Chewable fexofenadine tablets

Abstract

This disclosure is also based on the discovery that it is possible to eliminate the sweetener from a fexofenadine zwitterion dihydrate suspension and still achieve satisfactory taste masking by including the sweetener solely in the external phase. In addition, this disclosure is based on the discovery that it is possible to use an inert matrix containing only mannitol when turning suspensions of fexofenadine zwitterion dihydrate into granules. Accordingly, this disclosure is directed to sugar-free chewable fexofenadine tablets comprising sprayed and dried fexofenadine granules comprising a mannitol matrix and a composition devoid of a sweetener, said composition comprising fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer; and an external phase comprising a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, and one or more lubricant. The disclosure also includes methods of making these tablets. In one embodiment, the method of producing a sugar- free chewable fexofenadine tablet includes: generating fexofenadine granules by spraying and drying a liquid fexofenadine suspension devoid of a sweetener comprising fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer onto a mannitol matrix; and compressing the fexofenadine granules with an external phase comprising a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, one or more lubricant.

Description

CHEWABLE FEXOFENADINE TABLETSFIELD OF THE INVENTION

[0001] This disclosure relates to chewable fexofenadine in a format that is ready-to-use, does not need any water, and is easy to consume.BACKGROUND OF THE INVENTION

[0002] Fexofenadine hydrochloride is commonly used to treat allegories. Fexofenadine hydrochloride refers to 4- [1 -hydroxy-4- [4-(hydroxydiphenylmethyl)-l-piperidinyl] -butyl] - a,a-dimethyl benzeneacetic acid hydrochloride and has the following structure:

[0003] However, fexofenadine hydrochloride has a bitter taste requiring use of a taste masking agent in the formulation. Typically, taste masking agents are directly in contact with the fexofenadine or fexofenadine tablets are coated with the taste masking agent.

[0004] U.S. Patent No. 8,933,097 discloses and claims liquid fexofenadine suspensions containing a sweetener system of 5% to 40% of sucrose or invert sucrose, and 5% to 40% of xylitol, sorbitol, or sorbitol solution, or maltitol solution; provided that the ratio of the amount of (sucrose or invert sucrose): (xylitol, sorbitol, or sorbitol solution, or maltitol solution) is 1 :1 to 2.

[0005] WO 2023 / 126637 discloses a spray dried formulation containing fexofenadine which is formed by spray drying a fexofenadine zwitterion dihydrate suspensions on an inert matrix. Examples 2-26 of WO 2023 / 126637 disclose such suspensions containing the sweetener sucralose and fexofenadine on an inert matrix of mannitol, microcrystalline cellulose, and sodium starch glycolate.

[0006] However, the FDA recognized that depending on the source of starch for sodium starch glycolate, there is a potential for gluten content. See FDA Draft Guidance entitled “Gluten in Drug Products and Associated Labeling Recommendations Guidance forIndustry” (December 2017). Similarly, while microcrystalline cellulose is generally safe, some people have been known experience side effects such as gas, bloating, stomach cramps, and constipation. In rare cases, allergic reactions can occur, as a result of the cellulose, as such as e.g., rash, itching, swelling, severe dizziness, or trouble breathing.

[0007] What is therefore needed is a fexofenadine format that effectively taste masks the bitterness of fexofenadine, minimizes the number of excipients to reduce the potential for any allergic reactions, and is easily consumable.SUMMARY OF THE INVENTION

[0008] This disclosure provides for sugar-free chewable fexofenadine tablets, methods of making such tablets and using such tablets to treat allergy.

[0009] One embodiment of the disclosure is directed to sugar-free chewable fexofenadine tablet containing: sprayed and dried fexofenadine granules comprising a mannitol matrix and a composition devoid of a sweetener, said composition having fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer; and an external phase containing a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, and one or more lubricant.

[0010] In one embodiment, the mannitol matrix is 100% mannitol. In another embodiment the wetting agent in the sprayed and dried fexofenadine granules and the external phase is a poloxamer (e.g., poloxamer 407). In further embodiments, the binder in the sprayed and dried fexofenadine granules is hydroxypropyl methylcellulose.

[0011] In certain embodiments, the disintegrant in the external phase is sodium croscarmellose. In further embodiments, diluent in the external phase is xylitol. In some embodiments, the lubricant consists of magnesium stearate and polyethylene glycol.

[0012] In additional embodiments, the sweetener is sucralose. In one embodiment, the sprayed and dried fexofenadine granules having the mannitol matrix and the composition devoid of a sweetener, containing fexofenadine zwitterion dihydrate, a poloxamer as the wetting agent, hydroxypropyl methylcellulose as the binder, an alkalizing agent, and a buffer.

[0013] In certain embodiments, the external phase contains a flavoring agent, sodium croscarmellose as the disintegrant, xylitol as the diluent, sucralose as the sweetener, a poloxamer as the wetting agent, as well as polyethylene glycol and magnesium stearate as the lubricants.

[0014] One embodiment is a sugar-free chewable fexofenadine tablet in which: the sprayed and dried fexofenadine granules include a mannitol matrix and a composition devoid of a sweetener, said composition containing fexofenadine zwitterion dihydrate, a poloxamer, HPMC, an alkalizing agent, and a buffer; and wherein the external phase has a flavoring agent, sodium croscarmellose, xylitol, sucralose, poloxamer, polyethylene glycol, and magnesium stearate.

[0015] In one embodiment of the tablet, the sprayed and dried fexofenadine granules contain from about 15% to about 80% w / w of a mannitol matrix and a composition devoid of a sweetener, said composition containing from about 10 to about 200 mg of fexofenadine zwitterion dihydrate, from about 0.05% to about 10% of a poloxamer w / w, from about 0.5% to about 5% w / w of HPMC, from about 0.5 to about 5.0% w / w of an alkalizing agent, and a from about 0.2% to about 10% w / w buffer; and the external phase contains from about 0.05% to about 5% w / w of a flavoring agent, from about 3% to about 15% w / w of sodium croscarmellose, from about 30% to about 80% w / w of xylitol, from about 0.1 to about 3% w / w of sucralose, from about 0.5% to about 10% w / w of a poloxamer, from about 0.05% to about 10% w / w of a polyethylene glycol, and from about 0.3% to about 10% w / w of magnesium stearate.

[0016] In certain embodiments, the alkalizing agent in the sprayed and dried fexofenadine granules is sodium hydroxide. In other embodiments, the buffer includes sodium phosphate dibasic 2H2O and sodium phosphate monobasic. In certain embodiments, the mannitol is mannitol 200 SD. In further embodiments, the poloxamer is poloxamer 407.

[0017] In further embodiments, the xylitol is xylitol granulated with maize dextrin (Xylisorb XT AB 400). A variety of different polyethylene glycols can be used. In certain embodiments, the polyethylene glycol is PEG 6000. In other embodiments, the binder is HPMC 4 mPa.s and / or HPMC 5 mPa.s.

[0018] The sugar-free chewable fexofenadine tablets are formulated to deliver a desired dosage of fexofenadine such as a 30 mg, 60 mg, 120 mg, or 180 mg dosage of fexofenadine. In some embodiments, the tablet lacks a coating for bitter masking such as an Eudagrit polymer.

[0019] Further embodiments of the disclosure relate to using the sugar-free fexofenadine tablets to treat allergies or to relieve symptoms due to allergy. One embodiment is a method of treating allergy by administering (e.g., consuming) a sugar-free chewable fexofenadine tablet of disclosure. Another embodiment is a method for relieving symptoms due to an allergy by administering (e.g., consuming) a sugar-free chewable fexofenadinetablet of disclosure. Yet another embodiment is the use of the sugar-free chewable fexofenadine tablet of disclosure for relieving symptoms due to an allergy.

[0020] Another aspect of the disclosure is directed to a method of producing a sugar-free chewable fexofenadine tablet including: generating fexofenadine granules by spraying and drying a liquid fexofenadine suspension devoid of a sweetener containing fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer onto a mannitol matrix; and compressing the fexofenadine granules with an external phase containing a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, one or more lubricant. In certain embodiments, the method includes packaging the sugar-free chewable fexofenadine tablet. In certain embodiments, the method includes packaging the tablet in a bottle or a blister package. Accordingly, in certain embodiments, the disclosure is directed to bottles containing the sugar-free chewable tablets. In other embodiments, the disclosure is directed to blister packages containing the sugar-free tablets.

[0021] In one embodiment, the wetting agent in fexofenadine granules and the external phase is a poloxamer. In another embodiment of the method, the liquid fexofenadine suspension devoid of a sweetener includes a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and / or sodium phosphate monobasic.

[0022] In yet another embodiment of the method, the liquid fexofenadine suspension devoid of a sweetener includes a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and sodium phosphate monobasic.

[0023] In certain embodiments of the methods, the external phase includes a flavoring agent, sodium croscarmellose, xylitol, sucralose, poloxamer, polyethylene glycol and / or magnesium stearate.

[0024] In another embodiment of the methods, mannitol is mannitol 200 SD, the poloxamer is poloxamer 407, the xylitol is xylitol granulated with maize dextrin (Xylisorb XT AB 400), and / or the polyethylene glycol is PEG 6000.

[0025] In one embodiment, the method produces a sugar- free chewable tablet formulated to deliver a 30 mg or 60 mg dosage of fexofenadine.

[0026] Other features and advantages of the invention will be apparent from the detailed description and examples that follow.DETAILED DESCRIPTION

[0027] The disclosure is based on the discovery that it is possible to reduce the components of fexofenadine chewable tablets to eliminate certain potential allergens. Thisdisclosure is also based on the discovery that it is possible to eliminate the sweetener from a fexofenadine zwitterion dihydrate suspension and still achieve satisfactory taste masking by including the sweetener solely in the external phase. In addition, this disclosure is based on the discovery that it is possible to use an inert matrix containing only mannitol when turning suspensions of fexofenadine zwitterion dihydrate into granules.

[0028] The general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as defined in the appended claims. Other aspects of the present invention will be apparent to those skilled in the art in view of the detailed description of the invention as provided herein.

[0029] For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into subsections that describe or illustrate certain features, embodiments, or applications of the present invention.I. Definitions

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods, and materials are now described.

[0031] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0032] It is noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0033] Each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0034] As used herein, the term “about” when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ± 20% or ± 10%, more preferably ± 5%, even more preferably ± 1%, and still more preferably ± 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0035] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0036] As used herein, the terms “comprising,” “including,” “containing” and “characterized by” are exchangeable, inclusive, open-ended and do not exclude additional, unrecited elements or method steps. Any recitation herein of the term “comprising,” particularly in a description of components of a composition or in a description of elements of a device, is understood to encompass those compositions and methods consisting essentially of and consisting of the recited components or elements.

[0037] Throughout this specification, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0038] As used herein, the term “consisting of’ excludes any element, step, or ingredient not specified in the claim element.

[0039] Before certain embodiments are described in greater detail, it is to be understood that this invention is not limited to certain embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing certain embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0040] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are alsoencompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0041] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0042] A “subject” or “consumer,” as used therein, may be a human or non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the subject is a human.

[0043] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0044] As used herein, and as well-understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0045] The term “poloxamer” as used herein refers to nonionic triblock copolymers composed of consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol (PEG). Poloxamers are available in the art by the trade names Pluronic, Kolliphor, Lutrol, and Synperonic.

[0046] The terms “fexofenadine zwitterion” and “fexofenadine zwitterion dihydrate” are used interchangeably and refer to 4-[l -hydroxy-4- [4-(hydroxydiphenylmethyl)-l- piperidinyl]-butyl]-a,a-dimethyl benzeneacetic acid dihydrate. Fexofenadine zwitterion dihydrate has the following structure:IL Sugar-free Chewable Fexofenadine Tablets

[0047] One aspect of this disclosure is directed to sugar- free chewable fexofenadine tablets. The sugar- free chewable fexofenadine tablets contain sprayed and dried fexofenadine granules having mannitol matrix and a composition devoid of a sweetener and an external phase. The composition devoid of a sweetener contains fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer (prior to spraying and drying). The external phase contains a flavoring agent, a disintegrant, a wetting agent, a diluent, a sweetener, and one or more lubricant. The same wetting agent is used in the composition devoid of a sweetener and the external phase.

[0048] The sugar- free chewable fexofenadine tablets are based on the discovery that using a mannitol matrix it is possible to eliminate microcrystalline cellulose and sodium croscarmellose. The sugar-free chewable fexofenadine tablets are also based on the discovery that for sprayed and dried granules containing fexofenadine zwitterion dihydrate it is not necessary for the taste masking agent to be part of the granules; rather it is possible for the taste-masking agent (e.g., sweetener) to be part of the external phase.

[0049] The term “chewable” as used herein refers to a dosage form (tablet) that is intended to be chewed and then swallowed by the subject rather than swallowed whole. In some embodiments, the subject chews the tablets, thereby breaking the dosage form into finer particles having a higher surface area. Without wishing to be held to any particular theory, this higher surface area permits the fexofenadine zwitterion to be absorbed more quickly, as compared to an unchewed dosage form.Sprayed and dried Granules

[0050] As noted, the sugar-free chewable fexofenadine tablets contain sprayed and dried fexofenadine granules devoid of a sweetener, which include a fexofenadine zwitteriondihydrate containing composition devoid of a sweetener, a wetting agent, a binder, an alkalizing agent, and a buffer, on a mannitol matrix and a separate external phase.Mannitol Matrix

[0051] As used herein, the term “mannitol matrix” refers to a matrix containing mannitol as the only diluent and / or disintegrant. A mannitol matrix is devoid of diluent and / or disintegrant other than mannitol. In certain embodiments, the matrix is devoid of cellulose and / or sodium croscarmellose. In other embodiments, the mannitol matrix is 100% mannitol or consists of mannitol. In certain embodiments, sugar-free chewable fexofenadine tablets contain from about 15% to about 80% w / w, alternatively from about 30% to about 50% w / w, alternatively from about 30% to about 40% w / w of mannitol.

[0052] In certain embodiments, the sprayed and dried granules are generated by spraying and drying a sugar-free composition (e.g.) suspension devoid of a sweetener containing fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer onto the mannitol matrix.

[0053] In one embodiment, the sugar-free chewable fexofenadine tablets contain: sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition containing fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer; and an external phase containing a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, and one or more lubricant.Fexofenadine

[0054] The amount of the fexofenadine zwitterion dihydrate in the sugar- free chewable fexofenadine tablets may vary. In some embodiments, the sugar-free chewable fexofenadine tablets contain about 10 to about 200 mg of the fexofenadine zwitterion dihydrate. In some embodiments, the sugar-free chewable fexofenadine tablets contain about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, or about 200 mg of fexofenadine zwitterion dihydrate. In other embodiments, the sugar-free chewable fexofenadine tablets contain about 10 to about 180, about 10 to about 160, about 10 to about 140, about 10 to about 120, about 10 to about 100, about 10 to about 80, about 10 to about 60, about 10 to about 40, about 20 to about 200, about 20 to about 180, about 20 to about 160, about 20 to about 140, about 20 to about 120, about 20 to about 100, about 20 to about 80, about 20 to about 60, about 20 to about 40, about 30 to about 200, about 30 to about 180, about 30 to about 160, about 30 to about 140, about 30 to about 120, about 30 to about 100, about 30 to about 80, about 30 to about 60,about 40 to about 200, about 40 to about 180, about 40 to about 160, about 40 to about 140, about 40 to about 120, about 40 to about 100, about 40 to about 80, about 40 to about 60, about 50 to about 200, about 50 to about 180, about 50 to about 160, about 50 to about 140, about 50 to about 120, about 50 to about 100, about 50 to about 80, about 60 to about 200, about 60 to about 180, about 60 to about 160, about 60 to about 140, about 60 to about 120, about 60 to about 100, about 60 to about 80, about 70 to about 200, about 70 to about 180, about 70 to about 160, about 70 to about 140, about 70 to about 120, about 70 to about 100, about 80 to about 200, about 80 to about 180, about 80 to about 160, about 80 to about 140, about 80 to about 120, about 80 to about 100, about 90 to about 200, about 90 to about 180, about 90 to about 160, about 90 to about 140, about 90 to about 120, about 100 to about200, about 100 to about 180, about 100 to about 160, about 100 to about 140, about 100 to about 120, about 110 to about 200, about 110 to about 180, about 110 to about 160, about 110 to about 140, about 120 to about 200, about 120 to about 180, about 120 to about 160, about 120 to about 140, about 130 to about 200, about 130 to about 180, about 130 to about 160, about 140 to about 200, about 140 to about 180, about 140 to about 160, about 150 to about 200, about 150 to about 170, about 160 to about 200, about 160 to about 180, about 170 to about 200, about 180 to about 200, or about 190 to about 200.

[0055] In further embodiments, the sugar-free chewable fexofenadine tablets contain about 30 to about 180 mg of fexofenadine zwitterion dihydrate. In yet other embodiments, the sugar-free chewable fexofenadine tablets contain about 30 mg of fexofenadine zwitterion dihydrate. In still further embodiments, the sugar-free chewable fexofenadine tablets contain about 60 mg of the fexofenadine zwitterion dihydrate. In other embodiments, the sprayed and dried tablets contain about 120 mg of the fexofenadine zwitterion dihydrate. In further embodiments, the sprayed and dried tablets contain about 180 mg of the fexofenadine zwitterion dihydrate.

[0056] In certain embodiments, the tablets contain from about 10 to about 200 mg, alternatively from about 10 to about 100 mg, alternatively from about 20 to about 80 mg of the fexofenadine zwitterion dihydrate.Wetting Agent

[0057] As noted above, the sugar- fexofenadine tablets in preferred embodiments contain the same wetting agent in the fexofenadine composition (suspension) and the external phase. Without being bound by theory, doing so simplifies the compounding of the sugar- free chewable fexofenadine tablets and reduces the number of different components that need to be used during the process of generating the claimed tablets.

[0058] In one embodiment, the wetting agent is a poloxamer. In certain embodiments, the wetting agent is a poloxamer such as poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, or a combination thereof. In one embodiment, the poloxamer is poloxamer 407.

[0059] In some embodiments, the tablets contain from about 0.05% to about 10%, alternatively from about 0.5% to about 3%, alternatively from about 0.5% to about 1.5% of the wetting agent (e.g. poloxamer 407) in the suspension and from about 0.5% to about 10%, alternatively from about 0.5% to about 4%, alternatively from about 1% to about 3% of the wetting agent (e.g. poloxamer 407) in the external phase.

[0060] In certain embodiments, the tablets contain from about 0.05% to about 10% w / w, alternatively from about 0.5% to about 3% w / w, alternatively from about 0.5% to about 1.5% w / w of wetting agent in the suspension and from about 0.5% to about 10% w / w, alternatively from about 0.5% to about 4%, w / w alternatively from about 1% to about 3% w / w of wetting agent in the external phase.Disintegrant

[0061] A variety of different disintegrants can be used in the fexofenadine suspension (composition) devoid of a sweetener. Examples of disintegrants in the granules include, without limitation, sodium croscarmellose, sodium starch glycolate, crospovidone, starch pregelatinized, starch, or hydroxypropylcellulose (HPC), or a combination thereof. In some embodiments, the tablets contain from about 3% to about 15% w / w, alternatively from about 3% to about 10% w / w, alternatively from about 3% to about 8% w / w of the disintegrant.

[0062] In certain embodiments the disintegrant is sodium croscarmellose and no other disintegrants are used. In some embodiments, the tablets contain from about 3% to about 15% w / w, alternatively from about 3% to about 10% w / w, alternatively from about 3% to about 8% w / w of sodium croscarmellose and no other disintegrants are used.Binder

[0063] Examples of suitable binders include, without limitation, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), or carboxymethyl cellulose (CMC), hydroxyethylmethyl cellulose (HEMC), or hydroxyethylcellulose (HEC), or a combination thereof.

[0064] In some embodiments, the binder is HPMC, and no other binders are used. In another embodiment, the binder is HPMC having a viscosity of about 4 to about 100,000mPa.s. In further embodiments, the binder is HPMC 4 mPa.s and / or HPMC 5 mPa.s. In yet another embodiment, the binder is HPMC 5mPa.s.

[0065] In some embodiments, the tablets contain from about 0.5% to about 5% w / w, alternatively from about 0.5 to about 5% w / w, alternatively from about 1 to about 3 of the binder. In other embodiments, the tablets contain from about 0.5% to about 5% w / w, alternatively from about 0.5 to about 5% w / w, alternatively from about 1 to about 3 of HPMC and no other binders are used.Alkalizing agent

[0066] Generally, the alkalizing agent is a strong base. In certain embodiments, the alkalizing agent is potassium hydroxide, calcium hydroxide, sodium hydroxide, or barium hydroxide or a combination thereof. In some embodiments, the alkalizing agent is sodium hydroxide, and no other alkalizing agents are used.

[0067] In some embodiments, the tablets contain from about 0.5 to about 5.0% w / w, alternatively from about 0.5 to about 2.5% w / w, alternatively from about 1 to about 1.5% w / w of the alkalizing agent (e.g., sodium hydroxide).Buffers

[0068] A variety of different buffers can be used in the fexofenadine compositions devoid of a sweetener. Examples of suitable buffers include, without limitation, sodium phosphate dibasic 2H2O, sodium phosphate monobasic, citric acid / sodium phosphate dibasic, sodium phosphate dibasic hydrate, succinic acid / sodium hydroxide, citric acid / sodium citrate, sodium citrate hydrate, potassium citrate, maleic acid / sodium hydroxide, fumaric acid / sodium hydroxide, sodium phosphate monobasic hydrate, potassium phosphate monobasic / sodium phosphate dibasic, sodium phosphate dibasic hydrate, potassium phosphate dibasic, potassium phosphate dibasic hydrate. In some embodiments, the buffer is sodium phosphate monobasic, sodium phosphate monobasic hydrate, potassium phosphate monobasic / sodium phosphate dibasic, sodium phosphate dibasic hydrate, potassium phosphate dibasic, or potassium phosphate dibasic hydrate. In other embodiments, the buffer is sodium phosphate monobasic, sodium phosphate monobasic hydrate and sodium phosphate dibasic, or sodium phosphate dibasic hydrate, or a combination thereof.

[0069] A combination of buffers may be used in the fexofenadine compositions. For example, one, two, or three different buffers. One or more buffers may be used. In some embodiments, one buffer is used. In other embodiments, two buffers are used. In furtherembodiments, three buffers are used. In some embodiments, sodium phosphate monobasic hydrate and sodium phosphate dibasic are used.

[0070] In certain embodiments, the sugar- free chewable tablets contain from about 0.2% to about 10% w / w, alternatively from about 0.5 to about 4% w / w, alternatively from about 1% to about 4% w / w of a buffer. In further embodiments, the sugar-free chewable tablets contain from about 0.2% to about 10% w / w, alternatively from about 0.5 to about 4% w / w, alternatively from about 1% to about 4% w / w of sodium phosphate monobasic hydrate and sodium phosphate dibasic.

[0071] In one embodiment, the composition devoid of a sweetener contains fexofenadine zwitterion dihydrate, a poloxamer as the wetting agent, HPMC as the binder, an alkalizing agent, and a buffer. In another embodiment, the composition devoid of a sweetener contains fexofenadine zwitterion dihydrate, a poloxamer as the wetting agent, HPMC as the binder, sodium hydroxide, and a buffer. In yet another embodiment, the composition devoid of a sweetener contains fexofenadine zwitterion dihydrate, a poloxamer as the wetting agent, HPMC as the binder, sodium hydroxide, and a sodium phosphate monobasic hydrate and sodium phosphate dibasic buffer system.

[0072] In a further embodiment, the composition devoid of a sweetener contains fexofenadine zwitterion dihydrate, poloxamer 407, HPMC (e.g., HPMC 5 mPa.s), an alkalizing agent, and a buffer. In an alternate embodiment, the composition devoid of a sweetener contains fexofenadine zwitterion dihydrate, poloxamer 407, HPMC (e.g., HPMC 5 mPa.s), sodium hydroxide, and a buffer. In yet another embodiment, the composition devoid of a sweetener contains fexofenadine zwitterion dihydrate, poloxamer 407, HPMC (e.g., HPMC 5 mPa.s), sodium hydroxide, and a sodium phosphate monobasic hydrate and sodium phosphate dibasic buffer system.External Phase

[0073] The sugar-free chewable fexofenadine tablets of the disclosure have an external phase. The external phase includes a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, and one or more lubricant.Flavoring Agent

[0074] The external phase contains one or more of flavoring agent. Any flavoring agent approved U.S. FDA or an equivalent regional or local agency (e.g., European Medicines Agency (EMA), European Food Safety Authority (EFSA) and the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK) can be used. Examples of flavoring agents include agents having grape or mint flavors. In one embodiment, theflavoring agent is spearmint flavor, menthol flavor, or a combination thereof. In another embodiment, the flavoring agent is a grape flavor or golden syrup.

[0075] In certain embodiments, the sugar-free chewable tablets contain from about 0.05% to about 5% w / w, alternatively from about 0.1% to 1.5% w / w, alternatively from about 0.1% to about 1% w / w of a flavoring agent.Disintegrants

[0076] A variety of different disintegrants can be used in the external phase of the sugar- free chewable fexofenadine tablets. The external phase of the sugar-free chewable fexofenadine tablets of the disclosure are devoid of sodium starch glycolate, i.e., they do not contain and / or lack sodium starch glycolate. Examples of the disintegrant in the external phase include, without limitation, sodium starch glycolate, crospovidone, starch pregelatinized, starch, or hydroxypropylcellulose (HPC), or a combination thereof. In some embodiments, the disintegrant in the external phase is sodium croscarmellose. In other embodiments, the only disintegrant in the external phase is sodium croscarmellose.

[0077] The external phase contains a wetting agent. In certain embodiments, the wetting agent is the same wetting agent as used in the sugar-free fexofenadine composition (suspension). In one embodiment, the wetting agent is a poloxamer. In certain embodiments, the wetting agent is a poloxamer such as poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, or a combination thereof. In one embodiment, the poloxamer is poloxamer 407. In some embodiments, the sugar-free chewable tablets contain from about 0.5% to about 10% w / w, alternatively from about 0.5% to about 4%, w / w alternatively from about 1% to about 3% w / w of a wetting agent in the external phase.Sweetener

[0078] The external phase contains a sweetener. In preferred embodiments, the sweetener is sucralose. In certain embodiments, the external phase only contains sucralose as the sweetener. In certain embodiments, the sugar-free chewable tablets contain from about 0.1 to 3% w / w, alternatively from about 0.1 to about 1.5 w / w, alternatively from about O.lto about 1% w / w of a sweetener.Lubricant

[0079] In addition, the external phase contains a lubricant. In certain embodiments, the external phase contains two lubricants. Examples of lubricants include, without limitation, polyethylene glycol (PEG), magnesium stearate, sodium stearyl fumarate, stearic acid, sorbitan monostearate, sucrose monopalmitate, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, calcium stearate, zinc stearate, hydrated magnesium silicate, sodiumoleate, sterotex, sodium benzoate, talc, sodium acetate, a wax, sodium lauryl sulfate, or magnesium lauryl sulfate, or a combination thereof In certain aspects, the lubricant is PEG, such as a PEG greater than about 6000 (e.g., PEG 6000 PEG 8000, PEG 20000, or PEG 35000). In other aspects, the lubricant is magnesium stearate. In further aspects, the lubricant is PEG 6000. In further aspect the lubricant is magnesium stearate and PEG. In an alternate aspect, the lubricant is magnesium stearate and PEG 6000. In some embodiments, the external phase uses only two lubricants. In further embodiments, the external phase uses only the lubricants magnesium stearate and PEG (e.g., PEG 6000).

[0080] In some embodiments, the tablets contain from about 0.05% to about 10% w / w, alternatively from about 1% to about 8% w / w, alternatively from 2% to about 6% w / w of a lubricant.

[0081] In other embodiments, the tablets contain from about 0.3% to about 10% w / w, alternatively from about 0.3% to about 1.5% w / w, alternatively from about 0.3% to about 1% w / w of magnesium stearate and from about 0.05% to about 10% w / w, alternatively from about 1% to about 8% w / w, alternatively from 2% to about 6% w / w of another lubricant.Diluent

[0082] The external phase also contains a diluent. Examples of suitable diluents include, without limitation, microcrystalline cellulose, mannitol, maltitol, sucrose, erythritol, calcium phosphate dibasic, calcium phosphate tribasic, isomalt, xylitol, maltodextrin, lactose, starch, sorbitol, sucrose, a sucrose derivative, invert sucrose, lactitol, erythritol, fructose, glucose, calcium carbonate, cellulose, a cellulose derivative, calcium carbonate, calcium lactate, calcium sulfate, or calcium phosphate, or a combination thereof. In one embodiment, the lubricant in the external phase includes xylitol. In another embodiment, the external phase includes xylitol as the only diluent.

[0083] In some embodiments, the sugar-free chewable tablets contain from about 30% to about 80% w / w, alternatively from about 20% to about 40% w / w, alternatively from about 25% to about 35% w / w of a diluent.

[0084] In one embodiment, the external phase includes sodium croscarmellose as the disintegrant, xylitol as the diluent, sucralose as the sweetener, a flavoring agent, a poloxamer as a wetting agent, PEG, and magnesium stearate as lubricants. In another embodiment, the external phase contains sodium croscarmellose, xylitol, sucralose, a flavoring agent, poloxamer 407, PEG, and magnesium stearate. In yet another embodiment, the external phase only contains sodium croscarmellose, xylitol, sucralose, a flavoring agent, poloxamer 407, PEG, and magnesium stearate. In an alternate embodiment, theexternal phase contains sodium croscarmellose, xylitol, sucralose, a flavoring agent, a poloxamer, PEG 6000, and magnesium stearate.

[0085] In one embodiment, the sugar-free chewable fexofenadine tablets include sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition having fexofenadine zwitterion dihydrate, a poloxamer as a wetting agent, a HPMC as binder, an alkalizing agent, and a buffer; and an external phase having a flavoring agent, HPMC as a disintegrant, a poloxamer as a wetting agent, xylitol as a diluent, sucralose a sweetener, and PEG, and magnesium stearate as the lubricant. In another embodiment, the sugar-free chewable fexofenadine tablets include sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition containing fexofenadine zwitterion dihydrate, poloxamer 407, a HPMC, an alkalizing agent, and a buffer; and an external phase having a flavoring agent, sodium croscarmellose, poloxamer 407, xylitol, sucralose, PEG, and magnesium stearate. In an alternate embodiment, the sugar-free chewable fexofenadine tablet includes sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition containing fexofenadine zwitterion dihydrate, a poloxamer, a HPMC, sodium hydroxide, and a buffer; and an external phase having a flavoring agent, sodium croscarmellose, a poloxamer, xylitol, sucralose, PEG, and magnesium stearate. In yet another embodiment, the sugar-free chewable fexofenadine tablets include sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition having fexofenadine zwitterion dihydrate, a poloxamer, a HPMC, sodium hydroxide, and sodium phosphate monobasic hydrate and sodium phosphate dibasic; and an external phase having a flavoring agent, sodium croscarmellose, a poloxamer, xylitol, sucralose, PEG, and magnesium stearate.

[0086] In yet another embodiment, the sugar-free chewable fexofenadine tablets include sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition containing fexofenadine zwitterion dihydrate, poloxamer, HPMC 5mPa.s, an alkalizing agent, and a buffer; and an external phase having a flavoring agent, sodium croscarmellose, a poloxamer, xylitol, sucralose, PEG, and magnesium stearate. In another embodiment, the sugar-free chewable fexofenadine tablets include sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition containing fexofenadine zwitterion dihydrate, a poloxamer, a HPMC, an alkalizing agent, and a buffer; and an external phasehaving a flavoring agent, sodium croscarmellose, a poloxamer, xylitol, sucralose, PEG 6000, and magnesium stearate.

[0087] In another embodiment, the sugar-free chewable fexofenadine tablets include sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition having fexofenadine zwitterion dihydrate, poloxamer 407, a HPMC 5mPa.s, an alkalizing agent, and a buffer; and an external phase having a flavoring agent, sodium croscarmellose, poloxamer 407, xylitol, sucralose, PEG 6000, and magnesium stearate.

[0088] In yet another embodiment, the sugar-free chewable fexofenadine tablets include sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition having fexofenadine zwitterion dihydrate, poloxamer 407, a HPMC 5mPa.s, sodium hydroxide, and a buffer; and an external phase having a flavoring agent, sodium croscarmellose, poloxamer 407, xylitol, sucralose, PEG 6000, and magnesium stearate.

[0089] In an alternate embodiment, the sugar-free chewable fexofenadine tablets include sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition having fexofenadine zwitterion dihydrate, poloxamer 407, a HPMC 5mPa.s, an alkalizing agent, and sodium phosphate monobasic hydrate and sodium phosphate dibasic; and an external phase having a flavoring agent, sodium croscarmellose, poloxamer 407, xylitol, sucralose, PEG 6000, and magnesium stearate. In an additional embodiment, the sugar-free chewable fexofenadine tablets include sprayed and dried fexofenadine granules having a mannitol matrix and a composition devoid of a sweetener, said composition having fexofenadine zwitterion dihydrate, poloxamer 407, a HPMC 5mPa.s, sodium hydroxide, sodium phosphate monobasic hydrate and sodium phosphate dibasic; and an external phase having a flavoring agent, sodium croscarmellose, poloxamer 407, xylitol, sucralose, PEG 6000, and magnesium stearate.

[0090] In certain embodiments, the sugar-free chewable fexofenadine tablets contain:• from about 10 to about 200 mg, alternatively from about 10 to about 100 mg, alternatively from about 20 to about 80 mg of fexofenadine zwitterion dihydrate;• from about 0.05% to about 10% w / w, alternatively from about 0.5% to about 3% w / w, alternatively from about 0.5% to about 1.5% w / w of wetting agent (suspension);• from about 0.5 to about 5.0% w / w, alternatively from about 0.5 to about 2.5% w / w, alternatively from about 1 to about 1.5% w / w of an alkalizing agent;• from about 0.2% to about 10% w / w, alternatively from about 0.5 to about 4% w / w, alternatively from about 1% to about 4% w / w of a buffer;• from about 0.5% to about 5% w / w, alternatively from about 0.5 to about 5% w / w, alternatively from about 1 to about 3w / w of a binder;• from about 15% to about 80% w / w, alternatively from about 30% to about 50% w / w, alternatively from about 30% to about 40% w / w of mannitol;• from about 3% to about 15% w / w, alternatively from about 3% to about 10% w / w, alternatively from about 3% to about 8% w / w of disintegrant;• from about 30% to about 80% w / w, alternatively from about 20% to about 40% w / w, alternatively from about 25% to about 35% w / w of a diluent;• from about 0.1 to 3% w / w, alternatively from about 0.1 to about 1.5 w / w, alternatively from about O.lto about 1% w / w of a sweetener;• from about 0.05% to about 5% w / w, alternatively from about 0.1% to 1.5% w / w, alternatively from about 0.1% to about 1% w / w of a flavoring agent;• from about 0.5% to about 10% w / w, alternatively from about 0.5% to about 4%, w / w alternatively from about 1% to about 3% w / w of wetting agent (external phase); and / or• from about 0.05% to about 10% w / w, alternatively from about 1% to about 8% w / w, alternatively from 2% to about 6% w / w of a lubricant.

[0091] In further embodiments, the sugar-free chewable fexofenadine tablets contain:• from about 10 to about 200 mg, alternatively from about 10 to about 100 mg, alternatively from about 20 to about 80 mg of fexofenadine zwitterion dihydrate;• from about 0.05% to about 10% w / w, alternatively from about 0.5% to about 3% w / w, alternatively from about 0.5% to about 1.5% w / w of wetting agent (suspension);• from about 0.5 to about 5.0% w / w, alternatively from about 0.5 to about 2.5% w / w, alternatively from about 1 to about 1.5% w / w of an alkalizing agent;• from about 0.2% to about 10% w / w, alternatively from about 0.5 to about 4% w / w, alternatively from about 1% to about 4% w / w of a buffer;• from about 0.5% to about 5% w / w, alternatively from about 0.5 to about 5% w / w, alternatively from about 1 to about 3w / w of a binder;• from about 15% to about 80% w / w, alternatively from about 30% to about 50% w / w, alternatively from about 30% to about 40% w / w of mannitol;• from about 3% to about 15% w / w, alternatively from about 3% to about 10% w / w, alternatively from about 3% to about 8% w / w of disintegrant;• from about 30% to about 80% w / w, alternatively from about 20% to about 40% w / w, alternatively from about 25% to about 35% w / w of a diluent;• from about 0.1 to 3% w / w, alternatively from about 0.1 to about 1.5 w / w, alternatively from about O.lto about 1% w / w of a sweetener;• from about 0.05% to about 5% w / w, alternatively from about 0.1% to 1.5% w / w, alternatively from about 0.1% to about 1% w / w of a flavoring agent;• from about 0.5% to about 10% w / w, alternatively from about 0.5% to about 4%, w / w alternatively from about 1% to about 3% w / w of wetting agent (external phase);• from about 0.05% to about 10% w / w, alternatively from about 1% to about 8% w / w, alternatively from 2% to about 6% w / w of a lubricant; and / or• from about 0.3% to about 10% w / w, alternatively from about 0.3% to about 1.5% w / w, alternatively from about 0.3% to about 1% w / w of magnesium stearate.

[0092] In other embodiments, the sugar-free chewable fexofenadine tablets contain:• from about 10 to about 200 mg, alternatively from about 10 to about 100 mg, alternatively from about 20 to about 80 mg of fexofenadine zwitterion dihydrate;• from about 0.05% to about 10% w / w, alternatively from about 0.5% to about 3% w / w, alternatively from about 0.5% to about 1.5% w / w of poloxamer 407 (suspension):• from about 0.5 to about 5.0% w / w, alternatively from about 0.5 to about 2.5% w / w, alternatively from about 1 to about 1.5% w / w of sodium hydroxide;• from about 0.2% to about 10% w / w, alternatively from about 0.5 to about 4% w / w, alternatively from about 1% to about 4% w / w of a buffer;• from about 0.5% to about 5% w / w, alternatively from about 0.5 to about 5% w / w, alternatively from about 1 to about 3 w / w of HPMC;• from about 15% to about 80% w / w, alternatively from about 30% to about 50% w / w, alternatively from about 30% to about 40% w / w of mannitol;• from about 3% to about 15% w / w, alternatively from about 3% to about 10% w / w, alternatively from about 3% to about 8% w / w of sodium croscarmellose;• from about 30% to about 80% w / w, alternatively from about 20% to about 40% w / w, alternatively from about 25% to about 35% w / w of xylitol;• from about 0.1 to about 3% w / w, alternatively from about 0.1 to about 1.5 w / w, alternatively from about O.lto about 1% w / w of sucralose;• from about 0.05% to about 5% w / w, alternatively from about 0.1% to 1.5% w / w, alternatively from about 0.1% to about 1% w / w of a flavoring agent;• from about 0.5% to about 10% w / w, alternatively from about 0.5% to about 4% w / w, alternatively from about 1% to about 3% w / w of poloxamer 407 (external phase);• from about 0.05% to about 10% w / w, alternatively from about 1% to about 8% w / w, alternatively from 2% to about 6% w / w of PEG 6000; and / or • from about 0.3% to about 10% w / w, alternatively from about 0.3% to about 1.5% w / w, alternatively from about 0.3% to about 1% w / w of magnesium stearate.

[0093] In certain embodiments, the sugar- free chewable fexofenadine tablets contain the following components in the following amounts. The amount for any one of the components shown in any one of the embodiments in Tables below can be combined with the amount of a component for any of the other embodiments.

[0094] The sugar- free chewable fexofenadine tablets lack a coating lawyer for bitter taste masking. In some embodiments, the sugar-free chewable tablet lacks a coating that contains a Eudagrit polymer.

[0095] The disclosure also includes bottles containing the sugar-free chewable tablets. In other embodiments, the disclosure includes blister packages containing the sugar-free tablets. / / / . Methods of Making Sugar-Free Chewable Fexofenadine Tablets

[0096] The disclosure also provides methods of making the sugar-free chewable fexofenadine tablets of the disclosure. The methods produce sugar-free chewable fexofenadine tables that contain the fexofenadine in zwitterionic form.

[0097] In certain embodiments, the sugar-free chewable tablets are generated by a process that involves preparing the liquid fexofenadine zwitterion dihydrate suspension devoid of a sweetener, preparing of the sprayed and dried fexofenadine zwitterion dihydrate form, and the preparing the final tablets. In certain embodiments, the process includes: generating fexofenadine granules by spraying and drying a liquid fexofenadine suspension devoid of a sweetener containing fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer onto a mannitol matrix; and compressing the fexofenadine granules with an external phase containing a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, one or more lubricant.A. Preparation of the Liquid Fexofenadine Zwitterion Dihydrate Suspension Devoid of a Sweetener.

[0098] The fexofenadine zwitterion dihydrate suspensions devoid of a sweetener for use in the spraying and drying process is prepared as described herein. As used herein, a suspension is devoid of a sweetener when it does not contain (lacks) an added sweetener.

[0099] First, fexofenadine hydrochloride, water, and wetting agent are combined. In some embodiments, fexofenadine hydrochloride is combined with a solution comprising water and the wetting agent. The wetting agent is selected so as to facilitate the incorporation of fexofenadine hydrochloride in water and / or increase wettability. While a number of wetting agents may be utilized and include, without limitation, a poloxamer,polysorbate, or polyoxyl hydrogenated castor oil, to generate the sugar-free chewable fexofenadine tablets of the disclosure a poloxamer is used.

[0100] In some embodiments, the wetting agent is a poloxamer such as poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, or a combination thereof. In one embodiment, the poloxamer is poloxamer 407.

[0101] Following the step with the wetting agent, the composition is combined with an alkalizing agent. Without being bound by theory, it is thought that use of an alkalizing agent reduces the amounts of solids present in the compositions, thereby reducing viscosity, thereby permitting spraying, and drying of the in later steps, while simultaneously maintaining the highest concentration of fexofenadine hydrochloride. Typically, the alkalizing agent is a strong base. In certain embodiments, the alkalizing agent is potassium hydroxide, calcium hydroxide, sodium hydroxide, or barium hydroxide, among others. In one embodiment, the alkalizing agent is sodium hydroxide. The molar ratio of the alkalizing agent to fexofenadine hydrochloride is about 0.8:1 to about 1.2:1. In certain aspects, molar ratio of the alkalizing agent to fexofenadine hydrochloride is about 1 :1.

[0102] The pH of the resulting composition can be adjusted in situ to about 5.8 to about 7 using one or more of a buffer. In some embodiments, the pH is adjusted to about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7. In other embodiments, the pH is adjusted to about 5.8 to about 7, about 5.8 to about 6.8, about 5.8 to about 6.6, about 5.8 to about 6.4, about 5.8 to about 6.2, about 5.8 to about 6, 6 to about 7, about 6 to about 6.8, about 6 to about 6.6, about 6 to about 6.4, about 6 to about 6.2, about 6.2 to about 7, about 6.2 to about 6.8, about 6.2 to about 6.6, about 6.2 to about 6.4, about 6.4 to about 7, about 6.4 to about 6.8, about 6.4 to about 6.6, about 6.6 to about 7, about 6.6 to about 6.8, or about 6.8 to about 7. Examples of suitable buffers include, without limitation, sodium phosphate dibasic 2H2O, sodium phosphate monobasic, citric acid / sodium phosphate dibasic, sodium phosphate dibasic hydrate, succinic acid / sodium hydroxide, citric acid / sodium citrate, sodium citrate hydrate, potassium citrate, maleic acid / sodium hydroxide, fumaric acid / sodium hydroxide, sodium phosphate monobasic hydrate, potassium phosphate monobasic / sodium phosphate dibasic, sodium phosphate dibasic hydrate, potassium phosphate dibasic, potassium phosphate dibasic hydrate. In some embodiments, the buffer is sodium phosphate monobasic, sodium phosphate monobasic hydrate, potassium phosphate monobasic / sodium phosphate dibasic, sodium phosphate dibasic hydrate, potassium phosphate dibasic, or potassium phosphate dibasic hydrate. In other embodiments, the buffer is sodium phosphate monobasic, sodiumphosphate monobasic hydrate and sodium phosphate dibasic, or sodium phosphate dibasic hydrate, or a combination thereof. One or more buffers may be used. In some embodiments, one buffer is used. In other embodiments, two buffers are used. In further embodiments, three buffers are used. In one embodiment, sodium phosphate monobasic hydrate and sodium phosphate dibasic are used.

[0103] The process of the disclosure does not involve use of a sweetener when preparing the fexofenadine zwitterion dihydrate suspensions. Accordingly, the process does not include a step of combining the buffered suspension with a sweetener.

[0104] A binder can be combined with the resulting suspension lacking the sweetener. The binder is selected to stabilize the formulation, e.g., steric stabilizing, and to avoid particle agglomeration. Examples of binders include, without limitation, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), or carboxymethyl cellulose (CMC), hydroxyethylmethyl cellulose (HEMC), or hydroxyethylcellulose (HEC), or a combination thereof.

[0105] In one embodiment, the binder is HPMC. In another embodiment, the binder is HPMC having a viscosity of about 4 to about 100,000 mPa.s. In further embodiments, the binder is HPMC 4 mPa.s or HPMC 5 mPa.s.

[0106] The fexofenadine zwitterion dihydrate suspension devoid of a sweetener, including the alkalizing agent, buffer, and binder, has a pH of about 5.8 to about 7. In some embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about 7. In other embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 5.8. In further embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 5.9. In yet other embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 6. In still further embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 6.1. In other embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 6.2. In further embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 6.3. In still other embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 6.4. In yet further embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 6.5. In still further embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 6.6. In other embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 6.7. In further embodiments, the pH of the fexofenadine zwitterion dihydrate composition is about 5.8 to about 7, about5.8 to about 6.9, about 5.8 to about 6.8, about 5.8 to about 6.7, about 5.8 to about 6.6, about5.8 to about 6.5, about 5.8 to about 6.4, about 5.8 to about 6.3, about 5.8 to about 6.2, about5.8 to about 6.1, about 5.8 to about 6, about 5.8 to about 5.9, about 5.9 to about 7, about 5.9 to about 6.9, about 5.9 to about 6.8, about 5.9 to about 6.7, about 5.9 to about 6.7, about 5.9 to about 6.6, about 5.9 to about 6.5, about 5.9 to about 6.4, about 5.9 to about 6.3, about 5.9 to about 6.2, about 5.9 to about 6.1, about 5.9 to about 6, about 6 to about 7, about 6 to about 6.9, about 6 to about 6.8, about 6 to about 6.7, about 6 to about 6.6, about 6 to about 6.5, about 6 to about 6.4, about 6 to about 6.3, about 6 to about 6.2, about 6 to about 6.1, about 6.1 to about 7, about 6.1 to about 6.9, about 6.1, to about 6.8, about 6.1 to about 6.7, about 6.1 to about 6.6, about 6.1 to about 6.5, about 6.1 to about 6.4, about 6.1 to about 6.3, about 6.1 to about 6.2, about 6.2 to about 7, about 6.2 to about 6.9, about 6.2 to about 6.8, about 6.2 to about 6.7, about 6.2 to about 6.6, about 6.2 to about 6.5, about 6.2 to about 6.4, about 6.2 to about 6.3, about 6.3 to about 7, about 6.3 to about 6.9, about 6.3 to about 6.8, about 6.3 to about 6.7, about 6.3 to about 6.6, about 6.3 to about 6.5, about 6.3 to about 6.4, about 6.4 to about 7, about 6.4 to about 6.9, about 6.4 to about 6.8, about 6.4 to about 6.7, about 6.4 to about 6.6, about 6.4 to about 6.5, about 6.5 to about 6.9, about 6.5 to about 6.8, about 6.5 to about 6.7, about 6.5 to about 6.6, about 6.6 to about 7, about 6.6 to about 6.9, about 6.6 to about 6.8, about 6.6 to about 6.7, about 6.7 to about 7, about 6.7 to about 6.9, about 6.7 to about 6.8, about 6.8 to about 7, about 6.8 to about 6.9, or about 6.9 to about 7.

[0107] In one embodiment, the step of preparing the liquid fexofenadine zwitterion dihydrate suspension devoid of a sweetener uses only a poloxamer as the wetting agent, only sodium hydroxide as the alkalizing agent, and only hydroxypropylmethylcellulose (HPMC) as the binder. In certain embodiments, the buffers used are limited to sodium phosphate monobasic hydrate and sodium phosphate dibasic.

[0108] In one embodiment, step of preparing the liquid fexofenadine zwitterion dihydrate suspension devoid of a sweetener uses only poloxamer 407 as the wetting agent, only sodium hydroxide as the alkalizing agent, and only HPMC 5 mPa.s as the binder. In one embodiment, the poloxamer 407 is Kolliphor® P 407 Geismar. In certain embodiments, the step of preparing also includes use of sodium phosphate monobasic hydrate and sodium phosphate dibasic as the buffer.

[0109] The processes for forming fexofenadine zwitterion dihydrate suspension can be performed using equipment known in the art. In certain embodiments, the fexofenadine zwitterion dihydrate composition is prepared using a rotor-stator homogenizer. During thepreparation of the fexofenadine zwitterion dihydrate composition, the fexofenadine zwitterion dihydrate particles are suspended and air is incorporated into the composition.B. Preparation of the Sprayed and dried Fexofenadine Zwitterion Dihydrate Formulation

[0110] The fexofenadine zwitterion dihydrate suspension is then sprayed and dried to provide a sprayed and dried fexofenadine zwitterion dihydrate granules. The resultant granules are not bitter tasting and, regardless of subsequent steps that are performed to the granules, the fexofenadine zwitterion dihydrate does not convert to fexofenadine hydrochloride. The granules comprise a sprayed and dried formulation containing fexofenadine zwitterion dihydrate that is obtained by spraying and drying (i) a fexofenadine zwitterion dihydrate suspension; and (ii) an inert matrix.

[0111] Spraying and drying for use herein can be performed using several techniques and instruments. In some embodiments, the spraying and drying is performed using a fluid bed and a spray system. A fluid bed combines the granulation and drying steps. The spray system provides granules that are well granulated. In some embodiments, the spray system is top spraying. In other embodiments, the spray system is bottom spraying. In further embodiments, the spray system is tangential.

[0112] The spraying and drying are performed using an inert matrix. The components of the inert matrix include one or more pharmaceutically acceptable excipients. Desirably, the one or more pharmaceutically acceptable excipients maintain the fexofenadine zwitterion dihydrate form in the granules, i.e., the fexofenadine zwitterion dihydrate does not convert to fexofenadine hydrochloride. In some embodiments, the pharmaceutically acceptable excipients maintain a pH of about 5.5 to about 7 to avoid the formation of fexofenadine hydrochloride. In other embodiments, the pharmaceutically acceptable excipients maintain a pH of about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9 or about 7. In other embodiments, the pharmaceutically acceptable excipient is a diluent, binder, glidant, or disintegrant, or a combination thereof.

[0113] In certain embodiments, the inert matrix only contains a diluent.

[0114] Examples of suitable diluents include, without limitation, microcrystalline cellulose, mannitol, maltitol, sucrose, erythritol, calcium phosphate dibasic, calcium phosphate tribasic, isomalt, xylitol, maltodextrin, lactose, starch, sorbitol, sucrose, a sucrose derivative, invert sucrose, lactitol, erythritol, fructose, glucose, calcium carbonate, cellulose,a cellulose derivative, calcium carbonate, calcium lactate, calcium sulfate, or calcium phosphate, or a combination thereof.

[0115] In one embodiment, the diluent is mannitol, such as e.g., mannitol SD200. In another embodiment, the matrix is 100% mannitol. As noted in Example 4 below, in certain embodiments, the matrix used in tablets of the claimed invention is 100% mannitol.

[0116] The matrix can be a mannitol matrix as defined herein. Compared to using a combination of mannitol, microcrystalline cellulose, and sodium croscarmellose, use of a mannitol matrix provides several advantages including exclusion of intermediate drying steps during granulation. Mannitol is available in the art as a variety of products. In yet other aspects, the diluent is mannitol having a pH if about 6 to about 7, such as 6.3.

[0117] The matrix used in the methods of the disclosure is devoid of a disintegrant. In some embodiments, the matrix used in the methods of the disclosure is devoid of a diluent other than mannitol. In some embodiments, the matrix is devoid of diluent and / or disintegrant other than mannitol. In other embodiments, the matrix is devoid of cellulose and / or sodium croscarmellose.C. Preparation of the Fexofenadine Zwitterion Dihydrate Final Drug Product

[0118] After formation of the sprayed and dried granules the fexofenadine zwitterion dihydrate, which are devoid of a sweetener, additional steps may be performed to incorporate an external phase. In some embodiments, the external phase is included and integrates with the granules.

[0119] In some embodiments, an external phase is provided by combining the sprayed and dried formulation with a disintegrant, a diluent, one or more flavoring agents, a second portion of the wetting agent, one or more lubricants, or combination thereof. In other embodiments, an external phase is provided by combining the sprayed and dried formulation with a disintegrant, a diluent, one or more flavoring agents, a second portion of the wetting agent, one or more lubricants.

[0120] In certain embodiments, the preparation of the final drug product includes compressing fexofenadine granules (as generated above) into a chewable tablet. In certain embodiments, the method of a sugar-free chewable fexofenadine tablet includes: generating fexofenadine granules by spraying and drying a liquid fexofenadine suspension devoid of a sweetener comprising fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer onto a mannitol matrix; and compressing the fexofenadine granules with an external phase comprising a flavoring agent, a disintegrant, the wettingagent, a diluent, a sweetener, one or more lubricant. In certain embodiments of the method, the wetting agent in fexofenadine granules and the external phase is a poloxamer. In further embodiments, the liquid fexofenadine suspension devoid of a sweetener contains a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and / or sodium phosphate monobasic. In further embodiments, the liquid fexofenadine suspension devoid of a sweetener comprises a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and sodium phosphate monobasic. In further embodiments, the external phase comprises a flavoring agent, sodium croscarmellose, xylitol, sucralose, poloxamer, polyethylene glycol and / or magnesium stearate. In certain embodiments, the mannitol is mannitol 200 SD, the poloxamer is poloxamer 407, the xylitol is xylitol granulated with maize dextrin (Xylisorb XT AB 400), the polyethylene glycol is PEG 6000. In certain embodiments, the method produces a sugar- free chewable tablet formulated to deliver a 30 mg or 60 mg dosage of fexofenadine. The method can also include packaging the sugar-free chewable fexofenadine tablet in, for example, a bottle or a blister package.

[0121] In certain embodiments, the sprayed and dried formulation is combined with a disintegrant, whereby the granules are devoid of a disintegrant. In certain embodiments, the granules are devoid of diluent and / or disintegrant other than mannitol. Examples of the disintegrant in the external phase include, without limitation, crospovidone, starch pregelatinized, starch, or hydroxypropylcellulose (HPC), or a combination thereof. In some embodiments, the disintegrant in the external phase is sodium croscarmellose. In other embodiments, the only disintegrant in the external phase is sodium croscarmellose.

[0122] In further aspects, the sprayed and dried formulation is combined with the diluent. Examples of the diluent include, without limitation, microcrystalline cellulose, mannitol, maltitol, sucrose, erythritol, calcium phosphate dibasic, calcium phosphate tribasic, isomalt, xylitol, maltodextrin, lactose, starch, sorbitol, sucrose, a sucrose derivative, invert sucrose, lactitol, erythritol, fructose, glucose, calcium carbonate, cellulose, a cellulose derivative, calcium carbonate, calcium lactate, calcium sulfate, or calcium phosphate, or a combination thereof. In certain embodiments, the diluent is not mannitol. In one embodiment, the diluent is xylitol, such as e.g., xylitol granulated with maize dextrin (Xylisorb XT AB 400).

[0123] In yet other aspects, the sprayed and dried formulation is combined with a flavoring agent that has been approved for use in humans by the U.S. FDA or an equivalent regional or local agency (e.g., European Medicines Agency (EMA), European Food SafetyAuthority (EFSA) and the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK).

[0124] In still further aspects, the sprayed and dried formulation is combined with a second portion of the wetting agent used in A. above. Examples of wetting agents include, without limitation, a poloxamer, polysorbate, or polyoxyl hydrogenated castor oil. In some embodiments, the wetting agent is a poloxamer such as poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407, or a combination thereof. In one embodiment, the wetting agent is poloxamer 407.

[0125] In other aspects, the sprayed and dried formulation is combined with one or more lubricants. Examples of lubricants include, without limitation, polyethylene glycol (PEG), magnesium stearate, sodium stearyl fumarate, stearic acid, sorbitan monostearate, sucrose monopalmitate, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, calcium stearate, zinc stearate, hydrated magnesium silicate, sodium oleate, sterotex, sodium benzoate, talc, sodium acetate, a wax, sodium lauryl sulfate, or magnesium lauryl sulfate, or a combination thereof. In certain aspects, the lubricant is PEG, such as a PEG greater than about 6000 e.g., PEG 6000 PEG 8000, PEG 20000, or PEG 35000). In other aspects, the lubricant is magnesium stearate. In further aspects, the lubricant is PEG 6000. In further aspect the lubricant is magnesium stearate and PEG. In an alternate aspect, the lubricant is magnesium stearate and PEG 6000. In some embodiments, the external phase uses only two lubricants. In further embodiments, the external phase uses only the lubricants magnesium stearate and PEG (e.g., PEG 6000).

[0126] In one embodiment, the sprayed and dried formulation is combined with a disintegrant, a diluent, one or more flavoring agents, a second portion of the wetting agent, a sweetener, and one or more lubricants. In certain embodiments, the sprayed and dried formulation is combined with sodium croscarmellose, xylitol, one or more flavoring agents, Poloxamer 407, mannitol, PEG 6000, and magnesium stearate.

[0127] In further embodiments, the method of producing sugar-free chewable fexofenadine tablets includes: generating fexofenadine granules by spraying and drying a liquid fexofenadine suspension devoid of a sweetener containing fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer onto a mannitol matrix; and compressing the fexofenadine granules with an external phase containing a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, one or more lubricant. The method can also include packaging the sugar-free chewable fexofenadine tablet. In some embodiments, the wetting agent in fexofenadine granules and the externalphase is a poloxamer. In certain embodiments of the methods, the liquid fexofenadine suspension devoid of a sweetener contains a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and / or sodium phosphate monobasic.

[0128] In other embodiments, the liquid fexofenadine suspension devoid of a sweetener contains a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and sodium phosphate monobasic.

[0129] In other embodiments of the methods, the external phase comprises a flavoring agent, sodium croscarmellose, xylitol, sucralose, poloxamer, polyethylene glycol and / or magnesium stearate. In certain embodiments, the mannitol is mannitol 200 SD, the poloxamer is poloxamer 407, the xylitol is xylitol granulated with maize dextrin (Xylisorb XT AB 400), and the polyethylene glycol is PEG 6000.

[0130] In certain embodiments, the methods of the disclosure may be used to produce a sugar-free chewable tablet formulated to deliver a 30 mg or 60 mg dosage of fexofenadine.IV Uses of Sugar-Free Chewable Fexofenadine Tablets

[0131] The sugar-free chewable fexofenadine tablets described herein are useful in relieving symptoms due to an allergy in a patient in need thereof. The methods include administering a therapeutically effective amount of the sugar-free chewable fexofenadine tablets to the patient.

[0132] One of skill in the would be able to determine suitable allergies that may be treated using the described sugar-free chewable fexofenadine tablets. For example, the allergies may be due to indoor or outdoor allergens. In some embodiments, the allergy is due to one or more indoor allergens. A variety of indoor allergens are known and include dust mites, a pet allergen, or mold. In further embodiments, the allergy is due to dust mites. In other embodiments, the allergy is due to a pet allergen, e.g., such as in animal saliva, animal urine or animal dander. In still further embodiments, the allergy is due to indoor mold. In yet other embodiments, the allergy is due to one or more outdoor allergens. A few outdoor allergies are known in the part and include, without limitation, pollen, and mold. In some embodiments, the outdoor allergy is pollen such as from grass, weeds, or trees. In other embodiments, the outdoor allergy is from outdoor mold.

[0133] The allergy may result in any number of symptoms in the patient. For examples, the patient may develop one or more of red eye, itchy eye, watery eye, itchy nose, runny nose, stuffy nose, sneezing, nasal congestion, wheezing, coughing, chest tightness, facial pain, rash, hives, shortness of breath, cough, postnasal drip, itchy throat, dry skin, sinuspressure, decreased sense of smell, decreased sense of taste, or poor sleep quality. In some embodiments, the symptom is red eye. In other embodiments, the symptom is itchy eye. In further embodiments, the symptom is watery eye. In yet other embodiments, the symptom is an itchy nose. In still further embodiments, the symptom is a runny nose. In other embodiments, the symptom is a stuffy nose. In further embodiments, the symptom is sneezing. In still other embodiments, the symptom is nasal congestion. In yet further embodiments, the symptom is wheezing. In other embodiments, the symptom is coughing. In further embodiments, the symptom is chest tightness. In yet other embodiments, the symptom is facial pain. In still further embodiments, the symptom is rash. In other embodiments, the symptom is hives. In further embodiments, the symptom is shortness of breath. In yet other embodiments, the symptom is a cough. In still further embodiments, the symptom is postnasal drip. In other embodiments, the symptom is an itchy throat. In further embodiments, the symptom is dry skin. In still other embodiments, the symptom is sinus pressure. In yet further embodiments, the symptom is a decreased sense of smell. In other embodiments, the symptom is a decreased sense of taste. In further embodiments, the symptom is poor sleep quality. Thus, the methods described herein are useful in treating these symptoms. In some embodiments, the methods ameliorate one or more, or all, of the symptoms. In other embodiments, the methods reduce the number of symptoms in the patient. In further embodiments, the methods prevent the onset of one or more symptoms in the patient.

[0134] The sugar- free chewable fexofenadine tablets are, thus, useful in relieving symptoms due to an upper respiratory allergy in a patient in need thereof. The methods include administering a therapeutically effective amount of the sugar- free chewable fexofenadine tablets described herein to the patient. In some embodiments, the symptom is a runny nose, itchy, watery eye, sneezing, itching of the nose, itching of the throat, or a combination thereof. In further embodiments, the upper respiratory allergy is hay fever.

[0135] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples, therefore, specifically point out the preferred embodiments of the present invention and are not to be construed as limiting in any way the remainder of the disclosure.Examples

[0136] While the invention has been described and illustrated herein by references to various specific materials, procedures, and examples, it is understood that the invention is not restricted to the particular combinations of material and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary, only, with the true scope and spirit of the invention being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.Example 1 - Allegra chewable tablets - Developmental ChallengesObjective

[0137] In the target product profile, it was required to develop a chewable tablet for which consumer benefits are: a ready to use product; no need for water; and easy to consume for kids.

[0138] The excipients were chosen based on their function and the product has been formulated using common excipients complying with the current standards in effect (USP, NF monographs) except for flavors, which are controlled according to in-house monograph, as usual. The quantities used for the excipients (except flavors that are not listed) are below the quantities allowed for by the FDA for oral forms, as listed in the FDA Inactive Ingredients Database (IID).

[0139] To produce the product, initially a suspension is prepared to convert Fexofenadine Hydrochloride to Fexofenadine Zwitterion, and further, the suspension is sprayed & dried in an inter matrix, generating the granules (internal phase), that are associated to an external phase, resulting in the final product. The general process to create fexofenadine is described in WO 2023 / 126637, the disclosure of which is incorporated in its entirety to the extent it relates to spray-on formulations containing fexofenadine.

[0140] The formula is homothetic for the two strengths: 30mg and 60mg, having just different flavors.Development challenges

[0141] The main challenge to develop a chewable tablet of Fexofenadine Hydrochloride is the bitterness of fexofenadine. To solve this challenge, conversation of fexofenadineHydrochloride, which is bitter, to Fexofenadine Zwitterion, which is not bitter, through an acid-base reaction between Fexofenadine Hydrochloride and Sodium Hydroxide, followed by the addition of a buffer system, to maintain the pH in the great range to maintain Fexofenadine in the zwitterionic form (5.8 - 7.0), was proposed. Further, the resultant suspension was sprayed and dried over an inert matrix, resulting in not bitter granules that can be used in oral solid dosage forms, as chewable tablets.

[0142] The main advantages of combining chemical reaction and granulation process are:• The starting API used is Fexofenadine Hydrochloride salt, which is already registered and commercialized, thus no new salt of Fexofenadine to be developed or registered.• It is based on conventional processes, not requiring special technology for taste masking.

[0143] During the formula development, the main challenge was to reach the balance between good mouthfeel, maintaining a good tablet disintegration / dissolution. Even if disintegration is not relevant for a chewable tablet, since the tablet will be chewed before swallowed, the FDA recommends that chewable tablets should typically meet the same disintegration and dissolution specifications as IR tablets, meaning that the disintegration time should be short enough to prevent GI obstruction in the event a tablet is not completely chewed by the patient. Invitro disintegration testing, and in vitro dissolution testing should be conducted using intact tablets since it is possible that some patients might swallow the tablets without chewing.

[0144] The good balance was achieved by concentrating the API in the granules, which allowed to increase the percentage of excipients in the external phase, as the inclusion of Xylitol DC (Xylisorb XTab 400), a diluent that provides a good mouthfeel and a good compressibility.

[0145] The manufacturing process selected for the product was wet granulation in fluid bed, since the quantity of water used in the suspension is high, it is important during the granulation to associate spraying and drying process. The spray technology selected was the tangential spray (Huttlin equipment).Example 2 - Chewable Fexofenadine Formulations

[0146] As outlined in Examples 3-X, in certain embodiments chewable fexofenadine formulation of the disclosure can contain the following excipients.Suspension

[0147] Water: Water was selected as the solvent for suspension preparation / wet granulation. Water is removed during the granulation process, therefore, the concentration used is not listed in the final formula.

[0148] Poloxamer 407 micronized: Poloxamers are nonionic polyoxyethylenepolyoxypropylene co-polymers used in the formula as wetting agent in the suspension, to facilitate the incorporation of Fexofenadine in water. It was also tested to use Poloxamer 188 at the same concentration, but a bitter taste was noticed. Based on it, Poloxamer 407 was selected. The concentration used in the suspension is the quantity that does not impact the taste and ensures a good incorporation of Fexofenadine in the water.

[0149] Sodium Hydroxide: Alkalizing agent used in the formula at equimolar (1 :1) quantity of Fexofenadine Hydrochloride, to allow an in-situ conversion of Fexofenadine Hydrochloride to Fexofenadine zwitterion, through a simple acid-base reaction.

[0150] Sodium Phosphate Dibasic dihydrate: buffer agent included in the formula to maintain the pH in the range between 5.80 to about 7.0, that is important to have Fexofenadine in zwitterion form. Different quantities were tested, and this was the minimal quantity that enabled a stable pH even after 1 month of the suspension preparation.

[0151] Sodium Phosphate Monobasic hydrate: buffer agent included in the formula to maintain the pH in the range between 5.80 to about 7.0, that is important to have Fexofenadine in zwitterion form. Different quantities were tested, and this was the minimal quantity that enabled a stable pH even after 1 month of the suspension preparation. It is important to maintain the ratio between Sodium Phosphate Dibasic and Monobasic, to achieve the right range of pH (around 6.0 and 7.0).

[0152] HPMC (Hypromellose 5 mPa.s) was selected as binder for granules, to promote the cohesiveness between the API and the excipients present in the internal phase. HPMC was chosen also due to the stabilizer properties for suspension, by steric stabilization, avoiding particles agglomeration. Higher quantities were tested in the beginning of the prototyping phase, but it impacted the product dissolution profile. Eower concentrations are not enough to have the right API fixation in the inert matrix.

[0153] Povidone was not selected as binder, because it can form an unknown impurity with Fexofenadine Zwitterion.Granulation

[0154] The suspension is sprayed and dried in an inert matrix of mannitol.

[0155] Mannitol 200 SD: Mannitol 200 SD was selected as the diluent because of its negative heat of solution, sweetness, and “mouth feel”, that are great properties for chewable tablets, and due to its pH (Mannitol solution has a pH around 6.3), important to maintain Fexofenadine at zwitterionic form in the granules. Granulations containing mannitol have the advantage of being dried easily. The final concentration used in the granules was 38.48%. The quantity was determined to ensure the right fluid bed filling to start the granulation and to have the right quantity of solid support for the high level of suspension.External phase for tableting

[0156] Further, an external phase is integrated with the granules. The external phase is composed of the following:

[0157] Sodium croscarmellose: Sodium croscarmellose was selected as a super disintegrant, to promote a faster tablet disintegration. The concentration was defined based on the tablet disintegration time and the dissolution profiles at pH 1.2.

[0158] Xylitol DC (Direct compression) (Xylisorb XTAB 400 (Approximately 98% of Xylitol / 2%o of Sodium Carboxymethyl Cellulose): Xylitol was selected as diluent for the external phase, as xylitol has an equal sweetness intensity to sucrose, combined with a distinct cooling effect (higher than Mannitol), without the “chalky” texture experienced with some other tablet diluents. During the development, the Xylitol non-DC was already tested, however, the compressibility of the product was not good enough as using the Xylitol DC.

[0159] Sucralose: Sucralose was selected as the sweetening agent due to its strong sweetening power and no aftertaste. In the beginning of the development, sucralose was added in the suspension, to balance the salty taste observed due to the generation of sodium chloride during the conversion of Fexofenadine HC1 to Fexofenadine Zwitterion. However, it was decided to include sucralose in the external phase, due to the fact that (as explained in the Handbook of excipients) “[s]ucralose, when heated at elevated temperatures, may break down with the release of carbon dioxide, carbon monoxide, and minor amounts of hydrogenchloride”, what could provide a bitter taste to the product in case of forming Fexofenadine HC1. The final concentration used in the drug product was the maximum quantity with which an aftertaste of sucralose was not observed in the final product.

[0160] The polyols were included in the formulation, due to their good mouth feeling, however, they can negatively impact the bioavailability, since they accelerate the intestinal transit, reducing the timing of the API exposure in the absorption site (jejunum for Fexofenadine). As a result of the absorption site, it was recommended by PK team to include bioavailability enhancers in the formula (Poloxamer and PEG).

[0161] Poloxamer 407: Poloxamers can increase Fexofenadine solubility, when used at concentration > 5%, according to the solubility test carried out. Poloxamer is known to inhibit P-gp-mediated efflux activity and enhance the permeability of several P-gp substrate drugs across the intestine. Initially, it was tested to include all the Poloxamer of the formula in the suspension, however, a bitter taste was noticed since the percentage increased (above 1,15% of the final formula). As at this stage Fexofenadine was already dried, bitter taste was not noticed in the tablets. However, during the scale-up at 50 Kg, the dissolution profiles at pH 1.2 demonstrated a very low dissolution at this media. The analytical team observed gelling in the tablet in this media, not observed in the other pHs. According to the literature, Poloxamer at temperatures above 35°C and at acid pHs can form a gel. Then, it was decided to reduce the concentration of Poloxamer in the external phase, trying to reduce the impact in the tablet dissolution at pH 1.2.

[0162] PEG 6000: PEG 6000 was included in the external phase as solubility agent, to improve Fexofenadine bioavailability. According to the literature, the P-gp inhibitory activity of PEG increased the absorption of P-gp substrate drugs. (Improved Dissolution Rate and Intestinal Absorption of Fexofenadine Hydrochloride by the Preparation of Solid Dispersions: In Vitro and In Situ Evaluation - PMC (nih.gov)) Studies demonstrated that PEG low grades (as 200, 300 and 400) can enhance Fexofenadine bioavailability. However, the PEG low grades are liquid, and when included in the suspension, a bitter taste was noticed. It was decided to include a PEG with higher grade, not so efficient, but at solid form, and that does not impact the product taste. The final concentration used in the drug product was defined based on the quantities of PEG tested in vivo during the development of Allegra Oral Gum (3 and 6% of PEG).

[0163] Flavors: Two flavors for each dosage were selected. For the adults’ product, the two flavors selected were: spearmint flavor and menthol flavor. For the kids’ dosage, the flavors selected were grade flavor and golden syrup flavor. The flavors are incorporated asa dry powder in the external phase. The concentrations used were determined to ensure a good taste and, considering the maximum quantity allowed for toxicological / regulatory constraints.

[0164] Magnesium stearate: Magnesium stearate was selected as a lubricant; it is included in the external phase as a dry powder. It was tested different concentrations during the development and the minimum quantity necessary to ensure a good lubrication is 0.5%.Example 3 - Water Content

[0165] The purpose of the study in this Example was to concentrate the suspension to decrease the duration of the spraying step during granulation.

[0166] In the manufacturing process, water quantity is divided in three fractions: fraction 1 for sodium hydroxide solution, fraction 2 for phosphate buffers solution, fraction 3 for fexofenadine suspension.

[0167] To concentrate on the final suspension, it was considered to decrease by half the water quantities in fractions 2 and 3. In addition, the quantities of phosphate buffers decreased by half as well.

[0168] It was first intended to decrease the water content by 50% in fraction 3, which is used to prepare fexofenadine suspension. The grinding of fexofenadine is a critical step since it can generate a lot of foam due to air entrapment, depending on the type of rotorstator used. The most efficient equipment for grinding fexofenadine is Ultra-Turrax, limiting the formation of foam.

[0169] At the same time, it was considered to decrease by 50% the water content as well in fraction 2, which is used to prepare the solution with phosphate buffers. In parallel, it was considered to decrease by 50% the quantities of the two phosphate buffers. By doing all these changes, the suspension total water content was reduced by 45%.

[0170] These three modifications were tested in batch FRC7203, with a batch size of 78 kg. This suspension prepared on Olsa 150L tank allowed to produce a batch of each dosage (30 mg & 60 mg), and these batches were put in stability chambers to conduct an exploratory stability study.

[0171] A follow-up study of pH evolution was conducted to make sure that the decrease of phosphate buffers quantity was not impacting the final pH and its stability through time. To do that, three different suspensions (batches of 500 grams) were prepared withphosphate buffers quantities decrease of 20%, 50%, and 70%, respectively. The study was conducted over a one-month frame, with a daily pH check.

[0172] Based on this study results, the suspension pH remains stable whatever the quantities of phosphate buffers, although a slightly variability is observed for buffers reduction of 70%. Results are similar for buffers reduction of 50% and 20%, therefore it was decided to retain the option of 50% reduction of phosphate buffers to ensure good stability of suspension’s pH.Example 4 - Internal phase (Matrix)

[0173] Various compositions of the matrix were tested to improve the robustness of the suspension spraying process. In the beginning of the development, the internal matrix contained mannitol SD 200 as diluent, microcrystalline cellulose PHI 01 as diluent, and sodium croscarmellose as disintegrant. Considering the hygroscopic nature of microcrystalline cellulose PHI 01 and sodium croscarmellose, and to avoid a high humidity increase in the granules along the API spraying process, removal of two excipients from the internal phase matrix was considered. In addition, surprisingly, this change allows exclusion of intermediate drying steps during the granulation. Furthermore, while microcrystalline cellulose is generally safe, some people have been known to experience side effects such as gas, bloating, stomach cramps, and constipation. In rare cases, allergic reactions can occur, as a result of the cellulose, such as e.g. , rash, itching, swelling, severe dizziness, or trouble breathing. Thus, removal of microcrystalline further reduces the potential for allergic reactions.

[0174] This formula change was tested with a batch, in which the internal phase was composed of 100% mannitol SD 200. The quantities of microcrystalline cellulose PHI 01 and sodium croscarmellose which were removed were fully compensated by mannitol SD 200.

[0175] The removal of sodium croscarmellose from the internal phase led to studies testing the behavior of the final granule during compression step (compressibility and disintegration). Compressibility testing was performed on Styl’One tableting equipment. The results of the compressibility testing and disintegration testing were satisfactory as well as disintegration results.

[0176] The removal of sodium croscarmellose and microcrystalline cellulose PHI 01 from the internal phase was fully compensated by mannitol SD 200. As with other polyols, mannitol can have a negative impact on fexofenadine bioavailability if used in a highquantity. For this reason, it was considered to reduce the same quantity of mannitol SD 200 in the external phase. The testing demonstrated that this reduction of mannitol SD 200 in external phase had no impact on compressibility of the final granule. Finally, this change allowed reduction in the weight of the tablet. Later in the development, mannitol SD 200 was fully replaced by xylitol in external phase, to improve the product mouth feeling.

[0177] Beyond manufacturing process standpoint, the removal of the microcrystalline cellulose PH 101 improved the mouthfeel of the product, which is known to provide a chalky mouthfeel.

[0178] Results obtained for granulation were satisfactory since the granule’s relative humidity was controlled all along the API spraying process with a value of 8,15% at the end of the process. This formulation change was confirmed in two technical batches at laboratory scale (about 2.2 kg), with a matrix of 100% mannitol SD200.Example 5 - Screening of diluents (Mannitol SD200 vs Xylitol XTAB400)

[0179] The purpose of the study in this Example was to screen various excipients in the external phase. Initially, in the preliminary formula selected, the major excipient of external phase was Mannitol SD 200. However, to improve the final texture of the tablet and the mouthfeel, a screening study was performed on Mannitol SD200 and Xylitol. Indeed, according to literature, Xylitol would provide a pleasant texture and mouthfeel for a chewable tablet, by reducing the chalky mouthfeel and bringing freshness. Sucrose was also tested, but this option was not retained once it was required to develop a sugar free formula.

[0180] First screening with different ratios of Xylitol 300 was performed (see Table 5-1 below).

[0181] These batches were compared to a reference batch with 100% Mannitol SD200 in external phase. Based on these results, it was demonstrated that Xylitol 300 grade alone does not allow to maintain the same level of compressibility as when using Mannitol SD200. Therefore, Xylitol 300 was not selected to replace Mannitol SD200 in the external phase.

[0182] Another grade of Xylitol was tested in a second step: Xylitol XT AB 400 (for direct compression). Two different combinations were tested to improve compressibility of the product: 75% of Xylitol XT AB 400 and 25% of Xylitol 300 and 50% of Xylitol XT AB 400 and 50% Mannitol SD200, in comparison with a reference batch of 100% of Xylitol XT AB 40.

[0183] Compressibility was slightly better for the batch containing 50% of Mannitol 200SD and 50% of Xylitol XT AB 400 than for the batch containing 25% of Xylitol 300 and 75% of Xylitol XT AB 400. Surprisingly, compressibility was observed to be even better for the batch containing 100% of Xylitol XT AB 400. Based on these results, Mannitol 200SD was fully replaced by Xylitol XT AB 400 in the external phase.Example 6 - External Phase - PEG vs Poloxamer 407

[0184] It is well described in the literature that polyols (such as xylitol and mannitol) can have a negative impact on fexofenadine bioavailability. Due to that, including solubility enhancers in the formulation (such as poloxamer and PEG) was considered to improve fexofenadine solubility and permeability, to allow reaching bioavailability.

[0185] In 2015, an internal study was conducted to test the impact of PEG400 on fexofenadine containing formulations. This study observed:• a higher Cmaxfor formulations containing PEG 400;• the more PEG 400 the higher the Cmax; and• sorbitol and xylitol seem to reduce the Cmax.

[0186] Thus, the testing appears to indicate that PEG vs Sorbitol and Xylitol have antagonist effects. In fact, PEG could increase the permeability of the fexofenadine HC1 through the intestinal wall which increases the Cmax. Conversely, Sorbitol and Xylitol could reduce the intestinal residence time due to their possible laxative effects which reduces the Cmax-

[0187] The choice of PEG 6000 was made because it was not possible to use PEG low grades which are liquid and provided bitter taste in the suspension; however, PEG with a higher grade does not impact the taste and can still improve the solubility of fexofenadine. The concentration used for PEG 6000 was based on previous development work on Allegra oral gum.

[0188] As it is not possible to use the recommended grade of PEG in the chewable formula, Poloxamer was also used to increase Fexofenadine solubility and permeability, aiming to maximize the formula bioavailability. Poloxamer was initially included in the formula in the internal phase (suspension) to increase fexofenadine wettability in water, and therefore improve its dispersion in suspension. In addition, poloxamer is a solubility / permeability enhancer of Fexofenadine that can balance with polyols laxative effects, therefore poloxamer was also included in the external phase of the formula as well.

[0189] One key point is that Kolliphor® P 407 Geismar was the first grade identified for this formulation in both internal and external phase. However, it was observed that a non- homogeneous aspect of the tablets on the surface (visible dots) was linked to the specific grade of poloxamer. This is why the micronized grade was considered, Kolliphor® P 407 micro Geismar. This specific grade could have been used only in external phase for appearance optimization, but then it would require creating two different material references on the industrial site. Therefore, since there was no impact of the grade in the external phase, it was decided to use Kolliphor® P 407 micro Geismar both in internal and external phase.

[0190] At the initially tested poloxamer concentrations in external phase dissolution issues were observed at pH 1.2. Following investigation on why dissolution profiles at pH 1.2 were too slow, the concentration of poloxamer in the external phase was reduced to limit the gel formation phenomenon at acid pH.Example 7 - Screening of Disintegrants

[0191] Two disintegrants were initially identified for external phase, to improve tablet disintegration: sodium starch glycolate and sodium croscarmellose. The concentrations were proposed based on standard recommendations from suppliers and the handbook of excipients. However, the FDA recognized that depending on the source of starch for sodium starch glycolate, there is a potential for gluten content. See FDA Draft Guidance entitled “Gluten in Drug Products and Associated Labeling Recommendations Guidance for Industry” (December 2017).

[0192] To reach proper compressibility and disintegration time, a screening study was performed with these two disintegrants by varying their concentrations and assessing the impact on the tablet hardness and disintegration time. Based on hardness and disintegration results, it was decided to use sodium croscarmellose since disintegration time is quite short (4 min) for a satisfactory hardness of 83 N. Doing so also avoided the potential for gluten in the formulations.

[0193] At a later stage of the development, during the first technical scale-up at pilot scale, sodium croscarmellose concentration was adjusted following dissolution issues at pH 1.2. Dissolution profiles obtained at pH 1.2 were too slow, and formulation optimization was considered to improve dissolution profiles.Example 8 - Screening of Sweeteners

[0194] In the Allegra chewable formulation, the transformation of the fexofenadine HC1 form into the Zwitterion form allows a very important and effective reduction in bitterness. However, this chemical reaction generates a significant amount of salt that brings a slightly salty taste for the product. Commonly, sweeteners are used directly in the matrix containing the zwitterionic fexofenadine which makes it more difficult to mask the salty taste.

[0195] Accordingly, using sweeteners only in the external phase to reduce this phenomenon was investigated. A slight after taste was noticed in the final product, and the sweeteners can be used to reduce it. The following different sweeteners were tested in the formulation: sucralose; acesulfame potassium; and neotame.Sucralose

[0196] Sucralose has a sweetening power 600 to 650 greater than saccharose. Initially, sucralose was used directly in the suspension. However, an “after taste” persisted slightly on the final tablet. After investigation into sucralose literature, it was decided to removesucralose from the suspension to introduce it into the external phase. The principle is to avoid prolonged contact with heat during the coating step, which is known to potentially degrade sucralose and could cause this slight “after taste.”

[0197] In addition, with the support of an external flavorist, and of our “sensory lab” unit, a screening of sucralose concentration was performed, at different levels, knowing that sucralose at high levels can generate a bitter taste on the final product.

[0198] The following concentrations of sucralose were tested: 0%; 0.11%; 0.23%; and 0.44%. The best results were obtained with concentrations of 0.23% and 0.44% of sucralose.

[0199] It was then considered to combine sucralose with acesulfame potassium, but the added value was negligeable and finally, the concentration of sucralose was optimized at 0.35% (concentration of sucralose used for an exploratory stability batch).Acesulfame Potassium

[0200] Acesulfame potassium has a sweetening power 100 to 200 greater than saccharose. Still with the support of the external flavorist, as well as of our “sensory lab” unit, it was considered combining sucralose with acesulfame potassium, based on the knowledge that acesulfame potassium allows a faster sweetness effect, and sucralose has a later and longer effect.

[0201] A screening of different concentrations for the combination of sucralose and acesulfame potassium was performed. However, due to supply constraints, a second screening was performed before the clinical batches (for BDR study), to confirm the necessity of adding acesulfame potassium in the formulation. It was decided to remove acesulfame potassium from the formulation, considering that its improvement has been low.Neotame

[0202] Neotame has a sweetening power 7000 to 13000 greater than saccharose. A few tests were carried out with neotame; considering its very high sweetening power, the quantities to be used were observed to be very small. However, this option was not kept. The quantities to be used being extremely low, it was very difficult to homogenize in the final product.Example 9 - Granulation / Coating

[0203] During the development phase, a crucial aspect was establishing granulation parameters. This step was essential to produce granules that are not bitter and still compressible.

[0204] Due to the high quantity of liquid to spray and dry, the technology selected was the fluid bed granulator. In this method, both spraying and drying occur simultaneously, streamlining the process. Initially, granulation was considered, but further understanding of the process demonstrated that coating the inert matrix with the suspension was ideal.

[0205] It was key to determine the right parameters to strike a balance between suspension spraying and adequate airflow for granule’s drying. Maintaining the ideal residual humidity of the granules was essential (around 11% ± 5%), to ensure a homogeneous particle size distribution, and to privilege the matrix coating instead of the granulation. These parameters were adjusted for each scale of operation: laboratory, pilot, and industrial.EMBODIMENTS

[0206] The invention provides also the following non-limiting embodiments.

[0207] Embodiment 1 is a sugar-free chewable fexofenadine tablet comprising: sprayed and dried fexofenadine granules comprising a mannitol matrix and a composition devoid of a sweetener, said composition comprising fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer; and an external phase comprising a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, and one or more lubricant.

[0208] Embodiment 2 is the sugar-free chewable fexofenadine tablet of embodiment 1 , wherein the mannitol matrix is 100% mannitol.

[0209] Embodiment 3 is the sugar-free chewable fexofenadine tablet of embodiments 1 or 2, wherein the wetting agent in the sprayed and dried fexofenadine granules and the external phase is a poloxamer.

[0210] Embodiment 4 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 3, wherein the binder in the sprayed and dried fexofenadine granules is hydroxypropyl methylcellulose.

[0211] Embodiment 5 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 4, wherein the disintegrant in the external phase is sodium croscarmellose.

[0212] Embodiment 6 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 4, wherein the diluent in the external phase is xylitol.

[0213] Embodiment 7 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 5, wherein the lubricant consists of magnesium stearate and polyethylene glycol.

[0214] Embodiment 8 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 6, wherein the sweetener is sucralose.

[0215] Embodiment 9 is the sugar-free chewable fexofenadine tablet of embodiment 1 , wherein the sprayed and dried fexofenadine granules comprise the mannitol matrix and the composition devoid of a sweetener, comprises fexofenadine zwitterion dihydrate, a poloxamer as the wetting agent, hydroxypropyl methylcellulose as the binder, an alkalizing agent, and a buffer.

[0216] Embodiment 10 is the sugar-free chewable fexofenadine tablet of embodiments 1 or 9, wherein the external phase comprises a flavoring agent, sodium croscarmellose as the disintegrant, xylitol as the diluent, sucralose as the sweetener, a poloxamer as the wetting agent, and polyethylene glycol and magnesium stearate as the lubricants.

[0217] Embodiment 11 is the sugar-free chewable fexofenadine tablet of embodiment 1 , wherein the sprayed and dried fexofenadine granules comprise a mannitol matrix and a composition devoid of a sweetener, said composition comprising fexofenadine zwitterion dihydrate, a poloxamer, HPMC, an alkalizing agent, and a buffer; and wherein the external phase comprises a flavoring agent, sodium croscarmellose, xylitol, sucralose, poloxamer, polyethylene glycol, and magnesium stearate.

[0218] Embodiment 12 is the sugar-free chewable fexofenadine tablet of embodiment 11, wherein the sprayed and dried fexofenadine granules comprise a mannitol matrix and a composition devoid of a sweetener, said composition comprising fexofenadine zwitterion dihydrate, a poloxamer (w / w), HPMC, an alkalizing agent, and a buffer; and the external phase comprises a flavoring agent, sodium croscarmellose, xylitol, sucralose, a poloxamer, a polyethylene glycol, and magnesium stearate.

[0219] Embodiment 13 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 12, wherein the alkalizing agent in the sprayed and dried fexofenadine granules is sodium hydroxide.

[0220] Embodiment 14 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 13, wherein the buffer comprises sodium phosphate dibasic 2H2O and sodium phosphate monobasic.

[0221] Embodiment 15 is the sugar-free chewable fexofenadine tablet of any one of embodiments 2 to 14, wherein the mannitol is mannitol 200 SD.

[0222] Embodiment 16 is the sugar-free chewable fexofenadine tablet of any one of embodiments 3 to 15, wherein the poloxamer is poloxamer 407.

[0223] Embodiment 17 is the sugar-free chewable fexofenadine tablet of any one of embodiments 6 to 15, wherein the xylitol is xylitol granulated with maize dextrin (Xylisorb XT AB 400).

[0224] Embodiment 18 is the sugar-free chewable fexofenadine tablet of any one of embodiments 7 to 15, wherein the polyethylene glycol is PEG 6000.

[0225] Embodiment 19 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 18, wherein the tablet is formulated to deliver a 30 mg, 60 mg, 120 mg or 180 mg dosage of fexofenadine.

[0226] Embodiment 20 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 19, wherein the tablet lacks a coating for bitter masking such as an Eudagrit polymer.

[0227] Embodiment 21 is the sugar-free chewable fexofenadine tablet of any one of embodiments 1 to 20 for relieving symptoms due to an allergy.

[0228] Embodiment 22 is a method of producing a sugar- free chewable fexofenadine tablet comprising: generating fexofenadine granules by spraying and drying a liquid fexofenadine suspension devoid of a sweetener comprising fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer onto a mannitol matrix; and compressing the fexofenadine granules with an external phase comprising a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, one or more lubricant.

[0229] Embodiment 23 is the method of embodiment 22, wherein the wetting agent in fexofenadine granules and the external phase is a poloxamer.

[0230] Embodiment 24 is the method of embodiment 22, wherein the liquid fexofenadine suspension devoid of a sweetener comprises a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and / or sodium phosphate monobasic.

[0231] Embodiment 25 is the method of embodiment 24, wherein the liquid fexofenadine suspension devoid of a sweetener comprises a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and sodium phosphate monobasic.

[0232] Embodiment 26 is the method of embodiments 22, 24 or 25, wherein the external phase comprises a flavoring agent, sodium croscarmellose, xylitol, sucralose, poloxamer, polyethylene glycol and / or magnesium stearate.

[0233] Embodiment 27 is the method of any one of embodiments 22 to 25, wherein the mannitol is mannitol 200 SD.

[0234] Embodiment 28 is the method of any one of embodiments 23 to 27, wherein the poloxamer is poloxamer 407.

[0235] Embodiment 29 is the method of embodiment 26, wherein the xylitol is xylitol granulated with maize dextrin (Xylisorb XTAB 400).

[0236] Embodiment 30 is the method of embodiments 26 or 29, wherein the polyethylene glycol is PEG 6000.

[0237] Embodiment 31 is the method of any one of embodiments 22 to 30, wherein the method produces a sugar- free chewable tablet formulated to deliver a 30 mg, 60 mg, 120 mg or 180 mg dosage of fexofenadine.

[0238] Embodiment 32 is the method of any one of embodiments 22 to 31 further comprising packaging the sugar-free chewable fexofenadine tablet.

Claims

CLAIMS1. A sugar-free chewable fexofenadine tablet comprising: sprayed and dried fexofenadine granules comprising a mannitol matrix and a composition devoid of a sweetener, said composition comprising fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer; and an external phase comprising a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, and one or more lubricant.

2. The sugar- free chewable fexofenadine tablet of claim 1, wherein the mannitol matrix is 100% mannitol.

3. The sugar- free chewable fexofenadine tablet of claims 1 or 2, wherein the wetting agent in the sprayed and dried fexofenadine granules and the external phase is a poloxamer.

4. The sugar- free chewable fexofenadine tablet of any one of claims 1 to 3, wherein the binder in the sprayed and dried fexofenadine granules is hydroxypropyl methylcellulose.

5. The sugar- free chewable fexofenadine tablet of any one of claims 1 to 4, wherein the disintegrant in the external phase is sodium croscarmellose.

6. The sugar-free chewable fexofenadine tablet of any one of claims 1 to 4, wherein the diluent in the external phase is xylitol.

7. The sugar- free chewable fexofenadine tablet of any one of claims 1 to 5, wherein the lubricant consists of magnesium stearate and polyethylene glycol.

8. The sugar- free chewable fexofenadine tablet of any one of claims 1 to 6, wherein the sweetener is sucralose.

9. The sugar- free chewable fexofenadine tablet of claim 1, wherein the sprayed and dried fexofenadine granules comprise the mannitol matrix and the composition devoid of a sweetener, comprises fexofenadine zwitterion dihydrate, a poloxamer as the wetting agent, hydroxypropyl methylcellulose as the binder, an alkalizing agent, and a buffer.

10. The sugar- free chewable fexofenadine tablet of claims 1 or 9, wherein the external phase comprises a flavoring agent, sodium croscarmellose as the disintegrant, xylitol as thediluent, sucralose as the sweetener, a poloxamer as the wetting agent, and polyethylene glycol and magnesium stearate as the lubricants.

11. The sugar- free chewable fexofenadine tablet of claim 1 , wherein: the sprayed and dried fexofenadine granules comprise a mannitol matrix and a composition devoid of a sweetener, said composition comprising fexofenadine zwitterion dihydrate, a poloxamer, HPMC, an alkalizing agent, and a buffer; and wherein the external phase comprises a flavoring agent, sodium croscarmellose, xylitol, sucralose, poloxamer, polyethylene glycol, and magnesium stearate.

12. The sugar-free chewable fexofenadine tablet of claim 11, wherein: the sprayed and dried fexofenadine granules comprise from about 15% to about 80% w / w of a mannitol matrix and a composition devoid of a sweetener, said composition comprising from about 10 to about 200 mg of fexofenadine zwitterion dihydrate, from about 0.05% to about 10% of a poloxamer w / w, from about 0.5% to about 5% w / w of HPMC, from about 0.5 to about 5.0% w / w of an alkalizing agent, and a from about 0.2% to about 10% w / w buffer; and the external phase comprises from about 0.05% to about 5% w / w of a flavoring agent, from about 3% to about 15% w / w of sodium croscarmellose, from about 30% to about 80% w / w of xylitol, from about 0.1 to about 3% w / w of sucralose, from about 0.5% to about 10% w / w of a poloxamer, from about 0.05% to about 10% w / w of a polyethylene glycol, and from about 0.3% to about 10% w / w of magnesium stearate.

13. The sugar- free chewable fexofenadine tablet of any one of claims 1 to 12, wherein the alkalizing agent in the sprayed and dried fexofenadine granules is sodium hydroxide.

14. The sugar- free chewable fexofenadine tablet of any one of claims 1 to 13, wherein the buffer comprises sodium phosphate dibasic 2H2O and sodium phosphate monobasic.

15. The sugar- free chewable fexofenadine tablet of any one of claims 2 to 14, wherein the mannitol is mannitol 200 SD.

16. The sugar- free chewable fexofenadine tablet of any one of claims 3 to 15, wherein the poloxamer is poloxamer 407.

17. The sugar- free chewable fexofenadine tablet of any one of claims 6 to 15, wherein the xylitol is xylitol granulated with maize dextrin (Xylisorb XT AB 400).

18. The sugar- free chewable fexofenadine tablet of any one of claims 7 to 15, wherein the polyethylene glycol is PEG 6000.

19. The sugar- free chewable fexofenadine tablet of any one of claims 1 to 18, wherein the tablet is formulated to deliver a 30 mg, 60 mg, 120 mg or 180 mg dosage of fexofenadine.

20. The sugar- free chewable fexofenadine tablet of any one of claims 1 to 19, wherein the tablet lacks a coating for bitter masking such as an Eudagrit polymer.

21. The sugar- free chewable fexofenadine tablet of any one of claims 1 to 20 for relieving symptoms due to an allergy.

22. A method of producing a sugar-free chewable fexofenadine tablet comprising: generating fexofenadine granules by spraying and drying a liquid fexofenadine suspension devoid of a sweetener comprising fexofenadine zwitterion dihydrate, a wetting agent, a binder, an alkalizing agent, and a buffer onto a mannitol matrix; and compressing the fexofenadine granules with an external phase comprising a flavoring agent, a disintegrant, the wetting agent, a diluent, a sweetener, one or more lubricant.

23. The method of claim 22, wherein the wetting agent in fexofenadine granules and the external phase is a poloxamer.

24. The method of claim 22, wherein the liquid fexofenadine suspension devoid of a sweetener comprises a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and / or sodium phosphate monobasic.

25. The method of claim 24, wherein the liquid fexofenadine suspension devoid of a sweetener comprises a poloxamer, hydroxypropyl methylcellulose, sodium hydroxide, sodium phosphate dibasic 2H2O and sodium phosphate monobasic.

26. The method of claims 22, 24 or 25, wherein the external phase comprises a flavoring agent, sodium croscarmellose, xylitol, sucralose, poloxamer, polyethylene glycol and / or magnesium stearate.

27. The method of any one of claims 22 to 25, wherein the mannitol is mannitol 200 SD.

28. The method of any one of claims 23 to 27, wherein the poloxamer is poloxamer 407.

29. The method of claim 26, wherein the xylitol is xylitol granulated with maize dextrin (Xylisorb XT AB 400).

30. The method of claims 26 or 29, wherein the polyethylene glycol is PEG 6000.

31. The method of any one of claims 22 to 30, wherein the method produces a sugar- free chewable tablet formulated to deliver a 30 mg, 60 mg, 120 mg or 180 mg dosage of fexofenadine.

32. The method of any one of claims 22 to 31 further comprising packaging the sugar- free chewable fexofenadine tablet.

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