US 2013 0324481A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0324481 A1 Wong et al. (43) Pub. Date: Dec. 5, 2013

(54) SUSTAINED RELEASE EYE DROP Publication Classification FORMULATIONS (51) Int. Cl. (71) Applicant: Ramscor, Inc., Menlo Park, CA (US) A647/22 (2006.01) A647/4 (2006.01) (72) Inventors: Vernon G. Wong, Menlo Park, CA (US); A647/12 (2006.01) Louis L. Wood, Potomac, MD (US) A638/3 (2006.01) A 6LX3/573 (2006.01) (73) Assignee: Ramscor, Inc., Menlo Park, CA (US) (52) U.S. Cl. CPC ...... A61K 4 7/22 (2013.01); A61K 38/13 (21) Appl. No.: 13/963,574 (2013.01); A61 K3I/573 (2013.01); A61 K 1-1. 47/12 (2013.01); A61 K47/14 (2013.01) (22) Filed: Aug. 9, 2013 USPC ...... 514/20.5: 514/180: 514/383: 514/263.4: O O 514/152514f628: 514/253.08: 514f198: Relatede U.S. Applicationpplication DatUata 514/450;s 514/317;s 514/217.05;s 514/648:s (63) Continuation of application No. 12/236,877, filed on 514/226.2: 514/259.41; 514/291; 514/456 Sep. 24, 2008, now Pat. No. 8,541,413, which is a continuation-in-part of application No. 1 1/826,833, filed on Jul. 18, 2007, now abandoned, which is a (57) ABSTRACT continuation-in-part of application No. 1 1/236,426, This invention provides for biocompatible, biodegradable eye filed on Sep. 27, 2005, now Pat. No. 7,906,136. drop pharmaceutical formulations useful for the treatment of (60) Provisional application No. 60/960,315, filed on Sep. ocular indications. In particular, tocopherols and their esters 25, 2007, provisional application No. 60/831,991, of low water solubility, notably C-tocopheryl acetate, are filed on Jul. 19, 2006, provisional application No. exceptional vehicles for biocompatible, nonirritating topical 60/709,665, filed on Aug. 19, 2005, provisional appli eye drop formulations that provide Sustained release of active cation No. 60/614,484, filed on Oct. 1, 2004. agents. Patent Application Publication Dec. 5, 2013 Sheet 1 of 7 US 2013/0324481 A1

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SUSTAINED RELEASE EYE DROP invention disappear harmlessly after delivering active agent FORMULATIONS to the desired site. The formulations of the present invention provide for novel therapies that are easily used by qualified RELATED APPLICATIONS medical practitioners as well as by Subjects in need thereof. 0001. This application is a continuation of U.S. patent The formulations deliver therapeutic and non-toxic levels of application Ser. No. 12/236,877, filed on Sep. 24, 2008, active agents over the desired extended time frame, often which claims the benefit under 35 U.S.C. S 119(e) of U.S. primarily at the site of administration. Patent Ser. No. 60/960,315, filed Sep. 25, 2007, entitled Sus 0006. The embodiments of the present invention provide tained Release eye Drops and Conveniently Implantable Sus for formulations for topical administrations of active agents tained Release Drug Formulations, by Vernon G. Wong and to the eye. The present invention provides for eye drop for Louis L. Wood, and is a continuation-in-part of U.S. patent mulations comprising at least one active agent in a biocom application Ser. No. 1 1/826,833, filed Jul. 17, 2007, which patible, biodegradable excipient that sustains the release of claims the benefit under 35 U.S.C. S 119(e) of U.S. Patent the active agent, and which may be chosen from tocopherol Application Ser. No. 60/831,991, filed Jul. 19, 2006, and isomers and/or their esters; and tocotrienols and/or their which is a continuation-in-part and claims the benefit under esters, such as d. 1 and dl isomers of C, B, Ö, e, m tocopherols 35 U.S.C. S 120 of U.S. patent application Ser. No. 1 1/236, and similar isomers of the tocotrienols and the esters of these 426, filed Sep. 27, 2005, now U.S. Pat. No. 7,906,136, issued tocopherols and tocotrienols with straight and branched chain on Mar. 15, 2011, which is related to and claims the benefit C2 to C20 aliphatic acids, or their esters of C3 to C20 straight under 35 U.S.C. S119(e) of U.S. Patent Application Ser. Nos. chain dicarboxylic acids; the mono, di, and triesters of O-ace 60/709,665, filed Aug. 19, 2005, and 60/614,484, filed Oct. 1, tylcitric acid or O-propionylcitric acid or O-butyrylcitric acid 2004, each entitled Conveniently Implantable Sustained with C1 to C10 straight and branched chain aliphatic alco Release Drug Compositions, by Vernon G. Wong and Louis hols; the mono, di, and triesters of citric acid with C1 to C10 L. Wood. Each of the foregoing applications is incorporated straight and branched chain aliphatic alcohols. In another in its entirety herein. embodiment of the invention, the active agent or excipient may be an omega-3 fatty acid or an ester thereof. Another FIELD OF THE INVENTION embodiment of the present invention provides for a formula tion comprising a nonpolymeric, biodegradable, bioabsorb 0002 The present invention relates to the field of ophthal able excipient and the active agent is one or more antioxi mology involving biocompatible, biodegradable, Sustained dants, either alone or included with one or more steroids release formulations of beneficial, active agents for topical and/or quinolone anti-infectives. Typically, the formulations administration to the eye. of the present invention provide for the sustained release of BACKGROUND OF THE INVENTION the active agent for at least four days. 0007. The active agent envisioned in an embodiment of the 0003 Current topical eye drop formulations, in addition to present invention is at least one agent of the analgesics, anes often eliciting some degree of transient irritation, provide thetics, narcotics, angiostatic steroids, anti-inflammatory Ste only short term exposure of beneficial agents to the eye and roids, angiogenesis inhibitors, nonsteroidal anti-inflammato thus often require several administrations daily. Other modes ries, anti-infective agents, antibiotics, antifungals, antivirals, of drug delivery, such as oral delivery and injection, may alpha androgenergic agonists, beta adrenergic blocking result in high and low blood concentrations and/or shortened agents, carbonic anhydrase inhibitors, mast cell Stabilizers, half-life in the blood, in addition to systemic delivery of miotics, prostaglandins, antihistamines, antimicrotubule medicaments that are only required in the eye. In some cases, agents, antineoplastic agents, antipoptotics, aldose reductase achieving therapeutic efficacy with these standard adminis inhibitors, antihypertensives, antioxidants, growth factor trations requires large doses of medications that may result in agonists and antagonists, vitrectomy agents, adenosine recep toxic side effects. Additionally, Some eye drop formulations tor antagonists, adenosine deaminase inhibitors, glycosyla are unstable over the normal period of treatment, which may tion antagonists, anti-aging peptides, topoisemerase inhibi be exacerbated by patient mis-handling. The technologies tors, anti-metabolites, alkylating agents, oncogene activation relating to controlled drug release have been attempted in an inhibitors, telomerase inhibitors, antibodies or portions effort to circumvent some of the pitfalls of conventional thereof, fusion proteins, tyrosine kinase inhibitors, ribonucle therapy. Their aims are to deliver medications on a continuous otide reductase inhibitors, cytotoxins, IL2 therapeutics, neu and Sustained manner. rotensin antagonists, peripheral sigma ligands, endothelin 0004. There remains a need for a more economical, prac ETA/receptor antagonists, antihyperglycemics, anti-glau tical, and efficient way of producing and manufacturing drug coma agents, anti-chromatin modifying enzymes, insulins, delivery systems that may be used locally, in liquid, gel, or glucagon-like-peptides, immunosuppressive agents, tissue ointment formulations. In particular, there remains a need for repair agents, essential fatty acids, and nucleic acids such as Sustained-release formulations for topical administrations antisense oligonucleotides, siRNA or RNAi. (eye drops) of beneficial, active agents to the eye. 0008. In another aspect of the present invention, more than one biodegradable, biocompatible excipient may be used to SUMMARY OF THE INVENTION facilitate Sustained release of an active agent. For example, a 0005. An object of the present invention provides for eco relatively small amount of a tocopherol. Such as C. tocopheryl nomical, practical, and efficient drug delivery systems. acetate, may be added to a mixture of omega-3 fatty acid and According to the present invention, this drug delivery system prednisolone, increasing the Sustained release of predniso is produced easily, delivered easily to the site of indication, lone from the formulation. and is both biocompatible and biodegradable. In other words, 0009. In particular embodiments, the eye drop formula the biocompatible, biodegradable formulations of the present tion consists of C. tocopheryl acetate and cyclosporin A, rapa US 2013/0324481 A1 Dec. 5, 2013 mycin, or timolol, or a prostaglandin. In another embodiment 0021. The present invention relates to novel biocompat of the invention, the eye drop formulation consists of a toco ible, biodegradable Sustained release topical formulations pheryl acetate and latanoprost. suitable for administration to the eye. In various aspects of the invention these formulations are liquids, gels, ointments, or BRIEF DESCRIPTION OF THE DRAWINGS emulsified micells (oil in water or water in oil). The formu lations include at least one active agent which is delivered in 0010 FIG. 1 depicts dissolution profiles of dexametha a limited solubility, biocompatible, biodegradable (often sone (Dex) released from three formulations of Dex/d-toco referred to herein as LSBB) formulation. The LSBB formu pherol, and dl-tocopheryl acetate. lations of the present invention deliver therapeutic and non 0011 FIG. 2 shows cyclosporin A (CSA) release in rabbit toxic levels of active agents over the desired extended time tears following installation of one drop of a 45:55 (wt) CSA: frame. These formulations are both biocompatible and bio C-tocopheryl acetate (EA) formulation. degradable, and disappear harmlessly after delivering active 0012 FIG. 3 shows timolol release in rabbit tears follow agent. ing installation of one drop of a 10:90 (wt) timolol:dl-toco 0022. The present invention provides for sustained release pheryl acetate (EA) formulation. eye drop formulations for topical administrations of benefi 0013 FIG. 4 depicts Dex release from two different for cial, active agents to the eye. Topical eye drops are directed mulations of Dex:d-tocopherol and one formulation of Dex: generally to therapies for the anterior segments of the eye, dl-tocopherol acetate. which are the contemplated therapies for the formulations of 0014 FIGS. 5A-5D are charts showing the intraocular this invention. The anterior segment includes the anterior pressure of two rabbits treated with a saline in one eye; and a chamber, iris, ciliary body, lens, and the eye surface. The eye formulation of latanaprost in di-tocopheryl acetate in the Surface is composed of the cornea, conjunctiva, eye lids, other eye. lacrimal and meibomian glands, and the interconnecting 0015 FIG. 6 depicts the percent Dex released in vitro from nerves. The tocopherols and their esters of low water solubil a formulation of 24%. Dex and Triethyl O-Acetyl Citrate ity, notably C-tocopheryl acetate, are exceptional vehicles for (TEAC). biocompatible, nonirritating topical eye drop formulations 0016 FIG. 7 shows the percent Dex released in vitro from providing Sustained release of beneficial agents for periods of a formulation of 20% Dex and TEAC/Tocopheryl acetate. at least about four days from a single application without interfering with vision. DETAILED DESCRIPTION OF THE INVENTION 0023 Specific areas of the human or animal body to be 0017. It should be understood that this invention is not targeted for topical applications of the excipient/active agents limited to the particular methodology, protocols, and LSBB compositions include, but are not limited to: eyes, reagents, etc., described herein and as such may vary. The punctum lacrimale (tear ducts), nasal passages, mucosa of the terminology used herein is for the purpose of describing nasal cavity and throat. The formulations according to the particular embodiments only, and is not intended to limit the present invention have particular applicability in providing a scope of the present invention, which is defined solely by the controlled and Sustained release of active agents effective in claims. obtaining a desired local or systemic physiological or phar 0018. As used herein and in the claims, the singular forms macological effect relating at least to the treatment of eye “a,” “an,” and “the include the plural reference unless the infections, or modification of the immune response, such as context clearly indicates otherwise. Thus, for example, the preventing and treating transplant rejection, and providing reference to an excipient is a reference to one or more Such therapy for chronic dry eye syndrome. excipients, including equivalents thereof known to those 0024 More specifically, the LSBB formulations are useful skilled in the art. Other than in the operating examples, or for treating ocular conditions such as glaucoma, PVR, dia where otherwise indicated, all numbers expressing quantities betic retinopathy, uveitis, retinal edema, vein occlusion, of ingredients or reaction conditions used herein should be macular degeneration, Irvine-Gass Syndrome and CMV understood as modified in all instances by the term “about.” retinitis, corneal diseases such as keratitis, and corneal trans 0019 All patents and other publications identified are plantation rejection by mediating homograft rejection with incorporated herein by reference for the purpose of describ formulations comprising sirolimus or cyclosporine. The for ing and disclosing, for example, the methodologies described mulations may also be prepared as control-release eye drops in Such publications that might be used in connection with the for dry-eye or for controlling the immune response. Regard present invention, but are not to provide definitions of terms ing control of immune responses, the formulations may con inconsistent with those presented herein. These publications tain one or more of cyclosporine, sirolimus, or tacrolimus. are provided solely for their disclosure prior to the filing date Other intraocular uses include glaucoma treatments (e.g., of the present application. Nothing in this regard should be formulations including timolol or prostaglandins such as construed as an admission that the inventors are not entitled to latanoprost), antibiotic delivery, antibody delivery, and anti antedate such disclosure by virtue of prior invention or for any proliferatives delivery (e.g., paclitaxel). other reason. All Statements as to the date or representation as 0025. Additional maladies of the ocular tissues that may to the contents of these documents is based on information be treated with the formulations of the present invention available to the applicants and do not constitute any admis include eye lid indications such as hordeolum, chalazaion, sion as to the correctness of the dates or contents of these rosacea, blepharitis, squamous, and basal carcimona. Corneal documents. indications include corneal infections, dry eye, Fuchs' dys 0020. Unless defined otherwise, all technical and scien trophy, herpes Zoster (shingles), iridocorneal endothelial Syn tific terms used herein have the same meaning as those com drome, keratoconus, lattice dystrophy, map-dot-fingerprint monly understood to one of ordinary skill in the art to which dystrophy, herpes simplex, pterygium, Stevens-Johnson Syn this invention pertains. drome, acute or chronic focal immunological corneal graft US 2013/0324481 A1 Dec. 5, 2013 reaction or rejection and following any corneal transplant useful for lowering intraocular pressure, consists of a toco procedures. Diseases of the lacrimal glands include allergic, pheryl acetate and the prostaglandin, latanoprost. In vivo, eye inflammatory, infectious, traumatic, malignant, and autoim drops consisting of prostaglandin and tocopheryl acetate, mune diseases. Conjunctival indications include conjunctivi applied once weekly, maintained low intraocular pressure in tis (pink eye, allergic, bacterial, viral, giant papillary, kerato rabbit eyes for at least three months. conjunctivits, inclusion), neoplasms (dermoid cysts, 0029. A wide variety of other disease states are known by squamous cell carcinoma of the conjunctiva, papilloma, those of ordinary skill in the art, such as those described in acquired melanosis of the conjunctiva, malignant melanoma Goodman & Gilman, THE PHARMACOLOGICAL BASIS OF THERA of the conjunctiva, nevus of the conjunctiva, Vascular PEUTICs (McGraw Hill, 2001), and REMINGTON's PHARMACEUTI tumors), pterygium and pinguecula, Xerophalmia, Subconjuc CAL SCIENCES (Lippincott Williams & Wilkins; 20th ed., 2000). tival hemorrhage, dry-eye syndrome, and Sjögren's Syn Those to which the present invention may be applied may be drome. Glaucoma indications are open-angle glaucoma and determined by those with ordinary skill in the art without narrow angle glaucoma and neovascular glaucoma. Diseases undue experimentation. of the iris include albinism, aniridia, coloboma, iritis, mela 0030) Suitable classes of active agents for use in the sys noma, metastases and Waardenburg Syndrome, and epithelial tem of the present invention include, but are not limited to: cysts. Surgical indications are any post-Surgical inflamma Peptides and proteins such as cyclosporin, insulins, gluca tory and infection induced by Lasik corneal procedures, cata gon-like-peptides, growth hormones, insulin related growth ract extraction, glaucoma Surgery, conjunctival and/or factor, botulinum toxins (Botox, Allergan), antibodies, and mucous membrance transplantation. Other ocular maladies to heat shock proteins; Anesthetics and pain killing agents such be considered include exophthalmos, Scleritis, episcleritis, as lidocaine and related compounds, and benzodiazepam and Grave's disease, pseudotumor of the orbit, lymphoma of the related compounds; Anti-cancer agents such as 5-fluorou orbit, tumors of the orbit, orbital cellulitis, pre-phthisical racil, methotrexate and related compounds; Anti-inflamma ocular hypotomy, neovascular glaucoma, and anterior uveitis tory agents such as 6-mannose phosphate; Anti-fungal agents of inflammatory or infectious etiology. Such as fluconazole and related compounds; Antiviral agents 0026. Further regarding corneal indications, an aspect of Such as trisodium phosphomonoformate, trifluorothymidine, the invention provides for a formulation for limiting tissue acyclovir, cidofovir, ganciclovir, ddI, and AZT: Cell trans rejection following corneal transplant. Corneal transplant, port/mobility impeding agents such as colchicines, Vincris also known as a corneal graft or penetrating keratoplasty, tine, cytochalasin B, and related compounds; Anti-glaucoma involves the removal of the central portion (called a button) drugs such as beta-blockers: timolol, betaxolol, and atenolol; of the diseased cornea and replacing it with a matched donor Immunological response modifiers such as muramyl dipep button of cornea. Corneal grafts are performed on patients tide and related compounds; Steroidal compounds Such as whose damaged or Scarred corneas (a result of disease or dexamethasone, prednisolone, triamcinolone and related trauma), prevent acceptable vision. Formulations of the compounds; and Carbonic anhydrase inhibitors such as aceta present invention useful in corneal transplant contexts may Zolamide, brinzolamide, dorzolamide, and timolol maleate. include rapamycin, cyclosporin, or a combination of these 0031. In addition to the above agents, other active agents active agents. which are suitable for administration, especially to the eye 0027. Some common types of beneficial agents adminis and its Surrounding tissues, to produce a local or a systemic tered by topical eye drops for treatment of the maladies of the physiologic orpharmacologic effect can be used in the system eye and contemplated for the formulations of the present of the present invention. Examples of Such agents include invention include B-blockers, prostaglandin analogs, C2-adr antibiotics Such as tetracycline, chloramphenicol, ciprofloxa energic agonists, miotic agents, sympathomimetics, carbonic cin, amplicillin, and the like. anhydrase inhibitors, antibiotics, steroidal anti-inflammato 0032. The present formulations provide for the use of for ries, NSAIDs, antihistamines, immunosuppressive agents, mulations comprising excipients characterized as of limited and lubricants. solubility, biocompatible, and biodegradable (LSBB), for 0028. Further regarding glaucoma or increased intraocular controlled and Sustained release of an active agent or a com pressure, medication classes historically used in the manage bination of active agents. Liquid or gel controlled-Sustained ment of glaucoma include beta blockers, miotics, sympatho release systems can be fabricated by combining an LSBB mimetics and carbonic anhydrase inhibitors. Because topi excipient and an active agent. Formulations may include cally applied medications are more site-specific, they are more than one biodegradable component as well as more than preferred in the treatment of glaucoma. Compared with oral one active agent. Gels can be produced by Vortex or mechani medications, topical agents are associated with a decreased cal mixing. Liquid formulations can be made by pre-mixing incidence of systemic side effects. With current topical for in a suitable container, or mixing of the excipient and the mulations, conjunctival and localized skin allergic reactions active agent before or at the time of administration. A typical are fairly common, whereas severe reactions, including method of mixing an excipient and active agent uses Sonica death, are rare. Recently introduced topical agents for glau tion. comatherapy include dorzolamide and brinzolamide, the first 0033. As noted, the excipient of the present invention is topical carbonic anhydrase inhibitors; brimonidine and apra biodegradable or bioerodible. As used herein, the terms “bio clonidine, more ocular-specific alpha agonists; and latano erodible' and “biodegradable' are equivalent and are used prost, a prostaglandin analog, which is a new class of glau interchangeably. Biodegradable excipients are those which coma medication. Like their predecessors, the newer agents degrade in Vivo, and wherein erosion of the excipient over lower intraocular pressure by a statistically significant time is required to achieve the agent release kinetics accord degree. Preservation of visual field, the more substantial ing to the invention. patient-oriented end point, continues to be studied. An 0034. The excipient is also biocompatible, meaning that it example formulation of the present invention, particularly does not have undue toxicity or cause either physiologically US 2013/0324481 A1 Dec. 5, 2013 or pharmacologically harmful effects. In the context of topi Sustained release of pharmaceutical agents for periods up to cal formulations for the eye, it should be understood that one week from a single application, without interfering with Some initial 'stinging or minor discomfort is common with vision. eye drops, but such minor reactions do not render the present 0039. In another aspect of the invention, a low solubility formulations non-biocompatible. active agent may be combined with a biodegradable, biocom patible excipient of higher solubility to result in a LSBB 0035. In an aspect of the present invention, the novel bio formulation. For example, dimethylsulfone may be used as a compatible and biodegradable liquid and gel formulations, binder in a LSBB formulation of a limited solubility active which may be conveniently topically placed on the human or agent. Hence, the use of a soluble excipient in a LSBB for animal eye for the Sustained release of active agent(s), are mulation is within the scope of the present invention. obtained by admixing one or more excipients, such as, for 0040. In yet another aspect of the invention, a surfactant example: d. 1 and dl isomers of C, B, Ö, e, m tocopherols and may also be included in the formulation, particularly when similar isomers of the tocotrienols and the esters of these the active agent is in an aqueous solution or state. For tocopherols and tocotrienols with straight and branched chain example, TPGS is a pharmaceutically approved surfactant C2 to C20 aliphatic acids, or their esters of C3 to C20 straight constructed from lipophilic C. tocopherol attached to hydro chain dicarboxylic acids; the mono, di, and triesters of O-ace philic PEG 1000 through a succinate linkage. TPGS may be tylcitric acid or O-propionylcitric acid or O-butyrylcitric acid used in tocopherol formulations (such as dl-Ctocopheryl with C1 to C10 straight and branched chain aliphatic alco acetate) in which the aqueous component exceeds about 0.5% hols; the mono, di, and triesters of citric acid with C1 to C10 (wt). For example, a stable mixture of saline and a tocopheryl straight and branched chain aliphatic alcohols; and omega-3 acetate (EA) may be prepared (for example, by Sonication) in fatty acids or esters thereof; with a large number of estab ratios ranging from about 1:2 to 1:4 (saline:EA). water and lished and new active agents. EA may be prepared in stable formulations at ratios ranging 0036. In another aspect of the invention, the gel formula from about 1:2 to 1:4 (HO:EA) with TPGS added at about tions generally contain about 20% to about 80% of an LSBB 2.5% as an emulsifier. These emulsions are stable, and suit excipient, and liquid formulations generally contain about able for aqueous-based active agents. 30% to about 99.9% of an LSBB excipient. These proportions 0041 Any pharmaceutically acceptable form of the active depend on the nature (e.g., Solubility) of the particular active agents of the present invention may be employed in the prac agent and the particular LSBB excipient. It should be noted tice of the present invention, e.g., the free base or a pharma that the active agent and the LSBB excipient provides the ceutically acceptable salt or ester thereof. Pharmaceutically Sustained release of the active agent, rather than additional acceptable salts, for instance, include Sulfate, lactate, acetate, excipients (e.g., coatings) or delivery vehicles (e.g., struc Stearate, hydrochloride, tartrate, maleate, citrate, phosphate, tures). and the like. 0042. The active agents may also be used in combination 0037 Examples of excipients that may be useful as bio with pharmaceutically acceptable carriers in additional ingre compatible, biodegradable and/or bioerodible excipients in dients such as antioxidants, stabilizing agents, and diffusion the present invention, as determined by one of ordinary skill enhancers. For example, where water uptake by the active in the art in light of this specification, without undue experi agent is undesired, the active agent can be formulated in a mentation, include, but are not limited to d-C-tocopherol; hydrophobic carrier, Such as a wax or an oil, that would allow d.1-C-tocopherol; d-B-tocopherol; d.l-B-tocopherol; d-m-to sufficient diffusion of the active agent from the system. Such copherol; and d.l-m-tocopherol (including acetate); tocot carriers are well known in the art. rienol isomers, and their esters, tocotrienol isomers; the 0043. Examples of proteins and proteinaceous com mono, di, and triesters of O-acetylcitric acid or O-propionyl pounds which may beformulated and employed in the deliv citric acid or O-butyrylcitric acid with C1 to C10 straight and ery system according to the present invention include those branched chain aliphatic alcohols, the mono, di, and triesters proteins which have biological activity or which may be used of citric acid with C1 to C10 straight and branched chain to treat a disease or other pathological condition. They aliphatic alcohols; and omega three fatty acids and their include, but are not limited to antibodies, growth hormone, esterS. Factor VIII, Factor IX and other coagulation factors, chymot 0038. Further regarding tocopherols, this biodegradable/ rypsin, trysinogen, alpha-interferon, beta-galactosidase, lac biocompatible excipient useful in the present invention refers tate dehydrogenase, growth factors, clotting factors, to the family of tocopherols and tocotrienols and derivatives enzymes, immune response stimulators, cytokines, lymphok thereof. Tocopherols and tocotrienols are derivatives of the ines, interferons, immunoglobulins, retroviruses, interleu simplest tocopherol, 6-hydroxy-2-methyl-2-phytylchroman. kins, peptides. Somatostatin, Somatotropin analogues, Tocopherols are also known as a family of natural or synthetic Somatomedin-C, Gonadotropic releasing hormone, follicle compounds commonly called Vitamin E. Alpha-tocopherol is stimulating hormone, luteinizing hormone, LHRH, LHRH the most abundant and active form of this class of compounds. analogues such as leuprolide, nafarelin and geserelin, LHRH Other members of this class include B-, y-, and e-tocopherols agonists and antagonists, growth hormone releasing factor, and C-tocopherol derivatives such as tocopheryl acetate, suc calcitonin, colchicines, gonadotropins such as chorionic cinate, nicotinate, and linoleate, but the latter derivatives may gonadotropin, oxytocin, octreotide. Somatotropin plus and have limited solubility that renders them unsuitable for some amino acid, vasopressin, adrenocorticotrophic hormone, epi formulations. Useful tocotrienols include d-e-tocotreinols, dermal growth factor, prolactin, Somatotropin plus a protein, and d-B-, d-y-tocotrienols, and their esters. In particular, the cosyntropin, lypressin, polypeptides Such as thyrotropin tocopherols and their esters of low water solubility, notably releasing hormone, thyroid stimulation hormone, secretin, C-tocopheryl acetate, are exceptional vehicles for biocompat pancreozymin, enkephalin, glucagons, and endocrine agents ible nonirritating topical eye drop formulations that provide secreted internally and distributed by way of the bloodstream. US 2013/0324481 A1 Dec. 5, 2013

0044 Other agents, such as C. antitrypsin, insulin, gluca Valerate, and -21-phosphate disodium salts; beclomethasone; gon-like-peptides, and other peptide hormones, botulinum beclomethasone dipropionate; difloraSone; diflorasone diac toxins (Botox R, Allergan, Inc.), adrenal cortical stimulating etate; mometasone furoate; and acetazolamide (DiamoX(R), hormone, thyroid stimulating hormone, and other pituitary Lederle Parenterals, Inc., Carolina, Puerto Rico; several other hormones, interferons such as C. B. and Ö interferon, eryth manufacturers); ropoietin, growth factors such as GCSFm GM-CSF, insulin 0050 Anti-neovascularization Steroids such as 21-nor like growth factor 1, tissue plasminogen activator, CFA, 53-pregrian-3C.17C.20-triol-3-acetate; 21-nor-5C-pregnan dDAVP. tumor necrosis factor receptor, pancreatic enzymes, 3C, 17C, 20-triol-3-phosphate; 21-nor-5 f-pregn-17(20)en lactase, interleukin-1 receptor antagonist, interleukin-2, 3C, 16-diol; 21-nor-5 B-pregnan-3C.17C,20-triol: tumor Suppresser proteins, cytotoxic proteins, viruses, viral 20-acetamide-21-nor-5 f-pregnan-3ol.17C.-diol-3-acetate; 3 B proteins, recombinant antibodies, portions of antibodies, and acetamido-53-pregnan-113,17C.21-triol-20-one-21-acetate; antibody fragments and the like may be used. Analogs, 21-nor-5C.-pregnan-3ol. 17.3.20-triol; 21C.-methyl-5f-preg derivatives, antagonists, agonists, and pharmaceutically nan-3C., 11B,17C.21-tetrol-20-one-21-methyl ether; acceptable salts of the above may also be used. 20-azido-21-nor-5f-pregnan-3C, 17C.-diol; 200carbethoxym 0045. The protein compounds useful in the formulations ethyl)thio-21-nor-5?-pregnan-3ol.17C.-diol; 20-(4-fluo of the present invention can be used in the form of a salt, rophenyl)thio-21-nor-5f-pregnan-3C, 17o-diol; 16C.-(2-hy preferably a pharmaceutically acceptable salt. Useful salts droxyethyl)-17f8-methyl-5B-androstan-3C, 17C. diol; are known to those skilled in the art and include salts with 20-cyano-21-nor-53-pregnan-3ol.17C-diol; 17C.-methyl-5 f inorganic acids, organic acids, inorganic bases, or organic androstan-3C, 17 B-diol; 21-nor-53-pregn-17(20)en-3C-ol; bases. 21-nor -5.3-pregn-17(20)en-3C-ol-3-acetate; 21-nor-5- 0046. Other active agents encompassed in the present pregn-17(20)-en-3C-ol-16-acetic acid 3-acetate; 3 B-azido invention include prodrugs. Because prodrugs are known to 5 B-pregnan-113,17C.21-triol-20-one-21-acetate; and enhance numerous desirable qualities of pharmaceuticals 5 B-pregnan-113,17C.21-triol-20-one: 4-androsten-3-one (e.g., solubility, bioavailability, manufacturing, etc.) the phar 17 B-carboxylic acid; 17O-ethynyl-5(10)-estren-17 B-ol-3- maceutical dosage forms of the present invention may contain one; and 17O-ethynyl-1,3,5(10)-estratrien-3,173-diol; compounds in prodrug form. Thus, the present invention is 0051. Nonsteroidal Anti-inflammatories such as naproxin; intended to cover prodrugs of the presently claimed active diclofenac; celecoxib (Celebrex R, Pfizer); sulindac: agents, methods of delivering the same, and compositions diflunisal; piroxicam, indomethacin: etodolac, meloxicam, containing the same. ibuprofen, ketoprofen; r-flurbiprofen (Myriad Genetics, 0047 Analogs. Such as a compound that comprises a Inc.); mefenamic: nabumetone; tolmetin, and sodium salts of chemically modified form of a specific compound or class each of the foregoing, ketorolac bromethamine, ketorolac thereof, and that maintains the pharmaceutical and/or phar tromethamine (Acular R, Allergan, Inc.); choline magnesium macological activities characteristic of said compound or trisalicylate; rofecoxib; Valdecoxib; lumiracoxib: etoricoxib; class, are also encompassed in the present invention. Simi aspirin; salicylic acid and its sodium salt; Salicylate esters of larly, derivatives such as a chemically modified compound C. B. Y-tocopherols and tocotrienols (and all their d, 1, and wherein the modification is considered routine by the ordi racemic isomers); methyl, ethyl, propyl, isopropyl. n-butyl, nary skilled chemist, such as an ester or an amide of an acid, sec-butyl, t-butyl, esters of acetylsalicylic acid; tenoxicam, protecting groups, such as a benzyl group for an alcohol or aceclofenac; nimeSulide; nepafenac; amfenac; bromfenac; thiol, and tert-butoxycarbonyl group flufenamate; and phenylbutaZone; 0048 Active agents, or active ingredients, or beneficial 0052 Angiogenesis Inhibitors such as squalamine, agents, that may be useful in the present invention singly or in squalamine lactate (EvizonTM, Genaear Corp.) and curcumin; combination, as determined by one of ordinary skill in the art Vascular endothelial growth factor (VEGF) inhibitors includ in light of this specification without undue experimentation, ing pegaptainib (Macugen R, Eyetech/Pfizer), bevacizumab include but are not limited to the following agents and the (Avastin R, Genentech, Inc.), concentrated shark cartilage pharmaceutically acceptable salts thereof: extract (Neovastat(R), AEterna Zentaris), PTK787 (vatalanib, 0049 Angiostatic and/or Anti-inflammatory Steroids such Schering AG/Novartis), ribozyme anti-angiogenic (An as anecortive acetate (Retaane(R), Alcon, Inc., Fort Worth, giozyme(R), Sigma Therapeutics, Inc./Chiron Corp.); AZD Tex.): tetrahydrocortisol; 4.9(11)-pregnadien-17C,21-diol-3, 6474 (Zactima R, AstraZeneca AB Ltd.), anti-angiogenesis 20-dione (Anecortave) and its -21-acetate salt; 1'-epicortisol: chimeric monoclonal antibody specific VEGF receptor 2 17O-hydroxyprogesterone; tetrahydrocortexolone; corti (IMC-1C11, ImClone Sys. Inc.), isocoumarin 2-(8-hydroxy Sona; cortisone acetate; hydrocortisone; hydrocortisone 6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid acetate; fludrocortisone; fludrocortisone acetate; fludrocorti (NM-3, Ilex Oncology Inc.), SU668 (Pfizer), isopropoxym Sone phosphate; prednisone; prednisolone; prednisolone ethyl-12-(3-hydroxypropyl) ideno2,1-alpyrro3,4-ccarba Sodium phosphate; methylprednisolone; methylprednisolone Zole-5-one(CEP-5214, Cephalon), CEP-7055 (the N,N-dim acetate; methylprednisolone, Sodium Succinate; triamcino ethyl glycine ester prodrug of CEP-5214, Cephalon), and lone; triamcinolone-16,21-diacetate; triamcinolone PTC299 (PTC Therapeutics); Integrin antagonists such as acetonide and its -21-acetate, -21-disodium phosphate, and anti-CfB antibody (Vitaxin R, Medimmune Inc.); RDG pep -21-hemisuccinate forms; triamcinolone benetonide; triam tide mimetics such as S137 and S247 (Pfizer), conformation cinolone hexacetonide; fluocinolone and fluocinolone ally constrained bicyclic lactam Arg-Gly-Asp-containing acetate; dexamethasone and its 21-acetate, -21-(3.3-dimeth pseudopeptides such as ST1646 (Sigma Tau S.p.A.); DPC ylbutyrate), -21-phosphate disodium salt, -21-diethylami A803350 (Bristol-Myers Squibb), and o-guanidines (3D noacetate, -21-isonicotinate, -21-dipropionate, and -21 Pharmaceuticals Inc.); matrix metalloproteinase inhibitors palmitate forms; betamethasone and its -21-acetate, -21 such as prinomastat (AG 3340, Pfizer), (ISV-616, InSite adamantoate, -17-benzoate, -17.21-dipropionate, -17 Vision), (TIMP-3, NIH): 53304 (Shionogi); BMS 275291 US 2013/0324481 A1 Dec. 5, 2013

(Celltech/Bristol-Myers Squibb); SC 77964 (Pfizer); ranibi hydrochloride, Sulfate, or phosphate salt, tetracycline and its Zumab (Lucentis(R), Genentech, Inc.); ABT 518 (Abbott hydrochloride, Sulfate, orphosphate salt; oxytetracycline and Labs.); CV 247 (Ivy Medical): NX-278-L anti-VEGF its hydrochloride, sulfate, orphosphate salt; chlortetracycline aptamer (EyeTech Pharm.); 2'-O-methoxyethyl antisense and its hydrochloride, Sulfate, or phosphate salt; metronida C-raf oncogene inhibitor (ISIS-13650, Isis Pharm., Inc/iCo Zole; rifampin; dapsone; atovaquone; rifabutin: lineZolide; Therapeuticals, Inc.); vitronectin and osteopontinantagonists polymyxin Band its hydrochloride, Sulfate, orphosphate salt; (3D Pharm.); combretstatin A-4 phosphate (CA4P. OxiGene, Sulfacetamide and its sodium salt; minocycline; and clarithro Inc.); fab fragment C.-V/B-1 integrin antagonist (Eos-200-F, mycin; Protein Design Labs); O.-V/B-3 integrin antagonist (Abbott 0054 Anti-infective Agents such as 2,4-diaminopyrim Labs.); urokinase plasminogen activator fragment (A6, Ang idines (e.g., brodimoprim, tetroXoprim, trimethoprim); nitro strom Pharm.); VEGF antagonists (including AAV-PEDF, furans (e.g., furaltadone, furazolium chloride, nifuradene, Chiron Corp.; VEGF-R, Johnson & Johnson/Celltech: nifuratel, nifurfoline, nifurpirinol, nifurprazine, nifurtoinol, SU10944, Sugen/Pfizer; VEGF-TRAP, Regeneron; SP-(V5. nitrofurantoin); quinolones and analogs (e.g., cinoxacin, 2)C, Supratek Pharm. Inc.; endostatin VEGF antagonist, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, EntreMed, Inc. (Rockville, Md.): kdr tyrosine kinase inhibi flumequine, gatifloxacin, grepafloxacin, lomefloxacin, tor (EG-3306, Ark Therapeutics); cytochalasin E (NIH): kal miloxacin, nadifloxacin, nalidixic acid, norfloxacin, ofloxa likrinin-binding protein (Medical Univ. SC); combretastatin cin, oxolinic acid, paZufloxacin, pefloxacin, pipemidic acid, analog (MV-5-40, Tulane); pigment-epithelium derived piromidic acid, roSoxacin, rufloxacin, sparfloxacin, tema growth factor (Med. Univ. SC); AdPEDF, GenVec, Inc.); floxacin, toSufloxacin, trovalioxacin); Sulfonamides (e.g., plasminogenkringle (Medical Univ. SC); rapamycin; cytok acetyl Sulfamethoxypyrazine, benzylsulfamide, chloramine ine synthesis inhibitor/p38 mitogen-activated protein kinase b, chloramine-t, dichloramine t, n-formylsulfisomidine, inhibitor (SB-220025, GlaxoSmithKline); FGF1 receptor n-?3-d-glucosylsulfanilamide, mafenide, 4'-(methylsulfa antagonist/tyrosine kinase inhibitor (Pfizer/Sugen); bradyki moyl) sulfanilanilide, noprylsulfamide, phthalylsulfaceta nin B1 receptor antagonist (B-9858, Cortech, Inc.); bacteri mide, phthalylsulfathiazole, Salazosulfadimidine, Succinyl cidal/permeability-increasing protein (Neuprex R, Xoma sulfathiazole, Sulfabenzamide, Sulfacetamide, Ltd.); protein kinase C inhibitor (Hypericin, Sigma-Aldrich, Sulfachlorpyridazine, Sulfachrysoidine, Sulfacytine, Sulfadi St. Louis, Mo.); ruboxistaurinn mesylate (LY-333531, Eli azine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Sulfa Lilly & Co.); polysulphonic acid derivatives (Fuji Photo ethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Sulfaloxic Film); growth factorantagonists such as TBC-2653 and TBC acid, Sulfamerazine, Sulfameter, Sulfamethazine, Sulfame 3685 (Texas Biotech. Corp.); Tunica internal endothelial cell thizole, Sulfamethomidine, Sulfamethoxazole, Sulfamethoxy kinase (Amgen Inc.); pyridazine, Sulfametrole, Sulfamidochrysoidine, Sulfamox 0053 Anti-bacterials including aztreonam, cefotetan and ole, Sulfanilamide, 4-Sulfanilamidosalicylic acid, its disodium salt; loracarbef, cefoxitin and its Sodium salt; n-sulfanilylsulfanilamide, sulfanilylurea, n-sulfanilyl-3,4- cefazolin and its sodium salt, cefaclor, ceftibuten and its Xylamide, Sulfanitran, Sulfaperine, Sulfaphenazole, Sul Sodium salt, ceftizoxime; ceftizoxime Sodium salt, cefopera faproxyline, Sulfapyrazine, Sulfapyridine, Sulfasomizole, Sul Zone and its Sodium salt, cefuroxime and its sodium salt; fasymazine, Sulfathiazole, Sulfathiourea, Sulfatolamide, cefuroxime axetil, cefprozil; ceftazidime; cefotaxime and its Sulfisomidine, Sulfisoxazole); Sulfones (e.g., acedapsone, Sodium salt, cefadroxil, ceftazidime and its Sodium salt; acediasulfone, acetosulfone sodium, dapsone, diathymosul cephalexin, cefamandole nafate; cefepime and its hydrochlo fone, glucosulfone sodium, Solasulfone, Succisulfone, Sulfa ride, Sulfate, and phosphate salt, cefdinir and its sodium salt; nilic acid, p-sulfanilylbenzylamine, Sulfoxone sodium, thia ceftriaxone and its sodium salt, cefixime and its sodium salt; Zolsulfone); and others (e.g., clofoctol, hexedine, cefpodoxime proxetil; meropenem and its sodium salt; imi methenamine, methenamine anhydromethylene-citrate, penem and its sodium salt; cilastatin and its sodium salt; methenamine hippurate, methenamine mandelate, meth azithromycin; clarithromycin; dirithromycin; erythromycin enamine Sulfosalicylate, nitroxoline, taurolidine, and Xibo and hydrochloride, Sulfate, orphosphate salts ethylsuccinate, mol); moxilloxacin; and gatifloxacin; and Stearate forms thereof; clindamycin; clindamycin hydro 0055 Antivirals such as amprenavir; interferon alfa-n3; chloride, Sulfate, or phosphate salt; lincomycin and hydro interferon alfa-2b: interferon alfacon-1; peginterferon alfa chloride, sulfate, orphosphate salt thereof; tobramycin and its 2b; interferon alfa-2a; lamivudine; zidovudine; amadine hydrochloride, Sulfate, orphosphate salt; Streptomycin and its (Symmetrel(R), Endo Pharm. Inc.) and its hydrochloride, sul hydrochloride, Sulfate, or phosphate salt; Vancomycin and its fate, and phosphate salts; indinavir and its hydrochloride, hydrochloride, Sulfate, or phosphate salt; neomycin and its Sulfate, or phosphate salt; ganciclovir, ganciclovir Sodium hydrochloride, Sulfate, or phosphate salt; acetyl sulfisox salt; famciclovir, rimantadine and its hydrochloride, Sulfate, azole; colistimethate and its sodium salt, quinupristin; dalfo orphosphate salt, saquinavir mesylate; foscarnet; Zalcitabine; pristin; amoxicillin; amplicillin and its sodium salt; clavulanic ritonavir, ribavirin; Zanamivir; delavirdine mesylate: acid and its sodium or potassium salt; penicillin G., penicillin efavirenz; amantadine and its hydrochloride, Sulfate, orphos G benzathine, or procaine salt; penicillin G Sodium or potas phate salt; palivizumab, oseltamivir and its hydrochloride, sium salt; carbenicillin and its disodium or indanyl disodium Sulfate, or phosphate salt; abacavir and its hydrochloride, salt; piperacillin and its sodium salt; ticarcillin and its diso Sulfate, or phosphate salt; Valganciclovir and its hydrochlo dium salt; Sulbactam and its sodium salt; moxifloxacin; cipro ride, Sulfate, or phosphate salt; Valacyclovir and its hydro floxacing ofloxacin; levofloxacins; norfloxacin; gatifloxacin; chloride, Sulfate, or phosphate salt; didanosine; nelfinavir trovafloxacin mesylate; alatrofloxacin mesylate; trimethop mesylate; nevirapine; eidofovir, acyclovir, trifluridine; pen rim; Sulfamethoxazole; demeclocycline and its hydrochlo ciclovir, Zinc oxide; Zinc salicylate; Zinc salts of all isomers of ride, Sulfate, or phosphate salt, doxycycline and its hydro tocopherol hemisucenic acid; Zinc salts of straight, branched, chloride, Sulfate, or phosphate salt; minocycline and its saturated, and unsaturated chain C to Coaliphatic carboxy US 2013/0324481 A1 Dec. 5, 2013 lic acids; Zinc pyruvate; Zinc lactate; Zinc ester complexes; and its hydrochloride, Sulfate, or phosphate forms; and and Zinc acetoacetonate or Zinc acetoacetic ester complexes; promethazine and its hydrochloride, Sulfate, or phosphate 0056. Insulins such as NovologR) (insulin aspart rDNA forms; origin) and Novolin R products (Novo Nordisk Inc.); Huma 0.066 Antimicrotubule Agents such as Taxoids including log(R) (insulin lispro rDNA origin), HumalogR 75/25 and paclitaxel (Taxol.R., Bristol-Myers Squibb); Vincristine (On 50/50 (mixtures of insulin lispro protamine suspension and covinR), Eli Lilly & Co.) and its hydrochloride, sulfate, or insulin lispro), and Humulin(R) products (regular human insu phosphate salt forms; vinblastine (Velber, Eli Lilly & Co.) lin rDNA origin, Eli Lilly & Co.); Lantus(R) (insulin glargine and its hydrochloride, sulfate, or phosphate salt; vinorelbine IrDNA origin, Sanofi Aventis U.S. LLC); porcine and bovine (Navelbine(R, Fabre Pharm. Inc.); colchicines; docetaxel insulins; (TaxotereR, Sanofi-Aventis U.S. LLC); RPR-109881 0057 Glucagon-like Peptide-1 (Glp1) and analogs (for (Sanofi-Aventis); LIT 976 (Sanofi-Aventis); EMS 188797 diabetes therapy and appetite Suppression, cardiac protec and BMS 184476 (Bristol-Myers Squibb); DJ 927 (Daiichi tion) (see Keiffer et al., 20 Endocr Rev., 876-913 (1999) such Pharm. Inc.); DHA-paclitaxel (Taxoprexin R, Protarga, Inc.); as liraglutide (Novo Nordisk Inc.); Glp1 receptor stimulators Epothilones including epothiloneB such as patupilone (EPO Such as Such as Byetta R products (exenatide, and incretin 906, Novartis/generic), BMS 247550 and BMS-310705 mimetic, Amylin Pharm., Inc./Eli Lilly & Co.) and ZP-10 (Bristol-Myers Squibb), epothilone D (KOS 862, Kosan Bio (Zealand Pharma A/S); Glp-1-albumin (ConjuChem. Inc.); sci, Inc.), and ZK EPO (Schering AG); and Dpp-IV inhibitors (which inhibit enzyme attack on Glp 0067. Antineoplastic agents such as doxorubicin and its 1) such as Galvus(R (vildagliptin, formerly LAF237, Novar hydrochloride, Sulfate, or phosphate salt, idarubicin and its tis), Januvia(R) sitagliptin, formerly MK-0431, Merck & Co.); hydrochloride, Sulfate, or phosphate salt; daunorubicin and saxagliptin (formerly BMS-477188, Bristol-Myers Squibb), its hydrochloride, Sulfate, or phosphate salt, dactinomycin; epirubicin and its hydrochloride, Sulfate, or phosphate salt; and GSK23A (GlaxoSmithKline); dacarbazine; plicamycin; mitoxantrone (Novantrone.R., EMD 0058 Alpha Androgenergic Agonist such as brimonidine Serono Inc.) and its hydrochloride, Sulfate, or phosphate salt; tartrate; valrubicin; cytarabine; nilutamide: bicalutamide; flutamide: 0059 Beta Adrenergic Blocking Agents (Beta blockers) anastroZole; exemestane; toremifene; femara; tamoxifen and such as betaxolol (Betoptic(R), Betoptic(R) S betaxolol hydro tamoxifen citrate; temozolomide (Temador, Schering-Plough chloride Suspension, Alcon Labs., Inc.), and its hydrochlo Corp.); gemcitabine and its hydrochloride, Sulfate, or phos ride, sulfate, or phosphate salt; levobetaxolol and its hydro phate salt; topotecan and its hydrochloride, Sulfate, or phos chloride, Sulfate, or phosphate salt; and timolol maleate phate salt; Vincristine and its hydrochloride, Sulfate, or phos (Timoptic(R), Timoptic-XER, timolol maleate ophthalmic phate salt; liposomal Vincristine (Teva Pharm.); methotrexate gel-forming solution, Merck & Co.), levobunolol (Betagan R. and methotrexate Sodium salt; cyclophosphamide, estramus levobunolol hydrochloride ophthalmic solution, Allergan), tine sodium phosphate; leuprolide and leuprolide acetate; carteolol (Ocupress.(R), carteolol hydrochloride ophthalmic goserelin and goserelin acetate; estradiol; ethinyl estradiol; solution, CIBA Vision Sterile Mfg./Novartis Ophthalmics), Menest(R) esterified estrogens (Monarch Pharm., Inc.); metipranolol (OptiPranolol R, metipranolol ophthalmic solu 5-fluorouracil; bortezamib (Velcade(R), Millenium Pharm., tion, Bausch & Lomb): Inc.); 0060 Carbonic Anhydrase Inhibitors such as brinzola 0068 Antiapoptotics such as desmethyldeprenyl (DES, mide (Azopt R, brinzolamide hydrochloride, Alcon Labs. RetinaPharma Tech., Inc., Philadelphia, Pa.); Inc.), dorzolamide (Trusopter, dorzolamide hydrochloride, 0069. Aldose Reductase Inhibitors such as GP-1447 Merck & Co.), and its drochloride, sulfate, or phosphate salt; (Grelan): NZ-314 (parabanic acid derivative, Nippon Zoki); and dichlorphenamide (Merck); SG-210 (Mitsubishi Pharma/Senju); and SJA-7059 (Senju); 0061 Sympathomimtics such as epinephrine-like dipiv 0070 Antihypertensives such as candesartan cilexetil efrin (Propine(R), dipivefrin hydrochloride, Allergan), and (AtacandR, Takeda Pharm. Co./AstraZeneca AB); losartan clonodine-like bimonidine (Alphagan R., brimonidine tar (Cozaar R and Hyzaar R, Merck & Co.); and lisinopril trate, Allergan) and apraclonidine (Iopidine R, aprapcloni (ZestrilR), AstraZeneea AB and Prinivil(R), Merck & Co.); dine hydrochloride, Alcon); 0071 Antioxidants such as benfotiamine (Albert Einstein 0062 Mast Cell Stabilizers such as pemirolast (Alamast(R) College Med.../WorWag Pharma); ascorbic acid and its esters: pemirolast potassium ophthalmic Solution, Vistakon tocopherol isomers and their esters; and raxofelast (IRFI 016, metabolized to IRFI 005, Biomedica Panama); Pharma., LLC), and its potassium salt; nedocromil oph 0072 Vitrectomy Agents such as hyaluronidase (Vit thalmic (Alocril R. Allergan, Inc.) and its sodium salt; cro rase(R), ISTA Pharm., Inc.); molyn and its sodium salt (PendoPharm): 0073 Adenosine Receptor Antagonist such as A2B 0063 Miotics (Cholinesterase Inhibitors) such as deme adenosine receptor antagonist (ATL-754, Adenosine Thera carium bromide, pilocarpine (Isopto Carpine, Ocusert Pilo); peutics, LLC); 0.064 Prostaglandins and prostaglandin alalogs such as 0074 Adenosine Deaminase Inhibitor such as pentostatin bimatoprost (Lumigan R. bimatoprost ophthalmic solution, (Nipent(R), SuperGen Inc.); Allergan); travoprost (Travatan(R) travoprost ophthalmic Solu 0075 Glycosylation Antagonists such as pyridoxamine tion, Alcon Inc.); and latanoprost (Xalatan(R) latanaprostoph (PyridorinTM, NephroGenex Inc.); thalmic solution, Pfizer); 0076 Topoisomerase Inhibitors such as doxorubicin 0065 Antihistamines such as olopatadine and its hydro (Adriamycin R, Pfizer; CaelyxTM Schering-Plough Pharm.: chloride, Sulfate, or phosphate salt forms; feXofenadine and Doxil R. Johnson & Johnson/Pharmacial generics); daunoru its hydrochloride, Sulfate, orphosphate salt; azelastine and its bicin (DaunoXome(R), Gilead Sci.): etoposide (Vepesider) and hydrochloride, Sulfate, orphosphate forms; diphenhydramine Etopophos(R), Bristol-Myers Squibb); idarubicin (Idamycin US 2013/0324481 A1 Dec. 5, 2013

PFSR, Pfizer); irinotecan (Camptosar R, Pfizer); topotecan betamethasone-17,21-dipropionate; betamethasone-17-val (Hycamtin R, GlaxoSmithKline); epirubicin (Ellence(R), erate; betamethasone-21-phosphate disodium salt; naproxen; Pfizer); and raltitrexed (Tomudex(R), AstraZeneca); diclofenac; celecoxib: rofecoxib; Valdecoxib: etoricocib; 0077 Anti-metabolites such as methotrexate (generic) lumiracoxib; pegaptainib octasodium, 2-methoxyestradiol; and its sodium salt; 5-fluorouracil (Adrucil(R), Teva Pharm. combretstatin A-4 phosphate (CA4P. Oxigene); urokinase U.S.): cytarabine (Cytosar R, Upjohn Co.); fludarabine (Flu plasminogen activator fragment (A6, Angstrom Pharm.); dara R, Bayer HealthCare Pharm.) and its forms as salts with bradykinin B1 receptor antagonist (B-9858, Cortech); acetyl acids; gemcitabine (Gemzar(R), Eli Lilly & Co.); capecitabine cysteine; mannitol; antineoplaston; human corticotropin-re (Xeloda(R), Roche Labs. Inc.); and perillyl alcohol (POH, leasing factor; VN4010.1M (Pediatric Brain Tumor Consor Endorex): tium); everolimus; GW572016 (NCI); thalidomide: 0078. Therapeutic Antibodies including Herceptin R (tras temozolomide; tariquidar, doxorubicin; dalteparin, tarceva; tuzumab, Genentech, Inc.); MDX-H210 (Medarex, Inc.); SGN-15 (Seattle Genetics); H11 (Viventia); Therex (Anti CC-5013 (NCI);hCRF (Xerecept(R) corticorelinacetate injec soma); rituximan (Rituxan.R., Genentech); Campath (ILEX tion, Neurobiological Tech., Inc., Emeryville, Calif.); mel Oncology/Millennium/Shering); Mylotarg (Celltech/Wy phalan; thiotepa, depsipeptide; erlotinib.: tamoxifen; bort eth); Zevalin (IDEC Pharmaceuticals/Schering); to situmo eZomib; lenalidomide; Vorinostat; temsirolimus; modifinil; mab (Bexxar R, GlaxoSmithKline); epratuzumab (Lympho enzastuarin; motexafin gadolinium; F-18-OMFD-PET (Ad cide. Immunomedics/Amgen); OncolymR (Techniolone vanced Biochem. Compounds, Redeberg); pemetrexed diso Corp./Schering AG); Mab HulD10 antibody (Protein. dium; ZD6474 (NCI); valproic acid; Vincristine; irinotecan; Design Laboratories); ABX-EGF (Abgenix); infleximab PEG-interferon alpha-2b; procarbazine; lonafarnib: arsenic (Remicade(R), Centocor) and etanercept (Enbrel(R), Wyeth trioxide: GP96 (Univ. Cal., San Francisco, Calif.); carbopl Ayerst); atin; cyclophosphamide: 1311-TM-601 (Trans Molecular): 0079 Tyrosine Kinase Inhibitors/Epidermal Growth Fac lapatinib. O6-benzylguanine: TP-38 toxin (NCI); cilengitide: tor Receptor Inhibitors such as gefitinib (Iressa, AstraZeneca, poly-ICLC(NCI); FR901228 (NCI); TransMidTM (Xenova); ZD 1839); trastuzumab (Herceptin R, Genentech); erlotinib talabostat; ixabepilone: AEE788 (Jonson Comprehensive (Tarceva, OSI Pharmaceuticals, OSI774); cetuximab (Er Cancer Center); alanosine; Sorafenib; efaproxiral; carmus bitux, Imclone Systems, IMC 225); and pertuzumab (Omni tine; iodine 1131 monoclonal antibody TNT-1/B (NCI, targ, Genentech, 2C4); Bethesda, Md.); intratumoral TransMidTM:topatecan; lomus 0080 Cytotoxins such as Irofulven (MGI 114, MGI tine; phosphorus 32: 18F-fluorodeoxyglucose (Alberta Can Pharma); cer Board); vinblastine; BMS-247550 (NCI); CC-8490 0081 Neurotensin Antagonist such as SR 48692 (Sanofi (NCI); IL 13-PE38QQR (Neopharm); imatib mesylate: Synthelabo); hydroxyurea; G207 (MediCiene); radiolabeled monoclonal 0082 Peripheral Sigma Ligands such as SR 31747 antibody: 2-deoxyglucose: talampanel; retinoic acid; gefi (Sanofi-Synthelabo); tinib; tipifarnib. CPT-11 (Kentuckiana Cancer Inst); ritux 0083 Endothelin ETA/Receptor Antagonists such as imab: efaproxiral; PS-341 (FDA Office Orphan Prod. YM-598 (Yamanouchi); and atrasentan (ABT-627. Abbott); Devel.); capecitabine; G-CFS(NCI); vinorelbine; paclitaxel; 0084 Anti-glaucoma Agents such as prostaglandins: patipilone (Norvartis); iressa; methotrexate; ABT-751 (NCI): latanoprost, bimaloprost, travoprost; dorzolamide (CosoptTM oxaliplatin: MS-275 (NCI); trastuzumab: pertuzumab: dorzolamide hydrochlorise-timolol maleate ophthalmic solu PS-341 (NCI); 17AAG (NCI); lenalidomide; campath-1H: tion, Merck); B blockers: timolol (acid-free and amine salts somatostatin analog: resveratrol; CEP-7055 (Cephalon); forms), levobunolol, betaxolol (Kerlone(R) beta-adrenergic CEP-5214 (Cephalon); PTC-299 (PTC Therapeutics); inhibi blocking agent, Sanofi-Aventis), and its hydrochloride, Sul tors of hepatocyte growth factor (L2G7 mAb, Galaxy Bio fate, phosphate salts; atenolol, C2-adrenergic antagonists: tech); statins such as atorvastatin (Lipitor R, Pfizer), fluvas brimonidine; sympathmimetics: epinephrine, diplivetrin; tatin (Lescorr, Novartis), rosuvastatin (Crestor R, Astra miotic agents: philicarpine; carbonic anhydrase inhibitors: Zeneca), prevastatin (Provacol R, Teva Pharm.), simvastatin dorzolamide, brinzolamide, acetolamide; and chlorthalidone (Zocar(R), Merck & Co., Inc.), lovastatin (Mevorcor R, (PLIVAR, Inc., Easthanover, NJ): Merck), or cervastatin (Baycol R, Bayer AG) (HMG-CoA 0085. Immunsuppressive Agents such as sirolimus (rapa reductase inhibitors); and Receptor tyrosine kinase inhibi mycin, RaparnuneR, Wyeth-Ayerst); tacrolimus (FK506) tOrS. (Prograf R, Astella Pharma US, Inc.); and cyclosporins; I0088 Those of ordinary skill in the art will appreciate that I0086 Nucleic acids such as small interfering RNAs any of the foregoing disclosed active agents may be used in (siRNA) or RNA interference (RNAi), particularly, for combination or mixture in the pharmaceutical formulations example siRNAs that interfere with VEGF expression; anti of the present invention. Such mixtures or combinations may sense oligonucleotides such as Affinitac (Isis Pharma./Eli be delivered in a single formulation, or may be embodied as Lilly & Co.); and Genasence (Genta/Aventis); different formulations delivered either simultaneously or a 0087 Additional active agents include triamcinolone-16, distinct time points to affect the desired therapeutic outcome. 21-diacetate; triamcinolone acetonide; fluocinolone Additionally, many of the foregoing agents may have more acetonide; dexamethasone; dexamethasone-21-acetate; dex than one activity or have more than one therapeutic use, hence amethasone-21-(3.3-dimethylbutyrate); dexamethasone-21 the particular category to which they have been ascribed phosphate disodium salt; dexamethasone-21-diethylami herein is not limiting in any way. Similarly, various biode noacetate; dexamethasone-21-isonicotinate; gradable, biocompatible excipients may be used in combina dexamethasone-21-dipropionate; dexamethasone-21-palmi tion or in mixtures in single or multiple formulations as tate; betamethasone; betamethasone-21-acetate; betametha required for a particular indication. These mixtures and com Sone-21-adamantoate; betamethasone-17-benzoate: binations of active agents and excipients may be determined US 2013/0324481 A1 Dec. 5, 2013

without undue experimentation by those of ordinary skill in trolled-Sustained release systems can be fabricated by com the art in light of this disclosure. bining an excipient discussed herein and an active agent. 0089. The formulations of the present invention may be Systems can combine more than one of these excipients as sterilized for use by methods known to those of ordinary skill well as more than one beneficial agent. Gels can be produced in the art. Autoclaving and e-beam have been used in informal by Vortex or mechanical mixing. Liquid formulations can be studies of several embodiments and have not appeared to have made by pre-mixing in an appropriate container or mixing of significant impact. Similarly, informal stability studies indi the excipient and the beneficial agent at the time of adminis cate acceptable stability of several embodiments. Addition tration. ally, reproducilibity between aliquots and lots is very good, 0094. Another aspect of the present invention provides for with a standard deviation of less than five percent or better. embodiments comprising omega-3 fatty acids. The health Hence, standard pharmaceutical manufacturing techniques benefits of dietary Supplements of omega-3 fatty acids and are readily applied to the technologies described herein. their esters are well known. The particularly important 0090. An example embodiment of the present invention omega-3 fatty acids in human nutrition are O-linolenic acid comprises the active agent dexamethasone and the excipient (ALA, C18H30O2, fw 278.4) eicosapentaenioc acid (EPA, tocoperol. Dexamethasone is a glucocorticoid and typically C20H30O2, fw 306.5) and docosahexaenoic acid (DHA, used in the form of the acetate or disodium phosphate ester. C22H32O2, fiv 328.5). The term omega-3 signifies that the Glucocorticoids are adrenocortical steroids Suppressing the first double bond exists between the third and second carbon inflammatory response to a variety of agents that can be of atoms counting from the terminal methyl at the opposite end mechanical, chemical or immunological nature. Doses vary of the chain from the carbonyl group. depending on the condition treated and on the individual (0095. The human body cannot synthesize EPA or DHA patient response. In ophthalmology, dexamethasone sodium except by using ALA as an intermediate. But the presence of phosphate (Decadron(R), Merck & Co.) as a 0.1% solution has EPA and DHA in almost all tissues of the body indicates the been widely used since its introduction in 1957. The oph importance of these compounds to the body and thus the thalmic dose depends on the condition treated, but for control judicious injection into the body of their therapeutic formu of anterior chamber inflammation the topical dose is usually lations will be safe, efficient and effective. These benefits also around 0.5 mg per day. extend to the simple esters of EPA and DHA of the C to Cs 0091 For treatment following cateract surgery, or for straight and branched chain aliphatic alcohols such as ethyl other treatments or diseases of the eye, an aspect of the inven EPA and ethyl DHA. Recently, the FDA has approved ethyl tion provides for a composition comprising an active agent EPA and ethyl DHA for dietary supplements. One important and the LSBB excipient useful for the treatment of iris property of these ethyl esters is that they can be fractionally neovascularization from cataract Surgery, macular edema in distilled from their readily available but crude source, fish oil. central retinal vein occlusion, cellular transplantation (as in This purification process provides the EPA and DHA esters retinal pigment cell transplantation), cystiod macular edema, free from possible heavy metal and PCB contaminants. Thus, pSaudophakic cystoid macular edema, diabetic macular there remains a need for the development of these purified edema, pre-phthisical ocular hypotomy, proliferative vitreo esters as liquid excipient vehicles for injectable Sustained retinopathy, proliferative diabetic retinopathy, exudative age drug release in various areas of the human or animal body. related macular degeneration, extensive exudative retinal 0096. The embodiments thus provide for the novel con detachment (Coats disease), diabetic retinal edema, diffuse cept of injections of omega-3 fatty acids and their esters by diabetic macular edema, ischemic ophthalmopathy, chronic themselves or as novel and therapeutic formulations with focal immunalogic corneal graft reaction, neovascular glau active agents directly into strategic areas of the human or coma, pars plana vitrectomy (for proliferative diabetic retin animal bodies to provide for the sustained release of the opathy), pars plana vitrectomy for proliferative vitreoretin omega-3 compounds and therapeutic but nontoxic levels of opathy, sympathetic ophthalmia, intermediate uveitis, the active agents for periods of months to over a year. chronic uveitis, intraocular infection Such as endophthalmi 0097. Yet another embodiment of the present invention tis, and/or Irvine-Gass syndrome. relates generally to novel topically applied formulations con 0092 Another embodiment of the invention provides for taining both steroids and antioxidants. Specifically, the inclu mulations and uses of the tocopherols and/or tocotrienols and sion of antioxidants with steroids addresses the problem that their esters with insulins for the delivery of the insulins in the many steroids have harmful side effects arising from their management of diabetes. Tocopherols and/or the tocotrienols being initiators of destructive oxidative and photo-oxidative and their esters possess outstanding capabilities to carry radical chain reactions. These novel steroid-antioxidant for therapeutic agents, especially moderate molecular weight mulations are designed to be applied topically, externally for proteins such as the insulins, through the mucosa and mem the known steroid therapies of anti-inflammation and regula brane Surfaces of the eye area, or through the nasolacrimal tion of metabolic and immune functions, but also due to the drainage system, into the body. Pillion et al., 32 Invest. Oph presence of antioxidants to Suppress damaging oxidative free thalmol. & Visual Sci. 3021-27 (1991). Indeed, it is contem radical reactions initiated by the steroids in addition to harm plated that wide-variety of other therapeutic agents (such as ful oxidative chemistries normally present in cells. steroids, NSAIDs, antibiotics, hormones, growth factors, 0098. Although oxygen is required for many life sustain anti-cancer agents, etc.) may be available for effective deliv ing metabolic reactions, it also has damaging chemistries ery formulations with the tocopherols and/or tocotrienols and with cellular components, involving very reactive oxygen their esters via eye drops. components: Superoxide radicals, hydrogen peroxide, 0093. The present invention relates generally to the use of hydroxyl radicals, and organic peroxides and hydroperoX compounds that are liquid, of limited solubility, biocompat ides. Polyunsaturated lipids are important components of ible and biodegradable for controlled and sustained release of cells, but they are major substrates for oxidative attack lead an agent or a combination of an agents. Gel or liquid con ing to cell death. Thus, the dependence of cells on oxygen US 2013/0324481 A1 Dec. 5, 2013

places them a precarious position between the prolife and of the present invention may be combined with other thera toxic chemistries of oxygen. Cells contain protective antioxi pies or interventions following standard acceptable best prac dant molecules Such as tocopherol, ascorbic acid, glu tices. tathione, melatonin, carotenes, carnitine, and others. The 0101. Without further elaboration, one skilled in the art natural level of tocopherol in the human lens is around 2.2 having the benefit of the preceding description can utilize the ug/ml (Yeum et al., 19(6) Curr. Eye Res. 502-05 (1999)), and present invention to the fullest extent. The following the ascorbate level in tears is 3.52 ug/ml (Choy et al., 80(9) examples are illustrative only and do not limit the remainder Optom. Vis. Sci. 632-36 (2003)). Unfortunately the exposure of the disclosure in any way. of cells to some steroids, even though for very necessary therapeutic reasons, has been found to tip this balance EXAMPLES towards the toxic side. It has been demonstrated that these steroids, especially the glucocorticosteroids such as triamci Example 1 nolone and dexamethasone, readily interact with oxygen and/ or light to become initiators of damaging oxidative chain reactions. Miolo et al., 78(5) Photochem. & Photobiol. 425 The Assay Procedure for Measuring the Release 30 (2003); Calza et al., 12(12) J. Am. Soc. Mass. Spectrom. Profiles of Dexamethasone or Triamcinolone 1286-95 (2001). Although the co-administration of certain Acetonide from Sustained Release Formulations antioxidants with certain steroids has been shown to amelio rate the toxic oxidative processes initiated by the steroids 0102 The vials for the release studies were labeled and the (Kosano et al., 76(6) Exp. Eye Res., 643-48 (2001)), most weight of each vial was recorded. To each vial was added 3 commercially available injectable steroid formulations do not grams-4 grams of 0.9% saline solution and the weight was include antioxidants. See Fact sheet inserts for KenalogTM, recorded. Then the formulation was injected or placed at the Bristol-Myers Squibb, 2006: Depo MedroITM, Pharmacia, bottom of the vial. The weight of the formulation was 2003: DecadronTM, Merck Sharp & Dohme, 1995, (contains recorded. An additional amount of 0.9% saline solution was bisulfites, hydroxybenzoate esters which might have antioxi added to a total of 10 grams of saline. The resulting vial was dant effects). In formulating compositions containing anti kept in an incubator or water bath at 37° C. Samples were oxidant Supplements one must be very careful not to add too taken periodically to measure the release profile of dexam high a level of antioxidants, however, because it has been ethasone or triamcinolone acetonide using a HPLC instru demonstrated that at high levels many of these antioxidants ment. Sampling protocol was carried out according to the actually are pro-oxidants and may increase oxidative damage. following procedure: Using a disposable pipette, 8 grams of Bowry et al., 270.J. Biol. Chem. 5756-63 (1995); Halliwell, the saline solution containing dexamethasone or triamcino 25 Free Rad. Res. 439-54 (1996). Using the naturally occur lone acetonide was withdrawn carefully from each vial. Eight ring antioxidants and mimicking their levels in the cell envi (8) grams of 0.9% saline solution was then added to each vial. ronment would be good practice. The vials were kept at 37° C. after sampling. 0099. The steroid components and excipients of these 0103) The HPLC analysis was carried out using a Beck novel formulations and their therapeutic effects are well man Gold Instrument with an autosampler, Calibrators with described herein and in U.S. Patent Application Publication three different concentrations of dexamethasone or triamci No. 2008/00383.16. The possible adverse effects of the ste nolone acetonide in water were prepared. Calibrators and roids used in these formulations are in many cases believed to samples were injected onto a C18 column (Rainin, 250x4.6 arise from the aforementioned damaging oxidative chemis mm) containing a guard column (C18, 4.6 mmx1 cm) and tries initiated by these steroids in the absence of proper anti analyzed, respectively. The column was eluted using a mobile oxidants. The environment of the eye is particularly damag phase of 45% (or 50%) acetonitrile/water, flow rate 1.0 ing for it is exposed to both oxygen and light energy. The ml/min, and 7 min or 6 min run time at an ambient tempera phenolic or quinone-like structures of the steroid molecules ture. The detector wavelength of 238 DM was used. The readily absorb UV-A and UV-B radiation to convert these dexamethasone or triamcinolone acetonide (retention times, molecules to unpaired electron radical species. These radical 6 min-4 min) concentration of each sample was calculated species can damage cell components (especially unsaturated from the standard curve using the software of the Beckman lipids in cell membranes) or they can interact with oxygen to Gold instrument. instigate damaging peroxy chain reactions leading to cata 0104. A wash program to clean the HPLC column was set racts (Nishigoriet al., 35(9) Life Sci. 981-85 (1984); Boscia up during the HPLC run. After every three or four injections, et al., 41(9) Invest. Ophthalmol. Vis. Sci. 2461-65 (2000)), a sample containing 20 Lulofacetonitrile was injected onto the and glaucoma (Sacca et al., 84(3) Exp. Eye Res. 389-99 column, the column was eluted with a mobile phase of 99% (2007)). Cataract formation and glaucoma are maladies asso acetonitrile/water, flow rate 1 ml/min, and a run time 7 min. ciated with steroid therapies in the eye. In the case of intra Then the column was equilibrated back to the original mobile articular steroid therapies repeated injections are avoided phase by injecting 20 ul of acetonitrile, eluting with 45% (or because they lead to cartilage and bone degeneration. Reac 50%) acetonitrile/water, flow rate 1 ml/min, and a run time 7 tive oxygen species have been identified as causative agents. 1. Kim et al., 49(9) Free Radic. Biol. Med. 1483-93 (2006). 0105. The sampling times and the active ingredient (for 0100. In the context of the present formulation in which example dexamethasone or triamcinolone acetonide) concen the LSBB excipient/active agent formulation provides for the trations determined from HPLC were recorded and tabulated. Sustained release of the active agent, other components may The percent drug released and the amount of drug released be added to the formulation as are known in the art of eye were each calculated from a Microsoft Excel software pro drops or topical formulations. Additionally, the formulations gram. US 2013/0324481 A1 Dec. 5, 2013

Example 2 of anti-VEGF therapy similar amounts of Such agents as ranibizumab or bevacizumab could be employed in a similar Preparation of Mixtures of Dexamethasone in a manner with the omega-3 excipients. The extensive list of Tocopherol and their Release Profiles other beneficial agents employed for the list of a wide variety of maladies are disclosed herein and in U.S. No. 2008/ 0106 For the preparation of 10% dexamethasone (Dex) in d-tocopherol, one portion by weight of Dex was mixed with OO383.16. nine portions by weight of d-tocopherol. The resulting Sus Example 4 pension was stirred at an ambient temperature until a homolo gous mixture formed. The mixture was then aliquoted and analyzed for release profile as shown in FIG. 1. Formulations Containing Steroids and Antioxidants 0107 For the preparation of 20% Dex ind-tocopherol, two 0112 This embodiment relates generally to novel topi portions by weight of Dex was mixed with eight portions by cally applied formulations containing both Steroids and anti weight of d-tocopherol. The resulting Suspension was stirred oxidants. These formulations allow the application of steroids at an ambient temperature until the formation of a homolo to achieve their intended benefits (anti-inflammation, gous mixture. The mixture was then aliquoted and analyzed immune modulation) without initiation of harmful oxidative for release profile as shown in FIG. 1. chemistries. These example formulations are composed of 0108 For the preparation of 50% Dex in d1-tocopheryl one or more of the steroids listed in Group A combined with acetate, five portions by weight of Dex were mixed with five one or more of the antioxidants listed in Group B and all portions by weight of dl-tocopheryl acetate. The resulting dispersed or dissolved in one or more of the delivery vehicles Suspension was stirred at ambient temperature until a selected from the excipients described herein and listed in homologous mixture formed. The mixture was then aliquoted Group C and also described in U.S. No. 2008/00383.16. and analyzed for the release profile as shown in FIG. 1. 0113 Group A Steroids Example 3 triamcinolone dexamethasone diethylaminoacetate Omega-3 Fatty Acids and their Esters for Liquid triamcinolone acetonide dexamethasone isonicotinate Sustained Drug Release Formulations triamcinolone diacetate dexamethasone palmitate triamcinolone acetate prednisone 01.09. The embodiments provide for the novel concept of triamcinolone disodium phosphate prednisolone formulations of omega-3 fatty acids and their esters by them triamcinolone hemisuccinate prednisolone acetate triamcinolone benetonide prednisolone sodium phosphate selves or as novel and therapeutic formulations with active dexamethasone methylprednisolone agents directly into strategic areas of the human or animal dexamethasone acetate methylprednisolone acetate bodies to provide for the sustained release of the omega-3 dexamethasone disodium methylprednisolone sodium compounds and therapeutic but nontoxic levels of the active phosphate Succinate dexamethasone 3,3- paramethasone agents for periods of months to over a year. dimethylbutyrate 0110. The process of applying small amounts of these cortisone etrahydrocortexolone omega-3 fatty acid/ester alone or their formulations contain cortisone acetate betamethasone ing active agents at the site of the malady is not only maxi hydrocortisone betamethasone acetate hydrocortisone acetate betamethasone disodium phosphate mally effective and efficient but also avoids the waste and etrahydrocortisol betamethasone benzoate potentially increased danger of systemic oral administration. fludrocortisones betamethasone valerate These novel sustained drug release formulations of the fludrocortisone acetate betamethasone dipropionate fludrocortisone phosphate betamethasone adamantoate omega-3 liquids alone or in combination with the other anacortive beclomethasone excipients disclosed herein and in U.S. Patent Application anacortive acetate beclomethasone dipropionate Publication No. 2008/0038316 can be applied topically to the mometaSone furoate diflorasone eye. Among a number of maladies to be treated, as listed fluocinolone diflorasone diacetate herein and in U.S. No. 2008/0038316, are those of the retina Such as macular degeneration, retinitis pigmentosa, prolifera tive vitreoretinopathy, to name a few. A potentially advanta 0114 Group B Antioxidants geous property of DHA, EPA, and their esters is their impor tance in maintaining healthy retinal tissue and their required presence for proper development of neonatal retinal function. ascorbic acids and salts retinyl palmitate See, e.g., Jeffrey et al., 36(9) Lipids 859-71 (2001); SanGio ascorbyl palmitate probucol ascorbyl dipalmitate erythorbic acid vanni & Chew, 24(1) Prog Retin Eye Res. 87-138 (2005): ascorby Stearate sodium erythorbate Bazan, 29(5) Trends Neurosci. 263-71 (2006); King et al., ascorbyl-2,6-dibutyrate C-lipoic acid 26(17) J. Neurosci. 4672-80 (2006). d-tocopherol (C, f, Y, 8 isomers) isocitrate 0111 Some more specific, but not limiting, examples con dl-tocopherol (C, f, Y, 8 isomers) luteinizeaxanthin meso-zeaxanthin the acetate, hemisuccinate, nicotinate eugenol templated for ocular therapies are for inflammatory maladies and succinate-PEG ester derivatives isoeugenol of the eye. Topical administration may include, for example, of the above tocopherol isomers (-)-epicatechin 10 ul to 60 ul liquid microspheres of ethyl DHA/ethyl EPA glutathione (-)-epigallocatechin gallate alone or as mixtures containing 10% to 50% by weight of 3-carotine benzyl alcohol carnitine benzyl benzoate microcrystalline dexamethasone or triamcinolone acetonide. carnitine acetate 2,6-di-tertbutyl-4-methoxyphenol This provides for the maintenance of therapeutic levels of the trans reveratrol butylated hydroxytoluene omega-3 fatty acids or the therapeutic concentration of the retinoic acid butylated hydroxyanisole steroids in the area of the eye for extended periods. In the case US 2013/0324481 A1 Dec. 5, 2013

-continued these active agents were continuously released to the tears for periods of seven days. No indications of irritation were retinyl palmitate quercetin observed. melatonin catechin timolol rutin 0119 Regarding FIG. 2, a (45:55) by wt formulation of luteolin coenzyme Q cyclosporin A (CSA) in ATA was instilled topically as one eye kaempferol fisetin drop onto one eye of two NZW 4.0 kg rabbits. Droplet weigh thyroxine methyl gallate ing 6.6 mg (A) and 10.8 mg (0) were instilled. Tear samples pyrroloquinolone Superoxide dismutase were collected daily by filter paper, weighed, eluted in 300 ul MeOH, and analysed for CSA and ATA by LCMSMS. 0115 Group C Excipients I0120 Regarding FIG. 3, a (10:90) by wt formulation of timolol base (Sifavitor, Italy) in dl-C-tocopheryl acetate was instilled topically as eye one drop onto one eye of two NZW 4.0 kg rabbits. Droplets weighing 4.3 mg (0) and 6.0 mg (A) d-tocopherol (C, f, Y, 8 isomers) were instilled. Tear samples were collected daily by filter dl-tocopherol (C, f, Y, 8 isomers) the acetate and esters of C-3 to C-10 paper, weighed, eluted in 300 ul MeOH, and analysed for straight and branched chain aliphatic timolol base and tocopheryl acetate by LCMSMS. acids with the above tocopherol isomers Example 7 dimethylsulfone (MSM) omega-3 fatty acids and their ester with C-1 to C-10 straight and branched chain aliphatic alcohols Sustained Release Eye Drop Formulation Containing triethyl, tripropyl, or tribuyl esters of tri-straight and branched chain C-1 Dexamethasone O-acetyl, O-propionyl, or O-butyryl to C-10 aliphatic alcohol esters of citrate citric acid I0121 Eye drop formulations included 10% or 20% dex amethasone in d-tocopherol were prepared as follows: One portion by weight of dexamethasone was mixed with nine 0116. As mentioned above, to avoid harmful pro-oxidative portions by weight of d-tocopherol. The resulting Suspension chemistries care should be taken not to expose the cells to too was stirred at an ambient temperature until there was a for high a level of the antioxidants. This may presentaproblem as mation of a homogeneous mixture. The mixture was then formulators develop a one-shot formulation that administers aliquoted and analyzed for release profile. Two portions by steroids and antioxidants for months to a year or more. The weight of dexamethasone were mixed with eight portions by formulation must incorporate enough antioxidants to last this weight of d-tocopherol. The resulting Suspension was stirred long without releasing pro-oxidative concentrations. This is at an ambient temperature until there was a formation of a achieved in this embodiment of the invention by using lipo homogeneous mixture. The mixture was then aliquoted and phyllic prodrug forms of the antioxidants such as ascorbyl analyzed for release profile. For 50% dexamethasone in dl palmitate, tocopheryl acetate, benzyl benzoate, and the like, tocopheryl acetate, five portions by weight of dexamethasone which slowly release the active, more hydrophyllic form into were mixed with five portions by weight of dl-tocopheryl the cellular environment upon hydrolysis. acetate. The resulting Suspension was stirred at an ambient temperature until there was a formation of a homogeneous 0117 Examples of a sustained release formulation of this mixture. The mixture was then aliquoted and analyzed for embodiment include formulations such as: release profile, as shown in FIG. 4. 0122. It is contemplated that novel, non-irritating, long lasting Sustained drug release topical eye drop formulations (1) C-tocopheryl acetate 60 pts/wt comprise a tocopherol or omega-3 fatty acid selected from ascorbyl palmitate 10 pts/wt triamcinolone acetonate 40 pts/wt Group A, combined with at least one of the active agents listed (2) C-tocopheryl acetate 60 pts/wt in Group B. ascorbyl palmitate 10 pts/wt I0123 Group A Excipients: C, B, Y. 8 tocopherols; C, B, Y. dexamethasone 40 pts/wt 8 tocotrienols; the esters of tocopherol and tocotrienols iso mers with C1 to C10 straight and branched chain aliphatic carboxylic acids (such as acetates) d. 1, and dl isomers of the tocopherols, tocotrienols and theiresters, for example C. toco Example 6 pheryl acetate; the mono, di, and triesters of O-acetylcitric acid or O-propionylcitric acid or O-butyryleitric acid with C1 Sustained Release Eye Drop Formulation Containing to C10 straight and branched chain aliphatic alcohols; the Cyclosporin mono, di, and triesters of citric acid with C1 to C10 straight and branched chain aliphatic alcohols; and omega-3 fatty 0118. Instillation of droplets of about 10 mg of C-toco acids. pheryl acete (ATA) onto the front of the eyes of human vol 0.124 Group B Beneficial Agents, as discussed in many of unteers revealed that there was no irritation and the liquid the preceeding paragraphs: anti-glaucoma agents; immuno quickly spread around the periphery of the anterior Surface Suppressive agents; angiostatic and/or anti-inflammatory Ste leaving vision unblurred. Inspection showed that the ATA, roids; nonsteroidal anti-inflammatories; anti-infective probably because of its low water solubility, remained in the agents; anti-bacterials; antivirals; C. androgenergic agonists; eye for periods exceeding seven days. Subsequently, as Badrenergic blocking agents; mast cell stabilizers; antihista shown in FIG. 2 and FIG.3, formulations of ATA:cyclosporin mines; antimicrotubule agents; antineoplastic agents; topoi A (Chemwerth, Woodbridge, Conn.) or ATA:timolol were Somerase inhibitors; anti-metabolites; and antibody thera instilled into rabbit eyes to reveal that therapeutic levels of peutic agents. US 2013/0324481 A1 Dec. 5, 2013 13

Example 8 5. The pharmaceutical formulation of claim 1, wherein the anti-inflammatory is dexamethasone or triamcinolone. Tocopherol/Latanoprost Eye Drops Intraocular 6. The pharmaceutical formulation of claim 1, wherein a Pressure in the Rabbit Eye dosage unit of a single eye drop provides Sustained release of 0.125 Duplicate experiments were run in two NZW rab said active agent for at least four days. bits. Intraocular pressures (IOPs) were measured using Tono 7. A dosage dispensing container comprising the pharma PenR) tonometer (Reichert, Inc.). Each eye of each rabbit was ceutical eye drops formulation of claim 1. monitored for five days without treatment to establish base 8. A pharmaceutical eye drops formulation for the Sus line values. At day 5, one drop of approximately 50 ul drops tained release of an anti-infective consisting of of 0.005% latanoprost in C. tocopheryl acetate (EA) was an anti-infective agent or pharmaceutically acceptable salt placed into one eye of each rabbit. The other eye received a thereof, and drop of 0.9% NaCl in water. IOPs were monitored for another at least one biocompatible, biodegradable, non-polymeric ten days. excipient selected from the group consisting of d. 1 and 0126. As shown in FIGS. 5B and 5D, the eyes treated with dl isomers of C, B, Ö, e, m tocopherols and similar iso one drop of the latanoprost/EA formulation exhibited a mers of the tocotrienols and the esters of these toco decrease in IOP that was sustained over several days as com pherols and tocotrienols with straight and branched pared to the saline-treated eyes (FIGS.5A and 5C). chain C2 to C20 aliphatic acids, or their esters of C3 to Example 9 C20 straight chain dicarboxylic acids. 9. The pharmaceutical formulation of claim 8, wherein the In Vitro Study of Dexamethasone in Triethyl anti-infective agent is selected from the group consisting of O-Acetyl Citrate (TEAC) tetracycline, chloramphenicol, ciprofloxacin and amplicillin. 10. The pharmaceutical formulation of claim 8, wherein 0127. To 760 mg of TEAC was added 240 mg of Dexam the anti-infective agent is fluconazole. ethasone with ample stirring to form a homogeneous mixture. Six mg (25 Jul) and 12 mg (25ul) microdrops of this mixture 11. The pharmaceutical formulation of claim 8, wherein were each incubated in 10 ml of 0.9% saline at 37° C. Peri the anti-infective agent is acyclovir. odically, 8 ml portions were withdrawn for assaying and 12. The pharmaceutical formulation of claim 8, wherein a replaced with 8 ml of fresh 0.9% saline. The release of Dex dosage unit of a single eye drop provides Sustained release of from a formulation consisting of 24%. Dex in TEAC is said antibiotic agent for at least four days. depicted in FIG. 6. The release of Dex from a formulation 13. A dosage dispensing container comprising the pharma consisting of a 6 mg (25 ul) microdrop of 20% Dex in 1:1 ceutical eye drops formulation of claim 8. TEAC/Tocopheryl acetate is reflected in FIG. 7. In summary, 14. A pharmaceutical eye drops formulation for the Sus these results indicate that adding tocopheryl acetate to the tained release of an anti-allergy agent consisting of TEAC excipient can extend the sustained release of therapeu an anti-allergy agent or pharmaceutically acceptable salt tic levels of Dex up to 450 days. thereof, and 0128 Modifications of the above described modes for car at least one biocompatible, biodegradable, non-polymeric rying out the invention that are obvious to those of ordinary excipient selected from the group consisting of d. 1 and skill in the Surgical, pharmaceutical, or related arts are dl isomers of C, B, Ö, e, m tocopherols and similar iso intended to be within the scope of the appended claims. mers of the tocotrienols and the esters of these toco We claim: pherols and tocotrienols with straight and branched 1. A pharmaceutical eye drops formulation for the Sus chain C2 to C20 aliphatic acids, and their esters of C3 to tained release of an anti-inflammatory agent consisting of C20 straight chain dicarboxylic acids. an anti-inflammatory agent or pharmaceutically accept 15. The pharmaceutical formulation of claim 14, wherein able salt thereof, and the anti-allergy agent is selected from the group consisting of at least one biocompatible, biodegradable, non-polymeric olopatadine and its hydrochloride, Sulfate, or phosphate salt excipient selected from the group consisting of d. 1 and forms; fexofenadine and its hydrochloride, sulfate, or phos dl isomers of C. B. Ö, e, m tocopherols and similar iso phate salt forms; azelastine and its hydrochloride, Sulfate, or mers of the tocotrienols, and the esters of these toco phosphate salt forms; diphenhydramine and its hydrochlo pherols and tocotrienols with straight and branched ride, Sulfate, or phosphate salt forms; promethazine and its chain C2 to C20 aliphatic acids, and their esters of C3 to hydrochloride, Sulfate, orphosphate forms, pemirolast and its C20 straight chain dicarboxylic acids. potassium salt, nedocromil and its sodium salt, and cromolyn 2. The pharmaceutical formulation of claim 1, wherein the and its sodium salt. anti-inflammatory agent is an anti-inflammatory steroid or a non-steroidal anti-inflammatory. 16. The pharmaceutical formulation of claim 14, wherein 3. The pharmaceutical formulation of claim 1, wherein the the formulation provides sustained release of said active anti-inflammatory agent is cyclosporine or rapamycin. agent for at least four days. 4. The pharmaceutical formulation of claim 3, wherein the 17. A dosage dispensing container comprising the pharma anti-inflammatory agent is cyclosporine and the excipient is ceutical eye drops formulation of claim 14. C-tocopheryl acetate. k k k k k