Therapeutic liquid compositions

Abstract

Therapeutic liquid compositions for the treatment of various disorders comprise filled sweeteners derived from cereal or fruit sources.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application 63 / 493395, filed March 31, 2023, the entire disclosure of which is incorporated herein by reference for all purposes. Technical Field

[0003] This invention relates to liquid compositions, and more particularly to therapeutic liquid compositions. The invention also relates to methods for manufacturing liquid compositions and methods for alleviating symptoms in human subjects when the liquid composition is administered. Liquid compositions that may contain one or more therapeutically active agents are particularly useful for treating allergy symptoms, pain symptoms, and cough and cold symptoms, including but not limited to pain, cough, nasal congestion, rhinitis, and sore throat. Background Technology

[0004] Orally administered medications are given to patients in many forms, including solid forms such as capsules, tablets, soft capsules, or tablets, and liquid forms such as solutions, emulsions, or suspensions. Children, elderly patients, and many other patients (including those with disabilities or impairments) have difficulty swallowing solid forms (such as whole tablets or even capsules). Therefore, when the dosage form to be administered cannot be made into very small tablets or capsules, it is desirable to deliver the medication in a chewable solid or liquid form. For many patients (including pediatric and elderly patients), liquid oral dosage forms are preferred over chewable forms because they can be swallowed without chewing.

[0005] A suspension is a two-phase system having substantially water-insoluble solid active agent particles dispersed throughout a liquid medium. Suspensions do not include emulsions, which are intended to describe liquids suspended within a liquid carrier or syrup formulations containing only substantially completely dissolved pharmaceutical active agents. As used herein, “particles” can be crystals, granules, agglomerates, or any undissolved solid material. The particles of the present invention preferably have a median particle size (d50%) of about 2 micrometers to about 150 micrometers, more preferably about 10 micrometers to about 100 micrometers. The challenges of maintaining a substantially water-insoluble active agent in suspension, ensuring the stability of substantially water-insoluble active agents, and maintaining dosage uniformity over long periods have been previously addressed. See, for example, U.S. Patents 5,409,907 and 5,374,659.

[0006] In pharmaceutical suspensions, typically at least one active agent exists substantially as an undissolved solid particle, i.e., an active agent that is substantially insoluble in water. However, in any such system, a portion of such active agent can be in a dissolved state. In formulating such systems, it is advantageous to minimize the amount of drug that exists in a dissolved state. Minimizing the amount of active agent in solution is advantageous for both taste and chemical and / or physical stability of the product.

[0007] Liquid dosage forms can also exist in solution form where one or more therapeutic ingredients are substantially dissolved in a liquid blend. Therapeutic ingredients can be dissolved in solution when the dosage of the therapeutic ingredient is less than 50 g / 5 mL.

[0008] A common problem associated with liquid dosage forms is the generally unpleasant taste of the active agent exhibited by the liquid dosage form during its time in the mouth prior to swallowing. While suspensions generally provide superior taste masking over other liquid forms, those skilled in the art recognize that there are considerable technical difficulties in preparing stable and organoleptically acceptable suspensions.

[0009] Further, when formulating or reformulating over-the-counter ("OTC") oral solution or oral suspension products to use reduced ingredients or naturally-sourced ingredients, solutions to such challenges must be re-evaluated. The term "clean" or "clean drug" is an emerging trend in OTC drug products. While the term "clean" does not have an accepted definition, consumers generally understand it to mean any of the following: free of artificial flavors, dyes, preservatives, or sweeteners; derived from nature; and / or free of artificial, chemical, or unnecessary ingredients.

[0010] Formulating "clean" oral solution or oral suspension products can limit or exclude certain ingredients traditionally used in pharmaceutical suspensions to overcome the challenges of suspending active agents that are substantially insoluble in water, ensuring stability of active agents that are substantially insoluble in water, and maintaining dose uniformity over long periods of time. New ingredients that meet the definition of "clean" must be identified and evaluated to ensure that such newly formulated pharmaceutical solution or suspension products meet all safety and efficacy standards required of OTC drug products.

[0011] Traditionally, dyes are added to pharmaceutical suspensions for aesthetic and decolorization masking purposes. However, it has been discovered that some patients have allergic reactions to or are sensitive to dyed suspensions. Dyed suspensions can also stain clothing, furniture, carpets, etc. when spilled. Thus, there is a great need for dye-free suspensions.

[0012] Colorants are often added to pharmaceutical liquid products to produce a pharmaceutically acceptable characteristic, providing an identification factor and also providing consistency between product batches. Often, the color of the excipients used to manufacture OTC products can cause the product to appear inconsistent or“off-color” to the patient. The patient or consumer can perceive the inconsistency or color change as an indication that the product was manufactured improperly, has expired, or is generally ineffective, leading to product rejection.

[0013] In many cases, liquid dosage forms contain solvents or carriers to dissolve the active ingredients. Commonly used liquid solvents include propylene glycol or polyethylene glycol. Some of these solvents and carriers are artificial, or even if derived from natural sources, they undergo significant chemical processing. Common bulking sweeteners include sugar alcohols in solution, such as sorbitol solution. In many cases, these solvents and bulking sweeteners come from artificial sources, rather than from natural plant sources that many patients now prefer.

[0014] Even in cases where the solvents and bulking sweeteners are derived from natural plant sources, these ingredients often have high sugar content and / or high glycemic index, which can be undesirable to consumers; particularly young children, pre-diabetic or diabetic patients, or patients in general who are health conscious. For example, US20210290532A1 from GE Healthcare discloses a stable pharmaceutical formulation or suspension having a pharmaceutical active agent, agave, and a diluent. The formulation or suspension has a viscosity suitable for drinking, however, can have a high glycemic index due to the incorporation of agave syrup having a high fructose content.

[0015] Additionally, solvents and bulking sweeteners from natural sources can be difficult to incorporate, stabilize, or retain in oral suspension formulations. An example of a natural bulking sweetener is disclosed in US20080311272(A1) from Wild Valencia S.A., which describes a composition comprising a carbohydrate obtainable from carob bean and a carbohydrate obtainable from at least one other fruit, including apple and grape. This natural bulking sweetener or similar bulking sweeteners are sold by ADM Company under the trade name .

[0016] Accordingly, there remains a need for liquid pharmaceutical compositions that contain non-active materials derived from natural sources having a relatively low glycemic index. Such compositions should also be able to act quickly and provide excellent relief over a long period of time. SUMMARY

[0017] The present invention relates to liquid compositions that can be used to alleviate conditions such as those associated with allergies, coughs, colds, digestive health, or pain by carrying an active therapeutic ingredient. The active therapeutic ingredient can be a pharmaceutical active ingredient, a homeopathic ingredient, a herbal ingredient, or a nutritional supplement. These compositions will include a non-active ingredient that is a natural source or natural resource in large quantity.

[0018] According to one example, the liquid composition can include at least one therapeutic ingredient and at least one natural bulk sweetener, wherein the fructose content in the total amount of natural bulk sweetener in the composition is less than 75%.

[0019] According to an example, the liquid composition can include a therapeutic ingredient and a natural sweetener, the natural bulk sweetener having a fructose content that is less than 50% of the natural bulk sweetener. The natural bulk sweetener can be selected from the group consisting of glycerin, allulose syrup, rice syrup, tapioca syrup, apple syrup, carob syrup, and combinations thereof. The liquid composition can have a total fructose level that is less than 0.7 g / mL.

[0020] According to one example, the therapeutic ingredient can be a pharmaceutical active ingredient. According to other examples, the therapeutic ingredient can be a homeopathic active ingredient and / or a nutritional supplement. In another example, the therapeutic ingredient can be a combination of a pharmaceutical active ingredient with a homeopathic active ingredient and / or a nutritional supplement.

[0021] The liquid composition can be in the form of a suspension or a solution.

[0022] In one example, the pharmaceutical active ingredient can be selected from the group consisting of acetaminophen, diphenhydramine, dextromethorphan, guaifenesin, ibuprofen, cetirizine, loperamide, and phenylephrine. For example, the therapeutic ingredient can be an antihistamine.

[0023] In another example, the liquid composition can further include a sensate.

[0024] The liquid composition can include a second natural bulk sweetener. In one such example, the natural bulk sweetener can be glycerin and the second natural bulk sweetener can be tapioca syrup. In another example, the natural bulk sweetener can be glycerin and the second natural bulk sweetener can be brown rice syrup. In another example, the natural bulk sweetener can be glycerin and the second natural bulk sweetener can be allulose syrup.

[0025] In another example, the natural bulk sweetener can be glycerin and the second natural bulk sweetener can be a combination of apple syrup and carob syrup. In one example, the ratio of the combination of apple syrup and carob syrup to glycerin is about 3.30: 1.

[0026] In one example, the liquid composition can be substantially free or completely free of agave syrup. In another example, the liquid composition can be substantially free of any ingredient having a fructose content greater than 15%.

[0027] According to another aspect of the application, there can be a method of reducing a symptom in a subject selected from the group consisting of pain, fever, cough, nasal congestion, diarrhea, allergic rhinitis, and sore throat by administering a composition as disclosed herein. DETAILED DESCRIPTION

[0028] It is believed that one of ordinary skill in the art can, with adequate utility of the description herein, utilize the present application. The following specific examples and embodiments should be understood as illustrative only and are not to be construed in any way to limit the remainder of the disclosure in any manner.

[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this application belongs.

[0030] Unless otherwise indicated, all documents cited are, in relevant part, incorporated herein by reference; the citation of any document is not to be construed as an admission that it is prior art with respect to the present application. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to the term in this document shall control.

[0031] Unless otherwise indicated, all percentages as used herein are by weight. In addition, all ranges set forth herein are meant to include any combination of values between the two stated limits (including the limits themselves).

[0032] As used herein, the term "active ingredient" is used herein in a broad sense and can include any material that imparts a therapeutic effect. For example, an active ingredient can be a drug, a nutraceutical, a vitamin, a dietary supplement, a nutrient, an herb, a food, a dye, a nutraceutical, a mineral, a supplement, an oral care agent, or a flavoring agent (sensate), among others, and combinations thereof.

[0033] "Dosage form" applies to any composition that is designed to contain a specific predetermined amount (dose) of a certain ingredient and active ingredient as defined, for example, below. Suitable dosage forms can be drug delivery systems and systems for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorings, sensates, and the like. In a particularly preferred example, the dosage form is a system for oral administration for delivering a pharmaceutical active ingredient to the gastrointestinal tract of a human.

[0034] "Liquid dosage form" can non-exclusively include a suspension, a syrup, a solution, or an elixir in which one or more of the active ingredients are dissolved, partially dissolved, or in an undissolved or suspended state.

[0035] “Therapeutic effect” refers to any effect or action of an active ingredient intended to diagnose, cure, mitigate, or prevent disease or affect the structure or any function of the body.

[0036] Unless otherwise indicated, percentages used to express the amount of an ingredient are weight percentages (referred to as “weight %,” “wt%,” “percent by weight,” or “%(w / v)”). Similarly, weight ratios used to express the relative proportions of ingredients are also determined using weight percentages (i.e., by dividing the weight percent of one ingredient by the weight percent of another ingredient). Unless otherwise stated, all ranges include the end values, e.g., “4 to 9” includes the end values 4 and 9.

[0037] As used herein, the term “safe and effective amount” means an amount that is sufficient to induce the desired effect but low enough to avoid serious side effects. The safe and effective amount of a compound, extract, or composition will vary with such factors as the age, health, and environmental exposure of the end user, the duration and nature of the treatment, the particular extract, ingredient, or composition employed, and the particular carrier used, among others.

[0038] As used herein, the term “about” means within 5%, within 4%, within 3%, within 2.5%, within 2%, or within 1% by weight of the disclosed value.

[0039] In certain embodiments, the present application as disclosed herein can be practiced in the absence of any compound, method step, or element (or group of compounds or elements) not specifically disclosed herein.

[0040] Active ingredient

[0041] The dosage forms of the present application preferably contain one or more (or at least one) active ingredients. Suitable pharmaceutically active ingredients include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infectives, antipyretics, antiviral agents, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflatulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, cough suppressants, decongestants, expectorants, oral contraceptives, diuretics, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents, and pharmaceutically acceptable salts thereof, derivatives thereof, combinations thereof, and mixtures thereof.

[0042] According to one example, the active ingredient can be selected from (or selected from the group consisting of): acetylsalicylic acid; acetic acid derivatives such as indomethacin, diclofenac, sulindac and tolmetin; fenamic acid derivatives such as mefenamic acid, meclofenamic acid and flufenamic acid; biphenylcarboxylic acid derivatives such as diflunisal and flufenisal; and oxicams such as piroxicam, sudoxicam, isoxicam and meloxicam; as well as pharmaceutically acceptable salts thereof, derivatives thereof, combinations thereof and mixtures thereof.

[0043] Examples of useful NSAIDs include (as can be selected from or selected from the group consisting of): ibuprofen, naproxen, benoxaprofen, naproxen sodium, fenbufen, flurbiprofen, fenoprofen, fenbuprofen, ibuprofen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprofen, pranoprofen, miaroprofen, tioxaprofen, sulindac, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, celecoxib, as well as pharmaceutically acceptable salts thereof, derivatives thereof, combinations thereof and mixtures thereof.

[0044] The compositions of the present application can also comprise acetaminophen. As used herein, the term "APAP" means acetaminophen or N-acetyl-p-aminophenol, including but not limited to pharmaceutically acceptable salts, esters or derivatives thereof.

[0045] Examples of pharmaceutically active ingredients for cough and cold include antihistamines, antitussives, decongestants and expectorants, including (or can be selected from or selected from the group consisting of) but not limited to brompheniramine, carbinoxamine, acetylcysteine, guaifenesin, carboxymethylcysteine, chlorcyclizine, dexbrompheniramine, bromhexine, phenindamine, pheniramine, methdilazine, tripelennamine, pyrilamine, tripolidine, ephedrine, phenylephrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine, naphazoline, oxymetazoline, montelukast, propylhexedrine, triprolidine, clemastine, acrivastine, promethazine, oxomemazine, mequitazine, buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatomide, xylomezoline, loratadine, desloratadine, noberitamide, chlortrimeton, menthol, benzoxazoline, ethylmorphine, codeine, acetylcysteine, carboxymethylcysteine, ambroxol, belladonna alkaloids, sobrenol, guaicol and cetirizine; as well as pharmaceutically acceptable salts thereof, derivatives thereof, combinations thereof and mixtures thereof.

[0046] Preferably, the at least one active ingredient is an NSAID and / or acetaminophen, as well as pharmaceutically acceptable salts thereof.

[0047] Examples of suitable gastrointestinal agents include antacids such as (or which can be selected from or selected from the group consisting of) calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate; stimulant laxatives such as bisacodyl, frangula, danthron, senna, phenolphthalein, aloe, castor oil, ricin and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists such as famotidine, ranitidine, cimetidine and nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectives such as sucralfate and misoprostol; gastrointestinal prokinetics such as prucalopride, Helicobacter pylori antibiotics such as clarithromycin, amoxicillin, tetracycline and metronidazole; antidiarrheals such as diphenoxylate, loperamide and racecadotril; glycopyrronium bromide; antiemetics such as ondansetron; analgesics such as methadyl acetate.

[0048] Examples of suitable dimethicones include (which can be selected from or selected from the group consisting of) but are not limited to: dimethicone and simethicone, as disclosed in U.S. Patent Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each of which are expressly incorporated herein by reference. As used herein, the term "simethicone" refers to a broader class of dimethicones, including but not limited to simethicone and dimethicone.

[0049] A therapeutically effective amount of one or more active ingredients can be readily determined by one of skill in the art.

[0050] Suitable sensates include (which can be selected from or selected from the group consisting of): menthol, peppermint, mint flavor, fruit flavor, chocolate, vanilla, bubble gum flavor, coffee flavor, natural flavor, liqueur flavor, and combinations thereof, and the like.

[0051] According to examples, the composition comprises a polymer, also known as a mucoadhesive material. Suitable polymers include gelling materials such as hydrocolloids, for example (or which can be selected from or selected from the group consisting of) pectin, cellulose, alginate, carrageenan, and the like.

[0052] In examples, the mucoadhesive material is a thickening agent. Suitable thickening agents include (which can be selected from or selected from the group consisting of) but are not limited to carboxymethylcellulose (CMC), microcrystalline cellulose, and blends or mixtures thereof. Some suitable thickening agents are of natural origin, including xanthan gum and / or konjac gum. Other thickening agents include cellulose polymers such as hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, and mixtures thereof, and the like.

[0053] According to examples, the mucoadhesive material includes, but is not limited to, Avicel BV 2219, Avicel CL 611, Avicel LM 310 stabilizer (40% solids), Avicel RC 591, Carbopol 971P, CMC-7M8SF-PH, HPMC E4M, and Nutricol BV 5616.

[0054] The composition can contain about 0.05% to about 3% by weight of the polymer. The composition can contain about 0.2% to about 2% by weight of the polymer. These materials improve mucoadhesion and extend the duration of relief.

[0055] In another example, the composition can contain a surface active agent (also known as a surfactant). Suitable surface active agents can include polyoxyethylene-polyoxypropylene block copolymers. In examples, the surface active agent includes, but is not limited to, Lutrol F68 (Pluronic® 188); Lutrol F127 (Pluronic® 407), Tween 80, and mixtures thereof. 188); Lutrol F127 (Pluronic® 407), Tween 80, and mixtures thereof. 407), Tween 80, and mixtures thereof.

[0056] The composition can contain about 0.05% to about 2% by weight of the surface active agent. The composition can contain about 0.1% to about 1.5% by weight of the surface active agent. The composition can contain about 0.5% to about 1% by weight of the surface active agent. The surface active agent also enhances the perceived coating effect of the composition.

[0057] The resulting composition can be delivered in the form of a spray or a liquid. In examples, the composition can include an active ingredient. In another example, the composition can include a sensate.

[0058] Bulk sweetener

[0059] For the compositions of the present invention, a substantial portion of the bulking liquid comprises a natural bulking sweetener. As used herein, "natural bulking sweetener" is defined as a bulking sweetener that is derived from a plant source. The natural bulking sweetener can also have additional characteristics, such as characteristics from a vegan source, an organic source, a non-GMO source, or substantially free or completely free of gluten or alcohol. As used herein, "substantially free" is defined as less than 0.1% by weight / volume, preferably less than 0.05% by weight / volume, preferably less than 0.001% by weight / volume. The natural bulking sweetener can be used in the compositions of the present invention from about 20% to about 99% by weight / volume of the total composition.

[0060] The bulk sweetener or natural bulk sweetener of the present application can also have a low glycemic load as well as a specific level of fructose. For example, the bulk sweetener can have a fructose content of less than 75 wt.%, less than 70 wt.%, less than 50 wt.%, less than 40 wt.%, less than 30 wt.%, less than 25 wt.%, less than 20 wt.%, or less than 15 wt.%. In another example, the total fructose content of the liquid composition can be less than 0.9 g / mL, or less than 0.7 g / mL. In another example, the composition can be substantially free or completely free of fructose. As used herein, "substantially free" is defined as less than 0.1 wt / vol%, preferably less than 0.05 wt / vol%, preferably less than 0.001 wt / vol%. In another example, the total amount of sugar in the composition can be less than 0.9 g / mL or less than 0.7 g / mL.

[0061] Natural bulk sweeteners suitable for the present application include (or can be selected from or selected from the group consisting of) but are not limited to allulose syrup, rice syrup, tapioca syrup; apple syrup and carob syrup, and mixtures thereof, such as the product sold by ADM under the tradename A commercially available combination of apple syrup and carob syrup.

[0062] Other natural bulk sweeteners can include glycerol. Glycerol can be present in the composition from about 10 wt.% to about 98 wt.% of the composition. Glycerol can also be combined with a different (or second) natural bulk sweetener.

[0063] The composition can include a mixture of one or more of the natural bulk sweeteners in order to balance the sweetness and flavor profile of the final composition. The first natural bulk sweetener can be added in an amount from about 10 wt.% to about 90 wt.% of the composition, or from about 20 wt.% to about 50 wt.% of the composition; and the second natural bulk sweetener can be added in an amount from about 10 wt.% to about 90 wt.% of the composition, or from about 20 wt.% to about 50 wt.% of the composition. The composition can also include a third natural bulk sweetener (i.e., a natural bulk sweetener that is different from the first natural bulk sweetener and the second natural bulk sweetener), wherein the third bulk sweetener is added in an amount from about 5 wt.% to about 30 wt.% of the composition.

[0064] According to an example, the natural bulk sweetener can be a combination of glycerin and cassava syrup. The glycerin can be present in the composition in a range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example about 30% by weight. The cassava syrup can be present in the composition in a range of about 40% to about 60% by weight, or about 45% to about 55% by weight, for example about 50% by weight, or about 49% by weight. The ratio of cassava syrup to glycerin can be about 1 : 1 to about 2: 1, or about 1.4: 1 to about 1.8: 1, or about 1.6: 1.

[0065] According to an example, the natural bulk sweetener can be a combination of glycerin and cassava syrup. The glycerin can be present in the composition in a range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example about 30% by weight. The cassava syrup can be present in the composition in a range of about 40% to about 60% by weight, or about 45% to about 55% by weight, for example about 50% by weight, or about 49% by weight. The ratio of cassava syrup to glycerin can be about 1 : 1 to about 2: 1, or about 1.4: 1 to about 1.8: 1, or about 1.6: 1.

[0066] According to an example, the natural bulk sweetener can be a combination of glycerin and cassava syrup. The glycerin can be present in the composition in a range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example about 30% by weight. The cassava syrup can be present in the composition in a range of about 40% to about 60% by weight, or about 45% to about 55% by weight, for example about 50% by weight, or about 49% by weight. The ratio of cassava syrup to glycerin can be about 1 : 1 to about 2: 1, or about 1.4: 1 to about 1.8: 1, or about 1.6: 1.

[0067] According to another example, the natural bulk sweetener can be a combination of glycerin, apple syrup, and carob syrup. The combination of apple syrup and carob syrup can be available from Archer Daniels Midland (“ADM”) Company under the trademark The commercially available products are identical or similar and / or as described in European Patent EP 2002734 Bl entitled "Carbohydrate Composition Obtainable from Mediterranean Fruits," which is incorporated herein by reference, i.e., apple and carob syrups can be incorporated such that 35-60%, optionally 35-50%, optionally 35-45%, optionally 35-40%, optionally 35% (w / w) of the carbohydrates are obtainable from carob, 35-50%, optionally 35-45%, optionally 35-40%, optionally 40% (w / w) of the carbohydrates are obtainable from at least one other fruit (e.g., apple), where the percentages are based on dry matter.

[0068] In one example, glycerol can be present in the composition in a range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example about 30% by weight. The combination of apple syrup and carob syrup (e.g., as commercially available under the trademark In one example, glycerol can be present in the composition in a range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example about 30% by weight. The combination of apple syrup and carob syrup (e.g., as commercially available under the trademark In one example, glycerol can be present in the composition in a range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example about 30% by weight. The combination of apple syrup and carob syrup (e.g., as commercially available under the trademark In one example, glycerol can be present in the composition in a range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example about 30% by weight. The combination of apple syrup and carob syrup (e.g., as commercially available under the trademark

[0069] The composition can include a natural bulk sweetener plus a sugar alcohol solution. Suitable sugar alcohol solutions include (or can be selected from or selected from the group consisting of) but are not limited to sorbitol, maltitol, mannitol, xylitol, and erythritol. The first natural bulk sweetener can be added in an amount of about 10% to about 90% by weight of the composition, or about 20% to about 50% by weight of the composition; and the second sugar alcohol solution can be added in an amount of about 10% to about 90% by weight of the composition, or about 20% to about 50% by weight of the composition. Alternatively, the composition can be substantially free of a sugar alcohol solution.

[0070] In one example, the composition can include glycerin and an additional bulking sweetener derived from a grain or fruit source. In this example, the glycerin can be present at 10% to 40% by weight of the composition and the additional bulking sweetener can be present at 10% to 40% by weight of the composition. The glycerin can be added to mitigate an unpleasant taste or numbing sensation of the pharmaceutical active ingredient.

[0071] In one example, the weight ratio of glycerin to additional plant-based syrup is 1 :3 to about 3: 1, or about 1 :2 to about 2: 1. In this example, the additional plant-based syrup is selected from (or consists of a group consisting of) rice syrup, brown rice syrup, tapioca syrup, carob syrup, allulose syrup, and mixtures thereof.

[0072] In one example, the composition includes five or fewer ingredients. In another example, the composition includes four or fewer ingredients. In one version of this example, the composition is limited to diphenhydramine, glycerin, an additional plant-based syrup, and a flavoring agent. In this example, the additional plant-based syrup is selected from (or consists of a group consisting of) allulose syrup, carob syrup, rice syrup, brown rice syrup, tapioca syrup, and mixtures thereof.

[0073] Table 1 shows the sugar content of various bulking sweeteners.

[0074] Table 1: Sugar content of bulk sweeteners

[0075]

[0076] 1 : reported as 70% dry matter or Brix at 20°C, or a measure of dissolved solids in a liquid

[0077] Preservative

[0078] The composition of the present application can comprise a natural preservative, an artificial preservative, or a combination thereof. Suitable natural preservatives include potassium sorbate and citrus extract. Suitable artificial preservatives include (or can be selected from or chosen from the group consisting of) sodium benzoate, edetate (also known as salts of ethylenediaminetetraacetic acid or EDTA, such as disodium edetate), parabens (such as methyl paraben, ethyl paraben, propyl paraben, and butyl paraben), or mixtures thereof. The total preservative can be present at 0.01 wt% to 5 wt%. For example, the preservative of the composition can be potassium sorbate in an amount of about 0.1 wt% to about 0.5 wt%, or about 0.2 wt%. The composition of the present application can also be substantially free or completely free of preservatives. As used herein, “substantially free” is defined as less than 0.1 weight / volume %, preferably less than 0.05 weight / volume %, preferably less than 0.001 weight / volume %.

[0079] If the composition is substantially free of preservatives, the composition also has a water activity of less than 0.7 when tested using a water activity meter. The water activity (aw) of a composition is defined as the ratio between the vapor pressure of the composition when in equilibrium completely undisturbed with the surrounding air medium and the vapor pressure of distilled water under the same conditions. Water activity is described in detail later in this specification.

[0080] In certain examples, the composition can be substantially free or completely free of added water. Added water can be defined as water that is not present in the bulk sweetener or plant-based syrup. In some examples, the added water content is less than 5 wt%, or less than 2 wt%, or less than 1 wt% or less than 0.5 wt% of added water. In some examples, the total water content in the composition is less than 5 wt%, or less than 2 wt%, or less than 1 wt% or less than 0.5 wt% of total water in the composition.

[0081] pH adjuster

[0082] The composition can comprise a pH adjusting agent or buffer, including a salt, an acid, or a base. In certain examples, the pH adjusting agent includes anhydrous citric acid or sodium citrate. The pH adjusting agent can be added in an amount of less than 2 wt%, or less than 1 wt%, or less than 0.5 wt%, or less than 0.2 wt%, or about 0.1 wt%.

[0083] The pH of the composition can be less than 6 (or about 6), optionally between 5 (or about 5) and 6 (or about 6), for example between 5.8 and 5.9, or about 5.888.

[0084] Thickening agent

[0085] The suspensions of the present invention can employ a suspension system comprising, but not limited to, at least one thickening component as known in the art. The thickening component can include one or more thickening agents which can be selected from hydrophilic (i.e. water-soluble) polymers such as hydrocolloids, swelling polymers or gelling polymers, and the like. In one example, the thickening component can combine the attributes of a structurant and a swelling agent. In another preferred example, the thickening component can combine the attributes of at least two structurants, for example a primary structurant and a secondary structurant.

[0086] When introduced into an appropriate aqueous environment, the structurant can form an ordered structure believed to be stabilized by hydrogen bonding and molecular entanglement. Hydrocolloids are a particularly good class of structurant. Hydrocolloids are dispersions of particles around which water molecules and solvated ions form a shell-like structure through which fluid uptake occurs primarily by swelling and expansion of the structure.

[0087] Examples of suitable hydrocolloids include (or can be selected from, or consist of a group including) but are not limited to: alginates, agar, guar gum, locust bean gum, carrageenan, tara gum, gum arabic, gum tragacanth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, ceramid, laminarin, chitodextrin, arabinan, inulin, gum karaya, welan gum, rhubarb gum, curdlan, gellan gum, chitosan, cyclodextrin, cellulose polymers such as microcrystalline cellulose, carboxymethyl cellulose, and derivatives and combinations thereof. In certain examples of the present invention, the useful structurant can be selected from (or consist of a group including) hydrocolloid xanthan gum, microcrystalline cellulose, carboxymethyl cellulose, and derivatives, co-precipitates, and combinations thereof. In one particularly useful example, the thickening component can include xanthan gum as a primary structurant and a co-processed combination of microcrystalline cellulose and carboxymethyl cellulose (such as commercially available from FMC as Avicel-RC 591) as a secondary structurant.

[0088] Xanthan gum is a high molecular weight natural carbohydrate, specifically a polysaccharide. The xanthan gum suitable for use in this invention is a high molecular weight polysaccharide produced by *Xanthomonas campestris*. The techniques and strains used to produce this polysaccharide are described in U.S. Patents 4,752,580 and 3,485,719 (the disclosures of each of these patents are hereby incorporated by reference). The xanthan gum used in this invention should have a viscosity of about 1000 cP (mPa-sec) to about 1700 cP in a 1% salt solution. The viscosity of the 1% solution should be measured at 25°C using an LV Brookfield Synchro-Lectric viscometer at 60 rpm with a No. 3 rotor. Xanthan gum is available from several commercial suppliers such as RT Vanderbilt and CPKelco. Examples of suitable xanthan gums are Keltrol, Keltrol F, Keltrol T, Keltrol TF, Xantural180, and Vanzan NF-ST.

[0089] In one example, the secondary structuring agent used in this invention may be dried co-precipitated microcrystals of cellulose and sodium carboxymethyl cellulose. Sodium carboxymethyl cellulose is commonly used as a coprecipitant in microcrystalline cellulose. It is particularly usable if the content of sodium carboxymethyl cellulose ranges from about 8% to about 19% by weight of the total weight of the co-precipitated microcrystals of cellulose and sodium carboxymethyl cellulose. Microcrystalline cellulose products having sodium carboxymethyl cellulose in the range of about 8% to about 14% by weight are available. These mixtures as described above are commercially available from a variety of sources, including those marketed under trademarks. CL-611 RC-581 and The RC-591 was commercially acquired from FMC.

[0090] Thickening components can be swelling agents, which swell and can interact with structuring agents when exposed to a suitable aqueous environment. Pregelatinized starch is a particularly good swelling agent. Also known as "instant" starch, pre-cooked so that it swells immediately and begins to thicken when added to cold water. A particularly suitable pregelatinized starch is prepared from modified, stabilized, and waxy corn edible starch and is commercially available from National Starch as the instant starch Ultrasperse M.

[0091] In certain examples, an optional auxiliary suspending agent can be used. The auxiliary suspending agent can be selected from the group consisting of hydroxyethyl cellulose and pharmaceutically acceptable salts of carboxymethyl cellulose. Suitable pharmaceutically acceptable salts of carboxymethyl cellulose can include (or can be selected from or be selected from the group consisting of) sodium and / or calcium salts of polycarboxymethyl ethers of cellulose, which are commercially available as sodium carboxymethyl cellulose USP and calcium carboxymethyl cellulose NF. Sodium carboxymethyl cellulose USP contains about 6.5% to about 7.5% by weight of sodium, based on dry weight, and can be commercially obtained from Aqualon Co. under the product name Aqualon. Hydroxyethyl cellulose is a partially substituted poly(hydroxyethyl) ether of cellulose. Hydroxyethyl cellulose NF can be commercially obtained from Aqualon Co. under the product name Natrosol.

[0092] In examples where the composition is a suspension, the composition can further comprise at least one thickening agent. In examples where the composition is an oral solution, the composition can be substantially free or completely free of thickening agents. As used herein, "substantially free" is defined as less than 0.1 weight / volume %, preferably less than 0.05 weight / volume %, preferably less than 0.001 weight / volume %.

[0093] Additional sweetener

[0094] The second sweetener can be an artificial sweetener or a natural sweetener. Artificial sweeteners include, but are not limited to, aspartame, neotame, saccharin, and sucralose. Natural sweeteners include, but are not limited to, stevia or steviol glycosides, monk fruit extract, licorice root extract, and other derivatives of licorice. Additional sweeteners can be added in a range of about 0.01% to about 5% by weight, or about 0.1% to about 3% by weight, of the total composition.

[0095] In examples, the composition can further comprise stevia and / or monoammonium glycyrrhizate as such additional sweeteners. Stevia can be present in the composition in a range of about 0.01% to about 2% by weight, or about 0.1% to about 1% by weight, for example about 0.2% by weight, or about 0.15% by weight. Stevia can alternatively be present in the composition in a higher amount in a range of about 10% to about 30% by weight, for example about 20% by weight. Monoammonium glycyrrhizate can be present in the composition in a range of about 0.01% to about 2% by weight, or about 0.01% to about 0.1% by weight, for example about 0.04% by weight.

[0096] According to examples, the composition can further not include certain ingredients. The term "completely free" means that the composition is completely absent of a certain ingredient.

[0097] In an example, the composition is free of a bulk sweetener having a fructose amount greater than 75%, or greater than 70%, or greater than 50%. In another example, the total fructose content of the composition is less than 0.9 g / mL, or less than 0.7 g / mL. In another example, the total amount of sugar in the composition is less than 0.9 g / mL or less than 0.7 g / mL. The compositions of the present invention can be substantially free or completely free of agave syrup. The compositions of the present invention can be substantially free or completely free of corn syrup or high fructose corn syrup. The compositions of the present invention can be substantially free or completely free of fructose.

[0098] The amount of total sugar administered can be determined within the dosing regimen or method of using the compositions of the present invention. When calculating the therapeutic amount for dosing of the composition, the amount of sugar in a 24 hour dosing regimen can be less than 60 grams of sugar, or less than 50 grams of sugar, or less than 40 grams of sugar. Total sugar is defined as the combined amount of sugar including sucrose, maltose, lactose, glucose, and fructose.

[0099] In one embodiment, the composition is substantially free of aspartame, neotame, saccharin, and sucralose. In another embodiment, the composition is substantially free of stevia or steviol glycosides, monk fruit extract, licorice root extract, and other derivatives of licorice.

[0100] Density

[0101] The density of the composition can be about 1.00 g / mL to about 1.50 g / mL, or about 1.20 g / mL to about 1.40 g / mL, or about 1.25 g / mL to about 1.35 g / mL.

[0102] Stability

[0103] The compositions of the present invention can be stable when stored under accelerated conditions or ambient conditions for up to 24 months, or for up to 1 month, or for up to 3 months, or for up to 6 months, or for up to 12 months, or for up to 18 months under such conditions. Accelerated conditions can include storage at 30°C, 40°C, 50°C, 60°C, and under freeze-thaw conditions. Stability includes: physical stability such as, but not limited to, viscosity, water activity, and density; chemical stability such as degradation of active ingredients; and microbiological stability using the Antimicrobial Effect Test (AET).

[0104] Water activity

[0105] Water activity (aw) is a measure of the energy status of water in a system. It indicates how tightly water is "bound" within a material, either structurally or chemically. Water activity is the relative humidity of air in equilibrium with a sample in a sealed measurement chamber. Water activity is defined as the ratio of the vapor pressure of water in a sample to the vapor pressure of pure water at the same temperature. The concept of water activity is particularly important in determining product quality and safety.

[0106] Water activity is the best indicator of microbial growth. A product can contain a relatively large percentage of moisture, but if the water is chemically "bound" with a humectant or solute such as salt, sugar, or polyol, the water is not biologically available for microbial growth. Water activity measurements can be used to determine the amount of water (unbound) that is available for chemical and biochemical reactions and for microbial growth to occur. Each microorganism has a finite water activity level below which it cannot grow.

[0107] Understanding the water activity of drug substances (i.e., drugs and excipients) is critical to obtaining product formulations with optimal chemical, physical, microbiological, and shelf-life properties. Water activity affects the chemical stability, microbiological stability, flow properties, compaction, hardness, and dissolution rate of pharmaceutical dosage forms.

[0108] Instrument / method for measuring water activity :

[0109] Instrument: Aqualab Series 4 TEV dew point water activity meter (uses both a chilled mirror dew point sensor and a capacitance sensor for measuring non-volatile and volatile materials, respectively). The instrument has the following attributes:

[0110] Water activity range: 0.030 aw to 1.000 aw

[0111] Water activity precision: ± 0.003 (4TE Dew Point Mode)

[0112] Water activity precision: ± 0.015 (4TEV Capacitance Mode)

[0113] Reading time 1 : < 5 minutes.

[0114] Sample temperature range: 15 °C to 50 °C

[0115] Sample temperature precision: ± 0.2 °C

[0116] Sample pan capacity: 15 mL full

[0117] Operating environment: 5 °C to 50 °C, 20% to 80% humidity

[0118] Aw is performed after calibration verification of the Aqualab water activity to ensure optimal performance and accuracy. The verification standard is a specially prepared unsaturated salt solution with accurately measurable specific molality and water activity values. Calibration verification is performed using two known verification standards (0.760 aw and 0.250 aw) prior to use.

[0119] The Aqualab water activity meter uses a chilled-mirror dew point technique to measure the water activity of a sample. In an instrument using dew point technology, the sample is equilibrated with the headspace of a sealed chamber that contains a mirror and a means of detecting condensation on the mirror. At equilibrium, the relative humidity of the air in the chamber is the same as the water activity of the sample. In the AquaLab water activity meter, the mirror temperature is precisely controlled by a thermoelectric cooler. The detection of the exact point at which condensation first appears on the mirror is observed with a photoelectric cell. A beam of light is directed onto the mirror and reflected into a photo detector cell. When condensation appears on the mirror, the photo detector senses a change in reflectivity. A thermocouple attached to the mirror then records the temperature at which condensation appears. The AquaLab water activity meter then signals with a beep and displays the final water activity and temperature. In addition to the above technique, the AquaLab water activity meter uses an internal fan that circulates air within the sample chamber to shorten the equilibration time. Since both the dew point and the sample surface temperature are measured simultaneously, the requirement for complete thermal equilibration is eliminated, which shortens the measurement time to less than five minutes.

[0120] Example:

[0121] The compositions of the present application described in the following examples illustrate specific embodiments of the present application, but are not intended to limit it. Other modifications can be made by one skilled in the art without departing from the spirit and scope of the present application.

[0122] Example 1: Liquid diphenhydramine formulation comprising tapioca syrup

[0123] This example was prepared using the formulations in Table 2 using cassava syrup as a natural bulk sweetener.

[0124] Table 2. Formulation comprising tapioca syrup

[0125] Ingredient Function mg / 5mL % W / V (g / 100 mL) Glycerin USP Bulk liquid 1500 30 Steviol glycosides 1 ]]> Sweetener 7.5 0.15 Monoammonium glycyrrhizinate 2 ]]> Sweetener 2 0.04 Diphenhydramine hydrochloride API 12.5 0.25 Cherry flavor Flavor 25 0.5 Clarified cassava syrup 3 ]] Bulk sweetener QS 4 ]] q.s. to 100 mL Total 100 mL

[0126] 1 : available under the trademark RM95 a product commercially available from Icon Foods, Inc.

[0127] 2 : available under the trademark MM100 a product commercially available from MafCo, Inc.

[0128] 3 : can be trademarked CL42 product commercially available from Sweet Additions

[0129] 4: "QS" is a term indicating that the material is used to reach the final target volume

[0130] Processing direction

[0131] 1. To a tared container equipped with a high shear mixer, add glycerin to reach a volume suitable for mixing.

[0132] 2. Add approximately one-half of the tapioca syrup to the container and mix.

[0133] 3. Add stevia, monoammonium glycyrrhizinate, diphenhydramine, and flavoring agents, and mix until dissolved.

[0134] 4. Adjust the solution to the final volume with tapioca syrup, and mix under vacuum to degas.

[0135] Example 2: Liquid diphenhydramine formulation comprising rice syrup

[0136] This example was prepared using the formulation in Table 3, using brown rice syrup as a natural bulk sweetener.

[0137] Table 3. Formulation comprising brown rice syrup

[0138] Ingredient Function mg / 5mL % W / V (g / 100 mL) Glycerin USP Bulk liquid 1500 30 Steviol glycosides 1 ]] Sweetener 1000 20 Monoammonium glycyrrhizinate 2 ]] Sweetener 2 0.04 Anhydrous citric acid USP Acidifying agent 2.5 0.05 Diphenhydramine hydrochloride USP API 12.5 0.25 Inhibit Violet 3 )]]> Flavor 25 0.5 Rice syrup 4 ]]> Bulk sweetener 2150 49 Cherry flavor Flavor 25 0.5 Purified water USP QS 5 ]] q.s. to 100 mL Total 100 mL

[0139] 1: can be trademarked RM95 product commercially available from Icon Foods

[0140] 2: can be trademarked MM100 product commercially available from MafCo

[0141] 3: commercially available from Mezzoni Foods

[0142] 4: can be trademarked CL42 product commercially available from Sweet Additions

[0143] 5: "QS" is a term indicating that the material is used to reach the final target volume

[0144] Processing direction

[0145] 1. To a tared container equipped with a high shear mixer, add glycerin to reach a volume suitable for mixing.

[0146] 2. Add approximately one-half of the brown rice syrup to the container and mix.

[0147] 3. Add steviol sugar, monoammonium glycyrrhizinate, diphenhydramine, anhydrous citric acid, and flavoring agent, mix until dissolved.

[0148] 4. Adjust the solution to the final volume with purified water (“q.s.”) and mix under vacuum to degas.

[0149] Example 3: Liquid diphenhydramine formulation comprising allulose syrup

[0150] This example was prepared using the formulation in Table 4, using allulose syrup as the natural bulk sweetener.

[0151] Table 4. Formulation comprising allulose syrup

[0152]

[0153] 1: Available under the trademark AG9957 is a product commercially available from Anderson Advanced Ingredients, Inc.2: “QS” is a term indicating that the material is used to reach the final target volume

[0154] Processing direction

[0155] 1. Add glycerin to a tared container equipped with a high shear mixer to a volume appropriate for mixing.

[0156] 2. Add approximately one-half of the allulose syrup to the container and mix.

[0157] 3. Add steviol sugar, monoammonium glycyrrhizinate, diphenhydramine, and flavoring agent, mix until dissolved.

[0158] 4. Adjust the solution to the final volume with allulose syrup (“q.s.”) and mix under vacuum to degas.

[0159] Example 4: Liquid diphenhydramine formulation comprising syrup

[0160] This example was prepared using the formulation in Table 5, using a combination of apple syrup and carob syrup (e.g., commercially available under the trademark SWEETOS® from ADM Company) as the natural bulk sweetener.

[0161] Table 5. Formulation comprising syrup

[0162]

[0163]

[0164] 1: Tradename Optimized AG3240 product available from Anderson Advanced Ingredients

[0165] 2: Tradename MM100 product available from MafCo

[0166] 3: Tradename Premium product available from ADM

[0167] 4: "QS" is a term indicating that the material is used to reach the final target volume

[0168] Processing direction

[0169] 1. To a tared container equipped with a high shear mixer, add to reach a volume suitable for mixing.

[0170] 2. Add approximately one-half of the fruit syrup to the container and mix.

[0171] 3. Add stevia, monoammonium glycyrrhizinate, diphenhydramine, and flavoring agent, and mix until dissolved.

[0172] 4. Adjust the solution to the final volume with syrup, and mix under vacuum to degas.

[0173] Example 5: Liquid diphenhydramine formulation comprising syrup, wherein the ratio of syrup: glycerin is 3.30:1 Table 6. Formulation comprising

[0174] This example uses the formulation in Table 6, using a combination of apple syrup and carob syrup (e.g., available from ADM under the tradename Premium) as the natural bulk sweetener.

[0175] syrup Processing direction

[0176]

[0177] 1: Tradename Premium product available from ADM

[0178] 2: "QS" is a term indicating that the material is used to reach the final target volume

[0179] 3: % w / v = weight / volume %

[0180] 4: % w / w = weight / weight %

[0181] Example 6: Liquid cetirizine formulation comprising tapioca syrup

[0182] 1. To a tared container equipped with a high shear mixer, add to achieve a volume appropriate for mixing.

[0183] 2. Add approximately one-half of the syrup to the container and mix.

[0184] 3. Add sodium citrate dihydrate, dimethylglycine, and flavoring, mix until dissolved.

[0185] 4. Adjust the solution to the final volume with syrup, and mix under vacuum to degas.

[0186] Table 7. Cetirizine formulation comprising tapioca syrup

[0187] This example was prepared using the formulation in Table 7, using tapioca syrup as a natural bulk sweetener.

[0188] Ingredient

[0189] Function mg / 5mL % W / V (g / 100 mL) Glycerin USP Bulk liquid Sweetener 1500 30 steviol glycosides 1 ]]> Sweetener 7.5 0.15 Monoammonium glycyrrhizinate 2 ]]> Cetirizine hydrochloride 2 0.04 API Cherry flavor 5.0 0.5 Flavor Bulk sweetener 25 2.5 Clarified cassava syrup 3 ]]> q.s. to 100 mL QS 4 ]]> Total 100 mL Processing direction

[0190] 1 : Available under the trademark RM95 is a product commercially available from Anderson Advanced Ingredients

[0191] 2 : Available under the trademark MM100 is a product commercially available from MafCo

[0192] 3 : Available under the trademark CL42 is a product commercially available from Sweet Additions

[0193] 4 : “QS” is a term indicating that the material is used to achieve a final target volume

[0194] Example 7: Liquid loperamide formulation comprising tapioca syrup

[0195] 1. To a tared container equipped with a high shear mixer, add glycerin to achieve a volume appropriate for mixing.

[0196] 2. Add approximately one-half of the tapioca syrup to the container and mix.

[0197] 3. Add stevia, monoammonium glycyrrhizinate, cetirizine hydrochloride, and flavoring agent, and mix until dissolved.

[0198] 4. Adjust the solution to the final volume with tapioca syrup ("q.s.") and mix under vacuum to de-gas.

[0199] Table 8. Loperamide formulation comprising tapioca syrup

[0200] This example was prepared using the formulation in Table 8, using tapioca syrup as a natural bulk sweetener.

[0201] Ingredient

[0202] Function mg / 5mL % W / V (g / 100 mL) Glycerin USP Bulk liquid Sweetener 1500 30 steviol glycosides 1 ]] Sweetener 7.5 0.15 Monoammonium glycyrrhizinate 2 ]]> Loperamide hydrochloride 2 0.04 API Cherry flavor 5.0 0.5 Flavor Bulk sweetener 25 2.5 Clarified cassava syrup 3 ]]> q.s. to 100 mL QS 4 ]]> Total 100 mL Processing direction

[0203] 1 : available under the trademark RM95 a product commercially available from Anderson Advanced Ingredients

[0204] 2 : available under the trademark MM100 a product commercially available from MafCo

[0205] 3 : available under the trademark CL42 a product commercially available from Sweet Additions

[0206] 4 : "QS" is a term indicating that the material is used to reach a final target volume

[0207] Example 8: Liquid clarithromycin formulation comprising

[0208] 1. To a tared container equipped with a high shear mixer, add glycerin to the volume appropriate for mixing.

[0209] 2. Add approximately one-half of the tapioca syrup to the container and mix.

[0210] 3. Add stevia, monoammonium glycyrrhizinate, loperamide hydrochloride, and flavoring agent, and mix until dissolved.

[0211] 4. Adjust the solution to the final volume with tapioca syrup ("q.s.") and mix under vacuum to de-gas.

[0212] syrup natural bulk sweetener Table 9. Formulation comprising .

[0213] This example uses the recipe in Table 9, using a combination of apple syrup and carob syrup (e.g., sold under the trademark Optimum®) as a natural bulk sweetener to prepare.

[0214] syrup Ingredient

[0215] Function Mg / 5mL Amount (% w / v) Glycerin USP Bulk liquid Sweetener 1500 30 steviol glycosides 1 ]]> Sweetener 10 0.2 Monoammonium glycyrrhizinate 2 ]]> Bulk sweetener 2 0.04 Combination of apple syrup and carob syrup 3 ]]> Clarithromycin 2500 50.0 API Grape flavor 5.00 0.1 Flavor Bulk sweetener 17.5 0.35 Combination of apple syrup and carob syrup 3 ]]> q.s. to 100 mL QS 4 ]] Processing direction

[0216] 1 : Available under the trademark Optimized AG3240 from Anderson Advanced Ingredients

[0217] 2: Available under the trademark MM100 2 Product available from MafCo

[0218] 3: Available under the trademark Premium from ADM

[0219] 4: “QS” is a term indicating that the material is used to achieve the final target volume

[0220] Example 9: Rheology (viscosity) procedure

[0221] 1. To a tared container equipped with a high shear mixer, add glycerin to achieve a volume suitable for mixing.

[0222] 2. Add approximately one-half of the Frit-Up syrup to the container and mix.

[0223] 3. Add stevia, monoammonium glycyrrhizinate, loratadine, and flavoring agents, and mix until dissolved.

[0224] Shear sweep

[0225] The viscosity data provided in the table shows a snapshot of the viscosity measured at various shear rates. Viscosity measurements were made using a Brookfield DV2T LV viscometer in conjunction with a small sample adapter kit and a #31 spindle. For all samples, a measurement temperature of 25 °C was maintained with a temperature controlled water bath. For each measurement, 9 mL of sample was loaded without air bubbles. The spindle speed was set to 20 RPM, and the reading was recorded in cps after the spindle had rotated 5 times. The viscosity of Example 5 was measured to be about 328.5 centipoise.

[0226] pH

[0227] All testing was performed using a TA Instruments AR2000 rheometer with a 60 mm parallel plate geometry, with a gap set to 0.5 mm. For all samples, a measurement temperature of 25 °C was maintained with a Peltier plate. The rheometer was mounted on a vibration isolation platform and leveled. The sample was loaded without air bubbles, and excess sample was "trimmed" from the edges when the gap was 10% larger than the desired gap. A shear sweep experiment was run, with a shear rate range of 0.001 to 100 1 / s.

[0228] Example 10: Assay and stability

[0229] The pH of Example 5 was measured to be about 5.88.

[0230] Table 10: Assay and stability of Example 5

[0231] The formulation of Example 5 was tested for diphenhydramine assay and tested for stability at the following time points: initial (time 0) and 1 month, and stored under various conditions as shown in Table 10. The total diphenhydramine and degradant amounts were analyzed using a reference standard prepared at 100% of the labeled dose. The samples and standards were diluted and mixed in diluent consisting of 50 mM ammonium formate plus 0.1% formic acid in water with methanol at a ratio of 95:5.

[0232] Method: The diphenhydramine assay and degradants were analyzed using ultra- performance liquid chromatography (UPLC) with the following parameters:

[0233] Column: Waters Acquity UPLC HSS T3 2.1 x 150, 1.8 pm

[0234] Mobile phase: The first mobile phase was 30 mM potassium hexafluorophosphate plus 0.05% phosphoric acid in water, and the second mobile phase was acetonitrile: water (ratio of 80:20) plus 0.05% phosphoric acid, with a gradient method over a 14 minute run time. The method was run at a flow rate of 0.45 mL / min, a 2.0 pL injection volume, a UV detector at 220 nm, and a column temperature of 40 °C. The recommended run time was 14 minutes.

[0235] ​

[0236]

[0237] 1 : ND = not detected

[0238] It should be understood that, even though particular implementations of the present application have been described herein, the present application should not be limited to these described implementations. Rather, other aspects, advantages, and modifications are within the scope of the claims.

Claims

1. A liquid composition, wherein the liquid composition comprises at least one therapeutic ingredient and at least one natural bulk sweetener, wherein the fructose content in the total amount of natural bulk sweetener in the composition is less than 75%.

2. The liquid composition of claim 1, wherein the natural bulk sweetener is selected from the group consisting of glycerin, allulose syrup, rice syrup, brown rice syrup, tapioca syrup, apple syrup, carob syrup, and combinations thereof.

3. The liquid composition of claim 1, wherein the liquid composition has a total fructose level of less than 0.7 g / mL.

4. The liquid composition of claim 1, wherein the therapeutic ingredient is a pharmaceutically active ingredient.

5. The liquid composition of claim 1, wherein the therapeutic ingredient is a homeopathically active ingredient.

6. The liquid composition of claim 1, wherein the therapeutic ingredient is a nutritional supplement.

7. The liquid composition of claim 1, wherein the liquid composition is in the form of a suspension.

8. The liquid composition of claim 1, wherein the liquid composition is in the form of a solution.

9. The liquid composition of claim 4, wherein the pharmaceutically active ingredient is selected from the group consisting of acetaminophen, diphenhydramine, dextromethorphan, guaifenesin, ibuprofen, cetirizine, loperamide, and phenylephrine.

10. The liquid composition of claim 1, wherein the therapeutic ingredient is an antihistamine.

11. The liquid composition of claim 1, further comprising a sensate.

12. The liquid composition of claim 1, further comprising a second natural bulk sweetener.

13. The liquid composition of claim 12, wherein the natural bulk sweetener is glycerin and the second natural bulk sweetener is tapioca syrup.

14. The liquid composition of claim 12, wherein the natural bulk sweetener is glycerin and the second natural bulk sweetener is brown rice syrup.

15. The liquid composition of claim 12, wherein the natural bulk sweetener is glycerin and the second natural bulk sweetener is allulose syrup.

16. The liquid composition of claim 12, wherein the natural bulk sweetener is glycerin and the second natural bulk sweetener is a combination of apple syrup and carob syrup.

17. The liquid composition of claim 16, wherein the ratio of the combination of apple syrup and carob syrup to glycerin is about 3.30:

1.

18. The liquid composition of claim 1, wherein the liquid composition is substantially free of agave syrup.

19. The liquid composition of claim 1, wherein the liquid composition is substantially free of any ingredient having a fructose content greater than 15%.

20. A method of reducing a symptom in a subject, the symptom selected from the group consisting of pain, fever, cough, nasal congestion, diarrhea, allergic rhinitis, and sore throat, the method comprising administering the composition of claim 1.

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