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US 20140371179A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0371179 A1 Simmons (43) Pub. Date: Dec. 18, 2014

(54) METHODS AND COMPOSITIONS FOR (52) US. Cl. TREATING ESOPHAGEAL DISEASES CPC ...... A61K 31/58 (2013.01); A61K 45/06 (2013.01) (71) Applicant: Chris V. SimmOHS, Sugar Land, TX USPC ...... 514/170; 514/174; 514/ 171 (Us) (72) Inventor: Chris V. Simmons, Sugar Land, TX (57) ABSTRACT (Us) Compositions and methods for treating esophageal diseases (73) Assignee: PROFESSIONAL COMPOUNDING are disclosed. More speci?cally, these methods may refer to CENTERS OF AMERICA, Houston, the treament of esophageal varices and eosinophilic esoph TX (US) agitis using an oral suspension drug for humans. The oral suspension drug may include poloxamer f1 27 used as vehicle (21) Appl' N05 13/917,275 and budesonide as a corticosteroid. Poloxamer oral suspen - _ sion may be administrated by swallowing the poloxamer oral (22) Flled' Jun' 13’ 2013 suspension drug Which may slide down through the esoph Publication Classi?cation ageal and may be adhered in the affected site providing a longer residence time. Additionally, poloxamer oral suspen (51) Int. Cl. sion may be mixed With APls such as antifungals, antibacte A61K 31/58 (2006.01) rials, and corticosteroids, previously dissolved in a suitable A61K 45/06 (2006.01) liquid, such as water. Patent Application Publication Dec. 18, 2014 Sheet 1 0f 3 US 2014/0371179 A1

100

/,102 104 / \r ~ * ~ " * ~ * ~ "‘ * w I i \ Antibacterials , /112 106! I / i i / \\ Antifungals ' Polgxamef f127 110 ‘ ' Hydrophmc NOFHOHIC Surfactant l i I l i \ Budesonide i ‘ I Corticosteroid * POIOxamer Oral 108/L " * ‘ " * " " ‘ " * J \ Sus p ension 114

FIG. 1 Patent Application Publication Dec. 18, 2014 Sheet 2 0f3 US 2014/0371179 A1

FIG. 2 Patent Application Publication Dec. 18, 2014 Sheet 3 0f3 US 2014/0371179 A1

FIG. 3 US 2014/0371179 A1 Dec. 18, 2014

METHODS AND COMPOSITIONS FOR increase the micro circulation which may allow healing pro TREATING ESOPHAGEAL DISEASES cess of the body immune system. Consequently, when polox amer oral suspension is swallowed, poloxamer oral suspen CROSS-REFERENCE TO RELATED sion may slide down through the pharynx into the esophagus APPLICATIONS and may travel via peristalsis to the affected site in the esopha [0001] N/A gus where poloxamer oral suspension may be adhered, pro viding a longer residence time. BACKGROUND [0011] Numerous other aspects, features and bene?ts of the present disclosure may be made apparent from the following [0002] 1. Field ofthe Disclosure detailed description taken together with the drawing ?gures. [0003] The present disclosure relates generally to esoph ageal diseases, and more particularly, to compositions and BRIEF DESCRIPTION OF THE DRAWINGS methods for treating eosinophilic esophagitis and esophageal varices. [0012] The present disclosure can be better understood by [0004] 2. Background Information referring to the following ?gures. The components in the ?gures are not necessarily to scale, emphasis instead being [0005] Incidence of gastrointestinal functional diseases placed upon illustrating the principles of the disclosure. In the increases day by day, where the common esophageal diseases ?gures, reference numerals designate corresponding parts can be re?ux esophagitis, esophageal cancer, esophageal stenosis, esophageal varices, dyspepsia, and functional dys throughout the different views. [0013] FIG. 1 is an oral suspension components block dia phagia. In the course of medical diagnosis and treatment, a gram, according to an embodiment. continuous monitoring or treatment of the esophagus is often [0014] FIG. 2 depicts a close up view of lower esophageal, required. Currently, there are many types of esophagus treat where poloxamer oral suspension may be used in esophageal ments on the market such as endoscopic therapy, surgery, injection and oral suspension drugs, among others. varices, according to an embodiment. [0015] FIG. 3 depicts a close up view of lower esophageal, [0006] Oral suspension drugs may commonly include where poloxamer oral suspension may be used in eosino active pharmaceutical ingredients (APIs) for treating esoph philic esophagitis, according to an embodiment. ageal diseases. For example, esophageal varices is a common disease in humans that may be treated with budesonide oral DETAILED DESCRIPTION suspension with vehicles, such as methylcellulose, however, methylcellulose, used as thickener within budesonide oral [0016] The present disclosure is here described in detail suspension does not have bio-adhesive properties. with reference to embodiments illustrated in the drawings, [0007] Current oral suspensions for treating esophageal which form a part hereof. Other embodiments may be used diseases generally slide down without adhering to the and/or other changes may be made without departing from affected site. Therefore, there is a need for suitable pharma the spirit or scope of the present disclosure. The illustrative ceutical oral compositions that include a vehicle which allows embodiments described in the detailed description are not APIs remain or adhere (for a suitable period of time) on the meant to be limiting of the subject matter presented here. affected esophageal site and may allow a faster healing time. De?nitions SUMMARY [0017] As used here, the following terms may have the [0008] According to various embodiments, the present dis following de?nitions: closure relates to compositions and methods for the treatment [0018] “Treating” and “treatment” refers to a reduction in of eosinophilic esophagitis and esophageal varices in severity and/ or frequency of symptoms, elimination of symp humans. More speci?cally, the present disclosure refers to the toms and/or underlying cause, prevention of the occurrence application of an oral pharmaceutical composition in the of symptoms and/or their underlying cause, and improvement mouth which may enable an effective administration, thus or remediation of damage. improving treatment outcomes. The oral composition may [0019] “Poloxamer f127” refers to a non-toxic, di-block include about 5% to 10% of poloxamer f127 (as a vehicle); copolymer of polyoxyethylene and polyoxypropylene where with budesonide in an amount of about 1 to 2 ring/ 10 ml. in aqueous solutions (30% w/v) show therrnoreversible gela According to another embodiment poloxamer f1 27 may have tion, being liquid at temperatures <15 degrees C. and robust the ability to solubilize in soluble drugs and poloxamer f127 gels at temperatures >15 degrees C. may exhibit an effective and stable vehicle for oral composi [0020] “Budesonide” refers to a class of called tions. corticosteroids that may work by decreasing in?ammation [0009] In another embodiment, oral composition may (swelling) in the digestive tract of people or animals. include a second and/ or third API in combination with budes [0021] “Esophageal varices” refers to abnormal enlarged onide. In another embodiment, oral composition may include veins in the lower part of the esophagus and may occur most API or APIs other than budesonide. Poloxamer f127 may be often in people with serious liver diseases. used with any suitableAPI such as antibacterials, antifungals, [0022] “Eosinophilic esophagitis” refers to an allergic reac corticosteroids, antiparasitics, among others. According to tion that causes in?ammation and damage to the esophagus one embodiment, the poloxamer oral suspension may start to which may be usually caused by a food allergy. thicken when it is placed in the mouth because of the ther [0023] “Active pharmaceutical ingredient” refers to a moreversible properties. Poloxamer oral suspension may be chemical material or compound that induces a desired phar administrated once a day in the morning. macological, physiological effect, and includes agents that [0010] According to some embodiments, the poloxamer are therapeutically effective, prophylactically effective, or oral suspension may have bio-adhesive properties and may cosmeceutical effective. US 2014/0371179 A1 Dec. 18, 2014

[0024] “vehicles” refer to carrier materials suitable for proxil, tipranavir, tri?uridine, triZivir, , truvada, transdermal/topical or oral drug administration. valganciclovir, vicriviroc, vidarabine, viramidine, zalcitab ine, zanamivir, Zidovudine, and combinations thereof. Description of the Drawings [0032] Antibacterial Agents [0033] According to some embodiments antibacterial Oral Suspension Composition agents may include , , kanamycin, neo [0025] FIG. 1 is an oral suspension components block dia mycin, netilmicin, streptomycin, tobramycin, paromomycin, gram 100. According to some embodiments, APls 102 may geldanamycin, herbimycin, loracarbef, ertapenem, dorip include the active ingredients that may be used for treating the enem, imipenem, cilastatin, meropenem, cefadroxil, cefazo esophageal diseases. APls 102 may include antibacterials lin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, 104, antifungals 106, and corticosteroids 108. Suitable corti defprozil, cefuroxime, ce?xime, cefdinir, cefditoren, cefop costeroid 108 may be budesonide 110 compositions that may erazone, cefotaxime, cefpodoxime, ceftaZidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, teicopla include about 1 to 2 ring/ 10 ml of budesonide 110. nin, vancomycin, aZithromycin, clarithromycin, dirithromy [0026] According to one embodiment, APls 102 may be cin, erythromycin, roxithromycin, troleandomycin, telithro combined With a vehicle such as poloxamer f127 112. Suit able concentration of poloxamer f127 112 for the disclosed mycin, spectinomycin, aZtreonam, amoxicillin, ampicillin, aZlocillin, carbenicillin, cloxacillin, dicloxacillin, ?uclox oral suspension may be of about 5% to about 10%. Poloxamer acillin, meZlocillin, meticillin, nafcillin, oxacillin, penicillin, f 127 112 may have thermoreversible properties, for instance, piperacillin, ticarcillan, , colistin, polymyxin B, poloxamer f127 112 at room temperature is in liquid state cipro?oxacin, enoxacin, gati?oxacin, levo?oxacin, lom changing to a gel at body (or warm) temperature. e?oxacin, moxi?oxacin, nor?oxacin, o?oxacin, trov?oxacin, [0027] According to one embodiment, APls 102 may be , prontosil, sulfacetamide, , sulfani mixed With poloxamer f127 112, previously dissolved in a milimde, sulfasalaZine, sul?soxazole, trimetoprim, demeclo suitable solvent, resulting in poloxamer oral suspension 114 cycline, doxycycline, minocycline, , tetracy Which may be effective for treating esophageal varices, eosi cline, arsphenamine, , clindamycin, nophilic esophagitis, among other esophageal diseases.Addi lincomycin, ethambutol, fosfomycin, , furazoli tionally, APls 102 may be mixed With poloxamer f1 27 112 for done, isoniaZid, linezolid, , , nitro treating other esophageal disorders, such as structural abnor furantoin, platensimycin, pyraZinamide, quinuspristin/dalfo malities, motility abnormalities, in?ammatory disorders, and pristin, rifampin, tinidazole, AL-15469A (Alcon Research), malignancies. In one embodiment, suitable solvent to dis AL-38905 (Alcon Research) and combinations thereof. solve poloxamer f 127 112 may be water, other embodiments [0034] Antifungal Agents may include other suitable solvents. [0035] Accoriding to some embodiments, antifungal [0028] Other embodiments may include other suitable agents may include amrol?ne, utena?ne, nafti?ne, terbin additives such as pH adjusting agents, preservatives, emulsi a?ne, ?ucytosine, ?uconazole, itraconazole, ketoconazole, ?ers, opaci?ers, antioxidants, fragrances, colorant, gelling posaconazole, ravuconazole, voriconazole, clotrimazole, agents, thickening agents, stabilizers, surfactants, among oth econazole, miconazole, oxiconazole, sulconazole, tercona ers. Other agents may also be added, such as antimicrobial Zole, tioconazole, nikkomycin Z, caspofungin, micafungin, agents, to prevent spoilage upon storage, for example, to anidulafungin, amphotericin B, liposomal nystastin, pimari inhibit growth of microbes such as yeasts and molds. Suitable cin, griseofulvin, ciclopirox olamine, haloprogin, tolnaftate, antimicrobial agents are typically selected from the group undecylenate, clioquinol, and combinations thereof. consisting of the methyl and propyl esters of p-hydroxyben [0036] Aniparasitic Agents zoic acid, sodium benzoate, sorbic acid, imidurea and com binations thereof. [0037] According to some embodiments, antiparasitic agents may include amitraZ, amoscanate, avermectin, carba dox, diethylcarbamiZine, dimetridazole, diminazene, iver Active Pharmaceutical Ingredients mectin, macro?laricide, malathion, mitaban, oxamniquine, [0029] Poloxamer f127 may be used With any suitable API permethrin, praZiquantel, prantel pamoate, selamectin, such as antibacterials, antifungals, corticosteroids, antipara sodium stibogluconate, thiabendazole, and combinations sitics, among others. thereof. [0030] Antiviral Agents [0038] Corticosteroids [0031] According to some embodiments, antiviral agents [0039] According to some embodiments, corticosteroids may include acyclovir, famciclovir and valacyclovir. Other may include hydrocortisone, prednisone, ?uprednisolone, tri antiviral agents include abacavir, , adefovir, amanta amcinolone, dexamethasone, betamethasone, cortisone, dine, amprenavir, arbidol., atazanavir, artipla, brivudine, prednilosone, methylprednisolone, ?uocinolone acetonide, cidofovir, combivir, , efavirenZ, emtricitabine, ?urandrenolone acetonide, and ?uorometholone. enfuvirtide, entecavir, fomvirsen, fosamprenavir, foscamet, [0040] Anaesthetics Agents fosfonet, ganciclovir, gardasil, ibacitabine, immunovir, [0041] According to some embodiments, anaesthetics , , indinavir, , integrase inhibi agents may include benzocaine, butamben picrate, tetracaine, tors, interferons, including interferon type 111, interferon type dibucaine, prilocalne, etidocaine, mepivacaine, bupivicaine, II, interferon type I, lamivudine, lopinavir, loviride, and lidocaine. Preferred non-steroidal anti-in?ammatory MK-0518, maraviroc, moroxydine, nel?navir, nevirapine, agents may include, for example, detoprofen, diclofenac, nexavir, nucleoside analogues, oseltamivir, , per di?unisal, etodolac, fenoprofen, ?urbiprofen, indomethacin, amivir, pleconaril, , protease inhibitors, ketoprofen, mechlofenameate, mefenamic acid, meloxicam, reverse transcriptase inhibitors, ribavirin, rimantadine, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulin ritonavir, saquinavir, stavudine, tenofovir, tenofovir diso dac, tolmeting, celecoxib, rofecoxib, choline salicylate, sal US 2014/0371179 A1 Dec. 18, 2014

sate, sodium salicylate, magnesium salicylate, aspirin, ibu (a) budesonide in a concentration of about 1 mg/ 10 ml to profen, paracetamol, acetaminophen, and pseudoephedrine. about 2 mg/10 ml; and Preferred steroids may include, for example, hydrocortisone, (b) about 5% to about 10% by weight poloxamer f127; prednisone, ?uprednisolone, triamcinolone, dexamethasone, (c) imidurea; and betamethasone, cortisone, prednilosone, methylpredniso (d) optionally, an antimicrobial agent selected from the lone, ?uocinolone acetonide, ?urandrenolone acetonide, and group consisting of methyl ester of p-hydroxybenzoic ?uorometholone, and combinations thereof. acid, propyl ester of p-hydroxybenzoic acid, sodium benzoate, sorbic acid, and combinations thereof. Poloxamer Oral Suspension (Applications) 2. A composition according to claim 1, which is in the form of an oral suspension. [0042] FIG. 2 depicts close up view 200a oflower esopha 3. A composition according to claim 1, which is in the form gus 202 where poloxamer oral suspension 116 may be used for treating esophageal varices 204. Speci?cally, esophageal of a tablet. varices 204 may be abnormal, enlarged veins located in lower 4. A composition according to claim 1, further comprising esophagus 202 and upper stomach 206. Esophageal varices an antibacterial composition, an antifungal composition, a 204 may occur most often in people with serious liver dis corticosteroid, an antiparasitic composition, or a combination thereof. eases and may be developed when normal blood ?ow to the liver is slowed. Consequently, the blood may then back up 5. A method of treating esophageal disease, comprising into nearby smaller blood vessels, such as those in lower orally delivering to a patient an effective amount of a phar esophagus 202, causing the vessels to swell. Sometimes, maceutical composition that comprises budesonide and at esophageal varices 204 may rupture causing life-threatening least one poloxamer. bleeding. 6-8. (canceled) [0043] The primary aim for treating esophageal varices 204 9. The method according to claim 5, wherein the pharma is to prevent bleeding. Bleeding esophageal varices 204 are ceutical composition is administered once per day. life-threatening. According to some embodiments, polox 10. The method according to claim 5, wherein the pharma amer oral suspension 116 may be used for treating esophageal ceutical composition is administered in multiple doses per varices 204 applying a dosage of about 5 ml to about 10 ml day. once a day. Poloxamer oral suspension 116 may include bio 11. The method according to claim 5, wherein the pharma adhesive properties and may also increase micro-circulation. ceutical composition is in the form of an oral suspension. Poloxamer oral suspension 116 may be adhered to the walls 12. The method according to claim 5, wherein the pharma of lower esophagus 202 which may give a longer residence ceutical composition is in the form of a tablet. time. 13. The method according to claim 5, wherein the pharma [0044] FIG. 3 depicts close up view 2001) oflower esopha ceutical composition further comprising an antibacterial gus 202 where poloxamer oral suspension 116 may be used in composition, antimicrobial agent , an antifungal composi eosinophilic esophagitis 302. Speci?cally, eosinophilic tion, a corticosteroid, an antiparasitic composition, or a com esophagitis 302 may be an in?ammation which was primarily bination thereof. attributed to acid re?ux esophagitis, but in the last 5 years 14. (canceled) eosinophilic esophagitis 302 (also known as allergic esoph 15. The composition according to claim 1 further compris agitis, primary eosinophilic esophagitis, and idiopathic eosi ing a pH adjusting agent, preservative, emulsi?er, opaci?er, nophilic esophagitis) has emerged as an important indepen antioxidant, fragrance, colorant, gelling agent, thickening dent clinicopathologic entity found to affect children and agent, stabilizer, or surfactant. adults. Eosinophilic esophagitis 302 may commonly affect 16. The composition according to claim 4, wherein the lower esophagus 202 antiviral agent is selected from the group consisting of aba [0045] According to some embodiments, eosinophilic cavir, aciclovir, adefovir, amantadine, amprenavir, arbidol., esophagitis 302 may be treated using poloxamer oral suspen atazanavir, artipla, brivudine, cidofovir, combivir, edoxudine, sion 116 administrating a dosage of about 5 ml to about 10 ml efavirenZ, emtricitabine, enfuvirtide, entecavir, fomvirsen, once a day. Poloxamer oral suspension 116 may be adhered fosamprenavir, foscarnet, fosfonet, ganciclovir, gardasil, iba (because of the bio-adhesive properties) at the desired site of citabine, immunovir, idoxuridine, imiquimod, indinavir, action for a longer residence time. inosine, integrase inhibitors, interferons, including interferon type III, interferon type II, interferon type I, lamivudine, EXAMPLES lopinavir, loviride, MK-0518, maraviroc, moroxydine, nel? navir, nevirapine, nexavir, nucleoside analogues, oseltamivir, [0046] Example #1 is an embodiment of poloxamer oral penciclovir, peramivir, pleconaril, podophyllotoxin, protease suspension 116 application, which may be used in esophageal inhibitors, reverse transcriptase inhibitors, ribavirin, riman diseases in animals, administrating a dosage of about 0.25 ml tadine, ritonavir, saquinavir, stavudine, tenofovir, tenofovir to about 20.0 ml (depend on animal weight/size) of polox disoproxil, tipranavir, tri?uridine, triZivir, tromantadine, tru amer oral suspension 116 once a day. vada, valganciclovir, vicriviroc, vidarabine, viramidine, zal [0047] While various aspects and embodiments have been citabine, zanamivir, Zidovudine, and combinations thereof. disclosed here, other aspects and embodiments may be con 17. The composition according to claim 4, wherein the templated. The various aspects and embodiments disclosed antibacterial agent is selected from the group consisting of here are for purposes of illustration and are not intended to be amikacin, gentamicin, kanamycin, , netilmicin, limiting, with the true scope and spirit being indicated by the streptomycin, tobramycin, paromomycin, geldanamycin, following claims. herbimycin, loracarbef, ertapenem, doripenem, imipenem, 1. A pharmaceutical composition for oral administration cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefal comprising exin, cefaclor, cefamandole, cefoxitin, defprozil, cefuroxime, US 2014/0371179 A1 Dec. 18, 2014

ce?xime, cefdinir, cefditoren, cefoperazone, cefotaxime, cef zole, itraconazole, ketoconazole, posaconazole, ravucona podoxime, ceftaZidime, ceftibuten, ceftizoxime, ceftriaxone, zole, voriconazole, clotrimazole, econazole, miconazole, cefepime, ceftobiprole, teicoplanin, vancomycin, aZithromy oxiconazole, sulconazole, terconazole, tioconazole, nikko cin, clarithromycin, dirithromycin, erythromycin, roxithro mycin Z, caspofungin, micafungin, anidulafungin, amphot mycin, troleandomycin, telithromycin, spectinomycin, aZtre ericin B, liposomal nystastin, pimaricin, griseofulvin, ciclo onam, amoxicillin, ampicillin, aZlocillin, carbenicillin, pirox olamine, haloprogin, tolnaftate, undecylenate, cloxacillin, dicloxacillin, ?ucloxacillin, meZlocillin, meticil clioquinol, and combinations thereof. lin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillan, 19. The composition according to claim 4, Wherein the bacitracin, colistin, polymyxin B, cipro?oxacin, enoxacin, antiparasitic agent is selected from the group consisting gati?oxacin, levo?oxacin, lome?oxacin, moxi?oxacin, nor ofamitraZ, amoscanate, avermectin, carbadox, diethylcar ?oxacin, o?oxacin, trov?oxacin, mafenide, prontosil, sulfac bamiZine, dimetridazole, diminazene, ivermectin, macro?la etamide, sulfamethizole, sulfanimilimde, sulfasalaZine, ricide, malathion, mitaban, oxamniquine, permethrin, praZi sul?soxazole, trimetoprim, , doxycycline, quantel, prantel pamoate, selamectin, sodium stibogluconate, minocycline, oxytetracycline, , arsphenamine, thiabendazole, and combinations thereof. chloramphenicol, clindamycin, lincomycin, ethambutol, fos fomycin, fusidic acid, furazolidone, isoniaZid, linezolid, met 20. The composition according to claim 4, Wherein the ronidazole, mupirocin, nitrofurantoin, platensimycin, pyraZi corticosteroid is selected from the group consisting ofhydro namide, quinuspristin/dalfopristin, rifampin, tinidazole, cortisone, prednisone, ?uprednisolone, triamcinolone, dex AL-15469A, AL-38905, and combinations thereof. amethasone, betamethasone, cortisone, prednilosone, meth 18. The composition according to claim 4, Wherein the ylprednisolone, ?uocinolone acetonide, ?urandrenolone antifungal agent is selected from the group consisting ofam acetonide, and ?uorometholone. rol?ne, utena?ne, nafti?ne, terbina?ne, ?ucytosine, ?ucona * * * * *