Therapeutic liquid composition

Abstract

A therapeutic liquid composition useful for treating various conditions, containing a bulk sweetener derived from grain or fruit sources.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 493395, filed on March 31, 2023, the entire disclosure of which is incorporated herein by reference for all purposes.

[0002] (Field of the Invention) The present invention relates to liquid compositions, more specifically, therapeutic liquid compositions. The present invention also relates to a process for manufacturing a liquid composition and a method for alleviating symptoms in a human subject upon administration of the liquid composition. Liquid compositions that may contain one or more therapeutic active agents are particularly useful for the treatment of allergic symptoms, pain symptoms, and symptoms of cough and cold (including, but not limited to, pain, cough, nasal congestion, rhinitis, and pharyngolaryngitis).

Background Art

[0003] Pharmaceuticals or medicaments administered orally are provided to patients in many forms, including solid forms such as capsules, caplets, gelcaps, or tablets, and liquid forms such as solutions, for example, syrups, and elixirs, emulsions, or suspensions. Many other patients, including children, elderly patients, and patients with physical disabilities or incapacities, have problems swallowing solid forms, such as whole tablets and even capsules. Thus, when the dose to be administered cannot be formulated into very small tablets or capsules, it is desirable to provide the medicament in either a chewable solid form or a liquid form. For many patients, including pediatric patients and elderly patients, liquid oral dosage forms are preferably more preferred than chewable dosage forms because they can be easily swallowed without chewing the liquid dosage form.

[0004] A suspension is a two-phase system having solid, substantially water-insoluble active drug particles dispersed throughout a liquid medium. A suspension does not include an emulsion, meaning it describes a liquid suspended in a liquid carrier or syrup formulation containing only substantially completely dissolved pharmaceutically active agents. As used herein, “particles” can be crystals, granules, aggregates, or any undissolved solid material. The particles of the present invention preferably have a median particle size (d50%) of about 2 to about 150 microns, more preferably about 10 to about 100 microns. The challenges of keeping substantially water-insoluble active agents suspended, ensuring the stability of substantially water-insoluble active agents, and maintaining dose uniformity over long periods have been addressed previously. See, for example, U.S. Patents 5,409,907 and 5,374,659.

[0005] In pharmaceutical suspensions, typically, at least one active agent exists in the form of substantially undissolved solid particles, i.e., substantially water-insoluble active agents. However, in any such system, a portion of such active agents may be in a soluble state. When formulating such systems, it is advantageous to minimize the amount of drug present in a soluble state. Minimizing the amount of active agent in the solution is advantageous for both the taste of the product and its chemical and / or physical stability.

[0006] Liquid dosage forms may exist in the form of a solution, in which case the therapeutic component(s) are substantially dissolved in the liquid blend. If the dose of the therapeutic component is less than 50 g / 5 mL, the therapeutic component may be dissolved in the form of a solution.

[0007] A common problem associated with liquid dosage forms is often the unpleasant taste of the active ingredient that develops during the time the liquid dosage form is in the mouth before swallowing. Suspensions typically offer better taste masking than other liquid forms, but those skilled in the art recognize the considerable technical difficulties in producing stable, sensory-tolerable suspensions.

[0008] Furthermore, when over-the-counter ("OTC") oral solutions or oral suspension products are formulated or reformulated to use reduced or naturally derived ingredients, solutions to such challenges must be re-evaluated. The terms "clean" or "clean medicine" represent a newly emerging trend in OTC medicines. While there is no generally accepted definition of the term "clean," consumers generally understand it to mean one of the following: free from artificial flavors, dyes, preservatives, or sweeteners; derived from natural sources; and / or free from artificial, chemical, or unnecessary ingredients.

[0009] Formulating a “clean” oral solution or suspension product may involve limiting or eliminating certain components conventionally used in pharmaceutical suspensions to overcome the challenges of keeping substantially water-insoluble active agents suspended, ensuring the stability of substantially water-insoluble active agents, and maintaining dose uniformity over long periods. New components that fit the definition of “clean” must be identified and evaluated to ensure that such newly formulated pharmaceutical solution or suspension product meets the safety and efficacy standards required for all over-the-counter (OTC) medicines.

[0010] Dyes have traditionally been added to medicinal suspensions for elegance and to mask discoloration. However, some patients have been found to develop allergies to, be allergic to, or be sensitive to dyed suspensions. Furthermore, dyed suspensions can stain clothing, furniture, carpets, etc., if spilled. Therefore, dye-free suspensions are highly desirable.

[0011] Colorants are often added to pharmaceutical liquid products to produce pharmaceutically acceptable properties, to provide distinguishing factors, and to ensure consistency between product batches. Often, the color of excipients used in manufacturing over-the-counter (OTC) products can contribute to a product appearing inconsistent or "color-shifted" to the patient. Patients or consumers may perceive such inconsistencies or color changes as indicating that the product is poorly manufactured, expired, or generally ineffective, which can lead to product rejection.

[0012] In many cases, liquid dosage forms contain a solvent or carrier to dissolve the active ingredient. Common liquid solvents include propylene glycol or polyethylene glycol. Some of these solvents and carriers are either originally artificial or undergo considerable chemical processing even if they originate from natural sources. Common bulk sweeteners contain sugar alcohols in solution, such as sorbitol solution. In many cases, these solvents and bulk sweeteners are of artificial origin and not from natural plant sources, which are preferred by many patients today.

[0013] Even when solvents and bulk sweeteners are derived from natural plant sources, these components often have high sugar content and / or a high glycemic index, which may be undesirable for consumers, particularly infants, people with diabetes or prediabetes, or health-conscious individuals in general. For example, GE Healthcare's U.S. Patent Application No. 20210290532(A1) discloses a stable pharmaceutical formulation or suspension having a pharmaceutically active agent, agave, and a diluent. This formulation or suspension has a viscosity suitable for drinking, but may have a high glycemic index due to the incorporation of agave syrup with a high fructose content.

[0014] Furthermore, naturally derived solvents and bulk sweeteners may be difficult to incorporate into, stabilize, or store in oral suspension formulations. An example of a natural bulk sweetener is disclosed in U.S. Patent Application No. 20080311272(A1) by Wild Valencia SA, which describes a composition comprising a carbohydrate obtained from carob and a carbohydrate obtained from at least one further fruit, including apples and grapes. This natural bulk sweetener, or a similar bulk sweetener, is marketed by ADM Company under the trademark "Fruit-Up®". [Overview of the project] [Problems that the invention aims to solve]

[0015] Therefore, there remains a need for liquid pharmaceutical compositions containing inert substances derived from natural sources with relatively low glycemic index. Such compositions should also act rapidly and provide excellent relief over a long period. [Means for solving the problem]

[0016] The present invention relates to liquid compositions that can be used to alleviate conditions such as allergies, coughs, colds, digestive health issues, or pain, by supporting an active therapeutic component. This active therapeutic component may be a pharmaceutically active ingredient, a homeopathic ingredient, a herbal ingredient, or a nutritional supplement. These compositions contain a substantial amount of inactive components of natural origin or source.

[0017] For example, the liquid composition may contain at least one therapeutic ingredient and at least one natural bulk sweetener, wherein the fructose content of the total amount of natural bulk sweeteners in the composition is less than 75 percent.

[0018] For example, a liquid composition may contain a therapeutic ingredient and a natural bulk sweetener having a fructose content of less than 50 percent of the natural bulk sweetener. The natural bulk sweetener may be selected from glycerin, allulose syrup, rice syrup, tapioca syrup, apple syrup, carob syrup, and combinations thereof. The liquid composition may have a total fructose level of less than 0.7 g / mL.

[0019] In one example, the therapeutic component may be a pharmaceutically active ingredient. In another example, the therapeutic component may be a homeopathic active ingredient and / or a nutritional supplement. In yet another example, the therapeutic component may be a pharmaceutically active ingredient combined with a homeopathic active ingredient and / or a nutritional supplement.

[0020] The liquid composition may be in the form of a suspension or an aqueous solution.

[0021] For example, the pharmaceutically active ingredient may be selected from the group consisting of acetaminophen, diphenhydramine, dextromethorphan, guaifenesin, ibuprofen, cetirizine, loperamide, and phenylephrine. For instance, the therapeutic component may be an antihistamine.

[0022] In further examples, the liquid composition may further contain a sensory stimulant.

[0023] The liquid composition may contain a second natural bulk sweetener. In one such example, the natural bulk sweetener may be glycerin and the second natural bulk sweetener may be tapioca syrup. In another example, the natural bulk sweetener may be glycerin and the second natural bulk sweetener may be brown rice syrup. In yet another example, the natural bulk sweetener may be glycerin and the second natural bulk sweetener may be allulose syrup.

[0024] In another example, the natural bulk sweetener can be glycerin, and the second natural bulk sweetener can be a combination of apple syrup and locust bean gum syrup. In one example, the ratio of the combination of apple syrup and locust bean gum syrup to glycerin is about 3.30:1.

[0025] In one example, the liquid composition may not substantially contain or may not contain at all agave syrup. In another example, the liquid composition may not substantially contain any component having a fructose content of more than 15 percent.

[0026] According to another aspect of the present invention, there may be a method of alleviating symptoms selected from the group consisting of pain, fever, cough, nasal congestion, diarrhea, allergic rhinitis, and pharyngolaryngitis in a subject by administering the composition disclosed herein.

Mode for Carrying Out the Invention

[0027] Those skilled in the art will be able to make the most of the present invention based on the description herein. The following specific embodiments are merely illustrative and should not be construed as limiting the following disclosure in any way.

[0028] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention belongs.

[0029] Unless otherwise indicated, all documents cited are incorporated herein by reference in their relevant parts, but the citation of any document should not be construed as an admission that it is prior art relevant to this invention. Furthermore, all documents incorporated herein by reference are incorporated herein only to the extent that they are not inconsistent with this specification.

[0030] When used herein, all percentages are given by weight unless otherwise specified. Furthermore, all ranges described herein include both ends and encompass all combinations of values ​​between the two endpoints.

[0031] As used herein, the term “active ingredient” is used broadly and may encompass any material that imparts a therapeutic effect. For example, an active ingredient may be a pharmaceutical, nutraceutical, vitamin, dietary supplement, nutrient, herb, foodstuff, pigment, nutritional, mineral, supplement, oral care agent, or flavoring agent (sensory stimulant), and combinations thereof.

[0032] As used herein, the term “dosage form” applies to any composition designed to contain a specific amount (dose) of a particular ingredient, for example, an active ingredient as defined below. Preferred dosage forms may be pharmaceutical delivery systems, as well as systems for delivering minerals, vitamins, and other nutritional supplements, oral care agents, flavorings, sensory stimulants, and the like. In certain preferred embodiments, the dosage form is an orally administered system for delivering a pharmaceutically active ingredient to the human gastrointestinal tract.

[0033] "Liquid dosage form" may non-exclusively include suspensions, syrups, solutions, or elixirs in which one or more of the active ingredients are dissolved, partially dissolved, undissolved, or suspended.

[0034] "Therapeutic effect" means any effect or action of an active ingredient intended to diagnose, treat, cure, alleviate, or prevent a disease, or to affect the structure or any function of the body.

[0035] Unless otherwise specified, percentages used to express the quantity of an ingredient are weight percentages (referred to as "weight%", "wt%", "%by weight", or "%(w / volume)"). Similarly, weight ratios used to express the relative proportion of an ingredient are also determined using weight percentages (i.e., weight ratios are calculated by dividing the weight percentage of one ingredient by the weight percentage of another ingredient). Unless otherwise specified, all ranges include both endpoints; for example, "4-9" includes both endpoints, 4 and 9.

[0036] As used herein, the term “safe and effective amount” means an amount sufficient to induce the desired effect but small enough to avoid serious side effects. The safe and effective amount of a compound, extract, or composition will vary depending, for example, the age of the end user, their health and environmental exposure, the duration and nature of the treatment, the specific extract, component, or composition used, the specific carrier utilized, and similar factors.

[0037] As used herein, the term “about” means within 5% by weight, 4% by weight, 3% by weight, 2.5% by weight, 2% by weight, or 1% by weight of the disclosed value.

[0038] In certain embodiments, the present invention disclosed herein can be carried out without any compounds, method steps, or elements (or groups of compounds or groups of elements) not specifically disclosed herein.

[0039] Active ingredients (multiple ingredients allowed) The dosage form of the present invention preferably contains one or more (at least one) active ingredients. Suitable pharmaceutically active ingredients include analgesics, anti-inflammatory agents, anti-arthritis agents, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antipyretics, antiviral agents, anticoagulants, antidepressants, antidiabetic agents, antiemetics, anti-bloating agents, antifungal agents, anticonvulsants, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, cough suppressants, decongestants, expectorants, oral contraceptives, diuretics, gastrointestinal agents, anti-migraine preparations, motion sickness drugs, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, hypnotics, urinary tract agents, and pharmaceutically acceptable salts thereof, derivatives thereof, combinations thereof, and mixtures thereof.

[0040] For example, the active ingredient may be selected from (or from the group consisting of) acetylsalicylic acid, acetic acid derivatives (e.g., indomethacin, diclofenac, sulindac, and tolmetine); fenamic acid derivatives (e.g., mefenamic acid, meclofenamic acid, and flufenamic acid); biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal); and oxicam (e.g., piroxicam, sudoxicam, isoxicam, and meloxicam) and pharmaceutically acceptable salts thereof, derivatives thereof, combinations thereof, and mixtures thereof.

[0041] Examples of useful NSAIDs include ibuprofen, naproxen, benoxaprofen, naproxen sodium, fenbufen, flurbiprofen, fenoprofen, fenbuprofen, ibuprofen, ketoprofen, indoprofen, pirprofen, carpofen, oxaprofen, pranoprofen, microprofen, thioxaprofen, suprofen, aluminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, celecoxib, and their pharmaceutically acceptable salts, derivatives thereof, combinations thereof, and mixtures thereof (or can be selected from there, or can be selected from the group consisting of thereof).

[0042] The compositions of the present invention may also contain acetaminophen. As used herein, the term "APAP" means acetaminophen or N-acetylpara-aminophenol, and includes, but is not limited to, pharmaceutically acceptable salts, esters, or derivatives thereof.

[0043] Examples of pharmacologically active ingredients for cough and cold include, but are not limited to, antihistamines, antitussives, decongestants, and expectorants, bromopheniramine, carbinoxamine, acetylcysteine, guaifenesin, carbocysteine, chlorcyclidine, dexbrompheniramine, bromhexane, phenyndamine, pheniramine, pyriramine, tondillamine, prepositrine, ephedrine, phenylephrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine, naphazoline, oxymetazoline, montelukast, and propylhexa Dorin, triprolidine, clemastine, acribastine, promethazine, oxomemazine, mequitazine, buclidine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide, xylometazolin, loratadine, desloratadine, noscapine, clofedianol, menthol, benzonate, ethylmorphone, codeine, acetylcysteine, carbocysteine, ambroxol, belladonna alkaloids, sobrenol, guaiacol, and cetirizine; as well as pharmaceutically acceptable salts thereof, derivatives thereof, combinations thereof, mixtures thereof (or may be selected from there, or from the group consisting thereof).

[0044] Preferably, at least one active ingredient may be an NSAID, and / or acetaminophen, and pharmaceutically acceptable salts thereof.

[0045] Suitable gastrointestinal drugs include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, and sodium dihydroxyaluminum carbonate; stimulant laxatives such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists such as famotidine, ranitidine, cimetidine, and nizatidine; and plutonazole or lansoprazole. Examples of antidiarrheal agents include roton pump inhibitors; gastrointestinal cytoprotective agents such as scraflethrate and misoprostol; gastrointestinal motility enhancers such as pruccalopride; antibiotics against Helicobacter pylori such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheal agents such as diphenoxylate, loperamide, and racecadotril; glycol pyrolates; antiemetics such as ondansetron; and analgesics such as mesalamine (or may be selected from the group consisting of these).

[0046] Examples of suitable polydimethylsiloxanes include, but are not limited to, dimethicone and simethicone, as disclosed in U.S. Patents No. 4,906,478, No. 5,275,822, and No. 6,103,260 (the contents of each of these are expressly incorporated herein by reference), (or may be selected from thereto, or from the group comprising them). As used herein, the term “simethicone” refers to a broader class of polydimethylsiloxanes, including, but not limited to, simethicone and dimethicone.

[0047] The therapeutically effective amount of the active ingredient can be easily determined by those skilled in the art.

[0048] Suitable sensory stimulants include (or may be selected from, or selected from, a group consisting of) peppermint, mint flavorings, fruit flavorings, chocolate, vanilla, bubble gum flavorings, coffee flavorings, natural flavorings, liqueur flavorings, and combinations thereof.

[0049] For example, the composition includes a polymer also known as a mucosal adhesive material. Suitable polymers include gelling materials, such as hydrophilic colloids (plural) (e.g., pectin, cellulose derivatives, alginates, carrageenans, etc.) (or can be selected from these, or from the group consisting of these).

[0050] In one example, a mucosal adhesive material is a thickening agent. Suitable thickening agents include, but are not limited to, carboxymethylcellulose (CMC), microcrystalline cellulose, and blends of CMC and microcrystalline cellulose, or mixtures thereof (or may be selected from these, or from the group consisting of these). Some suitable thickening agents are naturally derived, including xanthan gum and / or konjac gum. Other thickening agents include cellulose polymers such as hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, and mixtures thereof.

[0051] For example, mucosal adhesive materials include, but are not limited to, Avicel BV 2219, Avicel CL 611, Avicel Plus® LM 310 stabilizer, 40% solid, Avicel RC 591, Carbopol 971P, Aqualon® CMC-7M8SF-PH, HPMC E4M, and Nutricol BV 5616.

[0052] The composition may contain about 0.05% to about 3% by weight of polymer. The composition may contain about 0.2% to about 2% by weight of polymer. These substances, which improve mucosal adhesion, increase the duration of relief.

[0053] In yet another example, the composition may contain a surfactant. Suitable surfactants include polyoxyethylene-polyoxypropylene block copolymers. Examples of surfactants include, but are not limited to, Lutrol F68 (Poloxamer® 188); Lutrol F127 (Poloxamer® 407); Tween 80; and mixtures thereof.

[0054] The composition may contain about 0.05% to about 2% by weight of surfactant. The composition may contain about 0.1% to about 1.5% by weight of surfactant. The composition may contain about 0.5% to about 1% by weight of surfactant. The surfactant further enhances the perceived coating effect of the composition.

[0055] The resulting composition may be delivered as a spray or liquid. In one example, the composition may contain an active ingredient. In another example, the composition may contain a sensory stimulant.

[0056] Bulk sweeteners In the compositions of the present invention, a substantial portion of the bulk liquid comprises a natural bulk sweetener. As used herein, “natural bulk sweetener” is defined as derived from a plant source. Natural bulk sweeteners may have additional properties, such as being from a vegan source, an organic source, a non-GMO source, or being substantially or completely gluten-free or alcohol-free. As used herein, substantially free is defined as less than 0.1 weight / volume percent, preferably less than 0.05 weight / volume percent, and preferably less than 0.001 weight / volume percent. Natural bulk sweeteners may be used in the composition in an amount of about 20% to about 99% of the total composition.

[0057] The bulk sweeteners of the present invention, or natural bulk sweeteners, may also have a low blood glucose load and specific levels of fructose. For example, a bulk sweetener may have a fructose content of less than 75% by weight, less than 70% by weight, less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 25% by weight, less than 20% by weight, or less than 15% by weight. In another example, the total fructose content of a liquid composition may be less than 0.9 g / mL or less than 0.7 g / mL. In another example, a composition may be substantially or completely fructose-free. As used herein, substantially fructose-free is defined as less than 0.1% by weight / volume, preferably less than 0.05% by weight / volume, and preferably less than 0.001% by weight / volume. In another example, the total amount of sugar in a composition may be less than 0.9 g / mL or less than 0.7 g / mL.

[0058] Suitable natural bulk sweeteners for the present invention include, but are not limited to, allulose syrup, rice syrup, tapioca syrup; and apple and carob syrup, and mixtures thereof, for example, the combination of apple syrup and carob syrup, which is marketed by ADM Company under the trademark "Fruit-Up®" (or can be selected from these, or from the group consisting of these).

[0059] Other natural bulk sweeteners may include glycerin. Glycerin may be present in the composition at a concentration of about 10% to about 98% by weight. Glycerin may also be combined with other (or second) natural bulk sweeteners.

[0060] The composition may contain a mixture of one or more natural bulk sweeteners to balance the sweetness and flavor profile of the final composition. The amount of the first natural bulk sweetener may be added in the form of about 10% to about 90% by weight of the composition, or about 20% to about 50% by weight of the composition, and the amount of the second natural bulk sweetener may be added in the form of about 10% to about 90% by weight of the composition, or about 20% to about 50% by weight of the composition. The composition may also contain a third natural bulk sweetener (i.e., a natural bulk sweetener different from the first and second natural bulk sweeteners), and the amount of the third bulk sweetener may be added in the form of about 5% to about 30% by weight of the composition.

[0061] For example, a natural bulk sweetener may be a combination of glycerin and tapioca syrup. Glycerin may be present in the composition in the range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example, about 30% by weight. Tapioca syrup may be present in the composition in the range of about 50% to about 80% by weight, or about 60% to about 75% by weight, for example, about 67% by weight, or about 69% by weight, or about 70% by weight. The ratio of tapioca to glycerin may be about 2:1 to about 3:1, or about 2.1:1 to about 2.5:1, or about 2.3:1.

[0062] For example, a natural bulk sweetener may be a combination of glycerin and brown rice syrup. Glycerin may be present in the composition in the range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example, about 30% by weight. Brown rice syrup may be present in the composition in the 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 brown rice syrup to glycerin may be about 1:1 to about 2:1, or about 1.4:1 to about 1.8:1, or about 1.6:1.

[0063] In another example, a natural bulk sweetener may be a combination of glycerin and allulose syrup. Glycerin may be present in the composition in the range of about 20% to about 40% by weight, or about 25% to about 35% by weight, for example, about 30% by weight. Allulose syrup may be present in the composition in the range of about 50% to about 90% by weight, or about 60% to about 80% by weight, or about 65% to about 75% by weight, for example, about 70% by weight, or about 69% by weight. The ratio of allulose syrup to glycerin may be about 2:1 to about 3:1, or about 2.1:1 to about 2.5:1, or about 2.3:1.

[0064] In another example, a natural bulk sweetener may be a combination of glycerin, apple syrup, and carob syrup. The combination of apple syrup and carob syrup may be identical or similar to the product marketed by Archer Daniels Midland ("ADM") Company under the trademark Fruit-Up®, and / or incorporated herein by reference, "Carbohydrate Composition Obtainable from Mediterranean The invention may be as described in European Patent No. 2002734(B1) entitled "Fruits," namely, apple and carob syrup may be incorporated such that 35–60%, optionally 35–50%, optionally 35–45%, optionally 35–40%, optionally 35% (w / w) of carbohydrates are obtained from carob, and 35–50%, optionally 35–45%, optionally 35–40%, optionally 40% (w / w) of carbohydrates are obtained from at least one further fruit (e.g., apple), the percentages being based on the dry material.

[0065] For example, glycerin may be present in the composition in an amount ranging from about 20% to about 40% by weight, or from about 25% to about 35% by weight, for example, about 30% by weight. A combination of apple syrup and carob syrup, for example, marketed by ADM Company under the trademark Fruit-Up®, may be present in the composition in an amount ranging from about 50% to about 90% by weight, or from about 60% to about 80% by weight, for example, about 68%, 69%, or 70% by weight. The ratio of the combination of apple syrup and carob syrup, for example, marketed by ADM Company under the trade name Fruit-Up®, may be about 2:1 to about 3:1, or about 2.1:1 to about 2.5:1, for example, about 2.3:1. In another example, the ratio of apple syrup and carob syrup to glycerin, for example, the one marketed by ADM Company under the trademark Fruit-Up®, may be approximately 2:1 to 4:1, or approximately 3:1 to 4:1, or approximately 3:1 to 3.5:1, for example, approximately 3.30:1.

[0066] The composition may contain a sugar alcohol solution in addition to a natural bulk sweetener. Suitable sugar alcohol solutions include, but are not limited to, sorbitol, maltitol, mannitol, xylitol, and erythritol (or may be selected from these, or from the group consisting of these). The amount of the first natural bulk sweetener may 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 amount of the second sugar alcohol solution may 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 may not contain a sugar alcohol solution substantially.

[0067] In one example, the composition may include glycerin and an additional bulk sweetener derived from a cereal or fruit source. In this example, glycerin may be present in an amount of 10% to 40% by weight of the composition, and the additional bulk sweetener may be present in an amount of 10% to 40% by weight of the composition. Glycerin may be added to reduce the unpleasant taste or numbing effect of the pharmaceutically active ingredient.

[0068] In one example, the weight ratio of glycerin to additional vegetable syrup is 1:3 to approximately 3:1, or approximately 1:2 to approximately 2:1. In this example, the additional vegetable syrup is selected from (or from a group consisting of) rice, brown rice, tapioca, carob allulose syrup, and mixtures thereof.

[0069] In one example, the composition contains five or fewer ingredients. In another example, the composition contains four or fewer ingredients. In one version of this example, the composition is limited to diphenhydramine, glycerin, additional vegetable syrup, and flavorings. In this example, the additional vegetable syrup is selected from (or from the group consisting of) allulose, carob, rice, brown rice, tapioca syrup, and mixtures thereof.

[0070] Table 1 shows the sugar content of various bulk sweeteners.

[0071] [Table 1] 1: Reported as a measure of 70% dry material at 20°C, or as Brix, or as a measure of dissolved solids in a liquid.

[0072] Preservatives The compositions of the present invention may contain natural preservatives, artificial preservatives, or combinations thereof. Suitable natural preservatives include potassium sorbate and citrus extracts. Suitable artificial preservatives include sodium benzoate, EDTA salts (ethylenediaminetetraacetic acid, or EDTA salts, e.g., also known as disodium EDTA), parabens (e.g., methyl, ethyl, propyl, and butyl p-hydroxybenzoates), and mixtures thereof (or can be selected from these, or from the group consisting of these). The total amount of preservatives may be between 0.01% and 5% by weight. For example, the preservative in the composition may be potassium sorbate in an amount of about 0.1% to about 0.5% by weight, or about 0.2% by weight. The composition may also be substantially or completely preservative-free. As used herein, substantially free is defined as less than 0.1 weight / volume percent, preferably less than 0.05 weight / volume percent, and preferably less than 0.001 weight / volume percent.

[0073] If a composition is substantially preservative-free, it 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 of the vapor pressure of the composition when in a perfectly calm balance with the ambient air medium to the vapor pressure of distilled water under the same conditions. Water activity is described in detail later herein.

[0074] In certain examples, the composition may contain substantially no or no added water. Added water may be defined as water not present in the bulk sweetener or vegetable syrup. In some examples, the amount of added water is less than 5% by weight, less than 2% by weight, less than 1% by weight, or less than 0.5% by weight of the added water. In some examples, the total water content in the composition is less than 5% by weight, less than 2% by weight, less than 1% by weight, or less than 0.5% by weight of the total water in the composition.

[0075] pH adjuster The composition may contain a pH adjuster or buffer, which may include a salt, acid, or base. In certain examples, the pH adjuster may include anhydrous citric acid or sodium citrate. The pH adjuster may be added in amounts of less than 2% by weight, less than 1% by weight, less than 0.5% by weight, less than 0.2% by weight, or about 0.1% by weight.

[0076] The pH of the composition may be less than 6 (or about 6), optionally between 5 (or about 5) and 6 (or about 6), for example, 5.8 to 5.9, or about 5.888.

[0077] Thickening agent The suspension of the present invention may use a suspension system known in the art, but is not limited to, that contains at least one thickening component. The thickening component may comprise one or more thickeners that can be selected from hydrophilic, i.e., water-soluble polymers, such as hydrophilic colloids, swelling polymers, or gelling polymers. In one example, the thickening component may combine the properties of a structuring agent and a leavening agent. In another preferred example, the thickening component may combine the properties of at least two structuring agents, e.g., a primary structuring agent and a secondary structuring agent.

[0078] Structuring agents, when introduced into a suitable aqueous environment, can form ordered structures that are stabilized by hydrogen bonding and molecular entanglement. Hydrophilic colloids are a particularly good type of structuring agent. Hydrophilic colloids are dispersions of particles around which water molecules and solvated ions form a shell-like structure, and fluid absorption occurs mainly through swelling and expansion of the structure.

[0079] Suitable hydrophilic colloids include, but are not limited to, alginates, agar, guar gum, locust bean, carrageenan, cod, gum arabic, tragacanth, pectin, xanthan gum, gellan, maltodextrin, galactomannan, pustulan, laminarin, scleroglucan, gum arabic, inulin, karaya, welan, ramsan, zouglan, methylene, chitin, cyclodextrin, chitosan, cellulose polymers, such as microcrystalline cellulose, carboxymethylcellulose, and their derivatives, and combinations thereof (or can be selected from these, or from the group consisting thereof). In specific examples of the present invention, useful structuring agents can be selected from (or from the group consisting thereof) hydrophilic colloid xanthan gum, microcrystalline cellulose, carboxymethylcellulose, and their derivatives, their coprecipitates, and combinations thereof. In one particularly useful example, the thickening agent may include xanthan gum as a primary structuring agent and a co-treated combination of microcrystalline cellulose and carboxymethylcellulose as a secondary structuring agent (such as the one commercially available from FMC as Avicel-RC 591).

[0080] Xanthan gum is a high molecular weight natural carbohydrate, particularly a polysaccharide. The xanthan gum suitable for use in this invention is a high molecular weight polysaccharide produced by Xanthomonas campestris. Techniques and strains for producing this polysaccharide are described in U.S. Patents 4,752,580 and 3,485,719 (each of which disclosures are incorporated herein by reference). The xanthan gum used in this invention should have a viscosity of about 1000 to about 1700 cP (mPa·seconds) in a 1 percent salt solution. The viscosity of the 1 percent solution should be measured at 25°C using an LV model Brookfield Synchro-Lectric viscometer at 60 rpm, No. 3 spindle. Xanthan gum is available from several commercial suppliers, including RT Vanderbilt Company and CP Kelco. Suitable examples of xanthan gum include Keltrol, Keltrol F, Keltrol T, Keltrol TF, Xantural 180, and Vanzan NF-ST.

[0081] For example, the secondary structuring agent used in the present invention may be dry coprecipitation microcrystals of cellulose and sodium carboxymethylcellulose. Sodium carboxymethylcellulose is commonly used as a coprecipitation in microcrystalline cellulose. Sodium carboxymethylcellulose is particularly useful when it is present in an amount ranging from about 8% to about 19% by weight of the total weight of the coprecipitation microcrystals of cellulose and sodium carboxymethylcellulose. Microcrystalline cellulose products having sodium carboxymethylcellulose in an amount ranging from about 8% to about 14% by weight are useful. These mixtures are available from various sources, including FMC's trademarks Avicel® CL-611, Avicel® RC-581, and Avicel® RC-591.

[0082] Thickening agents can be leavening agents that swell when exposed to a suitable aqueous environment and can interact with structuring agents. Pregelatinized starch is a particularly good leavening agent. Also known as "instant" starch, pregelatinized starch is pre-cooked so that it swells and begins to thicken immediately when added to cold water. One particularly suitable pregelatinized starch is prepared from modified, stabilized, and waxy corn food starch and is commercially available from the National Starch Company as Instant Starch, Ultrasperse M.

[0083] In certain cases, any auxiliary suspension agent may be used. The auxiliary suspension agent may be selected from the group consisting of pharmaceutically acceptable salts of hydroxyethylcellulose and carboxymethylcellulose. Suitable pharmaceutically acceptable salts of carboxymethylcellulose include (or may be selected from, or may be selected from, the group consisting of) sodium and / or calcium salts of polycarboxymethyl ethers of cellulose, which are commercially available as carboxymethylcellulose sodium USP and carboxymethylcellulose calcium NF. Carboxymethylcellulose sodium USP contains about 6.5 to about 7.5% by weight of sodium on a dry basis and is commercially available from Aqualon under the product name Aqualon. Hydroxyethylcellulose is a partially substituted poly(hydroxyethyl) ether of cellulose. Hydroxycellulose NF is commercially available from Aqualon under the product name Natrosol.

[0084] In examples where the composition is a suspension, the composition may also contain at least one thickening agent. In examples where the composition is an oral solution, the composition may not contain a thickening agent substantially or not at all. As used herein, substantially not containing a thickening agent is defined as less than 0.1 weight / volume percent, preferably less than 0.05 weight / volume percent, and preferably less than 0.001 weight / volume percent.

[0085] additional sweetener The second sweetener may be an artificial or natural sweetener. Examples of artificial sweeteners, but not limited to, include aspartame, neotame, saccharin, and sucralose. Examples of natural sweeteners, but not limited to, include stevia or steviol glycosides, monk fruit extract, licorice root extract, and other licorice derivatives. Additional sweeteners may be added to the total composition in amounts of about 0.01% to about 5% by weight, or about 0.1% to about 3% by weight.

[0086] In one example, the composition may further contain stevia and / or monoammonium glycyrrhizinate as additional sweeteners. Stevia may be present in the composition in an amount ranging from about 0.01% to about 2% by weight, or from about 0.1% to about 1% by weight, for example, about 0.2% by weight or about 0.15% by weight. Alternatively, stevia may be present in the composition in a higher amount ranging from about 10% to about 30% by weight, for example, about 20% by weight. Monoammonium glycyrrhizinate may be present in the composition in an amount ranging from about 0.01% to about 2% by weight, or from about 0.01% to about 0.1% by weight, for example, about 0.04% by weight.

[0087] For example, a composition may exclude certain components. The term "completely excluding" refers to a composition in which a component is completely absent.

[0088] In one example, the composition does not contain bulk sweeteners having a fructose content of more than 75 percent, more than 70 percent, or more than 50 percent. 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 yet 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 composition may not substantially contain or contain any agave syrup. The composition may not substantially contain or contain any corn syrup or high-fructose corn syrup. The composition may not substantially contain or contain any fructose.

[0089] The amount of total sugar administered may be determined within the administration regimen or method using the composition of the present invention. The amount of sugar in a 24-hour administration regimen, when calculated to administer a therapeutic dose of the composition, may be less than 60 grams of sugar, less than 50 grams of sugar, or less than 40 grams of sugar. Total sugar is defined as the sum of sugars, including sucrose, maltose, lactose, glucose, and fructose.

[0090] 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 licorice derivatives.

[0091] density The density of the composition may be approximately 1.00 g / mL to approximately 1.50 g / mL, or approximately 1.20 g / mL to approximately 1.40 g / mL, or approximately 1.25 to approximately 1.35 g / mL.

[0092] stability The compositions of the present invention may be stable when stored under accelerated conditions or ambient conditions for up to 24 months, or under such conditions for up to 1 month, up to 3 months, up to 6 months, up to 12 months, or up to 18 months. Accelerated conditions may include storage at 30°C, 40°C, 50°C, 60°C, and under freeze-thaw conditions. Stability includes, but is not limited to, physical stability such as viscosity, water activity, and density, chemical stability such as degradation of active ingredients, and microbial stability using antimicrobial efficacy testing (AET).

[0093] water activity Water activity (AW) is a measure of the energy state of water in a system. It indicates how tightly water is "bound" structurally or chemically within a substance. Water activity is the relative humidity of the air in equilibrium with the sample in a sealed measurement chamber. Water activity is defined as the ratio of the vapor pressure of water in the sample to the vapor pressure of pure water at the same temperature. The concept of water activity is particularly important in determining the quality and safety of a product.

[0094] Water activity is the best indicator of microbial growth. While products may contain a relatively large proportion of water, if the water is chemically "bound" to a wetting agent or solute, such as a salt, sugar, or polyol, it is not biologically available for microbial growth. Water activity measures the amount of water available (unbound) for chemical and biochemical reactions, as well as the amount of water available for microbial growth to occur. All microorganisms have a critical water activity level below which they cannot grow.

[0095] Knowledge of the water activity of pharmaceutical substances, i.e., drugs and excipients, is essential for obtaining product formulations with optimal chemical, physical, microbiological, and shelf-life characteristics. Water activity affects the chemical stability, microbiological stability, flow properties, compressibility, hardness, and dissolution rate of pharmaceutical dosage forms.

[0096] Instruments / methods for measuring water activity: Instrument: Aqualab Series 4 TEV Dew Point Water Activity Meter (using both a mirror-cooled dew point sensor and a capacitive sensor to measure non-volatile and volatile substances, respectively). This instrument has the following attributes: Water activity range: 0.030~1.000aw Water activity accuracy: ±0.003 (4TE dew point mode) Water activity accuracy: ±0.015 (4TEV capacitance mode) Reading time 1: ≤ 5 minutes Sample temperature range: 15~50℃ Sample temperature accuracy: ±0.2℃ Sample dish capacity: 15 mL full Operating environment: 5~50℃, 20~80% humidity

[0097] Aw is performed following validation of Aqualab's water activity calibration against known validation standards to ensure optimal performance and accuracy. Validation standards are specially prepared unsaturated salt solutions with specific molar concentrations and water activity values ​​that can be accurately measured. Calibration validation is performed before use using two known validation standards (0.760aw and 0.250aw).

[0098] The AquaLab water activity meter measures the water activity of a sample using mirror-cooled dew point technology. In an apparatus using dew point technology, the sample is equilibrated in the headspace of a sealed chamber, which includes a mirror and means for 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 precise detection of the point at which condensation first appears on the mirror is observed by a photocell. A light beam is directed onto the mirror and reflected into a photodetector cell. The photodetector senses the change in reflectivity when condensation occurs on the mirror. A thermocouple attached to the mirror then records the temperature at which condensation occurs. The AquaLab water activity meter then signals with a beep to display the final water activity and temperature. In addition to the above technology, the AquaLab water activity meter uses an internal fan to circulate the air in the sample chamber to shorten the equilibrium time. Since both the dew point and the sample surface temperature are measured simultaneously, the need for perfect thermal equilibrium is eliminated, thereby reducing the measurement time to less than 5 minutes. [Examples]

[0099] The compositions of the present invention, as described in the following examples, represent specific embodiments of the compositions of the present invention and do not limit the invention. Other modifications can be made by those skilled in the art without departing from the spirit and scope of the invention.

[0100] Example 1: Liquid diphenhydramine formulation containing tapioca syrup This example was prepared using tapioca syrup as the natural bulk sweetener, with the formulation shown in Table 2.

[0101] [Table 2] 1: A product marketed by Icon Foods Corporation under the trademark SteviaSweet® RM95. 2: A product sold by MafCo Corporation under the trademark MagnaSweet (registered trademark) MM100. 3: A product sold by Sweet Additions Corporation under the trademark TapiSweet(registered trademark)CL42. 4. "QS" is a term that indicates the material was used to achieve the final target volume.

[0102] Processing policy 1. Glycerin was added to a container with a tare weight equipped with a high-shear mixer to achieve a volume suitable for mixing. 2. Add about half of the tapioca syrup to the container and mix. 3. Add stevia, monoammonium glycyrrhizinate, diphenhydramine, and flavorings, and mix until dissolved. 4. The solution was brought to its final volume with tapioca syrup ("QS'd"), mixed under vacuum, and degassed.

[0103] Example 2: Liquid diphenhydramine formulation containing rice syrup This example was prepared using brown rice syrup as the natural bulk sweetener, with the formulation shown in Table 3.

[0104] [Table 3] 1: A product marketed by Icon Foods Corporation under the trademark SteviaSweet® RM95. 2: A product sold by MafCo Corporation under the trademark MagnaSweet (registered trademark) MM100. 3: It is sold commercially by Mezzoni Foods. 4: A product sold by Sweet Additions Corporation under the trademark RiceSweet (registered trademark) CL42. 5. "QS" is a term that indicates the material was used to achieve the final target volume.

[0105] Processing policy 1. Glycerin was added to a container with a tare weight equipped with a high-shear mixer to achieve a volume suitable for mixing. 2. Add about half of the brown rice syrup to the container and mix. 3. Add stevia, monoammonium glycyrrhizinate, diphenhydramine, anhydrous citric acid, and flavorings, and mix until dissolved. 4. The solution was brought to its final volume with purified water ("QS'd"), mixed under vacuum, and degassed.

[0106] Example 3: Liquid diphenhydramine formulation containing allulose syrup This example was prepared using allulose syrup as the natural bulk sweetener, with the formulation shown in Table 4.

[0107] [Table 4] 1: A product marketed by Anderson Advanced Ingredients Corporation under the trademark AllSWEET (registered trademark) AG9957. 2: "QS" is a term that indicates the material was used to reach the final target volume.

[0108] Processing policy 1. Add glycerin to a tare-measured container equipped with a high-shear mixer until a suitable volume for mixing is achieved. 2. Approximately half of the allulose syrup was added to the container and mixed. 3. Add stevia, monoammonium glycyrrhizinate, diphenhydramine, and flavorings, and mix until dissolved. 4. The solution was brought to its final volume with allulose syrup ("QS'd"), mixed under vacuum, and degassed.

[0109] Example 4: Liquid diphenhydramine formulation containing Fruit-Up® syrup This embodiment was prepared using the formulations shown in Table 5, with a combination of apple syrup and carob syrup as natural bulk sweeteners, such as those commercially available from ADM Company under the trademark Fruit-Up®.

[0110] [Table 5] 1: A product marketed by Anderson Advanced Ingredients Corporation under the trademark AudianaSweet® Optimized AG 3240. 2: A product sold by MafCo Corporation under the trademark MagnaSweet (registered trademark) MM100. 3: Products marketed by ADM Company under the trademark Fruit-Up (registered trademark) Premium. 4. "QS" is a term that indicates the material was used to achieve the final target volume.

[0111] Processing policy 1. Add Fruit-Up® to a tare-weighted container equipped with a high-shear mixer until a suitable volume for mixing is achieved. 2. Add about half of the fruit syrup to the container and mix. 3. Add stevia, monoammonium glycyrrhizinate, diphenhydramine, and flavorings, and mix until dissolved. 4. The solution was brought to its final volume with Fruit-Up® syrup ("QS'd"), mixed under vacuum, and degassed.

[0112] Example 5: Liquid diphenhydramine preparation containing Fruit-Up® syrup, Fruit-Up® syrup:glycerin ratio 3.30:1 This embodiment was prepared using the formulations shown in Table 6, with a combination of apple syrup and carob syrup as natural bulk sweeteners, such as those commercially available from ADM Company under the trademark Fruit-Up®.

[0113] [Table 6] 1: A product sold by ADM Company under the trademark Fruit-Up(registered trademark) Premium. 2: "QS" is a term that indicates the material was used to reach the final target volume. 3: %w / v = %weight / volume 4:%w / w=%w / w

[0114] Processing policy 1. Add Fruit-Up® to a tare-weighted container equipped with a high-shear mixer until a suitable volume for mixing is achieved. 2. Approximately half of the Fruit-Up® syrup was added to the container and mixed. 3. Add sodium citrate dihydrate, diphenhydramine, and flavorings, and mix until dissolved. 4. The solution was brought to its final volume with Fruit-Up® syrup ("QS'd"), mixed under vacuum, and degassed.

[0115] Example 6: Liquid cetirizine formulation containing tapioca syrup This example is prepared using tapioca syrup as the natural bulk sweetener, and the formulation shown in Table 7.

[0116] [Table 7] 1: A product marketed by Anderson Advanced Ingredients Corporation under the trademark SteviaSweet® RM95. 2: A product sold by MafCo Corporation under the trademark MagnaSweet (registered trademark) MM100. 3: A product sold by Sweet Additions Corporation under the trademark TapiSweet(registered trademark)CL42. 4. "QS" is a term that indicates the material was used to achieve the final target volume.

[0117] Processing policy 1. Add glycerin to a tare-measured container equipped with a high-shear mixer until a suitable volume for mixing is achieved. 2. Add about half of the tapioca syrup to the container and mix. 3. Add stevia, monoammonium glycyrrhizinate, cetirizine HCl, and flavorings, and mix until dissolved. 4. The solution was brought to its final volume with tapioca syrup ("QS'd"), mixed under vacuum, and degassed.

[0118] Example 7: Liquid loperamide formulation containing tapioca syrup This example was prepared using tapioca syrup as the natural bulk sweetener, and the formulation shown in Table 8.

[0119] [Table 8] 1: A product marketed by Anderson Advanced Ingredients Corporation under the trademark SteviaSweet® RM95. 2: A product sold by MafCo Corporation under the trademark MagnaSweet (registered trademark) MM100. 3: A product sold by Sweet Additions Corporation under the trademark TapiSweet(registered trademark)CL42. 4. "QS" is a term that indicates the material was used to achieve the final target volume.

[0120] Processing policy 1. Add glycerin to a tare-measured container equipped with a high-shear mixer until a suitable volume for mixing is achieved. 2. Add about half of the tapioca syrup to the container and mix. 3. Add stevia, monoammonium glycyrrhizinate, loperamide HCl, and flavorings, and mix until dissolved. 4. The solution was brought to its final volume with tapioca syrup ("QS'd"), mixed under vacuum, and degassed.

[0121] Example 8: Fruit-Up® syrup liquid loratadine formulation containing natural bulk sweetener. This embodiment was prepared using the formulations shown in Table 9, with a combination of apple syrup and carob syrup as natural bulk sweeteners, such as those commercially available from ADM Company under the trademark Fruit-Up®.

[0122] [Table 9] 1: A product sold by AudianaSweet Advanced Ingredients Corporation under the trademark Anderson® Optimized AG3240. 2: MagnaSweet (registered trademark) MM100 from MafCo Corporation 2 Products sold under the trademark [trademark name]. 3: A product sold by ADM Company under the trademark Fruit-Up(registered trademark) Premium. 4. "QS" is a term that indicates the material was used to achieve the final target volume.

[0123] Processing policy 1. Add glycerin to a tare-measured container equipped with a high-shear mixer until a suitable volume for mixing is achieved. 2. Add about half of the Frit-Up syrup to the container and mix. 3. Add stevia, monoammonium glycyrrhizinate, loratadine, and flavorings, and mix until dissolved.

[0124] Example 9: Rheology (viscosity) procedure The viscosity data shown in the table represents a snapshot of viscosity measured at various shear rates. Viscosity measurements were performed using a Brookfield DV2T LV viscometer coupled with a small sample adapter kit and spindle #31. For all samples, the measurement temperature was maintained at 25°C using a temperature-controlled water bath. For each measurement, 9 mL of sample was loaded without air bubbles. The spindle rotation speed was set to 20 RPM, and after 5 rotations of the spindle, the reading was recorded in units of cps. The viscosity of Example 5 was measured to be approximately 328.5 centipoise.

[0125] shear sweep All tests were performed using a TA Instruments AR2000 rheometer with a 60 mm parallel plate configuration and a 0.5 mm gap setting. The measurement temperature was maintained at 25°C using a Peltier plate for all samples. The rheometer was placed on a vibration isolation platform and positioned horizontally. Samples were loaded without air bubbles, and if the gap was 10% larger than the desired gap, excess sample was "trimmed" from the edge. Shear sweep experiments were performed at shear rates ranging from 0.001 to 100 1 / s.

[0126] pH The pH of Example 5 was measured to be approximately 5.88.

[0127] Example 10: Assay and Stability The formulations of Example 5 were tested for diphenhydramine assays, and their stability was tested at the following time points: initial (time 0), 1 month, and under various storage conditions as shown in Table 10. The total amount of diphenhydramine and degradation products was analyzed using a reference standard prepared at 100% of the label dose. The samples and standards were diluted and mixed in a diluent consisting of 50 mM ammonium formate + 0.1% aqueous formic acid solution in water:methanol in a 95:5 ratio.

[0128] Methods: Diphenhydramine assays and degradation products were analyzed using ultra-high pressure liquid chromatography (UPLC) with the following parameters: Column: Waters Acquity UPLC HSS T3 2.1×150, 1.8μm

[0129] A gradient method was used over a run time of 14 minutes, with a first mobile phase consisting of 30 mM potassium hexafluorophosphate + 0.05% phosphoric acid aqueous solution, and a second mobile phase consisting of acetonitrile:water + 0.05% phosphoric acid in an 80:20 ratio. This method was performed with a flow rate of 0.45 mL / min, an injection volume of 2.0 μL, a 220 nm UV detector, and a column temperature of 40°C. The proposed run time was 14 minutes.

[0130] [Table 10] 1: ND = Not detected.

[0131] Although the present invention has been described in connection with this detailed description, the foregoing description is illustrative of the scope of the invention and is not intended to limit the scope of the invention, and the scope of the invention is understood to be defined by the appended claims. Other aspects, advantages and modifications are within the scope of the claims.

[0132] [Implementation Method] (1) A liquid composition comprising at least one therapeutic ingredient and at least one natural bulk sweetener, wherein the fructose content of the total amount of natural bulk sweeteners in the composition is less than 75 percent. (2) The liquid composition according to Embodiment 1, wherein the natural bulk sweetener is selected from glycerin, allulose syrup, rice syrup, brown rice syrup, tapioca syrup, apple syrup, carob syrup, and combinations thereof. (3) The liquid composition according to Embodiment 1, wherein the liquid composition has a total fructose level of less than 0.7 g / mL. (4) The liquid composition according to Embodiment 1, wherein the therapeutic component is a pharmaceutically active ingredient. (5) The liquid composition according to Embodiment 1, wherein the therapeutic component is a homeopathic active ingredient.

[0133] (6) The liquid composition according to Embodiment 1, wherein the therapeutic component is a nutritional supplement. (7) The liquid composition according to Embodiment 1, wherein the liquid composition is in the form of a suspension. (8) The liquid composition according to Embodiment 1, wherein the liquid composition is in the form of a solution. (9) The liquid composition according to Embodiment 4, wherein the pharmaceutically active ingredient is selected from acetaminophen, diphenhydramine, dextromethorphan, guaifenesin, ibuprofen, cetirizine, loperamide, and phenylephrine. (10) The liquid composition according to Embodiment 1, wherein the therapeutic component is an antihistamine.

[0134] (11) The liquid composition according to Embodiment 1, further comprising a sensory stimulant. (12) The liquid composition according to Embodiment 1, further comprising a second natural bulk sweetener. (13) The liquid composition according to Embodiment 12, wherein the natural bulk sweetener is glycerin and the second natural bulk sweetener is tapioca syrup. (14) The liquid composition according to Embodiment 12, wherein the natural bulk sweetener is glycerin and the second natural bulk sweetener is brown rice syrup. (15) The liquid composition according to Embodiment 12, wherein the natural bulk sweetener is glycerin and the second natural bulk sweetener is allulose syrup.

[0135] (16) The liquid composition according to Embodiment 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 according to Embodiment 16, wherein the ratio of the combination of apple syrup and carob syrup to glycerin is about 3.30:1. (18) The liquid composition according to Embodiment 1, wherein the liquid composition is substantially free of agave syrup. (19) The liquid composition according to Embodiment 1, wherein the liquid composition substantially does not contain any component having a fructose content of more than 15 percent. (20) A method for alleviating a symptom selected from pain, fever, cough, nasal congestion, diarrhea, allergic rhinitis, and pharyngitis in a subject, comprising administering the composition described in Embodiment 1.

Claims

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

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

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

4. The liquid composition according to claim 1, wherein the therapeutic component is a pharmaceutically active component.

5. The liquid composition according to claim 1, wherein the therapeutic component is a homeopathic active ingredient.

6. The liquid composition according to claim 1, wherein the therapeutic component is a nutritional supplement.

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

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

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

10. The liquid composition according to claim 1, wherein the therapeutic component is an antihistamine.

11. The liquid composition according to claim 1, further comprising a sensory stimulant.

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

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

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

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

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

1.

18. The liquid composition according to claim 1, wherein the liquid composition substantially does not contain agave syrup.

19. The liquid composition according to claim 1, wherein the liquid composition substantially does not contain any component having a fructose content of more than 15 percent.

20. A method for alleviating a symptom selected from pain, fever, cough, nasal congestion, diarrhea, allergic rhinitis, and pharyngitis in a subject, comprising administering the composition described in claim 1.

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