TOHTUNUTUS009867834B2 MUUHHON (12 ) United States Patent ( 10 ) Patent No. : US 9 ,867 , 834 B2 Zhao et al. (45 ) Date of Patent: * Jan . 16 , 2018

(54 ) NON -SYSTEMIC TOPICAL COMPOSITIONS 8 , 324 , 192 B2 12 / 2012 Bastian COMPRISING 8 , 497 , 258 B2 7 / 2013 Hill 8 ,679 , 545 B2 3 /2014 Bastian 8 , 771 , 729 B2 7 / 2014 Perrett (71 ) Applicant: Banner Life Sciences LLC , High 8 , 865 , 692 B2 10 / 2014 Phillips Point, NC (US ) 8 , 975 ,243 B2 3 /2015 Bastian 9 , 050 , 368 B2 6 / 2015 Phillips (72 ) Inventors : Yinyan Zhao , Greensboro , NC (US ); 9 , 119, 863 B2 9 / 2015 Hill 9 , 387, 167 B2 7 / 2016 Perrett Justin Hughey, Asheboro , NC (US ) ; 2004 /0253312 A1 12 / 2004 Sowden Jason Vaughn , Browns Summit , NC 2009 /0123390 A1 5 / 2009 Hill ( US) ; Qi Fang , Oak Ridge, NC (US ) 2009 /0123550 AL 5 /2009 Deshmukh 2009 /0123551 A1 5 /2009 Phillips ( 73 ) Assignee: Banner Life Sciences LLC , High 2009/ 0131386 A1 * 5 /2009 Phillips A61K 9 / 006 514 / 178 Point, NC (US ) 2009 /0137540 A1 5 / 2009 Phillips 2009 /0143343 Al 6 / 2009 Hill ( * ) Notice : Subject to any disclaimer, the term of this 2009 / 0149433 A1 6 /2009 Phillips patent is extended or adjusted under 35 2009 /0181099 A1 7 / 2009 Bastian U . S . C . 154 ( b ) by 0 days. 2009 / 0191275 Al 7 / 2009 Hill 2009/ 0264392 Al 10 / 2009 Warndahl This patent is subject to a terminal dis 2010 / 0016754 Al 1 / 2010 Cohen claimer. 2011/ 0002998 AL 1 / 2011 Klein 2011/ 0081411 Al 4 / 2011 Perrett 2011/ 0097401 A1 4 / 2011 Simpson (21 ) Appl. No. : 15 /293 , 535 2012 / 0164080 A1 6 / 2012 Phillips 2012 / 0282335 A1 11 / 2012 Lai Jin ( 22 ) Filed : Oct. 14 , 2016 2013 / 0096096 A1 4 / 2013 Bastian 2013 / 0209554 Al 8 /2013 Keenan (65 ) Prior Publication Data 2013 /0296286 AL 11 / 2013 Hill 2014 /0187523 AL 7 / 2014 Dohil US 2017 /0065613 A1 Mar . 9 , 2017 2014 /0287051 AL 9 / 2014 Perrett 2014 / 0303131 Al 10 / 2014 Perrett Related U .S . Application Data 2014 /0363503 Al 12 /2014 Hassan (63 ) Continuation - in -part of application No . 15 / 181, 462 , (Continued ) filed on Jun . 14 , 2016 , and a continuation - in -part of application No . PCT/ US2016 / 037324 , filed on Jun . OTHER PUBLICATIONS 14 , 2016 . Carr and Watson , “ Eosinophilic esophagitis ,” Allergy, Asthma & Clinical Immunology 7 (Suppl 1 ) : S8 (2011 ) . (60 ) Provisional application No . 62 / 175 ,470 , filed on Jun . Gonsalves et al ., “ Elimination Diet Effectively Treats Eosinophilic 15 , 2015 . esophagitis in Adults ; Food Reintroduction Identifies Causative (51 ) Int. Ci. Factors ,” Gastoenterology142 : 1451- 1459 ( 2012 ) . Konikoff et al ., “ A Randomized , Double -Blind , placebo - Controlled A61K 31 /56 ( 2006 .01 ) Trial of Propionate for Pediatric Eosinophilic A61K 9 / 20 ( 2006 . 01) esophagitis, ” Gastroenterology 131 : 1381 - 1391 ( 2006 ) . A61K 45 /06 ( 2006 . 01 ) Noel et al . , “ Clinical and Immunopathologic Effects of Swallowed A61K 47 / 10 ( 2017 .01 ) Fluticasone for Eosinophilic esophagitis , " Clinical Gastroenterol A61K 9 /00 ( 2006 .01 ) ogy and Hepatology 2 : 568 - 575 ( 2004 ) . U .S . CI. Schaefer et al. , “ Comparison of Oral and Topical (52 ) Fluticasone in the Treatment of Eosinophilic esophagitis : A Ran CPC ...... A61K 31 /56 ( 2013 . 01 ); A61K 9 /0056 domized Trial in Children ," Clinical Gastroenterology and Hepatol (2013 .01 ) ; A61K 9 /2018 (2013 .01 ) ; A61K ogy 6 : 165 - 173 (2008 ). 9 / 2031 ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; A61K 47 / 10 (2013 .01 ) ( Continued ) (58 ) Field of Classification Search CPC ...... A61K 31 / 56 ; A61K 45 / 06 ; A61K 47 / 10 ; Primary Examiner — Snigdha Maewall A61K 47 / 42 ; A61K 9 / 2031 ; A61K (74 ) Attorney , Agent , or Firm — Brinks Gilson & Lione 9 / 2018 ; A61K 9 /0056 (57 ) ABSTRACT See application file for complete search history . Described herein are topical, non -systemic , slow releasing oral pharmaceutical compositions, methods for making the (56 ) References Cited same, and methods for treating subjects in need thereof with U . S . PATENT DOCUMENTS such compositions. In particular, the oral composition pro vides topical, non -systemic administration of one or more 3 ,511 , 914 A * 5 / 1970 Wolkoff ...... A61K 9 /0056 active pharmaceutical ingredients to the oral cavity and 514 /772 3 , 851, 051 A 11/ 1974 Miskel upper gastrointestinal track , including the esophagus. In one 5 ,510 , 339 A * 4 / 1996 Gleich ...... A61K 31/ 165 embodiment, the pharmaceutical composition provides topi 514 / 171 5 ,631 , 267 A 5 / 1997 Gleich cal corticosteroids to the esophagus and oral cavity . 5 , 837 ,713 A 11/ 1998 Gleich 30 Claims, 1 Drawing Sheet US 9 ,867 , 834 B2 Page 2

( 56 ) References Cited U . S . PATENT DOCUMENTS 2015 /0005270 A11 / 2015 Phillips 2016 /0078186 A1 3 / 2016 Hill OTHER PUBLICATIONS Teitelbaum et al. , “ Eosinophilic esophagitis in Children : Immunopathological Analysis and Response to , ” Gastroenterology 122: 1216 - 1225 (2002 ) International Search Report for PCT /US16 / 37324 , dated Sep . 16 , 2014 . Alexander et al ., “ Swallowed Fluticasone Improves Histologic but Not Symptomatic Response of Adults with Eosinophilic esophagitis, " Clinical Gastroenterology and Hepatology 10 : 742 749 (2012 ) . Amim et al . , " Eosinophilic esophagitis — Treatment of Eosinophilic esophagitis with Drugs : Corticosteroids, " Digestive Diseases 32 : 126 - 129 ( 2014 ) . Gonsalves et al ., “ Elimination Diet Effectively Treats Eosinophilic esophagitis in Adults ; Food Reintroduction Identifies Causative Factors, " Gastroenterology142 : 1451 - 1459 ( 2012 ) . Office Action dated Jun . 28 , 2017 for corresponding U . S . Appl . No . 15 / 181, 462 . * cited by examiner U . S . Patent Jan . 16 , 2018 US 9 ,867 , 834 B2

Test e Reference -068. AverageConc.(pg/ml)

-

10 20 30 40 50 Time (hours )

* * * + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

een

Averagecor e Reference

0 10 20 30 40 50 Time (hours ) US 9 , 867 , 834 B2 NON - SYSTEMIC TOPICAL COMPOSITIONS both pediatric and geriatric patients ; they can deliver limited COMPRISING CORTICOSTEROIDS quantities of the active ingredient to the oral cavity and upper gastric system with minimal systemic adsorption ; and CROSS REFERENCE TO RELATED they allow for the drug to remain in contact with the oral APPLICATIONS 5 cavity or esophagus for an extended period of time . Soft lozenges or liquid compositions comprising corticosteroids This application is a continuation in part of U . S . patent facilitate the topical , non -systemic delivery of corticoster application Ser. No . 15 / 181, 462 and International Patent oids for treating esophageal inflammation disorders . Application No. PCT/ US2016 / 037324 , both filed on Jun . 14 , One embodiment described herein is a topical, non 2016 , and both of which claim priority to U . S . Provisional 10 systemic , oral, slow releasing pharmaceutical composition Patent Application No . 62/ 175 ,470 , filed on Jun . 15 , 2015 , comprising : ( a ) about 1 % to about 5 % by mass of one or each of which is incorporated by reference herein in its more release modifiers ; ( b ) about 10 % to about 60 % by mass entirety. of one or more film - forming polymers ; ( c ) about 5 % to about 20 % by mass of one or more plasticizers ; and (d ) less than TECHNICAL FIELD 1 % by mass of one or more active pharmaceutical ingredi ents . In one aspect, the composition , further comprises : ( e ) Described herein are oral pharmaceutical compositions about 0 . 1 % to about 5 % by mass of one or more pH suitable for chewing , sucking , buccal dissolution , or swal- modifiers ; ( f ) about 10 % to about 80 % by mass of one or lowing comprising non - systemic corticosteroids soft loz more sweeteners ; and ( g ) about 5 % to about 30 % by mass enges , and methods for treating subjects in need thereof with 20 of one or more solvents . In another aspect, the composition , such compositions. In particular, the oral composition pro further comprises : ( h ) one or more opacifiers , coloring vides topical, non - systemic administration and slow -release agent, flavoring , thickening agents or combinations thereof; of one or more active pharmaceutical ingredients to the oral ( i ) one or more solubilizing agents ; and ( i ) one or more cavity and upper gastrointestinal track , including the second active pharmaceutical ingredients . In another aspect , esophagus. 25 the composition comprises a soft lozenge . In another aspect , the composition comprises a liquid . In another aspect, the BACKGROUND composition orally dissolves within about 10 to about 15 minutes upon administration to a subject. In another aspect , therapy has long been the therapy of choice for the composition achieves about 50 % dissolution in vitro at reducing inflammation by the application of a topical cor - 30 pH 7 . 4 within about 10 to about 30 minutes. In another ticosteroid to the affected area , such as in the case of eczema, aspect, the composition topically contacts the oral and asthma, or other allergic conditions. In order to reduce esophageal mucosa for at least about 1 minute to about 45 systemic toxicity associated with steroid use , topical prepa - minutes . In another aspect , the composition topically con rations were developed for inflammation disorders of the tacts the oral and esophageal mucosa for at least about 1 esophagus or gastrointestinal tract, such that the steroid 35 minute to about 15 minutes. In another aspect , the release could adhere to the esophageal mucosa and provide an modifier comprises one or more of polyethylene oxide , anti - inflammatory effect. However, topical methylcellulose, hydroxypropylmethyl cellulose, hydroxy therapy is limited . For these types of disorders, treatments propyl cellulose , hydroxyethyl cellulose , hydroxymethyl have typically involved patients swallowing inhaled corti - cellulose , polymethylmethacrylate , polyhydroxyethylmeth costeroid medications or corticosteroid suspensions. Treat- 40 acrylate , polyvinylpyrrolidone , copovidone, polyvinyl alco ment using inhaled corticosteroids is achieved via a " puff hol, copolymers of polyvinylpyrrolidone and polyvinyl and swallow ” technique , where the patient administers the acetate , or combinations thereof. In another aspect, the corticosteroid composition to the mouth , but swallows rather release modifier comprises polyethylene oxide . In another than inhaling . This technique is often difficult for children aspect, the release modifier comprises polyethylene oxide and geriatric patients , and can result in variable doses and 45 having a molecular weight ( M . ) of about 900 , 000 to about less than an effective dose of the steroid being delivered to 8 ,000 ,000 . In another aspect, the release modifier comprises the esophagus. In addition , oral administration of topical polyethylene oxide having a molecular weight ( M ) ofabout can also result in oropharyngeal or esophageal 7 ,000 ,000 . In another aspect, the film - forming polymer candidosis. comprises one or more of gelatin , partially hydrolyzed Thus, there is an unmet need for oral dosage forms of 50 gelatin , hydrolyzed gelatin , hydrolyzed collagen , or combi corticosteroids, where the dosage form can be chewed , nations thereof. In another aspect, the film - forming polymer sucked , permitted to dissolve in the mouth , or swallowed , comprises one or more gelatins, having a Bloom value of and has desirable organoleptic properties ; slowly releases about 50 Bloom to about 150 Bloom . In another aspect , the the active ingredient in the oral cavity and esophagus ; and plasticizer comprises one or more of glycerol, sorbitol, maintains drug contact with the oral and esophageal tissue 55 mannitol, maltitol, Xylitol, or combinations thereof. In for an extended period providing topical , non -systemic another aspect, the pH modifier comprises one or more of delivery . citric acid , acetic acid , lactic acid , malic acid , tartaric acid , fumaric acid , or combinations thereof. In another aspect, the SUMMARY sweetener comprises one or more of xylitol, maltitol, sucral 60 ose , mannitol aspartame, stevia , or combinations thereof. In Described herein are pharmaceutical compositions con - another aspect , the solubilizing agent comprises poloxamer, taining one or more active ingredients intended to dissolve polyoxyethylene 50 stearate , polyoxyl 35 castor oil , poly or disintegrate slowly in the oral cavity . They can be used for oxyl 40 hydrogenated castor oil , polyoxyl 10 oleyl ether, topical treatment where the drug is not absorbed through the polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate , polysor buccal or esophageal lining . In particular, soft lozenges can 65 bate 20 , polysorbate 40 , polysorbate 60 , polysorbate 80 , be chewed or allowed to dissolve slowly in the mouth . These propylene glycol diacetate , propylene glycol monostearate , dosage forms can be flavored and thus are administrable to sodium lauryl sulfate , sodium stearate , sorbitan monolau US 9 , 867 ,834 B2 rate , sorbitan monooleate , sorbitan monopalmitate , sorbitan topically contacts the oral and esophageal mucosa for at monostearate , or combinations thereof. In another aspect, least about 1 minute to about 45 minutes. In another aspect, the thickening agent comprises polyacrylic acid , methyl the composition provides one or more of the following cellulose, alginic acid , chitosan , carboxymethyl cellulose , pharmacokinetic parameters upon administration to a sub sodium carboxymethyl cellulose , locust bean gum , xanthum 5 ject: ( a ) a mean plasma fluticasone propionate Tmmar of about gum , high swelling crosslinked polymers, or combinations 1. 75 hours to about 3 hours ; ( b ) a mean plasma fluticasone thereof. In another aspect, the active pharmaceutical ingre - propionate Cmor??? of about 8 pg/ mL to about 11 pg/ mL ; (c ) a dient comprises one or more corticosteroids . In another mean plasma fluticasone propionate AUCO - , of about 105 aspect, the active pharmaceutical ingredient comprises one pg. h /mL to about 130 pg . h /mL ; ( d ) a mean plasma flutica or more of , , , 10 sone propionate AUC . - - . of about 150 pg . h /mL to about , , , , clo - 160 pg .h /mL ; ( e ) a mean fluticasone propionate half - life betasone , , , , ( 12 ) of about 0 .01 h to about 0 . 1 h ; or ( f ) a mean fluticasone deoxycorticosterone , , dexametha - terminal elimination rate constant ( a ) of about 10 h - to sone , , , , fluclo - about 20 h - ? . In another aspect, the composition is useful for rolone , , , flumetasone , fluni- 15 treating a subject suffering from one or more of oral or solide , acetonide , , , esophageal inflammation , eosinophilic esophagitis , inflam , , , fluticasone , matory bowel disease involving the esophagus , oral lichen fluticasone propionate , , , halcino - planus , aphthous stomatitis , Crohn ' s disease , esophageal nide , , aceponate , hydrocorti - inflammation secondary to caustic / irritant ingestion , recur sone buteprate , , , 20 rent esophageal strictures of any cause and including irritant , , , methyl- ingestion , pill - induced esophagitis , systemic diseases , con aceponate , furoate , parametha gential diseases , epidermolysis bullosa , trauma, or post sone , , prednisone, prednisolone , pred surgery inflammation . nylidene , , , , , Another embodiment described herein is a method for combinations thereof, pharmaceutically acceptable salts 25 treating , retarding the progression of, prophylaxis of , delay thereof, or esters thereof. In another aspect , the active ing the onset of, ameliorating , or reducing the symptoms of pharmaceutical ingredients comprise one or more of fluti one or more of esophageal, oral , or buccal inflammation , casone , budesonide , salts thereof, or combinations thereof. eosinophilic esophagitis , oral lichen planus, aphthous In another aspect, the active pharmaceutical ingredient com - stomatitis , odynophagia , acid reflux , dysphagia , oral, prises fluticasone or a salt thereof. In another aspect , the 30 esophageal or peptic ulcers , heart burn , chest pain , abdomi active pharmaceutical ingredient comprises fluticasone pro - nal pain , nausea , vomiting , coughing , sore throat, decrease pionate . In another aspect , the composition comprises about in appetite , or failure to thrive, comprising administering to 0 .025 % or about 0 .05 % fluticasone propionate . In another a subject in need thereof any of the pharmaceutical compo aspect , the composition comprises about 0 . 5 mg or about 1 . 0 sitions described herein . mg of fluticasone propionate . In another aspect, the second 35 Another embodiment described herein is a pharmaceuti active pharmaceutical ingredient comprises lidocaine , prilo c al composition useful for retarding the progression of , caine , or a combination thereof. In another aspect, the prophylaxis of, delaying the onset of, ameliorating , or reduc composition topically contacts the oral and esophageal ing the symptoms of one or more of esophageal, oral, or mucosa for about 1 minute to about 10 minutes . buccal inflammation , eosinophilic esophagitis , oral lichen Another embodiment described herein is topical, non - 40 planus , aphthous stomatitis , odynophagia , acid reflux , dys systemic oral pharmaceutical composition comprising : ( a ) phagia , oral , esophageal or peptic ulcers , heart burn , chest about 10 % to about 60 % by mass of one or more film - pain , abdominal pain , nausea , vomiting , coughing, sore forming polymers ; (b ) about 5 % to about 20 % by mass of throat, decrease in appetite , or failure to thrive , comprising one or more plasticizers ; ( c ) about 0 . 1 % to about 5 % by administering to a subject in need thereof any of the phar mass of one or more pH modifiers; ( d ) about 10 % to about 45 maceutical compositions described herein . 80 % by mass of one or more sweeteners ; ( e ) about 5 % to Another embodiment described herein is a method for about 30 % by mass of one or more solvents ; and ( g ) about treating for treating, retarding the progression of, prophy 1 % to about 5 % by mass of one or more release modifiers ; laxis of, delaying the onset of, ameliorating , or reducing the ( h ) about 0 . 1 % to about 5 % by mass of one or more symptoms of one or more of esophageal oral, or buccal solubilizing agents ; and ( i ) about 0 . 001 % to about 1 % by 50 inflammation , eosinophilic esophagitis , inflammatory bowel mass of fluticasone propionate . In one aspect, the composi disease involving the esophagus, oral lichen planus, aph tion further comprises (j ) about 0 . 1 % to about 50 % by mass thous stomatitis, Crohn ' s disease , esophageal inflammation of one or more thickening agents . In another aspect, the secondary to caustic /irritant ingestion , recurrent esophageal composition further comprises a second active pharmaceu strictures of any cause and including irritant ingestion , tical ingredient. In another aspect, the second active phar - 55 pill - induced esophagitis , systemic diseases , congential dis maceutical ingredient comprises about 0 .5 % to about 5 % by eases , epidermolysis bullosa , trauma , or post- surgery weight of lidocaine , prilocaine, or a combination thereof, inflammation comprising administering to a subject in need and the weight percentage of maltitol is reduced accordingly . thereof any of the pharmaceutical compositions described In another aspect , the composition comprises a liquid or herein . In one aspect , the composition provides one or more solid dosage form . In another aspect , the liquid dosage form 60 of the following pharmacokinetic parameters : ( a ) a mean comprises a solution , syrup , suspension , elixir , or concen - plasma fluticasone propionate TM of about 1 . 75 hours to trate . In another aspect , the solid dosage form comprises a about 3 hours ; ( b ) a mean plasma fluticasone propionate soft lozenge . In another aspect, the composition orally Cmar of about 8 pg /mL to about 11 pg/ mL ; ( c ) a mean plasma dissolves within about 10 to about 15 minutes upon admin - fluticasone propionate AUCO - s of about 105 pg .h /mL to istration to a subject . In another aspect , the composition 65 about 130 pg . h /mL ; ( d ) a mean plasma fluticasone propi achieves 50 % dissolution in vitro at pH 7 . 4 within about 10 onate AUCO - > of about 150 pg . h /mL to about 160 pg .h /mL ; to about 30 minutes. In another aspect, the composition (e ) a mean fluticasone propionate half - life (t12 ) of about US 9 , 867 , 834 B2 0 .01 h to about 0. 1 h ; or (f ) a mean fluticasone terminal shell comprising: (a ) one or more first film - forming poly elimination rate constant (a ) of about 10h - 1 to about 20 h - 7 . mers ; ( b ) one or more first plasticizers ; ( c ) one or more first Another embodiment described herein is a pharmaceuti pH modifiers ; ( d ) one or more first sweeteners; and ( e ) one cal combination comprising the one of the compositions or more first solvents ; and the matrix fill comprising: ( f ) one described herein comprising a corticosteroid and one or 5 or more second film - forming polymers ; ( g ) one or more more additional therapeutic compounds . In one aspect, the release modifiers ; ( h ) one or more second plasticizers ; ( i ) one or more additional therapeutic compound comprises one one or more second pH modifiers ; ( 1 ) one or more second or more of antacids ( e . g . , calcium hydroxide , magnesium sweeteners ; ( k ) one or more second solvents ; and ( 1 ) one or hydroxide , alluminum hydroxide , sodium bicarbonate , cal - more active pharmaceutical ingredients . In one aspect , the cium carbonate , bismuth subsalicylate , or others ; Maalox , 10 shell further comprises : ( m ) one or more opacifiers , coloring Mylanta , Gaviscon , Kaopectate , Pepto -Bismol ) sucralfate , agents , flavorings, or combinations thereof ; and the matrix esomeprazole , omeprazole , lansoprazole , dexlansoprazole , comprises: ( n ) one or more solubilizing agents ; and (o ) one esomeprazole , pantoprazole , rabeprazole , ilaprazole , cime - or more second active pharmaceutical ingredients . In tidine, ranitidine , famotidine , lafutidine, nizatidine , roxati - another aspect, the shell or matrix further comprises one or dine , tiotidine , salmeterol, albuterol, aclidinium , ipratro - 15 more pharmaceutically acceptable excipients . In another pium , tiotropium , umeclidinium , acrivastine , azelastine , aspect, the film - forming polymer comprises one or more of bilastine, brompheniramine , buclizine, bromodiphenhy - gelatin , partially hydrolyzed gelatin , hydrolyzed gelatin , dramine , carbinoxamine , chlorpromazine, cyclizine , chlo - hydrolyzed collagen , or combinations thereof. In another rphenamine , chlorodiphenhydramine, clemastine , cyprohep - aspect, the film - forming polymer comprises one or more tadine , dexbrompheniramine , dexchlorpheniramine , 20 gelatins, having a Bloom value of about 50 Bloom to about dimenhydrinate , dimetindene , diphenhydramine , doxylam - 150 Bloom . In another aspect, the plasticizer comprises one ine , ebastine , embramine, fexofenadine , hydroxyzine , lor - or more of glycerol, sorbitol, mannitol, maltitol, xylitol , or atadine, meclozine , mirtazapine , olopatadine , orphenadrine , combinations thereof. In another aspect, the pH modifier phenindamine pheniramine , phenyltoloxamine, promethaz - comprises one ormore of citric acid , acetic acid , lactic acid , ine , quetiapine , rupatadine , tripelennamine , triprolidine , 25 malic acid , tartaric acid , fumaric acid , or combinations clobenpropit , ciproxifan , conessine , thioperamide , montelu - thereof. In another aspect, the release modifier comprises kast , zafirlukast, pranlukast , mepolizumab , reslizumab , one or more of polyethylene oxide, methylcellulose , omalizumab , infliximab , azathioprine , 6 -mercaptopurine , hydroxypropylmethyl cellulose , hydroxypropyl cellulose , thioguanine , aspirin ( acetylsalicylic acid ), ibuprofen , hydroxyethyl cellulose, hydroxymethyl cellulose , polymeth naproxen , ketoprofen , celecoxib , diclofenac , amikacin , gen - 30 ylmethacrylate , polyhydroxyethylmethacrylate , polyvi tamicin , kanamycin , neomycin , netilmicin , tobramycin , nylpyrrolidone , copovidone , polyvinyl alcohol, copolymers paromomycin , streptomycin , spectinomycin , geldanamycin , of polyvinylpyrrolidone and polyvinyl acetate , or combina herbimycin , rifaximin , loracarber , ertapenem , doripenem , tions thereof . In another aspect, the release modifier com imipenem /cilastatin , meropenem , cefadroxil, cefazolin , prises polyethylene oxide . In another aspect, the release cefalotin , cefalexin , cefaclor, cefamandole , cefoxitin , cef - 35 modifier comprises polyethylene oxide having a molecular prozil , cefuroxime, cefixime, cefdinir , cefditoren , cefopera - weight ( M ) of about 900 ,000 to about 8 ,000 , 000 . In another zone, cefotaxime, cefpodoxime , ceftazidime, ceftibuten , aspect, the release modifier comprises polyethylene oxide ceftizoxime, ceftriaxone , cefepime, ceftaroline fosamil , having a molecular weight ( M ) of about 7 , 000 ,000 . In ceftobiprole , teicoplanin , vancomycin , telavancin , dalba another aspect, the sweetener comprises one or more of vancin , oritavancin , clindamycin , lincomycin , daptomycin , 40 xylitol , maltitol, sucralose , mannitol aspartame, stevia , or azithromycin , clarithromycin , dirithromycin , erythromycin , combinations thereof. In another aspect, the solubilizing roxithromycin , troleandomycin , telithromycin , spiramycin , agent comprises poloxamer , polyoxyethylene 50 stearate , aztreonam , furazolidone , nitrofurantoin , linezolid , posizolid , polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, radezolid , torezolid , amoxicillin , ampicillin , azlocillin , car - polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether , benicillin , cloxacillin , dicloxacillin , flucloxacillin , mezlocil - 45 polyoxyl 40 stearate , polysorbate 20 , polysorbate 40 , poly lin , methicillin , nafcillin , oxacillin , penicillin G , penicillin V , sorbate 60 , polysorbate 80 , propylene glycol diacetate , pro piperacillin , temocillin , ticarcillin , amoxicillin / clavulanate , pylene glycolmonostearate , sodium lauryl sulfate, sodium ampicillin / sulbactam , piperacillin / tazobactam , ticarcillin stearate , sorbitan monolaurate , sorbitan monooleate , sorbi clavulanate , bacitracin , colistin , polymyxin B , ciprofloxacin , tan monopalmitate , sorbitan monostearate , or combinations enoxacin , gatifloxacin , gemifloxacin , levofloxacin , lom - 50 thereof. In another aspect , the active pharmaceutical ingre efloxacin , moxifloxacin , nalidixic acid , norfloxacin , ofloxa - dient comprises one or more corticosteroids or glucocorti cin , trovafloxacin , grepafloxacin , sparfloxacin , temafloxa - costeroids . The composition of claim 1 , wherein the active cin , mafenide , sulfacetamide , sulfadiazine , silver pharmaceutical ingredient comprises one or more of alclo sulfadiazine , sulfadimethoxine, sulfamethizole , sulfame - metasone , amcinonide, beclometasone , betamethasone , thoxazole , sulfanilimide, sulfasalazine, sulfisoxazole , 55 budesonide , ciclesonide , clobetasol, , clocor trimethoprim - sulfamethoxazole , sulfamidochrysoidine , tolone, cloprednol, cortivazol, deflazacort ,deoxycorticoster demeclocycline , doxycycline ,minocycline , oxytetracycline , one , desonide desoximetasone , , diflorasone , tetracycline , clofazimine , dapsone , capreomycin , cycloser- diflucortolone, difluprednate , , fludrocortisone, ine , ethambutol, ethionamide , isoniazid , pyrazinamide , fludroxycortide , flumetasone , , fluocinolone rifampicin , rifabutin , rifapentine , streptomycin , arsphe - 60 acetonide , fluocinonide , fluocortin , fluocortolone, fluo namine, chloramphenicol, fosfomycin , fusidic acid , metron - rometholone, fluperolone, fluticasone, fluticasone propi idazole , mupirocin , platensimycin , quinupristin /dalfopristin , onate , fluprednidene, formocortal, , halometa thiamphenicol , tigecycline , tinidazole, trimethoprim , or sone , , , combinations thereof. hydrocortisone butyrate , loteprednol, medrysone , mepred One embodiment described herein comprises a topical , 65 nisone, methylprednisolone , methylprednisolone aceponate , non - systemic oral soft lozenge pharmaceutical composition mometasone furoate , , prednicarbate , pred comprising a shell encapsulating a semi solid matrix fill, the nisone , prednisolone , , rimexolone , tixocortol , US 9 , 867, 834 B2 triamcinolone , ulobetasol, combinations thereof, pharma - ( h ) about 0 .016 % or about 0 .032 % of one or more active ceutically acceptable salts thereof, or esters thereof. In pharmaceutical ingredients ; and ( i ) optionally , about 0 . 5 % of another aspect , the active pharmaceutical ingredients com one or more excipients comprising opacifiers , colorings, or prise one or more of fluticasone , budesonide , salts thereof, flavorings. or combinations thereof. In another aspect, the active phar - 5 Another embodiment described herein comprises a phar maceutical ingredient comprises fluticasone or a salt thereof. maceutical composition comprising a shell encapsulating a In another aspect, the active pharmaceutical ingredient com semi solid matrix fill, wherein the shell comprises : ( a ) about prises fluticasone propionate . In another aspect, the matrix 5 % to about 30 % of 150 Bloom gelatin ; (b ) about 5 % to comprises about 0 .025 % or about 0 .05 % fluticasone. In about 20 % of 100 Bloom gelatin ; ( c ) about 1 % to about 10 % another aspect , the matrix comprises about 0 . 5 mg or about 10 of gelatin hydrolysate ; ( d ) about 5 % to about 30 % of 1 . 0 mg of fluticasone. In another aspect, the second active glycerol; ( e ) about 0 . 1 % to about 5 % of citric acid ; ( f ) about pharmaceutical ingredient comprises lidocaine , prilocaine , 5 % to about 30 % of maltitol; (g ) about 1 % to about 10 % of or a combination thereof. xylitol; ( h ) about 0 . 1 % to about 2 % of sucralose ; and ( i ) Another embodiment described herein comprises a phar - about 5 % to about 30 % of water , and the matrix comprises: maceutical composition comprising a shell encapsulating a 15 ( 1 ) about 5 % to about 20 % of 150 Bloom gelatin ; ( k ) about semi solid matrix fill , wherein the shell comprises : ( a ) about 1 % to about 5 % of polyethylene oxide; (1 ) about 5 % to about 10 % to about 60 % of one or more first film - forming poly - 10 % of glycerol; ( m ) about 0 . 5 % to about 5 % of citric acid ; mers ; (b ) about 5 % to about 20 % of one or more first ( n ) about 30 % to about 65 % of maltitol; ( o ) about 1 % to plasticizers ; ( c ) about 0 . 1 % to about 5 % of one or more first about 10 % of xylitol; ( p ) about 0 . 1 % to about 2 % of pH modifiers ; ( d ) about 10 % to about 80 % of one or more 20 sucralose ; ( q ) about 0 . 1 % to about 1 % of polysorbate 80 ; ( r ) first sweeteners ; and ( e ) about 5 % to about 30 % of one or about 10 % to about 30 % of water , and ( s ) about 0 .001 % to more first solvents ; and the matrix comprises: ( f ) about 5 % about 1 % of fluticasone propionate . to about 30 % of one or more second film - forming polymers ; Another embodiment described herein comprises a phar ( g ) about 1 % to about 5 % of one or more release modifiers ; maceutical composition comprising a shell encapsulating a (h ) about 5 % to about 20 % of one or more second plasti - 25 semisolid matrix fill , the shell comprises : ( a ) about 19 % 150 cizers ; ( i ) about 0 . 5 % to about 5 % of one or more second pH Bloom gelatin ; ( b ) about 13 % 100 Bloom gelatin ; ( c ) about modifiers ; (j ) about 10 % to about 80 % of one or more 2 . 5 % gelatin hydrolysate ; ( d ) about 23 % glycerol; ( e ) about second sweeteners; (k ) about 0 .1 % to about 5 % of one or 0 . 5 % citric acid ; (f ) about 14 % maltitol; (g ) about 2 .5 % more solubilizing agents ; ( 1 ) about 5 % to about 30 % of one xylitol; ( h ) about 0 . 2 % sucralose ; and ( i ) about 25 % water ; or more second solvents ; and ( m ) about 0 .001 % to about 1 % 30 and the matrix comprises : (j ) about 7 . 5 % 150 Bloom gelatin ; of one or more active pharmaceutical ingredients. ( k ) about 3 % polyethylene oxide ; ( 1) about 5 % to about 10 % Another embodiment described herein comprises a phar - of glycerol; ( m ) about 1 % citric acid ; (n ) about 58 % maltitol ; maceutical composition comprising a shell encapsulating a ( 0 ) about 4 % of xylitol; ( p ) about 0 . 3 % sucralose ; ( q ) about semi solid matrix fill , wherein the shell comprises: ( a ) about 0 . 7 % polysorbate 80 ; ( r ) about 18 % water ; and ( s ) about 34 % of one or more first film -forming polymers ; (b ) about 35 0 .025 % or about 0 .05 % fluticasone propionate . 23 % of one or more first plasticizers ; ( c ) about 0 . 5 % of one Another embodiment described herein comprises a phar or more first pH modifiers ; ( d ) about 17 % of one or more maceutical composition comprising ( a ) about 5 % to about first sweeteners ; and ( e ) about 25 % of one or more first 30 % of 150 Bloom gelatin ; ( b ) about 5 % to about 20 % of solvents ; and the matrix comprises : ( f ) about 7 . 5 % of one or 100 Bloom gelatin ; ( c ) about 1 % to about 10 % of gelatin more second film - forming polymers ; ( g ) about 3 . 0 % of one 40 hydrolysate ; ( d ) about 1 % to about 5 % of polyethylene or more release modifiers ; (h ) about 7 . 5 % of one or more oxide ; ( e ) about 1 % to about 20 % of glycerol; ( f ) about 0 . 1 % second plasticizers ; (i ) about 1 % of one or more second pH to about 5 % of citric acid ; ( g ) about 20 % to about 60 % of modifiers ; ( j ) about 62 % of one or more second sweeteners ; maltitol; ( h ) about 0 . 5 % to about 5 % of xylitol; ( i ) about ( k ) about 0 . 7 % of one or more solubilizing agents ; ( 1 ) about 0 . 1 % to about 2 % of sucralose ; (j ) about 0 . 1 % to about 1 % 18 % of one or more second solvents ; and ( m ) about 0 .025 % 45 of polysorbate 80 ; ( k ) about 5 % to about 30 % of water ; ( 1 ) or about 0 . 05 % of one or more active pharmaceutical about 0 .01 % or about 0 . 1 % of one or more active pharma ingredients . ceutical ingredients ; and (m ) optionally , about 0 .1 % to about Another embodiment described herein comprises a phar - 1 % of one or more excipients comprising opacifiers , color maceutical composition comprising ( a ) about 15 % to about ings, or flavorings . 20 % of one or more film - forming polymers ; ( b ) about 0 . 5 % 50 Another embodiment described herein comprises a phar to about 3 % of one or more release modifiers ; ( c ) about 10 % maceutical composition comprising ( a ) about 12 % 150 to about 15 % of one or more plasticizers ; ( d ) about 0 . 5 % to Bloom gelatin ; ( b ) about 5 % 100 Bloom gelatin ; ( c ) about about 1. 5 % of one or more pH modifiers ; ( e ) about 40 % to 1 % gelatin hydrolysate ; ( d ) about 2 % polyethylene oxide ; about 55 % of one or more sweeteners ; ( f ) about 0 . 1 % to ( e ) about 13 % glycerol; ( f ) about 0 . 8 % citric acid ; ( g ) about about 1 % of one or more solubilizing agents ; ( g ) about 15 % 55 42 % maltitol; ( h ) about 4 % xylitol; ( i ) about 0 . 3 % sucralose ; to about 25 % of one or more solvents ; ( h ) about 0 .01 % or (j ) about 0 . 4 % polysorbate 80 ; ( k ) about 20 % water; and ( 1 ) about 0 . 1 % of one or more active pharmaceutical ingredi- about 0 .025 % or about 0 .05 % fluticasone propionate . ents ; and ( i ) optionally , about 0 . 1 % to about 1 % of one or Another embodiment described herein comprises a phar more excipients comprising opacifiers , colorings , or flavor- maceutical composition comprising a second active ingre ings . 60 dient, wherein the second active pharmaceutical ingredient Another embodiment described herein comprises a phar - comprises about 0 . 5 % to about 5 % by weight of lidocaine, maceutical composition comprising ( a ) about 17 % of one or prilocaine , or a combination thereof, and the weight per more film - forming polymers ; ( b ) about 2 % of one or more centage of maltitol is reduced accordingly . release modifiers ; (c ) about 13 % of one or more plasticizers ; Another embodiment described herein comprises a phar ( d ) about 0 . 8 % of one or more pH modifiers ; ( e ) about 46 % 65 maceutical composition comprising any of the compositions of one or more sweeteners ; (f ) about 0 .4 % of one or more described herein for treating , retarding the progression of, solubilizing agents ; ( g ) about 20 % of one or more solvents ; prophylaxis of , delaying the onset of, ameliorating , or reduc US 9 , 867, 834 B2 10 ing the symptoms of one or more of esophageal, oral, or Another embodiment described herein comprises a soft buccal inflammation , eosinophilic esophagitis , oral lichen lozenge produced by the methods described herein . In one planus , aphthous stomatitis , odynophagia , acid reflux , dys aspect, the soft lozenge comprises any of the composition phagia , oral, esophageal or peptic ulcers , heart burn , chest described herein . pain , abdominal pain , nausea , vomiting , coughing , sores Another embodiment described herein comprises a kit for throat, decrease in appetite , or failure to thrive . dispensing any of the oral pharmaceutical compositions Another embodiment described herein comprises a phar described herein , comprising: ( a ) at least one oral pharma maceutical composition comprising any of the compositions ceutical composition suitable for chewing , sucking , or buc cal dissolution comprising one or more corticosteroids ; ( b ) described herein for treating a subject suffering from one or 10 at least one receptacle comprising a tamper evident, mois more of oral or esophageal inflammation , eosinophilic ture proof packaging that reduces the ability of removing the esophagitis , inflammatory bowel disease involving the oral, enteric pharmaceutical composition comprising blister esophagus , oral lichen planus, aphthous stomatitis, Crohn ' s or strip packs , aluminum blister , transparent or Opaque disease , esophageal inflammation secondary to caustic / irri polymer blister with pouch , polypropylene tubes , colored tant ingestion , recurrent esophageal strictures of any cause 15 blister materials , tubes, bottles , and bottles optionally con and including irritant ingestion , pill - induced esophagitis , taining a child -resistant feature , optionally comprising a systemic diseases , congential diseases, epidermolysis desiccant, such as a molecular sieve or silíca gel; and ( c ) bullosa , trauma, or post - surgery inflammation . optionally , an insert comprising instructions or prescribing Another embodiment described herein comprises a information for the oral pharmaceutical composition . In one method for treating , retarding the progression of, prophy - 20 aspect, the oral pharmaceutical composition comprises any laxis of, delaying the onset of, ameliorating , or reducing the of the compositions described herein . symptoms of one or more of esophageal , oral, or buccal Another embodiment described herein comprises a phar inflammation , eosinophilic esophagitis, oral lichen planus, maceutical combination comprising a pharmaceutical com aphthous stomatitis , odynophagia , acid reflux , dysphagia , position described herein and one or more additional thera oral, esophageal or peptic ulcers , heart burn , chest pain , 25 peutic compounds . In one aspect, the one or more additional abdominal pain , nausea , vomiting , coughing , sore throat , therapeutic compound comprises one or more of antacids decrease in appetite , or failure to thrive, comprising admin ( e . g . , calcium hydroxide , magnesium hydroxide , alluminum istering to a subject in need thereof any of the pharmaceu hydroxide , sodium bicarbonate, calcium carbonate , bismuth subsalicylate , or others ; Maalox , Mylanta , Gaviscon , Kao tical compositions described herein . ses 30 pectate , Pepto -Bismol ) sucralfate , esomeprazole , omepra Another embodiment described herein comprises a 30 pzole , lansoprazole , dexlansoprazole , esomeprazole , panto method for treating a subject suffering from one or more of prazole , rabeprazole , ilaprazole , cimetidine , ranitidine , esophageal oral , or buccal inflammation , eosinophilic famotidine , lafutidine , nizatidine , roxatidine , tiotidine, sal esophagitis , inflammatory bowel disease involving the meterol, albuterol, aclidinium , ipratropium , tiotropium , esophagus , oral lichen planus , aphthous stomatitis , Crohn ' s 35 umeclidinium , acrivastine , azelastine , bilastine , brompheni disease , esophageal inflammation secondary to caustic / irri tant ingestion , recurrent esophageal strictures of any cause chlorpromazineramine , buclizine , cyclizine bromodiphenhydramine chlorrhenamine, carbinoxaminechlorodinhen ., and including irritant ingestion , pill- induced esophagitis , hydramine , clemastine , cyproheptadine , dexbrompheni systemic diseases, congential diseases , epidermolysis ramine , dexchlorpheniramine , dimenhydrinate , dimet bullosa, trauma, or post -surgery inflammation comprising 40 indene , diphenhydramine , doxylamine , ebastine , administering to the subject in need thereof any of the embramine , fexofenadine , hydroxyzine, loratadine , pharmaceutical compositions described herein . meclozine, mirtazapine , olopatadine , orphenadrine , phenin Another embodiment described herein comprises a means damine pheniramine , phenyltoloxamine , promethazine , que for treating a subject suffering from one or more of esopha - tiapine , rupatadine , tripelennamine, triprolidine , clobenpro geal oral, or buccal inflammation , eosinophilic esophagitis , 45 pit , ciproxifan , conessine , thioperamide, montelukast, inflammatory bowel disease involving the esophagus , oral zafirlukast , pranlukast, mepolizumab , reslizumab , omali lichen planus, aphthous stomatitis , Crohn ' s disease, esopha - zumab , infliximab , azathioprine , 6 -mercaptopurine , thiogua geal inflammation secondary to caustic /irritant ingestion , nine, aspirin ( acetylsalicylic acid ), ibuprofen , naproxen , recurrent esophageal strictures of any cause and including ketoprofen , celecoxib , diclofenac , amikacin , gentamicin , irritant ingestion , pill - induced esophagitis , systemic dis - 50 kanamycin , neomycin , netilmicin , tobramycin , paromomy eases , congential diseases , epidermolysis bullosa , trauma, or c in , streptomycin , spectinomycin , geldanamycin , herbimy post - surgery inflammation comprising administering to the cin , rifaximin , loracarbef, ertapenem , doripenem , imipenem / subject in need thereof an oral topical non -systemic phar - cilastatin , meropenem , cefadroxil , cefazolin , cefalotin , maceutical composition comprising any of the pharmaceu cefalexin , cefaclor, cefamandole , cefoxitin , cefprozil , cefu tical compositions described herein . 55 roxime, cefixime, cefdinir , cefditoren , cefoperazone, cefo A method for manufacturing an oral topical non -systemic taxime, cefpodoxime, ceftazidime, ceftibuten , ceftizoxime, pharmaceutical dosage form suitable for chewing, sucking , ceftriaxone , cefepime, ceftaroline fosamil, ceftobiprole , tei or buccal dissolution comprising : ( a ) combining gelatin , coplanin , vancomycin , telavancin , dalbavancin , oritavancin , glycerol, water , maltitol, xylitol, sucralose , citric acid , poly - clindamycin , lincomycin , daptomycin , azithromycin , sorbate 80 and one or more active pharmaceutical ingredient 60 clarithromycin , dirithromycin , erythromycin , roxithromy to produce a matrix fill solution ; ( b ) combining one or more cin , troleandomycin , telithromycin , spiramycin , aztreonam , gelatins, glycerol , water, maltitol, xylitol, sucralose , and furazolidone , nitrofurantoin , linezolid , posizolid , radezolid , citric acid to produce a shell gel mass ; ( c ) casting the shell torezolid , amoxicillin , ampicillin , azlocillin , carbenicillin , gel mass into filmsusing heat- controlled drums or surfaces ; cloxacillin , dicloxacillin , flucloxacillin , mezlocillin , methi and ( d ) injecting the matrix fill solution between the shell 65 cillin , nafcillin , oxacillin , penicillin G , penicillin V , pipera ribbons, and forming a soft lozenge using rotary die encap - cillin , temocillin , ticarcillin , amoxicillin / clavulanate , ampi sulation technology. cillin / sulbactam , piperacillin / tazobactam , ticarcillin / US 9 , 867 , 834 B2 12 clavulanate, bacitracin , colistin , polymyxin B , ciprofloxacin , active pharmaceutical ingredients to the oral cavity and enoxacin , gatifloxacin , gemifloxacin , levofloxacin , lom - esophagus. In one aspect , the soft lozenge can dissolve efloxacin , moxifloxacin , nalidixic acid , norfloxacin , ofloxa passively over time in the subject' s saliva . In another aspect, cin , trovafloxacin , grepafloxacin , sparfloxacin , temafloxa the soft lozenge can be sucked by the subject. In another cin , mafenide , sulfacetamide , sulfadiazine , silver 5 aspect, the soft lozenge can be chewed by the subject. In sulfadiazine , sulfadimethoxine, sulfamethizole, sulfame another aspect , the soft lozenge may be ingested by a thoxazole , sulfanilimide , sulfasalazine, sulfisoxazole , combination of dissolving , sucking, or chewing by the trimethoprim - sulfamethoxazole , sulfamidochrysoidine , subject. Regardless of the mode of oral dissolution , the soft demeclocycline , doxycycline ,minocycline , oxytetracycline , lozenge provides topical delivery of one or more active tetracycline , clofazimine , dapsone, capreomycin , cycloser - 10 pharmaceutical ingredients to the oral cavity and esophagus . ine , ethambutol, ethionamide , isoniazid , pyrazinamide , rifampicin , rifabutin , rifapentine, streptomycin , arsphe The terms " active ingredient” or “ active pharmaceutical namine , chloramphenicol, fosfomycin , fusidic acid , metron ingredient” as used herein refer to a pharmaceutical agent, idazole, mupirocin , platensimycin , quinupristin /dalfopristin , active ingredient, compound , or substance , compositions , or thiamphenicol, tigecycline , tinidazole , trimethoprim , or 15 mixtures thereof, that provide a pharmacological, often combinations thereof. beneficial, effect. In one embodiment, the active pharma Another embodiment described herein comprises a ceutical ingredient is one or more corticosteroids. method for treating , retarding the progression of, prophy The term “ topical ” as used herein refers to the adminis laxis of, delaying the onset of, ameliorating , or reducing the tration of an active pharmaceutical ingredient directly to a symptoms of one or more of esophageal oral, or buccal 20 portion of a subject ' s body , particularly to the mucus mem inflammation , eosinophilic esophagitis , inflammatory bowel branes. In one embodiment describe herein , topical refers to disease involving the esophagus , oral lichen planus , aph - the administration of one or more corticosteroids or other thous stomatitis , Crohn ' s disease , esophageal inflammation active pharmaceutical ingredients to the inner lumen of the secondary to caustic/ irritant ingestion , recurrent esophageal oral cavity and esophagus. strictures of any cause and including irritant ingestion , 25 The term “ contact” as used herein refers to the presence pill - induced esophagitis , systemic diseases , congential dis - of the dissolved dosage form directly on the mucous mem eases , epidermolysis bullosa , trauma, or post -surgery branes or tissues of the oral cavity or esophagus. inflammation comprising administering to a subject in need The term " non -systemic ” as used herein refers to the thereof any of the pharmaceutical combinations described administration of an active pharmaceutical ingredient that is herein . 30s not sufficiently absorbed to a significant extent so that it is transported throughout the body via the circulatory system BRIEF DESCRIPTION OF THE DRAWINGS or detectable in blood or plasma. In one embodiment described herein , an active pharmaceutical ingredient is FIG . 1 . ( A ) Linear scale plot of the mean plasma con 35 topically administered at a dosage insufficient to become centration over time for the Test fluticasone propionate 35 systemically circulated . lozenge and the Reference fluticasone propionate aerosol. The term " delayed release " as used herein refers to the ( B ) Log scale plot of the same data shown in ( A ) . release of the active ingredient over a period of time that is DETAILED DESCRIPTION subsequent to the dissolution of the dosage form . 40 The term “ dissolution " as used herein refers to the com Described herein are topical, non - systemic , slow - release plete disintegration of the dosage form either intra - orally or oral pharmaceutical compositions comprising chewable , in - vitro . suckable , dissolvable soft lozenges or swallowable liquid The terms " dosage ” or “ dose ” as used herein denote any formulations comprising one or more active pharmaceutical forms of the active ingredient formulation that contain an ingredients . 45 amount sufficient to produce a therapeutic effect with a The oral pharmaceutical compositions described herein single administration . The dosage form described herein is suitable for chewing , sucking , buccal dissolution , or swal- for oral administration . The oral dosage form may also be a lowing comprising one or more corticosteroids as at least liquid comprising a suspension , syrup , elixir or concentrate , one of the active pharmaceutical ingredients , and methods wherein the corticosteroid may be formulated as a viscous for preparation thereof. The oral composition provides topi- 50 liquid suspension having enough viscosity such that upon cal, non - systemic administration and slow release of one or drinking , the suspension adheres to the esophageal surface . more active pharmaceutical ingredients to the oral cavity The oral dosage form may also be a soft lozenge . and upper gastrointestinal track , including the esophagus . The terms " active pharmaceutical ingredient load ” or The soft lozenge comprises a firm , gelatinous solid or “ drug load ” as used herein refer to the quantity (mass ) of the semi- solid matrix fill encapsulated by a gelatin capsule shell . 55 active pharmaceutical ingredient comprised in a single liq Liquid formulations comprise solutions , syrups, suspen - uid dosage or soft lozenge . sions , elixirs or concentrates. The phrase " organoleptic The term “ formulation " or " composition " as used herein properties ” as used herein refers to the sensory aspects refers to the drug in combination with pharmaceutically experienced by one or more subjects , including but not acceptable excipients . This term includes orally adminis limited to , sight, smell , taste , mouth feel , moisture content/ 60 trable formulations as well as formulations administrable by dryness , plasticity , chewability , dissolution , residue , and other means . aftertaste . As used herein , the term “ pharmaceutical composition " The phrase " suitable for chewing , sucking , or buccal refers to a composition comprising at least on active ingre dissolution " as used herein refers to the propensity of the dient , nutraceutical, nutritional , or vitamin . soft lozenges described herein to dissolve in a subject' s 65 The term “ release modifier" as used herein refers to a mouth by passive incubation in the oral cavity , or actively by substance that slows the dissolution and release of the active sucking , chewing , or mastication to deliver one or more ingredient from the soft lozenge. US 9 ,867 , 834 B2 13 14 The term “ pH modifier” as used herein refers to a sub - herein , the pharmaceutical composition slowly dissolves in stance that adjusts the pH of a composition . In one embodi a subject ' s oral cavity and provides contact of the active ment described herein , pH modifiers comprise one or more pharmaceutical ingredient to the oral cavity and esophagus organic acids. over a prolonged period . In one aspect, the pharmaceutical The term “ absolute bioavailability ” as used herein refers 5 composition can be chewed or masticated . In another aspect , to the fraction of a drug or active pharmaceutical ingredient the pharmaceutical composition can be sucked . In another absorbed through non - intravenous administration ( e . g ., oral aspect, the pharmaceutical composition can be swallowed , administration ) as compared to intravenous administration particularly when the composition is a liquid . In another of the same drug or active pharmaceutical ingredientnt. aspect, the pharmaceutical composition can be allowed to The term “ Cmax " as used herein refers to the maximum 10 observed blood (plasma , serum , or whole blood ) concentra slowly dissolve in the oral cavity . In another aspect, the tion or the maximum blood concentration calculated or pharmaceutical composition can be masticated , sucked , and / estimated from a concentration to time curve , and is or allowed to passively dissolve in the oral cavity at the expressed in units of mg /L or ng/ mL , as applicable . subject ' s discretion . Regardless of the mode of oral disso The term " Cmin ” as used herein refers to the minimum 15 lution , the compositions described herein provide slow observed blood ( plasma, serum , or whole blood ) concentra releasing and prolonged topical contact of the active phar tion or the minimum blood concentration calculated or maceutical to the oral cavity and esophagus. estimated from a concentration to time curve , and is In one embodiment described herein , the pharmaceutical expressed in units ofmg / L or ng /mL , as applicable . composition comprises one or more corticosteroids that are The term “ Cave " as used herein refers to the blood 20 slowly released in the oral cavity and provide topical, (plasma , serum , or whole blood) concentration of the drug non - systemic treatment of the oral cavity and esophagus . within the dosing interval, is calculated as AUC / dosing The dosage form of corticosteroid is topically administered interval, and is expressed in units of mg/ L or ng /mL , as to the oral cavity and esophagus , but the dosage quantity of applicable . corticosteroid is insufficient to be systemically circulated . In The term " Two " as used herein refers to the time after 25 one aspect, the dosage form coats the esophagus . In one administration at??? which may occurs , and is expressed in aspect, the oral pharmaceutical composition described units of hours ( h ) or minutes (min ), as applicable . herein is for the topical treatment of esophagitis or eosino The term “ AUCO > T " as used herein refers to the area philic esophagitis ( EOE ) . under the blood (plasma , serum , or whole blood ) concen - In one embodiment described herein , the oral pharmaceu tration versus time curve from time zero to time tau ( T ) over 30 tical composition comprises a chewable , suckable , or dis a dosing interval at steady state, where tau is the length of solvable soft lozenge . In another embodiment, the soft the dosing interval, and is expressed in units of h ·mg / L or lozenge comprises a gelatinous solid or semi- solid fill or hing /mL , as applicable . For example , the term AUCO - as matrix composition that is encapsulated within a soft shell used herein refers to the area under the concentration versus composition . In one embodiment, the pharmaceutical com time curve from 0 to 12 hours . 35 position comprises a fill composition as shown in Tables 1 - 2 The term " AUCO - > 00 " as used herein refers to the area and a shell composition as shown in Tables 3 - 4 . In another under the blood ( plasma, serum , or whole blood ) concen - embodiment, the pharmaceutical composition comprises the tration versus time curve from time 0 hours to infinity , and formulation shown in Table 5 . is expressed in units of h mg/ L or hing / mL , as applicable . One embodiment described herein , is an oral pharmaceu The term “ room temperature ” as used herein refers to 40 tical composition comprising a gel mass suitable for forming common ambient temperatures found in pharmaceutical a soft lozenge fill or matrix composition . In one embodi laboratories ranging from about 20° C . to about 27° C . ment, the soft lozenge fill or matrix composition comprises The term “ titration ” as used herein refers to the incre - the composition shown in Table 1 . mental increase in drug dosage to a level that provides the optimal therapeutic effect. 45 TABLE 1 The term “ treating” refers to administering a therapy in an amount, manner , or mode effective to improve a condition , Exemplary Soft Lozenge Matrix Fill Composition symptom , or parameter associated with a disorder . Exemplary Ingredients Weight Percentage ( % ) The term “ prophylaxis ” refers to preventing or reducing the progression of a disorder, either to a statistically signifi - 50 Film - forming Polymer( s) 5 - 30 Release Modifier ( s ) 0 . 5 - 10 cant degree or to a degree detectable to one skilled in the art . Plasticizer ( s ) 5 - 20 The term “ substantially ” as used herein means to a great pH Modifier ( s ) 0 . 5 - 5 or significant extent , but not completely . Sweetener( s ) 10 - 80 The term " about” as used herein refers to any values, Solubilizing Agent ( s ) 0 . 1 - 5 Solvent ( s ) 5 - 30 including both integers and fractional components that are 55 Active Pharmaceutical Ingredients (API ) 0 .001 - 1 within a variation ofup to + 10 % of the value modified by the Second API 1 - 10 term “ about. ” Excipients , optional 0 - 10 As used herein , “ a ” or “ an ” means one or more unless otherwise specified . TOTAL 100 % Terms such as “ include, " " including, " " contain ," " con - 60 taining, " " have ,” “ having, " and the like mean “ comprising. ” Another embodiment described herein is an oral soft The term “ or” can be conjunctive or disjunctive . lozenge fill composition comprising one or more film One embodiment described herein , is a topical, non - forming polymers , one or more plasticizers , one or more pH systemic , slow - releasing oral pharmaceutical composition modifiers, one or more solubilizing agents , one or more comprising a chewable , suckable , or dissolvable soft loz - 65 release modifiers, one or more solvents, one or more sweet enge or liquid formulation comprising one or more active eners , and one or more active pharmaceutical ingredients . In pharmaceutical ingredients . In one embodiment described another embodiment the soft lozenge fill composition com US 9 ,867 , 834 B2 15 16 prises one or more excipients , including but not limited to TABLE 4 coloring agents , flavorings, or the like . In one embodiment described herein , the soft lozenge fill Exemplary Soft Lozenge Shell Composition composition comprises that shown in Table 2 . Weight 5 Functional Component Exemplary Components Percentage ( % ) TABLE 2 Film - forming Gelatin , 150 Bloom ( or other 5 - 30 Polymers high Bloom ) Exemplary Soft Lozenge Matrix Fill Composition Gelatin , 100 Bloom (or other 0 - 20 10 low Bloom ) Gelatin Hydrolysate 0 - 10 Weight Partially Hydrolyzed Gelatin 0 - 10 Functional Component Exemplary Components Percentage ( % ) Plasticizer( s ) Glycerol 5 - 30 pH Modifier( s ) Citrate , Lactate or Fumarate 0 . 1 - 5 Film - forming Polymers Gelatin , 80 -180 Bloom 5 - 20 Sweetener ( s ) Mannitol, Maltitol 5 - 30 15 Sucralose 0 . 1 - 2 Gelatin Hydrolysate 0 - 10 Xylitol 1 - 10 Release Modifier ( s ) Polyethylene oxide, 6 x 105 0 . 5 - 10 Solvent Water 5 - 30 7 x 106 MW Excipients flavorings , colorings, opacifiers , 0 - 10 optional Plasticizer( s ) Glycerol 5 - 20 etc pH Modifier( s ) Citrate , Lactate , Fumarate 0 . 1 - 5 TOTAL 100 % Sweetener( s ) Maltitol, Mannitol 10 - 70 Xylitol 0 - 10 Another embodiment described herein is an oral soft Sucralose 0 . 1 - 5 lozenge composition . The soft lozenge composition com Solubilizing Agent( s ) Polysorbate 80 0 . 1 - 2 prises a shell as described herein that enrobes or encapsu Solvent Water 5 - 30 lates a soft lozenge fill or matrix composition as described Active Pharmaceutical fluticasone , budesonide, 0 . 001 - 0 . 5 herein . In one embodiment , the soft lozenge composition Ingredients (API ) prednisone , other comprises that shown in Table 5 . corticosteroids 30 Second API Lidocaine , Prilocaine , 1 - 10 TABLE 5 Excipients, optional flavorings , colorings , etc 0 - 10 Exemplary Soft Lozenge Total Composition (Shell and Fill ) Exemplary Ingredients Weight Percentage ( % ) TOTAL 100 % 35 Film - forming Polymer ( s ) 10 - 40 Release Modifier( s ) 0 . 5 - 10 Plasticizer ( s ) 5 - 30 Another embodiment described herein is an oral soft pH Modifier( s ) 0 . 5 - 5 Sweetener ( s ) 10 - 70 lozenge shell composition . The shell composition is used to Solubilizing Agent( s ) 0 . 1 - 1 enrobe or encapsulate the soft lozenge fill or matrix com - 40 Solvent( s ) 5 - 30 positions described herein . In one embodiment, the soft Active Pharmaceutical Ingredients 0 .005 - 0 . 5 ( API, e . g . , corticosteroids ) lozenge shell composition comprises that shown in Table 3 . Second API ( topical anesthetic , e . g ., lidocaine ) 1 - 10 Excipients 0 - 10 TABLE 3 45 TOTAL 100 % Exemplary Soft Lozenge Shell Composition Exemplary Ingredients Weight Percentage ( % ) In one embodiment described herein , the soft lozenge Film - forming Polymer( s ) 10 -50 composition comprises that shown in Table 6 . Plasticizer( s ) 5 - 20 50 pH Modifier ( s ) 0 . 1 - 5 Sweetener (s ) 10 - 80 TABLE 6 Solvent( s ) 5 - 30 Excipients , optional 0 - 10 Exemplary Soft Lozenge Total Composition ( Shell and Fill ) Weight TOTAL 100 % Percentage Component Exemplary Components Another embodiment described herein is a composition Film - forming Gelatin , 150 Bloom 1 - 20 Polymers Gelatin , 100 Bloom 1 - 20 for a soft lozenge shell composition comprising one or more Gelatin Hydrolysate 0 - 10 film - forming polymers , one or more plasticizers , one or Partially Hydrolyzed Gelatin 0 - 10 more pH modifiers , one or more solvents , and one or more O Release Polyethylene oxides , 6 x 10 ^ - 7 0 . 5 - 10 Modifier ( s ) 10 MW sweeteners. In another embodiment the soft lozenge shell Plasticizer ( s ) Glycerol 1 - 20 composition comprises one or more excipients , including pH Modifier ( s ) Citric Acid , Anhydrous 0 . 1 - 5 but not limited to coloring agents , flavorings, opacifiers , or Sweetener ( s ) Maltitol (75 % solution ; e . g. , Lycasin ® 10 - 60 the like . 80 /55 ) 65 Xylitol 0 . 5 - 5 In one embodiment described herein , the soft lozenge Sucralose 0 .01 - 5 shell composition comprises that shown in Table 4 . US 9 , 867 , 834 B2 17 18 TABLE 6 - continued Type A gelatin . In addition , at neutral pH values , Type A gelatins (e . g. , acid -processed gelatins ) are typically net Exemplary Soft Lozenge Total Composition ( Shell and Fill ) cationic ( e . g . , isoelectric point of about 7 - 9 ) and Type B Weight gelatins ( e . g . , alkali - processed gelatins ) are typically net Percentage 5 anionic ( e . g . , isoelectric point of about 4 . 5 - 5 . 3 ). Type A Component Exemplary Components ( % ) gelatin typically has higher plasticity and elasticity than type Solubilizing Polysorbate 80 0 .01 - 5 B gelatin ; type B gelatin typically has higher gel strength Agent( s ) than type A gelatin . Solvent Water 5 - 40 The strength of gelatins is typically defined by “ Bloom Active Fluticasone propionate 0 . 005 - 0 . 5 10 Pharmaceutical strength ” or grade . The Bloom test determines the weight ( in Ingredient grams) needed by a 0 .5 - inch diameter probe to deflect the Second API Lidocaine , Prilocaine, combination 1 - 10 thereof surface of a gel 4 -mm without breaking it . The result is Excipients Titanium dioxide , FD & C colorings , 0 - 10 expressed as “ Bloom ” or “ Bloom strength .” The pharma flavors ceutical compositions described herein utilize gelatins with - 15 Bloom strengths in the range of about 20 Bloom to about TOTAL 100 % 400 Bloom , including each integer within the specified range . In one embodiment, Bloom strengths for the phar In one embodiment described herein , the soft lozenge maceutical compositions described herein are about 50 composition comprises a shell composition and a fill com - 20 Bloom to about 250 Bloom including each integer within the position that have similar compositions . In one embodiment, specified range . In some embodiments , the gelatin Bloom the soft lozenge fill composition comprises similar compo strength is about 50 Bloom , about 80 Bloom , about 100 nents as the soft lozenge shell composition except that the Bloom , about 120 Bloom , about 150 Bloom , about 180 fill composition comprises one or more solubilizing agents Bloom , about 200 Bloom , or about 250 Bloom . In one and one or more release modifiers and the shell composition 25 embodiment, the gelatin Bloom strength is about 100 can optionally comprise one or more opacifiers, colors , or Bloom . In another embodiment, the gelatin Bloom strength flavors . In one embodiment described herein , the matrix fill is about 150 Bloom . In another embodiment, the gelatin composition is firmer and slower to dissolve in the oral cavity compared with the shell composition . Bloom strength is 195 Bloom . In another embodiment, the In one embodiment described herein , the pharmaceutical 30 gelatin Bloom strength is 200 Bloom . In another aspect, the compositions comprise liquid dosage forms. In one aspect film - forming polymers comprise one or more of gelatin with the liquid dosage form comprises a suspension . In another various Bloom strengths, partially hydrolyzed gelatin , aspect , the liquid dosage form comprises syrup . In another hydrolyzed gelatin , or combinations thereof. aspect the liquid dosage form comprises a concentrate . In another embodiment described herein , the pharmaceu Another embodiment described herein is a composition 35 tical1 compositions described herein comprises one or more for a liquid dosage form comprising one or more release plasticizers. As used herein , a plasticizer is a substance , modifiers , one or more film forming polymers , one or more often a polyol that provides flexibility and softens the plasticizers, one or more , pH modifiers , one or more sweet lozenge . In one embodiment, the plasticizer comprises one eners , one or more solubilizing agents , one or more solvents . or more of glycerol, sorbitol, partially dehydrated sorbitol ( a In another embodiment, the liquid dosage form comprises 40 blend of D - sorbitol, 1, 4 -sorbitan , mannitol, and water; e. g ., one or more excipients , including but not limited to coloring Sorbitol Special® (SPI Pharma ) ; Anidrisorb® or Polysorb® , agents , flavorings, opacifiers , thickeners or the like. (Roquette ) , corn syrup , xylitol, mannitol, propylene glycol, In one embodiment described herein , the pharmaceutical low molecular weight polyethylene glycols , poly - alcohols compositions described herein comprise one or more film with 3 to 6 carbon atoms, or combinations thereof. In one forming polymers. Film - former polymers that are useful for 45 embodiment, the plasticizer comprises glycerol, sorbitol, or the pharmaceutical compositions described herein are gela - combinations thereof. tin , partially hydrolyzed gelatin , collagen , partially hydro In another embodiment described herein , the pharmaceu lyzed collagen ; sodium or calcium alginate ; natural and modified starch , starch hydrolysates , pectins or amylopec tical compositions described herein comprise one or more tins; hydroxypropylmethylcellulose (HPMC ) , methylcellu - 50 sweeteners . In one embodiment, the sweetener comprises lose , cellulose; carrageenan (e . g ., iota carrageenan and one or more of maltitol (e . g ., hydrogenated starch hydroly kappa carrageenan ), or combinations thereof. In one sates; e . g ., Lycasin® 80 / 55 , Roquette ) , xylitol (Xylisorb embodiment described herein , the pharmaceutical composi 300® ) , sucralose , aspartame, steviol glycosides ( e . g . , Ste tions comprise one or more film - forming polymers compris via® , Truvia® ) , thaumatin ( e . g . , Talin® ) , glycyrrhizic acid ing one or more gelatins or gelatin hydrolysates . salts (MagnaSweet® ) , mannitol, or combinations thereof. In Examples of gelatin compositions that are useful for the one aspect, the sweetener comprises sucralose , sucrose , pharmaceutical compositions described herein comprise xylitol , or combinations thereof. acid bone gelatin , pig skin gelatin , chicken skin gelatin , fish In another embodiment described herein , the pharmaceu gelatin , acid hide gelatin , gelatin hydrolysate , lime bone tical composition comprises one or more pH modifiers. In gelatin , or combinations thereof. Gelatins are often classified 60 one embodiment, the pH modifier comprises one or more as either “ Type A ” or “ Type B ” gelatin . Type A gelatin is organic acids . In another embodiment, the pH modifier derived from the acid hydrolysis of collagen (e .g ., acid bone comprises one or more of citric acid , acetic acid , lactic acid , gelatin or pig skin gelatin ), while Type B gelatin (e .g ., lime malic acid , tartaric acid , glutamic acid , aspartic acid ,malic bone gelatin ) is derived from the alkaline hydrolysis of acid , succinic acid , fumaric acid , or combinations thereof. In collagen . Traditionally , bovine bones and skins are used as 65 one aspect, the pH modifier comprises citric acid , lactic acid , raw materials for manufacturing Type A and Type B gelatin , or fumaric acid . In one aspect, the pH modifier comprises while porcine skins are used extensively for manufacturing citric acid . US 9 ,867 , 834 B2 19 20 In another embodiment described herein , the pharmaceu an approximate molecular weight ( M ) of 600 , 000 when a tical composition comprises one ormore solubilizing agents . 5 % (by wt) aqueous solution of polyethylene oxide using a In one embodiment, the solubilizing agent comprises one or Brookfield viscometer Model RVF, spindle No . 2 , at 2 rpm , more of polysorbate 20 , polysorbate 40 , polysorbate 60 , at 25° C . shows a viscosity range of 30 to 50 mPa s ( CP ) . polysorbate 80 , diethanolamine , glyceryl monostearate , 5 Polyethylene oxide is considered to have an approximate lanolin alcohols , lecithin , mono - and di- glycerides , molecular weight ( M ) of 1 , 000 , 000 when a 2 % (by wt) monoethanolamines, oleic acids, oleyl alcohols , poloxamer, aqueous solution of polyethylene oxide using a Brookfield polyoxyethylene 50 stearate , polyoxyl 35 castor oil , poly viscometer Model RVF , spindle No. 1 , at 10 rpm , at 25° C . oxyl 40 hydrogenated castor oil , polyoxyl 10 oleyl ether, shows a viscosity range of 400 to 800 mPas (cP ) . Polyeth polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate , propyl - 10 ylene oxide is considered to have an approximate molecular ene glycol diacetate , propylene glycol monostearate , sodium weight ( M ) of 2 ,000 , 000 when a 2 % (by wt) aqueous lauryl sulfate , sodium stearate , sorbitan monolaurate , sorbi- solution of polyethylene oxide using a Brookfield viscom tan monooleate, sorbitan monopalmitate , sorbitan monoste eter Model RVF, spindle No. 3 , at 10 rpm , at 25° C . shows arate , stearic acid , trolamine, emulsifying wax , or combina - a viscosity range of 2000 to 4000 mPa s (CP ) . Polyethylene tions thereof . In one aspect, the solubilizing agent comprises 15 oxide is considered to have an approximate molecular polysorbate 80 . weight ( M ) of 4 ,000 ,000 when a 1 % (by wt) aqueous In another embodiment described herein , the pharmaceu solution of polyethylene oxide using a Brookfield viscom tical composition comprises one or more release modifiers . eter Model RVF, spindle No . 2 , at 2 rpm , at 25° C . shows a Suitable release modifiers comprise one or more of poly - viscosity range of 1650 to 5500 mPa s ( CP ) . Polyethylene ethylene oxides, methylcellulose , hydroxypropylmethyl cel- 20 oxide is considered to have an approximate molecular lulose, hydroxypropyl cellulose , hydroxyethyl cellulose, weight ( M ) of 4 , 000 , 000 when a 2 % (by wt) aqueous hydroxymethyl cellulose , polymethylmethacrylate , polyhy solution of polyethylene oxide using a Brookfield viscom droxyethylmethacrylate , polyvinylpyrrolidone , copovidone , eter Model RVF, spindle No . 2 , at 2 rpm , at 25° C . shows a polyvinyl alcohol, copolymers of polyvinylpyrrolidone and viscosity range of 3300 to 11000 mPa s ( CP ) . Polyethylene polyvinyl acetate , or combinations thereof. For example , 25 oxide is considered to have an approximate molecular MethocelTM K100M , MethocelTM A4M , Premium LV CR , weight ( M ) of 5 ,000 , 000 when a 1 % ( by wt) aqueous K4M Premium CR , K 15M Premium CR , K100 Premium solution of polyethylene oxide using a Brookfield viscom CR , E4M Premium CR , E1OM Premium CR , or E4M eter Model RVF, spindle No. 2 , at 2 rpm , at 25° C . shows a Premium (Dow Chemical Co . ) , CELLOSIZETM , or WALO - viscosity range of 5500 to 7500 mPa s ( CP ) . Polyethylene CELTM CRT may be used as release modifiers in the 30 oxide is considered to have an approximate molecular compositions described herein . In one embodiment weight ( M ) of 5 , 000 , 000 when a 1 . 5 % (by wt) aqueous described herein , the release modifier comprises one or more solution of polyethylene oxide using a Brookfield viscom polyethylene oxides . eter Model RVF, spindle No . 2 , at 2 rpm , at 25° C . shows a In one embodiment described herein , the release modifier viscosity range of 8250 to 11250 mPa s (CP ). Polyethylene comprises a polyethylene oxide . As described herein , poly - 35 oxide is considered to have an approximate molecular ethylene oxide polymers have an approximate molecular weight ( M ) of 7 ,000 , 000 when a 1 % (by wt) aqueous weight ( M ) of at least about 600 , 000 to about 10 ,000 , 000 or solution of polyethylene oxide using a Brookfield viscom greater. In one aspect , the release modifier may comprise a eter Model RVF, spindle No . 2 , at 2 rpm , at 25° C . shows a high molecular weight polyethylene oxide having a molecu - viscosity range of 7500 to 10 , 000 mPa s ( CP ) . Polyethylene lar weight ( M ) of about 600 , 000 to about 10 , 000, 000 , 40 oxide is considered to have an approximate molecular including each integer within the specified range . In another weight ( M ) of 8 ,000 , 000 when a 1 % (by wt) aqueous aspect, the release modifier may comprise a high molecular solution of polyethylene oxide using a Brookfield viscom weight polyethylene oxide having a molecular weight ( M ) eter Model RVF, spindle No . 2 , at 2 rpm , at 25° C . shows a of about 4 , 000 ,000 to about 10 ,000 , 000 , including each viscosity range of 10 ,000 to 15 ,000 mPa s (cP ) . Suitable integer within the specified range . In another aspect, the 45 polyethylene oxide polymers with the above described vis release modifier may comprise a high molecular weight cosity and molecular weight ( M ) values that are useful for polyethylene oxide having a molecular weight ( M ) of about the matrices described are , for example , POLYOXTM poly 4 ,000 ,000 to about 8 ,000 ,000 , including each integer within mers , such as WSR - 205 , WSR - 1105 , WSR N - 12K , WSR the specified range . In another aspect, the release modifier N -60K , WSR - 301, WSR Coagulant , WSR -303 , WSR 308 , may comprise a polyethylene oxide having a molecular 50 UCARFLOC Polymers 300 , 302, 304 , and 309 commer weight ( M ) of about 600 ,000 , about 700 ,000 , about 800 , cially available from Dow . In one embodiment described 000 , about 900 ,000 , about 1 ,000 , 000 , about 2 ,000 ,000 , herein , the release modifier comprises the polyethylene about 3 ,000 ,000 , about 4 ,000 , 000 , about 5 , 000 , 000 , about oxide polymer PolyoxTM WSR -303 that has an approximate 6 ,000 ,000 , about 7 ,000 , 000 , about 8 , 000 ,000 , about 9 ,000 , molecular weight (viscosity average, M ) of 7 , 000 , 000 and 000 or about 10 , 000 , 000 . In another aspect, the release 55 a 1 % solution of the polymer has a viscosity of 7 , 500 - 10 , 000 modifier may comprise a high molecular weight polyethyl- CP at 25° C . using a Brookfield Model RVF viscometer, ene oxide having a molecular weight ( M ) of about 4 , 000 , spindle No. 2 , at 2 rpm . 000 . In another aspect, the release modifier may comprise a The one or more release modifiers may comprise a high molecular weight polyethylene oxide having a molecu - viscosity of about 50 cP to about 100 ,000 CP , including each lar weight ( M ) of about 5 , 000 , 000 . In another aspect , the 60 integer within the specified range . For example , the release release modifier may comprise a high molecular weight modifiers comprise a viscosity of about 50 CP , about 100 cP , polyethylene oxide having a molecular weight ( M ) of about about 200 cP, about 300 CP , about 400 CP , about 500 CP , 7 , 000 , 000 . about 750 CP , about 1 ,000 CP , about 1 ,500 CP , about 2 , 000 CP , The molecular weight measurements of polyethylene about 2 , 500 CP , about 3 ,000 cP , about 3 , 500 CP , about 4 , 000 oxide may be approximated using rheological measurements 65 CP, about 4 ,500 CP , about 5 ,000 CP , about 6 ,000 CP, about using a viscometer ( e . g . , weight average molecular weight, 7 ,000 cP , about 8 ,000 CP , about 9 , 000 CP , or about 10 , 000 CP , My) . For example , polyethylene oxide is considered to have about 15 ,000 CP , about 20 , 000 CP , about 30 ,000 cP, about US 9 , 867 , 834 B2 40 ,000 CP, about 50 , 000 CP, about 60 , 000 cP , about 70 ,000 the specified range . In one aspect , one or more plasticizers cP , about 80 ,000 cP , about 90 ,000 cP , about 100 , 000 cp, comprise about 5 % to about 20 % ; about 1 % to about 10 % ; greater than 100 , 000 CP, or even greater. about 5 % to about 15 % ; about 1 % to about 5 % ; about 10 % In one embodiment described herein , the one or more to about 20 % ; about 15 % to about 20 % ; about 10 % to about release modifiers provide slow release of the active phar - 5 15 % , or about 1 % to about 5 % by weight of the composition , maceutical ingredient by retarding the dissolution of the including each integer within the specified ranges. dosage form . In another embodiment described herein , one or more In another embodiment described herein , in addition to plasticizers comprise about 5 % , about 6 % , about 7 . 5 % , the release modifiers, thickening agents may be used to about 8 % , about 9 % , about 10 % , about 11 % , about 12 % , control the release of the active pharmaceutical ingredient 10 about 13 % , about 14 % , about 15 % , about 16 % , about 17 % , and may comprise one or more of polyacrylic acid , methyl about 18 % , about 19 % , about 20 % , about 21 % , about 22 % , cellulose , alginic acid , chitosan , carboxymethyl cellulose , about 23 % , about 24 % , about 25 % , about 26 % , about 27 % , sodium carboxymethyl cellulose , locust bean gum , xanthum about 28 % , about 29 % , or about 30 % by weight of the gum , high swelling crosslinked polymers , or combinations composition . thereof. 15 In one embodiment , one or more pH modifiers comprise In another embodiment described herein , the pharmaceu about 0 . 1 % to about 5 % by weight of the composition , tical compositions described herein comprises one or more including each integer within the specified range . In another solvents . In one aspect , the solvent comprises water. embodiment, one or more pH modifiers comprise about In another embodiment described herein , the pharmaceu - 0 . 1 % to about 1 % by weight of the composition , including tical compositions described herein comprises one or more 20 each integer within the specified range . In another embodi active pharmaceutical ingredients . In one embodiment the ment, one or more pH modifiers comprise about 0 . 5 % to active pharmaceutical ingredient comprises one or more about 1 % by weight of the composition , including each corticosteroids. In another embodiment , the active pharma- integer within the specified range . In another embodiment , ceutical ingredient comprises one or more corticosteroids one or more pH modifiers comprise about 0 . 1 % to about and one or more topical anesthetics . In one embodiment , the 25 0 . 5 % by weight of the composition , including each integer active pharmaceutical composition comprises fluticasone within the specified range . In one aspect, one or more pH propionate , lidocaine , prilocaine , or combinations thereof. modifiers comprise about 0 . 1 % to about 0 . 5 % ; about 0 . 5 % In one embodiment described herein , one or more film - to about 1 % ; about 0 . 25 % to about 0 .75 % ; about 0 . 75 % to forming polymers comprise about 5 % to about 70 % by about 1 % ; about 1 % to about 2 % ; about 0 . 5 % to about 1 . 5 % ; weight of the composition , including each integer within the 30 about 0. 5 % to about 0. 75 % , or about 0 .25 % to about 0 .5 % specified range . In another embodiment, one or more film - by weight of the composition , including each integer within forming polymers comprise about 5 % to about 30 % by the specified ranges . weight of the composition , including each integer within the In another embodiment described herein , one or more pH specified range . In another embodiment, one or more film - modifiers comprise about 0 . 1 % , about 0 . 2 % , about 0 . 35 , forming polymers comprise about 10 % to about 60 % by 35 about 0 .4 % , about 0 . 5 % , about 0 .6 % , about 0 .7 % , about weightof the composition , including each integer within the 0 . 8 % , about 0 . 9 % , about 1 % , about 1 . 2 % , about 1 . 3 % , about specified range . In another embodiment, one or more film - 1 . 4 % , about 1 . 5 % , about 1 . 6 % , about 1 . 7 % , about 1 . 8 % , forming polymers comprise about 10 % to about 40 % by about 1 . 9 % , about 2 % , about 2 . 5 % , about 3 % , about 4 % , or weight of the composition , including each integer within the about 5 % by weight of the composition . specified range . In one aspect , one or more film - forming 40 In one embodiment, one or more release modifiers com polymers comprise about 5 % to about 20 % ; about 1 % to prise about 0 . 5 % to about 10 % by weight of the composi about 10 % ; about 5 % to about 15 % ; about 1 % to about 5 % ; tion , including each integer within the specified range . In about 10 % to about 20 % , about 15 % to about 20 % ; about another embodiment, one or more release modifiers com 10 % to about 15 % , or about 1 % to about 5 % by weight of prise about 1 % to about 5 % by weight of the composition , the composition , including each integer within the specified 45 including each integer within the specified range . In another ranges . embodiment, one or more release modifiers comprise about In another embodiment described herein , one or more 2 % to about 5 % by weight of the composition , including film - forming polymers comprise about 0 . 5 % , about 1 % , each integer within the specified range . In one aspect, one or about 2 % , about 2 . 5 % , about 3 % , about 4 % , about 5 % , about more release modifiers comprise about 0 . 5 % to about 2 % ; 6 % , about 7 . 5 % , about 8 % , about 9 % , about 10 % , about 50 about 1 % to about 3 % , about 2 % to about 4 % ; about 2 . 5 % 11 % , about 12 % , about 13 % , about 14 % , about 15 % , about to about 5 % ; about 0 . 5 % to about 1 % , about 1 % to about 16 % , about 17 % , about 18 % , about 19 % , about 20 % , or 2 % ; about 2 % to about 3 % ; about 3 % to about 4 % ; or about about 25 % by weight of the composition . 4 % to about 5 % by weight of the composition , including In one embodiment described herein , one or more plas - each integer within the specified ranges. ticizers comprise about 5 % to about 30 % by weight of the 55 In another embodiment described herein , one or more composition , including each integer within the specified release modifiers comprise about 0 . 2 % , about 0 . 5 % , about range . In another embodiment, one or more plasticizers 1 % , about 2 % , about 3 % , about 4 % , about 5 % , about 1 . 1 % , comprise about 5 % to about 20 % by weight of the compo about 1. 2 % , about 1. 3 % , about 1. 4 % , about 1. 5 % , about sition , including each integer within the specified range . In 1 . 6 % , about 1 . 7 % , about 1 . 8 % , about 1 . 9 % , about 2 . 2 % , another embodiment, one or more plasticizers comprise 60 about 2 .4 % , about 2 .6 % , about 2. 8 % , about 2 .9 % about about 10 % to about 30 % by weight of the composition , 3 . 1 % , about 3 . 2 % , about 3 . 4 % , about 3 .6 % , about 3 . 8 % , including each integer within the specified range . In another about 4 . 1 % , about 4 . 2 % , about 4 . 4 % , about 4 .6 % , about embodiment, one or more plasticizers comprise about 5 % to 4 . 8 % , about 5 . 5 % , about 6 % , about 7 % , about 8 % , about about 10 % by weight of the composition , including each 9 % , or about 10 % by weight of the composition . integer within the specified range . In another embodiment, 65 In one embodiment described herein , one or more sweet one or more plasticizers comprise about 10 % to about 20 % eners comprise about 10 % to about 80 % by weight of the by weight of the composition , including each integer within composition , including each integer within the specified US 9 ,867 , 834 B2 23 24 range . In another embodiment described herein , one or more 20 % ; about 10 % to about 15 % ; about 10 % to about 20 % ; sweeteners comprise about 30 % to about 70 % by weight of about 15 % to about 20 % ; about 15 % to about 25 % ; about the composition , including each integer within the specified 15 % to about 30 % ; about 20 % to about 25 % ; about 20 % to range . In another embodiment described herein , one or more about 30 % ; or about 25 % to about 30 % by weight of the sweeteners comprise about 15 % to about 30 % by weight of 5 composition , including each integer within the specified the composition , including each integer within the specified ranges. range. In another embodiment described herein , one or more In another embodiment described herein , one or more sweeteners comprise about 20 % to about 60 % by weight of solvents comprise about 5 % , about 7 . 5 % , about 10 % , about the composition , including each integer within the specified 11 % , about 12 % , about 13 % , about 14 % , about 15 % , about range . In one aspect , one or more release modifiers comprise 10 16 % , about 17 % . about 18 % , about 19 % , about 20 % , about about 0 . 1 % to about 0 . 2 % ; about 0 . 1 % to about 0 . 3 % ; about 21 % , about 22 % , about 23 % , about 24 % , about 25 % , about 0 . 1 % to about 2 % ; about 1 % to about 2 . 5 % ; about 1 % to 26 % , about 27 % , about 28 % , about 29 % , or about 30 % by about 5 % ; about 2 .5 % to about 5 % ; about 1 % to about 10 % ; weight of the composition . about 10 % to about 15 % , about 15 % to about 20 % ; about In one embodiment described herein , one or more active 20 % to about 30 % , about 30 % to about 40 % ; about 40 % to 15 pharmaceutical ingredients comprise about 0 . 005 % to about about 45 % ; about 45 % to about 50 % ; about 40 % to about 5 % by weight of the composition , including each integer 50 % ; about 50 % to about 60 % ; about 55 % to about 60 % ; within the specified range . In another embodiment described about 60 % to about 65 % ; about 60 % to about 70 % ; or about herein , one or more active pharmaceutical ingredients com 70 % to about 80 % by weight of the composition , including prise about 0 . 025 % to about 0 .05 % by weight of the com each integer within the specified ranges . 20 position , including each integer within the specified range. In another embodiment described herein , one or more In another embodiment described herein , one or more active sweeteners comprise about 0 . 1 % ; about 0 .2 % , about 0 .3 % , pharmaceutical ingredients comprise about 0 .015 % to about about 0 . 4 % , about 0 . 5 % , about 1 % , about 2 % , about 3 % ; 0 .035 % by weight of the composition , including each inte about 4 % , about 5 % , about 6 % , about 7 % , about 8 % , about ger within the specified range . In one aspect described 9 % , about 10 % , about 11 % , about 12 % , about 13 % ; about 25 herein , one or more active pharmaceutical ingredients com 14 % , about 15 % , about 16 % , about 17 % , about 18 % , about prise about 0 .005 % to about 0 .01 % ; about 0 .01 % to about 19 % , about 20 % , about 25 % , about 30 % , about 35 % , about 0 .05 % ; about 0 .01 % to about 0 .025 % ; about 0 .025 % to 40 % , about 42 % , about 45 % , about 50 % , about 55 % , about about 0 . 1 % ; about 0 .05 % to about 0 . 1 % ; about 0 .016 % to 58 % , about 60 % , about 62 % , about 65 % , or about 70 % by about 0 .032 % ; about 0 .02 % to about 0 .04 % ; about 0 .02 % to weight of the composition . 30 about 0 .05 % ; about 0 .01 % to about 0 .04 % ; or about 0 . 02 % In one embodiment described herein , one or more solu - to about 0 .04 % by weight of the composition , including each bilizing agents comprise about 0 . 1 % to about 1 % by weight integer within the specified ranges . of the composition , including each integer within the speci - In another embodiment described herein , one or more fied range . In another embodiment described herein , one or active pharmaceutical ingredients comprise about 0 .01 % , more solubilizing agents comprise 0 . 1 % to about 0 .5 % by 35 about 0 .016 % , about 0 .02 % , about 0 .025 % , about 0 .03 % , weightof the composition , including each integer within the about 0 .032 % , about 0 . 04 % , about 0 . 05 % , about 0 . 06 % , specified range . In another embodiment described herein , about 0 .07 % , about 0 .08 % , about 0 .09 % , about 0 . 1 % , about one or more solubilizing agents comprise 0 . 1 % to about 0 . 2 % , about 0 .3 % , about 0 .4 % , about 0 . 5 % , about 0 .6 % , 0 .25 % by weight of the composition , including each integer about 0 . 7 % , about 0 . 8 % , about 0 . 9 % , about 1 % , about 2 % , within the specified range . In one aspect, one or more 40 about 3 % , about 4 % , or about 5 % by weight of the com solubilizing agents comprise about 0 . 1 % to about 0 . 5 % ; position . about 0 . 5 % to about 0 . 75 % ; about 0 .25 % to about 0 . 5 % ; In another embodiment described herein , one or more about 0 . 2 % to about 0 . 7 % ; about 0 . 5 % to about 1 % ; about second active pharmaceutical ingredients comprise about 0 .75 % to about 1 % ; about 0 . 4 % to about 0 . 7 % ; about 0 . 3 % 0 . 1 % , about 0 . 2 % , about 0 . 3 % , about 0 . 4 % , about 0 . 5 % , to about 0 . 6 % ; about 0 . 4 % to about 0 . 8 % ; about 0 .25 % to 45 about 0 .6 % , about 0 . 7 % , about 0 . 8 % , about 0 . 9 % , about 1 % , about 0 .75 % ; about 0 . 3 % to about 0 . 9 % ; or about 0 .75 % to about 2 % , about 3 % , about 4 % , or about 5 % by weight of about 1 % by weight of the composition , including each the composition . integer within the specified ranges . In one embodiment described herein , one or more phar In another embodiment described herein , one or more maceutically acceptable excipients comprise about 0 .0001 % solubilizing agents comprise about 0 . 1 % , about 0 . 2 , about 50 to about 10 % by weight of the composition , including each 0 . 3 , about 0 .35 , about 0 . 4 % , about 0 .45 % , about 0 . 5 % , about integer within the specified range . In another embodiment 0 .6 % , about 0 . 7 % , about 0 . 8 % , about 0 . 9 % , or about 1 % , by described herein , one or more pharmaceutically acceptable weight of the composition . excipients comprise about 0 .1 % to about 2 % by weight of In one embodiment described herein , one or more sol the composition , including each integer within the specified vents comprise about 5 % to about 30 % by weight of the 55 range . In another embodiment described herein , one or more composition , including each integer within the specified pharmaceutically acceptable excipients comprise about range . In another embodiment described herein , one or more 0 . 1 % to about 1 % by weight of the composition , including one or more solvents comprise about 10 % to about 20 % by each integer within the specified range . In one aspect, one or weight of the composition , including each integer within the more pharmaceutically acceptable excipients comprise specified range . In another embodiment described herein , 60 about 0 . 1 % to about 0 .4 % ; 0 . 1 % to about 0 .5 % ; about 0 . 5 % one or more one or more solvents comprise about 20 % to to about 1 % ; about 1 % to about 1 . 5 % , about 0 . 4 % to about about 30 % by weight of the composition , including each 1 . 2 % ; about 2 % to about 5 % ; or about 5 % to about 10 % by integer within the specified range . In another embodiment weight of the composition , including each integer within the described herein , one or more one ormore solvents comprise specified ranges. about 20 % to about 25 % by weight of the composition , 65 In another embodiment described herein , one or more including each integer within the specified range . In one pharmaceutically acceptable excipients comprise about aspect, one or more solvents comprise about 5 % to about 0 . 0006 % , about 0 .0017 % , about 0 . 1 % , about 0 . 2 % , about US 9 ,867 , 834 B2 25 26 0 . 3 % , about 0 . 4 % , about 0 . 5 % , about 0 .6 % , about 0 . 7 % , about 1 % to about 10 % ; about 5 % to about 15 % ; about 1 % about 0 . 8 % , about 0 . 9 % , about 1 % , about 1 . 1 % , about 1 . 2 % , to about 5 % ; about 10 % to about 20 % ; about 15 % to about about 1 . 3 % , about 1 . 4 % , about 1 . 5 % , about 1 . 6 % , about 20 % ; about 10 % to about 15 % ; or about 1 % to about 5 % by 1 . 7 % , about 1 . 8 % , about 2 % , about 3 % , about 4 % , or about weight of the composition , including each integer within the 5 % by weight of the composition . 5 specified ranges . In one aspect, glycerol comprises about In another embodiment described herein , the one or more 5 % , about 6 % , about 7 . 5 % , about 8 % , about 9 % , about 10 % , film - forming polymers comprise gelatin having a Bloom of about 11 % , about 12 % , about 13 % , about 14 % , about 15 % , about 100 to about 150 and a weight percentage of about 5 % about 16 % , about 17 % , about 18 % , about 19 % , about 20 % , to about 30 % by weight of the composition , including each about 21 % , about 22 % , about 23 % , about 24 % , about 25 % , integer within the specified range . In one embodiment, 10 about 26 % , about 27 % , about 28 % , about 29 % , or about gelatin having a Bloom of about 50 to 150 comprises about 30 % by weight of the composition . 5 % to about 10 % ; about 10 % to about 15 % ; 10 % to about In another embodiment described herein , the one or more 20 % ; about 15 % to about 20 % ; about 20 % to about 25 % ; or pH modifiers comprise citric acid (citrate ) about 0 . 1 % to about 25 % to about 30 % by weight of the composition , about 5 % by weight of the composition , including each including each integer within the specified ranges . In one 15 integer within the specified range . In one embodiment, aspect , gelatin having a Bloom of about 50 to 150 comprises citrate comprises about 0 . 1 % to about 0 . 5 % ; about 0 . 5 % to about 5 % , about 7 . 5 % , about 8 % , about 9 % , about 10 % , about 1 % ; about 0 .25 % to about 0 .75 % ; about 0 .75 % to about 11 % , about 12 % , about 13 % , about 14 % , about 15 % , about 1 % ; about 1 % to about 2 % ; about 0 . 5 % to about 1 . 5 % ; about 16 % , about 17 % , about 18 % , about 19 % , about 20 % , about 0 . 5 % to about 0 .75 % , or about 0 . 25 % to about 0 . 5 % about 25 % , or about 30 % by weight of the composition . 20 by weight of the composition , including each integer within In another embodiment described herein , the one or more the specified ranges . In one aspect, citrate comprises com film -forming polymers comprise a gelatin having a Bloom prise about 0 .1 % , about 0 . 2 % , about 0 .35 , about 0 .4 % , about of about 50 to about 100 and a weight percentage of about 0 . 5 % , about 0 .6 % , about 0 . 7 % , about 0 . 8 % , about 0 . 9 % , 1 % to about 20 % by weight of the composition , including about 1 % , about 1 .2 % , about 1 . 3 % , about 1 . 4 % , about 1. 5 % , each integer within the specified range. In another embodi- 25 about 1 .6 % , about 1. 7 % , about 1. 8 % , about 1. 9 % , about 2 % , ment, gelatin having a Bloom of about 50 to about 100 about 2 . 5 % , about 3 % , about 4 % , or about 5 % by weight of comprises about 1 % to about 5 % ; about 2 .5 % to about 5 % ; the composition . about 5 % to about 10 % ; about 10 % to about 15 % ; about In one embodiment described herein , the one or more 2 . 5 % to about 10 % ; or about 4 . 7 % to about 13 % by weight release modifiers comprise a polyethylene oxide polymer, of the composition , including each integer within the speci - 30 having a molecular weight between 6x10 % and 7x10 MW , fied ranges . In one aspect, gelatin having a Bloom of about at a weight percentage of about 1 % to about 10 % by weight 100 comprises about 1 % , about 2 % , about 2 . 5 % , about 3 % , of the composition , including each integer within the speci about 4 % , about 4 . 7 % , about 5 % , about 6 % , about 7 % , about fied range . In one embodiment, the polyethylene oxide 8 % , about 9 % , about 10 % , about 11 % , about 12 % , about polymer comprises about 0 . 5 % to about 2 % ; about 1 % to 13 % , about 14 % , about 15 % , about 16 % , about 17 % , about 35 about 3 % , about 2 % to about 4 % ; about 2 . 5 % to about 5 % ; 18 % , about 19 % , or about 20 % by weight of the composi - about 0 . 5 % to about 1 % , about 1 % to about 2 % ; about 2 % tion . to about 3 % ; about 3 % to about 4 % ; or about 4 % to about In another embodiment described herein , the one or more 5 % by weight of the composition , including each integer film - forming polymers comprise gelatin hydrolysate at a within the specified ranges . In one aspect, the polyethylene weight percentage of about 0 . 5 % to about 5 % by weight of 40 oxide polymer, having a molecular weightbetween 1 million the composition , including each integer within the specified and 7 million , comprises about 0 . 2 % , about 0 . 5 % , about 1 % , range . In one embodiment, gelatin hydrolysate comprises about 2 % , about 3 % , about 4 % , about 5 % , about 1 . 1 % , about about 0 .5 % to about 1 % ; about 1 % to about 2 .5 % ; or about 1. 2 % , about 1 .3 % , about 1. 4 % , about 1 . 5 % , about 1. 6 % , 0 .5 % to about 2 .5 % by weight of the composition , including about 1 . 7 % , about 1 . 8 % , about 1 . 9 % , about 2 . 2 % , about each integer within the specified ranges. In one aspect, 45 2. 4 % , about 2 .6 % , about 2 .8 % , about 2 . 9 % about 3 . 1 % , gelatin hydrolysate comprises about 0 . 1 % , about 0 . 25 % , about 3 . 2 % , about 3 . 4 % , about 3 . 6 % , about 3 . 8 % , about about 0 . 5 % , about 0 .75 % , about 0 . 9 % , about 1 % , about 4 . 1 % , about 4 . 2 % , about 4 . 4 % , about 4 . 6 % , about 4 . 8 % , 1 .5 % , about 2 % , about 2 . 5 % , about 3 % , about 4 % , or about about 5 . 5 % , about 6 % , about 7 % , about 8 % , about 9 % , or 5 % , by weight of the composition . about 10 % by weight of the composition . In another embodiment described herein , the one or more 50 In another embodiment described herein , the sweetener film - forming polymers comprise partially hydrolyzed gela - comprises maltitol ( e . g . , Lycasin® 80 /55 ) at a weight per tin at a weight percentage of about 0 . 5 % to about 5 % by centage of about 10 % to about 60 % , by weight of the weight of the composition , including each integer within the composition , including each integer within the specified specified range . In one embodiment, the partially hydrolyzed range . In one embodiment, maltitol comprises about 40 % to gelatin comprises about 0 . 5 % to about 1 % ; about 1 % to 55 about 60 % ; about 5 % to about 20 % ; about 30 % to about about 2 . 5 % ; or about 0 . 5 % to about 2 . 5 % by weight of the 45 % by weight of the composition , including each integer composition , including each integer within the specified within the specified ranges . In one embodiment, maltitol ranges . In one aspect , partially hydrolyzed gelatin comprises comprise about 5 % , about 7 . 5 % , about 10 % , about 12 % , about 0 % , 0 . 1 % , about 0 . 25 % , about 0 . 5 % , about 0 .75 % , about 14 % about 16 % , about 18 % , about 20 % , about 22 % , about 0 . 9 % , about 1 % , about 1 . 5 % , about 2 % , about 2 .5 % , 60 about 24 % ; about 26 % , about 28 % , about 30 % , about 32 % , about 3 % , about 4 % , or about 5 % , by weight of the about 34 % , about 35 % , about 36 % , about 38 % , about 40 % , composition . about 41 % , about 42 % , about 44 % about 45 % , about 46 % , In another embodiment described herein , one or more about 48 % , about 50 % , about 52 % , about 54 % , about 56 % , plasticizers comprise glycerol at a weight percentage of about 58 % , or about 60 % by weight of the composition . about 5 % to about 30 % by weight of the composition , 65 In another embodiment described herein , the sweetener including each integer within the specified range . In one comprises xylitol ( e . g ., Xylisorb 300® ) at a weight percent embodiment, glycerol comprises about 5 % to about 20 % ; age of about 1 % to about 10 % by weight of the composition , US 9 , 867 , 834 B2 27 28 including each integer within the specified range . In one 0 .2 % , about 0 . 3 % , about 0 .4 % , about 0 . 5 % , about 0 .6 % , embodiment, xylitol comprises about 1 % to about 5 % , about about 0 .7 % , about 0 . 8 % , about 0 . 9 % , or about 1 % by weight 0 . 5 % to about 4 % , about 1 % to about 3 . 5 % ; about 1 . 5 % to of the composition . about 3 % , about 2 . 5 % to about 5 % ; or about 2 . 5 % to about In another embodiment described herein , the second 3 .5 % by weight of the composition , including each integer 5 active pharmaceutical ingredient comprises lidocaine , prilo within the specified ranges. In one aspect , xylitol comprises caine , or a combination thereof, or a pharmaceutically acceptable salt thereof at a weight percentage of about 0 . 5 % about 1 % , about 1. 5 % , about 2 % , about 2. 5 % , about 3 % , to about 10 % by weight of the composition , including each about 3 . 5 % , about 3 . 6 % , about 4 % , about 4 . 3 % , about 4 . 5 % , integer within the specified range . In one embodiment, or about 5 % by weight of the composition . 10 fluticasone comprises about 0 .5 to about 1 % ; about 1 % to In another embodiment described herein , the sweetener about 1 . 5 % ; about 1 % to about 3 % ; about 1 % to about 5 % ; comprises sucralose comprise a weight percentage of about about 2 % to about 5 % ; about 3 % to about 5 % ; about 4 % to 0 . 1 % to about 2 % by weight of the composition , including about 5 % ; about 0 .5 % to about 5 % ; about 2. 5 % to about 5 % ; each integer within the specified range . In one embodiment, or about 0 . 5 % to about 2 . 5 % by weight of the composition , sucralose comprises about 0 . 1 % to about 0 . 2 % ; about 0 . 2 % 15 including each integer within the specified ranges . In one to about 0 . 3 % ; about 0 .3 % to about 0 .4 % ; about 0 .25 % to aspect, fluticasone comprises about 0 . 5 % , about 0 .75 % , about 0 . 4 % ; or about 0 . 2 % to about 0 . 5 % by weight of the about 1 % , about 1 . 5 % , about 2 % , about 2 .5 % , about 3 % , composition , including each integer within the specified about 3 . 5 % , about 4 % , about 4 . 5 % , about 5 % , about 6 % , ranges . In one aspect , sucralose comprises about 0 . 2 % , about 7 % , about 8 % , about 9 % , or about 10 % by weight of about 0 .3 % , about 0 .4 % , or about 0 . 5 % by weight of the 20 the composition . composition . In another embodiment described herein , the pharmaceu In one embodiment described herein , the one or more tical composition described herein comprises one or more solubilizing agents comprise polysorbate 80 at a weight optional pharmaceutically acceptable excipients . In one percentage of about 0 . 1 % to about 1 % by weight of the embodiment the excipient comprises an opacifier such as composition , including each integer within the specified 25 titanium dioxide at a weight percentage of about 0 . 2 % to range . In one embodiment, polysorbate 80 comprises about about 2 % , including each integer within the specified range . 0 . 2 % to about 1 % ; about 0 . 3 % to about 0 . 8 % ; about 0 . 3 % to In another embodiment, the excipient comprises one ormore about 0 . 5 % ; about 0 .6 % to about 0 . 8 % ; 0 . 35 % to about coloring agents at a weight percentage of about 0 . 0001 % to 0 .45 % ; or about 0 .65 % to about 0 .75 % by weight of the about 0 .5 % , including each integer within the specified composition including each integer within the specified 30 range . In another embodiment , the excipient comprises one ranges . In one aspect, polysorbate 80 comprises comprise or more flavor at a weight percentage of about 0 . 1 % to about about 0 . 1 % , about 0 . 2 , about 0 . 3 , about 0 . 35 , about 0 . 4 % , 4 % , including each integer within the specified range. In about 0 .45 % , about 0 . 5 % , about 0 . 6 % , about 0 . 7 % , about another embodiment, the pharmaceutical composition com 0 . 8 % , about 0 . 9 % , or about 1 % , by weight of the compo prises a combination of excipients , including opacifiers , sition . 35 coloring agents , or flavors . In another embodiment described herein , the solvent Additional pharmaceutical excipients useful for the phar comprises water at a weight percentage of about 5 % to about maceutical composition as described herein include, for 30 % by weight of the composition , including each integer example , the following : acidifying agents ( acetic acid , gla within the specified range . In another embodiment, water c ial acetic acid , citric acid , fumaric acid , hydrochloric acid , comprises 5 % to about 20 % , about 10 % to about 15 % ; about 40 diluted hydrochloric acid , malic acid , nitric acid , phosphoric 10 % to about 20 % ; about 15 % to about 20 % ; about 15 % to acid , diluted phosphoric acid , sulfuric acid , tartaric acid ) ; about 25 % ; about 15 % to about 30 % ; about 20 % to about alkalizing agents ( ammonia solution, ammonium carbonate , 25 % ; about 20 % to about 30 % ; or about 25 % to about 30 % diethanolamine , diisopropanolamine, potassium hydroxide , by weight of the composition , including each integer within sodium bicarbonate , sodium borate , sodium carbonate , the specified ranges . In one aspect, water comprises about 45 sodium hydroxide , trolamine ) ; antifoaming agents (dimethi 5 % , about 7 . 5 % , about 10 % , about 11 % , about 12 % , about cone , simethicone ) ; antimicrobial preservatives ( benzalko 13 % , about 14 % , about 15 % , about 16 % , about 17 % . about nium chloride , benzalkonium chloride solution , benzetho 18 % , about 19 % , about 20 % , about 21 % , about 22 % , about nium chloride , benzoic acid , benzyl alcohol, butylparaben , 23 % , about 24 % , about 25 % , about 26 % , about 27 % , about cetylpyridinium chloride , chlorobutanol, chlorocresol, 28 % , about 29 % , or about 30 % by weight of the composi - 50 cresol, dehydroacetic acid , ethylparaben , methylparaben , tion . methylparaben sodium , phenol, phenylethyl alcohol, phe In another embodiment described herein , the active phar- nylmercuric acetate , phenylmercuric nitrate , potassium ben maceutical ingredient comprises fluticasone or a pharma - zoate , potassium sorbate , propylparaben , propylparaben ceutically acceptable salt thereof at a weight percentage of sodium , sodium benzoate , sodium dehydroacetate , sodium about 0 . 005 % to about 5 % by weight of the composition , 55 propionate , sorbic acid , thimerosal, thymol) ; antioxidants including each integer within the specified range . In one (ascorbic acid , ascorbyl palmitate , butylated hydroxyani embodiment , fluticasone comprises about 0 . 005 to about sole , butylated hydroxytoluene , hypophosphorous acid , 0 .01 % ; about 0 .01 % to about 0 .05 % ; about 0 .01 % to about monothioglycerol, propyl gallate , sodium formaldehyde sul 0 .025 % ; about 0 .025 % to about 0 . 1 % ; about 0 .05 % to about foxylate , sodium metabisulfite , sodium thiosulfate , sulfur 0 . 1 % ; about 0 .016 % to about 0 .032 % ; about 0 .02 % to about 60 dioxide , tocopherol, tocopherols excipient) ; buffering agents 0 .04 % ; about 0 . 02 % to about 0 . 05 % ; about 0 .01 % to about (acetic acid , ammonium carbonate , ammonium phosphate , 0 .04 % ; or about 0 .02 % to about 0 .04 % by weight of the boric acid , citric acid , lactic acid , phosphoric acid , potas composition , including each integer within the specified sium citrate , potassium metaphosphate , potassium phos ranges . In one aspect , fluticasone comprises about 0 .01 % , phate monobasic , sodium acetate , sodium citrate , sodium about 0 .016 % , about 0 .02 % , about 0 .025 % , about 0 .03 % , 65 lactate solution , dibasic sodium phosphate, monobasic about 0 .032 % , about 0 .04 % , about 0 .05 % , about 0 .06 % , sodium phosphate ) ; chelating agents (edetate disodium , eth about 0 . 07 % , about 0 . 08 % , about 0 . 09 % , about 0 . 1 % , about ylenediaminetetraacetic acid and salts , edetic acid ) ; coating US 9 , 867 , 834 B2 29 30 agents ( sodium carboxymethylcellulose , cellulose acetate , carbonate, dibasic calcium phosphate , tribasic calcium phos cellulose acetate phthalate , ethylcellulose , gelatin , pharma phate , calcium sulfate , microcrystalline cellulose , powdered ceutical glaze , hydroxypropyl cellulose, hydroxypropy1 cellulose , dextrates, dextrin , dextrose excipient, fructose , methylcellulose , hydroxypropyl methylcellulose phthalate , kaolin , lactose, mannitol, sorbitol, starch , pregelatinized methacrylic acid copolymer, methylcellulose , polyvinyl 5 starch , sucrose , compressible sugar, confectioner ' s sugar ) ; acetate phthalate , shellac , sucrose , titanium dioxide , car - tablet disintegrants ( alginic acid , microcrystalline cellulose , nauba wax , microcrystalline wax , zein ) ; colorants (caramel , croscarmellose sodium , crospovidone , polacrilin potassium , red , yellow , black or blends, ferric oxide ) ; complexing sodium starch glycolate , starch , pregelatinized starch ) ; Tab agents ( ethylenediaminetetraacetic acid and salts ( EDTA ) , let and / or capsule lubricants ( calcium stearate , glyceryl edetic acid , gentisic acid ethanolamide, oxyquinoline sul - 10 behenate , magnesium stearate , light mineral oil , sodium fate ); desiccants (calcium chloride , calcium sulfate , silicon stearyl fumarate , stearic acid , purified stearic acid , talc , dioxide ); emulsifying and /or solubilizing agents ( acacia , hydrogenated vegetable oil, zinc stearate ) ; tonicity agent cholesterol, diethanolamine ( adjunct ) , glyceryl monostear - ( dextrose , glycerol, mannitol, potassium chloride , sodium ate , lanolin alcohols , mono - and di- glycerides , monoetha - chloride ) ; vehicle : flavored and /or sweetened (aromatic nolamine (adjunct ) , lecithin , oleic acid ( adjunct ) , oleyl alco - 15 elixir , compound benzaldehyde elixir , iso - alcoholic elixir , hol (stabilizer ), poloxamer , polyoxyethylene 50 stearate , peppermint water, sorbitol solution , syrup , tolu balsam polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil , syrup ) ; vehicle : oleaginous ( almond oil , corn oil , cottonseed polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, oil , ethyl oleate , isopropyl myristate , isopropyl palmitate , polyoxyl 40 stearate , polysorbate 20 , polysorbate 40 , poly - mineral oil, light mineral oil, myristyl alcohol, octyldode sorbate 60 , polysorbate 80 , diacetate , monostearate , sodium 20 canol, olive oil, peanut oil , persic oil, sesame oil , soybean lauryl sulfate , sodium stearate , sorbitan monolaurate , sorbi - oil , squalane ) ; vehicle : solid carrier (sugar spheres ) ; vehicle : tan monooleate , sorbitan monopalmitate , sorbitan monoste sterile ( bacteriostatic water for injection , bacteriostatic arate , stearic acid , trolamine , emulsifying wax ) ; filtering sodium chloride injection ); viscosity - increasing (see sus aids (powdered cellulose , purified siliceous earth ) ; flavors pending agent) ; water repelling agent ( cyclomethicone , and perfumes ( anethole , benzaldehyde , ethyl vanillin , men - 25 dimethicone , simethicone ) ; and / or solubilizing agent (ben thol, methyl salicylate , monosodium glutamate , orange zalkonium chloride , benzethonium chloride , cetylpyri flower oil, peppermint, peppermint oil, peppermint spirit, dinium chloride , docusate sodium , nonoxynol 9 , nonoxynol rose oil, stronger rose water , thymol, tolu balsam tincture , 10 , octoxynol 9 , poloxamer, polyoxyl 35 castor oil , polyoxyl vanilla , vanilla tincture , vanillin ) ; humectants ( glycerol, 40 , hydrogenated castor oil , polyoxyl 50 stearate , polyoxyl hexylene glycol, sorbitol) ; plasticizers ( e . g ., castor oil , 30 10 oleyl ether , polyoxyl 20 , cetostearyl ether, polyoxyl 40 diacetylated monoglycerides , diethyl phthalate , glycerol, stearate , polysorbate 20 , polysorbate 40 , polysorbate 60 , mono - and di- acetylated monoglycerides , propylene glycol, polysorbate 80 , sodium lauryl sulfate , sorbitan monolaurate , triacetin , triethyl citrate ) ; polymers ( e . g ., cellulose acetate , sorbitan monooleate , sorbitan monopalmitate , sorbitan alkyl celluloses, hydroxyalkyl, acrylic polymers and copo monostearate , tyloxapol) . This list is not meant to be exclu lymers ) ; solvents (acetone , alcohol, diluted alcohol , amylene 35 sive , but instead merely representative of the classes of hydrate , benzyl benzoate , butyl alcohol, carbon tetrachlo excipients and the particular excipients that may be used in ride, chloroform , corn oil , cottonseed oil , ethyl acetate , oral dosage forms as described herein . glycerol, hexylene glycol, isopropyl alcohol, methyl alco - In one embodiment described herein , the compositions hol, methylene chloride , methyl isobutylketone , mineral oil , described herein comprise one or more active pharmaceu peanut oil , propylene carbonate , sesame oil, water for injec - 40 tical ingredients . In one embodiment, one active pharma tion , sterile water for injection , sterile water for irrigation , ceutical ingredient is the only active ingredient in the purified water ) ; Sorbents ( powdered cellulose , charcoal, pharmaceutical composition . In another embodiment, one or purified siliceous earth ) ; carbon dioxide sorbents (barium more active pharmaceutical ingredients or drugs are hydroxide lime, soda lime) ; stiffening agents (hydrogenated included in the pharmaceutical composition . In another castor oil, cetostearyl alcohol, cetyl alcohol, cetyl esters 45 embodiment, one or more active pharmaceutical ingredients wax , hard fat, paraffin , polyethylene excipient, stearyl alco - or drugs are included in a solid or semi- solid pharmaceutical hol, emulsifying wax , white wax , yellow wax ) ; Suspending composition comprising a soft lozenge . and/ or viscosity - increasing agents (acacia , agar, alginic acid , In one embodiment, the compositions described herein aluminum monostearate, bentonite , purified bentonite , comprise one or more active pharmaceutical ingredients magma bentonite , carbomer, carboxymethylcellulose cal- 50 useful for treating , retarding the progression of, delaying the cium , carboxymethylcellulose sodium , carboxymethylcellu - onset of, prophylaxis of, amelioration of, or reducing the lose sodium 12 , carrageenan , microcrystalline and car- symptoms of esophagitis , eosinophilic esophagitis , esopha boxymethylcellulose sodium cellulose , dextrin , gelatin , guar geal inflammation , acid reflux, dysphagia , odynophagia , gum , hydroxyethyl cellulose , hydroxypropyl cellulose , ulcers, heart burn , chest pain , abdominal pain , nausea , hydroxypropyl methylcellulose , magnesium aluminum sili- 55 vomiting, coughing, sore throat, decrease in appetite or cate , methylcellulose , pectin , polyethylene oxide , polyvinyl failure to thrive . alcohol, povidone, alginate , silicon dioxide , colloidal silicon In one embodiment described herein , the active pharma dioxide , sodium alginate , tragacanth , xanthum gum ) ; sweet - ceutical ingredient comprises one or more corticosteroids . In ening agents ( aspartame, dextrates , dextrose , excipient dex - one embodiment, the one or more corticosteroids include but trose , fructose , mannitol, saccharin , calcium saccharin , 60 are not limited to alclometasone , amcinonide , beclometa sodium saccharin , sorbitol, solution sorbitol, sucrose, com - sone , betamethasone , budesonide , ciclesonide , clobetasol, pressible sugar , confectioner ' s sugar, syrup ) ; tablet binders clobetasone, clocortolone , cloprednol, cortivazol, deflaza ( acacia , alginic acid , sodium carboxymethylcellulose , cort, deoxycorticosterone , desonide desoximetasone , dex microcrystalline cellulose , dextrin , ethylcellulose , gelatin , amethasone , diflorasone , diflucortolone , difluprednate, flu liquid glucose , guar gum , hydroxypropyl methylcellulose , 65 clorolone , fludrocortisone, fludroxycortide , flumetasone, methylcellulose , polyethylene oxide , povidone , pregelati - flunisolide , , fluocinonide , fluocortin , nized starch , syrup ) ; tablet and /or capsule diluents ( calcium fluocortolone , fluorometholone, fluperolone , fluticasone, US 9 ,867 , 834 B2 31 32 fluticasone propionate , fluprednidene, formocortal , halcino - these factors are determined by those of skill in the medical nide , halometasone, hydrocortisone aceponate , hydrocorti - and pharmaceutical arts in view of the present disclosure . sone buteprate , hydrocortisone butyrate , loteprednol, In one embodiment described herein the pharmaceutical medrysone, meprednisone , methylprednisolone, methyl - composition comprises one or more corticosteroids com prednisolone aceponate , mometasone furoate , parametha - 5 prising a therapeutically effective dose . A therapeutically sone, prednicarbate , prednisone , prednisolone , pred effective dose comprises an amount of one or more corti costeroids that results in a degree of amelioration of symp nylidene, rimexolone, tixocortol, triamcinolone and toms or inflammation relative to the status of such symptoms ulobetasol, or combinations thereof, pharmaceutically or inflammation prior to treatment. In one embodiment, the acceptable salts or esters thereof. me 10 amount of one or more corticosteroids used in a composition In one embodiment described herein , the active pharma or in a method described herein is from about 7 ug /kg to ceutical ingredient comprises one or more corticosteroid , about 70 ug /kg of body mass per day. including but not limited to , fluticasone , budesonide , pred In one embodiment, the amount of corticosteroid used in nisone , or combinations thereof. In another aspect, the active a method , in a composition , or in a dose of a composition pharmaceutical ingredient comprises budesonideonide . In one 15 described herein comprises about 500 ug to about 2 mg, 500 aspect the active pharmaceutical ingredient comprises flu ug to about 1 mg, about 1 mg to about 2 mg , about 1 mg, ticasone. In another aspect, the active pharmaceutical ingre about 3 mg, about 1 mg to about 4 mg, about 1 mg to about dient comprises fluticasone propionate . 5 mg, or any amount suitable . In one embodiment, the In another embodiment, the active pharmaceutical ingre - dosage is provided in a volume that treats the esophagus dients described herein may comprise pharmaceutically 20 with an effective amount . In one embodiment the effective acceptable salts of any of the above mentioned active drug amount is about 0 . 5 mg, about 1 mg, about 1 . 5 mg, or about substances . The term “ pharmaceutically acceptable salts ” of 2 mg of a corticosteroid . an active pharmaceutical ingredient includes alkali metal The dosage may, for example , be administered at least salts such as , for example , sodium or potassium salts , once a day, e . g . , in five , four, three , two, or one dose a day . alkaline earth metal salts such as , for example , calcium and 25 In one illustrative example , the dose is provided once a day. magnesium salts , and salts with organic or inorganic acid In specific embodiments , administration of any composition such as, for example , hydrochloric acid , hydrobromic acid , described herein ( e. g ., for the treatment of gastrointestinalor nitric acid , sulfuric acid , phosphoric acid , citric acid , formic esophageal inflammation including eosinophilic esophagi acid , maleic acid , succinic acid , tartaric acid , methanesul- tis ) is once a day . In other specific embodiments, adminis phonic acid , toluenesulphonic acid etc . In another embodi- 30 tration ( e . g . , for the treatment of gastrointestinal or esopha ment, the active pharmaceutical ingredient may also be in geal inflammation including eosinophilic esophagitis ) is the form of pharmaceutically acceptable salts , uncharged or b . i. d . In still other embodiments , administration ( e . g ., for the charged molecules , molecular complexes, solvates , or anhy - treatment of gastrointestinal or esophageal inflammation drates thereof, and, if relevant, single isomers , enantiomers, including eosinophilic esophagitis ) is t. i .d . In another racemic mixtures , or mixtures thereof . 35 embodiment, administration ( e . g . , for the treatment of gas In another embodiment, the active pharmaceutical ingre- trointestinal or esophageal inflammation including eosino dient may be in any of its crystalline, polymorphous, semi- philic esophagitis ) is q .i . d . In another embodiment , the dose crystalline , amorphous or polyamorphous forms or mixtures is administered at night. In another aspect, the dose is thereof. administered about 30 minutes prior to bed , with no food or In one embodiment described herein , the pharmaceutical 40 water given after administration of the compositions herein . composition is a soft lozenge dosage form . The soft lozenge In another embodiment, the dose is administered prior to comprises a solid or semisolid matrix encapsulated by a bedtime, wherein after administration of the composition , gelatinous shell . In one embodiment described herein , the the patient or individual is in a substantially supine position soft lozenge dosage form comprises about 0 .5 mg or 1 . 0 mg for at least 30 minutes, at least 1 hour, at least 2 hours , at of corticosteroid per dose . This comprises 0 .016 % or 45 least 4 hours , at least 8 hours , about 30 minutes to about 8 0 .032 % by weight of a 3162 . 7 mg soft lozenge dosage form hours, about 30 minutes to about 4 hours , about 1 hour to as described herein . Assuming an average body mass of 70 about 8 hours , or , about 1 hour to about 6 hours . In some kg , the soft lozenge dosage formsprovide a dose of 7 . 14 ug embodiments provided herein , the dose is administered prior corticosteroid per kg body mass (ug /kg ; 0 . 5 mg dose ) or 14 . 3 to the individual being in a substantially supine position for ug /kg ( 1 . 0 mg dose ) . 50 at least 30 minutes , at least 1 hour, at least 2 hours , at least In another embodiment described herein , the pharmaceu - 4 hours , at least 8 hours , about 30 minutes to about 8 hours , tical composition is a liquid dosage form . The liquid dosage about 30 minutes to about 4 hours, about 1 hour to about 8 form can comprise a suspension , syrup , elixir or concentrate . hours , or, about 1 hour to about 6 hours . In specific embodi In one embodiment described herein the liquid dosage from ments , a corticosteroid or composition is administered comprises about 0 . 5 mg or 1 .0 mg of corticosteroid per dose . 55 according to any method described herein , wherein admin A typical dose of a liquid dosage form comprises about 1 mL i stration of the corticosteroid or composition is once a day , to about 20 mL of liquid , including all integers within the no more than once a day, more than once a day, twice a day, specified range . two to four times a day, three times a day, or four times a day . The exact dosage will depend upon the route of admin - In some embodiments , the administration of the corticoster istration , the form in which the composition is administered , 60 oid or composition provided herein is administered at night , the subject to be treated , the age , body weight/ height of the e . g . , not more than once a day at night. subject to be treated , and the preference and experience of In one embodiment described herein , the corticosteroid is the attending physician . In certain embodiments , the optimal present in a pharmaceutical composition described herein in concentration of the corticosteroid in the composition any effective amount . In some embodiments , an effective depends upon the specific corticosteroid used , the charac - 65 amount is an amount sufficient to reduce inflammation or teristics of the patient, and the nature of the inflammation for symptoms of inflammation associated with an allergic or which the treatment is sought. In various embodiments, caustic inflammatory disorder or condition of the gastroin US 9 , 867 , 834 B2 33 34 testinal tract ( e . g ., the esophagus ) as compared to the level 30 seconds to about 2 minutes , about 1 minute to about 5 of inflammation or symptoms of inflammation associated minutes , about 5 minutes to about 10 minutes, about 10 with an inflammatory disease prior to administration of the minutes to about 15 minutes , about 10 minutes to about 20 effective amount. In certain embodiments , effective amount minutes , about 15 minutes to about 20 minutes, about 20 is an amount sufficient to maintain a reduction in inflam - 5 minutes to about 30 minutes, about 20 minutes to about 45 mation or symptoms of inflammation achieved in any man - minutes , about 30 minutes to about 45 minutes , about 30 ner including , but not limited to , by the administration of an minutes to about 1 hour, about 45 minutes to about 60 effective amount sufficient to achieve such a reduction in minutes , about 45 minutes to about 75 minutes, about 60 inflammation . minutes to about 75 minutes , or about 60 minutes to about In one embodiment, the effective amount is about 0 . 5 mg 10 90 minutes. to about 5 mg, about 0 . 5 mg to about 1 mg, about 0 . 5 mg to In another embodiment described herein , the dosage form about 2 mg, about 0 . 5 mg to about 3 mg ; about 0 . 5 mg to dissolves in vitro in aqueous media at neutral pH over a about 4 mg; about 1 mg to about 5 mg, about 1 mg to about period of time comprising about 30 seconds to about 2 2 mg, about 1 mg to about 3 mg, about 1 mg to about 4 mg, minutes , about 1 minute to about 5 minutes , about 5 minutes about 2 mg to about 3 mg, about 2 mg to about 4 mg, about 15 to about 10 minutes , about 10 minutes to about 15 minutes , 2 mg to about 5 mg, about 3 mg to about 4 mg, about 3 mg about 10 minutes to about 20 minutes, about 15 minutes to to about 5 mg, or about 4 mg to about 5 mg. about 20 minutes , about 20 minutes to about 30 minutes , In another embodiment, the effective amount of corticos - about 20 minutes to about 45 minutes , about 30 minutes to teroid is about 0 .25 mg, about 0 . 5 mg, about 1 mg. , about 1 .5 about 45 minutes , about 30 minutes to about 1 hour, about mg. , about 2 mg. , about 2 . 5 mg. , about 3 mg , about 3 . 5 mg , 20 45 minutes to about 60 minutes , about 45 minutes to about about 4 mg, about 4 . 5 mg, or about 5 mg, of corticosteroid . 75 minutes , about 60 minutes to about 75 minutes , or about In another embodiment , the corticosteroid is present in a 60 minutes to about 90 minutes . pharmaceutical composition at any concentration suitable In another embodiment , the dosage form has an in vitro for providing a therapeutically effective amount of corticos - dissolution rate in a neutral aqueous media ( e . g . , pH 7 . 4 ) of teroid to a surface of the gastrointestinal tract ( e . g . , the 25 about 5 % to about 50 % after about 2 minutes to about 40 surface of the esophagus ), e . g ., at a dosage of about 0 .01 mg minutes , including each integer within the specified ranges to about 2 mg of composition . In another embodiment, the of dissolution and time. In one aspect, the in vitro dissolution corticosteroid is present in a pharmaceutical composition at rate in a neutral aqueous media ( e . g ., PH 7 . 4 ) is about 50 % a dose of about 0 . 5 mg to about 1 mg, about 0 . 5 mg to about after about 2 minutes. In one aspect, the in vitro dissolution 1. 5 mg, about 0 . 5 mg to about 2 mg, about 0 . 5 mg to about 30 rate in a neutral aqueous media ( e . g ., pH 7 . 4 ) is about 50 % 2 . 5 mg, about 0 . 5 mg to about 3 mg, about 0 . 5 mg to about after about 2 . 5 minutes . In one aspect, the in vitro dissolu 3 . 5 mg, about 0 . 5 to about 4 mg, about 0 . 5 to about 4 . 5 mg, tion rate in a neutral aqueous media ( e . g ., pH 7 . 4 ) is about or about 0 . 5 mg to about 5 mg. In another embodiment, the 50 % after about 5 minutes . In one aspect , the in vitro corticosteroid is present in a pharmaceutical composition at dissolution rate in a neutral aqueous media ( e . g . , pH 7 . 4 ) is a dose of about 0 . 5 mg to about 1 mg. In another embodi- 35 about 50 % after about 7 . 5 minutes . In one aspect , the in vitro ment, any composition described herein comprises an dissolution rate in a neutral aqueous media ( e . g . , pH 7 . 4 ) is amount or dose of corticosteroid sufficient to provide about about 50 % after about 10 minutes . In one aspect, the in vitro 0 . 5 mg to about 5 mg of corticosteroid per day , about 0 . 5 mg dissolution rate in a neutral aqueous media ( e . g ., pH 7 . 4 ) is to about 2 mg of corticosteroid per day, about 1 mg to about about 50 % after about 12 . 5 minutes. In one aspect , the in 2 mg of corticosteroid per day , about 2 mg to about 3 mg of 40 vitro dissolution rate in a neutral aqueous media ( e . g . , pH corticosteroid per day, about 3 mg to about 4 mg of corti - 7 . 4 ) is about 50 % after about 15 minutes . In one aspect, the costeroid per day , about 4 mg to about 5 mg of corticosteroid in vitro dissolution rate in a neutral aqueous media ( e . g ., pH per day , or about 5 mg of corticosteroid per day. 7 . 4 ) is about 50 % after about 20 minutes. In one aspect , the In another embodiment described herein , the therapeuti - in vitro dissolution rate in a neutral aqueous media ( e . g . , pH cally effective dose is about 2 mg of corticosteroid per day , 45 7 . 4 ) is about 50 % after about 25 minutes . In one aspect , the administered b . i . d or q . i . d . in vitro dissolution rate in a neutral aqueous media ( e . g . , pH In another embodiment described herein , the dosage form 7 . 4 ) is about 50 % after about 30 minutes . can be administered , for example , 1x , 2x , 3x , 4x , 5x , 6x , 7x , In another embodiment described herein , the dosage form or 8x , per day . One or more dosage form can be adminis - releases the active ingredient over a period of time com tered , for example , for 1 , 2 , 3 , 4 , 5 , 6 , 7 days , or even longer . 50 prising about 30 seconds to about 2 minutes , about 1 minute One or more dosage forms can be administered , for to about 5 minutes , about 5 minutes to about 10 minutes , example , for 1 , 2 , 3 , 4 weeks , or even longer. One or more about 10 minutes to about 15 minutes , about 10 minutes to dosage forms can be administered , for example , for 1 , 2 , 3 , about 20 minutes , about 15 minutes to about 20 minutes , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11, 12 months, or even longer. One or about 20 minutes to about 30 minutes , about 20 minutes to more dosage forms can be administered until the patient, 55 about 45 minutes , about 30 minutes to about 45 minutes , subject, mammal, mammal in need thereof, human , or about 30 minutes to about 1 hour , about 45 minutes to about human in need thereof, does not require treatment, prophy - 60 minutes , about 45 minutes to about 75 minutes , about 60 laxis , or amelioration of any disease or condition such as , for minutes to about 75 minutes , or about 60 minutes to about example , inflammation or pain . In some aspects, the dosage 90 minutes . form may be co - administered with other pharmaceutical 60 In another embodiment described herein , the dosage form compositions until the patient, subject, mammal, mammal in is in contact with the oral and esophageal mucosa for a need thereof, human , or human in need thereof, does not period of time comprising about 30 seconds to about 45 require treatment , prophylaxis , or amelioration of any dis minutes, including all integers within the specified range. In ease or condition including but not limited to inflammation one aspect, the dosage form is in contact with the oral and or pain . 65 esophagealmucosa for a period of time comprising about 30 In another embodiment described herein , the dosage form seconds , about 1 minutes , about 2 minutes, about 3 minutes , dissolves intra - orally over a period of time comprising about about 4 minutes, about 5 minutes, about 6 minutes, about 7 US 9 , 867 , 834 B2 35 36 minutes , about 8 minutes, about 9 minutes , about 10 min promoting health of one or more of esophageal , oral, or utes, about 11 minutes , about 12 minutes , about 15 minutes , buccal inflammation , eosinophilic esophagitis , oral lichen about 20 minutes , about 25 minutes, about 30 minutes, about planus, aphthous stomatitis , odynophagia , acid reflux , dys 35 minutes, about 40 minutes , about 45 minutes, about 50 phagia , oral, esophageal or peptic ulcers , heart burn , chest minutes, about 55 minutes, about 60 minutes, about 65 5 pain , abdominal pain , nausea , vomiting , coughing , sore minutes, about 70 minutes, about 75 minutes, about 80 throat, decrease in appetite , or failure to thrive , comprising minutes, about 85 minutes , about 90 minutes, or even longer. administering to a subject in need thereof an oral pharma In another embodiment described herein , the dosage form ceutical composition suitable for chewing , sucking, or buc is in contact with the oral and esophageal mucosa for a cal dissolution as described herein . period of time comprising at least about 30 seconds to about 10 Another embodiment described herein is a topical, non 45 minutes , including all integers within the specified range . systemic , slow -release pharmaceutical composition suitable In one aspect , the dosage form is in contact with the oral and for chewing, sucking , buccal dissolution or swallowing as esophagealmucosa for a period of time comprising at least described herein for treating a subject suffering from one or about 30 seconds , about 1 minutes , about 2 minutes , about more of oral or esophageal inflammation , eosinophilic 3 minutes , about 4 minutes , about 5 minutes , about 6 15 esophagitis , inflammatory bowel disease involving the minutes, about 7 minutes , about 8 minutes, about 9 minutes , esophagus, oral lichen planus , aphthous stomatitis , Crohn ' s about 10 minutes, about 11 minutes, about 12 minutes , about disease , esophageal inflammation secondary to caustic /irri 15 minutes , about 20 minutes , about 25 minutes , about 30 tant ingestion , recurrent esophageal strictures of any cause minutes , about 35 minutes, about 40 minutes, about 45 and including irritant ingestion , pill - induced esophagitis , minutes, about 50 minutes, about 55 minutes, about 60 20 systemic diseases , congential diseases , epidermolysis minutes, about 65 minutes , about 70 minutes , about 75 bullosa , trauma, or post - surgery inflammation . minutes , about 80 minutes , about 85 minutes, about 90 Another embodiment described herein is a method for minutes, or even longer. treating a subject suffering from oral or esophageal inflam In another embodiment described herein , the dosage form mation , eosinophilic esophagitis , inflammatory bowel dis is in contact with the oral and esophageal mucosa for a 25 ease involving the esophagus , oral lichen planus , aphthous period of time comprising about 30 seconds to about 90 stomatitis , Crohn ' s disease , esophageal inflammation sec minutes including all integers within the specified range. In ondary to caustic / irritant ingestion , recurrent esophageal one aspect , the dosage form is in contact with the oral and strictures of any cause and including irritant ingestion , esophagealmucosa for a period of time comprising about 30 pill - induced esophagitis , systemic diseases , congential dis seconds to about 2 minutes, about 1 minute to about 5 30 eases, epidermolysis bullosa, trauma, or post - surgery minutes, about 1 minutes to about 10 minutes, about 1 inflammation , including comprising administering to the minute to about 15 minutes , about 1 minute to about 20 subject in need thereof an topical, non -systemic , slow minutes, about 1 minute to about 20 minutes , about 1 minute releasing oral pharmaceutical composition suitable for to about 30 minutes, about 1 minute to about 45 minutes, chewing , sucking , buccal dissolution , or swallowing as about 1 minute to about 1 hour , about 1 minute to about 75 35 described herein . minutes , or about 1 minute to about 90 minutes . Another embodiment described herein is a topical, non In another embodiment described herein , the dosage form systemic , slow -releasing oral pharmaceutical composition is in contact with the oral and esophageal mucosa for a suitable for chewing, sucking, buccal dissolution , or swal period of time comprising at least about 30 seconds to about lowing as described herein for treating disease , allergic , 90 minutes including all integers within the specified range . 40 idiopathic , immunogenic , traumatic , caustic or general In one aspect, the dosage form is in contact with the oral and inflammation of the oral cavity, esophagus, or upper gastro esophageal mucosa for a period of time comprising at least intestinal tract, or a symptom thereof comprising about 0 . 5 about 30 seconds to about 2 minutes , about 1 minute to about mg to about 5 mg of corticosteroid , about 0 . 5 mg to about 5 minutes , about 5 minutes to about 10 minutes , about 10 1 mg of corticosteroid , about 1 mg to about 2 mg of minutes to about 15 minutes, about 10 minutes to about 20 45 corticosteroid , about 2 mg to about 3 mg of corticosteroid , minutes, about 15 minutes to about 20 minutes , about 20 about 3 mg to about 4 mg of corticosteroid , or about 4 mg minutes to about 30 minutes , about 20 minutes to about 45 to about 5 mg of corticosteroid . minutes, about 30 minutes to about 45 minutes , about 30 Another embodiment described herein is a method for minutes to about 1 hour , about 45 minutes to about 60 treating disease , allergic , idiopathic , immunogenic , trau minutes , about 45 minutes to about 75 minutes , about 60 50 matic , caustic or general inflammation of the oral cavity , minutes to about 75 minutes , or about 60 minutes to about esophagus, or upper gastrointestinal tract , or a symptom 90 minutes. thereof , by administering a sufficient amount of a pharma Another embodiment described herein is a topical, non ceutical composition suitable for chewing, sucking , or buc systemic , slow -release oral pharmaceutical composition cal dissolution as described herein to provide about 0 . 5 mg suitable for chewing , sucking, buccal dissolution or swal- 55 to about 5 mg of corticosteroid per day , about 0 . 5 mg to lowing as described herein for treating , retarding the pro - about 1 mg of corticosteroid per day , about 1 mg to about 2 gression of, prophylaxis of, delaying the onset of, amelio mg of corticosteroid per day, about 2 mg to about 3 mg of rating , reducing the symptoms of , or promoting health , corticosteroid per day , about 3 mg to about 4 mg of corti including but not limited to of one or more of esophageal, costeroid per day, or about 4 mg to about 5 mg of corticos oral, or buccal inflammation , eosinophilic esophagitis , oral 60 teroid per day to an individual in need thereof . lichen planus , aphthous stomatitis , odynophagia , acid reflux , Initial treatment may continue , for example , for about 3 dysphagia , oral, esophageal or peptic ulcers, heart burn , days to 2 weeks for an acute condition , or about 4 weeks to chest pain , abdominal pain , nausea , vomiting , coughing , about 16 weeks for a chronic condition , or about 8 weeks to sore throat, decrease in appetite , or failure to thrive . about 12 weeks for a chronic condition . Longer therapy may Another embodiment described herein is a method for 65 also be needed , such as, for example , therapy similar to treating , retarding the progression of, prophylaxis of, delay - chronic therapy for persistent asthma . Patients may , for ing the onset of, ameliorating , reducing the symptoms of, or example , be treated for up to 6 months, or up to one year . US 9 ,867 ,834 B2 37 38 Maintenance treatment can last up to or longer than one year. torezolid , amoxicillin , ampicillin , azlocillin , carbenicillin , Patients may be treated on a maintenance basis or on an as cloxacillin , dicloxacillin , flucloxacillin ,mezlocillin , methi needed basis during a problematic episode , depending on the cillin , nafcillin , oxacillin , penicillin G , penicillin V, pipera severity of the condition . Patients can also be treated on a cillin , temocillin , ticarcillin , amoxicillin / clavulanate , ampi rotating treatment basis , where treatment is provided for a 5 cillin / sulbactam , piperacillin / tazobactam , ticarcillin / period of time and then the patient is taken off of the drug clavulanate , bacitracin , colistin , polymyxin B , ciprofloxacin , for a period before treatment resumes again . When off the enoxacin , gatifloxacin , gemifloxacin , levofloxacin , lom drug, the patient may be given no treatment, treatment with efloxacin , moxifloxacin , nalidixic acid , norfloxacin , ofloxa another medication , or treatment with a reduced dosage . cin , trovafloxacin , grepafloxacin , sparfloxacin , temafloxa Patients may be given treatment with a higher dose of the 10 cin , mafenide, sulfacetamide , sulfadiazine , silver composition until a desired reduced disease state is sulfadiazine , sulfadimethoxine , sulfamethizole , sulfame achieved , and then continued on a lower dose of the com thoxazole , sulfanilimide , sulfasalazine , sulfisoxazole , position . trimethoprim - sulfamethoxazole , sulfamidochrysoidine , Another embodiment described herein comprises admin demeclocycline , doxycycline , minocycline, oxytetracycline , istering one or more of the pharmaceutical compositions or 15 tetracycline, clofazimine , dapsone, capreomycin , cycloser dosage forms described herein in combination with one or ine, ethambutol, ethionamide, isoniazid , pyrazinamide , more additional active pharmaceutical ingredients . Such rifampicin , rifabutin , rifapentine, streptomycin , arsphe combinations may be formulated into a single dosage form namine , chloramphenicol, fosfomycin , fusidic acid , metron or alternatively co -administered as separate dosage forms in idazole , mupirocin , platensimycin , quinupristin /dalfopristin , a treatment regimen . Co - administration may be simultane - 20 thiamphenicol , tigecycline, tinidazole , trimethoprim , or ously or at a different time. Suitable combinations include combinations thereof. administering one or more corticosteroids as described In another embodiment the pharmaceutical compositions herein with one or more antacids, synthetic corticosteroids, described herein can be administered in combination with proton pump inhibitors ( e . g ., H , and H , antagonists ) , B2 elimination or elemental diets . In one embodiment, the adrenergic receptor agonists , anticholinergic bronchodila - 25 subject eliminates milk products, eggs, wheat, soy, peanut/ tors , antihistamines , leukotriene receptor antagonists , inter - tree nuts , and fish / shellfish from the diet for at least 6 weeks . leukin - 5 antibodies , anti - IgE antibodies , anti - TNF antibod - In another embodiment, foods are reintroduced while moni ies , purine analogues , non - steroidal anti - inflamatory drugs toring symptoms. Foods most frequently associated with (NSAIDS ) , one or more antibiotics , or combinations thereof. eosinophilic esophagitis in adults were wheat and milk . In one embodiment the pharmaceutical compositions 30 Gonsalves et al . , Gastroenterology 142 ( 7 ) : 1451 - 1459 described herein can be combined with one or more of (2012 ) , incorporated herein by reference for the specific antacids ( e . g ., calcium hydroxide , magnesium hydroxide, teachings thereof. Elemental diets comprising monomeric alluminum hydroxide , sodium bicarbonate , calcium carbon - food elements , including amino acids , fats , sugars , vitamins, ate , bismuth sub salicylate , or others ; Maalox , Mylanta , and minerals , can also be used in combination with the Gaviscon , Kaopectate , Pepto - Bismol) sucralfate , esomepra - 35 pharmaceutical compositions described herein . Such zole, omeprazole , lansoprazole , dexlansoprazole , esomepra elemental diets can reduce the symptoms of eosinophilic zole, pantoprazole , rabeprazole , ilaprazole , cimetidine , esophagitis . Vashi and Hirano , Curr. Opin . Gastroenterol. ranitidine , famotidine , lafutidine , nizatidine, roxatidine, 29 ( 4 ) :407 -415 ( 2013 ) , incorporated herein by reference for tiotidine , salmeterol, albuterol, aclidinium , ipratropium , the specific teachings thereof. tiotropium , umeclidinium , acrivastine, azelastine , bilastine , 40 In another embodiment, the pharmaceutical composition brompheniramine, buclizine , bromodiphenhydramine , car - may contain one or more active pharmacetical ingredients . binoxamine , chlorpromazine, cyclizine , chlorphenamine , For example, the pharmaceutical composition may contain chlorodiphenhydramine , clemastine, cyproheptadine, dex one or more corticosteroids and one or more topical anes brompheniramine , dexchlorpheniramine , dimenhydrinate , thetics such as lidocaine, prilocaine , or a eutectic mixture of dimetindene , diphenhydramine , doxylamine, ebastine , 45 idocaine /prilocaine , at a concentration of about 2 % to about embramine , fexofenadine , hydroxyzine, loratadine , 5 % of anesthetic by weight of the total pharmaceutical meclozine , mirtazapine , olopatadine , orphenadrine , phenin - composition . Such pharmaceutical compositions may be damine pheniramine , phenyltoloxamine , promethazine, que used for treating pain associated with oral or esophageal tiapine , rupatadine , tripelennamine , triprolidine , clobenpro - inflammation , including but not limited to infection , trauma, pit, ciproxifan , conessine, thioperamide, montelukast , 50 post - surgical inflammation , oral lichen planus , or other zafirlukast, pranlukast, mepolizumab , reslizumab , omali - painful inflammatory condition or disorder . zumab , infliximab , azathioprine , 6 -mercaptopurine , thiogua - Another embodiment described herein is a process of nine , aspirin (acetylsalicylic acid ), ibuprofen , naproxen , manufacturing pharmaceutical compositions comprising the ketoprofen , celecoxib , diclofenac, amikacin , gentamicin , soft lozenges as described herein . The process includes kanamycin , neomycin , netilmicin , tobramycin , paromomy- 55 preparing the matrix fill composition is prepared by com cin , streptomycin , spectinomycin , geldanamycin , herbimy. bining gelatin , glycerol, and water and maintaining the cin , rifaximin , loracarbef, ertapenem , doripenem , imipenem / mixture and adding maltitol syrup to create a fill gel solu cilastatin , meropenem , cefadroxil , cefazolin , cefalotin , tion ; separately , combining water , xylitol, sucralose , and cefalexin , cefaclor , cefamandole , cefoxitin , cefprozil , cefu - citric acid together to create a fill sweetener solution ; roxime , cefixime, cefdinir , cefditoren , cefoperazone, cefo - 60 separately , combining the active pharmaceutical ingredient taxime , cefpodoxime , ceftazidime, ceftibuten , ceftizoxime, (API ) and polysorbate 80 ; combining the API and polysor ceftriaxone , cefepime, ceftaroline fosamil, ceftobiprole , tei- bate 80 with the fill sweetener solution to create an API coplanin , vancomycin , telavancin , dalbavancin , oritavancin , solution ; combining the API solution and the fill gel solu clindamycin , lincomycin , daptomycin , azithromycin , tion ; further mixing the combined API and fill gel solution clarithromycin , dirithromycin , erythromycin , roxithromy - 65 at least about 65° C . ; slowly introducing solid polyethylene cin , troleandomycin , telithromycin , spiramycin , aztreonam , oxide into the combined API and fill gel solution and mixing furazolidone , nitrofurantoin , linezolid , posizolid , radezolid , and deaerating at least about 65° C . creating a matrix fill US 9 ,867 , 834 B2 39 40 composition . The gel mass is prepared by combining gela resistant” refers to a packaging of any kind that readily tins, glycerol, and water and maintaining the mixture at least displays or allows an individual to observe any physical about 65° C . ; adding maltitol syrup to create a shell gel interference or manipulation of said packaging . The tamper solution ; separately, combining water, xylitol, sucralose , and evident packaging provides reasonable evidence to consum citric acid together to create a shell sweetener solution ; 5 ers that tampering has occurred . The tamper evident pack combining the shell sweetener solution and shell gel solution aging additionally contains appropriate labelling statements and mixing the combined shell sweetener and shell gel describing the features and evidences of the tamper evident solution at least about 65° C . to create a gel mass . The soft packaging . In one aspect, the tamper evident packaging lozenge is prepared by casting the gel mass into shell films comprises : bottles , film wrappers, blister or strip packs, or ribbons using heat -controlled drums or surfaces; and 10 bubble packs, heat shrink bands or wrappers , foil, paper , or injecting the matrix fill solution between the shell ribbons, plastic pouches , container mouth inner seals , tape seals , and creating soft lozenges using rotary die technology . breakable caps, sealed metal tubes or plastic heat - sealed Rotary die encapsulation may be performed using an appa tubes , sealed cartons , aerosol containers , cans including ratus as described in U . S . Pat . Nos . 5 , 459 , 983 ; 5 , 146 ,730 ; metal and composite materials , or any combination thereof. and 6 ,482 ,516 , each of which are incorporated by reference 15 The packaging may also contain instructions for prescribing , herein for such teachings . instructions for use , warnings , or other appropriate informa Another embodiment described herein includes a process tion . of manufacturing soft lozenges comprising the pharmaceu It will be apparent to one of ordinary skill in the relevant tical compositions as described herein . The process includes art that suitable modifications and adaptations to the com preparing a gel mass composition comprising one or more 20° positions , formulations, methods, processes , and applica polymers , one or more plasticizers, one or more pH modi tions described herein can be made without departing from fiers , one or more solvents , one or more active pharmaceu - the scope of any embodiments or aspects thereof. The tical ingredients , and appropriate flavorings , sweeteners , compositions and methods provided are exemplary and are coloring agents , or other excipients ; casting the gel mass into not intended to limit the scope of any of the specified films or ribbons using heat - controlled drums or surfaces , and 25 embodiments . All of the various embodiments , aspects , and manufacturing a soft capsule comprising a matrix fill using options disclosed herein can be combined in any and all rotary die technology . The thickness of the films or ribbons variations or iterations . The scope of the compositions, that form the soft lozenge is from about 0 .010 inches formulations, methods , and processes described herein ( ~ 0 . 254 mm ) to about 0 . 050 inches ( ~ 1 . 27 mm ), including include all actual or potential combinations of embodiments , all integers within the specified range . The shell thickness 30 aspects , options, examples, and preferences herein described . The exemplary compositions and formulations can be about 0 .010 inch (20 .254 mm ), about 0 .015 inch described herein may omit any component, substitute any ( + 0 .381 mm ) , about 0 .02 in ( 0 .508 mm ) , about 0 .03 in component disclosed herein , or include any component ( ~ 0 . 762 mm ) , about 0 .04 in ( ~ 1 .02 mm ), or about 0 .05 in disclosed elsewhere herein . The ratios of the mass of any ( - 1 . 27 mm ). In one embodiment, the thickness is about 0 . 02 component of any of the compositions or formulations inches ( ~ 0 . 508 mm ) to about 0 .040 inches (~ 1 .02 mm ). In 35 disclosed herein to the mass of any other component in the one embodiment , the shell thickness is about 0 .028 inches formulation or to the total mass of the other components in ( - 0 .711 mm ) . In another embodiment, the shell thickness is the formulation are hereby disclosed as if they were about 0 .033 inches ( ~ 0 .838 mm ). In another embodiment, expressly disclosed . Should themeaning of any terms in any the shell thickness is about 0 .038 inches ( ~ 0 . 965 mm ) . In of the patents or publications incorporated by reference some embodiments , the fill of the soft lozenge can comprise 40 conflict with the meaning of the terms used in this disclo the same components of the “ shell ” and can be injected into sure , the meanings of the terms in this disclosure are the “ shell ” to form a uniform soft lozenge . In other embodi controlling. Furthermore, the foregoing discloses and ments , the shell can have a different formulation as compare describes exemplary embodiments . All patents and publica to the fill . tions cited herein are incorporated by reference herein for In another embodiment described herein , the soft lozengeGe 1645 "the le specific teachings thereof. comprises an outer dimension from about 2 oval to about 30 oval including all iterations of typical soft capsule sizes EXAMPLES within the specified range ( e . g . , 2 oval, 3 oval, 4 oval, 5 oval, Example 1 6 oval, 7 oval , 8 oval, 10 oval, 12 oval , 16 oval , 20 , or 30 oval ). In another embodiment described herein , the soft 50 Soft Lozenge Compositions lozenge comprises an outer dimension from about 2 round to Exemplary soft lozenges were prepared by rotary die about 28 round including all iterations of capsule size within encapsulation using the respective fill and shell composi the specified range ( e . g ., 2 round , 3 round , 4 round , 5 round. tions shown in Tables 7 - 8 . The weight of the fill is 2000 mg 6 round , 7 round , 8 round , 10 round , 12 round , 16 round, 20 and the shell is 1162 . 7 mg . The total weight of the soft round or 28 round ) . In another embodiment described 55 lozenge is 3162 . 7 mg. After drying, the final mass of the soft herein , the soft lozenge comprises an outer dimension from lozenge is about 2800 mg . About 300 - 400 mg of water is about 2 oblong to about 22 oblong including all iterations of evaporated during drying (~ 910 % water lost ). capsule size within the specified range ( e . g ., 2 oblong , 3 oblong , 4 oblong , 5 oblong , 6 oblong , 7 oblong , 8 oblong , 10 TABLE 7 oblong , 11, oblong , 12 oblong , 14 oblong , 16 oblong, 20 60 oblong , or 22 oblong ). See Remington ' s Essentials of Phar Exemplary Soft Lozenge Fill Composition maceutics , Pharmaceutical Press Publishing Company, Lon Weight Percent don , UK , 1st Edition , 2013 ,which is incorporated by refer Ingredient Mass (mg ) ( % ) ence herein for such teachings . Gelatin , 150 Bloom 150 7 . 5 In another embodiment, the pharmaceutical composition 65 Glycerol 150 NN27. 5 described herein is contained and dispensed from a tamper Citric Acid 20 evident packaging . The term “ tamper evident” or “ tamper US 9, 867 ,834 B2 41 42 TABLE 7 - continued TABLE 9 Exemplary Soft Lozenge Fill Composition Exemplary Soft Lozenge Fill Composition Weight Percent Ingredient Mass (mg ) Weight Percent (% ) Ingredient Mass (mg ) Gelatin , 150 Bloom 150 7. 5 Mannitol Syrup 1154 57. 7 Glycerol 150 7 . 5 Xylitol (Xylisorb 300 ® ) 85 4 . 3 Polyethylene Oxide , 7 , 000 ,000 MW , 60 Sucralose 0 . 3 (e .g ., Polyox ® WSR - 303 ) Water 433 21 . 7 Citric Acid 20 Fluticasone 1 . 8 0 . 1 10 Mannitol Syrup 1154 57. 7 Xylitol ( e . g ., Xylisorb 300 ® ) 85 4 . 3 TOTAL 2000 100 % Sucralose 6 0 . 3 Polysorbate 80 ( e . g . , Tween ® 80 ) 14 0 . 7 Water 360 18 Fluticasone propionate 1. 8 0 . 1 TABLE 8 15 TOTAL 2000 100 % Exemplary Soft Lozenge Shell Composition Weight Ingredient Mass (mg ) Percent ( % ) TABLE 10 20 Gelatin , 150 Bloom 219 . 9 18. 9 Exemplary Soft Lozenge Shell Composition Gelatin , 100 Bloom 149 . 9 12 . 9 Gelatin Hydrolysate 27 . 7 2 . 4 Mass Weight Percent Glycerol 264 . 6 22 . 8 Ingredient (mg ) ( % ) Citric Acid , Anhydrous 6 . 3 0 . 5 ne Maltitol (75 % solution ; 163 . 7 14 . 1 Gelatin , 150 Bloom 219 . 9 18 . 9 e . g ., Lycasin ® 80 /55 ) 25 Gelatin , 100 Bloom 149. 9 12. 9 Xylitol ( e . g . , Xylisorb 300 ® ) 29 . 1 2 .5 Gelatin Hydrolysate 27 . 7 2 . 4 Sucralose 2 . 4 0 . 2 Glycerol 264 . 6 22 . 8 Water 286 . 6 24 . 6 Citric Acid , Anhydrous 6 . 3 0 . 5 Titanium Dioxide 12 . 5 1 . 1 Maltitol (75 % solution ; e . g . , 163 . 7 14 . 1 Lycasin ® 80 /55 ) TOTAL 1162. 7 100 % 30 Xylitol (e .g ., Xylisorb 300 ® ) 29 . 1 2 . 5 Sucralose 2 . 4 0 . 2 Water 286 . 6 24 . 6 Example 2 Titanium Dioxide 12 . 5 1 . 1 TOTAL 1162 . 7 100 % Based on the results of solubility and bioavailability 35 testing of the Example 1 formulation (data not shown ) , a second formulation was developed that included a solubi lizing agent comprising polysorbate 80 and release modifier Example 3 comprising a high molecular weight polyethylene oxide to further solubilize and control the release of the active 40 Exemplary soft lozenges can be prepared by rotary die pharmaceutical ingredient. Batches of soft lozenges were encapsulation using the compositions shown in Tables prepared by rotary die encapsulation using the fill and shell 11- 12 . The weight of the fill is 2000 mg and the shell is compositions shown in Tables 9 - 10 . The total weight of the 1162 . 7 mg. The total weight of the soft lozenge is 3162 . 7 soft lozenge was 3162 . 7 mg. After drying, the finalmass of mg . After drying , the finalmass of the soft lozenge is about the soft lozenge was about 2800 mg . About 300 - 400 mg of 45 2800 mg. About 300 -400 mg of water is evaporated during water is evaporated during drying ( ~ 9 - 10 % water lost ) . drying ( ~ 9 - 10 % water lost ) . TABLE 11 Exemplary Soft Lozenge Fill Compositions Weight Percent ( % ) EX1 EX2 EX3 EX4 EX5 EX6 EX EX8 Ingredient

Gelatin , 150 Bloom 7 . 0 10 . 0 9 . 0 8 . 0 9 . 0 10 . 0 4 . 5 11 . 0 Polyethylene Oxide , 7 ,000 , 000 1 . 0 5 .0 2 . 8 3 . 0 4 . 1 4 . 0 4 . 3 5 . 0 MW , ( e . g. , Polyox® WSR -303 ) Glycerol 11. 0 10 . 0 9 . 0 8 .0 7 . 0 66 .. 0 5 . 0 4 .. 0 Citric Acid 5 . 0 4 . 3 3 .5 3 . . 0 2 .0 1 . . 5 5 1 . 0 0 . 5 Maltitol ( 75 % solution ; e .g . , 34. 7 24 . 7 45 . 3 54 . 0 58 . 2 2 60 . 9 7070 . 2 66 . 3 Lycasin ® 80 /55 ) Xylitol ( e . g . , Xylisorb 300 ® ) 10 . 0 9 . 0 6 . 0 55 .. 55 4 . 8 3 . 5 2 . 0 1 . 0 Sucralose 0 . 1 2 . 0 0 . 6 1 . 00 1 . 55 1 . 88 1 . 8 2 . 1 Polysorbate 80 ( e . g . , Tween ® 80 ) 1 . 2 1 . 0 0 . 8 0 . 5 0 . 4 0 . 33 0 . 3 0 . 1 US 9 ,867 , 834 B2 43 44 TABLE 11- continued Exemplary Soft Lozenge Fill Compositions

Weight Percent ( % ) EX1 EX2 EX3 EX4 EX5 EX6 EX7 EX8 Water 30 .0 34 .0 23. 0 17. 0 13. 0 12. 0 11. 0 10. 0 Fluticasone propionate 0 .. 03 0 .. 05 0 . 08 0 . 01 0 . 10 10 0 .. 05 0 . 04 04 0 . .03 TOTAL 100. 0 100. 0 100 .0 100. 0 100 . 0 100. 0 100. 0 100 . 0 Subcomponent Totals

Film - forming Polymer 77 . 0 010 . 0 9 9 . 0 8 . 0 9 .0 010 . 0 4 4 . 5 1111 . 0 Release Modifier 1 . 0 5 . 0 22 . 8 3 . 0 4 . 1 4 . 0 44 . 3 5 .0 Plasticizer 11. 0 10 . 0 99 .. 0 8 . 0 0 7 . 0 66 .. 0 5. . 0 4 . 0 pH Modifier 5 . 0 4 . 3 3 . 5 5 3 . 00 2 . 0 1 . 5 5 1 . 0 0 . 5 Sweetener 44 . 8 35 . 7 51. 9 60 . 5 64 . 4 66 . 2 74 . 0 69 . 4 . Solubilizing Agent 1 . 2 1 .. 0 00 .. 8 0 . 5 0 .4 0 . 3 0 . 3 20 . 1 Solvent 30 . 0 34 . 0 23 . 0 17 . 0 13 . 0 12 . 0 11. 0 10 . 0 ??? 0 . 0 0 . 1 0 . 1 0 . 0 Relational Ratios

API: Total Fill Composition 2 . 5E - 4 5 .0E - 4 7 . 5E - 4 1 .0E - 4 1 .0E - 4 5 .0E - 4 4 . 0E - 4 2 .5E - 4 PEO :Gelatin 00 . . 14 14 0 . 50 0 . 31 31 0 . 38 38 0 .. 46 0 .. 40 40 0 . 94 0 . 45 PEO :Plasticizer 00 .09 09 0 . 50 0 . 31 0 . 38 0 . 59 00 .67 67 0 . 85 11 . 25

TABLE 12 Exemplary Soft Lozenge Shell Compositions

Weight Percent ( % ) EX1 EX2 EX3 EX4 EX5 EX6 EX EX8 Ingredient Gelatin , 150 Bloom 20 . 0 20 . 0 19 . 0 17 . 0 15 . 0 12 . 0 11 . 0 10 . 0 Gelatin , 100 Bloom 10 . 0 12 . 0 14 . 0 12 . 0 14 . 0 14 . 0 17 . 0 10 . 0 Gelatin hydrolysate 0 . 5 0 . 5 1 . 0 2 . 0 3 . 0 4 . 0 5 . 0 5 . 0 Glycerol 10 . 0 12 . 0 15 . 0 17 . 0 22 . 0 25 . 0 27 . 0 30 . 0 Maltitol (75 % solution ; e . g . , 5 .0 4 . 5 4 . 0 3 . 0 2 . 5 1 . 0 0 . 8 0 . 1 Lycasin ® 80 /55 ) Citric Acid 5 .0 10 . 0 9 .2 14 . 5 12 .7 18 . 9 19 . 3 20 . 3 Xylitol 10 .0 9 . 0 7 . 0 5 . 0 3 . 0 1. 0 1 . 5 8. 0 Sucralose 2 . 5 2 . 0 1 . 8 1 . 5 1 . 0 0 . 1 0 .4 0 . 1 Water 35 . 0 29 . 0 27 .0 26 . 0 24 . 0 22. 0 15 . 0 12 . 0 Titanium dioxide 0 .0 0 . 0 00 . 1 0 . 5 0 . 8 1 . 0 1 . 5 2 . 5 Coloring (FD & C dyes ) 0 .020 0 .0100 .015 0 .020 0 .020 0 .010 0 .015 0 .020 Flavoring ( e . g ., cherry , orange ) 2 . 0 1 . 0 2 . 0 1 . 5 2 . 0 1 . 0 1 . 5 2 . 0 TOTAL 100 . 0 100 . 0 100 .0 100 . 0 100 . 0 100 . 0 100 . 0 100 . 0 Subcomponent Totals

Film - forming Polymers 30 .5 32. 5 34 . 0 31. 0 32 . 0 30 . 0 33 . 0 25 . 0 Plasticizer 10 . 0 12 . 0 15 . 0 17 . 0 22 . 0 25 . 0 27 . 0 30 . 0 pH Modifier 5 . 0 4 . 5 4 . 0 3 . 0 2 . 5 1 . 0 0 . 8 0 . 1 Total Sweetener 17 . 5 21 . 0 17 . 9 21. 0 16 . 7 20 . 0 21. 2 28 . 4 Solvent 35 .0 29 . 0 27 . 0 26 . 0 24 . 0 22 . 0 15 .0 12 . 0 Excipients 2 . 0 1 .0 0 2 . 1 2 . . 0 2 . 8 8 2 . 0 33 . 00 4 . 5 5 Relational Ratios Gelatin : Plasticizer 3 . 1 2 . 7 2 . 3 1 . 8 1 .5 1 . 2 1. 2 0 .8 US 9 , 867, 834 B2 45 46 Example 4 the fill is 2000 mg and the shell is 1162 . 7 mg. The total weight of the soft lozenge is 3162 . 7 mg. After drying , the Exemplary soft lozenges can be prepared by rotary die final mass of the soft lozenge is about 2800 mg. About encapsulation using the fill composition in Table 13 with the 300 -400 mg of water is evaporated during drying (~ 9 - 10 % shell compositions shown in Tables 10 or 12 . The weight of water lost) .

TABLE 13 Exemplary Soft Lozenge Fill Compositions

Weight Percent ( % )

EX1 EX2EX2 EX3 EX4EX4 EX5 EX6 EX7EX7 EX8 Ingredient

7 . 5 7 .5 7 . 5 ? 7 . 5 7 . 5 Gelatin , 150 Bloom l? 7. 5 Polyethylene Oxide, 4 ,000 ,000 4 . 6 1 MW , ( e. g. , Polyox® WSR -303 ) po Polyethylene Oxide, 5 ,000 ,000 I 4 . 0 L MW Polyethylene Oxide, 7 , 000 , 000 2 . 8 1 i 4 . 0 L 3 . 2 MW Polyethylene Oxide, 10 ,000 , 000 I i 2 . 5 2 . 1 MW Glycerol 7. 5 7 .5 7 . 5 7 .5 7 .5 7 . 5 7 . 5 7 . 5 Citric Acid 1 . 0 1 . 0 1 . 0 1 . 0 1 . 0 1 . 0 1 .0 1 . 0 Maltitol (75 % solution ; e .g ., 57 . 9 56 . 1 56 . 7 57 . 2 56 . 7 58. 2 58 . 6 57 .5 Lycasin ® 80 /55 ) Xylitol 4 . 3 4 . 33 4 .3 44 . 3 4 .. 3 4 . 3 44 . 33 4 . 3 Sucralose 0 . 3 0 . 3 0. ??3 0. 3 0 .3 0 . 3 0. ??3 0. 3

O Polysorbate 80 (e . g ., Tween ® 80 ) 0 . 7 0 . 7 - 0 .7 0 . 7 0 .?? 7 0 . 7 Water 18 . 0 18 .0 18. 0 18 .0 18 . 0 18 .0 18 .0 18. 0 Fluticasone propionate 0 . 025 0 .025 0 .025 0 .025 0 .025 0 . 025 0 .025 0 .025

TOTAL 100 . 0 100 . 0 100 . 0 100 .0 100. 0 100 . 0 100 . 0 100 . 0

Subcomponent Totals

Film -forming Polymer 7 . 5 5 77. . 5 7 .. 5 7. . 5 5 77 . 5 7 . 5 7 . 5 7 .. 5

w Release Modifier 2 . 8 44 . 6 4 . 0 W3 . 5 4 . 0 2 .5 5 22 . . 1 3 .2 Plasticizer 7 . 5 7 . .5 7 . 5 7. . 5 5 77 .5 71. 5 7 .. 5 7 . 5 pH Modifier 1 . 0 1 .. 0 1 . 0 1 . . 0 1 . 0 1 .. 0 1 . . 0 0 11 .0 Sweetener 6262 . 5 6060 .7 6161. 3 61.. 8 61. 3 62. . 8 6363 . 2 62 . 1 Solubilizing Agent 0 .7 0 . 7 0 .1 0 . 7 0 . 7 0 .7 0 . 7 0 . 7 Solvent 18. 0 18 . 0 18 . 0 18 . 0 18. 0 18 . 0 18 . 0 18 . 0 API 0 . 025 0 .025 0 .025 0 . 025 0 .025 0 .025 0 .025 0 .025 Relational Ratios API: Total Fill Composition 2. 5E -4 2. 5E 4 2. 5E -4 2. 5E -4 2. 5E 4 2. 5E -4 2. 5E -4 2. 5E -4 PEO :Gelatin 0 . 373 0 .613 0 .533 0 . 467 0 .533 0 .333 0 .280 0 .427 PEO :Plasticizer 0 . 373373 0 . 613 613 0 . 533 533 00 . 467 00 . . 533 533 0 . 333 0 . 280 0 . 427 Gelatin : Plasticizer 1 .0 1. 0 1. 0 1. 0 1. 0 59851. 0 1. 0 1 .0 US 9 , 867, 834 B2 47 48 Example 5 total weight of the soft lozenge is 3162 .7 mg. After drying, Exemplary soft lozenges can be prepared by rotary die the final mass of the soft lozenge is about 2800 mg. About encapsulation using compositions shown in Table 14 . The 300 -400 mg of water is evaporated during drying ( ?9 -10 % weight of the fill is 2000 mg and the shell is 1162. 7 mg. The- 11e water lost) .

TABLE 14 Exemplary Soft Lozenge Total Compositions (Shell and Fill) weight Percent ( % ) EX1EX2EX3EX4 EX5EX6 EX7EX8 Ingredient

Gelatin , 150 Bloom 11 . 7 ) 12. 33 11 . 07 12. 65 10. 12 7 . 59 5 . 06 11 . 54 Gelatin, 10O Bloom 4 . 74 3 . 79 . 06 3 .16 6 .32 9 . 49 11 . 38 4 . 9 ) Gelatin hydrolysate 0 . 89 0 . 63 ( 0 . 95 0. 32 0 , 79 0 . 47 (0 . 89 ( ) . 79 PEO, 1x 106- 7x 106 MW 1 . 9 ) 1 . 58 2 . 06 2 . 21 1 . 96 1 . 74 1 . 9 ) 2 . 02 Glycerol 13 . 12 12. 65 13. 28 13 . 12 12. 96 13 . 28 13. (03 13 . 6 ) Maltitol ( e. g. , Lycasin ® 80/ 55 ) 0 . 85 0 . 76 () . 95 ( 0. 79 1 . 26 0. 89 O. 82 ) . 79 Citric Acid 41 . 53 44 . 24 41 . 29 42. 94 41 . 46 41 . 43 42 .12 41 . 39 Xylitol 3 . 64 3 .16 3 . 79 3 . 48 4 . 11 3 . 95 3 . 64 3 .16 Sucralose 0 . 25 0 .22 0. 28 0 .19 (3 . 25 () . 22 ( ) . 21 j . 32 Polysorbate 80 ( 0 . 44 0 . 38 O . 32 ( 0 . 41 ( ) . 25 0 . 47 (0 . 41 0 . 51 Water 20 . 49 20 . 24 20. 55 20. 39 19. 92 20 . 24 20. 08 20 . 55 Fluticasone propionate - 01 (0 . 02 0j. 020( 02 (0 .030 03 () .050 ( 05 (0 . 02002 .030 ( 03 0 .- 02 Titanium dioxide O . 38 (0 . ( 0 ) ) .32 ( 3 . 25 0. 47 0 . 19 0 . 40 ) . 35 Coloring ( FD & C dyes) 6 .3E 40 - .004 .7E 46 - .3E 46 - .3E 43 - .2E 44 - .7E 46- .3E -4 Flavoring ( e . g ., cherry, orange) 0 .060 .000 .060 .050 .060 .030 .050 . 06

TOTAL 1001 ] 0 ._ (0 ) 100 . 0 ) 10t100 ). . 0 ) 100.. 0 100. 0 0 100. 0 0 10100 .. ( 0 ) 100. . 0 )

Subcomponent Totals

Film - forming Polymers 17. 33 16. 76 17. j7 16. 13 17. 23 17. 55 17. 33 17. 23 Release Modifiers 1 . 9 ) 1 . 58 2 . 06 2 . 21 1 . 96 1 . 4 1 . 9 ) 2 . 02 Plasticizer 13. 12 12. 65 13. 28 13. 12 12. 96 13 . 28 13 . 03 13. 6 ) pH Modifier 0. 85 0. 76 (0 . 95 () . 79 1 . 26 0 . 89 O . 82 () . 79 Sweetener 45. 42 47 . 62 45. 37 46. 61 45 . 82 45. 6 ) 45. 96 44. 86 Solubilizing Agent ( 0 . 44 (0 . 38 (0 . 32 0 . 41 0 .25 0 . 47 0 . 41 ( 0 . 51 Solvent 20. 49 20. 24 20. 55 20. 39 19. 92 20. 24 20. 08 20 . 55 API 0 . 01 ( ) . 02 O . 02 0. 03 (0 . (05 () , 02 () . j3 Excipients 0 . 44 ( 0 . 00 0 . 38 j . 3 ) (0 . 54 0. 22 ( 0 . 44 ( ) . 41 Relational Ratios

API: Total Composition 7. 9E - 5 1 . 6E - 4 2 . 4E - 4 3 . 2E4 4 . 7E - 4 1 . 6E = 4 3 . 2E - 4 2 .4E - 4 PEO :Gelatin 0 .109 0 . 094 ( ) .120 () .137 ( 0 . 114 ( 0 . 099 () . 1 ( ) 9 ( 0 . 117 PEO :Plasticizer 0 . 145 O. 125 0 ,155 0 .169 ( . 151 ) . 131 ( j .146 0 . 149 Gelatin : Plasticizer 1 . 32 ) 1 . 325 1 . 286 1 . 229 ?0291 . 329 1 . 321 1 . 33 ) 1 . 267 US 9 , 867 , 834 B2 49 50 Example 6 1 . 0 mg. The weight of the fill is 2000 mg and the shell is 1162. 7 mg. The total weight of the soft lozenge is 3162 . 7 Exemplary soft lozenges comprising fluticasone can be mg. After drying , the finalmass of the soft lozenge is about prepared by rotary die encapsulation using compositions 2869. 5 mg. Accordingly , about 293 . 2 mg of water is evapo shown in Tables 15 - 16 with two dosage strengths: 0 . 5 mg or rated during drying ( ~ 9 . 3 % water lost ) .

TABLE 15 Exemplary Soft Lozenge Fill Composition 0 .5 mg API 1. 0 mg API

Mass (mg ) Percent Wt ( % ) Mass (mg ) Percent Wt ( % ) Ingredient

Gelatin , 150 Bloom 150150 7 .5 5 150150 7 .5 5 Polyethylene Oxide, 7 ,000 ,000 60 . 0 3 . 0 60 . 0 3 . 0 MW (e . g . , Polyox® WSR - 303) Glycerol 150 7 . 5 150 7 . 5 Citric Acid 20 . 0 1 . 0 20 . 0 1 . 0 Maltitol ( 75 % solution ; e . g . , 1154 . 7 57 . 7 1154 . 2 57 . 2 Lycasin ® 80 / 55 ) Xylitol (e . g . , Xylisorb 300 ® ) 85 . 0 4 . 3 85 . 0 4 . 3 Sucralose 5 . 8 0 . 3 5 . 8 0 . 3 Polysorbate 80 (e . g ., Tween ® 80 ) 14 . 0 0 . 7 14 . 0 0 . 7 Water 360 18 . 0 360 18 . 0 Fluticasone propionate 0 . 50 0 .025 1 . 0 0 . 050

TOTAL 2000 100 . 0 % 2000 100 . 0 %

Subcomponent Totals

Film -forming Polymer 150 . 0 7 . 5 150 . 0 7 . 5 Release Polymer 60 . 0 3 . 0 60 . 0 3 . 0 Plasticizer 150 . 0 7 .5 150 . 0 7 . 5 pH Modifier 20 . 0 1 . 0 20 . 0 1 . 0 Sweetener 1245 . 5 62. 3 1245 . 0 62 . 3 Solubilizing Agent 14 . 0 0 . 7 14 . 0 0 .7 Solvent 360 . 0 18 . 0 360 . 0 18 . 0 API 0 .50 0 .025 1. 00 0 .05

Relational Ratios

API: Total Fill Composition 0 . 00025 0 .00025 0 .0005 0 .0005 PEO :Gelatin 0 . 4 00 . 4 00 . 4 0 . 4 PEO : Plasticizer 0 . 4 00 .4 4 00. .44 0 . 4 Gelatin : Plasticizer 1 . 0 1 , 0 1 . 0 US 9, 867 ,834 B2 51 52 TABLE 16 TABLE 17 - continued Exemplary Soft Lozenge Shell Composition Exemplary Soft Lozenge Total Composition

Percent Wt Percent Percent Percent Mass (mg ) ( % ) Mass (mg ) Wt (% ) 5 Mass (mg ) Wt ( % ) Mass (mg ) Wt ( % ) Ingredient Sweetener 1438 . 7 45 . 5 1440 . 2 45 . 5 Solubilizing Agent 14 . 0 0 . 4 14 . 0 0 . 4 Gelatin , 150 Bloom 219 . 9 18 . 9 219 . 9 18 . 9 Solvent 646 . 6 20 . 4 646 . 6 20 . 4 Gelatin , 100 Bloom 149 . 9 12 . 9 149 . 9 12 . 9 API 0 . 5 0 .016 1 . 0 0 .032 Gelatin Hydrolysate 27. 7 2 . 4 27 . 7 2 . 4 10 Excipients 14 . 5 0 . 5 12. 5 0 . 4 Glycerol 264 . 6 22 . 8 264 . 6 22 . 8 (opacifier , Citric Acid , Anhydrous 6 . 3 0 .54 6 . 3 0 .54 coloring, flavoring ) Maltitol (75 % solution ; 161. 7 13 . 9 163 . 7 14 . 1 Relational Ratios e . g . , Lycasin ® 80 /55 ) Xylitol (e . g ., Xylisorb 29 . 1 2 . 5 29 . 1 2 . 5 API: Total 0 . 00016 0 . 00016 0 . 00032 0 . 00032 300 ® ) PEO :Gelatin 0 . 11 0 . 11 0 . 11 0 . 11 Sucralose 2 . 4 0 . 21 2 . 4 0 .21 15 PEO : Plasticizer 0 . 14 0 . 14 0 . 14 0 . 14 Water 286 . 6 24 . 7 286 . 6 24 . 7 Gelatin : Plasticizer 1 . 32 1 . 32 1 . 32 1 . 32 Titanium Dioxide 12. 5 1 . 1 12 . 5 1 . 1 Coloring (FD & C dyes) 0 . 02 0 . 0017 0 Flavoring (e . g. , cherry ) 2 . 0 0 . 17 0 Example 7 TOTAL 1162. 7 100 . 0 % 1162. 7 100. 0 % 20 Subcomponent Totals Manufacturing Process Film - forming Polymer 397 . 5 34 . 2 397. 5 34 . 2 The soft lozenge compositions described herein were Plasticizer 264 . 6 22 . 8 264 . 6 22 . 8 manufactured according to the following processes : pH Modifier 6 . 3 0 . 5 6 . 3 0 .5 25 the matrix fill composition is prepared by : Sweetener 193 . 2 16 . 6 195 . 2 16 . 8 Solvent 286 . 6 24 . 6 286 . 6 24 . 6 (a ) combining gelatin , glycerol, and water and maintaining Excipients 14 . 5 1 . 2 12 . 5 1 . 1 the mixture at least about 65° C . for at least 5 minutes ; Relational Ratios adding maltitol syrup to create a fill gel solution ; ( b ) separately , combining water, xylitol, sucralose , and citric Gelatin : Plasticizer 1. 5 1 .5 1 . 5 1 . 5 30 acid together to create a fill sweetener solution ; ( c ) separately , combining the active pharmaceutical ingre dient ( API) and polysorbate 80 ; TABLE 17 ( d ) combining the API and polysorbate 80 with the fill sweetener solution to create an API solution ; Exemplary Soft Lozenge Total Composition 35 ( e ) combining the API solution and the fill gel solution ; Percent Percent ( f) further mixing the combined API and fill gel solution at Mass (mg ) Wt ( % ) Mass (mg ) Wt ( % ) least about 65° C . for at least 5 minutes ; ( g ) slowly introducing solid polyethylene oxide into the Ingredient combined API and fill gel solution and mixing and Gelatin , 150 Bloom 369. 9 11. 7 369. 9 11 . 7 40 deaerating at least about 65° C . for at least 5 minutes to Gelatin , 100 Bloom 149. 9 4 .7 149 . 9 4 . 7 create a matrix fill composition ; Gelatin hydrolysate 27 . 7 0 . 9 27 . 7 0 . 9 the shell gel mass is prepared by : Polyethylene oxide , 60 . 0 1 . 9 60 . 0 1 . 9 ( h ) combining gelatins, glycerol, and water and maintaining 7 ,000 ,000 MW ( e . g . , Polyox ® the mixture at least about 65° C . for at least 5 minutes ; WSR - 303) 45 adding maltitol syrup to create a shell gel solution ; Glycerol 414 . 6 13 . 1 414 . 6 13 . 1 (1 ) separately , combining water, xylitol, sucralose , and citric Citric Acid 26 . 3 0 . 8 26 . 3 0 . 8 Maltitol (75 % 1316 . 4 41. 6 1317 . 9 41. 7 acid together to create a shell sweetener solution ; solution ; e . g . , ( i) combining the shell sweetener solution and shell gel Lycasin ® 80 / 55 ) solution and mixing the combined shell sweetener and Xylitol 114 . 1 3 . 6 114 . 1 3 .6 50 shell gel solution at least about 65° C . for at least 5 Sucralose 8 . 2 0 . 3 8 . 2 0 .3 Polysorbate 80 14 . 0 0 . 4 14 . 0 0 . 4 minutes to create a gel mass ; and Water 646 . 6 20 . 4 646 . 6 20 . 4 the soft lozenge is prepared by : Fluticasone abari0 . 5 0 .016 1 . 0 0 .032 ( k ) casting the shell gel mass into shell films or ribbons using propionate heat - controlled drums or surfaces ; Titanium dioxide 12 . 5 0 . 4 12 . 5 0 . 4 5555 (1 ) injecting the matrix fill solution between the shell rib Coloring 0 .02 0 . 0006 0 . 0 o (FD & C dyes) bons, and creating soft lozenges using rotary die technol Flavoring 2 . 0 0 . 1 o o ogy . ( e . g ., cherry ) Example 8 TOTAL 3162 . 7 100 . 0 % 3162 . 7 100 .0 % Subcomponent 60 Totals Soft lozenges as described in Tables 15 - 17 comprising 1 mg of fluticasone propionate were manufactured and pack Film - forming 547 . 5 17 . 3 547 . 5 17 . 3 Polymer aged in 30 -count HDPE bottles and stored at 30° C . and 65 % Release Modifier 60 . 0 1. 9 60 . 0 1 . 9 relative humidity or 40° C . and 75 % relative humidity for Plasticizer 414 . 6 13 . 1 414 . 6 13 . 1 65 stability testing . Samples were evaluated at 2 -weeks , pH Modifier 26 . 3 0 . 8 26 . 3 0 . 8 1 -month , and 2 -months after packaging ; results are shown in Tables 18 - 20 . US 9 ,867 , 834 B2 53 54 TABLE 18 Stability and Disintegration after storage at 40° C . and 75 % relative humidity Test Specification (1 ) Initial 2 weeks 1 month Physical Description White , opaque , pillow Pass Pass Pass shape soft gelatin lozenge Physical Evaluation Passes visual quality Pass Fail (sticking Fail ( sticking /mis inspection : lozenges ) shaped lozenges) Shell / Color/ Print / Shape : meets requirements for abnormalities in capsule shell, capsule seams, color consistency, print , and misshapen units , Sticking/ Package Integrity : meets requirements for sticking , nesting, bricking , and package integrity . Assay 90 . 0 - 110 . 0 % of label 96 . 7 % of label 98. 8 % of label 96 . 1 % of label claim ( 0 . 9 - 1 . 1 mg claim ( 1 . 0 mg claim ( 1 . 0 mg claim ( 1 . 0 mg lozenge ) lozenge ) lozenge ) lozenge ) Degradation Report Results EP Impurity A = EP Impurity A = EP Impurity A = Products (method 1 ) ND ) ND2) ND ) USP Impurity A = USP Impurity A = USP Impurity A = ND ND ND EP Impurity F = EP Impurity F = EP Impurity F = ND ND ND RRT 1 .23 = ND RRT 1 . 23 = ND RRT 1 . 23 = ND Total (methods 1 Total (methods 1 Total (methods 1 and 2) = NR (3 ) and 2 ) = NR (3 ) and 2 ) = NR (3 ) Degradation Report Results EP Impurity H = EP Impurity H = EP Impurity H = Products (method 2 ) NR (3 ) NR (3 ) NR (3 ) Disintegration Report Results 39 :32 , 40 : 15 , 33 :00 , 33 :00 , 35 :00 , 35 :00 , (minutes :seconds ) 40 : 24 , 40 : 30 , 35 :00 , 35 :00 , 38: 00 , 38 :00 , 40 :44 , 41 : 51 35 :00 , 35 :00 38 :00 , 40 :00 Microbial Limits Total Plate Count - Total Plate Count : Not Scheduled Not Scheduled NMT 1000 cfu / g < 10 cfu / g Yeast & Mold - NMT Yeast & Mold : < 10 cfu / g 100 cfu / g E . coli : Absent E . coli - Absent Salmonella : Absent Salmonella - Absent S . aureus: Absent S . aureus - Absent P . aeruginosa : P . aeruginosa - Absent Absent ( 1) Use current version of method or compendium . (2 ) None detected . ( Not reported ( reporting limit = 0 .05 % ) .

TABLE 19 Stability and Disintegration after storage at 40° C . and 75 % relative humidity Test Specification (1 ) Initial 2 months Physical Description White , opaque, pillow Pass Pass shape soft gelatin lozenge Physical Evaluation Passes visual quality Pass Fail ( sticking & misshapen inspection : lozenges ) Shell/ Color / Print / Shape : meets requirements for abnormalities in capsule shell, capsule seams, color consistency , print, and misshapen units. Sticking /Package Integrity : meets requirements for sticking, nesting, bricking , and package integrity . Assay 90 .0 - 110 . 0 % of label 96 . 7 % of label claim ( 1 . 0 mg 97. 9 % of label claim ( 1 . 0 mg claim ( 0 . 9 - 1 . 1 mg lozenge ) lozenge) lozenge ) US 9 ,867 , 834 B2 55 56 TABLE 19 - continued Stability and Disintegration after storage at 40° C . and 75 % relative humidity Test Specification (1 ) Initial 2 months Degradation Report Results EP Impurity A = ND2) EP Impurity A = ND2) Products (method 1 ) USP Impurity A = ND USP Impurity A = ND EP Impurity F = ND EP Impurity F = ND RRT 1 .23 = ND RRT 1 . 23 = ND Total (methods 1 and 2 ) = Total (methods 1 and 2 ) = NR (3 ) NR (3 ) Degradation Report Results EP Impurity H = NR( 3 ) EP Impurity H = NR ( 3) Products (method 2 ) Disintegration Report Results 39 : 32 , 40 : 15 , 40 : 24 , 36 :00 , 38 :00 , 38 : 00 , 41: 00 , 41 : 00 , (minutes : seconds ) 40 : 30 , 40 : 44 , 41 : 51 48 : 00 Microbial Limits Total Plate Count - Total Plate Count: < 10 cfu / g Not Scheduled NMT 1000 cfu / g Yeast & Mold : < 10 cfu / g Yeast & Mold - NMT E . coli : Absent 100 cfu / g Salmonella : Absent E . coli - Absent S . aureus : Absent Salmonella - Absent P. aeruginosa : Absent S . aureus - Absent P . aeruginosa - Absent ( 1 ) Use current version of method or compendium . ( None detected. (3 )Not reported ( reporting limit = 0 .05 % ).

TABLE 20 Stability and Disintegration after storage at 30° C . and 65 % relative humidity Test Specification (1 ) Initial 2 weeks 1 month Physical White , opaque , pillow Pass Pass Pass Description shape soft gelatin lozenge Physical Passes visual quality Pass Pass Pass Evaluation inspection : Shell / Color /Print / Shape : meets requirements for abnormalities in capsule shell, capsule seams, color consistency, print, and misshapen units . Sticking /Package Integrity : meets requirements for sticking , nesting , bricking , and package integrity . Assay 90 . 0 - 110 . 0 % of label 96 . 7 % of label 97 . 2 % of label 97. 7 % of label claim ( 0 . 9 - 1 . 1 mg/ claim ( 1 . 0 mg/ claim ( 1 . 0 mg claim ( 1 . 0 mg lozenge ) lozenge ) lozenge ) lozenge ) Degradation Report Results EP Impurity A = EP Impurity A = EP Impurity A = Products (method ND2 ND2) ND2 USP Impurity A = USP Impurity A = USP Impurity A = ND ND ND EP Impurity F = EP Impurity F = EP Impurity F = ND ND ND RRT 1 . 23 = ND RRT 1 . 23 = ND RRT 1 .23 = ND Total (methods 1 Total (methods 1 Total (methods 1 and 2 ) = NR (3 ) and 2 ) = NR ( 3 ) and 2 ) = NR (3 ) Degradation Report Results EP Impurity H = EP Impurity H = EP Impurity H = Products (method NR (3 ) NR (3 ) NR ( 3 ) Disintegration Report Results 39 : 32 , 40 : 15 , 30 :00 , 30 : 00 , 32 :00 , 32 :00 , (minutes :seconds ) 40 :24 , 40 :30 , 32 :00 , 33 :00 , 35 :00 , 35 :00 , 40 : 44 , 41 :51 33 :00 , 33 :00 35 :00 , 35 :00 Microbial Limits Total Plate Count - NMT Total Plate Count: Not Scheduled Not Scheduled 1000 cfu / g < 10 cfu / g Yeast & Mold - NMT 100 cfu / g Yeast & Mold : < 10 cfu / g E . coli - Absent E . coli : Absent Salmonella - Absent Salmonella : Absent S . aureus - Absent S . aureus: Absent P . aeruginosa - Absent P . aeruginosa : Absent (1 )Use current version of method or compendium . ( None detected . ( Not reported (reporting limit = 0 .05 % ) . US 9 , 867 ,834 B2 57 58 Example 9 method according to the principles of Good Laboratory Practice. The Analysis of Variance ( ANOVA ) for In - trans A single -dose , randomized , open - label , crossover, com formed AUCO - > , AUC . , and Cmax , and untransformed parative bioavailability and placebo - controlled , double - Tmax , à and t1 /2 : Tmax was also analyzed using an additional blind taste - test study of fluticasone 1 mg lozenge and 5 nonparametric test (Wilcoxon test ) . The 90 % confidence Flovent® HFA 220 ug ( swallowed and inhaled ) was per - intervals (CI ) for the Test/ Reference ratios of geometric formed in healthy male and female volunteers under fasting means for AUCO - , AUC0 - - , and Cmor were calculated conditions. based on the least square means ( LSMEANS) and ESTI The primary objective of this pilot study was to estimate MATE of the ANOVA . the intrasubject variability of, and to compare the bioavail - 10 Palatability scores were calculated for the lozenges and ability of fluticasone administered via a fluticasone 1 mg summarized with descriptive statistics . Within - subject lozenge and Flovent® HFA 220 ug , swallowed and inhaled paired differences in characteristic scores between placebo (GlaxoSmithKline ) in healthy male and non - pregnant and test lozenges were analyzed using nonparametric Wil female volunteers under fasting conditions . coxon Signed -Rank tests if data permitted . The secondary objective of this study was to evaluate the 15 Taste - test Study — Period 1 taste of the fluticasone and placebo lozenges . This part of the study was a single -dose , randomized , The study was designed as a single - dose , randomized , double - blind , crossover , single - period , two - sequence, two four -period , three - sequence ( comparative BA ) and two - treatment taste study of fluticasone lozenge 1 mg ( Banner sequence (taste test ), five - treatment ( 2 treatments for taste Life Sciences ) and placebo lozenge (Banner Life Sciences ) . test and 3 treatments for comparative BA ) , combined com - 20 In this treatment period , 24 healthy , adult nonsmoking ( for parative bioavailability and double -blind taste -test study. at least 6 months prior to first drug administration )male and Twenty - four ( 24 ) subjects were enrolled made up of non -pregnant female volunteers were administered 1x1 mg healthy, non -smoking ( for at least 6 months prior to first fluticasone propionate lozenge and 1 AUC . -> placebo loz study drug administration ) , male and non - pregnant female enge under fasting conditions. volunteers , between 18 and 65 years, with a bodymass index 25 Comparative Bioavailability Study — Periods 2 , 3 and 4 (BMI ) within 18 . 5 - 29 . 9 kg/ m², inclusive . This was a single - dose , randomized , open - label , 3 -way The specific drugs tested were ( a ) Fluticasone Lozenge 1 crossover, three -period , three sequence , three - treatment, mg (Banner Life Sciences ) , ( b ) Flovent HFA 220 mcg , single - center, comparative bioavailability study of flutica Inhalation Aerosol (GlaxoSmithKline NC ) and ( c ) a placebo sone lozenge 1 mg and Flovent® HFA 220 ug , both swal lozenge, to evaluate the taste difference between the placebo 30 lowed and inhaled (GlaxoSmithKline ) . In 3 separate treat and the Fluticasone lozenge 1 mg. ment periods , the 24 healthy , adult nonsmoking ( for at least A taste test study was performed by administering both 6 months prior to first drug administration ) male and non the test drug 1 , 1 mg Fluticasone Lozenge ( Banner Life pregnant female volunteers were administered 1x1 mg flu sciences) and the placebo lozenge . ticasone propionate lozenge, 4x220 ug inhalation aerosol to A comparative bioavailability study was performed using 35 swallow or 4x220 ug inhalation aerosol to inhale under ( a ) the test drug Fluticasone Lozenge 1 mg (Banner Life fasting conditions. Sciences ) or a first reference drug (R1 ) , 4x220 ug , inhalation There was at least a 4 - day washout period between the aerosol ( for oral ingestion ) or a second reference drug (R2 ) study periods . The washout period of at least 4 days was 4x220 mcg , inhalation aerosol ( to inhale ) in each study estimated to be adequate in avoiding potential carry -over period . 40 effects of the preceding treatments . Blood samples were Safety monitoring will be conducted and the duration of collected in Period 2 , Period 3 and Period 4 , at pre -dose and confinement will be broken up into four periods of time. at 0 .083 , 0 . 167 , 0 . 333 , 0 . 5 , 0 . 75 , 1 , 1 .25 , 1 . 5 , 1 . 75 , 2 , 3 , 4 , Period 1 was from at least ten hours prior to , and until at least 6 , 8 , 16 , 24 and 48 hours post dose in each study period . eight hours after the first dose administration , for a total of Study Duration and Confinement at least 18 -hours for study Period 1 . Periods 2 , 3 and 4 was 45 Period 1 from at least ten hours prior to dosing until at least 24 -hours Subjects were confined to the clinic from at least 10 -hours post - dose , for a total of at least 34 -hours for each of three prior to , and until at least 8 -hours after the first dose , for a study periods with a minimum of at least four days between total of at least 18 - hours for study Period 1 . each dosing . Vital signs (blood pressure and heart rate ) were Period 2 , Period 3 and Period 4 measured for each period . Period 1 vital signs will be 50 Subjects were confined to the clinic from at least 10 hours measured at pre - dose and at one , three and eight hours after prior to dosing until at least 24 - hours post- dose , for a total the first dose . Vital signs for the remaining time periods was of at least 34 -hours for each study period . Subjects were measured at pre - dose and at one , three , five , eight and 24 required to return to the clinical facility for the 48 - hour hours after the first dose . blood draw in study Period 2 , Period 3 and Period 4 . The Principal Investigator /Sub - Investigator was present 55 Randomization and Blinding from approximately 30 -minutes prior to dosing until at least In this study , assignment of two separate treatment groups four hours after the last subject was dosed in each study (randomization scheme) for taste test and comparative BA period . The Principal Investigator /Sub - Investigator was generated by a computer program designed and run in remained on - call throughout the duration of thele study. SAS® Version 9. 4 . All blood samples were collected in a 6 mL , pre - chilled , 60 Comparative Bioavailability Study sodium fluoride / potassium oxalate Vacutainer® at the fol- The comparative bioavailability study was open - label, lowing time intervals for Periods 2 , 3 and 4 : 0 , 0 .083 , 0 . 167, and subjects as well as the study staff will were not blinded 0 .333 , 0 . 5 , 0 .75 , 1 , 1 . 25 , 1 . 5 , 1. 75 , 2 , 3 , 4 , 6 , 8 , 16 , 24 and to the randomization . The bioanalytical laboratory did not 48 -hours post - dose in each study period . have access to the randomization scheme until the bioana Approximately 353 mL of blood , including ~ 29 mL for 65 lytical analysis is complete . To avoid any study evaluation pre - and post -study procedures were drawn . Plasma samples bias , the taste test study was double -blinded , where the were assayed for fluticasone using a validated analytical fluticasone lozenge and its matching placebo were blinded to US 9 , 867, 834 B2 59 60 both subjects and clinic staff in charge of reviewing and Following completion of the after taste assessment for the evaluating adverse events and safety . first dose , subjects were served two cookies and 50 mL of In the taste -test portion of the study , un -blinding was only orange juice . Subjects were also provided with 60 mL of permitted in case of an emergency involving a subject where water to rinse the mouth and swallow that water . it was necessary to know which treatment the subiect 5 Second Dose Administration received prior to the subject receiving medical aid . The Subject fasted for one hour before the second lozenge administration . Subject rinsed the mouth with 20 mL of investigator and the Sponsor had the ability to un -blind the water for approximately five seconds and swallowed that treatment assignment for subjects enrolled in the study. water prior to lozenge administration . Subjects swallowed Subjects who met the eligibility criteria were randomly+ 10 saliva before dosing . Staff placed the lozenge directly on the assigned equally into both of the following treatment subject ' s tongue, and asked the subject to close his /her groups : mouth in a natural way, without swallowing, chewing , biting or breaking the lozenge , permitting complete lozenge dis Period 1 : Two Sequence Groups integration . After subjects indicated complete disintegration of the lozenge ( confirmed by visual inspection , they were Period 1 allowed to swallow . After completion of the after - taste Sequence 1 assessment for the second lozenge , 60 mL of water was SequenceSequence 2 ] AE provided to rinse the mouth and subjects swallowed the water. Periods 2 , 3 and 4 : Three Sequence Groups 20 Following the administration of each lozenge , hands and mouth were checked in order to confirm the consumption . Period 2 Period 3 Period 4 In the taste test questionnaire , the taste was categorized Sequence 1 I R1 R2 using a specific scoring grid with values from 1 - 5 for Sequence 2 R1 R2 T bitterness , sweetness , mouth feel ( grittiness ) , flavor, and Sequence 3 R2 T R1 25 overall acceptability ; adapted from Reddy et al, “ Evaluation T = fluticasone lozenge ; Study of Oral Disintegrating Tablets by Human Volunteers .” P = placebo lozenge ; Internat. J . Pharm . Science Res. 1 ( 8 ) :326 - 346 ( 2010 ) , which R1 = Flovent HFA ingestion ; is incorporated by reference herein for such teachings. Three R2 = Flovent HFA inhalation minutes after placing the lozenge on the tongue , the subject Each subiect was scheduled to receive a total of five 30 recorded their feedback in the table based on a scoring grid . The taste scoring , once completed , was taken from the treatments by the end of the study . subject . Dosing Once the lozenge has completely disintegrated , the sub Subjects took their assigned formulation after a fast of at ject recorded their feedback again in the questionnaire based least 10 -hours at their scheduled time point. 35 on the scoring grid . When completing the second scoring Period 1 ( Taste -test ) grid , subjects were not permitted to see their prior responses . The subject received the fluticasone propionate ' test drug Period 2 . Period 3 and Period 4 Lozenge Administration lozenge (T ) and the placebo lozenge ( P ) approximately 2 (Test ) hours apart. The subject was asked to complete a question . The subjects were instructed by the designated study staff naire in 3 minutes after administering the lozenge for the 40 to move his /her tongue around the mouth ( front and back initial- taste assessment, and after the lozenge completely part of gums, teeth and palate ) two times and document any disintegrated for after - taste assessment, to evaluate the taste signs of oral irritation and / or any mouth , tongue or gum characteristics of the lozenge . Disintegration time should ulcer ( s ) were investigated . Just prior to drug administration , have been documented by clinic staff . The subject was NOT each subject rinsed his /her mouth for approximately 5 to be informed whether the lozenge had active drug or 45 seconds with approximately 20 mL of room temperature placebo . water, and then swallowed the water. Subjects were First Dose Administration instructed to swallow saliva before dosing . Subsequently , Subjects were asked to rinse their mouth with 20 mL of staff placed the lozenge directly on the subject' s tongue , and ambient temperature water for approximately five seconds asked the subject to close his /her mouth in a natural way , and swallow that water prior to lozenge administration . 50 without swallowing , chewing , biting or breaking the loz Subjects were instructed to swallow saliva before dosing . enge , in order to permit complete lozenge disintegration . If Subsequently, staff placed the lozenge directly on the sub - the subject chewed , swallowed or moved the study drug ject' s tongue , and asked the subject to close his /her mouth before it was completely dissolved , the subject was removed in a natural way , without swallowing , chewing , biting or from the study. After subjects indicated complete disinte breaking the lozenge , to permit complete lozenge disinte - 55 gration of the lozenge (confirmed by visual inspection ) they gration . If the subject chewed or swallowed or moved the were allowed to swallow . Dosing time was set to the time the study drug before it was completely dissolved , the subject lozenge was placed on the subject ' s tongue . Subjects were was removed from the study . After subjects indicated com instructed to inform study staff when they believed that the plete disintegration of the lozenge ( confirmed by visual lozenge had completely disintegrated . inspection ) they were allowed to swallow . Dosing time was 60 Visual inspection of the lozenge was conducted by the set to the time the lozenge was placed on the subject' s study staff every 2 -minutes until either disintegration was tongue . Subjects were instructed to inform study staff when noted or until the subject alerted the study staff to complete they believed that the lozenge was completely disintegrated disintegration of the lozenge by raising their hand . Subjects Visual inspection of the lozenge was conducted by the should refrain from talking until complete disintegration of study staff every two minutes until either disintegration was 65 the lozenge is verified by study staff . noted or until the subject alerted the study staff to complete The study staff recorded the actual time of lozenge disintegration of the lozenge by raising their hand . placement and the actual time of disintegration . Subjects US 9 ,867 , 834 B2 62 were instructed to notify study staff if the lozenge was AUCO - > Area under the concentration - time curve from accidentally swallowed before it was completely disinte time zero until the last measurable concentration or last grated . Study staff recorded the time the lozenge was swal sampling time t , whichever occurs first . AUCO- is lowed . estimated using the trapezoidal method Following the administration of the lozenge . hands and 5 AUC0 -? Area under the concentration - time curve from time zero to infinity , calculated as AUC - X + Clash , mouth were checked in order to confirm the consumption . where Ciast is the last measurable concentration . Following complete dissolution of the lozenge , the subject à Terminal elimination rate constant, estimated by linear rinsed his/ her mouth with 60 mL of water and then swal regression analysis of the terminal portion of the In lowed the water. concentration vs. time plot . The subject was asked to move his/ her tongue around Thethe 10 t12 Terminal elimination half - life , estimated as ln ( 2 ) . mouth (front and back part of gums, teeth and palate ) two During PK and statistical analyses, drug concentrations times. below the lower limit of quantitation (BLQ ) of an assay were considered as zero except when they occurred following the Reference Drug (R1 - FLOVENT® Ingested ) appearance of quantifiable concentration in the time course ; Just prior to drug administration , each subject rinsed 15 thereafter they were considered as missing during PK cal his /her mouth for approximately 5 seconds with approxi culations and estimations. mately 20 mL of room temperature water , and then swal Missed samples and non - reportable concentrations ( e . g . lowed this water. Subjects were assigned to take four inha quantity not sufficient ) from the analytical laboratory were lations , swallowed approximately 30 seconds apart . treated as missing in the PK analysis . Following the fourth and final inhalation /swallow , the sub - 20 The à , ty , and AUC . . parameters were estimated for ject rinsed his /her mouth with 60 mL of water and then plasma concentration - time profiles where the terminal linear swallowed the water. phase was not clearly defined , ( i . e . the RP of the terminal Reference Drug (R2 — FLOVENT® Inhaled ) linear regression is not > 0 .700 ) . The reference drug was delivered using a “ spacer” (also Statistical Analysis known as aerosol- holding chambers , add - on devices and 25 The PK and statistical analysis was performed at BPSI spacing devices ) . using SAS® Version 9. 4 . Just prior to drug administration , each subject rinsed Descriptive statistics (min , max , median , mean , standard his /her mouth for approximately 5 seconds with approxi - deviation and coefficient of variability ) of all PK parameters mately 20 mL of room temperature water, and then will in the PK population were provided for fluticasone for the swallowed this water. Subjects were assigned to take four 30 Test and Reference products . inhalations , 30 seconds apart . Following the fourth and final ANOVA including sequence , subjects nested within inhalation /swallow , the subject rinsed his /her mouth with 60 sequence , period and treatment were performed on the mL of water and then swallowed the water. In - transformed data for AUCO - X , AUC0 - - 00 , and mar and on Pharmacokinetic and Palatability Analysis Data Set the untransformed data for Tmaxz à , and t1/ 2 . Tmax were Two populations were defined for the final PK and sta - 35 analyzed using an additional nonparametric test (Wilcoxon tistical analysis as follows: test ) . 1 . The PK population includes all subjects for whom PK The 90 % CI of the Test/ Reference ratios of geometric can be determined following a fluticasone ( T ) dose and means for AUC . - > , AUC . - - , and Cmax were calculated at least 1 reference dose (R1 or R2) . based on the LSMEANS and ESTIMATE of the ANOVA . 2 . The full population is comprises of all subjects who 40 The following statistical comparisons were performed : received at least one study dose either placebo or test Treatment T vs . Treatment R1 lozenge . This population was also used for the Taste Treatment T vs . Treatment R2 Test analysis . Treatment R1 vs Treatment R2 Data from subjects who were dismissed /withdrawn or Palatability Analyses who withdrew was evaluated by a BPSI PK specialist and /or 45 Using the full population , palatability of the fluticasone the Sponsor for inclusion in the PK and statistical analysis . and placebo lozenges was measured as described by Reddy Subjects with emesis within 4 -hours post- dose from period et al, Internat. J . Pharm . Science Res. 1 ( 8 ) : 326 - 346 ( 2010 ) , 2 , period 3 , and period 4 , may have been included in the PK incorporated by reference herein for these specific teachings . analysis , at the discretion of the pharmacokinetic scientist. The analysis differs marginally because this study is evalu All other subject data were reported separately . Non -com - 50 ating only two lozenges ( Test and Placebo ) . Initial and pliant subject data were not included in the PK population , post - dissolution palatability was evaluated on four charac but will be reported separately . teristics: bitterness , sweetness, mouth feel, and pleasantness Analysis of Data of flavor. Descriptive statistics of the ordinal characteristic Pharmacokinetic and statistical analysis was performed scores ( 1 - 5 ) were presented for the placebo and fluticasone on all data from all subjects in the PK population . Any 55 lozenges; the statistics included frequency distributions of bioanalytical and /or PK data from subjects not included in the scores , as well as summary statistics (mean , standard the PK population but in the full population will be reported deviation . ) of the scores. Within -subject paired differences separately . between Placebo and Test scores were evaluated using The PK and /or statistical analyses outlined in this protocol nonparametric Wilcoxon Signed -Rank tests , assessing the may be altered with appropriate justification . 60 null hypothesis of zero difference in scores . Pharmacokinetic Analysis Additional statistical tests were performed as necessary Pharmacokinetic parameters were calculated using non ( e . g . , initial vs. post - dissolution scores ). compartmental analysis (NCA ) method . The following PK parameters were estimated (where possible ) for fluticasone : Example 10 Cmax The maximal observed plasma concentration . 65 Tmax Time when the maximal plasma concentration is Summary of pharmacokinetic parameters from the bio observed . availability study described in Example 10 are shown in US 9 ,867 , 834 B2 63 Tables 21 and 22 . Plots of mean fasting plasma concentra assessment phase and post - dissolution taste assessment tions versus time are shown in FIG . 1 . The quantity of phase , respectively. systemic Test fluticasone provided by the pharmaceutical compositions described herein is very low ~ 10 pg /mL and is These results show that patients did not detect any difference about 30 - times lower than the Reference . 5 in taste associated with the fluticasone formulation in loz enge dosage form as described herein as compared to the TABLE 21 placebo lozenge lacking fluticasone . Mean Fasting Plasma Concentrations for Fluticasone propionate After Dosing TABLE 23 Test Reference Summary of P - Values Using Wilcoxon Signed - Rank Test for Differences between Placebo and Test Scores Conc. Conc. Time (h ) (pg / mL ) Std DevDev . (pg / mL ) Std Dev. Evaluation Taste Test P - Value Significant Pre -dosing 0 .07 0 . 28 0 15 Bitter Initial 0 . 8234 No 0 .083 0 . 08 0 . 32 38 . 26 56 .55 Sweet Initial 0 . 2100 No 0 . 167 0 . 09 0 . 32 59 .67 74 . 26 Mouth Feel Initial 0 . 9727 No 0 . 333 0 . 35 0 .72 110 .88 108 . 34 Flavor Initial 0 .6292 0 . 5 1 . 59 1 .87 180 . 55 177 . 48 Bitter Post - dissolution 0 . 8750 0 . 75 3 . 41 2 .46 217 . 10 193 .06 Sweet Post- dissolution 0 . 2051 1 5 .64 3 . 81 256 . 39 233 .54 20 Mouth Feel Post - dissolution 0 . 4465 ZZZZ 1 . 25 7 . 54 4 .65 272 .78 223 . 70 Flavor Post - dissolution 0 . 2432 No 1 . 5 9 . 15 5 . 26 287 . 90 224 . 13 1 . 75 9 . 95 5 . 34 298 . 25 229 . 88 Test : Fluticasone Propionate Lozenge , 1 . 0 mg; Lot No : 147000651A ; Banner Life Sciences LLC ) 2 . 0 10 . 43 5 . 76 308 .25 245 . 92 Placebo : Fluticasone Propionate Lozenge Placebo Lot No : 147000655A ; (Banner Life 3 . 0 10 . 14 5 .67 284 .04 218 .94 Sciences LLC ) 4 . 0 8 . 73 4 . 82 270 . 80 212 . 48 6 . 0 5 . 85 2 .62 183 .73 145 . 34 25 8 . 0 4 .60 2 . 22 166 . 96 136 . 21 Example 11 16 . 0 2 . 58 1 . 12 69 . 52 62 .88 24 . 0 1 . 91 1 . 12 42 . 57 38 . 86 A non -controlled oral dissolution study was performed 48 . 0 0 .91 1 . 18 10 . 78 9 . 31 where five subjects were given the lozenge of Examples 15 N = 14 subjects 30 and 17 . Subjects were given no instructions or restrictions other than to communicate when their lozenge was com TABLE 22 Summary of Comparative Bioavailability Analysis for Fluticasone 1 mg Lozenge Single - dose , randomized , open - label, crossover, comparative bioavailability Geometric Mean * Arithmetic Mean ( % CV ) AUCOT AUC0 - 00 Cmax AUCO Sample (pg · h /mL ) (pg · h /mL ) (pg / mL ) Tmax (h ) * t12 (h ) * ^ ( 1/ h ) * AUC _ 0 * Reference 1523 . 19 1533 . 60 121. 50 1 . 76 12 . 06 0 .0591 0 . 9551 ( R ) 3852 .78 4045 . 56 322 . 17 (1 . 00 -4 .08 ) (17 . 05 ) ( 17. 96 ) (1 . 49 ) (81 . 51 ) ( 81 .51 ) ( 79 .75 ) Test ( T ) 108 .91 154 .56 9 . 06 2 .00 0 .0604 15 .39 0 .7532 125 .51 157 .69 10 . 86 ( 1. 75 -3 .00 ) (54 . 01 ) ( 56 .78 ) (13 . 79 ) (58 . 11 ) (60 .75 ) (53 . 39 ) Ratio of Geometric 90 % Confidence Intra - subject CV Means ( T : R ) Interval ( % ) Test ( T ) AUCO 7 . 15 4 .64 - 11 .02 55 . 54 AUC0- - 00 10 . .08 6 . 04 - 16 . 83 63 . 11 ???? 7 . 46 4 . 66 - 11. 95 61 . 25 Reference ( R ) : Flovent ® HFA 220 ug ( fluticasone propionate 220 ug; Inhalation Aerosol) (GlaxoSmithKline ) Test ( T ) : Fluticasone propionate 1. 0 mg lozenge (Banner Life Sciences) ; see Tables 15 and 17 * Arithmetic mean % CV ) only *Median and range only

Example 11 pletely dissolved without chewing or biting the lozenge . Subjects were provided the lozenge and were asked to place it in their mouth , at which point timing began . Palatability Data Assessment Complete oral dissolution occurred over a range of about 10 to about 15 minutes , with an average oral dissolution time The nonparametric Wilcoxon Signed -Rank Test showed1 of0 12 . 5 minutes. that there were not any statistically significantly differences 65 What is claimed is : for scores of bitterness, sweetness, mouth feel, and flavor 1 . A topical, non - systemic , oral, slow releasing , solid , soft between Test and Placebo groups for both initial- taste lozenge pharmaceutical composition comprising: US 9 ,867 , 834 B2 65 66 (a ) about 1 % to about 5 % by mass of one or more release 13. The composition of claim 12 , further comprising: modifiers comprising polyethylene oxide polymers ( 1) about 0 . 1 % to about 50 % by mass of one or more comprising a molecular weight of about 900 ,000 to thickening agents . about 8 , 000 , 000 ; 14 . The composition of claim 12 , further comprising a (b ) about 10 % to about 60 % by mass of one or more 5 second active pharmaceutical ingredient. film - forming polymers comprising gelatins ; 15 . The composition of claim 14 , wherein the second ( c ) about 5 % to about 20 % by mass of one or more active pharmaceutical ingredient comprises about 0 . 5 % to plasticizers comprising glycerol, sorbitol, or combina about 5 % by weight of lidocaine , prilocaine , or a combina tions thereof; and tion thereof. ( d ) less than 1 % by mass of one or more corticosteroids. 10 16 . The composition of claim 12, wherein the composi 2 . The composition of claim 1, further comprising : tion orally dissolves within about 10 to about 15 minutes ( e ) about 0 . 1 % to about 5 % by mass of one or more pH upon administration to a subject . modifiers comprising citric acid , acetic acid , lactic acid , 17. The composition of claim 12 , wherein the composi malic acid , tartaric acid , fumaric acid , or combinations tion achieves 50 % dissolution in vitro at pH 7 . 4 within about thereof; 15 10 to about 30 minutes. ( f) about 10 % to about 80 % by mass of one or more 18 . The composition of claim 12 , wherein the composi sweeteners comprising maltitol , Xylitol, mannitol, tion topically contacts the oral and esophageal mucosa for at sucralose , aspartame, stevia , or combinations thereof; least about 1 minutes to at least about 45 minutes . and 19 . The composition of claim 12 , wherein the composi ( g ) about 5 % to about 30 % by mass water . 20 tion provides one or more of the following pharmacokinetic 3 . The composition of claim 1 , further comprising : parameters upon administration to a subject: ( h ) one or more opacifiers, coloring agents , flavorings, ( a ) a mean plasma fluticasone propionate Tmax of about thickening agents or combinations thereof; 1. 75 hours to about 3 hours ; ( i ) one or more solubilizing agents ; or ( b ) a mean plasma fluticasone propionate Cmax of about 8 ( j ) one or more second active pharmaceutical ingredients . 25 pg /mL to about 11 pg /mL ; 4 . The composition of claim 1 , wherein the composition ( c ) a mean plasma fluticasone propionate AUC0 - of orally dissolves within about 10 to about 15 minutes upon about 105 pg. h /mL to about 130 pg. h /mL ; administration to a subject. (d ) a mean plasma fluticasone propionate AUC . -- . of 5 . The composition of claim 1 , wherein the composition about 150 pg . h /mL to about 160 pg . h /mL ; achieves about 50 % dissolution in vitro at pH 7 . 4 within 30 ( e ) a mean fluticasone propionate half - life ( t ) of about about 10 to about 30 minutes . 0 . 01 h to about 0 . 1 h ; or 6 . The composition of claim 1 , wherein the composition (f ) a mean fluticasone terminal elimination rate constant topically contacts the oral and esophageal mucosa for at a ) of about 10 h - 1 to about 20 h - 1 . least about 1 minute to at least about 45 minutes. 20 . The pharmaceutical composition of claim 12, wherein 7 . The composition of claim 1 , wherein the polyethylene 35 the composition is useful for treating a subject suffering oxide polymer comprises a molecular weight ( M ) of about from one or more of oral or esophageal inflammation , 7 , 000 , 000 . eosinophilic esophagitis , inflammatory bowel disease 8 . The composition of claim 1, wherein the corticosteroid involving the esophagus, oral lichen planus, aphthous comprises fluticasone or a salt thereof . stomatitis , Crohn 's disease, esophageal inflammation sec 9 . The composition of claim 1 , wherein the corticosteroid 40 ondary to caustic / irritant ingestion , recurrent esophageal comprises fluticasone propionate . strictures of any cause and including irritant ingestion , 10 . The composition of claim 1 , wherein the composition pill- induced esophagitis , systemic diseases, congential dis comprises about 0 .025 % or about 0 .05 % fluticasone propi eases , epidermolysis bullosa , trauma, or post - surgery onate . inflammation . 11 . The composition of claim 1 , wherein the composition 45 21 . A method for treating, retarding the progression of, comprises about 0 . 5 mg or about 1 . 0 mg of fluticasone prophylaxis of, delaying the onset of, ameliorating , or reduc propionate ing the symptoms of one or more of esophageal, oral, or 12 . A topical, non -systemic , oral, slow releasing , solid , buccal inflammation , eosinophilic esophagitis , oral lichen soft lozenge pharmaceutical composition comprising: planus , aphthous stomatitis , odynophagia , acid reflux , dys ( a ) about 10 % to about 60 % by mass of one or more 50 phagia , oral, esophageal or peptic ulcers , heart burn , chest gelatins ; pain , abdominal pain , nausea , vomiting, coughing, sore ( b ) about 5 % to about 20 % by mass of one or more of throat, decrease in appetite , or failure to thrive , comprising glycerol, sorbitol, or combinations thereof; administering to a subject in need thereof the pharmaceutical ( c ) about 0 . 1 % to about 5 % by mass of one or more of composition of claim 12 . citric acid , acetic acid , lactic acid , malic acid , tartaric 55 22 . A method for treating for treating , retarding the acid , fumaric acid , or combinations thereof; progression of, prophylaxis of, delaying the onset of, ame ( d ) about 10 % to about 80 % by mass of one or more of liorating , or reducing the symptoms of one or more of maltitol, xylitol , mannitol, sucralose , aspartame, stevia , esophageal oral, or buccal inflammation , eosinophilic or combinations thereof; esophagitis , inflammatory bowel disease involving the ( e ) about 5 % to about 30 % by mass of water ; 60 esophagus, oral lichen planus, aphthous stomatitis , Crohn 's ( g ) about 1 % to about 5 % by mass of one or more disease , esophageal inflammation secondary to caustic / irri polyethylene oxide polymers comprising a molecular tant ingestion , recurrent esophageal strictures of any cause weight of about 900 ,000 to about 8 , 000 ,000 ; and including irritant ingestion , pill - induced esophagitis , ( h ) about 0 . 1 % to about 5 % by mass of one or more systemic diseases, congential diseases, epidermolysis polysorbates ; and 65 bullosa , trauma, or post - surgery inflammation comprising ( i ) about 0 . 001 % to about 1 % by mass of fluticasone administering to a subject in need thereof the pharmaceutical propionate . composition of claim 12 . US 9 , 867 , 834 B2 67 68 23 . The method of claim 22, wherein administering the 29 . The composition of claim 12 , wherein the polyethyl composition provides one or more of the following phar ene oxide polymer comprises a molecular weight ( M ) of about 7 , 000 ,000 . macokinetic parameters : 30 . A topical , non -systemic , oral slow releasing, solid , ( a ) a mean plasma fluticasone propionate Tmax of about 5 soft lozenge pharmaceutical dosage form comprising a shell 1 . 75 hours to about 3 hours ; encapsulating a semisolid matrix fill , the shell comprising : ( b ) a mean plasma fluticasone propionate Cmax of about 8 ( a ) about 10 % to about 60 % by mass of one or more pg/ mL to about 11 pg /mL ; gelatins ; ( c ) a mean plasma fluticasone propionate AUCO- of ( b ) about 5 % to about 20 % by mass of glycerol; about 105 pg . h /mL to about 130 pg . h /mL ; ( c ) about 0 . 1 % to about 5 % by mass of citric acid , acetic ( d ) a mean plasma fluticasone propionate AUCO - s , of acid , lactic acid , malic acid , tartaric acid , fumaric acid , about 150 pg . h / mL to about 160 pg. h /mL ; or combinations thereof; ( e ) a mean fluticasone propionate half - life (t12 ) of about (d ) about 10 % to about 80 % by mass of one or more of 0 .01 h to about 0 . 1 h ; or maltitol, xylitol, sucralose or combinations thereof; and ( e ) about 5 % to about 30 % by mass of water; and (f ) a mean fluticasone terminal elimination rate constanta15 the matrix comprising : (a ) of about 10 h - to about 20 h - 1 . ( f ) about 5 % to about 30 % by mass of one or more 24 . A pharmaceutical combination comprising the com gelatins ; position of claim 12 and one or more additional therapeutic ( g ) about 1 % to about 5 % by mass of one or more compounds . polyethylene oxides comprising a molecular weight of 25 . The composition of claim 1 , wherein the gelatins 20 about 900 , 000 to about 8 , 000 , 000 ; comprise gelatin , partially hydrolyzed gelatin , hydrolyzed ( h ) about 5 % to about 20 % by mass of glycerol ; gelatin , hydrolyzed collagen , or combinations thereof. (i ) about 0 .5 % to about 5 % by mass of one or more of 26 . The composition of claim 1 , wherein the plasticizer citric acid , acetic acid , lactic acid , malic acid , tartaric comprises glycerol. acid , fumaric acid , or combinations thereof; 27 . The composition of claim 3 , wherein the one or more 25 ( 1 ) about 10 % to about 80 % by mass of one of maltitol. solubilizing agents comprise about 0 .5 to about 1 % of xylitol, sucralose , or combinations thereof; polysorbate 20 , polysorbate 40 , polysorbate 60 , or polysor ( k ) about 0 . 1 % to about 1 % by mass of polysorbate 20 , bate 80 . polysorbate 40 , polysorbate 60 , or polysorbate 80 ; 28 . The composition of claim 3 , wherein the one or more ( 1 ) about 5 % to about 30 % by mass of water ; and second active pharmaceutical ingredients comprises about 30 ( m ) about 0 .001 % to about 1 % by mass of fluticasone or 0 . 5 % to about 5 % by weight of lidocaine , prilocaine , or a a salt thereof. combination thereof . * * * * *