethyl) trimethy increases the bioavailability of the Latanoprost, allowing for lammonium iodide O.O-diethyl phosphorothioate) is a long administration of a reduced dose of API and more effective acting cholinesterase inhibitor which enhances the effect of treatment of conditions for which treatment with Latanoprost endogenously liberated acetylcholine in iris, ciliary muscle, is useful, including glaucoma and ocular hypertension. and other parasympathetically innervated structures of the 0222 For example, a prior art course of treatment to eye when applied topically, thereby causing miosis, increase reduce ocular hypertension includes application of one drop in facility of outflow of aqueous humor, fall in intraocular (approximately 39 microliters) of Xalatan(R) once a day to pressure, and potentiation of accommodation. Echothiophate each eye. In contrast, in embodiments of the present invention iodide will depress both plasma and erythrocyte cholinest to reduce ocular hypertension includes administering erase levels in most patients after a few weeks of therapy. between about 1 microliter and about 40 microliters, prefer Echothiophate iodide is approved for the treatment of chronic ably between 1 microliters and 20 microliters of a composi open-angle glaucoma, Subacute or chronic angle-closure tion including Latanoprost and a highly irritant penetration glaucoma after iridectomy or where Surgery is refused or contraindicated and certain non-uveitic secondary types of enhancer to each eye once a day. The composition is admin glaucoma, especially glaucoma following cataracet Surgery. istered is a mist using a nebulizing device Such as a device of Kits for preparation of Echothiphate Iodide instillable solu the present invention. tions are commercially available under the tradename Phos Bimatoprost pholine IodideR of Wyeth Pharmaceuticals (Collegeville, Pa., USA) 0223 Bimatoprost ((Z)-7-(1 R, 2 R, 3 R, 5 S)-3, 5-dihy 0218. In an embodiment of the present invention, a com droxy-2-1 E. 3 S)-3-hydroxy-5-phenyl-1-pentenylcyclo position is provided comprising an ophthalmic carrier, a pentyl-5-N-ethylheptenamide) is a prostamide, a synthetic highly irritant penetration enhancer (e.g., Saponin, fusidate, structural analog of prostaglandin with ocular hypotensive aZone, bile acid salts such as glycholate and cholate) and activity. It selectively mimics the effects of naturally occur Echothiophate iodide and is administered in accordance with ring Substances, prostamide. Bimatoprost is believed to lower the teachings of the present invention. The coadministration intraocular pressure inhumans by increasing outflow of aque of Echothiophate iodide and a highly irritant penetration ous humor through both the trabecular meshwork and uveo enhancer in accordance with the teachings of the present scleral routes. Bimatoprost is approved for the treatment of invention generally increases the bioavailability of the elevated intraocular pressure in patients with open angle glau Echothiophate iodide, allowing for administration of a coma or ocular hypertension. Bimatoprost is commercially reduced dose of API and more effective treatment of condi available in 0.03% instillable solutions under the tradename tions for which treatment with Echothiophate iodide is useful, Lumigan R of of Allergan Inc (Irvine, Calif., USA). including glaucoma and ocular hypertension. 0224. In an embodiment of the present invention, a com 0219 For example, a prior art course of treament to reduce position is provided comprising an ophthalmic carrier, a ocular hypertension includes application of one drop (ap highly irritant penetration enhancer (e.g., Saponin, fusidate, proximately 39 microliters) of Phospholine IodideR 0.125% aZone, bile acid salts such as glycholate and cholate) and twice daily to each eye. In contrast, in embodiments of the Bimatoprost and is administered in accordance with the present invention to reduce ocular hypertension includes teachings of the present invention. The coadministration of administering between about 1 microliter and about 40 Bimatoprost and a highly irritant penetration enhancer in microliters, preferably between 1 microliters and about 20 accordance with the teachings of the present invention gen microliters of a composition including 0.125% Phospholine erally increases the bioavailability of the Bimatoprost, allow Iodide and a highly irritant penetration enhancer to each eye ing for administration of a reduced dose of API and more effective treatment of conditions for which treatment with twice daily. The composition is administered is a mist using a Bimatoprost is useful, including glaucoma and ocular hyper nebulizing device Such as a device of the present invention. tension. Latanoprost 0225. For example, a prior art course of treatment to reduce ocular hypertension includes application of one drop 0220 Latanoprost (isopropyl-(Z)-7(1R, 2R, 3R, 5S)3, (approximately 39 microliters) of Lumigan R once a day to 5-dihydroxy-2-(3R)-3-hydroxy-5-phenylpentyl)cyclopen each eye. In contrast, in embodiments of the present invention tyl-5-heptenoate) is a prostanoid selective FP receptor ago to reduce ocular hypertension includes administering nist that is believed to reduce the intraocular presssure (IOP) between about 1 microliter and about 40 microliters, prefer by increasing the outflow of aqueous humor. Studies in ani ably between 1 microliters and about 20 microliters of a US 2014/0171490 A1 Jun. 19, 2014 composition including Bimatoprost and a highly irritant pen of phospholipase A2 inhibitory proteins, collectively called etration enhancer to each eye once a day. The composition is lipocortins. It is postulated that these proteins control the administered is a mist using a nebulizing device Such as a biosynthesis of potent mediators of inflammation Such as device of the present invention. prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is Flurbiprofen Sodium released from membrane phospholipids by phospholipase A2. Prednisolone Acetate is approved for steroid responsive 0226 Flurbiprofen Sodium (Sodium (+)-2-(2-fluoro-4-bi inflammatory conditions of the palpebral and bulbar conjunc phenyl)-propionate dihydrate) is a phenylalkanoic acids hav tiva, cornea, and anterior segment of the globe Such as allergic ing analgensic, antipyretic, and anti-inflammatory activity in conjunctivitis, acne rosacea, Superficial punctate keratitis, animal inflammatory diseases. Its mechanism of action is herpes Zoster keratitis, iritis, cyclitis, selected infective con believed to be through inhibition of the cyclo-oxygenase junctivitides, when the inherent hazard of steroid use is enzyme that is essential in the biosynthesis of prostaglandins. accepted to obtain an advisable diminution in edema and Prostaglandins have been shown in many animal models to be inflammation; corneal injury from chemical radiation, or mediators of certain kinds of intraocular inflammation. In thermal burns, or penetration of foreign bodies. Prednisolone studies performed on animal eyes, prostaglandins have been Acetate is commercially available in a 1% instillable suspen shown to produce disruption of the blood-aqueous humor sion under the tradename Pred ForteR of Allergan Inc (Irvine, barrier, vasodilation, increased vascular permeability, leuko Calif., USA). cytosis, and increased intraocular pressure. Prostaglandins 0230. In an embodiment of the present invention, a com also appear to play a role in the miotic response produced position is provided comprising an ophthalmic carrier, a high during ocular Surgery by constricting the iris sphincter inde irritant penetration enhancer (e.g., Saponin, fusidate, aZone, pendently of cholinergic mechanisms. Flurbiprofen Sodium bile acid salts such as glycholate and cholate) and Predniso is approved for the inhibition of intraoperative miosis Flurbi lone Acetate and is administered in accordance with the profen Sodium is commercially available in 0.03% instillable teachings of the present invention. The coadministration of solutions under the tradename Ocufen R) of Allergan Inc (Irv Prednisolone Acetate and a highly irritant penetration ine, Calif., USA). enhancer in accordance with the teachings of the present 0227. In an embodiment of the present invention, a com invention generally increases the bioavailability of the Pred position is provided comprising an ophthalmic carrier, a nisolone Acetate, allowing for administration of a reduced highly irritant penetration enhancer (e.g., Saponin, fusidate, dose of API and more effective treatment of conditions for aZone, bile acid salts such a glycholate and cholate) and which treatment with Prednisolone Acetate is useful, includ Flurbiprofen Sodium and is administered in accordance with ing inhibition of inflammation. the teachings of the present invention. The coadministration 0231. For example, a prior art course of treatment of ocular of Flurbiprofen Sodium and a highly irritant penetration inflammation includes application of one or two drop (ap enhancer in accordance with the teachings of the present proximately 39 microliters each) of Pred ForteR) once every invention generally increases the bioavailability of the Flur hour during the day and once every two hours in during the biprofen Sodium, allowing for administration of a reduced night to an appropriate eye. In contrast, in embodiments of the dose of API and more effective treatment of conditions for present invention to treat ocular inflammation includes which treatment with Flurbiprofen Sodium is useful, includ administering between about 1 microliter and about 40 ing inhibition of intraoperative miosis. microliters, preferably between 1 microliters and about 20 0228. For example, a prior art course of treatment to microliter and about 40 microliters, preferably between 1 inhibit intraoperative miosis includes application of one drop microliters and about 20 microliters of a composition includ (approximately 39 microliters) of Ocufen R once every half ing Prednisolone Acetate and a highly irritant penetration hour four times starting two hours before Surgery to an appro enhancer once every hour during the day and once every two priate eye. In contrast, in embodiments of the present inven hours during the night to an appropriate eye. The composition tion to inhibit intraoperative miosis includes administering is administered is a mist using a nebulizing device Such as a between about 1 microliter and about 40 microliters, prefer device of the present invention. ably between 1 microliters and about 20 microliters of a composition including Flurbiprofen Sodium and a highly Dexamethasone irritant penetration enhancer once every half hour four times starting two hours before Surgery to an appropriate eye. The 0232 Dexamethasone (9-fluoro-11b, 17, 21-trihydroxy composition is administered is a mist using a nebulizing 16a-methylpregna-1, 4-diene-3,20-dione). Dexamethasone device Such as a device of the present invention. is a synthetic glucocorticod analog. Glucocorticoids, natu rally occurring and synthetic, are adrenocortical steroids that Prednisolone Acetate cause varied metabolic effects and modify the body’s immune responses to diverse stimuli. Naturally occurring 0229. Prednisolone Acetate (1,4-pregnadiene-11-beta, glucocorticoids (hydrocortisone and cortisone), which also 17-alpha-21-triol-320-dione 21-acetate). Corticosteroids have sodium-retaining properties, are used as replacement inhibit the inflammatory response to a variety of inciting therapy in adrenocortical deficiency states. Synthetic analogs agents and probably delay or slow healing. Corticosteroids including dexamethasone are primarily used for their anti inhibit the edema, fibrin deposition, capillary dilation, leuko inflammatory effects in disorders of many organ systems. At cyte migration, capillary proliferation, fibroblast prolifera equipotent anti-inflammatory doses dexamethasone almost tion, deposition of collagen, and scar formation associated completely lacks the Sodium-retaining property of hydrocor with inflammation. There is no generally accepted explana tisone and closely related derivatives of hydrocortisone. Dex tion for the mechanism of action of ocular corticosteroids. amethasone is approved for Allergic states such as control of However, corticosteroids are thought to act by the induction severe or incapacitating allergic conditions intractable to US 2014/0171490 A1 Jun. 19, 2014

adequate trials of conventional treatment in asthma, atopic 0234 For example, a prior art course of treatment of ocular dermatitis, contact dermatitis, drug hypersensitivity reac inflammation includes application of one or two drop (ap tions, perennial or seasonal allergic rhinitis, and serum sick proximately 39 microliters each) of MaxidexTM once 30-60 ness; dermatologic diseases such as Bullous dermatitis her minutes to an appropriate eye. In contrast, in embodiments of petiformis, exfoliative erythroderma, mycosis fungoides, the present invention to treat ocular inflammation includes pemphigus, and severe erythema multiforme (Stevens administering between about 1 microliter and about 40 Johnson syndrome); endocrine disorders such as primary or microliters, preferably between 1 microliters and about 20 secondary adrenocortical insufficiency (hydrocortisone or microliters of a composition including Dexamethasone and a cortisone is the drug of choice; may be used in conjunction highly irritant penetration enhancer once every 30-60 minutes with synthetic mineralocorticoid analogs where applicable; to an appropriate eye. The composition is administered is a in infancy mineralocorticoid supplementation is of particular mist using a nebulizing device such as a device of the present importance), congenital adrenal hyperplasia, hypercalcemia invention. associate with cancer, and nonsuppurative thyroiditis; gas trointestinal diseases to tide the patient over a critical period Triamcinolone Acetonide of the disease in regional enteritis and ulcerative colitis; hematologic disorders such as acquired (autoimmune) 0235 Triamcinolone acetonide (9-Fluoro-11b, 16a, 17, hemolytic anemia, congenital (erythroid) hypoplastic anemia 21-tetrahydroxypregna-1, 4-diene-3, 20-dione cyclic 16, (Diamond-Blackfan anemia), idiopathic thrombocytopenic 17-acetal). Triamcinolone acetonide is a potent steroid. Tri purpura in adults, pure red cell aplasia, and selected cases of amcinolone acetonide is approved as an injection into the secondary thrombocytopenia. Miscellaneous: Diagnostic vitreous cavity for treating ocular inflammation and Swelling, testing of adrenocortical hyperfunction, trichinosis with neu lile cystoid macular edema, diabetic macular edema and wet rologic or myocardial involvement, tuberculous meningitis AMD. Triamcinolone acetonide is commercially available as with subarachnoid block or impending block when used with an intravitreal injectable solution from Bristol-Myers Squibb appropriate antituberculous chemotherapy; neoplastic dis Company (New York, N.Y., USA). eases for the palliative management of leukemias and lym 0236. In an embodiment of the present invention, a com phomas; for renal diseases to induce a diuresis or remission of position is provided comprising an ophthalmic carrier, a proteinuria in diopathic nephrotic syndrome or that due to highly irritant penetration enhancer (e.g., Saponin, fusidate, lupus erythematosus; respiratory diseases such Berylliosis, aZone, bile acid salts such as glycholate and cholate) and fulminating or disseminated pulmonary tuberculosis when Triamcinolone acetonide and is administered in accordance used concurrently with appropriate antituberculous chemoth with the teachings of the present invention. The coadminis eapy, idiopathic cosinophilic pneumonias, symptomatic sar tration of Triamcinolone acetonide and a high irritant pen coidosis; rheumatic disorders as adjunctive therapy for short etration enhancer in accordance with the teachings of the term administation (to tide the patient over an acute episode present inventionallows topical application of Triamcinolone or exacerbation) in acute gouty arthritis, acute rheumatic acetonide instead of the unpleasant intravitreal injection carditis, ankylosing spondylitis, psoriatic arthritis, rheuma known in the art, allowing effective treatment of conditions toid arthritis, including juvenile rheumatoid arthritis (se for which treatment with Triamcinolone acetonide is useful, lected cases may require low-dose maintenance therapy) and including ocular inflammatory conditions. for the treatment of dermatomyositis, polymyositis, and sys 0237 For example, a prior art course of treatment of ocular temic lupus erythematosus; in the nervous system to treat inflammation includes injection of 4 mg. Triamcinolone acute exacerbations of multiple Sclerosis, cerebral edema acetonide into the eye. In contrast, in embodiments of the associated with primary or metastatic brain tumor, cran present invention to treat ocular inflammation includes iotomy, or head injury and ophthalmic diseases such as cycli administering between 4 mg and 20 mg Triamcinolone tis, Herpes Zoster ophthalmicus, iridocyclitis, iritis, sympa acetonide in between about 1 microliter and about 100 micro thetic ophthalmia, temporal arteritis, uveitis, nonpurulent liters, preferably between 1 microliters and about 50 micro conjunctivitis (including Vernal, allergic, catarrhal, especially liters of a composition including Triamcinolone acetonide where allergy inflammatory reactions, recurrent marginal and a highly irritant penetrartion enhancer to an appropriate ulceration of toxic or allergic etiology, thermal burns, chemi eye. The composition is administered is a mist using a nebu cal burns and ocular inflammatory conditions unresponsive to lizing device Such as a device of the present invention. topical corticosteroids. Dexamethasone is commercially available in a 0.1% instillable suspension under the trade Nepafenac name MaxidexTM of Alcon Inc (Fort Worth, Tex., USA). 0238 Nepafenac, the amide analog of 2-amino-3-ben 0233. In an embodiment of the present invention, a com Zoylbenzeneacetic acid (amfenac), has been extensively stud position is provided comprising an ophthalmic carrier, a ied (Takahashi et al. Invest. Ophthalmol. Vis. Sci. 2003, highly irritant penetration enhancer (e.g., Saponin, fusidate, 44(1), 409–415: Gamache et al. Inflammation 2000, 24(4), aZone, bile acid salts such as glycholate and cholate) and 357-370; de Souza et al. Eye 2005, Jun. 17: Kapin et al. Dexamethasone and is administered in accordance with the Inflammation 2003, 27(5) 281-291; Keet al. Inflammation teachings of the present invention. The coadministration of 2000, 24(4),371-384; Koevary Curr. Drug Metabl. 2003, 4(3) Dexamethasone and a highly irritant penetration enhancer in 213-222). accordance with the teachings of the present invention gen 0239 Nepafenac is characterized in having excellent per erally increases the bioavailability of the Dexamethasone, meability into the eye through the cornea when applied topi allowing for administration of a reduced dose of API and cally. When inside the eye, nepafenac is metabolized into more effective treatment of conditions for which treatment amfenac, a high potent COX-1 and COX-2 inhibiting non with Dexamethasone is useful, including ocular inflamma steroid anti-inflammatory drug. Compositions including tory conditions. nepafenac are considered to be useful for the treatment ocular US 2014/0171490 A1 Jun. 19, 2014 20 inflammation, postoperative ocular pain, posterior segment addition to a penetration enhancer and/or a protein or peptide edema, retinoblastoma, retinal edema, prostaglanding forma active ingredient in a ophthalmically acceptable carrier, at tion and for COX-1 and COX-2 inhibition. least one additional component. It is important to note that in 0240. In an embodiment of the present invention, a com Some cases a specific additional component also serves as a position is provided comprising an ophthalmic carrier, a component of the carrier or serves two or more additional highly irritant penetration enhancer (e.g., Saponin, fusidate, functions. Typical additional components include but are not aZone, bile acid salts such as glycholate and cholate) and limited to bioadhesives, buffering agents, chelating agents, nepafenac and is administered in accordance with the teach humectants, pH-adjusting agents, preservatives, solubilizers, ings of the present invention. The coadministration of Viscosity modifiers and vitamins. nepafenac and a highly irritant penetration enhancer gener 0246. In embodiments of the present invention, a compo ally allows for increased bioavailability and more effective sition includes a bioadhesive, especially a bioadhesive poly treatment of conditions for which treatment with Nepafenac mer, especially a bioadhesive that is useful to keep and admin is useful including ocular inflammation, postoperative ocular istered API a longer than usual time on rhe cornea. Suitable pain, posterior segment edema, retinoblastoma, retinal bioadhesives include but are not limited to polyvinyl alcohol, edema, glaucoma, prostaglandin formation, retinal and cho thiolated polyacrylic acid, carbomer and gellan gum. roidal neovascularization and for COX-1 and COX-2 inhibi 0247. In embodiments of the present invention, a compo tion. sition includes a buffering agent. Suitable buffering agents 0241 Embodiments of a composition of the present inven include but are not limited to borate buffers, citrate buffers, tion include an API and/or a penentration enhancer in an acetic acid/sodium acetate buffers and a phosphoric acid/ ophthalmically acceptable carrier and optionally other ingre sodium phosphate buffers. dients. 0248. In embodiments of the present invention, a compo 0242 Ophthalmically acceptable carriers are generally sition includes a humectant. Suitable humectants include but sterile, essentially free of foreign particles, and have a pH in are not limited to ammonium lactate, guanidine, glycolic the range of 5-8. Preferably, the pH is as close to the pH of tear acid, glycolate salts, ammonium glycolate, quaternary alkyl fluid (7.4) as possible. Ophthalmically acceptable carriers ammonium glycolate, lactic acid, lactate salts, ammonium are, for example, Sterile isotonic Solutions such as isotonic lactate, quaternary alkyl ammonium lactate, aloe Vera, aloe sodium chloride or boric acid solutions. Such carriers are Vera gel, allantoin, urazole, polyhydroxy alcohol, Sorbitol, typically aqueous solutions contain sodium chloride or boric glycerol, hexanetriol, propylene glycol, butylene glycol, acid. Also useful are phosphate buffered saline (PBS) solu hexylene glycol, a hexylene glycol derivative, polyethylene tions. glycol, a Sugar, a starch, a Sugar derivative, a starch derivative, 0243 In embodiments of the present invention, a compo alkoxylated glucose, hyaluronic acid, lactamide monoetha sition includes an effective amount of an active pharmaceu nolamine and accetamide monoethanolamine, urea, or a com tical incredient (API). In embodiments of the present inven bination thereof. tion the API is a peptide or protein. An effective amount of an 0249. In embodiments of the present invention, a compo API, as used herein, means an amount needed to achieve the sition includes a pH-adjusting agent. Suitable pH-adjusting desired outcome prophylactic, therapeutic, pharmaceutical or agents include but are not limited to adipic acid, borics acid, cosmeceutical effect, which is generally to prevent, alleviate citric acid, glycine, calcium hydroxide, magnesium alumi or ameliorate the condition or symptoms of the condition nometasilicates, hydrochloric acid, lactic acid, phosphoric which is being treated. Determination of the effective acid, Sodium hydroxide, Sorbic acid, Sulfuric acid and tartaric amount, and consequently the dose and dose frequency, is acid, derivatives thereofs, salts thereofs or combinations within the capability of one skilled in the art, especially in thereof. light of the detailed disclosure provided herein. Factors in 0250 In embodiments of the present invention, a compo determining the effective amount vary with severity of the sition include preservative. Suitable preservatives include but condition as well as such factors as the concentration of the are not limited to alkanols, C12 to C15 alkylbenzoates, alkyl active pharmaceutical ingredient or ingredients, the Subject p-hydroxybenzoates, aloe Vera extract, ascorbic acid, benza being treated, the severity of the condition, the age, body Ikonium chloride, benzoic acid, benzoic acid esters of C9 to weight and response of an individual patient and the judgment C15 alcohols, butylated hydroxytoluene, castor oil, cetyl of the prescribing physician. Generally, the concentration of alcohols, chlorobutanol, chlorocresol, citric acid, cocoa but an API does not exceed 10% (w/v, e.g., mg ul') and is ter, coconut oil, diazolidinyl urea, diisopropyl adipate, dim generally not more than about 5%, not more than about 2.5% ethyl polysiloxane, DMDM hydantoin, disodium EDTA (eth and even not more than about 1%. ylenediamine tetraacetate), EDTA salts, EDTA fatty acid 0244. In embodiments of the present an API is encapsu conjugates, ethanol fatty acids, fatty alcohols, hexadecyl lated in or contained within some structure, whether to protect alcohol, hydroxybenzoate esters, iodopropynylbutylcarbam the API or to provide another desired property such as ate, isononyl iso-nonanoate, isothiazolinone, jojoba oil, lano increased penetration or adhesion to a Surface. Such struc lin oil, methylparaben, mineral oil, oleic acid, olive oil, para tures include beads, ethosome (Novel Therapeutic Technolo bens, polyethers, polyoxypropylene butyl ether, gies, Zichron Yakov, Israel), liposomes, lipospheres, polyoxypropylene cetyl ether, potassium Sorbate, propylene micelles, microcapsule, microspheres, nanocapsules, nano glycols, propylparaben, silicone oils, sodium propionate, particles, nanospheres. A review of suitable such structures is Sodium benzoate, sodium bisulfite, Sorbic acid, Sorbates, found, for example, in Kumar, M. N. V. R. J. Pharm. Phar Stearic fatty acid, vitamin E. Vitamin F. acetate and derivativ maceut. Sci. 2000, 3(2), 234-258. es, esters, salts and mixtures thereof. 0245. It is often desired to provide a composition with 0251. In embodiments of the present invention, a compo additional useful properties. Therefore, in some embodi sition include solubilizer. suitable solubilizers include but are ments, a composition of the present invention includes, in not limited to citric acid, ethylenediamine-tetraacetate, US 2014/0171490 A1 Jun. 19, 2014

Sodium meta-phosphate. Succinic acid, urea, cyclodextrin, maceutical composition of the prewent invention Such as a polyvinylpyrrolidone, diethylammonium-ortho-benzoate, pharamaceutical composition including a peptide or protein micelle-forming solubilizers, TWEENS, SPANS, polyoxy API, a pharmaceutical composition including a peptide or ethylene sorbitan fatty acid ester, polyoxyethylene n-alkyl protein API for treatment of nerves and especially of the ethers, n-alkyl amine n-oxides, poloxamers, phospholipids central nervous system or a pharmaceutical composition and cyclodextrines. including irritant penetration enhancers, whether inherently 0252. In embodiments of the present invention, a compo or by virtue of a high concentration. In FIG.1, pharmaceutical sition includes a viscosity modifier. A suitable viscosity composition 12 is a liquid, but embodiments of the present modifier is methylcellulose. invention are configured to administer by nebulization phar 0253) In embodiments of the present invention, a compo maceutical compositions in other states such as Solids, semi sition includes a vitamin. Suitable vitamins include but are Solids, gels and the like. not limited to retinoids, vitamin A, retinol, retinal, retinyl 0259. As seen in FIGS. 1A-1E, device 10 is formed of a palmitate, retinoic acid, tretinoin, iso-tretinoin, vitamin E, body 14, which defines an X:y:Z coordinate system, with X tocopherol, vitamin C, L-ascorbic acid, vitamin B, niacina being the direction of gravity, upper and lower ends 17 and 19 mide, alpha hydroxy acids, glycoli acid, lactic acid, tartaric respectively, along the X-axis, with respect to the direction of acid, malic acid, citric acid, beta hydroxy acids, Salicylic acid, gravity, and a proximal end 11, along the y-axis, with respect esters thereof and derivatives thereof. to eye 20 (FIG. 1C). Body 14 includes a mist-generator head 0254. In embodiments of the present invention, a compo 40, which includes: sition is formulated to ophthalmically deliver an active phar 0260 a holding sturcture 21, generally at upper end 17. maceutical ingredient. It is therefore preferred that such com for receiving an off-the-shelf container 18 in an inverted position be packages in a packaging material and identified in position, wherein container 18 contains pharmaceutical print, in or on the packaging material, as an ophthalmically composition 12; deliverable composition for use for a need. By “need” is 0261 an adaptor 16, for providing fluid communication meant a need selected from the group consisting of curing a with off-the-shelf container 18: condition, treating a condition, preventing a condition, treat 0262 an actuating mechanism 22, adapted to commu ing symptoms of a condition, curing symptoms of a condi nicate in mechanical communication with off-the-shelf tion, ameliorating symptoms of a condition, treating effects container 18, for causing a predetermined amount of of a condition, ameliorating effects of a condition, and pre pharmaceutical composition 12 to be issed therefrom; venting results of a condition. A specific condition and spe and cific use is dependent on the exact formulation of a specific, 0263 a nebulizer 24, in cluif communication with off including the identity and amount of the one or more active the-shelf container 18, for receiving and nebulizing a pharmaceutical ingredients therein. pharmaceutical composition 12, to form a mist 26 (FIG. 0255 Aspects of the present invention are implemented 1C). using any nebulizing device known in the art for ophthalmic 0264 Container 18 is inverted and fitting into adapter 16, administration of a pharmaceutical composition Such as which may be an inner thread, adapted to fit onto an external described in the introduction herein. Most preferably such thread 15, of container 18 (FIG. 1A). aspects are implemented using an embodiment of a device of 0265 Alternatively, adapter 16 is a rubber-like opening, the present invention. for forming a tight seal around container 18. 0256 Embodiments of a device of the present invention 0266 Actuating mechanism 22 may be a manual device, include many features useful for an ophthalmic delivery sys for example, operated by a lever 27. The issue of pharmaceu tem including accepting off-the-shelf bottles, (and also tical composition 12 takes place by pressing lever 27 in the bottles and unidose cartridges), dosage control, production of direction indicated by arrow 29 (FIGS. 1A and 1B). nano-size droplets to overcome protective mechanisms of the 0267 As seen in FIGS. 1D and 1E, container 18 is formed eye by not activating the blinking reflex and not stimulating of a flexible material and holding strucrture 21 includes a tear generation sensory receptors, employ a computerized narrow portion 25 so that the pressing of lever 27 causes system to program a predetermined medication-application container 18 to be squeezed into narrow portion 25. Alterna regimen, call or beep the user, at the schedule time for medi tively, container 18 is formed of a rigid material, but contains cation application, store data related to the medication appli a small air vent, so that narrow portion 25 need not be used; cation, and communicate with a computer or a health clinic pharmaceutical composition 12 flows out in the direction of concerning the treatment regimen for follow-up and evalua gravity whener container 18 is inverted. tion. Embodiments of a device of the present invention 0268 Additionally, as seen in FIG. 1A, a plate 37 with a include a feature to direct a generated mist only at an open hole 37A, is preferably controlled by actuating mechanism 22 eye, increasing dosage accuracy and reducing composition and includes “on” and “off positions. In the “off position of Wastage. FIG. 1A plate 37 presses against container 18 so as to keep 0257 Embodiments of a device of the present invention pharmaceutical composition 12 from issuing. include a self-sterlizing feature increasing the safey of the 0269. As seen in FIG. 1C, in the “on” position, when lever device and allowing the device to be easily used in hospitals 27 is pressed plate 37 moves in they direction so that hole and in situation that require high-throughput administration 37A is directly under container 18 allowing pharmaceutical of a pharmaceutical composition. composition 12 to issue. 0258 Referring now to the drawings, FIGS. 1A-1H sche 0270 Preferably, each actuation of lever 27 causes a single matically depict an embodiment of a device 10 for applying a drop 28 (FIg. 1C) of pharmaceutical composition 12 to be pharmaceutical composition 12 to an eye 20, in accordance issued. with the present invention. As ciscussed above a preferred 0271 When a dose of several drops is required, lever 27 is pharmaceutical composition 12 is an embodiment of a phar actuated several times, each time causing a single drop to be US 2014/0171490 A1 Jun. 19, 2014 22 issued. It will be appreciated that lever 27 may be spring body 14 is received in receptor 62, UV source 64 ios aimed at operated or otherwise biased, so as to return to its position of ring-shaped Surface 42, of application noZZle 46, for effecting FIG. 1A, when released. sterilization thereof. 0272. As seen in FIG. 1C, single drop 28 of pharmaceuti 0285 UV source 64 may be for example, UV laser diodes, cal composition 12 lands on nebulizer 24, preferably includ whether stationary rotating, or Sweeping. ing a poezoelectric crystal, which when activated, vibrates so 0286 Additionally, UV source 64 may be aimed at inter as to turn drop or drops 28 to mist 26. nal Surface 44 of application noZZle 46, for sterilizing it as 0273 A fan 13 may be used, also activated by lever 27, to well. lightly blow mist 26 towards eye 20. 0287. Additionally, UV source 64 may be aimed at the internal components of mist-generator head 40, for sterilizing (0274. As seen in FIG. 1C, upon the release of lever 27, them as well. These may include mist generator 24, cap 37. plate 37 seals container 18. the external surfaces of threads 16 and 15, sensor 34, fan 13 0275. In accordance with a preferred embodiment of the and related Surfaces. present invention, device 10 includes an application nozzle 0288. It will be appreciated that sterilization is performed 46, having a ring-shaped surface 42, on proximal end 11, with without affecting pharmaceutical composition 12 in con respect to eye 20, for fitting around eye 20. tainer 18. In accordance with one preferred embodiment, 0276 Application nozzle 46 may be adapted for replace sterilization is performed after container 18 is removed from ment between uses, allowing it to be disposable, in order to device 10. Adapter 16 (FIG. 1A) may then be plugged with a increase hygiene. Alternatsively, application nozzle 46 may plug 65, for keeping nebulizer 24 dust free. be sterilized between uses, as will be described hereinbelow. 0289 Alternatively, container 18 is arranged so that geo (0277 Preferably, nebulizer 24 is adapted for variable fre metrically, it is not in the line of sight of the UV radiation. quency and (or) intensity, so as to vary a mean diameter size 0290 Preferably, complementary stand 60 cinoruses a of droplets of mist 26. In accordance with the present inven recgargubg. deVuce 66 for charging battery 68, which powers tion, the mean diameter size of mist 26 is less than 10 microns, nebulizer 24 and preferably also fan 13 and where used, less than 8 microns, less than 5 microns, less than 3microns optical sensor 34. Where actuating mechanism 22 is motor and even less than 1 micron. ized, battery 68 may power the motor as well. 0278. It will be appreciated that small sized droplets are 0291. Further in accordance with the present invention, advantageous for ophthalmic administration due to the reduc device 10 may include a computerized device 50. tion of the initiation of the blinking reflex. 0292. As seen in FIGS. 2A and 2B, illustrating external 0279. As seen in FIGS. 1 F-1H, actuating mechanism 22 and internal features, respectively, computerized device 50 may be motor operated. For example, a motor shaft 33 includes a processor 52, which preferably includes a control attached to a cam 31 may be used, rotatable in the direction of unit, a logic unit (ALU) and memory. Additionally, comput arrow 35 (FIG. 1H), and pressed against container 18. Con erized device 50 may include a fixed data storage device 54, tainer 18 may be held in place by an anchoring device 39. such as a hard disk, and a drive 56 for reading from and (or) Cam 31 Squeezes container 18 as it rotates, causing the issue writing to a removable data storage device 54, Sch as a hard of one drop 28 with each cycle. the number of cycles of motor disk, and a drive 56 for reading from and (or) writing to a shaft 33 determines the number of drops 28. Additionally, the removable data storage device, such as a minidisk, control rotation of motor shaft 33 may be controlled by a computer buttons 53, preferably, a display screen 57, and possibly also ized device, as will be discussed hereinbelow, in conjunction a USB connector 51. Computerized device 50 may also with FIGS 2A-2E and 3A-3E. include a transceiver 58, and preferably also an antenna 55. for RF or IR communication, for example, using Bluetooth 0280 Alternatively, the motor may be activated by a prtocol. It will be appreciated that a receiver and (or) a trans switch 59, located on device 10. mitter may be used, in place of transceiver 58. 0281. A sensor 34, preferably, an optical sensor, adapted to 0293 Additionally, device 10 may include a scanner 95, detect light reflected from eye 20 may be used, in order to located, for example, on holding structure 21, adapted for determine that eye 20 is open, prior to the activation of device reading a bar code 97, so as to identify the medication prior to 10. its application. Alternatively, scanner 95 is adapted for read 0282. It will be appreciated that a computerized device, as ing letters, so as to identify the medication prior to its appli discussed hereinbelow, in conjunction with FIGS. 2A-2E and cation. 3A-3E, may be used to automatically activate device 10, 0294 Preferably, actuating mechanism 22 is motorized when sensor 34 senses a reflection from eye 20. and computerized device 50 may be programmed to turn 0283 Referring further to the drawings, reference is made motor shaft 33 a predetermined number of times, for each to FIGS. 2A-2E, which schematically illustrate an embodi application. In this manner, computerized device 50 may ment of a device 10 of the present invention as part of a system control the application dose. Additionally, the programming 30, comprising, device 10, a complementary stand 60, and a may be carried out via control buttons 53, via a remote con remote control 90, in accordance with a preferred embodi trol, or by the insertion of a removable data storage device, ment of the present invention. such as a minidisk to drive 56. 0284 As seen in FIG. 2A, device 10, includes a nebulizer 0295. It will be further appreciated that data related to the portio mist-genertor head 40, which includes nebulizer 24 application regimen, for example, the application Substance, and actuating mechanism 22 (FIGS. 1A-1D). Additionally, the dosage that was applied, the oeprating parameters of mist device 10 may include a computerized device 50, and a power generator 24, the frequency of applications, and the exact Source Such as a rechargeable battery 68. Complementary timing of each application may be stored on fixed data storage stand 60 preferably includes a receptor 62, for receiving body device 54, or on a removable data storage device, associated 14 of device 10, and a UV source 74, arranged so that when with drive 56. Additionally or alternatively, the data may be US 2014/0171490 A1 Jun. 19, 2014 displayed on screen 57. Additionally or alternatively, the data drives 76 or 86. Additionally or alternatively, the data may be may be forwarded to a computer or to a medical center, as will displayed on screen 77 or on screen 92. Additionally or alter be described hereinbelow, in conjunction with FIGS. 2A-2E natively, the data may be forwarded to another computer or to and 3A-3E, for follow-up. Tie data may be important for a medical clinic. reviewing the effectiveness of the application Substance, and (0308 Additionally, computerized devices 70 or 80 may to ensure compliance. call, beep, or otherwise remind a user of a schedule applica 0296. Additionally, computerized device 50 may call, tion time, to ensure that the user does not miss an application, beep, or otherwise remind a user of a scheduled application for example, due to forgetfulness. time, to ensure that the user does not miss an applicaation, for (0309. It will be appreciated that device 10 need not be example, due to forgetfulness. positioned on complementary stand 60 constantly; rather, it 0297. In accordance with the present invention, comple may be carried, for example, in a pocket, or in a purse, for use mentary stand 60 may include a computerized device 70, during the day. whucg may work in tandem with computerized device450, or 0310 Referring further to the drawings, FIGS. 3A-3E replace it, partially or completely. schematically illustrate additional computerized devices, 0298 As seen in FIGS. 2A and 2C, illustrating external which may be used together with ophthalmic delivery system and internal features, respectively, computerized device 70 30 (FIG. 2A), in accordance with the present invention. may include a fixed data storage device 74. Such as a hard 0311 as seen in FIG. 3A, a palmtop 102 may be used, in disk, and a drive 76 for reading from and (or) writing to a place of, or in addition to remote control unit 90. Additionally, removable data storage device, such as a minidisk, control or alternatively, as seen in FIG. 3B, a PDA 104 may be used. buttons 73, preferably a display screen 77, and possibly also, Additionally, or alternatively, as seen in FIG. 3C, a personal a USB connector 71. Computerized device 70 may also computer 106 having a modem may be used. Additionally, or include a transceiver 78, and preferably also an antenna 75. alternatively, as seen in FIG. 3D, a laptop 108 may be used. for RF or IR communication, for example, using BlueTooth 0312 These may be used for remotely controlling oph protocol. thalmic delivery system 30, for receiving data from oph 0299 Computerized device 70 may be used to control thalmic delivery system 30, and for storing, displaying, and device 10 and to store and (or) display data relating to the (or) analyzing the data. Additionally or alternatively, these application. Additionally or alternatively, computerized may be used for forwarding data from ophthalmic delivery device may be used to control and monitor UV source 64. system 30 to a medical clinic 140, which preferably includes 0300 Additionally, device 10 may include a scanner 79, an attendant 110, a computer 120 and a phone 130. It will be for example, in place of scanner 95 of device 10. Scanner 79 appreciated that medical clinic 140 may be a clinic on the go, may be adapted for reading bar codes or letters, so as to for example, of a doctor, his mobile phone, and his laptop. identify the medication bottle prior to its application. Medical clinic 140 may be used for follow-up of the medical 0301 A cable 61 connects complementary stand 60 with treatment, for example, in order to evaluate the effectiveness the grid. of a particular drug, and in order to Verify compliance. 0302 Additionally, a cable 63 may provide internet and 0313 Referring further to the drawings, FIG. 4 is a flow (or) phone connections. chart of an embodiment of a method 200 of using the oph 0303 Additionally or alternatively, complementary stand thalmic delivery system of the present invention: 60 may include remote control unit 90, which may work in 0314. In a box 202: predetermine for a user of a given ID, tandem with computerized devices 50 and 70 or replace them, a medication-application regimen of: 1. medication type; 2. partially or completely. dosage, in drops; and 3. frequency, or schedule times. 0304. As seen in FIGS. 2A, 2D, and 2E, remote control 0315. In a box 204: program ophthalmic delivery system unit 90 is preferably adapted to fit into a receptor 67 of 30 to provide the predetermined medication-application regi complementary stand 60, and may recharge its battery 98, via a recharging device 69. Preferably, remote control unit 90 C. includes a computerized device 80, which may include a fixed 0316. In a box 206: ring user's phone or cell phone, or data storage device 84, such as a hard disk, and a drive 86 for beep user, to notify him of a scheduled time to take his reacing from and (or) writing to a removable data storage medication. device, such as a minidisk, control buttons 94, preferably, a 0317. In a box 208: identify, by a scanner, the medication display screen 92 and possibly also a USB connector 91. type. Remote control unit 90 may also include a transceiver 88, and 0318. In a box 210: set actuating mechanism 22 to issue preferably also an antenna 85, for RF or IR communication, the desired number of drops for the medication type. for example, using BlueTooth protocol. 0319. In a box 212: confirm, by optical sensor 34, that 0305 Remote control unit 90 may be used to control device 10 is position for medical application and the eye is device 10 and to store and (or) display data relating to the open. application. Additionally or alternatively, remote control unit 0320 In a box 214: activate simultaneously; 1. actuating 90 may be used to control and monitor UV source 64. mechanism 22: 2. nebulizer 24; and 3. fan 13. 0306 Additionally, remote control unit 90 may include a 0321. In a box 216: store on a fixed or removable data scanner99, for example, in place of scanner 95 of device 10, storage device: 1. the user's ID: 2. the medication type: 3. and (or) in place of scanner 79 of complementary stand 60. mist-generator operating parameters; 4. the dosage; and 5... the Scanner 99 may be adapted for reading barcodes or letters, so application times. as to identify the medication bottle prior to its application. 0322. In a box 220: sterilize, by UV radiation application 0307. It will be appreciated that data relating to the appli nozzle 46 of device 10 cation regimen may be stored on fixed data storage devices 74 0323. It will be appreciated that only a portion of the steps or 84, or on removable data storage devices, associated with described may be employed. It will be further appreciated that US 2014/0171490 A1 Jun. 19, 2014 24 other methods that utilize the features of ophthalmic delivery Surface and a ligh detecting diode (e.g., a silicon PIN photo system 30 may similarly be used. diode) configured to detect light reflected from the eye sur 0324. As described above and with reference to device 10 face. inflGS. 1A-1H and 2A-2D it is advantageous to direct a mist 0331 Embodiments of a device of the present invention towards and eye only when the eye is open. Thus an adddi include an easily replaceable contact Surface, allowing the tional aspect of the present invention relates to a device for contact surface to be disposable. Specifically, a nozzle 46 is ophthalmic administration comprising a nebulizer, a mist configured to be easily attachable to and detachable from the director to to direct a generated mist at an eye, an eye-state rest of the device. Between every administration, a user detector to detect if an eye is open or closed, and a Switch detaches the used nozzle and attaches a clean (preferably new associated with both the eye-state detector and the mist direc or sterile) nozzle. The used nozzle is discarded or cleaned torto direct mist at the eye only when open. Thus, in embodi and/or sterilized. ments of the present invention there is provided a device (e.g., 0332 An additional aspect of the present invention relates 10) for ophthalmic administration of a composition (prefer to a device for ophthalmic administration that is self-steriliz ably a pharmaceutical composition), comprising: a) a misting ing. As describe above and with reference to device 10 in unit (e.g., 40) including i) a nebulizer (e.g., 24), configured to FIGS. 1A-1H and 2A-2D it is advantageous to sterilize an generate a mist from a composition (e.g., 12); ii) a mist ophthalmic delivery device between individual administra director (e.g., 13), configured to direct mist generated by the tions. A device that is quick and easy to serilize allows high nebulizer at an eye; b) an eye-state detector (e.g., 34), con throughput and safe ophthalmic administration of a pharma figured to detect if the eye is open or shut; and c) a Switch ceutical composition, for example in a hospital or clinic functionally associated with the misting unit and with the where many patients may be treated with one device, or in eye-state detector having at least two states, an “ON” state high-throughput situations, for example when desired to treat wherein a mist is directed at the eye and an "OFF' state a population for an epidemic or endemic condition or to wherein a mist is not directed at the eye. inoculate or immunize a population. For example, the use of 0325 In embodiments of the present invention, the switch an embodiment of a pharmaceutical composition of the sets to the “ON” state when the eye-state detector detects that present invention including an antibody as an API together the eye is open and/or the switch sets to the “OFF' state when with an easily sterilizable device, allows a large population to the eye-state detector detects that the eye is shut. be immunized against an illness. 0326 In embodiments, the mist director is a physical com 0333. Thus, an additional aspect of the present invention ponent distinct from the nebulizer. In embodiments, the mist relates to a device for ophthalmic administration of a phar director is not a physical component distinct from the nebu maceutical composition to an eye of a Subject, comprising: a) lizer. For example, in embodiment the mist director is simply a contact component with a contact surface (e.g., 42), the a tube or passageway between the nebulizer and the eye. contact Surface configured to contact a portion of the body of 0327. In embodiments direction of the mist to the eye is the Subject during the administration (e.g., the eye, the area performed by controlling the nebulizer. In such embodi around the eye, the eyelids); and b) a reversibly actuatable ments, the nebulizer (e.g., 24) is deactivated when the Switch radiation-source (e.g., 64), configured to irradiate the contact is set to the 'OFF' state and the nebulizer is activated when Surface with sterilizing radiation. As noted above, such a the Switch is set to the “ON” state. radiation-source is advantageously configured to irradiate 0328. In embodiments direction of the mist to the eye is other components of a respective device also. performed by controlling a valve or similar component, not 0334. An suitable sterilizing radiation is useful for imple depicted in the figures above. In Such embodiments, the mist menting the sterilizing aspect teachings of the present inven ing unit further comprises a valve functionally associated tion. Embodiments of the present invention include steriliz with the mist director, and the valve is configured to close ing radiation comprising radiation selected from the group when the switch is set to the 'OFF' state and the valve consisting of coherent radiation, incoherent radiation, micro configured to open when the switch is set to the “ON” state. wave radiation, infrared radiation and ultraviolet radiation. 0329. In embodiments direction of the mist to the eye is 0335. In embodiments, such as device 10 as depicted in performed by controlling a blower, e.g., a fan 13, compressor FIG. 2A, the contact component is an integral element of a other Such component. In such embodiments, the misting unit first unit of the device (e.g., 10) and the radiation source is an further comprises a blower functionally associated with the integral element of a second unit of the device (e.g., 60), mist director, the blower being deactivated when the switch is wherein the first unit and the second unit are physically dis set to the “OFF' state and the blower being activated when the tinct. As described above, whenactivated the radiation source Switch is set to the “ON” state. sterilizes the contact component by projecting sterilizing 0330 Many different technologies and components are radiation at the contact surface. In Such embodiments, it is useful in implementing an eye state detector, including cam advantageous that the first unit has a power source Such as a eras associated with an image processing unit to identify rechargeable battery, and the second unit includes a recharger, when an eye is open or shut, for example by identifying the so that the first unit is sterilized during recharging, as iris, the pupil, eyelashes, eyelid or distinct color, for example described above. of the sclera. Due to the fact that the anterior surfaces of the 0336. In embodiments of the present invention, both a Sclera and cornea are reflective, detection of reflection Such as contact component and a radiation source are both integral specular reflection from the anterior portion of the eye, in elements of a single unit of the device. Such an embodiment embodiments of the present invention the eye state detector is of the present invention 148 is depicted in FIG.5. In FIG. 5 is configured to detect light reflecting from the Surface of an depicted a nozzle 46 with ring-shaped contact Surface 46 at a anteriorportion of an open eye. One method of implementing distal end and a ring of sterilizing radiation sources 150. Such a reflector is with the use of a light-emitting diode (e.g., Sources 150 are functionally associated with a UV-lamp 152 projecting visible or near-infrared light) to illuminate the eye (Spectronics Corporation, Westbury, N.Y., USA) powered by US 2014/0171490 A1 Jun. 19, 2014

a battery 154. When activated, UV-lamp 152 produces steril 10 Hz and 100 mHz, frequencies of no less than about 1 kHz, izing radiation that is transported through optical fibers 156 to frequencies of no less than about 10 kHz or frequencies of no sources 150. Nozzle 46 is transparent to the radiation pro less than about 1 mHz. duced by UV-lamp 152 and is configured to act as a wave 0347 Generally any period oftime of vibration is effective guide for the UV light, guiding the light to contact Surface 42 in increasing the bioavailability of an ophthalmically admin to sterilize contact surface 142. istered API according to the present invention to some extent. 0337. In embodiments of the present invention, a radiation That said, in embodiments of the present invention the vibrat Source is user-actuated, for example by the press of a button ing is for at least 10 seconds, for at least 30 seconds or even for when desired. at least 60 seconds. 0338. In embodiments of the present invention, such as depicted in FIG. 2A, the radiation-source is automatically 0348 Useful for vibrating an eyelid in accordance with the activated: when device 10 is placed in stand 60, UV-source 64 teachings of the present invention is an eyelid vibrating is activated. device of the present invention. 0339. In embodiments of the present invention, such as 0349 An eyelid vibrating device of the present invention depicted in FIG. 5, the radiation source is autonomously is a device for increasing the bioavailability of an ophthalmi activated, that is the device is configured to activate a respec cally administered API in a pharmaceutical composition, tive radiation source when needed. In FIG. 5, device 148 is comprising: a) an eyelid contact component, configured to provided with a sensor 34 as described above functionally physically contact an eyelid of an eye and maintain the eyelid associated with logic unit 160 that is configured to activate in a shut position; and b) a vibration generator configured to UV-lamp 152. When device 148 is actuated to dispense a generate vibrations and transfer the vibrations to the eyelid pharmaceutical composition, logic unit 160 interrogates sen contact component. sor 34 whether an eye (or any object) is positioned in front of 0350. An embodiment of an eyelid vibrating device 162, nozzle 46. If yes, logic unit 160 waits until the front of nozzle Substantially an eyepatch, of the present invention is depicted 46 is clear. When nozzle 46 is clear, logic unit 160 activates in FIG. 6A fixed to the head of a person and in FIG 6B in side UV-lamp 152 to sterilize contact surface 42. During steriliza view. Device 162 is configured with a headband 164 to act as tion, logic unit 160 monitors sensor 34 a holder to hold a contact component 166 (a silicon rubber 0340. In such a way, device 148 is provided with a fail-safe disk) against the shut eyelid of a person. mechanism preventing inadvertent irradiation of an eye that 0351 Contact component 166 is a soft silicon rubber disk may cause damage, making such a device exceptionally use configured to effectively transfer vibrations generated by ful for high-throughput situations, even when an operator is vibratioen generator 168 to the eyelid of a person with dam not highly skilled. age Such as chafing or scratching. In embodiments of the 0341 Embodiments of a device of the present invention present invention, a contact component is a sack or bag hold are equipped with a timer to ensure that irradiation is per ing a liquid (e.g., a Saturated Saline Solution) to transfer vibra formed for a sufficiently long time for effective sterilization. tions. 0342. An additional aspect of the present invention is a 0352 Vibration generator 168 is functionally associated method and a device for increasing the bioavailability of an with contact component 166 and includes a piezoelectric ophthalmically administered API, whether for systemic or crystal (not depicted) as a vibration generator, a power Source local delivery, whether through the conjunctiva, Sclera, cor (not depicted) and a switch 170. In embodiments of the nea or other route, by vibrating the eyelid subsequent to the present invention, instead of or in addition to a piezoelectric ophthalmic administration. crystal other vibration generating components are use. For 0343 As discussed herein, a problem with ophthalmic example, in embodiments a vibrating diaphragm (such as in administration is that it often a significant portion of an an audio speaker) is used as a vibrating generating component administered API does not penetrate into the body. A method of a vibration generator. of the present invention to increase the bioavailability of an ophthalmically administered API comprises a) contacting a 0353. When switch 170 is set to an “ON” state, vibration composition, preferably a pharmaceutical composition, with generator 168 generates vibrations (of a desired frequency, as a posterior section of an eye; b) shutting the eye with a described above, in embodiments comprising ultrasonic or respective eyelid; and c) vibrating the eyelid. As a result of the Sonic frequencies) that are transferred to the eyelid of a person vibrations, the API in the pharmaceutical composition pen through contact component 166. etrates the ocular tissue more easily and quickly, increasing 0354 Additional objects, advantages, and novel features the bioavailability thereof. of the present invention will become apparent to one ordi 0344 Any suitable method of contacting the composition narily skilled in the art upon examination of the following is suitable, including insilling eyedrops with an eye dropper examples, which are not intended to be limiting. Additionally, or other device, spraying, or with a mist, for example using an each of the various embodiments and aspects of the present embodiment of a device of the present invention. invention as delineated hereinabove and as claimed in the 0345. In an embodiment of the present invention, the eye claims section below finds experimental Support in the fol lid is vibrated using a vibrating physical component, see lowing examples. below. 0346 Various frequencies of vibration are effective in EXAMPLES increasing the bioavailability of an ophthalmically adminis tered API according to the present invention. In embodiments 0355 Reference is now made to the following examples, of the present invention the vibration are include sonic and/or which together with the above description, illustrate the ultrasonic frequencies, such as frequencies of between about invention in a non-limiting fashio. US 2014/0171490 A1 Jun. 19, 2014 26

Nebulization Device 0366. The second leptin/saponin composition was admin istered for 2 minutes as a mist to the eyes of a first group of rats 0356) Ophthalmic administration of pharmaceutical com and 1 drop (about 30 ul) instilled into the eyes of a second positions as a mist in accordance with embodiments of the group of rats. the rats of the two groups were sacrificed 20 present invention was performed with a nebulization device minutes after administration. The retina leptin levels were constructed by the inventor. compared to those of a control group. The results are depicted in FIG.7C. In FIG. 7C it is seen that both administration by Materials instillation and as a mist deliver similar levels of leptin to the 0357 Materials and reagents were purchased from Sigma retina in the presence of 1% saponin. Chemical Company (St. Louis, Mo., USA). 0358 Animal studies were carried out on Lewis female b. Delivery of Middle Sized Protein to the Central rats (6-8 weeks of age) from Harlan Laboratories Inc. (Reho Nervous System Vot, Israel). In some cases as noted below, the rats were anesthetized with ketamin/xylazine using a 27 G cannula 0367 The first leptin composition was administered for 2 through the cisterna magna. minutes as a mist to the eyes of a first group of rats and 1 drop 0359 ELISA tests were performed using commercially (about 30 ul) instilled into the eyes of a second group of rats. available ELISA kits from Assay Designs (Ann Arbor, Mich. the rats of the two groups were sacrificed 10 minutes after USA) in accordance with the manufacturers instructions in administration. The levels of leptin in the CSF were compared the usual way in conjunction with a BioTek EL-310 plate to those of a control group. The results are depicted in FIG. reader (Cambridge Scientific Products, Cambridge, Mass. 8A. In FIG. 8A it is seen that neither instillation nor admin USA). istration as a mist deliver a statistically significant amount of 0360 Pharmaceutical compositions were administered by leptin to the CSF. instillation in the eyes of rats or administered as a mist using 0368. The second leptin/saponin composition was admin the nebulization device described above at a rate of 10 ul istered for 2 minutes as a mist to the eyes of a first group of rats minute'. Subsequent to administration and a waiting time, and 1 drop (about 30 ul) instilled into the eyes of a second the rats were sacrificed. group of rats. The rats of both groups were sacrificed 10 0361 Subsequent to sacrifice, serum, cerebrospinal fluid minutes and 20 minutes after administration. The retina leptin (CSF, 50-100 ul), retina, optic nerve, sclera, and aqueous levels were compared to those of a control group. The results humor (AH) of an animal were harvested. The retina, optic are depicted in FIG. 8B. In FIG. 8B it is seen that whereas nerve, and Sclera of each animal was individually homog administration by instillation did not deliver a statistically enized in 120 ul assay buffer on ice and centrifuged. The significant amount of leptin to the CSF, administration as a serum, CSF, AH and the homogenized retina, optic nerve and mist did deliver a statistically significan amount of leptin to sclera were assayed for the presence of leptin using ELISA. the CSF. 0362 Data below is expressed as pg. ml for serum, CSF 0369 Thus, it is demonstrated that ophthalmic adminis and AH and as pg mg for tissue (determined using the tration of a pharmaceutical composition of an API Such as a Lowry method). middle-sized protein with a penetration enhancer Such as saponin as a mist is effective in delivery of the API to the Example 1 central nervous system. Delivery of Middle Sized Protein by Ophthalmic c. Route of Delivery of Middle Sized Protein to the Administration Central Nervous System 0363 A first leptic composition was prepared including 0370. The second leptin/saponin composition was admin 0.6 mg ml leptin (16 kDa) in a standard phosphate buffered istered for a period of 15 second, 30 seconds, 1 minute and 2 saline (PBS) ophthalmic vehicle having a pH of 7.4. minutes as a mist to the eyes of groups of rats. The rats were 0364. A second leptin/saponin compositions was prepared sacrificed 10 minutes after administration. The levels of leptin including 0.6 mg ml leptin and 1% saponin as a penetration in the optic nerve and the Sclera were compared to those of a enhancer in a standard phosphate buffered saline (PBS) oph control group. The results for accumulation of leptin in the thalmic vehicle having a pH of 7.4. optic nerve are depicted in the table of FIG.9A in units of pg ug', where “low” indicates below the lower limit of detec a. Delivery of Middle Sized Protein to the Retina tion of the ELISA assay. In FIG. 9A it is seen that 2 minutes 0365. The first leptin composition was administered for 2 were reqired for delivery of a detectable amount of leptin to minutes as a mist to the eyes of a first group of rats and 1 drop the optic nerve. The results for accumulation of leptin in the (about 30 ul) instilled into the eyes of a second group of rats. sclera are depicted in FIG.9B in units of pgug'. In FIG.9B The rats of the two groups were sacrificed 10 minutes after it is seen that 2 minutes were required for delivery of a administration. The levels of leptin in the retina and in the AH significant amount of leptin to the Sclera. were compared to those of a control group. the results are 0371. It should be noted that the leptin concentration in depicted in FIGS. 7A and 7B. In FIG. 7A it is seen that both both the optic nerve and Sclera was markedly higher than in instillation and administration as a mist deliver similar levels the the retina. Taken together with the results depicted in of leptinto the retina. In FIG. 7B it is seen that administration FIGS. 9A and 9B, together with the absence of leptin in the by instillation delivers significantly more leptinto the AH that AH (FIG. 7B) suggest that protein delivery when adminis does administration as a mist, Suggesting that the delivery of tered as a mist is preferentially through the Sclera and appar leptin to the posterior portion of the eye occurs by a route ently through a different mechanism then when administered different than that of instillation. by instillation. US 2014/0171490 A1 Jun. 19, 2014 27

d. Effect of Continuous Administration of a Protein 0380. To first group of anesthetized rats the second leptin composition was administered continuously for 10 minutes 0372. The second leptin composition was administered for as a mist to the eyes and the rats sacrificed after the 10 2 minutes as a mist to the eyes of a first group of rats and 1 minutes. To a second group of anesthetized rats were admin drop (about 30 ul) instilled into the eyes of a second group of istered drops of the second leptin composition by instillation rats. The rats of both groups were sacrificed 5 or 10 minutes over a period of 10 minutes So as to ensure a continuous after administration. A third group of rats was anesthetized Supply of the composition in the eye and the rats sacrificed and the second leptin composition administered continuously after the 10 minutes. The results are depicted in FIG. 11C. In for 10 minutes as a mist to the eyes of rats and the rats were FIG. 11C it is seen that instillation provides systemic delivery sacrificed after the 10 minutes. A fourth group of rats was of a leptin but administration as a mist does not provide anesthetized and drops of the second leptin composition significant systemic deliver. instilled over a period of 10 minutes so as to ensure a con tinuous Supply of the composition in the eye and the rats were 0381. Thus is is demonstrated that ophthalmic administra sacrificed after the 10 minutes. tion of a pharmaceutical composition of an API Such as a 0373) Because of the low number of rats in each group, middle-sized protein as a mist is effective in selective delivery statistical analysis could not be performed. of the API to the eye and to the central nervous system. 0374. The retina leptin levels after the full 10 minutes of administration by both methods were compared to those of a f. Irritation Effect of Penetration Enhancers control group. The results are depicted in FIG. 10A. In FIG. 0382. Throughout the studies above it was noted that, as 10A it is seen that continuous administration for 10 minutes expected, rats to which a composition including 1% saponin of composition both by instillation and by administration delivers significant amounts of leptin to the retina in the was administered by instillation into the eyes instilled exhib presence of 1% saponin. ited marked irritation, see FIG. 12A. 0375. The sclera leptin levels of rats sacrificed 5 or 10 0383. In contrast and unexpectedly, rats to which a com minutes after either administration of 1 drop by instillation or position including 1% saponin was administered as a mist 2 minutes administration as a mist of the composition were exhibited no signs of irritation. compared to those of a control group. The results are depicted 0384 Thus, it is demonstrated that ophthalmic adminis in FIG. 10B. In FIG. 10B it is seen that both instillation and tration of a pharmaceutical composition including an irritant administration as a mist deliver significant amounts of leptin penetration enhancer as a mist is possible without causing eye to the sclera in the presence of 1% saponin. irritation. 0376. The optic nerve leptin levels after the full 10 minutes of administration by both methods were compared to those Example 2 found in of rats sacrificed after 5 or 10 minutes subsequent to either administration by instillation of a drop or by 2 minutes Delivery of an Antibody by Ophthalmic administration as a mist of the composition to those of a Administration to the CNS control group. The results are depicted in FIG. 10C. In FIG. 10A it is seen that continuous administration for 10 minutes 0385) A composition containing mouse 2.5 ug ml IgGl of composition both by instillation and by administration as a and 1% saponin in a standard phosphate buffered saline mist delivers significant amounts of leptinto the optic nerve in (PBS) ophthalmic vehicle having a pH of 7.4 was prepared. the presence of 1% saponin. 0386. Using the nebulizer device described above, 20ll of 0377. It is thus seen that continuous administration both the IgG1 composition was administered over a period of 2 by instillation and by administration as mist delivers signifi minutes to each eye of 30 rats making up a first group of rats. cant amounts of leptin to the retina, Sclera and optic nerve in Using a nebulizer device, 50 ul of the IgG1 solution was the presence of 1% saponin. administered over a period of 5 minutes to each eye of 30 rats making up a second group of rats. Using a nebulizer device, e. Systemic Delivery of Middle Sized Protein 100 ul of the IgG1 solution was administered over a period of 10 minutes to each eye of 30 rats making up a third group of 0378. The first leptin composition was administered for 2 rats. Using a nebulizer device, 100 ul of the IgG1 solution was minutes as a mist to the eyes of a first group of rats and 1 drop administered over a period of 10 minutes to each eye of 30 rats (about 30 ul) instilled into the eyes of a second group of rats. making up a fourth group of rats. A group of 30 untreated rats The rats of both groups were sacrificed 10 minutes after make up a control group. administration. The serum levels of leptin were compared to 0387. The rats of the first, second and third group were those of a control group. The results are depicted in FIG. 11A. sacrificed 10 minutes after initiation of nebulization. The rats In FIG. 11A it is seen that instillation provides systemic delivery of a leptin but administration as a mist does not of the fourth group were sacrificed 20 minutes after initiation provide significant systemic deliver. of nebulization. The control group was also sacrificed. 0379 The second leptin/saponin composition was admin 0388. From each rat, the two retina and the two optic istered for 2 minutes as a mist to the eyes of a first group of rats nerves were harvested, homogenized and the Supernatant and 1 drop (about 30 ul) instilled into the eyes of a second assayed for the presence of mouse IgG1 in the usual way using group of rats. Rats of both groups were sacrificed after 10 and ELISA. 20 minutes. The serum leptin levels were compared to those 0389. No significant amount of mouse IgG1 was found in of a control group. The results are depicted in FIG. 11B. In any of the retina. FIG. 11B it is seen that neither instillation nor administration 0390 There was a significant accumulation of mouse IgG1 as a mist deliver provide significant systemic delivery of in the optic nerves of the rats, see FIG. 13. The greatest levels leptin in the presence of 1% saponin. of mouse IgG1 were found in the rats to which the composi US 2014/0171490 A1 Jun. 19, 2014 28 tion was continuously administered for ten minutes and then Prophetic Example 5 allowed an additional ten minutes to reach the posterior sec tion of the eye. Administration of Dipivefrin HCl 0391 As the mouse IgG1 accumulated in the optic nerve, 0397 To a commercially available pharmaceutical com and as the optic nerve is surrounded by CSF and is directly position including 0.15% Dipivefrin HCl in an ophthalmi connected to the brain, it is expected that large proteins. Such cally acceptable carrier (comprising benzalkonium chloride as antibodies such as IgG1 are deliverable to the central ner (0.05 mg/ml) as a preservative, edetate disodium, sodium Vous system using the teachings of the present invention as chloride, hydrochloric acid to adjust pH to about 2.5-3.5, and demonstrated for leptin. purified water) such as Propine(R) is added 1% fusidic acid to provide an ophthalmic composition of the present invention. Prophetic Example 1 0398. 1 microliter of the ophthalmic composition of the present invention is applied twice daily as a mist using a Administration of GDNF (Glial Derived device of the present invention to a subject suffering from Neurotrophic Factor) ocular hypertension. Marked reduction of the intraocular pressure is observed. 0392 A composition containing GDNF as an API with 2% benzalkonium chloride in a standard phosphate buffered Prophetic Example 6 saline (PBS) ophthalmic vehicle with a pH of 7.4 is prepared and administered as a mist in accordance with the teachings of Administration of Apraclonidine HCl the present invention to accumulate in the retina, optic nerve, 0399. To a commercially available pharmaceutical com CSF, and brain of a subject, and thus treat conditions of the position including 5.75 mg/ml Apraclonidine HCl (equiva retina and central nervous (CNS), such as Parkinson's dis lent to 0.5% Apraclonidine) in an ophthalmically acceptable ease, see Sherer, T. B. et al. Exp. Neurol. 2003, 179,9-16. carrier (comprising benzalkonium chloride (0.01 mg/ml) as a preservative, sodium chloride, sodium acetate, sodium Prophetic Example 2 hydroxide and/or hydrochloric acid (to adjust pH to about 2.5-3.5) and purified water) such as Iopidine(R) is added 1% Administration of Bevacizumab Sodium deoxycholate to provide and ophthalmic composition of the present invention. 0393 Bevacizumab is an inhibitor of Vascular Endothelial 0400 1 microliter of the ophthalmic composition of the Growth Factor (VEGF), a protein that plays an important role present invention is applied three times daily as a mist using in tumor angiogenesis and maintenance of existing tumor a device of the present invention to a Subject Suffering from vessels. By inhibiting VEGF, Bevacizumab interferes with ocular hypertension. Marked reduction of the intraocular the blood Supply to tumors, a process that is critical to tumor pressure is observed. growth and metastasis. 0394. A composition containing Bevacizumab as an API Prophetic Example 7 in a standard phosphate buffered saline (PBS) ophthalmic vehicle with a pH of 7.4 is prepared and administered as a mist Administration of Dapiprazole in accordance with the teachings of the present invention to 04.01 To a commercially available pharmaceutical com treat cancers. Such as metastatic colon or rectum cancer and position including 0.5%; Dapiprazole in an ophthalmically also for delivery to the retina and central nervous (CNS) to acceptable carrier (comprising benzalkonium chloride treat cancers therein. (0.01%) as a preservative, mannitol (2%), sodium chloride, hydroxypropyl methylcellulose (0.4%), edetate sodium Prophetic Example 3 (0.01%), sodium phosphate dibasic, sodium phosphate monobasic and purified water having a pH of 6.6) Such as Administration of Ranibizumab Rev-Eyes (R) is added 2% fusidate, to provide an ophthalmic composition of the present invention. 0395. A composition containing Ranibizumab as an API 0402 2 microliter of the ophthalmic composition of the with 0.5% deoxycholic acid as a penetration enhancer in a present invention is administered to the eye of a Subject hav standard phosphate buffered saline (PBS) ophthalmic vehicle ing diagnostic mydriasis. After 5 minutes, an additional 2 with a pH of 7.4 is prepared and administered as a mist in microliters of the ophthalmic composition of the present accordance with the teachings of the present invention to treat invention is administered. Marked reduction of pupil size is a subject in need thereof. observed. Prophetic Example 4 Prophetic Example 8 Administration of Dorzolamide Administration of Ieredelimumab 0403. To a commercially available pharmaceutical com 0396. A composition containing Ieredelimumab as an API position including 2% Dorzolamide (22.3 mg/ml of dorzola with 0.1% digitonin as a penetration enhancer in a standard mide hydrochloride) in an ophthalmically, acceptable carrier phosphate buffered saline (PBS) ophthalmic vehicle with a (comprising benzalkonium chloride (0.0075%) as a preser pH of 7.4 is prepared and administered as a mistinaccordance Vative, hydroxyethyl cellulose, mannitol, Sodium citrate with the teachings of the present invention to treat a Subject in dihydrate, sodium hydroxide (to adjust pH to 5.6) and purified need thereof. water Such as Trusopt(R) is added 2% ammonium glycyrrhiz US 2014/0171490 A1 Jun. 19, 2014 29 ideas a penetration enhancer to provide an ophthalmic com Prophetic Example 12: Administation of position of the present invention. Levobunolol 0404 1 microliter of the ophthalmic composition of the 0411 To a commercially available pharmaceutical com present inventio is applied three times daily as a mist using a position including 0.25% Levobunolol (as Levobunolol HCl) device of the present invention to a subject suffering from in an ophthalmically acceptable carrier (comprising benza ocular hypertension. Marked reduction of the intraocular lkonium chloride (0.004%) as a preservative, edetate diso pressure is observed. dium, polyvinyl alcohol, potasium phosphate monobasic, Sodiu chloride, sodium metabisulfite, sodium phosphate Prophetic Example 9 dibasic and hydrochloric acid or sodium hydroxide (to adjust pH to 5.5-7.5) and purified water such as Betagan LiquifilmR) Administration of Timolol is added 3% cholic acid as a penetration enhancer to provide an ophthalmic composition of the present invention. 04.05 To a commercially available pharmaceutical com 0412 1 microliter of the ophthalmic composition of the position including 0.25% Timolol (3.4 mg/ml Timolol Male present invention is applied twice times daily as a mist using ate) in an ophthalmically acceptable carrier (comprising ben a device of the present invention to a Subject Suffering from Zalkonium chloride (0.01%) as a preservative, monobasic and ocular hypertension. Marked reduction of the intraocular dibasic sodium phosphate, sodium hydroxide (to adjust pH) pressure is observed. and purified water such as Timoptic(R) is added 3% Brij 35 as a penetration enhancer to provide an ophthalmic composition Prophetic Example 13 of the present invention. 0406 1 microliter of the ophthalmic composition of the Administration of Betaxolol present invention is applied twice daily as a mist using a 0413 To a commercially available pharmaceutical com device of the present invention to a subject suffering from position including 0.25% Betaxolol (as 2.8 mg/ml Betaxolol ocular hypertension. Marked reduction of the intraocular Hcl) in an ophthalmically acceptable carrier (comprising ben pressure is observed. Zalkonium chloride (0.01%) as a preservative, mannitol, Poly (Seyrene-Divinyl Benzene) sulfonic acid, Carbomer 934P. Prophetic Example 10 edetate disodium, hydrochloric acid or sodium hydroxide (to adjust pH) and purified water such as Betoptic S(R) is added Administration of Dorzolamide with Timolol 4% decamethonium bromide as a penetration enhancer to provide an ophthalmic composition of the present invention. 04.07 To a commercially available pharmaceutical com 0414. 1 microliter of the ophthalmic composition of the position including 2% Dorzolamide (22.3 mg/ml of dorzola present invention is applied twice times daily as a mist using mide hydrochloride) and 0.5% Timolol (6.83 mg/ml Timolol a device of the present invention to a Subject Suffering from Maleate) in an ophthalmically acceptable carrier (comprising ocular hypertension. Marked reduction of the intraocular prs benzalkonium chloride (0.0075%) as a preservative, sure is observed. hydroxyethyl cellulose, mannitol, Sodium citrate, sodium hydroxide (to adjust pH to 5.6) and purified water such as Prophetic Example 14 Cosopter) is added 4% Brij-98 as a penetration enhancer to provde an ophthalmic composition of the present invention. Administration of Pilocarpine 0408. 1 microliter of the ophthalmic composition of the 0415. To a commercially available pharmaceutical com present invention is applied twice daily as a mist using a position including 5 mg/ml Pilocarpine as Pilocarpine nitrate device of the prewsent invention to a subject suffering from in an ophthalmically acceptable carrier (comprising benza ocular hypertension. Marked reduction of the intraocular Ikonium chloride as a preservative, boric acid, potassium pressure is observed. chloride, hydroxypropylmethyl cellulose, Sodium carbonate, edetate disodium and purified water Such as Pilagan Liqui Prophetic Example 11 filmR) is added 0.5% saponin to provide an ophthalmic com position of the present invention. Administration of Unoprostone Isopropyl 0416) 1 microliter of the ophthalmic composition of the present invention is applied three times daily as a mist using 04.09 To a commercially available pharmaceutical com a device of the present invention to a Subject Suffering from position including 0.15% Unoprostone Isopropyl (1.5 mg/ml ocular hypertension. Marked reduction of the intraocular of Unoprostone Isopropyl) in an ophthalmically acceptable pressure is observed. carrier (comprising benzalkonium chloride (0.015%) as a preservative, mannitol, polysorbate 80, edetate disodium, Prophetic Example 15 sodium hydroxide or hydrochloric acid (to adjust pH to 5.0- 6.5) and purified water such as Rescula R is added 2% Administration of Echothiophate Iodide cetylpyridium chloride as a penetration enhancer to provide 0417. To a commercially available pharmaceutical com an ophthalmic composition of the present invention. position including 0.125% Echothiophate Iodide (6.25 0410 1 microliter of the ophthalmic composition of the mg/ml) in an ophthalmically acceptable carrier (comprising present invention is applied twice times daily as a mist using 40 mg/ml potassium acetate, chlorobutanol, mannitol, boric a device of the present invention to a Subject Suffering from acid and exsiccated Sodium phosphate Such as Phospholine ocular hypertension. Marked reduction of the intraocular Iodide(R) is added 0.5% saponin to provide an ophthalmic pressure is observed. composition of the present invention. US 2014/0171490 A1 Jun. 19, 2014 30

0418) 1 microliter of the ophthalmic composition of the (0.01 mg/ml) as a preservative, hydroxpropyl methylcellu present invention is applied twice times daily as a mist using lose 2910, dibasic sodium phosphate, Polysorbate 80, ddetate a device of the present invention to a Subject Suffering from disodium, glycerin, citric acid and/or sodium hydroxide (to ocular hypertension. Marked reduction of the intraocular adjust pH) and purified water such as Pred ForteR) is added pressure is observed. 0.5% saponin to provide an ophthalmic composition of the present invention. Prophetic Example 16 0426 1 microliter of the ophthalmic composition of the present invention is applied once an hour as a mist using a Administration of Latanoprost device of the present invention to a subject suffering from 0419. To a commercially available pharmaceutical com ocular inflammation. Marked reduction of inflammation is position including 0.005% Latanoprost (50 mcg/ml) in an observed. ophthalmically acceptable carrier (comprising benzalkonium chloride (0.02%) as a preservative, Sodium chloride, sodium Prophetic Example 20 dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous (to adjust pH to 6.7) and purified water Administration of Dexamethasone such as Xalatan(R) is added 0.5% saponin to provide an oph 0427. To a commercially available pharmaceutical com thalmic composition of the present invention. position including 0.1% Dexamethasone in an ophthalmi 0420 1 microliter of the ophthalmic composition of the cally acceptable carrier (comprising benzalkonium chloride present invention is applied once a day as a mist using a device (0.01%) as a preservative, sodium chloride, hydroxypropyl of the present invention to a subject Suffering from ocular methylcellulose, dibasic sodium phosphate, polysorbate 80, hypertension. Marked reduction of the intraocular pressure is edetate disodium, citric acid and/or Sodium hydroxide (to observed. adjust pH) and purified water such as MaxidexTM) is added 0.5% saponin to provide an ophthalmic composition of the Prophetic Example 17 present invention. 0428 1 microliter of the ophthalmic composition of the Administration of Bimatoprost present invention is applied once an hour as a mist using a 0421. To a commercially available pharmaceutical com device of the present invention to a subject suffering from position including 0.03%. Bimatoprost (0.3 mg/ml) in an oph ocular inflammation. Marked reduction of inflammation is thalmically acceptable carrier (comprising benzalkonium observed. chloride (0.05 mg/ml) as a preservative, sodium chloride, dibasic sodium phosphate, citric acid, Sodium hydroxide and/ Prophetic Example 21 or hydrochloric acid (to adjust pH to 6.8-7.8) and purified water such as Lumigan.R.) is added 0.5% saponin to provide Administration of Triamcinolone Acetonide an ophthalmic composition of the present invention. 0429. A composition including an appropriate concentra 0422 1 microliter of the ophthalmic composition of the tion of Triamcinolone acetonide and a penetration enhancer present invention is applied once a day as a mist using a device (e.g., 1% saponin, fusidate, aZone, bile acid salts such as of the present invention to a subject Suffering from ocular glycholate and cholate) in an ophthalmically acceptable car hypertension. Marked reduction of the intraocular pressure is rier (comprising benzalkonium chloride (0.01%) as a preser observed. Vative, Sodium chloride, hydroxypropyl methylcellulose, dibasic sodium phosphate, polysorbate 80, citric acid and/or Prophetic Example 18 sodium hydroxide (to adjust pH) and purified water) to pro vide an ophthalmic composition of the present invention. Administration of Fluribrofen Sodium 0430. An appropriate amount (a Volume including 0423 To a commercially available pharmaceutical com between about 4 and 20 mg Triamcinolone acetonide, gener position including 0.03% fluribrofen Sodium (0.3 mg/ml) in ally between 1 microliter and 100 microliter) of the oph an ophthalmically acceptable carrier (comprising thimerosal thalmic composition of the present invention is applied as a (0.005%) as a preservative, polyvinyl alcohol 1.4%: edetate mist using a device of the present invention to a subject disodium; potassium chloride; sodium chloride; sodium cit suffering from ocular inflammation. Marked reduction of rate; citric acid; hydrochloric acid and/or sodium hydroxide inflammation is observed. (to adjust pH to 6.0–7.0) and purified water such as Ocufen R.) is added 0.5% saponin to provide an ophthalmic composition Prophetic Example 22 of the present invention. 0424. 1 microliter of the ophthalmic composition of the Administration of Brimonidine Tartrate present invention is applied once every half hour four times 0431. To a commercially available pharmaceutical com starting two hours before surgery in order to effectively position including 0.15% brimonidine tartrate in an oph inhibit intraoperative miosis. thalmically acceptable carrier (comprising benzalkonium chloride (0.05 mg/ml) as a preservative, citric acid, polyvinyl Prophetic Example 19 alcohol, Sodium chloride, Sodium citrate and purified water with hydrochloric acid and/or sodium hydroxide to adjust Administration of Prednisolone Acetate pH) such as Alphagan R P is added 0.5% escinto provide an 0425 To a commercially available pharmaceutical com ophthalmic composition of the present invention. position including 1% Prednisolone Acetate in an ophthalmi 0432 1 microliter of the ophthalmic composition of the cally acceptable carrier (comprising benzalkonium chloride present invention is applied three times daily as a mist using US 2014/0171490 A1 Jun. 19, 2014

a device of the present invention to a Subject Suffering from tion of any reference in this application shall not be construed ocular hypertension. Marked reduction of the intraocular as an admission that such reference is available as prior art to pressure is observed. the present invention. 1. A method of delivering a composition, comprising: Prophetic Example 23 a) providing a pharmaceutical composition comprising one or more penetration enhancers and an ophthalmically Administration of Nepafenac acceptable carrier; 0433. A composition including 0.1% nepafenac solution b) generating a mist of said composition; and in a standard phosphate buffered saline (PBS) ophthalmic c) contacting said mist with a posterior Surface of an eye of vehicle having a pH of 7.4 is prepared. The composition is a subject in need thereof wherein said penetration diluted, once 1:1 with PBS to produce a 0.05% nepafenac enhancer comprises at least 0.05% by weight of said composition (composition I) and once 1:1 with a 2% saponin pharmaceutical composition. composition to produce a 0.05% nepafenac/1% saponincom 2. The method claim 1, wherein said penetration enhancer position (composition II). (s) is(are) selected from the group consisting of 0434 Mice with oxygen-induced ischemic retinopathy Benzalkonium chloride, BL-9, digitonin, escin, acetone, are divided into four groups. acyllactylates, acyl peptides, acylsarcosinates, alcohols, alkanolamine salts of fatty acids, alkylbenzene Sulpho 0435 Each eye of the first group of mice is instilled with nates, alkyl ether Sulphates, alkyl Sulphates, allantoin, 100 microliters of composition I (nepafenac) four times daily. ammonium glycyrrhizide, anionic Surface-active 0436 Each eye of the second group of mice is instilled agents, 1-substituted azacycloheptan-2-ones, benzyl with 100 microliters of composition II (nepafenac/penetra benzoate, benzyl salicylate, bile salts Brij 35, Brij78/35. tion enhancer) four times daily. butan-1,4-diol, butyl benzoate, butyl laurate, butyl 0437. Each eyes of the third group of mice is exposed to 25 myristate, buty Stearate, cationic Surface-active agents, microliters of composition I nebulized (nepafenac) in a cetylpyridium chloride, chenodeoxycholic acid, cho device of the present invention four times daily. late, cholic acid, citric acid, cocoamidopropylbetaine, 0438. Each eyes of the fourth group of mice is exposed to decamethonium, decamethonium bromide, decyl 25 microliters of composition II nebulized (nepafenac/pen methyl sulfoxide, decyl oleate, deoxycholic acid, dibu etration enhancer) in a device of the present invention four tyl azelate, dibutyl phthalate, dibenzyl sebacate, dibutyl times daily. sebacate, dibutyl suberate, dibutyl succinate, dicapryl 0439. The mice of the second group are observed to suffer adipate, didecyl phthalate, diethylene glycol, diethyl extensive irritation and continually scratch at their eyes, so Sebacate, diethyl-m-toluamide, di(2-hydroxypropyl) the experiment with the second group is discontinued. ether, diisopropyl adiptate, diisopropyl sebacate, N.N- 0440. After 5 days of treatment, the mice of the first, third dimethyl acetamide, dimethyl azelate, N,N-dimethyl and fourth group are sacrificed, the eyes rapidly removed and formamide, 1,5-dimethyl-2-pyrrolidone, dimethyl seba frozen in OCT. The extent of ocular neovascularization (NV) cate, dimethyl Sulphoxide, dioctyl adipate, dioctyl aze in terms of mean cross-sectional area of intravitreal NV is late, dioctyl sebacate, 1.4 dioxane, 1-dodecylazacylo evaluated in accordance with methods known in the art (see heptan-2-one, dodecyl dimethyl amine oxides, EDTA Takahashi et. Invest. Ophthalm. Vis. Sci. 2003, 44(1), 409 and disodium EDTA, ethyl caprate, ethyl caproate, ethyl 415). It is seen that the least NV occurred with the fourth caprylate, 2-ethyl-hexyl pelargonate, ethyl-2-hydrox group (nebulized composition II (nepafenac/penetration ypropanoate, ethyl laurate, ethyl myristate, 1-ethyl-2- enhancer)) followed by the the third group (nebulized com pyrrolidone, ethyl salicylate, fusidic acid, fusidate, postion I (nepafenac)) followed by the first group (instilled fusidic acid derivatives, glycerol monolaurate, hexyl composition I (nepafenac)). laurate, glycocholate, glycocholic acid, glycodeoxy cholic acid, glycyrrhizic acid, 2-hydroxyoctanoic acid, 0441. It is appreciated that certain features of the inven 2-hydroxypropanoic acid, 2-hydroxypropionic acid, tion, which are, for clarity, described in the context of separate isethionates, isopropyl isostearate, isopropyl palmitate, embodiments, may also be provided in combination in a guar hydroxypropyltrimonium chloride, hex-2,5-diol, single embodiment. Conversely, various features of the khellin, lamepons, lauryl alcohol, lecithin, maypons, invention, which are, for brevity, described in the context of a metal salts of fatty acids, methyl nicotinate, 2-methyl single embodiment, may also be provided separately or in any propan-2-ol. 1-methyl-2-pyrrolidone, 5-methyl-2-pyr suitable subcombination. rolidone, methyl taurides, miranol, nonionic Surface 0442. Although the invention has been described with ref active agents, octyl alcohol, octylphenoxy polyethoxy erence to specific embodiments thereof, it is evident that ethanol, oleic ethanolamide, pleyl alcohol, pentan-2,4- many alternatives, modifications and variations will be appar diol, phenoxyethanol, phosphatidylcholine, phosphine ent to those skilled in the art. Accordingly, the present inven oxides, polyalkoxylated ether glycolates, poly(dial tion is intended to embrace all Such alternatives, modifica lylpiperidinium chloride), poly(dipropyldiallylammo tions and variations that fall within the spirit and broad scope nium chloride), polyethylene glycol monolaurate, of the appended claims. polyglycerol esters, polyoxyethylated castor oil, poly 0443 All publications, patents and patent applications oxyethylene, polyoxyethylene ethers of fatty acids such mentioned in this specification are herein incorporated in as polyoxyethylene 4-, 9-,10-, and 23-lauryl ether, poly their entirety by reference into the specification, to the same oxyethylene 10- and 20-cetyl ether, polyoxyethylene extent as if each individual publication, patent or patent appli 10- and 20-stearyl ether, polyoxyethylene monolaurate, cation was specifically and individually indicated to be incor polyoxyethylene Sorbitans, polyoxyethylene Sorbitan porated herein by reference. That said, citation or identifica monolaurate, polyoxy:polyoxyethylene Stearate, poly US 2014/0171490 A1 Jun. 19, 2014 32

oxypropylene 15 Stearyl ether, poly(vinyl pyridinium selected from the consisting of betaxolol, carteolol. chloride), propan-1-ol, propan-2-ol, propylene glycol, levobunolol, metipranolol and timolol maleate. propylene glycol diperlargonate, propylene glycol monolaurate, pyroglutamic acids, 2-pyrrolidone, pyru 13. The method of claim 8, said active pharmaceutical Vic acids, Quaternium 5. Quaternium 18, Quaternium ingredient(s) comprising a carbonic anhydrase inhibitor 19, Quaternium 23, Quaternium 31, Quaternium 40, selected from the group consisting of acetazolamide, brin Quaternium 57, quartenary amine salts, quaternised Zolamide, dorzolamide, methazolamide, neptzane and uno poly (dimethylaminoethylmethacrylate), quaternised prostone isopropyl. poly (vinyl alcohol), Sapamin hydrochloride, sodium 14. The method of claim 8, said active pharmaceutical cocaminopropionate, Sodium dioctyl Sulphonsuccinate, ingredient(s) comprising a prostaglandin analog selected Sodium laurate, Sodium lauryl ether Sulphate, sodium lauryl Sulphate, Sodium cholate, Sodium glycocholate, from the group consisting of bimatoprost, latanoprost, tra glycocholate, sodium deoxycholate, sodium taurocho voprost and unoprostone. late, sodium glycodeoxycholate, Sodium taurodeoxy 15. The method of claim 1, said composition comprising at cholate, Sorbitan monooleate, Sorbitan monolaurate, least one humectant. Sugar esters, Sulphosuccinate, taurocholic acid, taurode oxycholic acid, tetrahydrofuran, tetrahydrofurfural 16. The method of claim 15, said humectant(s) selected alcohol, transcutol, triethanolamine dodecyl benzene from the group consisting of ammonium lactate, guanidine, sulphonate, triethanolamine oleate, TWEEN 20, ura glycolic acid, glycolate salts, ammonium glycolate, quater Zole, urea, urosdeoxycholic acid, saponin, Saponins, Brij nary alkyl ammonium glycolate, lactic acid, lactate salts, 78, Brij 98, paraben, sodium ursodeoxycholate, and ammonium lactate, quaternary alkyl ammonium lactate, aloe esters, salts and mixtures thereof Vera, aloe Vera gel, allantoin, urazole, polyhydroxy alcohol, 3. The method of claim 1, said penetration enhancer(s) Sorbitol, glycerol, hexanetriol, propylene glycol, butylene comprising at least 0.1% by weight of said pharmaceutical glycol, hexylene glycol, a hexylene glycol derivative, poly composition. ethylene glycol, a Sugar, a starch, a Sugar derivative, a starch 4. The method of claim 1, said penetration enhancer(s) derivative, alkoxylated glucose, hyaluronic acid, lactamide comprising at least 0.2% by weight of said pharmaceutical monoethanolamine and acetamide monoethanolamine, urea, composition. or a combination thereof. 5. The method of claim 1, said penetration enhancer(s) comprising at least 0.5% by weight of said pharmaceutical 17. The method of claim 1, said composition comprising at composition. least one preservative. 6. The method of claim 1, said penetration enhancer(s) comprising at least 1% by weight of said pharmaceutical 18. the method of claim 17, said preservative(s) selected composition. from the group consisting of alkanols, C12 to C15 alkyl 7. The method of claim 1, said penetration enhancer(s) benzoates, alkyl p-hydroxybenzoates, aloe Vera extract, comprising at least 2% by weight of said pharmaceutical ascorbic acid, benzalkonium chloride, benzoic acid, benzoic composition. acid esters of C9 to C15 alcohols, butylated hydroxytoluene, 8. The method of claim 1, said composition further com castor oil, cetyl alcohols, chlorobutanol, chlorocresol, citric prising one or more active pharmaceutical ingredients. acid, cocoa butter, coconut oil, diazolidinyl urea, diisopropyl 9. The method of claim 1, said active pharmaceutical ingre adipate, dimethyl polysiloxane, DMDM hydantoin, disodium dient(s) is(are) selected from the group consisting of alpha-2 EDTA (ethylenediamine tetraacetate), EDTA salts, EDTA adrenergic agonists, analgesics, anesthetics, antibiotics, anti fatty acid conjugates, ethanol, fatty acids, fatty alcohols, depressants, antihistamines, antipsychotics, antivascular hexadecyl alcohol, hydroxybenzoate esters, iodopropynyl agents, antiviral agents, aptamers, artificial tears, beta-adren butylcarbamate, isononyl iso-nonanoate, isothiazolinone, ergic blocking agents, carbonic anhydrase inhibitors, cata jojoba oil, lanolin oil, methylparaben, mineral oil, oleic acid, lytic antioxidants, chemotherapeutics, cholinesterase inhibi olive oil, parabens, polyethers, polyoxypropylene butyl ether, tors, corticosteroids, direct acting miotics, hormones, light polyoxypropylene cetyl ether, potassium Sorbate, propylene activated drugs, non-steroidal anti-inflammatory drugs, glycols, propylparaben, silicone oils, sodium propionate, ocular lubricants, ophthalmic decongestant agents, oph Sodium benzoate, sodium bisulfite, Sorbic acid, Sorbates, thalmic antiseptics, ophthalmic antifungals, peptides, pros Stearic fatty acid, vitamin E, Vitamin E acetate and deriva taglandinanalogs, proteins, catalytic antioxidants), sedatives, tives, esters, salts and mixtures thereof. steroid, stimulants, Sulfonamides, vasoconstrictors and 19. The method of claim 1, said composition comprising at vasodilators. least one solubilizer. 10. the method of claim 8, said active pharmaceutical ingredient(s) comprising an alpha-2 adrenergic agonist 20. The method of claim 19, said solubilizer9s) selected selected from the group consisting of apraclonidine, brimoni from the group consisting of citric acid, ethylenediamine dine tartrate, dapiprazole and diplivefrin. tetraacetate, sodium meta-phosphate. Succinic acid, urea, 11. The method of claim 8, said active pharmaceutical cyclodextrin, polyvinylpyrrolidone, diethylammonium-orth ingredient(s) comprising an antivascular agent selected from benzoate, micelle-forming solubilizers, TWEENS, SPANS, the group consisting of anecortave acetate, pegaptainib and polyoxyethylene Sorbitan fatty acid ester, polyoxyethylene squalamine. n-alkyl ethers, n-alkylaminen-oxides, poloxamers, phospho 12. The method of claim 8, said active pharmaceutical lipids and cylodextrines. ingredient(s) comprising a beta-adrenergic blocking agent k k k k k