Paraben-free fexofenadine formulation

Abstract

Fexofenadine zwitterionic dihydrate form I of formula (I) Paraben-free aqueous pharmaceutical suspension formulations and uses thereof are provided, including JPEG2026501487000031.jpg4390. In certain embodiments, the formulations include polypropylene glycol, edetate disodium, potassium sorbate, xanthan gum, poloxamer 407, titanium dioxide, sodium phosphate monobasic monohydrate, sodium phosphate dibasic heptahydrate, artificial raspberry cream flavor, sucrose, xylitol, and purified water. The disclosure also includes methods of making such formulations.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 440,356 (filed January 20, 2023), the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present disclosure relates to paraben-free liquid formulations of fexofenadine and uses of such formulations. [Background technology]

[0002] Background of the Invention Fexofenadine hydrochloride refers to 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetic acid hydrochloride. Fexofenadine hydrochloride has the following structure and is available in products such as Goodsense® Aller-ease, Aller-Fex™, Wal-Fex® Allergy, Allegra®, Allegra® Allergy 12 Hour, Allegra® Allergy 24 Hour, Children's Allegra® Allergy, and Mucinex Allergy, Allegra® Allergy, and Children's Wal-Fex®. Fexofenadine is generally known to have poor solubility and poor permeability. [ka]

[0003] Fexofenadine hydrochloride is also known to have an unpalatable bitter taste. The currently marketed suspension formulation of fexofenadine (Allegra®) contains, among other things, propylparaben and butylparaben. Propylparaben and butylparaben were used as preservative systems due to their common use in oral liquid dosage forms at the time of their development, their microbial activity and stability at pharmaceutical pH (approximately 6.2), and their broad spectrum of activity. Specifically, this suspension is a white, homogeneous suspension, generally containing 6 mg of fexofenadine hydrochloride per mL and the following excipients: polypropylene glycol, edetate disodium, propylparaben, butylparaben, xanthan gum, poloxamer 407, titanium dioxide, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, artificial raspberry cream flavor, sucrose, xylitol, and purified water. This suspension is specifically designed to provide optimal stability and mask the bitter taste associated with fexofenadine.

[0004] Parabens were used to prevent and inhibit the growth of harmful bacteria and mold and to extend the shelf life of products. In recent years, formulators have begun to remove parabens. However, “finding substitute ingredients to parabens, needing to be both efficient against microbiological contamination, and ensuring the safety of formulas and the success of products to consumers, is not an easy task.” Frick, R. “Formulating without parabens? Alternatives to handle with care,” Premium Beauty News (July 23, 2011) (available online at www.premiumbeautynews.com / en / formulating-without-parabens,3268 (last accessed January 18, 2023)). “Unfortunately, there aren't any universal solutions and work must be carried out on a case by case basis with regard to the type of formula to protect, its nature, its pH, its method of use.” Ibid. (quoting Jean-Pierre Arnaud, CEO of Lucas Meyer Cosmetics).

[0005] Therefore, what is needed is a paraben-free fexofenadine formulation that is bioequivalent to current fexofenadine suspension formulations. Summary of the Invention

[0006] The present disclosure provides: pH 5.8 to 7.0 0.03% to 1.20% (wt / wt) of fexofenadine zwitterionic dihydrate Form I of formula (I) [ka] and; with 0.01%~0.20% wetting agent; a suspending agent comprising 0.10% to 0.50% (wt / wt) of a hydrocolloid gum; a sweetener system comprising 5% to 40% (weight / weight) sucrose and 5% to 40% (weight / weight) xylitol, optionally in an amount ratio of 1:1 to 2:1 (sucrose:xylitol); (i) potassium sorbate, domiphen bromide, cetylpyridinium chloride, or sodium benzoate, and a preservative system comprising 0.01% to 0.25% (wt / wt) edetate disodium; 0.06% to 1.05% (wt / wt) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate, or 0.06% to 1.05% (wt / wt) monobasic potassium phosphate, and a buffer system comprising 0.32% to 2.69% (wt / wt) dibasic sodium phosphate or its equivalent dibasic sodium phosphate hydrate, or 0.32% to 2.69% (wt / wt) dibasic potassium phosphate or its equivalent dibasic potassium phosphate hydrate; 1.0% to 10.0% (wt / wt) propylene glycol; 0.20% to 0.70% (wt / wt) of flavoring agent The present invention relates to paraben-free aqueous pharmaceutical suspensions comprising: (a) a paraben-free aqueous pharmaceutical suspension comprising: (b) a paraben-free aqueous pharmaceutical suspension ...b) a paraben-free aqueous pharmaceutical suspension comprising: (

[0007] In certain embodiments, the preservative system comprises potassium sorbate and 0.01% to 0.25% (w / w) disodium edetate. In certain embodiments, the preservative system comprises domiphen bromide and 0.01% to 0.25% (w / w) edetate. In certain embodiments, the preservative system comprises cetylpyridinium chloride and 0.01% to 0.25% (w / w) edetate. In certain embodiments, the preservative system comprises sodium benzoate and 0.01% to 0.25% (w / w) edetate.

[0008] In particular, the present disclosure has a pH of 5.8 to 7.0, 0.03% to 1.20% (wt / wt) of fexofenadine zwitterionic dihydrate Form I of formula (I) [ka] and; 0.01% to 0.20% (wt / wt) of a wetting agent; a suspending agent comprising 0.10% to 0.50% (wt / wt) of a hydrocolloid gum; a sweetener system comprising 5% to 40% (weight / weight) sucrose and 5% to 40% (weight / weight) xylitol, optionally in an amount ratio of 1:1 to 2:1 (sucrose:xylitol); a preservative system comprising 0.1% to 2% (wt / wt) potassium sorbate and 0.01% to 0.25% (wt / wt) edetate disodium; 0.06% to 1.05% (wt / wt) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate, or 0.06% to 1.05% (wt / wt) monobasic potassium phosphate, and a buffer system comprising 0.32% to 2.69% (wt / wt) dibasic sodium phosphate or its equivalent dibasic sodium phosphate hydrate, or 0.32% to 2.69% (wt / wt) dibasic potassium phosphate or its equivalent dibasic potassium phosphate hydrate; 1.0% to 10.0% (wt / wt) propylene glycol; 0.20% to 0.70% (wt / wt) of flavoring agent The present invention relates to paraben-free aqueous pharmaceutical suspensions comprising: (a) a paraben-free aqueous pharmaceutical suspension comprising: (b) a paraben-free aqueous pharmaceutical suspension ...b) a paraben-free aqueous pharmaceutical suspension comprising: (

[0009] In certain embodiments, the suspension comprises 0.03% to 1.20% fexofenadine zwitterionic dihydrate Form I of Formula (I), wherein at least 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than 280 μm. In other embodiments, at least 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than 50 μm. In other embodiments, at least 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than 40 μm.

[0010] In certain embodiments, the fexofenadine zwitterionic dihydrate Form I is present in an amount of 0.3% to 0.7% (wt / wt). In certain embodiments, the fexofenadine zwitterionic dihydrate Form I is present in an amount of 0.4% to 0.6% (wt / wt). In certain embodiments, the humectant is 0.01-0.07% (w / w) or 0.02-0.07% (w / w). In certain embodiments, the humectant is ionic. In certain embodiments, the humectant is Poloxamer 188. In another particular embodiment, the humectant is Poloxamer 407. In certain embodiments, the hydrocolloid gum is 0.1-0.5% (w / w) or 0.2-0.4% (w / w). In certain embodiments, the hydrocolloid gum is xanthan gum. In certain embodiments, the xylitol is 7.5 to 10% (w / w) or 8.5 to 9.5% (w / w), and in certain embodiments, the sucrose is 17.3 to 18.5% (w / w), or 17.5 to 18.0% (w / w), or 17.5 to 18.5% (w / w). In certain embodiments, the potassium sorbate is present in an amount of 0.1 to 0.6% (wt / wt), and in certain embodiments, the potassium sorbate is present in an amount of 0.2 to 0.5% (wt / wt). In particular embodiments, the edetate disodium is 0.05 to 0.2% (w / w) or 0.10 to 0.18% (w / w). In certain embodiments, the buffer system comprises 0.4% to 0.9% (w / w) monobasic sodium phosphate or its equivalent monobasic sodium phosphate hydrate; and 0.5% to 0.8% (w / w) dibasic sodium phosphate or its equivalent dibasic sodium phosphate hydrate. In particular embodiments, the propylene glycol is 1.8 to 2.5% (w / w) or 1.9 to 2.4%. In certain embodiments, the flavoring agent is present in an amount of 0.2 to 0.6% (w / w).In certain embodiments, the flavoring agent is an artificial raspberry cream flavor or an artificial orange cream flavor.

[0011] In certain embodiments, the paraben-free aqueous pharmaceutical suspension of the present invention further comprises 0.07% to 1.1% (w / w) of an opacifying agent, which in certain embodiments is titanium dioxide. In certain embodiments, the paraben-free aqueous pharmaceutical suspension of the present invention comprises 0.4% to 0.6% (wt / wt) fexofenadine zwitterionic dihydrate Form I, 1.9% to 2.4% (wt / wt) propylene glycol, 0.15% to 0.5% (wt / wt) potassium sorbate, 0.10% to 0.18% (wt / wt) edetate disodium, 0.9% to 1.2% (wt / wt) dibasic sodium phosphate heptahydrate. , 0.5% to 0.8% (w / w) monobasic sodium phosphate monohydrate, 0.2% to 0.4% (w / w) xanthan gum, 0.02% to 0.05% (w / w) poloxamer 407, 0.08% to 1.0% (w / w) titanium dioxide, 17.5% to 18.0% (w / w) sucrose, 8.5 to 9.50% (w / w) xylitol, and 0.3% to 0.5% (w / w) flavorings. In a further embodiment, 17.5% to 18.5% (w / w) sucrose is used in the formulation.

[0012] In certain embodiments, the paraben-free aqueous pharmaceutical suspension of the present invention comprises 0.4% to 0.6% (wt / wt) fexofenadine zwitterionic dihydrate Form I, 1.9% to 2.4% (wt / wt) propylene glycol, 0.001% to 10.0% (wt / wt) domiphen bromide, 0.10% to 0.18% (wt / wt) edetate disodium, 0.9% to 1.2% (wt / wt) dibasic sodium phosphate heptahydrate. The formulation comprises 0.5% to 0.8% (w / w) monobasic sodium phosphate monohydrate, 0.2% to 0.4% (w / w) xanthan gum, 0.02% to 0.05% (w / w) poloxamer 407, 0.08% to 1.0% (w / w) titanium dioxide, 17.5% to 18.0% (w / w) sucrose, 8.5 to 9.50% (w / w) xylitol, and 0.3% to 0.5% (w / w) flavorings. In a further embodiment, 17.5% to 18.5% (w / w) sucrose is used in the formulation.

[0013] In certain embodiments, the paraben-free aqueous pharmaceutical suspension of the present invention comprises 0.4% to 0.6% (wt / wt) fexofenadine zwitterionic dihydrate Form I, 1.9% to 2.4% (wt / wt) propylene glycol, 0.0001% to 1.000% (wt / wt) cetylpyridinium chloride, 0.10% to 0.18% (wt / wt) edetate disodium, 0.9% to 1.2% (wt / wt) dibasic sodium phosphate heptanoate. hydrate, 0.5% to 0.8% (w / w) monobasic sodium phosphate monohydrate, 0.2% to 0.4% (w / w) xanthan gum, 0.02% to 0.05% (w / w) poloxamer 407, 0.08% to 1.0% (w / w) titanium dioxide, 17.5% to 18.0% (w / w) sucrose, 8.5 to 9.50% (w / w) xylitol, and 0.3% to 0.5% (w / w) flavorings. In a further embodiment, 17.5% to 18.5% (w / w) sucrose is used in the formulation.

[0014] In certain embodiments, the paraben-free aqueous pharmaceutical suspension of the present invention comprises 0.4% to 0.6% (wt / wt) fexofenadine zwitterionic dihydrate Form I, 1.9% to 2.4% (wt / wt) propylene glycol, 0.001% to 10.0% (wt / wt) sodium benzoate, 0.10% to 0.18% (wt / wt) edetate disodium, 0.9% to 1.2% (wt / wt) sodium phosphate dibasic heptahydrate. The formulation comprises 0.5% to 0.8% (w / w) monobasic sodium phosphate monohydrate, 0.2% to 0.4% (w / w) xanthan gum, 0.02% to 0.05% (w / w) poloxamer 407, 0.08% to 1.0% (w / w) titanium dioxide, 17.5% to 18.0% (w / w) sucrose, 8.5 to 9.50% (w / w) xylitol, and 0.3% to 0.5% (w / w) flavorings. In a further embodiment, 17.5% to 18.5% (w / w) sucrose is used in the formulation. Methods for preparing the paraben-free aqueous pharmaceutical suspensions of the present invention are also provided. Other features and advantages of the present invention will become apparent from the following detailed description and examples.

[0015] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, the drawings show embodiments of the invention. It should be understood, however, that the invention is not limited to the precise arrangements, examples, and instrumentalities shown. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the conversion of fexofenadine Form I anhydrate to Form I zwitterionic dihydrate. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description The present disclosure is based on the discovery that paraben-free liquid suspension formulations of fexofenadine can be produced. These formulations avoid the safety concerns recently associated with current products without altering their critical quality attributes and bioequivalence. The present disclosure overcomes challenges associated with reformulating the API fexofenadine, which has a susceptible stability and poor pH-dependent solubility. Thus, the present disclosure provides a preservative system for existing fexofenadine suspension formulations without altering any of their critical product attributes. The present disclosure is based on the discovery that despite the synergistic effect of parabens and EDTA, a paraben-free fexofenadine liquid suspension formulation can be produced by replacing parabens with domiphen bromide, cetylpyridinium chloride, sodium benzoate, or potassium sorbate. In particular, the present disclosure is based on the discovery that potassium sorbate has comparable preservative performance to parabens and maintains the physical and chemical characteristics of a highly challenging API (fexofenadine) and the pH range of its formulation.

[0018] Thus, the paraben-free (i.e., paraben-free) fexofenadine liquid suspension of the current embodiment is bioequivalent to currently marketed fexofenadine suspension formulations. For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into subsections that describe or illustrate particular features, embodiments, or uses of the invention.

[0019] definition As used herein, the term "about," when referring to a measurable value such as an amount, duration, etc., is meant to encompass variations of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, and even more preferably ±0.1% from the specified value as such variations are appropriate for practicing the disclosed methods. As used herein, the singular forms "a," "an," and "the" include plural referents. A reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. Thus, for example, a reference to a "substance" refers to at least one of such substance and equivalents thereof known to those skilled in the art, and so forth.

[0020] When values ​​are expressed as approximations by using "about," it will be understood that the particular value forms another embodiment. Generally, the use of "about" indicates an approximation that may vary depending on the desired properties sought to be obtained by the disclosed subject matter and should be interpreted in the specific context in which it is used. This can be routinely interpreted by those skilled in the art. In some cases, the number of significant figures used for a particular value can be a non-limiting method for determining the scope of the term "about." In other cases, the gradations used in a series of values ​​can be used to determine the intended range available for the term "about" for each value. Where present, all ranges are inclusive and combinable. That is, when values ​​are stated in a range, they include all values ​​within that range. As used herein, data are presented with full disclosure of all significant figures, but one skilled in the art will understand that the data may be understood when rounded to one or two decimal places.

[0021] Where lists are presented, it is to be understood that each individual element of the list, and every combination of that list, is a separate embodiment unless otherwise stated. For example, a list of embodiments presented as "A, B, or C" should be interpreted as including the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C." For clarity, it should be understood that certain features of the invention that are described herein in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless clearly contradictory or excluded, individual embodiments are considered combinable with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, for brevity, various features of the invention that are described in the context of a single embodiment may also be provided separately or in any subcombination. Furthermore, it should be noted that the claims may be drafted to exclude optional elements. Accordingly, this statement is intended to serve as a prerequisite for using exclusive language, such as "only," "only," or the like, or for using negative limitations in connection with the recitation of claim elements. Finally, while embodiments may be described as part of a series of steps or as part of a more general structure, each step may also be considered an independent embodiment in itself. Before describing particular embodiments in more detail, it should be understood that the invention is not limited to the specific embodiments described, as such may, of course, vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0022] Where a range of values ​​is recited, unless the context clearly indicates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limits of that range, and any other stated or intervening value within this stated range, is included in the invention. The upper and lower limits of these smaller ranges can independently be included in the smaller ranges and are also included in the invention, unless there is a specifically excluded limit in the stated range. When the stated range includes one or both limits, ranges excluding either or both of those included limits are also included in the invention.

[0023] Unless otherwise defined, 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 methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative exemplary methods and materials are now described. All publications and patents cited herein are incorporated by reference to disclose and describe the methods and / or materials for which the publications are cited, to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. The citation of a 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.

[0024] As used herein, the terms "patient" and "subject" are used interchangeably and refer to a mammalian animal. In some embodiments, the patient or subject is a human. In other embodiments, the patient or subject is a veterinary or agricultural animal, a livestock or pet, or an animal commonly used in clinical research. In some embodiments, the patient is an adult, i.e., 18 years of age or older. In other embodiments, the patient is a child, i.e., under 18 years of age. The term "treating" includes ameliorating a disease or disorder (i.e., arresting or alleviating the progression of a disease or at least one of its clinical symptoms). In some embodiments, "treating" refers to improving at least one physical parameter, which may not be discernible to the subject. In other embodiments, "treating" refers to modifying a disease or disorder physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In further embodiments, "treating" refers to delaying the onset of a disease or disorder.

[0025] The terms "fexofenadine zwitterion" and "fexofenadine zwitterion dihydrate" are used interchangeably and refer to 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetic acid dihydrate. Fexofenadine zwitterion dihydrate has the following structure: [ka] .

[0026] The "buffer system" is used to adjust the pH of the suspension to minimize the solubility of the component fexofenadine and maintain the fexofenadine as fexofenadine zwitterionic dihydrate Form I for a minimum of about 18 months; more particularly, at least about 24 months. Examples of buffer systems include a citric acid / dibasic sodium phosphate or dibasic sodium phosphate hydrate system, a succinic acid / sodium hydroxide system, a citric acid / sodium citrate, sodium citrate hydrate, or potassium citrate system, a maleic acid / sodium hydroxide system, a fumaric acid / sodium hydroxide system, a monobasic sodium phosphate, monobasic sodium phosphate hydrate, or monobasic potassium phosphate / dibasic sodium phosphate, dibasic sodium phosphate hydrate, dibasic potassium phosphate, or dibasic potassium phosphate hydrate system, particularly a monobasic sodium phosphate, monobasic sodium phosphate hydrate, or monobasic potassium phosphate / dibasic sodium phosphate, dibasic sodium phosphate hydrate, dibasic potassium phosphate, or dibasic potassium phosphate hydrate system, more particularly a monobasic sodium phosphate or monobasic sodium phosphate hydrate / dibasic sodium phosphate or dibasic sodium phosphate hydrate system, and even more particularly a monobasic sodium phosphate monohydrate / dibasic sodium phosphate heptahydrate system. "Monopotassium phosphate" means KH2PO4. "Dibasic potassium phosphate" means K2HPO4. "Dibasic potassium phosphate hydrate" includes, for example, dibasic potassium phosphate trihydrate and dibasic potassium phosphate hexahydrate. "Monobasic sodium phosphate" means NaH2PO4. "Monobasic sodium phosphate hydrate" includes, for example, monobasic sodium phosphate monohydrate and monobasic sodium phosphate dihydrate. "Dibasic sodium phosphate" means Na2HPO4. "Dibasic sodium phosphate hydrate includes, for example, dibasic sodium phosphate dihydrate, dibasic sodium phosphate heptahydrate, and dibasic sodium phosphate dodecahydrate.

[0027] "Poloxamer" is an α-hydro-ω-hydroxypoly(oxyethylene) poly(oxypropylene) poly(oxyethylene) block copolymer. Examples of poloxamers include Poloxamer 407 and Poloxamer 188. "Particle size" is determined using Low-Angle Laser Light-Scattering (LALLS) and is calculated as a sphere of equal diameter to the test sample. Particle size distribution is reported as the volume percent above or below the stated diameter. For example, Dv 10 , Dv 50 , and Dv 90 correspond to particle sizes where 10%, 50%, and 90% of the total particle size distribution volume is below the stated diameter, respectively.

[0028] Paraben-free aqueous fexofenadine suspension It is an object of the present invention to provide a paraben-free aqueous pharmaceutical suspension containing fexofenadine zwitterionic dihydrate Form I that maintains the zwitterionic form of fexofenadine while not affecting the quality and safety of the aqueous composition. In a general aspect, the present invention provides fexofenadine zwitterionic dihydrate Form I of formula (I): [ka] Wetting agent; suspending agents; Sweetener systems; Preservative system; a buffer system; and Flavoring agents The present invention relates to a paraben-free aqueous pharmaceutical suspension comprising: The aqueous pharmaceutical suspension formulation may optionally include an opacifying agent, such as, for example, titanium dioxide. As used herein, an aqueous pharmaceutical suspension is "paraben-free" or "paraben-free" if the formulation does not contain or does not include parabens (i.e., the formulation does not contain parabens).

[0029] One particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension having a pH of about 5.00 to about 8.00; or more particularly, 5.80 to about 7.00. Another embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension, wherein at least about 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than about 50 μm; or, more particularly, 40 μm. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension having fexofenadine zwitterionic dihydrate Form I in an amount of about 0.03% to 1.20% (wt / wt); more particularly about 0.3 to 0.7% (wt / wt), and even more particularly about 0.4 to 0.6% (wt / wt).

[0030] Another embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension, wherein the wetting agent is from about 0.01% to about 0.07% (wt / wt); more particularly from about 0.02% to about 0.05% (wt / wt). Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the wetting agent is non-ionic, for example, poloxamer 407 and poloxamer 188. In a particular embodiment, the wetting agent is poloxamer 407.

[0031] Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the suspending agent is a hydrocolloid gum. Another embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension, wherein the hydrocolloid gum is from about 0.1% to about 0.5% (wt / wt); more particularly from about 0.2% to about 0.4% (wt / wt). Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the hydrocolloid gum is xanthan gum.

[0032] Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the sweetener system contains one or more of xylitol, sorbitol, maltitol, sucrose, or invert sucrose. Another specific embodiment of the invention is a paraben-free aqueous pharmaceutical suspension, wherein the xylitol, sorbitol or sorbitol solution, or maltitol solution is 0% to about 20% (wt / wt); more particularly, about 10% to about 20% (wt / wt); more particularly, about 7.5% to about 10% (wt / wt); more particularly, about 8.5% to about 9.5% (wt / wt). Another particular embodiment of the invention is a paraben-free aqueous pharmaceutical suspension, wherein the sucrose or invert sucrose is from about 10% to about 40% (wt / wt); more particularly from about 10% to about 20% (wt / wt); more particularly from about 17.3% to about 18.5% (wt / wt); more particularly from about 17.5% to about 18.0% (wt / wt); and even more particularly from about 17.5% to about 18.5% (wt / wt). Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the sweetener system comprises xylitol and sucrose. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the sweetener system comprises xylitol and sucrose. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension, wherein the sweetener system comprises xylitol and sucrose, and the ratio of the amount of sucrose to xylitol is about 2:1. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the sweetener system comprises sucralose and sucrose. Another specific embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the sweetener system comprises about 7.5% to about 10% (wt / wt) xylitol and about 17.3% to about 18.5% (wt / wt) sucrose. Another specific embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the sweetener system comprises about 8.5% to about 9.50% (wt / wt) xylitol and about 17.5% to about 18.0% (wt / wt) sucrose. Another specific embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the sweetener system comprises about 8.5% to about 9.50% (wt / wt) xylitol and about 17.5% to about 18.5% (wt / wt) sucrose.

[0033] Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension having an amount ratio of (sucrose or inverted sucrose):(xylitol, sorbitol or sorbitol solution, or maltitol solution) of about 1:1 to 2:1. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension having an amount ratio of (sucrose or inverted sucrose):(xylitol, sorbitol or sorbitol solution, or maltitol solution) of about 2:1. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension having an amount ratio of (sucrose or inverted sucrose):(xylitol, sorbitol or sorbitol solution, or maltitol solution) of about 1:1.

[0034] One particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system comprises potassium sorbate and disodium edetate. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system comprises domiphen bromide and edetate disodium. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system comprises cetylpyridinium chloride and edetate disodium. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system comprises sodium benzoate and disodium edetate. Another specific embodiment of the invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system comprises edetate disodium and one or more of domiphen bromide, cetylpyridinium chloride, sodium benzoate, or potassium sorbate. Another specific embodiment of the invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system contains only edetate disodium and one or more of domiphen bromide, cetylpyridinium chloride, sodium benzoate, or potassium sorbate. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system contains only edetate disodium and domiphen bromide. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system contains only edetate disodium and cetylpyridinium chloride. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system contains only edetate disodium and sodium benzoate. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system contains only edetate disodium and potassium sorbate.

[0035] Another specific embodiment of the invention is where the preservative system comprises potassium sorbate at about 0.1% to about 2% (w / w), alternatively from about 0.1% to about 4% (w / w), alternatively from about 0.35% to about 4% (w / w), alternatively from about 0.35% to about 2% (w / w), alternatively from about 0.35% to about 1.5% (w / w), alternatively from about 0.3% to about 2% (w / w), alternatively from about 0.25% to 0.6% (w / w), or alternatively from about 0.25% to 0.6% (w / w). or a paraben-free aqueous pharmaceutical suspension containing about 0.35% to 0.6% (mass / mass), alternatively about 0.36% to 0.6% (mass / mass), alternatively more than 0.3% to about 1% (mass / mass), alternatively 0.3% to about 0.7% (mass / mass), alternatively at least 0.4% to about 2% (mass / mass), more particularly about 0.1% to about 0.6% (mass / mass), and even more particularly about 0.15 to about 0.5% (mass / mass). Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system comprises from about 0.0001% to about 10%, particularly 0.0001% to about 5% (wt / wt), and even more particularly from about 0.001 to about 1.0% (wt / wt) of domiphen bromide. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system comprises from about 0.0001% to about 1%, particularly from about 0.0001% to about 0.6% (wt / wt), and even more particularly from about 0.005 to about 0.01% (wt / wt) of cetylpyridinium chloride. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the preservative system comprises from about 0.001% to about 10%, particularly from about 0.01% to about 1% (wt / wt), and even more particularly from about 0.3 to about 0.8% (wt / wt) sodium benzoate. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension comprising edetate disodium in an amount of from about 0.01% to about 0.25% (wt / wt), particularly from about 0.05 to 0.2% (wt / wt), and even more particularly from about 0.10 to 0.18% (wt / wt).

[0036] Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the buffer system comprises monobasic sodium phosphate monohydrate and dibasic sodium phosphate heptahydrate. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension wherein the buffer system contains only sodium phosphate monobasic monohydrate and sodium phosphate dibasic heptahydrate. Another particular embodiment of the present invention provides a buffering agent for the buffering effect. about 0.06% to about 1.05% (wt / wt) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate, or about 0.069% to about 1.190% (wt / wt) monobasic potassium phosphate; and Approximately 0.32% to approximately 2.69% (mass / mass) dibasic sodium phosphate or an equivalent amount of dibasic sodium phosphate hydrate, or approximately 0.39% to approximately 3.30% (mass / mass) dibasic potassium phosphate or an equivalent amount of dibasic potassium phosphate hydrate A paraben-free aqueous pharmaceutical suspension is used in which a buffer system comprising: Another particular embodiment of the present invention provides a buffering agent for the buffering effect. about 0.22% to about 0.87% (w / w) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate, or about 0.25% to about 0.99% (w / w) monobasic potassium phosphate; and Approximately 0.32% to approximately 1.15% (mass / mass) dibasic sodium phosphate or its equivalent amount of dibasic sodium phosphate hydrate, or approximately 0.39% to approximately 1.41% (mass / mass) dibasic potassium phosphate or its equivalent amount of dibasic potassium phosphate hydrate A paraben-free aqueous pharmaceutical suspension is used in which a buffer system comprising: Another particular embodiment of the present invention provides a buffering agent for the buffering effect. about 0.06% to about 1.05% (w / w) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate; and About 0.32% to about 2.69% (wt / wt) dibasic sodium phosphate or a corresponding amount of dibasic sodium phosphate hydrate A paraben-free aqueous pharmaceutical suspension is used in which a buffer system comprising: Another specific embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension in which the buffering uses a buffer system comprising about 0.4% to about 0.9% (wt / wt) monobasic sodium phosphate monohydrate and about 0.8% to about 1.3% (wt / wt) dibasic sodium phosphate heptahydrate. Another specific embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension in which the buffering uses a buffer system comprising about 0.5% to about 0.8% (wt / wt) monobasic sodium phosphate monohydrate and about 0.9% to about 1.2% (wt / wt) dibasic sodium phosphate heptahydrate.

[0037] Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension further comprising as a co-solvent. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension further comprising propylene glycol as a co-solvent. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension comprising a co-solvent, e.g., propylene glycol, in an amount of from about 0.1% to about 15.0% (wt / wt); more particularly from about 1.0% to about 10.0%; or more particularly from about 1.8% to about 2.5% (wt / wt); or even more particularly from about 1.9% to about 2.4% (wt / wt). Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension comprising 0% to about 4% (wt / wt); more particularly 0% to about 2% (wt / wt); or even more particularly 0% to about 1% (wt / wt) of a co-solvent, such as polyethylene glycol 200, polyethylene glycol 300, or polyethylene glycol 400.

[0038] Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension, optionally further comprising an opacifying agent. Yet another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension, optionally further comprising titanium dioxide. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension optionally further comprising an opacifying agent, e.g., titanium dioxide, at 0% to about 2% (w / w); more particularly, at about 0.07% to about 1.1%; or even more particularly, at about 0.08% to about 1.0% (w / w).

[0039] Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension comprising about 0.20% to about 0.70% (w / w); more particularly about 0.2% to about 0.6% (w / w); or even more particularly about 0.3% to about 0.5% (w / w) of a flavoring agent, for example, artificial raspberry cream flavor or artificial orange cream flavor. Another particular embodiment of the present invention is a paraben-free aqueous pharmaceutical suspension comprising artificial raspberry cream flavor, artificial vanilla, and / or artificial orange cream flavor as the favoring agent.

[0040] Another specific embodiment of the present invention has a pH of 5.8 to 7.0, Fexofenadine zwitterionic dihydrate form I of formula (I) [ka] ; Wetting agent; suspending agents, including hydrocolloid gums; a sweetener system including sucrose and xylitol; a preservative system comprising potassium sorbate and disodium edetate; a buffer system comprising monobasic sodium phosphate or an equivalent amount of monobasic sodium phosphate hydrate, or monobasic potassium phosphate, and dibasic sodium phosphate or an equivalent amount of dibasic sodium phosphate hydrate, or dibasic potassium phosphate or an equivalent amount of dibasic potassium phosphate hydrate; Propylene glycol; Flavoring agents In a particular embodiment of this suspension, the ratio of the amounts of (sucrose):(xylitol) is about 1:1 to about 2:1. This embodiment of the paraben-free aqueous pharmaceutical suspension can include any of the ingredients in the amounts described above. In another embodiment of this embodiment of the paraben-free aqueous pharmaceutical suspension, the preservative system contains only potassium sorbate and disodium edetate.

[0041] Another specific embodiment of the present invention has a pH of 5.8 to 7.0, Fexofenadine zwitterionic dihydrate form I of formula (I) [ka] ; Wetting agent; suspending agents, including hydrocolloid gums; a sweetener system including sucrose and xylitol; edetate disodium and a preservative system comprising one of (i) domiphen bromide, (ii) cetylpyridinium chloride, and (iii) sodium benzoate; a buffer system comprising monobasic sodium phosphate or an equivalent amount of monobasic sodium phosphate hydrate, or monobasic potassium phosphate, and dibasic sodium phosphate or an equivalent amount of dibasic sodium phosphate hydrate, or dibasic potassium phosphate or an equivalent amount of dibasic potassium phosphate hydrate; propylene glycol; and Flavoring agents In a particular embodiment of this suspension, the ratio of the amounts of (sucrose):(xylitol) is about 1:1 to about 2:1. This embodiment of the paraben-free aqueous pharmaceutical suspension can include any of the ingredients in the amounts described above. In another embodiment of this embodiment of the paraben-free aqueous pharmaceutical suspension, the preservative system contains only edetate disodium and domiphen bromide. In another embodiment of this embodiment of the paraben-free aqueous pharmaceutical suspension, the preservative system contains only edetate disodium and cetylpyridinium chloride. In another embodiment of this embodiment of the paraben-free aqueous pharmaceutical suspension, the preservative system contains only edetate disodium and sodium benzoate.

[0042] In certain embodiments of the present disclosure, the paraben-free aqueous formulations include Formulations A1-A8 (shown in Table A below). In certain embodiments of Formulations A1-A8, the flavoring agent is an artificial raspberry cream flavor. Titanium oxide may be omitted in certain embodiments of Formulations A1-A8. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0043] Also provided is a kit comprising a bottle or vial containing a paraben-free aqueous pharmaceutical suspension according to the present invention and a syringe or cup.

[0044] Treatment method The paraben-free aqueous pharmaceutical suspensions described herein are useful for alleviating allergy symptoms in a patient in need thereof. These methods include administering a therapeutically effective amount of the paraben-free aqueous pharmaceutical suspension to the patient. Another embodiment of the present disclosure is the use of the paraben-free aqueous pharmaceutical suspensions described herein in the treatment of allergies. Those skilled in the art will be able to determine suitable allergies that can be treated using the described compositions and dosage forms. For example, these allergies can be caused by indoor allergens or outdoor allergens. In some embodiments, the allergy is caused by one or more indoor allergens. Various indoor allergens are known, including dust mites, pet allergens, or mold. In further embodiments, the allergy is caused by dust mites. In other embodiments, the allergy is caused by pet allergens, such as those found in animal saliva, animal urine, or animal dander. In still further embodiments, the allergy is caused by indoor mold. In yet other embodiments, the allergy is caused by one or more outdoor allergens. Numerous outdoor allergies are known in the art, including, but not limited to, pollen and mold. In some embodiments, the outdoor allergy is pollen from grasses, weeds, or trees. In other embodiments, the outdoor allergy is caused by outdoor mold.

[0045] The allergy can cause any number of symptoms in the patient. For example, the patient can experience one or more of the following: redness, itchy eyes, watery eyes, itchy nose, runny nose, stuffy nose, sneezing, nasal congestion, wheezing, coughing fits, chest tightness, facial pain, rash, hives, shortness of breath, cough, postnasal drip, itchy throat, dry skin, sinus pressure, decreased sense of smell, decreased sense of taste, or poor sleep quality. In some embodiments, the symptom is redness of the eyes. In other embodiments, the symptom is itchy eyes. In further embodiments, the symptom is watery eyes. In yet other embodiments, the symptom is itchy nose. In still further embodiments, the symptom is runny nose. In other embodiments, the symptom is stuffy nose. In further embodiments, the symptom is sneezing. In yet other embodiments, the symptom is stuffy nose. In yet further embodiments, the symptom is wheezing. In still other embodiments, the symptom is stuffy nose. In yet further embodiments, the symptom is wheezing. In other embodiments, the symptom is wheezing. In further embodiments, the symptom is chest tightness. In yet other embodiments, the symptom is facial pain. In even further embodiments, the symptom is a rash. In other embodiments, the symptom is hives. In further embodiments, the symptom is shortness of breath. In still other embodiments, the symptom is a cough. In even 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 still 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 for treating these symptoms. In some embodiments, the methods improve 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. Thus, the liquid compositions and dosage forms are useful for alleviating upper respiratory tract allergy symptoms in patients in need thereof. These methods include administering to the patient a therapeutically effective amount of the spray-dried formulation or oral solid dosage form described herein. In some embodiments, the symptoms are runny nose, itchy or watery eyes, sneezing, itchy nose, itchy throat, or a combination thereof. In further embodiments, the upper respiratory tract allergy is hay fever.

[0046] Preparation of paraben-free suspension The paraben-free aqueous pharmaceutical suspension of the present invention can be prepared by adding the components of the sweetener system predissolved in purified water. A dispersion of the suspending agent in a suitable cosolvent is then added to an aliquot of water preheated to approximately 25-80°C, specifically 35-80°C, more specifically 35-45°C. Addition of the dispersion using this method facilitates hydration and dissolution of the suspending agent. The temperature is maintained by the subsequent addition of a portion of the buffer system (to maintain pH control). The preservative system is then added to form the bulk solution. The active agent is dispersed in an aqueous solution of the remaining components of the buffer system and the humectant. The pH of this solution is controlled prior to adding the active agent to maintain the appropriate physical form. The opacifier, if any, is added thereafter, and the active dispersion is added to the bulk solution, previously cooled to 20-35°C, specifically 20-30°C, to form a suspension. The flavoring agent and remaining water, if necessary, are added to the desired mass. The bulk suspension is then milled and degassed. This suspension can be prepared using conventional processing equipment.

[0047] In some embodiments, the described process produces suspension formulations having the characteristics of Formulations B1-B8 (shown in Table B below). In one embodiment of Formulations B1-B8, the flavoring agent is an artificial raspberry cream flavor. In certain embodiments of Formulations B1-B8, titanium oxide may be omitted. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0048] In one embodiment, the method for preparing the paraben-free aqueous pharmaceutical suspension comprises: a) adding the components of the sweetener system previously dissolved in purified water; b) adding the dispersion of the suspending agent in polypropylene to purified water; c) adding a portion of the buffer system to maintain pH control; d) adding the preservative system described above; e) dispersing fexofenadine in an aqueous solution of the remaining components of the buffer system and the wetting agent; f) adding the fexofenadine dispersion; g) optionally adding an opacifying agent; h) adding the flavoring agent; i) Add purified water to adjust the total volume; j) homogenizing the mixture; and k) grinding and degassing the mixture Includes.

[0049] Embodiment The present invention also provides the following non-limiting embodiments. Embodiment 1 is pH 5.8 to 7.0 0.03% to 1.20% (wt / wt) of fexofenadine zwitterionic dihydrate Form I of formula (I) [ka] and; 0.01% to 0.20% (wt / wt) of a wetting agent; a suspending agent comprising 0.10% to 0.50% (wt / wt) of a hydrocolloid gum; a sweetener system comprising 5% to 40% (weight / weight) sucrose and 5% to 40% (weight / weight) xylitol, wherein the ratio of the amounts of (sucrose):(xylitol) is 1:1 to 2:1; (a) one of 0.0001% to 10.0% (wt / wt) domiphen bromide, 0.0001% to 10.0% (wt / wt) cetylpyridinium chloride, 0.4% to 10% sodium benzoate, and 0.25% to 2% (wt / wt) potassium sorbate, and (b) a preservative system comprising 0.01% to 0.25% (wt / wt) edetate disodium; 0.06% to 1.05% (wt / wt) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate, or 0.06% to 1.05% (wt / wt) monobasic potassium phosphate, and a buffer system comprising 0.32% to 2.69% (wt / wt) dibasic sodium phosphate or its equivalent dibasic sodium phosphate hydrate, or 0.32% to 2.69% (wt / wt) dibasic potassium phosphate or its equivalent dibasic potassium phosphate hydrate; 1.0% to 10.0% (wt / wt) propylene glycol; 0.20% to 0.70% (wt / wt) of flavoring agent The paraben-free aqueous pharmaceutical suspension contains

[0050] Embodiment 2 is a paraben-free aqueous pharmaceutical suspension according to embodiment 1, wherein the preservative system comprises 0.0001% to 10.0% (wt / wt) domiphen bromide and 0.01% to 0.25% (wt / wt) edetate disodium, and is free of parabens. Embodiment 3 is a paraben-free aqueous pharmaceutical suspension according to embodiment 1, wherein the preservative system comprises 0.0001% to 10.0% (wt / wt) cetylpyridinium chloride bromide and 0.01% to 0.25% (wt / wt) edetate disodium. Embodiment 4 is the paraben-free aqueous pharmaceutical suspension of embodiment 1, wherein the preservative system comprises 0.4% to 10% sodium benzoate and sodium bromide, and 0.01% to 0.25% (wt / wt) edetate disodium.

[0051] A fifth embodiment has a pH of 5.8 to 7.0. 0.03% to 1.20% (wt / wt) of fexofenadine zwitterionic dihydrate Form I of formula (I) [ka] and; 0.01% to 0.20% (wt / wt) of a wetting agent; a suspending agent comprising 0.10% to 0.50% (wt / wt) of a hydrocolloid gum; a sweetener system comprising 5% to 40% (weight / weight) sucrose and 5% to 40% (weight / weight) xylitol, wherein the ratio of the amounts of (sucrose):(xylitol) is 1:1 to 2:1; a preservative system comprising 0.25% to 2% (wt / wt) potassium sorbate and 0.01% to 0.25% (wt / wt) edetate disodium; 0.06% to 1.05% (wt / wt) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate, or 0.06% to 1.05% (wt / wt) monobasic potassium phosphate, and a buffer system comprising 0.32% to 2.69% (wt / wt) dibasic sodium phosphate or its equivalent dibasic sodium phosphate hydrate, or 0.32% to 2.69% (wt / wt) dibasic potassium phosphate or its equivalent dibasic potassium phosphate hydrate; 1.0% to 10.0% (wt / wt) propylene glycol; 0.20% to 0.70% (mass / mass) of flavoring agent The paraben-free aqueous pharmaceutical suspension contains

[0052] Embodiment 6 is a paraben-free aqueous pharmaceutical suspension of any one of Embodiments 1 to 4, comprising 0.03% to 1.20% fexofenadine zwitterionic dihydrate Form I of Formula (I), wherein at least 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than 280 μm. Embodiment 7 is a paraben-free aqueous pharmaceutical suspension according to embodiment 6, wherein at least 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than 50 μm. Embodiment 8 is a paraben-free aqueous pharmaceutical suspension according to embodiment 7, wherein at least 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than 40 μm. Embodiment 9 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 8, wherein the fexofenadine zwitterionic dihydrate Form I is 0.3% to 0.7% (wt / wt). Embodiment 10 is a paraben-free aqueous pharmaceutical suspension of embodiment 9, wherein the fexofenadine zwitterionic dihydrate Form I is 0.4% to 0.6% (wt / wt).

[0053] Embodiment 11 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 10, wherein the wetting agent is 0.01% to 0.07% (wt / wt). Embodiment 12 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 10, wherein the wetting agent is 0.02% to 0.05% (wt / wt). Embodiment 13 is a paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 12, wherein the wetting agent is about 0.04% (w / w). Embodiment 14 is a paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 12, wherein the wetting agent is ionic. Embodiment 15 is a paraben-free aqueous pharmaceutical suspension according to embodiment 14, wherein the wetting agent is poloxamer 188. Embodiment 16 is a paraben-free aqueous pharmaceutical suspension according to embodiment 14, wherein the wetting agent is poloxamer 407.

[0054] Embodiment 17 is a paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 16, wherein the hydrocolloid gum is 0.1% to 0.5% (wt / wt). Embodiment 18 is a paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 16, wherein the hydrocolloid gum is 0.2% to 0.4% (wt / wt). Embodiment 19 is a paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 18, wherein the hydrocolloid gum is about 0.31% (wt / wt). Embodiment 20 is a paraben-free aqueous pharmaceutical suspension of any one of embodiments 1 to 19, wherein the hydrocolloid gum is xanthan gum. Embodiment 21 is the paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 20, wherein the xylitol is 7.5% to 10% (w / w). Embodiment 22 is the paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 20, wherein the xylitol is 8.5% to 9.50% (wt / wt). Embodiment 23 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 22, wherein the sucrose is 17.3% to 18.5% (wt / wt). Embodiment 24 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 22, wherein the sucrose is 17.5% to 18.0% (wt / wt).

[0055] Embodiment 25 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 24, wherein the potassium sorbate is 0.1% to 0.6% (wt / wt). Embodiment 26 is the paraben-free aqueous pharmaceutical suspension of Embodiment 21, wherein the potassium sorbate is 0.15% to 0.5% (wt / wt). Embodiment 27 is the paraben-free aqueous pharmaceutical suspension of any one of Embodiments 1 to 26, wherein the edetate disodium is 0.05% to 0.2% (wt / wt). Embodiment 28 is the paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 26, wherein the edetate disodium is 0.10% to 0.18%.

[0056] Embodiment 29 is the paraben-free aqueous pharmaceutical suspension of any one of Embodiments 1 to 28, wherein the buffer system comprises 0.4% to 0.9% (wt / wt) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate; and 0.5% to 0.8% (wt / wt) dibasic sodium phosphate or its equivalent amount of dibasic sodium phosphate hydrate. Embodiment 30 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 29, wherein the propylene glycol is 1.8% to 2.5% (wt / wt). Embodiment 31 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 29, wherein the propylene glycol is 1.9% to 2.4% (wt / wt). Embodiment 32 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 31, wherein the flavoring agent is 0.2% to 0.6% (w / w). Embodiment 33 is a paraben-free aqueous pharmaceutical suspension according to any one of Embodiments 1 to 31, wherein the flavoring agent is 0.3% to 0.5% (w / w).

[0057] Embodiment 34 is a paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 33, further comprising 0.07% to 1.1% (wt / wt) of an opacifying agent. Embodiment 35 is a paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 33, further comprising 0.08% to 1.0% (wt / wt) of an opacifying agent. Embodiment 36 is a paraben-free aqueous pharmaceutical suspension according to embodiment 34 or 35, wherein the opacifying agent is titanium dioxide.

[0058] Embodiment 37 is a pharmaceutical composition comprising 0.4% to 0.6% (wt / wt) fexofenadine zwitterionic dihydrate Form I, 1.9% to 2.4% (wt / wt) propylene glycol, 0.25% to 0.6% (wt / wt) potassium sorbate, 0.10% to 0.18% (wt / wt) edetate disodium, 0.9% to 1.2% (wt / wt) dibasic sodium phosphate heptahydrate, 0.5% to 0.8 ... 36. The paraben-free aqueous pharmaceutical suspension of any one of embodiments 3 to 36, comprising sodium phosphate monohydrate, 0.2% to 0.4% (wt / w) xanthan gum, 0.02% to 0.05% (wt / w) poloxamer 407, 0.08% to 1.0% (wt / w) titanium dioxide, 17.5% to 18.0% (wt / w) sucrose, 8.5 to 9.50% (wt / w) xylitol, and 0.3% to 0.5% (wt / w) flavoring.

[0059] Embodiment 38 has a pH of 5.8 to 7.0; 0.4% to 0.6% (wt / wt) of fexofenadine zwitterionic dihydrate Form I of formula (I) [ka] and; 0.02% to 0.05% (wt / wt) of poloxamer 407; with a suspending agent containing 0.2% to 0.4% xanthan gum; a sweetener system comprising 17.5% to 18.0% (wt / wt) sucrose and 8.5% to 9.50% (wt / wt) xylitol; a preservative system comprising 0.25% to 0.6% (wt / wt) potassium sorbate and 0.10% to 0.18% (wt / wt) edetate disodium; a buffer system comprising 0.9% to 1.2% (wt / wt) dibasic sodium phosphate heptahydrate and 0.5% to 0.8% (wt / wt) monobasic sodium phosphate monohydrate; 1.9% to 2.4% (wt / wt) propylene glycol; 0.08% to 1.0% (wt / wt) titanium dioxide; 0.3% to 0.5% (mass / mass) of flavoring agent The paraben-free aqueous pharmaceutical suspension contains Embodiment 39 is a paraben-free aqueous pharmaceutical suspension of any one of embodiments 1 to 38, wherein the flavoring agent is artificial raspberry cream flavor or artificial orange cream flavor. Embodiment 40 is a kit comprising a bottle or vial containing the paraben-free aqueous pharmaceutical suspension of any one of embodiments 1 to 35, and a syringe or cup.

[0060] Embodiment 41 is the use of the paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 39 for the relief of symptoms due to allergies, such as upper respiratory tract allergies, in a patient in need thereof. Embodiment 42 is the use according to embodiment 41, wherein the allergy is due to a pet allergen such as that found in dust mites, animal saliva, animal urine or animal dander, or an indoor allergen such as mold, or pollen from grasses, weeds or trees, e.g., hay fever, or an outdoor allergen such as mold.

[0061] Embodiment 43 is a paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 39 for the relief of symptoms due to allergies, such as upper respiratory tract allergies, in a patient in need thereof. Embodiment 44 is the paraben-free aqueous pharmaceutical suspension of embodiment 43, wherein the allergy is due to a pet allergen such as found in dust mites, animal saliva, animal urine, or animal dander, or an indoor allergen such as mold, or pollen from grasses, weeds, or trees, e.g., hay fever, or an outdoor allergen such as mold.

[0062] Embodiment 44 is a method of alleviating symptoms of an allergy in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the paraben-free aqueous pharmaceutical suspension of any one of Embodiments 1 to 39. Embodiment 46 is the method of embodiment 45, wherein the patient is an adult. Embodiment 47 is the method of embodiment 46, wherein the patient is a child. Embodiment 48 is the method of any one of embodiments 45 to 47, wherein the allergy is due to an indoor allergen or an outdoor allergen. Embodiment 49 is the method of claim 48, wherein the indoor allergen is a dust mite, a pet allergen such as that contained in animal saliva, animal urine, or animal dander, or a mold. Embodiment 50 is the method of claim 48, wherein the outdoor allergen is pollen, such as from grasses, weeds, or trees, such as hay fever, or mold. Embodiment 51 is the method of any one of embodiments 45-50, wherein the symptom is one or more of redness, itchy eyes, watery eyes, itchy nose, runny nose, stuffy nose, sneezing, nasal congestion, wheezing, coughing fits, chest tightness, facial pain, rash, hives, shortness of breath, cough, postnasal drip, itchy throat, dry skin, sinus pressure, decreased sense of smell, decreased sense of taste, or decreased sleep quality.

[0063] Embodiment 52 is a method for preparing a paraben-free aqueous pharmaceutical suspension according to any one of embodiments 1 to 39, comprising: a) adding the components of the sweetener system pre-dissolved in purified water; b) adding the dispersion of the suspending agent in polypropylene to purified water; c) adding a portion of the buffer system to maintain pH control; d) adding the preservative system described above; e) dispersing fexofenadine in an aqueous solution of the remaining components of the buffer system and the wetting agent; f) adding the fexofenadine dispersion; g) optionally adding an opacifying agent; h) the flavoring agent; i) Add purified water to adjust the total volume; j) homogenizing the mixture; and k) grinding and degassing the mixture The method includes:

[0064] 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 use the present invention and practice the claimed methods. The following examples therefore specifically point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure. [Example]

[0065] Example 1 - Preparation of a Fexofenadine Suspension Formulation In a jacketed main blending tank, sucrose and xylitol are added to the purified water and dissolved. The xanthan gum in propylene glycol is slowly added and uniformly dispersed. The recirculation loop is turned on and the dispersion is transferred to a jacketed main blending tank containing purified water and the sweetener system, which has been preheated and mixed to 35-45°C. The batch is continuously mixed until the end of processing. The temperature is maintained until the preservative addition step. The vessel is rinsed with the remaining propylene glycol and a portion of the purified water, and the rinse is transferred to the main blending tank. Dibasic sodium phosphate heptahydrate and a portion of monobasic sodium phosphate monohydrate are added to the jacketed vessel and dissolved. Potassium sorbate and disodium edetate are added to the jacketed vessel and dissolved. The solution in the jacketed vessel is cooled to 20-30°C. The pH of the solution is measured.

[0066] In a separate container, the remaining portions of dibasic sodium phosphate heptahydrate and monobasic sodium phosphate monohydrate are added to purified water and dissolved in a high shear mixer. Poloxamer 407 is added and dissolved. The pH of this solution is measured. Fexofenadine hydrochloride anhydrous Form I is slowly added to this solution to form a uniform dispersion. Titanium dioxide is slowly added to this dispersion to form a uniform dispersion. This dispersion is transferred to the solution in the jacketed main blend tank. The tank containing this dispersion is rinsed with a portion of purified water and transferred to the main blend tank. Raspberry cream flavor is added to the main blend tank via a pressure watering can and dissolved. Sufficient purified water is added as needed to achieve the target net weight (10,000 kg). Mixing is continued to form a uniform suspension. The pH is measured. The suspension is milled (i.e., URSCHEL® milled) and degassed. The resulting suspension contains 30 mg of fexofenadine zwitterionic dihydrate Form I (converted from anhydrous Form I of fexofenadine hydrochloride) per 5 mL of suspension.

[0067] The components of the existing fexofenadine suspension formulation are shown in Table 1-1 below. In the existing formulation, EDTA is a chelating agent that has a synergistic effect with the preservative system, suppressing the effects of metals / ions, preventing the decomposition of the ingredients of the formulation, and ensuring the quality and shelf life of the final product. [Table 3]

[0068] Example 2 - Preparation of a Paraben-Free Suspension Formulation Fexofenadine and its pharmaceutically acceptable salts are useful as antihistamines, as disclosed in U.S. Pat. No. 4,254,129, the contents of which are incorporated herein by reference in their entirety. Fexofenadine anhydrous form (I) is used in the manufacture of Allegra® suspension because it converts to the base and Form I zwitterionic dihydrate (Figure 1), eliminating the bitter taste characteristic of this anhydrous form in the product. Conversion of the anhydrous form to the zwitterionic form is controlled by the pH of the suspension, which is monitored throughout the product's manufacture and controlled by the addition of monobasic sodium phosphate buffer and dibasic sodium phosphate buffer. The ideal pH to maintain the product's sensory properties is 5.8-7.0, where 97% of the fexofenadine is in the zwitterionic form. The current preservative system for Allegra® Suspension consists of the preservatives propylparaben and butylparaben, a system commonly used in oral liquid dosage forms, that provides microbial activity and stability at the pH of the suspension (approximately 6.2) and a broad spectrum of activity. The formulation and testing of Allegra® Suspension is disclosed in International Publication No. WO 2007 / 070517 and U.S. Patent No. 8,933,097, the contents of which are incorporated herein by reference in their entireties. This formulation is also shown in Table 1-1 above.

[0069] The existing formulations disclosed in International Publication No. WO2007 / 070517, U.S. Patent No. 8,933,097, and Table 1-1 above contain parabens and disodium edetate (EDTA). These existing formulations have been highly optimized. As shown in Table 1-1, disodium edetate is known to have a synergistic effect with parabens against certain microorganisms. Because parabens are potentially harmful, a study was conducted to identify a paraben-free preservative system that would not affect the quality and safety of the aqueous composition and would maintain the organoleptic properties of this suspension and the zwitterionic form of fexofenadine. Indeed, the use of butylparaben is currently banned in the European Union, but not elsewhere. The screening objective was to replace butylparaben with another preservative system, avoiding propylparaben while maintaining all other properties of the formulation.

[0070] Initial screening The selection of a new preservative system began with a literature search, which identified 55 preservatives approved for pharmaceutical use. Of these, 29 were suitable for use in oral products, although most were effective at pH below 5.0, outside the preferred pH range of existing formulations. Therefore, the most promising preservatives, considering the target pH range of the products, were: methylparaben, methylparaben sodium, methylparaben potassium, ethylparaben, ethylparaben sodium, ethylparaben potassium, butylparaben, butylparaben sodium, propylparaben, propylparaben sodium, propylparaben potassium, domiphen bromide, propyl gallate, sodium benzoate, cetylpyridinium chloride, and potassium sorbate. Further testing After excluding paraben derivatives, and in accordance with the scope of the project, four preservatives were selected for further testing: domiphen bromide, sodium benzoate, cetylpyridinium chloride, and potassium sorbate.

[0071] Example 3 - Testing Paraben Alternatives Four selected preservatives (domiphen bromide, sodium benzoate, cetylpyridinium chloride, and potassium sorbate) were tested in laboratory batches, producing over 276 laboratory batches, conducting over 1,535 analytical tests, and conducting approximately 143 preservative efficacy studies. These studies were used to identify suitable paraben replacements that exhibited similar preservative efficacy as the synergistic combination of preservatives in the existing formulation. To generate the formulation, the parabens in the existing formulation were replaced with the putative paraben replacements tested. The formulation was otherwise kept the same. Therefore, all of these preservatives were tested in combination with EDTA.

[0072] result Domiphen bromide Domiphen bromide demonstrated favorable preservative system efficacy test (PET) results (see Tables 3-1 and 3-2 below). Because domiphen bromide is not currently approved in the United States due to a lack of toxicity studies, no further testing was performed. [Table 4-1] [Table 4-2]

[0073] Cetylpyridinium chloride Pilot batches have been manufactured on an industrial scale using cetylpyridinium chloride, and stability studies have been performed for up to 24 months with satisfactory results (see Tables 3-3 and 3-4). Because cetylpyridinium chloride is not currently FDA-approved for use in pediatric oral solutions, no further studies were performed. [Table 5]

[0074] Sodium Benzoate Studies carried out with this preservative system showed satisfactory results, however, the pH change required to ensure its microbiological action altered the organoleptic properties of the product (flavor and odor) (see Tables 3-5 and 3-6). [Table 6-1] [Table 6-2]

[0075] potassium sorbate Potassium sorbate has only previously been identified as a preservative aid, but unexpectedly, potassium sorbate has proven to be a suitable preservative. Initial studies have shown that paraben-free suspensions using a potassium sorbate preservative system turn yellow during accelerated stability studies at 24 and 36 months. Investigations into the color change of suspensions began with a comparison of the color of the paraben-free suspensions.

[0076] Example 4 - Further studies using potassium sorbate as a preservative Further studies were conducted to test the efficacy of potassium sorbate use as an antimicrobial preservative in formulations containing potassium sorbate, confirming the definition of minimum use levels and specifications, and further developing the US and European monographs to meet the various regulatory requirements of the countries where this new formulation will be submitted. Stability studies were conducted over a 36-month period. [Table 7-1] [Table 7-2] [Table 7-3]

[0077] Considering the above results, potassium sorbate was considered effective as a preservative at a concentration of 0.4% considering the acceptance criteria of both pharmacopoeias, failing at a concentration of 0.3% in the European Pharmacopoeia and 0.10 in the United States Pharmacopoeia due to differences in specifications between the studies. Potassium sorbate has been shown to be effective for up to 36 months of stability. Surprisingly, despite the known synergistic effect of parabens and EDTA, a suspension formulation of fexofenadine using a preservative system containing only potassium sorbate and EDTA was found to be bioequivalent to a solution containing parabens. It has been found that it is possible to reduce the overall amount of preservatives in a suspension formulation of fexofenadine by using a preservative system containing only potassium sorbate and EDTA.

[0078] Although the invention has been described and illustrated herein with reference to various specific materials, procedures, and examples, it is understood that the invention is not limited to the particular combination of materials and procedures selected for that purpose. Numerous variations of such details are possible, as will be apparent to those skilled in the art. It is intended that the specification and examples be considered 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 incorporated herein by reference in their entirety.

Claims

1. having a pH of 5.8 to 7.0; 0.03% to 1.20% (wt / wt) of fexofenadine zwitterionic dihydrate Form I of formula (I) 【Chemistry 1】 and; 0.01% to 0.20% (wt / wt) of a wetting agent; a suspending agent comprising 0.10% to 0.50% (w / w) of a hydrocolloid gum; a sweetener system comprising 5% to 40% (wt / wt) sucrose and 5% to 40% (wt / wt) xylitol, wherein the ratio of the amounts of (sucrose):(xylitol) is 1:1 to 2:1; a preservative system comprising 0.25% to 2% (w / w) potassium sorbate and 0.01% to 0.25% (w / w) edetate disodium; 0.06% to 1.05% (wt / wt) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate, or 0.06% to 1.05% (wt / wt) monobasic potassium phosphate, and a buffer system comprising 0.32% to 2.69% (wt / wt) dibasic sodium phosphate or its equivalent dibasic sodium phosphate hydrate, or 0.32% to 2.69% (wt / wt) dibasic potassium phosphate or its equivalent dibasic potassium phosphate hydrate; 1.0% to 10.0% (wt / wt) propylene glycol; 0.20% to 0.70% (wt / wt) of a flavoring agent; A paraben-free aqueous pharmaceutical suspension comprising:

2. having a pH of 5.8 to 7.0; 0.03% to 1.20% (wt / wt) of fexofenadine zwitterionic dihydrate Form I of formula (I) 【Chemistry 2】 and; 0.01% to 0.20% of a humectant; a suspending agent comprising 0.10% to 0.50% (w / w) of a hydrocolloid gum; a sweetener system comprising 5% to 40% (wt / wt) sucrose and 5% to 40% (wt / wt) xylitol, wherein the ratio of the amounts of (sucrose):(xylitol) is 1:1 to 2:1; (a) one of 0.0001% to 10.0% (wt / wt) domiphen bromide, 0.0001% to 10.0% (wt / wt) cetylpyridinium chloride, 0.4% to 10% sodium benzoate, and 0.25% to 2% (wt / wt) potassium sorbate; and (b) 0.01% to 0.25% (wt / wt) edetate disodium. a preservative system comprising: 0.06% to 1.05% (wt / wt) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate, or 0.06% to 1.05% (wt / wt) monobasic potassium phosphate, and a buffer system comprising 0.32% to 2.69% (wt / wt) dibasic sodium phosphate or its equivalent dibasic sodium phosphate hydrate, or 0.32% to 2.69% (wt / wt) dibasic potassium phosphate or its equivalent dibasic potassium phosphate hydrate; 1.0% to 10.0% (wt / wt) propylene glycol; 0.20% to 0.70% (wt / wt) of a flavoring agent; A paraben-free aqueous pharmaceutical suspension comprising:

3. 3. The paraben-free aqueous pharmaceutical suspension of claim 2, wherein the preservative system comprises 0.0001% to 10.0% (wt / wt) domiphen bromide and 0.01% to 0.25% (wt / wt) edetate disodium.

4. 3. The paraben-free aqueous pharmaceutical suspension of claim 2, wherein the preservative system comprises 0.0001% to 10.0% (w / w) cetylpyridinium chloride bromide and 0.01% to 0.25% (w / w) edetate disodium.

5. 3. The paraben-free aqueous pharmaceutical suspension of claim 2, wherein the preservative system comprises 0.4% to 10% sodium benzoate and sodium bromide and 0.01% to 0.25% (wt / wt) disodium edetate.

6. 6. The paraben-free aqueous pharmaceutical suspension of any one of claims 1 to 5, comprising 0.03% to 1.20% of fexofenadine zwitterionic dihydrate Form I of formula (I), wherein at least 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than 280 μm.

7. 7. The paraben-free aqueous pharmaceutical suspension of claim 6, wherein at least 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than 50 μm.

8. 8. The paraben-free aqueous pharmaceutical suspension of claim 7, wherein at least 90% of the fexofenadine zwitterionic dihydrate Form I has a particle size of less than 40 μm.

9. 9. The paraben-free aqueous pharmaceutical suspension of any one of claims 1 to 8, wherein the fexofenadine zwitterionic dihydrate Form I is 0.3% to 0.7% (w / w).

10. 10. The paraben-free aqueous pharmaceutical suspension of claim 9, wherein the fexofenadine zwitterionic dihydrate Form I is 0.4% to 0.6% (w / w).

11. 11. The paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 10, wherein said wetting agent is 0.02% to 0.05% (w / w).

12. 12. The paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 11, wherein the wetting agent is ionic.

13. 13. The paraben-free aqueous pharmaceutical suspension of claim 12, wherein the wetting agent is poloxamer 188.

14. 13. The paraben-free aqueous pharmaceutical suspension of claim 12, wherein the wetting agent is poloxamer 407.

15. 16. The paraben-free aqueous pharmaceutical suspension of any one of claims 1 to 15, wherein the hydrocolloid gum is 0.2% to 0.4% (w / w).

16. 16. The paraben-free aqueous pharmaceutical suspension of any one of claims 1 to 15, wherein said hydrocolloid gum is xanthan gum.

17. 17. The paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 16, wherein the xylitol is 7.5% to 10% (w / w).

18. 18. The paraben-free aqueous pharmaceutical suspension of claim 17, wherein the xylitol is 8.5% to 9.50% (w / w).

19. 19. The paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 18, wherein the sucrose is 17.3% to 18.5% (w / w).

20. 20. The paraben-free aqueous pharmaceutical suspension of claim 19, wherein the sucrose is 17.5% to 18.0% (w / w).

21. 21. The paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 20, wherein the potassium sorbate is 0.1% to 0.6% (wt / wt).

22. 22. The paraben-free aqueous pharmaceutical suspension of claim 21, wherein said potassium sorbate is 0.15% to 0.5% (w / w).

23. 23. The paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 22, wherein said edetate disodium is 0.05% to 0.2% (wt / wt).

24. 24. The paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 23, wherein the buffer system comprises 0.4% to 0.9% (wt / wt) monobasic sodium phosphate or its equivalent amount of monobasic sodium phosphate hydrate; and 0.5% to 0.8% (wt / wt) dibasic sodium phosphate or its equivalent amount of dibasic sodium phosphate hydrate.

25. 25. The paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 24, wherein the propylene glycol is 1.8% to 2.5% (wt / wt).

26. 26. The paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 25, wherein said flavoring agent is 0.2% to 0.6% (w / w).

27. 27. The paraben-free aqueous pharmaceutical suspension of any one of claims 1 to 26, further comprising 0.07% to 1.1% (w / w) of an opacifying agent.

28. 28. The paraben-free aqueous pharmaceutical suspension of claim 27, wherein said opacifying agent is titanium dioxide.

29. 0.4% to 0.6% (wt / wt) fexofenadine zwitterionic dihydrate Form I, 1.9% to 2.4% (wt / wt) propylene glycol, 0.25% to 0.6% (wt / wt) potassium sorbate, 0.10% to 0.18% (wt / wt) edetate disodium, 0.9% to 1.2% (wt / wt) dibasic sodium phosphate heptahydrate, 0.5% to 0.8% (wt / wt) monobasic sodium phosphate monohydrate 29. The paraben-free aqueous pharmaceutical suspension of any one of claims 5 to 28, comprising 0.2% to 0.4% (wt / w) xanthan gum, 0.02% to 0.05% (wt / w) poloxamer 407, 0.08% to 1.0% (wt / w) titanium dioxide, 17.5% to 18.0% (wt / w) sucrose, 8.5 to 9.50% (wt / w) xylitol, and 0.3% to 0.5% (wt / w) of a flavoring agent.

30. 30. The paraben-free aqueous pharmaceutical suspension of any one of claims 1 to 29, wherein said flavoring agent is artificial raspberry cream flavor or artificial orange cream flavor.

31. A kit comprising a bottle or vial containing the paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 20, and a syringe or cup.

32. 31. Use of the paraben-free aqueous pharmaceutical suspension according to any one of claims 1 to 30 for the relief of symptoms due to allergies, such as upper respiratory tract allergies, in a patient in need thereof.

33. 33. The use according to claim 32, wherein the allergy is due to a pet allergen such as contained in dust mites, animal saliva, animal urine or animal dander, or an indoor allergen such as mold, or pollen from grasses, weeds or trees, e.g. hay fever, or an outdoor allergen such as mold.

34. 31. The paraben-free aqueous pharmaceutical suspension of any one of claims 1 to 30 for the relief of symptoms due to allergies, such as upper respiratory tract allergies, in a patient in need thereof.

35. 35. The paraben-free aqueous pharmaceutical suspension of claim 34, wherein the allergy is due to a pet allergen such as contained in dust mites, animal saliva, animal urine or animal dander, or an indoor allergen such as mold, or pollen from grasses, weeds or trees, e.g., hay fever, or an outdoor allergen such as mold.

36. 31. A method of alleviating symptoms due to allergies in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the paraben-free aqueous pharmaceutical suspension of any one of claims 1 to 30.

37. 37. The method of claim 36, wherein the patient is an adult.

38. 38. The method of claim 37, wherein the patient is a child.

39. The method according to any one of claims 36 to 38, wherein the allergy is due to an indoor allergen or an outdoor allergen.

40. 40. The method of claim 39, wherein the indoor allergen is a dust mite, a pet allergen such as that found in animal saliva, animal urine or animal dander, or a mold.

41. 41. The method of claim 40, wherein the outdoor allergen is pollen, such as from grasses, weeds, or trees, such as hay fever, or mold.

42. 42. The method of any one of claims 36-41, wherein the symptom is one or more of redness, itchy eyes, watery eyes, itchy nose, runny nose, stuffy nose, sneezing, nasal congestion, wheezing, coughing fits, chest tightness, facial pain, rash, hives, shortness of breath, cough, postnasal drip, itchy throat, dry skin, sinus pressure, decreased sense of smell, decreased sense of taste, or decreased sleep quality.

43. 31. A method for preparing the paraben-free aqueous pharmaceutical suspension of any one of claims 1 to 30, comprising: a) adding the ingredients of the sweetener system pre-dissolved in purified water; b) adding the dispersion of suspending agent in polypropylene to purified water; c) adding a portion of said buffer system to maintain pH control; d) adding said preservative system; e) dispersing fexofenadine in an aqueous solution of the remaining components of the buffer system and the wetting agent; f) adding said dispersion of fexofenadine; g) optionally adding an opacifier; h) adding said flavoring agent; i) adding purified water to adjust the total volume; j) homogenizing the mixture; and k) grinding and degassing the mixture A method comprising:

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