US 2015033,5704A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0335704 A1 KAROLCHYK (43) Pub. Date: Nov. 26, 2015

(54) PHARMACEUTICAL COMPOSITIONS Publication Classification COMPRISING GELS AND METHODS FOR FABRICATING THEREOF (51) Int. Cl. A638/4 (2006.01) (71) Applicant: IMPRIMIS PHARMACEUTICALS, A619/00 (2006.01) INC., San Diego, CA (US) A647/34 (2006.01) A613 L/7036 (2006.01) (72) Inventor: John Scott KAROLCHYK, Lake (52) U.S. Cl. Hopatcong, NJ (US) CPC ...... A61K 38/14 (2013.01); A61 K3I/7036 (2013.01); A61 K9/0048 (2013.01); A61 K (73) Assignee: IMPRIMIS PHARMACEUTICALS, 47/34 (2013.01) INC., San Diego, CA (US) (21) Appl. No.: 14/719,157 (57) ABSTRACT (22) Filed: May 21, 2015 Pharmaceutical compositions are described, the composi tions comprising a therapeutically effective quantity of an Related U.S. Application Data active component and a quantity of a sterile gel. Methods for (60) Provisional application No. 62/002,711, filed on May fabricating the compositions and using them for ophthalmic 23, 2014. or burn-treating applications are also described. US 2015/0335704 A1 Nov. 26, 2015

PHARMACEUTICAL COMPOSITIONS tion for treating burns is provided, the composition compris COMPRISING GELS AND METHODS FOR ing a therapeutically effective quantity of an active compo FABRICATING THEREOF nent that is free of any of fluconazole, methazolamide, aZitromycin, mitomycin, pilocarpine, povidone-iodine, dex CROSS REFERENCE TO RELATED amethasone, flurbiprofen, bromfenac, nepafenac, diclofenac, APPLICATIONS ketorolac, indomethacin, Suprofen, norfloxacin, ciprofloxa 0001. This application claims priority under 35 U.S.C. cin, antiseptics comprising the NH' cation or pharmaceuti S119(e) to U.S. Provisional Application No. 62/002,711 filed cally acceptable isomers, salts, hydrates or Solvates thereof. on May 23, 2014 entitled “Pharmaceutical Compositions and a quantity of a thermoreversible gel component that is Comprising Gels and Methods for Fabricating Thereof the free of any of chitosan, carbopol or polysorbate. entire contents of which is hereby incorporated by reference. 0008 According to another embodiment of the invention, the active component of the pharmaceutical ophthalmologi FIELD OF THE INVENTION cal composition comprises at least one anesthetic, at least one non-steroid anti-inflammatory drug (NSAID), at least one 0002 The present invention relates generally to the phar anti-bacterial agent, at least one antiviral medicament, at least maceutical field of and more specifically to compositions one antifungal medicament, at least one immunosuppressant, comprising gels based on thermoreversible polymers and to at least one corticosteroid, at least one keratopathy agent, at methods of preparing and using Such compositions. least one antioxidant, at least one vitamin, at least one medi cament for treating glaucoma, at least one mydriatic agent, at BACKGROUND least one antihistamine agent, at least one anti-VEGF medi 0003. In ophthalmological treatments and procedures, cament, at least one medicament for corneal pain treatment or many typical ophthalmic drug delivery systems encounter at least one medicament for severe dry eye syndrome treat difficulties and problems due to physiological conditions of ment. the eye. More specifically, when a liquid ophthalmic formu 0009. According to other embodiments of the invention, lation is applied to the eye, upon instillation, it is quickly an ophthalmological pharmaceutical composition is pro eliminated due to lacrimal secretion and drainage. As a result, vided, the composition comprising atherapeutically effective only a limited number of ophthalmic drugs can be utilized by quantity of an corticosteroid selected from the group consist patients to achieve efficient treatment; otherwise a frequent ing of triamcinolone, dexamethasone, betamethasone, fluo administration of concentrated solutions is often required to rometholone, fluocinolone, prednisone, prednisolone, hydro achieve the desired effects. It naturally follows that increasing cortisone and combinations thereof; a therapeutically the retention time of a liquid ophthalmic formulation after it effective quantity of an anti-bacterial agent selected from the has been administered is often very desirable. Similarly, the group consisting of moxifloxacin, gatifloxacin, nalidixic same is desirable for topical drug formulations that are acid, oxolinic acid, piromidic acid, pipemidic acid, roSoxa applied to skin of burn patients to relieve the burn symptoms cin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, ofloxa and to accelerate the process of healing or gun-shot victims to cin, pefloxacin, rufloxacin, balofloxacin, levofloxacin, paZu seal wound and prevent loss of blood. floxacin, sparfloxacin, to Sufloxacin, clinafloxacin, 0004. In the field of ophthalmology, to lengthen the reten gemifloxacin, sitafloxacin, prulifloxacin and combinations tion time of instilled drug in the eye and to enhance its bio thereof, and a quantity of a thermoreversible gel component availability, various ophthalmic vehicles, such as ointments, comprising a polymer selected from the group consisting of aqueous gels, Suspensions inserts and implants, have been poly(oxyethylene-co-oxypropylene) block copolymer, poly developed and used. However, these ophthalmic vehicles are (N-isopropylacrylamide), poly(N-isopropylacrylamide-co not free of flaws and drawbacks. For example, the use of acrylic acid), poly(vinyl pyrrolidone), poly(4-vinylpyridine ointments often causes blurred vision. Using inserts caused co-ethylacrylate) block copolymer, poly(N- serious problems due to low patient compliance. Implants isopropylacrylamide-co-butyl methacrylate-co-ethylene require Surgical intervention with concomitant risks of infec glycol) block copolymer and combinations thereof. tion and inflammation. 0010. According to yet another embodiment of the inven 0005 Gel forming systems have been especially popular tion, the active component of the pharmaceutical composition for increasing the pre-corneal retention time and improving for treating burns comprises at least one anesthetic, at least bioavailability of the ophthalmic drugs. Typically, such gels one non-steroid anti-inflammatory drug, at least one anti comprise thermoreversible polymers that can undergo a rapid bacterial agent, at least one antifungal medicament, at least liquid-to-gel phase transition once they have been adminis one burn-healing agent or at least one medicament for treating tered to the eye. However, typical in situ gel-forming compo neuropathic pain. sitions require the use of high concentrations of polymer to 0011 Examples of suitable specific active components as form the gel and therefore typically are not suitable for use in well as concentrations thereofare further provided herein, for ophthalmic drug delivery. both ophthalmological compositions and compositions for 0006. This patent specification discloses alternative in situ treating burns. gel-forming compositions that are free of the above described 0012. According to another embodiment of the invention, drawbacks and deficiencies making them better suitable for the gel component of pharmaceutical compositions described both ophthalmological and burn-healing treatments, and herein includes thermoreversible polymer(s), for example, methods of fabricating and administering the same. poly(oxyethylene-co-oxypropylene) block copolymer, Such as Poloxamer 407(R), including thermoreversible polymers SUMMARY having cross-linked portion(s). 0007 According to one embodiment of the invention, a 0013. According to yet another embodiment of the inven pharmaceutical ophthalmological composition or a composi tion, the gel component of pharmaceutical compositions US 2015/0335704 A1 Nov. 26, 2015

described herein is sterile, and methods of sterilization of the cate, multiply and reproduce; accordingly the term “antiviral gel component are also provided herein. for the purposes of the present application is inclusive of 0014. According to other embodiment of the invention, viricides. methods of preparing and using the pharmaceutical compo 0025. The term “antifungal refers to substances or com sitions are also described herein. pounds that destroy or prevent the growth of fungi by selec tively eliminating fungal pathogens from a host. DETAILED DESCRIPTION 0026. The term “immunosuppressant refers to sub stances or compounds that are capable of Suppressing the A. Terms and Definitions immune response of the body that may be otherwise triggered by any disease, condition or pathology. 0015. Unless specific definitions are provided, the nomen clatures utilized in connection with, and the laboratory pro 0027. The term “corticosteroid' is defined as a compound cedures and techniques of analytical chemistry, synthetic belonging to a Sub-genus of Steroids that are derivatives of organic and inorganic chemistry described herein, are those corticosterone, the latter having the chemical structure: known in the art. Standard chemical symbols are used inter changeably with the full names represented by such symbols. Thus, for example, the terms “hydrogen' and “H” are under stood to have identical meaning. Standard techniques may be used for chemical syntheses, chemical analyses, formulating compositions and testing them. The foregoing techniques and procedures can be generally performed according to conven tional methods well known in the art. 0016. It is to be understood that both the foregoing general description and the following detailed description are exem plary and explanatory only and are not restrictive of the inven tion claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. The section 0028. The term “keratopathy agent” refers to substances headings used herein are for organizational purposes only and or compounds that can be used for treating any noninflam are not to be construed as limiting the subject matter matory disease of the cornea, e.g., but not limited to, band described. keratopathy, acid-fast keratopathy or bullous keratopathy. 0017. As used herein, “or” means “and/or unless stated 0029. The term “antioxidant” refers to substances or com otherwise. Furthermore, use of the term “including as well pounds that inhibit, eliminate or reduce the damage caused by as other forms, such as “includes, and “included is not oxidation, e.g., that caused by free radicals. limiting. 0030 The term “mydriatic' refers to substances or com 0.018 “About as used herein means that a number pounds that can causing dilation of the pupil of an eye. referred to as “about comprises the recited number plus or 0031. The term “antihistamine” refers to substances or minus 1-10% of that recited number. For example, “about compounds that counteract the physiological effects (e.g., 100 degrees can mean 95-105 degrees or as few as 99-101 allergic reactions) of histamine. degrees depending on the context. Whenever it appears 0032. The term "salt” refers to an ionic compound which herein, a numerical range such as "1 to 20 refers to each is a product of the neutralization reaction of an acid and a integer in the given range; i.e., meaning only 1, only 2, only 3, base. etc., up to and including only 20. 0033. The terms “solvate” and “hydrate” are used hereinto 0019. The term “pharmaceutical composition' is defined indicate that a compound or a substance is physically or as a chemical or a biological compound or Substance, or a chemically associated with a solvent for “solvates' such as mixture or combination of two or more Such compounds or water (for “hydrates'). Substances, intended for use in the medical diagnosis, cure, 0034. The term “gel” refers to a solid three-dimensional treatment, or prevention of disease or pathology. network that spans the Volume of a liquid medium and 0020. The term “anesthetic' refers to substances or com ensconces this liquid medium. pounds that induce insensitivity to pain Such as a temporary 0035. The terms “thermoreversible' or “thermoreversible loss of sensation. gel for the purposes of the present invention refer to a swol len polymer network formed through the physical aggrega 0021. The term “anti-inflammatory” refers to substances tion of polymer chains or through thermally reversible glassy or compounds that counteract or Suppress inflammation via domains (e.g., one based on block copolymers), where the any mechanism or route. product comprising this network is solid, semi-solid or gel 0022. The term “non-steroid anti-inflammatory drug or like at the room temperature or a higher temperature but is “NSAID' refer to substances or compounds that are free of fluid at a temperature that is lower than the room temperature. steroid moieties and provide analgesic, antipyretic and/or 0036. The term “block copolymer refers to macromol anti-inflammatory effects. ecules that comprise two or more homopolymer Subunits 0023 The terms “anti-bacterial,” “antibiotic' and “anti linked by covalent bond, having at least one structural feature septic” used herein interchangeably, refer to Substances or (i.e., an intermediate non-repeating Subunit) that is not compounds that destroy bacteria and/or inhibit the growth present in the adjacent portions. For the purposes of the thereof via any mechanism or route. present specification, block copolymers are defined as both 0024. The term “antiviral” refers to substances or com linear, branched and partially or fully cross-linked macromol pounds that destroy a virus or suppresses its ability to repli ecules. US 2015/0335704 A1 Nov. 26, 2015

0037. The term “burn” refers to an injury to skin, tissue or 0049. This limitation, however, is intended to convey the flesh of a mammal caused by heat, flame, electricity, chemical meaning that each excluded compound, and any combination exposure, friction or radiation. thereof, cannot be used only if no other compound (i.e., no 0038. The term “topical medication” refers to substances compound that is not on this list) is present in the active or compounds that a medication that are applied locally to the component of the composition. If other, non-excluded com skin or mucous membranes of a mammal to treat various pounds are present, then compounds that are otherwise diseases or pathologies. excluded can be also used. 0039. The term “carrier refers to a substance that serves 0050. In other words, the excluded compounds mentioned as a vehicle for improving the efficiency of delivery and the above, can be still included in the active component of the effectiveness of a pharmaceutical composition. composition so long as other compounds are also present in 0040. The term “excipient” refers to a pharmacologically the active component composition. For example, dexametha inactive substance that is formulated in combination with the sone is specifically excluded above. However, the active com pharmacologically active ingredient of pharmaceutical com ponent of the composition may still include dexamethasone if position and is inclusive of bulking agents, fillers, diluents at least one of an anti-bacterial agent(s) such as moxifloxacin, and products used for facilitating drug absorption or solubil gatifloxacin, nalidixic acid, OXolinic acid, piromidic acid, ity or for other pharmacokinetic considerations. pipemidic acid, rosoxacin, enoxacin, fleroxacin, lomefloxa 0041. The term “therapeutically effective amount” is cin, nadifloxacin, ofloxacin, pefloxacin, rufloxacin, balof defined as the amount of the compound or pharmaceutical loxacin, levofloxacin, paZufloxacin, sparfloxacin, to Sufloxa composition that will elicit the biological or medical response cin, clinafloxacin, gemifloxacin, sitafloxacin or prulifloxacin of a tissue, System, animal or human that is being sought by is also a part of the active component of the composition. the researcher, medical doctor or other clinician. 0051 Similarly, bromfenac, nepafenac, diclofenac and 0042. The term “pharmaceutically acceptable' is defined ketorolac are NSAID's that are specifically excluded can still as a carrier, whether diluent or excipient, that is compatible be used in combination with other compounds in the active with the other ingredients of the formulation and not delete component of the composition. For instance, bromfenac, rious to the recipient thereof. nepafenac, diclofenac or ketorolac can still be used in com bination with one or more corticosteroid(s) (e.g., triamcino 0043. The terms “administration of a composition' or lone, dexamethasone, betamethasone, fluorometholone, fluo “administering a composition' are defined to include an act of cinolone, prednisone, prednisolone or hydrocortisone) and/or providing a compound of the invention or pharmaceutical with one or more anti-bacterial agent(s) (e.g., moxifloxacin, composition to the subject in need of treatment. gatifloxacin, nalidixic acid, OXolinic acid, piromidic acid, 0044. The term “instillation” refers to an introduction of a pipemidic acid, rosoxacin, enoxacin, fleroxacin, lomefloxa liquid pharmaceutical composition, such as eye drops, in a cin, nadifloxacin, ofloxacin, pefloxacin, rufloxacin, balof drop-by-drop fashion. loxacin, levofloxacin, paZufloxacin, sparfloxacin, to Sufloxa 0045. The term “intraocular injection” refers to an injec cin, clinafloxacin, gemifloxacin, sitafloxacin or tion that is administered by entering the eyeball of the patient. prulifloxacin). 0.052 Any other compounds may be used in the active B. Embodiments component and the compounds as well as the active compo 0046 According to embodiments of the present invention, nent as a whole may be the same or different for ophthalmo pharmaceutical compositions intended to prevent and/or treat logical and burn-treating applications, as further explained ophthalmological diseases, conditions, pathologies or Syn below. dromes in mammals, and/or treat burns and/or gun-shot wounds in mammals, are provided, the compositions com Ophthalmological Pharmaceutical Compositions. prising, consisting essentially of, or consisting of an active 0053 For ophthalmological applications, the composi component and a gel, and optionally further include one or tions include at least one active component comprising, con several pharmaceutically acceptable excipient(s) and one or sisting essentially of or consisting of a therapeutically effec several pharmaceutically acceptable carrier(s). tive quantity of any of the following, or any combination 0047. It is provided that the same or different gel compo thereof: nent(s) may be present in the pharmaceutical compositions 0054 (a) at least one anesthetic; and/or for both ophthalmological and burn-treating applications, 0055 (b) at least one non-steroid anti-inflammatory drug with no limitations other than the gel component be thermor (NSAID); and/or eversible as further explained below. 0056 (c) at least one anti-bacterial agent (i.e., an antibiotic 0048. With respect to the active component, however, it is or antiseptic); and/or provided in some embodiments that, for both ophthalmologi 0057 (d) at least one antiviral medicament; and/or cal and burn-treating applications, certain compounds are 0.058 (e) at least one antifungal medicament; and/or specifically excluded (“excluded compounds') from the 0059 (f) at least one immunosuppressant; active component of the composition. Such excluded com pounds are fluconazole, methazolamide, azitromycin, mito 0060 (g) at least one corticosteroid; and/or mycin, pilocarpine, povidone-iodine, dexamethasone, flurbi 0061 (h) at least one keratopathy agent; and/or profen, bromfenac, nepafenac, diclofenac, ketorolac, 0062 (i) at least one antioxidant; and/or indomethacin, Suprofen, norfloxacin, ciprofloxacin, antisep 0063 () at least one vitamin; and/or tics comprising the NH' cation or pharmaceutically accept 0064 (k) at least one medicament for treating glaucoma; able isomers, salts, hydrates or solvates thereof, and therefore and/or in these embodiments the compositions of the present inven 0065 (1) at least one mydriatic agent; and/or tion are free of any of them. 0.066 (m) at least one antihistamine agent; and/or US 2015/0335704 A1 Nov. 26, 2015

0067 (n) at least one anti-VEGF (i.e., vascular endothelial 0075. The concentration of the antifungal medicament(s) growth factor) medicament; in the ophthalmological compositions of the present applica 0068 (o) at least one medicament for corneal pain treat tion may be between about 0.01 mg/mL and about 75.0 ment and/or mg/mL, such as between about 1 mg/mL and about 50.0 0069 (p) at least one medicament for severe dry eye syn mg/mL, for example, about 20.0 mg/mL. One non-limiting drome treatment. example of the antifungal medicament that may be used is 0070 Any ophthalmological pharmaceutical composition ketoconazole. may be formulated that includes at least one or possibly 0076. The concentration of the immunosuppressant(s) in several or all active components (a)-(p) listed above. One the ophthalmological compositions of the present application having ordinary skill in the art will determine, taking into may be between about 0.01 mg/mL and about 50.0 mg/mL, account medical, pharmaceutical and other requirements and such as between about 0.1 mg/mL and about 30.0 mg/mL, for limitations, which active components are to be used depend example, about 20.0 mg/mL. Non-limiting examples of the ing on the kind of disease, disorder, pathology or syndrome immunosuppressants that may be used include tacrolimus, that the ophthalmological pharmaceutical composition is cyclosporine and combinations thereof. intended for treating. For example, the composition may 0077. The concentration of the corticosteroid(s) in the include one or several antibiotics and one or several corticos ophthalmological compositions of the present application teroids and no further active ingredients, or may in addition may be between about 0.01 mg/mL and about 50.0 mg/mL, contain other active components, as desired. The following such as between about 0.1 mg/mL and about 40.0 mg/mL, for general guidelines may be followed when determining what example, about 25.0 mg/mL. Non-limiting examples of the specific active components may be used and at which con corticosteroids that may be used include triamcinolone, centrations. betamethasone, dexamethasone fluorometholone, fluocino 0071. The concentration of the anesthetic(s) in the oph lone, prednisone, prednisolone, hydrocortisone and combi thalmological compositions of the present application may be nations thereof. between about 0.01 mg/mL and about 100.0 mg/mL, such as 0078. The concentration of the keratopathy agent(s) in the between about 5.0 mg/mL and about 50.0 mg/mL, for ophthalmological compositions of the present application example, about 25.0 mg/mL. Non-limiting examples of the may be between about 0.01 mg/mL and about 100.0 mg/mL, anesthetics that may be utilized include lidocaine, tetracaine, such as between about 0.1 mg/mL and about 75.0 mg/mL, for proparacaine, procaine, dyclonine and combinations thereof. example, about 30.0 mg/mL. One non-limiting example of 0072 The concentration of the non-steroid anti-inflam the keratopathy agent that may be used is ethylenediamine matory drug(s) in the ophthalmological compositions of the tetraacetic acid. present application may be between about 0.1 mg/mL and 007.9 The concentration of the antioxidant(s) in the oph about 100.0 mg/mL, such as between about 5.0 mg/mL and thalmological compositions of the present application may be about 50.0 mg/mL, for example, about 15.0 mg/mL. Non between about 0.1 mg/mL and about 200.0 mg/mL, such as limiting examples of the NSAIDs that may be utilized include between about 1.0 mg/mL and about 100.0 mg/mL, for ketoprofen, ibuprofen and combinations thereof. example, about 50.0 mg/mL. Non-limiting examples of the 0073. The concentration of the anti-bacterial agent(s) in antioxidants that may be used include acetylcysteine, glu the ophthalmological compositions of the present application tathione and combinations thereof. may be between about 0.01 mg/mL and about 50.0 mg/mL, 0080. The concentration of the vitamin(s) in the ophthal such as between about 0.5 mg/mL and about 10.0 mg/mL, for mological compositions of the present application may be example, about 1.0 mg/mL. Non-limiting examples of the between about 0.1 mg/mL and about 100.0 mg/mL, such as anti-bacterial agents that may be used include fluoroquinolo between about 1.0 mg/mL and about 50.0 mg/mL, for nes other than those specifically excluded above, such, as, for example, about 5.0 mg/mL. One non-limiting example of the example, moxifloxacin, gatifloxacin, nalidixic acid, OXolinic vitamin that may be used is riboflavin. acid, piromidic acid, pipemidic acid, roSoxacin, enoxacin, I0081. The concentration of the medicament(s) for treating fleroxacin, lomefloxacin, nadifloxacin, ofloxacin, pefloxacin, glaucoma in the ophthalmological compositions of the rufloxacin, balofloxacin, levofloxacin, paZufloxacin, spar present application may be between about 0.1 mg/mL and floxacin, toSufloxacin, clinafloxacin, gemifloxacin, sitafloxa about 100.0 mg/mL, such as between about 1.0 mg/mL and cin, prulifloxacin and combinations thereof. Non-limiting about 50.0 mg/mL, for example, about 25.0 mg/mL. Non examples of anti-bacterial agents other than fluoroquinolones limiting examples of the medicaments for treating glaucoma that may be used include Vancomycin, teicoplanin, telavan that may be used include of bimatoprost, latanoprost, tra cin, decaplanin, ramoplanin, gentamicin, tobramycin, amika voprost, apraclonidine, brimonidine, diplivefrin, physostig cin, cefuroxime, neomycin, neosporin, amoebicides (e.g., mine, betoxolol, timolol, carbachol, acetazolamide and com metronidazole, tinidazole, secnidazole, ornidazole, polyhex binations thereof. amethylene biguanide or chlorohexidine), polymyxin, clin I0082. The concentration of the mydriatic agent(s) in the damycin, bacitracin, chloramphenicol, erythromycin, nata ophthalmological compositions of the present application mycin, blephamide, Sulfacetamide, Sodium bicarbonate and may be between about 0.001 and about 0.5 mass %, such as combinations thereof. between about 0.01 and about 0.3 mass %, for example, 0074 The concentration of the antiviral medicament(s) in between about 0.03 and about 0.1 mass %. Non-limiting the ophthalmological compositions of the present application examples of the mydriatic agents that may be used include may be between about 0.01 mg/mL and about 75.0 mg/mL, epinephrine, phenylephrine, tropicamide and combinations such as between about 1 mg/mL and about 50.0 mg/mL, for thereof. example, about 20.0 mg/mL. Non-limiting examples of the I0083. The concentration of the antihistamine agent(s) in antiviral medicaments that may be used include idoxuridine, the ophthalmological compositions of the present application Vidarabine and combinations thereof. may be between about 0.1 mg/mL and about 100.0 mg/mL, US 2015/0335704 A1 Nov. 26, 2015

such as between about 1.0 mg/mL and about 50.0 mg/mL, for 0097. The concentration of the anti-bacterial agent(s) in example, about 25.0 mg/mL. Non-limiting example of the the burn-treating compositions of the present application may antihistamine agents that may be used is olopatadine, keto be between about 0.01 mg/mL and about 100.0 mg/mL, such tifen fumarate and combinations thereof. as between about 0.5 mg/mL and about 75 mg/mL, for 0084. The concentration of the anti-VEGF medicament(s) example, about 10.0 mg/mL. Non-limiting examples of the in the ophthalmological compositions of the present applica anti-bacterial agents that may be used include fluoroquinolo tion may be between about 0.1 mg/mL and about 100.0 nes (other than those specifically excluded as stated above), mg/mL, such as between about 1.0 mg/mL and about 50.0 Vancomycin, moxifloxacin, gatifloxacin, teicoplanin, tella mg/mL, for example, about 2.0 mg/mL. Non-limiting vancin, decaplanin, ramoplanin, gentamicin, tobramycin, examples of the anti-VEGF medicaments that may be used amikacin, cefuroxime, neomycin, neosporin, amoebicides include bevacizumab, pegaptainib, ranibizumab, lapatinib, (e.g., metronidazole, tinidazole, secnidazole, ornidazole, Sunitinib, Sorafenib, axitinib, paZopanib and combinations polyhexamethylene biguanide or chlorohexidine), poly thereof. myxin, clindamycin, bacitracin, chloramphenicol, erythro 0085. The concentration of the medicament(s) for corneal mycin, natamycin, blephamide, Sulfacetamide, Sodium bicar pain treatment in the ophthalmological compositions of the bonate and combinations thereof. present application may be between about 0.1 mg/mL and 0098. The concentration of the antifungal medicament(s) about 100.0 mg/mL, such as between about 1.0 mg/mL and in the burn-treating compositions of the present application about 50 mg/mL, for example, about 25.0 mg/mL. Non may be between about 0.01 mg/mL and about 75.0 mg/mL, limiting examples of the medicaments for corneal pain treat such as between about 1.0 mg/mL and about 50.0 mg/mL, for ment that may be used include nalbuphine, morphine and example, about 20.0 mg/mL. One non-limiting example of other opioids and combinations thereof. the antifungal medicament that may be used is ketoconazole. I0086. The concentration of the medicament(s) for severe 0099. The concentration of the burn healing agent(s) in the dry eye syndrome treatment in the ophthalmological compo burn-treating compositions of the present application may be sitions of the present application may be between about 0.1 between about 0.025 mg/mL and about 10.0 mg/mL, such as mg/mL and about 100.0 mg/mL, such as between about 1.0 between about 0.25 mg/mL and about 5.0 mg/mL, for mg/mL and about 50.0 mg/mL, for example, about 20.0 example, about 1.0 mg/mL. One non-limiting example of the mg/mL. Non-limiting examples of the medicament(s) for burn healing agent that may be utilized is misoprostol. severe dry eye syndrome treatment that may be used include 0100. The concentration of the medicament(s) for treating albumin, plasminogen and combinations thereof. neuropathic pain in the burn-treating compositions of the 0087. Those having ordinary skill in the art can determine present application may be between about 0.1 mg/mL and the optimal concentration for each specific active component about 100.0 mg/mL, such as between about 1.0 mg/mL and that is used, based on medical pharmaceutical and other con about 75.0 mg/mL, for example, about 50.0 mg/mL. Non siderations that are commonly taken into account. limiting examples of the medicaments for treating neuro pathic pain that may be used include ketamine, morphine, Pharmaceutical Compositions for Treating Burns. fentanyl, pregabalin, carbamazepine, gabapentin, clonidine 0088 For burn-treating applications, and in some embodi and combinations thereof. ments, for applications intended to treatgun-shot wounds, the 0101 Again, the same as for the ophthalmological com compositions include an active component comprising, con positions, those having ordinary skill in the art can determine sisting essentially of, or consisting of a therapeutically effec the optimal concentration for each specific active component tive quantity of any of the following, or any combination that is used in the burn-treating compositions, based on medi thereof: cal pharmaceutical and other considerations that are com 0089 (a) at least one anesthetic; and/or monly taken into account. 0090 (b) at least one non-steroid anti-inflammatory drug 0102. As stated above, all the compositions of the present (NSAID); and/or invention, both for ophthalmological and burn-treating appli 0091 (c) at least one anti-bacterial agent (i.e., an antibiotic cations, include a gel. A typical gel that is useful for the or an antiseptic); and/or purposes of the present invention is a thermoreversible gel as 0092 (d) at least one antifungal agent; and/or defined above, i.e., being in a solid or gel-like State at a room 0093 (e) at least one burn-healing agent; and/or temperature of about 20°C. or higher and being in a fluid state 0094 (f) at least one medicament for treating neuropathic at lower temperatures, such as having the value of dynamic pain. viscosity of about 10 centipoise or less, such as about 1.3 0095. The concentration of the anesthetic(s) in the burn centipoise or less. To form a thermoreversible gel, a suitable treating compositions of the present application may be thermoreversible polymer is combined with water. A concen between about 0.01 mg/mL and about 250.0 mg/mL, such as tration of the polymer in water may be between about 1.0 between about 1.0 mg/mL and about 100.0 mg/mL, for mg/mL and about 500.0 mg/mL, such as between about 50.0 example, about 50.0 mg/mL. Non-limiting examples of the mg/mL and about 350.0 mg/mL, for example, about 200.0 anesthetics that may be utilized include lidocaine, tetracaine, mg/mL. proparacaine, procaine, dyclonine and combinations thereof. 0103) A variety of polymers can be used for forming a 0096. The concentration of the non-steroid anti-inflam thermoreversible gel. Those skilled in the art will select poly matory drug(s) in the burn-treating compositions of the mers and their concentrations that are most appropriate. Some present application may be between about 0.1 mg/mL and non-limiting examples of Such polymers include poly(oxy about 100.0 mg/mL, such as between about 5.0 mg/mL and ethylene-co-oxypropylene) block copolymers, poly(N-iso about 50.0 mg/mL, for example, about 25.0 mg/mL. Non propylacrylamide), poly(N-isopropylacrylamide-co-acrylic limiting examples of the NSAIDs that may be utilized include acid), poly(Vinyl pyrrolidone), poly(4-vinylpyridine-co ketoprofen, ibuprofen and combinations thereof. ethylacrylate) block copolymers and poly(N-isopropylacry US 2015/0335704 A1 Nov. 26, 2015

lamide-co-butyl methacrylate-co-ethylene glycol) block 30 to 40 minutes at a pressure of about 30 bars (i.e., about 29.6 copolymers. Such block copolymers may include cross atm or 3 MPa) in a standard autoclaving apparatus. The ster linked portions. ilized gel can be then dispensed into a Suitable container (e.g., 0104. According to one non-limiting embodiment, a a sterile ophthalmic dropper bottle or, alternatively, a sterile reversible gel-forming polymer that can be used is a non-ionic vial or a sterile Syringe, if desired). A complete testing for poly(oxyethylene-co-oxypropylene) block copolymer hav sterility and the presence of endotoxin in the gel may be ing the following general structure: performed according to commonly used methods known to those having ordinary skill in the art. A sterile thermorevers ible gel that is prepared by any sterilization method disclosed above can then be used to fabricate a pharmaceutical compo wherein in some further non-limiting embodiments, X is an sition. integer that can have the value of at least 8 and y is an integer 0110. To prepare a pharmaceutical composition, a sterile that can have the value of at least 38. thermoreversible gel prepared as described above is to be 0105. One non-limiting example of an even more specific combined with a selected active component by any accept non-ionic poly(oxyethylene-co-oxypropylene) block copoly able mixing method; for example, the gel and the active mer that can be used is the product known under the trade component may be mixed in a single sterile container Such as name Poloxamer 407R (poly(ethylene glycol)-block-poly an ophthalmic dropper bottle, a sterile vial or a Syringe and (propylene glycol)-block-poly(ethylene glycol)) available Such quantities of the gel and the active component are to be from Sigma-Aldrich Corp. of St. Louis, Mo. (the trade name selected as to achieve a desired, pre-determined concentra is owned by BASF Corp.), with the molecular weight of the tion of the active component in the overall composition, as polyoxypropylene portion of about 4,000 Daltons, about a disclosed above. 70% polyoxyethylene content, the overall molecular weight 0111. In one, non-limiting specific embodiment, a phar of between about 9,840 Daltons and about 14,600 Daltons maceutical composition formulated for delivery as topical and having the following chemical structure ophthalmic drops can be prepared, the composition compris ing an active component that includes therapeutically effec tive quantities of a corticosteroid such as triamcinolone and of CH an anti-bacterial agent such as moxifloxacin. The composi tion can be prepared by combining this active component H -O O y Su-Nz OH with a quantity of pre-sterilized gel, based, for example, on Poloxamer 407(R). 0112 Pharmaceutical compositions prepared as described wherein each X and Z is an integer having the value between above can be used for treating any disease, complication, about 78 and about 116, and y is an integer having the value pathology or syndrome that the active component is intended of about 69. to treat. Typically, a pharmaceutical composition described 0106 Other similar products of the Poloxamer(R) family above will be administered to a mammalian Subject (e.g., are useful for forming the thermoreversible gel of the com humans, cats, dogs, other pets, domestic, wild or farm ani positions of the present invention are, for example, the prod mals) in need of emergent, urgent or planned ophthalmic ucts of the PluronicR) family, Kolliphor(R) family (the trade treatment or, alternatively, in need of a burn treatment or a names are also owned by BASF) or Symperonics(R family gun-shot wound treatment. (Croda International plc). Any polymer of Poloxamer R, Plu 0113 A pharmaceutical composition described above can ronic R, Kolliphor(R) or Symperonics(R family that is used may be delivered in a variety of ways, such as, for ophthalmic contain any portion that is cross-linked. applications, topical ophthalmic drops, eye sprays or they can 0107 According to further embodiments, methods for be injected (e.g., via Subconjunctival injection) using meth fabricating the above-described pharmaceutical composi ods and techniques known to those having ordinary skilled in tions are provided. In one embodiment, the thermoreversible the art of ophthalmology. The composition at the pre-delivery gel can be prepared first followed by adding a pre-determined stage (i.e., at a point of time that is immediately preceding the quantity of an active component, or vice versa. If more than administration) is cool (i.e., below the room temperature) and one active component is to be used, the active component(s) is, therefore, a fluid. Following the act of administering the may be added to the thermoreversible gel in any order to be composition, as the composition arrives to the cul-de-sac or a selected by one of ordinary skill in the art and may be added Surface of the patient’s eye (for ophthalmic compositions), its either simultaneously or consecutively, or be pre-mixed first temperature rapidly rises to that of the body of the patient to followed by adding the mixture to the gel component. whom it is being administered, and becomes gel-like within 0108. In one exemplary, non-limiting procedure, a sterile seconds. thermoreversible gel is prepared first, for example, by com 0114. Similarly, for burn gun-shot wound treatments, bining a suitable thermoreversible polymer with sterile water when a composition is delivered and topically applied to the followed by further sterilization of the resulting gel, for site of burn or gun-shot wound, its temperature rises to that of example by autoclaving, treatment by gamma-radiation or by the body of the patient whose burns gun-shot wounds are exposing it to a flow of ethylene oxide. Those having ordinary being treated, and quickly gels up upon reaching the body skill in the art can determine which sterilization method is temperature. best Suited in a particular procedure. 0.115. It will be understood by those having ordinary skill 0109 For example, if a standard autoclaving method of in the art that the specific dose level and frequency of dosage sterilization is to be used, the thermoreversible gel prepared for any particular patient may be varied and will depend upon as described above can be subjected to a temperature between a variety of factors including the activity of the specific com about 200° C. and about 300° C., e.g., about 250° C., for about pound employed, the metabolic stability and length of action US 2015/0335704 A1 Nov. 26, 2015 of that compound, the age, body weight, general health, gen Example 3 der, diet, and the severity of the particular ophthalmological or burn condition being treated. Preparing a Topical Pharmaceutical Composition for 0116. In additional embodiments, pharmaceutical kits are Treating Burns provided. The kit includes a sealed sterile container approved 0.124. A pharmaceutical composition can be prepared as for the storage of pharmaceutical compositions, the container described below. A pre-determined quantity of an active com containing a sterile gel prepared as described above. An ponent can be mixed with a pre-determined quantity of the instruction is to be included in the kit providing directions on how to prepare a mixture of the sterile gel with one or more sterilized poloxamer-based gel obtained as described in active compounds to make a pharmaceutical composition. Example 1. Further instructions on how to use the composition may be (0.125. About 950.0 mL of 20% sterile poloxamer can be further provided. placed in a pre-sterilized 1.0 L bottle. Concentrated medica tions such as about 25.0 mL gentamicinat about 40.0 mg/mL 0117 The following examples are provided to further elu can be added, filtered to the sterilegel and mixed well. Final cidate the advantages and features of the present invention, concentration can, therefore, be about 1 mg/ml gentamicin, but are not intended to limit the scope of the invention. The still leaving room for addition of up to about 25.0 mL diluent examples are for the illustrative purposes only. USP pharma or another medication Such as lidocaine, if desired. The com ceutical grade products were used in preparing the formula position is to be kept refrigerated until use. tions described below. 0.126 Although the invention has been described with ref erence to the above examples, it will be understood that C. Examples modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is Example 1 limited only by the following claims. What is claimed is: Preparing a Sterile Thermoreversible Gel 1. An ophthalmological pharmaceutical composition or a pharmaceutical composition for treating burns, comprising: 0118. A thermoreversible gel was prepared as described below. The following products were used in the amounts (a) a therapeutically effective quantity of an active compo nent that is free of any of fluconazole, methazolamide, specified: aZitromycin, mitomycin, pilocarpine, povidone-iodine, 0119 (a) about 20.0 g of Pluronic F127R NF (Poloxamer dexamethasone, flurbiprofen, bromfenac, nepafenac, 407R); and diclofenac, ketorolac, indomethacin, Suprofen, nor floxacin, ciprofloxacin, antiseptics comprising the NH 0120 (b) about 100.0 mL of sterile water, cation, or pharmaceutically acceptable isomers, salts, 0121. The solution of Pluronic F127(RNF was placed into hydrates or solvates thereof; and a vessel, then refrigerated water was added. The mixture was (b) a quantity of a thermoreversible gel component that is kept refrigerated for at least about 12 hours to allow the free of any of chitosan, carbopol or polysorbate. mixture to become a solution. The thermoreversible gel so obtained was sterilized. To sterilize the gel, it was placed into 2. The pharmaceutical composition of claim 1, wherein the an autoclaving apparatus and Subjected to a temperature of gel component comprises a polymer that optionally includes cross-linked portions, the polymer being selected from the about 300° C., for about 40 minutes at a pressure of about 30 group consisting of poly(oxyethylene-co-oxypropylene) bars. The Sterilized gel was then dispensed into an ophthalmic block copolymer, poly(N-isopropylacrylamide), poly(N-iso dropper bottle and tested for sterility and the presence of propylacrylamide-co-acrylic acid), poly(vinyl pyrrolidone), endotoxin. The final product can then be used as a stock poly(4-vinylpyridine-co-ethylacrylate) block copolymer, Solution for preparing a pharmaceutical formulation. poly(N-isopropylacrylamide-co-butyl methacrylate-co-eth Example 2 ylene glycol) block copolymer and combinations thereof. 3. The pharmaceutical composition of claim 2, wherein the polymer is poly(oxyethylene-co-oxypropylene) block Preparing an Ophthalmic Pharmaceutical copolymer selected from the group consisting of Poloxamer Composition 407(R), Pluronic 127(R) and combinations thereof. 0122 A pharmaceutical composition can be prepared as 4. The pharmaceutical composition of claim 1, wherein the described below. A pre-determined quantity of an active com composition is the ophthalmological composition in which ponent can be mixed with a pre-determined quantity of the the active component comprises at least one anesthetic, at sterilized poloxamer-based gel obtained as described in least one non-steroid anti-inflammatory drug (NSAID), at Example 1. least one anti-bacterial agent, at least one antiviral medica ment, at least one antifungal medicament, at least one immu (0123. About 9.0 mL of 20% sterile poloxamer can be nosuppressant, at least one corticosteroid, at least one kerat placed in a pre-sterilized dropper. About 1.0 mL of a concen opathy agent, at least one antioxidant, at least one vitamin, at trated Vancomycin solution, at about 250.0 mg/mL, can be least one medicament for treating glaucoma, at least one filtered into droptainer and shaken inside hood. Final result mydriatic agent, at least one antihistamine agent, at least one ant concentration can, therefore, be about 25.0 mg/mL van anti-VEGF medicament, at least one medicament for corneal comycin, in about 10.0 mL. Sterile gel. The composition is to pain treatment or at least one medicament for severe dry eye be kept refrigerated until use. syndrome treatment. US 2015/0335704 A1 Nov. 26, 2015

5. The pharmaceutical composition of claim 4, wherein the 21. The pharmaceutical composition of claim 4, wherein anesthetic is selected from the group consisting of lidocaine, the medicament for corneal pain treatment is selected from tetracaine, proparacaine, procaine, dyclonine and combina the group consisting of nalbuphine, morphine and other opio tions thereof. ids and combinations thereof. 6. The pharmaceutical composition of claim 4, wherein the 22. The pharmaceutical composition of claim 4, wherein NSAID is selected from the group consisting of ketoprofen, the medicament for severe dry eye syndrome treatment is ibuprofen and combinations thereof. selected from the group consisting of albumin, plasminogen 7. The pharmaceutical composition of claim 4, wherein the and combinations thereof. anti-bacterial agent is a fluoroquinolone. 23. The pharmaceutical composition of claim 4, the com 8. The pharmaceutical composition of claim 7, wherein the position consisting ofatherapeutically effective quantity of at anti-bacterial agent selected from the group consisting of least one anti-bacterial agent, a therapeutically effective moxifloxacin, gatifloxacin, nalidixic acid, oxolinic acid, piro quantity of at least one corticosteroid and wherein the gel midic acid, pipemidic acid, roSoxacin, enoxacin, fleroxacin, component is Poloxamer 407(R). lomefloxacin, nadifloxacin, ofloxacin, pefloxacin, rufloxacin, 24. The pharmaceutical composition of claim 4, wherein balofloxacin, levofloxacin, paZufloxacin, sparfloxacin, to Su the active component comprises triamcinolone and moxi floxacin, clinafloxacin, gemifloxacin, sitafloxacin, pruli floxacin and the gel component comprises Poloxamer 407(R). floxacin and combinations thereof. 25. The pharmaceutical composition of claim 1, wherein 9. The pharmaceutical composition of claim 4, wherein the the composition is the composition for treating burns in which anti-bacterial agent is selected from the group consisting of the active component comprises: Vancomycin, teicoplanin, telavancin, decaplanin, ramopla nin, gentamicin, tobramycin, amikacin, cefuroxime, neomy (a) at least one anesthetic selected from the group consist cin, neosporin, metronidazole, tinidazole, secnidazole, ing of lidocaine, tetracaine, proparacaine, procaine, ornidazole, polymyxin, clindamycin, polyhexamethylene dyclonine and combinations thereof; biguanide, chlorohexidine, bacitracin, chloramphenicol, (b) at least one NSAID, erythromycin, natamycin, blephamide, Sulfacetamide, (c) at least one anti-bacterial agent selected from the group Sodium bicarbonate and combinations thereof. consisting of Vancomycin, teicoplanin, telavancin, deca 10. The pharmaceutical composition of claim 4, wherein planin, ramoplanin, gentamicin, tobramycin, amikacin, the antiviral medicament is selected from the group consist cefuroxime, neomycin, mitomycin, neosporin, metron ing of idoxuridine, Vidarabine and combinations thereof. idazole, tinidazole, secnidazole, ornidazole, polymyxin, 11. The pharmaceutical composition of claim 4, wherein clindamycin, sulfa drugs, polyhexamethylene bigu the antifungal medicament is ketoconazole. anide, chlorohexidine, bacitracin, chloramphenicol, 12. The pharmaceutical composition of claim 4, wherein erythromycin, natamycin, blephamide, Sulfacetamide, the immunosuppressant is selected from the group consisting Sodium bicarbonate and a combination thereof, of tacrolimus, cyclosporine and combinations thereof. (d) a quantity of an antifungal medicament ketoconazole; 13. The pharmaceutical composition of claim 4, wherein (e)a quantity of a burn-healing agent misoprostol or the corticosteroid is selected from the group consisting of (f) at least one medicament for treating neuropathic pain triamcinolone, betamethasone, fluorometholone, fluocino Selected from the group consisting of ketamine, mor lone, prednisone, prednisolone, hydrocortisone and combi phine, fentanyl, pregabalin, carbamazepine, gabapentin, nations thereof. clonidine and combinations thereof. 14. The pharmaceutical composition of claim 4, wherein 26. An ophthalmological pharmaceutical composition, the keratopathy agent is ethylenediaminetetraacetic acid. comprising: 15. The pharmaceutical composition of claim 4, wherein (a) a therapeutically effective quantity of an corticosteroid the antioxidant is selected from the group consisting of ace Selected from the group consisting of triamcinolone, tylcysteine, glutathione and combinations thereof. dexamethasone, betamethasone, fluorometholone, fluo 16. The pharmaceutical composition of claim 4, wherein cinolone, prednisone, prednisolone, hydrocortisone and the vitamin is riboflavin. combinations thereof; 17. The pharmaceutical composition of claim 4, wherein (b) a therapeutically effective quantity of an anti-bacterial the medicament for treating glaucoma is selected from the agent selected from the group consisting of moxifloxa group consisting of bimatoprost, latanoprost, travoprost, cin, gatifloxacin, nalidixic acid, oxolinic acid, piromidic apraclonidine, brimonidine, diplivefrin, physostigmine, acid, pipemidic acid, roSoxacin, enoxacin, fleroxacin, betoxolol, timolol, carbachol, acetazolamide and combina lomefloxacin, nadifloxacin, ofloxacin, pefloxacin, tions thereof. rufloxacin, balofloxacin, levofloxacin, paZufloxacin, 18. The pharmaceutical composition of claim 4, wherein sparfloxacin, to Sufloxacin, clinafloxacin, gemifloxacin, the mydriatic agent is selected from the group consisting of sitafloxacin, prulifloxacin and combinations thereof; epinephrine, phenylephrine, tropicamide and combinations and thereof. (c) a quantity of a thermoreversible gel component com 19. The pharmaceutical composition of claim 4, wherein prising a polymer selected from the group consisting of the antihistamine agent is selected from the group consisting poly(Oxyethylene-co-oxypropylene) block copolymer, of olopatadine, ketotifen fumarate and combinations thereof. poly(N-isopropylacrylamide), poly(N-isopropylacryla 20. The pharmaceutical composition of claim 4, wherein mide-co-acrylic acid), poly(vinyl pyrrolidone), poly(4- the anti-VEGF medicament is selected from the group con vinylpyridine-co-ethylacrylate) block copolymer, poly sisting of bevacizumab, pegaptainib, ranibizumab, lapatinib, (N-isopropylacrylamide-co-butyl methacrylate-co Sunitinib, Sorafenib, axitinib, paZopanib and combinations ethylene glycol) block copolymer and combinations thereof. thereof. US 2015/0335704 A1 Nov. 26, 2015

27. The pharmaceutical composition of claim 26, wherein the corticosteroid is dexamethasone, the anti-bacterial agent is moxifloxacin and the polymer in the thermoreversible gel component is poly(oxyethylene-co-oxypropylene) block copolymer selected from the group consisting of Poloxamer 407(R), Pluronic 127(R) and combinations thereof. 28. The pharmaceutical composition of claim 26, further comprising a non-steroid anti-inflammatory drug selected from the group consisting of bromfenac, nepafenac, diclofenac, ketorolac and combinations thereof. 29. The pharmaceutical composition of claim 28, wherein the corticosteroid is prednisone, the anti-bacterial agent is moxifloxacin, the polymer in the thermoreversible gel com ponent is poly(oxyethylene-co-oxypropylene) block copoly mer selected from the group consisting of Poloxamer 407(R), Pluronic 127(R) and combinations thereof and a non-steroid anti-inflammatory drug is ketarolac. k k k k k