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US 20140371 179A1 (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) U.S. Cl. TREATING ESOPHAGEAL DISEASES CPC ...... A6 IK3I/58 (2013.01); A61K 45/06 (2013.01) (71) Applicant: Chris V. Simmons, 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 specifically, 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 fl27 used as vehicle (21) Appl. No.: 13/917,275 and budesonide as a corticosteroid. Poloxamer oral Suspen 1-1. sion may be administrated by Swallowing the poloxamer oral (22) Filed: Jun. 13, 2013 Suspension drug which may slide down through the esoph Publication Classification 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 APIs such as antifungals, antibacte A6 IK3I/58 (2006.01) rials, and corticosteroids, previously dissolved in a Suitable A6 IK 45/06 (2006.01) liquid, such as water. Patent Application Publication Dec. 18, 2014 Sheet 1 of 3 US 2014/0371179 A1

---. Antibacterials 106 N Antifungals POOxamer f127 110 Hydrophic Non-ionic Surfactant

N Budesonide y Corticosteroid POOxamer Ora - - - 7 ------Suspension Ios is

FIG. 1 Patent Application Publication Dec. 18, 2014 Sheet 2 of 3 US 2014/0371179 A1

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

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FIG. 3 US 2014/0371 179 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 gus where poloxamer oral Suspension may be adhered, pro 0001 N/A viding a longer residence time. BACKGROUND 0011 Numerous other aspects, features and benefits of the present disclosure may be made apparent from the following 0002 1. Field of the Disclosure detailed description taken together with the drawing figures. 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 figures. The components in the 0005 Incidence of gastrointestinal functional diseases figures are not necessarily to scale, emphasis instead being increases day by day, where the common esophageal diseases placed upon illustrating the principles of the disclosure. In the can be reflux esophagitis, esophageal cancer, esophageal figures, reference numerals designate corresponding parts Stenosis, esophageal varices, dyspepsia, and functional dys throughout the different views. phagia. In the course of medical diagnosis and treatment, a 0013 FIG. 1 is an oral suspension components block dia continuous monitoring or treatment of the esophagus is often gram, according to an embodiment. required. Currently, there are many types of esophagus treat 0014 FIG. 2 depicts a close up view of lower esophageal, ments on the market Such as endoscopic therapy, Surgery, where poloxamer oral Suspension may be used in esophageal injection and oral Suspension drugs, among others. Varices, according to an embodiment. 0006 Oral suspension drugs may commonly include 0015 FIG.3 depicts a close up view of lower esophageal, active pharmaceutical ingredients (APIs) for treating esoph where poloxamer oral Suspension may be used in eosino ageal diseases. For example, esophageal Varices is a common philic esophagitis, according to an embodiment. 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. Definitions SUMMARY 0017. As used here, the following terms may have the 0008 According to various embodiments, the present dis following definitions: 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 specifically, 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 thermoreversible gela According to another embodiment poloxamer fl27 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 inflammation 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 Suitable API Such as antibacterials, antifungals, 0022 "Eosinophilic esophagitis' refers to an allergic reac corticosteroids, antiparasitics, among others. According to tion that causes inflammation 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 2014/0371 179 A1 Dec. 18, 2014

0024 “vehicles' refer to carrier materials suitable for proxil, tipranavir, , trizivir, tromantadine, truvada, transdermal/topical or oral drug administration. , Vicriviroc, , 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, APIs 102 may geldanamycin, herbimycin, loracarbef, ertapenem, dorip include the active ingredients that may be used for treating the enem, imipenem, cilastatin, meropenem, cefadroxil, cefazo lin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, esophageal diseases. APIs 102 may include antibacterials defprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefop 104, antifungals 106, and corticosteroids 108. Suitable corti eraZone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, costeroid 108 may be budesonide 110 compositions that may 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, APIs 102 may be cin, erythromycin, roXithromycin, troleandomycin, tellithro combined with a vehicle such as poloxamer f127112. Suit mycin, spectinomycin, aztreonam, amoxicillin, ampicillin, able concentration of poloxamer f127112 for the disclosed azlocillin, carbenicillin, cloxacillin, dicloxacillin, fluclox oral suspension may be of about 5% to about 10%. Poloxamer acillin, mezlocillin, meticillin, nafcillin, oxacillin, penicillin, f127112 may have thermoreversible properties, for instance, piperacillin, ticarcillan, , colistin, polymyxin B, poloxamer f127 112 at room temperature is in liquid state ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lom changing to a gel at body (or warm) temperature. efloxacin, moxifloxacin, norfloxacin, ofloxacin, trovfloxacin, 0027. According to one embodiment, APIs 102 may be , prontosil, Sulfacetamide, , Sulfani mixed with poloxamer f127 112, previously dissolved in a milimde, Sulfasalazine, Sulfisoxazole, 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, APIs 102 may be mixed with poloxamer f127112 for done, isoniazid, lineZolid, , , nitro treating other esophageal disorders, such as structural abnor furantoin, platensimycin, pyrazinamide, quinuspristin?dalfo malities, motility abnormalities, inflammatory 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 f127112 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 amrolfine, utenafine, naftifine, terbin additives such as pH adjusting agents, preservatives, emulsi afine, flucytosine, fluconazole, itraconazole, ketoconazole, fiers, opacifiers, 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 0037 According to some embodiments, antiparasitic binations thereof. agents may include amitraz, amoscanate, avermectin, carba dox, diethylcarbamizine, dimetridazole, diminaZene, iver Active Pharmaceutical Ingredients mectin, macrofilaricide, malathion, mitaban, oxaminiquine, 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, and valacyclovir. Other may includehydrocortisone, prednisone, fluprednisolone, tri antiviral agents include abacavir, , , amanta amcinolone, dexamethasone, betamethasone, cortisone, dine, amprenavir, arbidol. atazanavir, artipla, , prednilosone, methylprednisolone, fluocinolone acetonide, , combivir, , efavirenz, emtricitabine, flurandrenolone acetonide, and fluorometholone. enfuvirtide, , fomvirsen, foSamprenavir, , 0040 Anaesthetics Agents foSfonet, , gardasil, , immunovir, 0041 According to some embodiments, anaesthetics , , indinavir, , integrase inhibi agents may include benzocaine, butamben picrate, tetracaine, tors, , including type Ill, interferon type dibucaine, prilocalne, etidocaine, mepivacaine, bupivicaine, II, interferon type I, , lopinavir, loviride, and lidocaine. Preferred non-steroidal anti-inflammatory MK-0518, maraviroc, , nelfinavir, nevirapine, agents may include, for example, detoprofen, diclofenac, nexavir, nucleoside analogues, oseltamivir, , per diflunisal, etodolac, fenoprofen, flurbiprofen, indomethacin, amivir, pleconaril, , protease inhibitors, ketoprofen, mechlofenameate, mefenamic acid, meloxicam, reverse transcriptase inhibitors, , , nabumeone, naproxen Sodium, oxaprozin, piroxicam, Sulin ritonavir, saquinavir, stavudine, tenofovir, tenofovir diso dac, tolmeting, celecoxib, rofecoxib, choline salicylate, Sal US 2014/0371 179 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, fluprednisolone, triamcinolone, dexamethasone, (c) imidurea; and betamethasone, cortisone, prednilosone, methylpredniso (d) optionally, an antimicrobial agent selected from the lone, fluocinolone acetonide, flurandrenolone acetonide, and group consisting of methyl ester of p-hydroxybenzoic fluorometholone, 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 0042 FIG. 2 depicts close up view 200a of lower esopha of an oral Suspension. gus 202 where poloxamer oral suspension 116 may be used 3. A composition according to claim 1, which is in the form for treating esophageal varices 204. Specifically, 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 eases and may be developed when normal blood flow to the thereof. 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 200b of lower 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. Specifically, eosinophilic tion, a corticosteroid, an antiparasitic composition, or a com esophagitis 302 may be an inflammation which was primarily bination thereof. attributed to acid reflux 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, emulsifier, opacifier, 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, , 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, nelfi 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, trifluridine, 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 2014/0371 179 A1 Dec. 18, 2014

cefixime, 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, tellithromycin, spectinomycin, aztre ericin B, liposomal nystastin, pimaricin, griseofulvin, ciclo onam, amoxicillin, amplicillin, azlocillin, carbenicillin, piroX olamine, haloprogin, tolnaftate, undecylenate, cloxacillin, dicloxacillin, flucloxacillin, 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, ciprofloxacin, enoxacin, antiparasitic agent is selected from the group consisting gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nor ofamitraz, amoscanate, avermectin, carbadox, diethylcar floxacin, ofloxacin, trovfloxacin, mafenide, prontosil, Sulfac bamizine, dimetridazole, diminaZene, ivermectin, macrofila etamide, Sulfamethizole, Sulfanimilimde. Sulfasalazine, ricide, malathion, mitaban, oxamniquine, permethrin, prazi Sulfisoxazole, trimetoprim, , doxycycline, quantel, prantel pamoate, Selamectin, sodium Stibogluconate, minocycline, oxytetracycline, , arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fos thiabendazole, and combinations thereof. 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 of hydro namide, quinuspristin/dalfopristin, rifampin, tinidazole, cortisone, prednisone, fluprednisolone, triamcinolone, dex AL-15469A, AL-38905, and combinations thereof. amethasone, betamethasone, cortisone, prednilosone, meth 18. The composition according to claim 4, wherein the ylprednisolone, fluocinolone acetonide, flurandrenolone antifungal agent is selected from the group consisting of:am acetonide, and fluorometholone. rolfine, utenafine, naftifine, terbinafine, flucytosine, flucona k k k k k