WO2023018661A1 - Formulations liquides comprenant de l'acide alginique, de la pectine et du carraghénane et leurs procédés d'utilisation - Google Patents

Formulations liquides comprenant de l'acide alginique, de la pectine et du carraghénane et leurs procédés d'utilisation Download PDF

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WO2023018661A1
WO2023018661A1 PCT/US2022/039721 US2022039721W WO2023018661A1 WO 2023018661 A1 WO2023018661 A1 WO 2023018661A1 US 2022039721 W US2022039721 W US 2022039721W WO 2023018661 A1 WO2023018661 A1 WO 2023018661A1
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liquid formulation
pectin
formulation
carrageenan
liquid
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PCT/US2022/039721
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English (en)
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Reginald Bradley
Debanjan DAS
Gerard MEISEL
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Bayer Healthcare Llc
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Publication of WO2023018661A1 publication Critical patent/WO2023018661A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present disclosure relates generally to liquid formulations as a general delivery formulation for active pharmaceutical ingredients, and more specifically to oral liquid formulations comprising alginic acid or pharmaceutically acceptable salts thereof, pectin and/or carrageenan for treatment of cough and cold.
  • the formulations provided herein can serve as a platform technology to accommodate and deliver a wide array of active pharmaceutical ingredients to treat various disorders.
  • the formulations provided herein possess unique combinations of naturally mucoadhesive and viscous polysaccharide components that allow the formulations to be specifically tailored for certain physical properties, such as high mucoadhesiveness.
  • the present disclosure also provides methods of using the formulations described herein for treatment of cough and cold.
  • compositions are often specifically developed and designed with respect to the active pharmaceutical ingredient to be delivered and the intended mode of administration.
  • active pharmaceutical ingredient for example, for treatment of cough and cold, multi-ingredient oral tablet and liquid gel formulations are largely favored for their compact size, convenience, and facile administration.
  • tablets and liquid gel capsules are highly effective at delivering the desired active pharmaceutical ingredients to the body, formulation development can be a costly and complicated process, particularly when different active pharmaceutical ingredients have different, or even competing, stability requirements and storage constraints.
  • Compatible excipients for a given active pharmaceutical ingredient such as acetaminophen, may be high incompatible with another active pharmaceutical ingredient, phenylephrine, and, thus, formulation design for one active pharmaceutical ingredient may be non-transferrable to other active ingredients.
  • liquid formulations comprising combinations of pectin, carrageenan, and/or alginic acid or pharmaceutically acceptable salts thereof as part of a highly mucoadhesive hydrocolloid system that may be combined with various active pharmaceutical ingredients for treatment of various disorders, such as cold and cough.
  • the liquid formulations described herein demonstrate high mucoadhesion characteristics and may provide direct physical, symptomatic relief from cold and cough by soothing and coating the pharynx.
  • the long-lasting mucoadhesion of these formulations may also promote alleviation and prevention of irritation and damage to throat tissue caused by excessive coughing.
  • a liquid formulation comprising: at least two of pectin, carrageenan, and alginic acid or a pharmaceutically acceptable salt thereof; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin, and any carrageenan present in the liquid formulation is 2-60% w/w.
  • a liquid formulation comprising: 1-18% w/w alginic acid or a pharmaceutically acceptable salt thereof; 1-10% w/w pectin, carrageenan, or a combination thereof; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, any pectin, and any carrageenan present in the liquid formulation is 3.5-20% w/w.
  • a liquid formulation comprising: 1-8% w/w alginic acid or a pharmaceutically acceptable salt thereof; 3.5-10% w/w pectin, carrageenan, or a combination thereof; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, any pectin, and any carrageenan present in the liquid formulation is 4.5-15% w/w.
  • a container comprising a liquid formulation as described herein.
  • a method for treating cough comprising administering to a human in need thereof a liquid formulation as described herein.
  • a method for treating barking cough comprising administering to a human in need thereof a liquid formulation as described herein.
  • FIG. 1A and FIG. IB depict an exemplary apparatus for bioadhesion tests using a texture analyzer fitted with a polyethylene attachment.
  • FIGS. 2A-2D depict the migration of sample formulations subjected to bioadhesion tests using a transparent sample tray at an initial position of 0° (horizontal, FIG. 2A and FIG. 2C) and after being held for thirty seconds at a 45° angle (FIG. 2B and FIG.
  • FIGS. 3A-3D show photographs of Formulations #1-4 before (FIGS. 3A and 3C) and after (FIGS. 3B and 3D) storage at 40°C and 75% relative humidity (RH) for 1 month.
  • FIGS. 4A and 4B show photographs of Formulations #1-4 before (FIG. 4A) and after (FIG. 4B) three cycles of freeze-thaw cycling (-20°C for 3 days and 25°C, 60% relative humidity for 4 days, for each cycle).
  • freeze-thaw cycling -20°C for 3 days and 25°C, 60% relative humidity for 4 days, for each cycle.
  • mucoadhesion For example, in a formulation containing one or more of a cough suppressant, an expectorant, a decongestant, and/or an analgesic, additional mucoadhesive properties for the treatment of cough and cold may be desired.
  • Each of the individual active pharmaceutical ingredients possess different specifications for storage stability and chemical reactivity, which should be accounted for throughout the various stages of formulation design.
  • the added physical properties of the formulation such as mucoadhesion, are preferably also considered throughout formulation development.
  • the ability of a formulation to adhere to and coat mucous membranes which may be referred to herein interchangeably as “mucoadhesion” or “bioadhesion”, exists in a delicate balance.
  • a formulation If a formulation is too thin, the liquid formulation may not coat and adhere to the mucosae; however, if too thick or viscous, the liquid formulation may adhere to itself but form an overly thick coating which fails to bond to the mucous membranes due to its weight. Even greater difficulty arises in maintaining mucoadhesion for extended periods of time, particularly when exposed to swallowed saliva that could contribute to the removal of the coating over time. From the standpoint of palatability, highly viscous formulations may be off-putting when consumed whereas overly thin formulations may be palatable but ineffectual.
  • liquid oral formulations employing unique combinations of naturally mucoadhesive polysaccharide ingredients.
  • the liquid oral formulations are readily adapted to accommodate a range of classes of active pharmaceutical ingredients.
  • the formulations of the naturally mucoadhesive polysaccharide ingredients may be optimized in the relative quantities of each polysaccharide ingredient to adjust specific physical properties, such as viscosity, without deleteriously affecting other properties, like mucoadhesion.
  • the present disclosure details liquid formulations that employ at least two of alginic acid or a pharmaceutically acceptable salt thereof, pectin and/or carrageenan to produce hydrocolloid systems which possess substantial mucoadhesion and high storage stability, as evidenced by their ability to retain mucoadhesiveness after exposure to elevated temperature conditions.
  • alginic acid or a pharmaceutically acceptable salt thereof, pectin, and/or carrageenan could achieve the both the degree of gelation and adhesiveness to mucous membranes to provide a highly mucoadhesive coating as a platform delivery system for various treatments.
  • the liquid formulations provided herein not only combine active pharmaceutical ingredients with a uniformly flowing, highly mucoadhesive coating to provide a single formulation that provides complementary medicinal effect and sensory relief.
  • the liquid formulations of the present disclosure can be tailored to exhibit the desired flowability and superior mucoadhesion both before and after storage.
  • the mucoadhesive properties of the liquid formulations provided herein not only provide a physical barrier against direct contact of irritated mucosae to foreign substances but may also provide enhanced healing effect to the irritated or damaged membranes themselves.
  • the ability of the hydrocolloid formulations of the present disclosure to maintain mucoadhesion over extended periods of time may, in concert with particular active pharmaceutical ingredients, provide long-term treatment.
  • the liquid formulations of the present disclosure include suspensions, syrups, emulsions, and solutions.
  • typical oral suspensions not all of the ingredients provided in the formulation may be fully dissolved in liquid.
  • the majority of end consumers may find these typical oral suspensions unpalatable and displeasing.
  • the liquid formulations provide improved taste-masking, mouthfeel, and aroma as compared to existing liquid oral suspensions.
  • Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. In some embodiments, the term “about” when used in association with a measurement, or used to modify a value, a unit, a constant, or a range of values, refers to variations of +/- 2%.
  • Reference to “between” two values or parameters herein includes (and describes) embodiments that include those two values or parameters per se.
  • description referring to “between x and y” includes description of “x” and “y” per se.
  • liquid formulations comprising at least two of pectin, carrageenan, and alginic acid or a pharmaceutically acceptable salt thereof; at least one active pharmaceutical ingredient; and water.
  • the liquid formulation is an oral suspension.
  • liquid formulations for use in the treatment of cold and cough- related disorders.
  • the liquid formulations of the present disclosure include liquid formulations provided in an oral suspension, which may further form a hydrocolloid coating on mucous membranes, such as the throat and esophagus.
  • the liquid formulations not only manage to achieve a highly mucoadhesive formulation but further demonstrate superior mucoadhesion as compared to existing, commercially available treatments.
  • the superior therapeutic properties arise from a unique selection of naturally bioadhesive, cross-linking polysaccharides that, when used in combination, confer the physical characteristics that allow long-lasting mucoadhesion.
  • the naturally bioadhesive, cross-linking ingredients include at least two of alginic acid or a pharmaceutically acceptable salt thereof, pectin and carrageenan.
  • the liquid formulation comprises at least two of pectin, carrageenan, and alginic acid or a pharmaceutically acceptable salt thereof.
  • alginic acid or the pharmaceutically acceptable salts thereof, pectin and carrageenan all contribute to the resulting mucoadhesion, viscosity, and other properties of the liquid formulations.
  • the liquid formulation comprises alginic acid or a pharmaceutically acceptable salt thereof.
  • Alginic acid is a naturally occurring hydrophilic polysaccharide that is found in brown seaweed. When exposed to water, alginic acid and its salts may form viscous gels and biofilms.
  • alginic acid or pharmaceutically acceptable salts thereof may be incorporated for any number of functionalities, including but not limited to as a thickening agent, viscosity increaser/enhancing agent, a stabilizer, or a gelling agent.
  • Common alginate salts may include but are not limited to sodium alginate and calcium alginate.
  • the liquid formulation comprises alginic acid. In certain other embodiments, the liquid formulation comprises a pharmaceutically acceptable salt of alginic acid. In certain other embodiments, the liquid formulation comprises sodium alginate, calcium alginate, potassium alginate, ammonium alginate, magnesium alginate, or any combinations thereof. In still certain other embodiments, the liquid formulation comprises sodium alginate.
  • the quantity of any ingredients provided in the liquid formulations herein may be expressed as a weight percentage of the total weight of the liquid formulation.
  • the liquid formulation comprises at least about 0.1% w/w, at least about 0.5% w/w, at least about 1% w/w, at least about 2% w/w, at least about 3% w/w, at least about 4% w/w, at least about 5% w/w, at least about 6% w/w, at least about 7% w/w, at least about 8% w/w, at least about 9% w/w, at least about 10% w/w, at least about 12% w/w, at least about 15% w/w, or at least about 18% w/w alginic acid or a pharmaceutically acceptable salt thereof.
  • the liquid formulation comprises at least about 1% w/w, at least about 5% w/w, or at least about 8% w/w alginic acid or a pharmaceutically acceptable salt thereof.
  • the liquid formulation comprises less than or equal to about 20% w/w, less than or equal to about 18% w/w, less than or equal to about 15% w/w, less than or equal to about 12% w/w, less than or equal to about 10% w/w, less than or equal to about 8% w/w, less than or equal to about 7% w/w, less than or equal to about 6% w/w, less than or equal to about 5% w/w, less than or equal to about 4% w/w, less than or equal to about 3% w/w, less than or equal to about 2% w/w, or less than or equal to about 1% w/w alginic acid or a pharmaceutically acceptable salt thereof.
  • the liquid formulation comprises less than or equal to about 18% w/w, less than or equal to about 15% w/w, less than or equal to about 12% w/w, less than or equal to about 10% w/w, or less than or equal to about 8% w/w alginic acid or a pharmaceutically acceptable salt thereof.
  • the liquid formulation comprises about 0.1-20% w/w, about 0.1-18% w/w, about 0.1-15% w/w, about 0.1-12% w/w, about 0.1-10% w/w, about 0.1- 8% w/w, about 0.1-7% w/w, about 0.1-6% w/w, about 0.1-5% w/w, about 0.1-4% w/w, about 0.1-3% w/w, about 0.1-2% w/w, about 0.1-1% w/w, about 0.5-20% w/w, about 0.5-18% w/w, about 0.5-15% w/w, about 0.5-12% w/w, about 0.5-10% w/w, about 0.5-8% w/w, about 0.5- 7% w/w, about 0.5-6% w/w, about 0.5-5% w/w, about 0.5-4% w/w, about 0.5-3% w/w, about
  • the liquid formulation comprises pectin.
  • Pectin broadly refers to a complex group of heterogeneous polysaccharides derived from plants. Similar to alginic acid, pectin may be employed in pharmaceutical formulations and food products as a thickening agent, viscosity enhancing agent, gelling agent, and stabilizer. As utilized in the present disclosure, pectin provides gelling, thickening and stabilizing properties as well as natural mucoadhesive properties to the resulting liquid formulations.
  • pectin encompasses a variety of heteropolysaccharides
  • the term “pectin” as used herein may refer to and encompass the set of heteropolysaccharides generally known as pectic polysaccharides, or alternatively may be used to refer to particular subcategories of heteropolysaccharides within the broader class of pectic polysaccharides.
  • the pectin used herein may be further characterized by other chemical characteristics, such as the degree of methoxylation of the saccharide units within polysaccharide molecules, which may influence the physical properties of the liquid formulations.
  • Suitable pectins for the formulations of the present disclosure may include but are not limited to high-methoxylated (HM) pectin, low- methoxlated (LM) pectin, and/or amidated low-methoxylated (LM) pectin.
  • HM high-methoxylated
  • LM low- methoxlated
  • LM amidated low-methoxylated
  • the terms “high-methoxylated”, “high-methoxy”, “high- methoxyl” and “high-ester” pectin refers to pectic polysaccharides having greater than or equal to about 50% of saccharide carboxyl groups esterified or methoxylated.
  • the terms “low-methoxylated”, “low-methoxy”, “low-methoxyl” and “low-ester” pectin refers to pectic polysaccharides having less than about 50% of saccharide carboxyl groups esterified or methoxylated.
  • Both high-methoxylated and low-methoxylated pectin may form continuous gel structures but may do so under differing conditions. For example, highly methoxylated pectin may readily form cross-linked gels under acidic conditions, whereas low-methoxylated pectin may require calcium ions to facilitate gelation but can form cross-linked gels at higher pH levels.
  • the liquid formulation comprises high-methoxylated pectin, low-methoxylated pectin, a combination thereof.
  • the pectin present in the liquid formulations comprises high-methoxylated pectin, low-methoxylated pectin, a combination thereof.
  • the liquid formulation comprises low- methoxylated pectin.
  • the pectin is low-methoxylated pectin.
  • the liquid formulation comprises amidated low-methoxylated pectin.
  • the pectin is amidated low-methoxylated pectin.
  • the liquid formulation further comprises calcium ions.
  • the at least one active pharmaceutical ingredient in the liquid formulation comprises a pharmaceutically acceptable calcium salt.
  • the liquid formulation comprises high-methoxylated pectin. In other embodiments, the pectin is high-methoxylated pectin.
  • the liquid formulation comprises at least about 0.1% w/w, at least about 0.5% w/w, at least about 0.8% w/w, at least about 1% w/w, at least about 2% w/w, at least about 3% w/w, at least 3.5% w/w, at least about 4% w/w, at least about 5% w/w, at least about 6% w/w, at least about 7% w/w, at least about 8% w/w, at least about 9% w/w, at least about 10% w/w, at least about 12% w/w, at least about 15% w/w, or at least about 18% w/w pectin.
  • the liquid formulation comprises at least about 0.5% w/w, at least about 0.8% w/w, at least about 1% w/w, at least 3.5% w/w, at least about 5% w/w, or at least about 8% w/w pectin.
  • the liquid formulation comprises less than or equal to about 20% w/w, less than or equal to about 18% w/w, less than or equal to about 15% w/w, less than or equal to about 12% w/w, less than or equal to about 10% w/w, less than or equal to about 8% w/w, less than or equal to about 7% w/w, less than or equal to about 6% w/w, less than or equal to about 5% w/w, less than or equal to about 4% w/w, less than or equal to about 3% w/w, less than or equal to about 2% w/w, or less than or equal to about 1% w/w pectin.
  • the liquid formulation comprises less than or equal to about 18% w/w, less than or equal to about 15% w/w, less than or equal to about 12% w/w, less than or equal to about 10% w/w, less than or equal to about 8% w/w, less than or equal to about 5% w/w, or less than or equal to about 3% w/w pectin.
  • the liquid formulation comprises about 0.1-20% w/w, about 0.1-18% w/w, about 0.1-15% w/w, about 0.1-12% w/w, about 0.1-10% w/w, about 0.1- 8% w/w, about 0.1-7% w/w, about 0.1-6% w/w, about 0.1-5% w/w, about 0.1-4% w/w, about 0.1-3% w/w, about 0.1-2% w/w, about 0.1-1% w/w, about 0.5-20% w/w, about 0.5-18% w/w, about 0.5-15% w/w, about 0.5-12% w/w, about 0.5-10% w/w, about 0.5-8% w/w, about 0.5- 7% w/w, about 0.5-6% w/w, about 0.5-5% w/w, about 0.5-4% w/w, about 0.5-3% w/w, about
  • the liquid formulation comprises carrageenan.
  • Carrageenan is a sulfated polysaccharide derived from red seaweed. Similar to alginic acid and pectin, carrageenan is commonly used as a multifunctional agent for its gelling, thickening and stabilizing properties. As incorporated in the liquid formulations of the present disclosure, carrageenan contributes to the mucoadhesion properties of the resulting oral suspension.
  • Carrageenan exists in three main varieties with respect to the degree of sulfation present per disaccharide unit. Kappa-carrageenan contains one sulfate group per disaccharide unit, iota-carrageenan has two sulfates per disaccharide, and lambda-carrageenan possesses three sulfate groups. Higher levels of sulfation result in lower strength gels or, in the case of lambda-carrageenan may even inhibit gelation.
  • the carrageenan is kappa-carrageenan, iota-carrageenan, lambda-carrageenan, or any combination thereof. In other embodiments, the carrageenan is kappa-carrageenan.
  • the liquid formulation comprises at least about 0.1% w/w, at least about 0.5% w/w, at least about 0.8% w/w, at least about 1% w/w, at least about 2% w/w, at least about 3% w/w, at least 3.5% w/w, at least about 4% w/w, at least about 5% w/w, at least about 6% w/w, at least about 7% w/w, at least about 8% w/w, at least about 9% w/w, at least about 10% w/w, at least about 12% w/w, at least about 15% w/w, or at least about 18% w/w carrageenan.
  • the liquid formulation comprises at least about 0.5% w/w, at least about 0.8% w/w, at least about 1% w/w, at least 3.5% w/w, at least about 5% w/w, or at least about 8% w/w carrageenan.
  • the liquid formulation comprises less than or equal to about 20% w/w, less than or equal to about 18% w/w, less than or equal to about 15% w/w, less than or equal to about 12% w/w, less than or equal to about 10% w/w, less than or equal to about 8% w/w, less than or equal to about 7% w/w, less than or equal to about 6% w/w, less than or equal to about 5% w/w, less than or equal to about 4% w/w, less than or equal to about 3% w/w, less than or equal to about 2% w/w, or less than or equal to about 1% w/w carrageenan.
  • the liquid formulation comprises less than or equal to about 18% w/w, less than or equal to about 15% w/w, less than or equal to about 12% w/w, less than or equal to about 10% w/w, less than or equal to about 8% w/w, less than or equal to about 5% w/w, or less than or equal to about 3% w/w carrageenan.
  • the liquid formulation comprises about 0.1-20% w/w, about 0.1-18% w/w, about 0.1-15% w/w, about 0.1-12% w/w, about 0.1-10% w/w, about 0.1- 8% w/w, about 0.1-7% w/w, about 0.1-6% w/w, about 0.1-5% w/w, about 0.1-4% w/w, about 0.1-3% w/w, about 0.1-2% w/w, about 0.1-1% w/w, about 0.5-20% w/w, about 0.5-18% w/w, about 0.5-15% w/w, about 0.5-12% w/w, about 0.5-10% w/w, about 0.5-8% w/w, about 0.5- 7% w/w, about 0.5-6% w/w, about 0.5-5% w/w, about 0.5-4% w/w, about 0.5-3% w/w, about
  • alginic acid and pharmaceutically acceptable salts thereof, pectin and carrageenan exhibit properties that make them multifunctional ingredients, the specific classification of which may depend on the quantity present.
  • each of the three polysaccharide components share multiple functionalities in common, it was surprisingly observed that the combinations of the ingredients yielded more favorable properties than those commercial formulations containing only one of the components.
  • the liquid formulations of the present disclosure demonstrated improved mucoadhesion.
  • the liquid formulation comprises alginic acid or a pharmaceutically acceptable salt thereof and pectin. In still other embodiments, the liquid formulation comprises alginic acid or a pharmaceutically acceptable salt thereof and carrageenan. In still yet other embodiments, the liquid formulation comprises alginic acid or a pharmaceutically acceptable salt thereof, pectin and carrageenan.
  • the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, any pectin and any carrageenan present in the liquid formulation is at least about 2% w/w, at least about 3% w/w, at least about 3.5% w/w, at least about 4% w/w, at least about 4.5% w/w at least about 5% w/w, at least about 7% w/w, at least about 10% w/w, at least about 12% w/w, at least about 15% w/w, at least about 17% w/w, or at least about 20% w/w of the total weight of the liquid formulation.
  • the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, any pectin and any carrageenan present in the liquid formulation is at least about 2% w/w, at least about 3.5% w/w, or at least about 4.5% w/w of the total weight of the liquid formulation.
  • the combined weight percentage of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin and any carrageenan present in the liquid formulation is less than or equal to about 60% w/w, less than or equal to about 55% w/w, less than or equal to about 50% w/w, less than or equal to about 45% w/w, less than or equal to about 40% w/w, less than or equal to about 36% w/w, less than or equal to about 35% w/w, less than or equal to about 30% w/w, less than or equal to about 27% w/w, less than or equal to about 25% w/w, less than or equal to about 22% w/w, less than or equal to about 20% w/w, less than or equal to about 17% w/w, less than or equal to about 15% w/w, less than or equal to about 12% w/w, less than or equal to about 10% w/w, less than or equal to about 7%
  • the combined weight percentage of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin and any carrageenan present in the liquid formulation is less than or equal to about 60% w/w, less than or equal to about 55%, less than or equal to about 54%, less than or equal to about 50% w/w, or less than or equal to about 45% w/w of the total weight of the liquid formulation.
  • the combined weight percentage of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin and any carrageenan present in the liquid formulation is less than or equal to about 20% w/w, less than or equal to about 15%, less than or equal to about 10% w/w, or less than or equal to about 5% w/w of the total weight of the liquid formulation.
  • the combined weight percentage of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin and any carrageenan present in the liquid formulation is about 2-60% w/w, about 2-55% w/w, about 2-54% w/w, about 2-50% w/w, about 2-45% w/w, about 2-40% w/w, about 2-36% w/w, about 2-35% w/w, about 2- 30% w/w, about 2-27% w/w, about 2-25% w/w, about 2-22% w/w, about 2-20% w/w, about 2-17% w/w, about 2-15% w/w, about 2-12% w/w, about 2-10% w/w, about 2-7% w/w, about
  • the combined weight percentage of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin and any carrageenan present in the liquid formulation is about 2-60% w/w, about 2-54% w/w, or about 2-50% w/w of the total weight of the liquid formulation. In certain other embodiments, the combined weight percentage of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin and any carrageenan present in the liquid formulation is about 2-20% w/w, about 3.5-20% w/w, or about 4.5-15% w/w of the total weight of the liquid formulation.
  • the liquid formulation comprises two of pectin, carrageenan, and alginic acid or a pharmaceutically acceptable salt thereof
  • the combined weight percentage of the two of alginic acid or a pharmaceutically acceptable salt thereof, pectin and carrageenan present in the liquid formulation is about 2-40% w/w, about 2-36% w/w, or about 2-30% w/w of the total weight of the liquid formulation.
  • liquid formulations comprising: at least two of pectin, carrageenan, and alginic acid or a pharmaceutically acceptable salt thereof; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin and any carrageenan present in the liquid formulation is about 2-60% w/w of the total weight of the liquid formulation.
  • each of any pectin, any carrageenan, and any alginic acid or a pharmaceutically acceptable salt thereof, if present, is independently present at less than or equal to 18% w/w of the total weight of the liquid formulation.
  • each of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin, or any carrageenan, if present is independently present at 0.5-18% w/w of the total weight of the liquid formulation. In certain other embodiments, each of any alginic acid or a pharmaceutically acceptable salt thereof, any pectin, or any carrageenan, if present, is independently present at 1-18% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising alginic acid or a pharmaceutically acceptable salt thereof; pectin; at least one pharmaceutically active ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and pectin present in the liquid formulation is about 2-40% w/w of the total weight of the liquid formulation.
  • each of pectin, carrageenan, and alginic acid or a pharmaceutically acceptable salt thereof, if present is present at less than or equal to 18% w/w of the total weight of the liquid formulation.
  • liquid formulations comprising alginic acid or a pharmaceutically acceptable salt thereof; carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and carrageenan present in the liquid formulation is about 2-36% w/w of the total weight of the liquid formulation.
  • liquid formulations comprising alginic acid or a pharmaceutically acceptable salt thereof; pectin; carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, pectin and carrageenan present in the liquid formulation is about 2-54% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 0.5-18% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 0.5-18% w/w pectin, 0.5-18% w/w carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, pectin, and carrageenan present in the liquid formulation is about 2-54% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1-18% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 1-18% w/w pectin, 1- 18% w/w carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, pectin, and carrageenan present in the liquid formulation is about 2-54% w/w of the total weight of the liquid formulation.
  • liquid formulations comprising about 1-18% w/w alginic acid or a pharmaceutically acceptable salt thereof; about
  • the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and pectin present in the liquid formulation is about 2-40% w/w of the total weight of the liquid formulation. In certain embodiments, the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and pectin present in the liquid formulation is about
  • the present disclosure provides liquid formulations comprising about 1-18% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 1-18% w/w carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and carrageenan present in the liquid formulation is about 2-40% w/w of the total weight of the liquid formulation. In certain embodiments, the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and carrageenan present in the liquid formulation is about 2-36% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1-18% w/w pectin; about 1-18% w/w carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of pectin and carrageenan present in the liquid formulation is about 2-40% w/w of the total weight of the liquid formulation. In certain embodiments, the combined weight percentage of pectin and carrageenan present in the liquid formulation is about 2-36% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1-18% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 1-10% w/w pectin, carrageenan, or a combination thereof; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, any pectin, and any carrageenan present in the liquid formulation is about 3.5-20% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1- 18% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 1-10% w/w pectin; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and pectin present in the liquid formulation is about 3.5-20% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1- 18% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 1-10% w/w carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and carrageenan present in the liquid formulation is about 3.5-20% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1-18% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 1-10% w/w a combination of pectin and carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, pectin, and carrageenan present in the liquid formulation is about 3.5-20% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1-8% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 3.5-10% w/w pectin, carrageenan, or a combination thereof; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, any pectin, and any carrageenan present in the liquid formulation is about 4.5-15% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1- 8% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 3.5-10% w/w pectin; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and pectin present in the liquid formulation is about 4.5-15% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1- 8% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 3.5-10% w/w carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof and carrageenan present in the liquid formulation is about 4.5-15% w/w of the total weight of the liquid formulation.
  • the present disclosure provides liquid formulations comprising about 1-8% w/w alginic acid or a pharmaceutically acceptable salt thereof; about 3.5-10% w/w a combination of pectin and carrageenan; at least one active pharmaceutical ingredient; and water, wherein the combined weight percentage of alginic acid or a pharmaceutically acceptable salt thereof, pectin, and carrageenan present in the liquid formulation is about 4.5-15% w/w of the total weight of the liquid formulation.
  • the quantities of pectin and carrageenan may be described in relative terms to one another, such as in a weight ratio.
  • the liquid formulation has a ratio of pectin-to-carrageenan of about 10-to-l, about 7-to-l, about 5-to-l, about 2-to-l, about 1-to-l, about l-to-2, about l-to-5, about l-to-7, or about l-to-10.
  • the liquid formulation has a ratio of pectin-to-carrageenan between about 10-to-l and about l-to- 10.
  • the liquid formulation has a ratio of pectin-to-carrageenan between about 5-to-l and about l-to-5.
  • the liquid formulation comprises at least one active pharmaceutical ingredient.
  • the liquid formulations of the present disclosure may be used as general delivery vehicles for many different classes of active pharmaceutical ingredients and, consequently, may be used for the treatment of various disorders, such as cold and cough.
  • Many commercially available treatments for cough and cold employ various active pharmaceutical ingredients to treat the symptoms associated with cough and cold, including actives such as but not limited to expectorants, cough suppressants, decongestants and/or analgesics. It should be recognized that, depending upon the disorder and/or symptoms to be treated, any suitable active pharmaceutical ingredient or any combinations of suitable active pharmaceutical ingredients may be utilized in the liquid formulations provided herein.
  • the liquid formulations described herein comprise at least one active pharmaceutical ingredient.
  • Suitable active pharmaceutical ingredients may include but are not limited to analgesics, antacids, antihistamines, cough suppressants/antitussives, decongestants, expectorants, and demulcents, and any combinations thereof.
  • the at least one active pharmaceutical ingredient comprises an analgesic, a cough suppressant, a decongestant, or an expectorant, or any combinations thereof.
  • the at least one active pharmaceutical ingredient comprises dextromethorphan, guaifenesin, or phenylephrine or a pharmaceutically acceptable salt thereof (e.g., phenylephrine hydrochloride), pseudoephedrine or a pharmaceutically acceptable salt thereof (e.g., pseudoephedrine hydrochloride), brompheniramine or a pharmaceutically acceptable salt thereof (e.g., brompheniramine maleate), chlorpheniramine or a pharmaceutically acceptable salt thereof (e.g., chlorpheniramine maleate), diphenhydramine or a pharmaceutically acceptable salt thereof (e.g., diphenhydramine hydrochloride), doxylamine or a pharmaceutically acceptable salt thereof (e.g., doxylamine hydrochloride), acetaminophen, fexofenadine, loratadine, cetirizine, triprolidine or a pharmaceutically acceptable salt thereof (e.g., triprol
  • the at least one active pharmaceutical ingredient comprises ingredient comprises an antacid.
  • the antacid comprises calcium carbonate, magnesium carbonate, magnesium hydroxide, aluminum hydroxide, or any combination thereof.
  • the at least one antacid comprises calcium carbonate and magnesium hydroxide.
  • the liquid formulation comprises at least about 5% w/w, at least about 7% w/w, at least about 10% w/w, at least about 11% w/w, or at least about 12% w/w at least one active pharmaceutical ingredient. In certain embodiments, the liquid formulation comprises at least about 10% w/w at least one active pharmaceutical ingredient.
  • the liquid formulation comprises less than or equal to about 30% w/w, less than or equal to about 20% w/w, less than or equal to about 17% w/w, less than or equal to about 15% w/w, less than or equal to about 14% w/w, less than or equal to about 13% w/w, or less than or equal to about 12% w/w at least one active pharmaceutical ingredient. In certain other embodiments, the liquid formulation comprises less than or equal to about 20% w/w at least one active pharmaceutical ingredient.
  • the liquid formulation comprises about 5-20% w/w, about 5-17% w/w, about 5-15% w/w, about 5-14% w/w, about 5-13% w/w, about 5-12% w/w, about 5-11% w/w, about 5-10% w/w, about 5-7% w/w, about 7-20% w/w, about 7-17% w/w, about 7-15% w/w, about 7-14% w/w, about 7- 13% w/w, about 7-12% w/w, about 7-11% w/w, about 7-10% w/w, about 10-20% w/w, about 10-17% w/w, about 10-15% w/w, about 10-14% w/w, about 10-13% w/w, about 10-12% w/w, about 10-11% w/w, about 11-20% w/w, about 11-17% w/w, about 11-15% w/w, about 11-14%
  • the liquid formulations of the present disclosure are liquid formulations containing water.
  • the liquid formulations comprise water. More specifically, the liquid formulations of the present disclosure include waterbased suspensions.
  • the liquid formulation comprises at least about 50 % w/w, at least about 60 % w/w, at least about 70% w/w, at least about 72% w/w, at least about 75% w/w, at least about 77% w/w, at least about 80% w/w water. In other embodiments, the liquid formulation comprises less than or equal to about 85% w/w, less than or equal to about 82% w/w, less than or equal to about 80% w/w, less than or equal to about 77%, less than or equal to about 75% w/w, or less than or equal to about 72% w/w water.
  • the liquid formulation comprises about 70-85% w/w, about 70-82% w/w, about 70-80% w/w, about 70-77% w/w, about 70-75% w/w, about 70-72% w/w, about 72-85% w/w, about 72- 82% w/w, about 72-80% w/w, about 72-77% w/w, about 72-75% w/w, about 75-85% w/w, about 75-82% w/w, about 75-80% w/w, about 75-77% w/w, about 77-85% w/w, about 77- 82% w/w, about 77-80% w/w, about 80-85% w/w, about 80-82% w/w, or about 82-85% w/w water.
  • the liquid formulation comprises about 70-82% w/w water.
  • the liquid formulations of the present disclosure may also comprise one or more additional solvents.
  • the liquid formulations of the present disclosure may also comprise one or more additional solvents, wherein the one or more additional solvents are ethanol, propyl glycol, glycerin, or any combinations thereof.
  • the one or more additional solvents are present in the liquid formulation at less than or equal to about 20% w/w, less than or equal to about 15% w/w, less than or equal to about 10% w/w, less than or equal to about 7% w/w, less than or equal to about 5% w/w, less than or equal to about 2% or less than or equal to about 1% w/w of the total weight of the liquid formulation.
  • the one or more additional solvents are present in the liquid formulation at greater than or equal to about 0.5% w/w, greater than or equal to about 1% w/w, greater than or equal to about 2% w/w, greater than or equal to about 5% w/w, greater than or equal to about 7% w/w, greater than or equal to about 10% w/w, greater than or equal to about 12% w/w, or greater than or equal to about 15% w/w of the total weight of the liquid formulation.
  • the liquid formulation comprises about 0-20% w/w, about 0-15% w/w, about 0-10% w/w, about 0-5% w/w, about 1-20% w/w, about 1-15% w/w, about 1-10% w/w, or about 1-5% w/w one or more additional solvents by total weight of the liquid formulation. In certain embodiments, the liquid formulation comprises about 0-10% w/w one or more additional solvents by total weight of the liquid formulation.
  • liquid formulations of the present disclosure which comprise alginic acid or a pharmaceutically acceptable salt thereof, at least one of pectin and carrageenan, at least one active pharmaceutical ingredient and water, may further comprise one or more additional pharmaceutically acceptable excipients.
  • the liquid formulations of the present disclosure may comprise viscosity -modifying agents, in addition to alginic acid, pectin and carrageenan, such as various gums, including but not limited to guar gum, gellan gum, gum Arabic, xanthum gum, and locust bean gum, starch and starch derivatives, and gelatin.
  • viscosity-modifying agents are incorporated in addition to the principal components of alginic acid or a pharmaceutically acceptable salt thereof, pectin and carrageenan, which serve as the primary components conferring the observed mucoadhesive properties to the liquid formulations herein.
  • the liquid formulation may comprise less than or equal to 1.5% w/w, less than or equal to about 1% w/w, less than or equal to about 0.5% w/w, less than or equal to about 0.2% w/w, less than or equal to about 0.1% w/w, less than or equal to about 0.05%, or less than or equal to about 0.02% w/w viscosity -modifying agents.
  • the liquid formulations provided herein may contain one or more pH modifying agents.
  • the liquid formulation further comprises one or more preservatives and/or one or more flavorants.
  • the liquid formulation comprises one or more sweeteners.
  • the one or more sweeteners comprises sugar or an artificial sweetener, such as sucralose.
  • the liquid formulation s one or more flavorants.
  • the one or more flavorants comprises chocolate flavor or mint flavor.
  • the liquid formulation comprises one or more preservatives.
  • Suitable preservatives may include but are not limited to sodium benzoate, benzyl alcohol, methyl paraben, propyl paraben, and edetate sodium.
  • the liquid formulations of the present disclosure may not include cellulosic polymers, such as hypromellose, hydroxypropylcellulose, hydroxymethylcellulose.
  • the liquid formulations provided herein may not include a surfactant.
  • liquid formulations of the present disclosure were found to exhibit exemplary properties suitable for the treatment of various cough and cold disorders.
  • the liquid formulations provided herein may be described or characterized by these properties, which may include but are not limited to pH, mucoadhesion, viscosity, and storage stability.
  • the liquid formulations of the present disclosure may be characterized by their pH values. Due to their intended route of administration, the liquid formulations provided herein are preferably maintained within suitable pH range to avoid irritation to the digestive tract of the person consuming the liquid formulation. Below pH 5.5 or above pH 9.5, a liquid formulation may also cause irritation of the mouth, throat, esophagus and/or stomach and result in immense discomfort to the end consumer. [0078] In some embodiments, the liquid formulation has a pH of at least about pH 5.5, at least about pH 6, at least about pH 6.5, or at least about pH 7.
  • the liquid formulation has a pH greater than or equal to about pH 7, greater than or equal to about pH 7.5, greater than or equal to about pH 8, greater than or equal to about pH 8.5, or greater than or equal to about pH 9. In certain other embodiments, the liquid formulation has a pH less than or equal to pH 9.5, less than or equal to pH 9, less than or equal to pH 8.5, less than or equal to pH 8, or less than or equal to pH 7.5. In other embodiments, the liquid formulation has a pH of between about pH 5.5 and about pH 9.5 or between about pH 7 and about pH 9.5.
  • the liquid formulations of the present aspect may contain one or more active pharmaceutical ingredients or excipients that influence the acidity or basicity of the liquid formulation.
  • the formulations of the present disclosure may include ingredients or excipients that modulate the pH of the formulation in view of the specific acidity or alkalinity of any active ingredients or excipients utilized.
  • the liquid formulations provided herein may contain one or more pH modifying agents.
  • the liquid formulations as described herein may be characterized by their ability to adhere to mucous membranes. Their mucoadhesiveness may be evaluated by various in vitro methods, for example, employing biologically simulated conditions (tripe with saliva/saline) or a proxy for a mucosal surface, such as a plastic tray or attachment.
  • a polyethylene attachment attached to a texture analyzer is dipped into a sample of the liquid formulation to be tested in five separate trials (or dips). The quantity of sample retained on the polyethylene attachment after each trial is recorded. The amount of the liquid formulation removed from the initial sample is used to calculate the percentage of formulation adhered to (and retained by) the polyethylene attachment after five dips and, thus, provide a measure of bioadhesion.
  • the liquid formulation has a bioadhesion of at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9% or at least about 10%, at least about 12%, at least about 14%, at least about 16%, at least about 18%, at least about 20%, at least about 25%, at least about 30% or at least about 35% as determined by the in vitro bioadhesion test using a texture analyzer described herein.
  • the liquid formulation has bioadhesion of at least about 10% as determined by the in vitro bioadhesion test using a texture analyzer described herein.
  • the liquid formulation has a bioadhesion of less than or equal to about 50%, less than or equal to about 45%, less than or equal to about 40%, less than or equal to about 37%, less than or equal to about 35%, less than or equal to about 32%, or less than or equal to about 30% as determined by the in vitro bioadhesion test using a texture analyzer described herein.
  • the liquid formulation has a bioadhesion of between about 4% and about 50%, between about 4% and about 45%, between about 4% and about 40%, between about 4% and about 37%, between about 4% and about 35%, between about 4% and about 32%, between about 4% and about 30%, between about 5% and about 50%, between about 5% and about 45%, between about 5% and about 40%, between about 5% and about 37%, between about 5% and about 35%, between about 5% and about 32%, between about 5% and about 30%, between about 7% and about 50%, between about 7% and about 45%, between about 7% and about 40%, between about 7% and about 37%, between about 7% and about 35%, between about 7% and about 32%, between about 7% and about 30%, between about 10% and about 50%, between about 10% and about 45%, between about 10% and about 40%, between about 10% and about 37%, between about 10% and about 35%, between about 10% and about 32%, between about 10% and about 30%, between about 10% and about 50%, between about
  • the liquid formulations of the present disclosure may be characterized by their mucoadhesion as determined by the mucoadhesion test using tripe as described herein.
  • the adhesiveness of the liquid formulations provided herein are assessed with respect to a biological membrane (tripe).
  • a fixed quantity of the liquid formulation to be tested is applied to a sample of tripe having a known weight (uncoated tripe).
  • the coated tripe sample is then washed with controlled volumes of artificial saliva solution (e.g., 1.5 mL per rinse), and the weight of the coated tripe sample is measured after each rinse to determine the amount of liquid formulation retained by the sample after each rinse.
  • the percentage of liquid formulation retained by the tripe is calculated as a percentage of the total weight of the uncoated tripe sample.
  • the mucoadhesion of the liquid formulation to the tripe samples may be characterized by either the number of rinses required to wash away formulation such that the weight of the tripe sample is approximately the same as the original uncoated weight, or alternatively by the weight of formulation retained on the tripe sample after a fixed number of rinses, e.g., 10 rinses.
  • the liquid formulation has a mucoadhesion of at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 7%, at least about 10%, or at least about 12% as determined by the mucoadhesion test with tripe described herein. In certain embodiments, the liquid formulation has a mucoadhesion of at least about 2% as determined by the mucoadhesion test with tripe described herein.
  • the liquid formulation has a mucoadhesion of less than or equal to about 20%, less than or equal to about 17%, less than or equal to about 15%, less than or equal to about 12%, or less than or equal to about 10%, as determined by the mucoadhesion test with tripe described herein. In certain embodiments, the liquid formulation has a mucoadhesion of less than or equal to about 20% as determined by the mucoadhesion test with tripe described herein.
  • the liquid formulation has a mucoadhesion of between about 2% and about 20%, between about 2% and about 17%, between about 2% and about 15%, between about 2% and about 12%, between about 2% and about 10%, between about 4% and about 20%, between about 4% and about 17%, between about 4% and about 15%, between about 4% and about 12%, between about 4% and about 10%, between about 5% and about 20%, between about 5% and about 17%, between about 5% and about 15%, between about 5% and about 12%, between about 5% and about 10%, between about 7% and about 20%, between about 7% and about 17%, between about 7% and about 15%, between about 7% and about 12%, between about 7% and about 10%, between about 10% and about 20%, between about 10% and about 17%, between about 10% and about 15%, between about 10% and about 12%, between about 12% and about 20%, between about 10% and about 17%, between about 10% and about 15%, between about 10% and about 12%, between about 12% and about 20%, between about 10% and
  • the liquid formulations of the present disclosure may be characterized by their mucoadhesion as determined by the surface adhesion test described herein.
  • the adhesiveness of the liquid formulations provided herein are assessed with respect to the extent of sample migration observed when the samples are monitored on a plastic tray angled at a 45° tilt.
  • the protocol for the surface adhesion test in brief, is as follows: A fixed quantity of each liquid formulation to be tested is applied to a plastic sample tray held horizontal (parallel to the floor). The liquid formulations are applied to the tray as single circular masses along one edge of the plastic tray, in which the centers of each circular mass are equidistant from the central rotational axis of the tray.
  • the tray is subsequently tilted at a 45° angle so that the end of the tray at which the liquid formulations were applied is elevated.
  • the tray is held at the 45° tilt for 30 seconds.
  • gravity causes less mucoadhesive samples to migrate down the tray in a linear path, whereas more mucoadhesive formulations are expected migrate to a lesser extent or not at all.
  • the tray is reverted back to its horizontal position and the distance migrated by each sample is recorded. The distance traveled may be measured as the distance between the initial edge of the liquid formulation closest to the central rotational axis at the prior to being tilted and the edge of the liquid formulation sample farthest from the initial position after being held at 45° tilt for 30 seconds.
  • the distance migrated by the liquid formulations as determined by the surface adhesion test may be described in any suitable unit of length, such as inches, centimeters, or millimeters.
  • the liquid formulations provided herein have a migration of less than or equal to about 2.5 inches, less than or equal to about 2 inches, less than or equal to 1.5 inches, less than or equal to 1 inch, less than or equal to 0.5 inches, or less than or equal to about 0.2 inches as determined by the surface adhesion test.
  • the liquid formulations provided herein have a migration of less than or equal to about 6 cm, less than or equal to about 5.5 cm, less than or equal to about 5 cm, less than or equal to about 4.5 cm, less than or equal to about 4 cm, less than or equal to about 3.5 cm, less than or equal to about 3 cm, less than or equal to about 2.5 cm, less than or equal to about 2 cm, less than or equal to about 1.5 cm, less than or equal to about 1 cm, or less than or equal to about 0.5 cm.
  • the liquid formulations provided herein may not exhibit any discernible or measurable migration. In some embodiments, the liquid formulation has a negligible migration.
  • the liquid formulations comprising alginic acid or a pharmaceutically acceptable salt thereof, in combination with pectin and/or carrageenan may be further characterized by their viscosity and/or thixotropic behavior.
  • the liquid formulations of the present disclosure demonstrate viscosity reflective of their mucoadhesiveness as well as their thixotropic behavior.
  • Thixotropy is a property of certain viscous fluids which exhibit a change in viscosity to become less viscous over time when exposed to agitation (such as stirring or shaking) or shear force.
  • Thixotropy which is also known as time-dependent shear thinning, may further reflect the ability of the liquid formulations described herein to flow during administration and provide even coating of administration but also to remain static and securely adhered to the mucosae once administered.
  • the thixotropic behavior achieved in the liquid formulations of the present disclosure enables the liquid formulations to provide a long-lasting but uniformly distributed coating to mucous membranes for short-term and longterm relief.
  • the liquid formulations provided herein may be characterized by their viscosities.
  • Viscosity (q, centipoise) of the liquid formulation as provided herein may be determined by viscosity testing methods known in the art including, for example, a three-interval thixotropy test.
  • a three-interval thixotropy test measures the time-dependent viscosity under different conditions of applied shear, including the viscosity at rest, the viscosity during application or administration (e.g., shear thinning behavior), and the viscosity after application or administration (e.g., hysteresis effects and structural recovery from applied forces).
  • a liquid sample is subjected to shear force applied by a rotational rheometer at three discrete intervals of shear speed or rate (y, s' 1 ), with a constant shear stress (T, pascal) for a defined period of time (e.g., two minutes): (1) low shear rate (such as 1/s), (2) high shear rate (such as 1000/s); and (3) low shear rate (identical to shear rate of the first interval).
  • T constant shear stress
  • the liquid sample is subject to three intervals of shear stress: (1) low shear stress, (2) high shear stress; and (3) low shear stress. It should be recognized that additional parameters for the operation of the rheometer and for the measurement may be specified, including cone plate diameter, active length, position length, trim position, and torsional com.
  • the viscosity of the liquid formulation may be characterized by the initial viscosity (measured at the start of the first interval at low shear) and/or the recovery viscosity (measured at the end of the third interval at low shear).
  • the liquid formulation has an initial viscosity of at least about 1000 centipoise (cP), at least about 2500 cP, at least about 5000 cP, or at least about 10000 cP as determined by the three-interval thixotropy test described herein. In certain embodiments, the liquid formulation has an initial viscosity of at least about 1000 centipoise (cP) as determined by the three-interval thixotropy test described herein.
  • the liquid formulation has an initial viscosity of less than or equal to about 25000 cP, less than or equal to about 20000 cP, less than or equal to about 15000 cP, or less than or equal to about 10000 cP as determined by the three-interval thixotropy test described herein. In certain embodiments, the liquid formulation has an initial viscosity of less than or equal to about 20000 cP as determined by the three-interval thixotropy test described herein. In still other embodiments, the liquid formulation has an initial viscosity of between about 1000 cP and about 25000 cP, between about 1000 cP and about 20000 cP, between about
  • the liquid formulation has a recovery viscosity of at least about 1000 centipoise (cP), at least about 2000 cP, at least about 5000 cP, or at least about 7500 cP as determined by the three-interval thixotropy test described herein. In certain embodiments, the liquid formulation has a recovery viscosity of at least about 1000 centipoise (cP) as determined by the three-interval thixotropy test described herein.
  • the liquid formulation has a recovery viscosity of less than or equal to about 15000 cP, less than or equal to about 12000 cP, less than or equal to about 10000 cP, or less than or equal to about 7500 cP as determined by the three-interval thixotropy test described herein. In certain embodiments, the liquid formulation has a recovery viscosity of less than or equal to about 15000 cP as determined by the three-interval thixotropy test described herein.
  • the liquid formulation has a recovery viscosity of between about 1000 cP and about 15000 cP, between about 1000 cP and about 12000 cP, between about 1000 cP and about 10000 cP, between about 1000 cP and about 7500 cP, between about 2000 cP and about 15000 cP, between about 2000 cP and about 12000 cP, between about 2000 cP and about 10000 cP, between about 2000 cP and about 7500 cP, between about 5000 cP and about 15000 cP, between about 5000 cP and about 15000 cP, between about 5000 cP and about 10000 cP, between about 5000 cP and about 7500 cP, between about 7500 cP and about 15000 cP, between about 7500 cP and about 12000 cP, or between about 7500 cP and about 10000 cP as determined by the three-interval thixotropy test described herein.
  • the viscosity of the liquid formulation may be described as having an initial viscosity and a recovery viscosity.
  • the liquid formulation has an initial viscosity of between about 1000 cP and about 25000 cP, between about 1000 cP and about 20000 cP, between about 1000 cP and about 15000 cP, between about 1000 cP and about 10000 cP, between about 2500 cP and about 25000 cP, between about 2500 cP and about 20000 cP, between about 2500 cP and about 15000 cP, between about 2500 cP and about 10000 cP, between about 5000 cP and about 25000 cP, between about 5000 cP and about 20000 cP, between about 5000 cP and about 15000 cP, between about 5000 cP and about 10000 cP, between about 10000 cP and about 25000 cP, between about 10000 cP cP, between about 10000 cP and about 25
  • the liquid formulations described herein may be characterized by viscosity range, for example, as set by the initial viscosity and recovery viscosity as measured by the three-interval thixotropy test under a specified shear rate or specified shear stress.
  • the liquid formulation has a between about 1000 cP and about 25000 cP, between about 1000 cP and about 20000 cP, between about
  • the liquid formulation has a viscosity of between about 1000 centipoise (cP) and about 20000 cP as determined by the three-interval thixotropy test described herein.
  • the viscosity of the liquid formulation may be characterized by the thixotropy index, which is calculated as difference of the logarithm of the viscosity measured at low shear at the end of the third interval (e.g., after 360 seconds) and the logarithm of the viscosity measured at high shear the end of the second interval (e.g., after 240 seconds).
  • the thixotropy index provides a measure of how readily a liquid will flow during dispensing but will stay in place once dispensed.
  • the liquid formulations described herein may be characterized by any of the preceding metrics after storage.
  • the ability of the liquid formulations of the present disclosure not only to demonstrate the properties detailed above but to demonstrate them after storage, especially under extreme conditions, reflects the storage stability and overall shelf-life of the liquid formulations.
  • the storage stability of the liquid formulations provided herein is evaluated after storage at a specified time, temperature and/or humidity. In some embodiments, the storage stability of the liquid formulation is evaluated after storage at 25°C or storage at 40°C. In some embodiments, the storage stability of the liquid formulation is evaluated at no humidity, e.g. s isolated from external humidity, at ambient relative humidity, at 60% relative humidity or at 75% relative humidity. In other embodiments, storage stability of the liquid formulation is evaluated after 1 month of storage, after 3 months of storage, or after 6 months of storage. In certain embodiments, the storage stability of the liquid formulation is evaluated after 1 month of storage at 25°C and 60% relative humidity (RH). In certain other embodiments, the storage stability of the liquid formulation is evaluated after 1 month of storage at 40°C and no humidity. In still other embodiments, the storage stability of the liquid formulation is evaluated after 1 month of storage at 40°C and 75% relative humidity.
  • RH 60% relative humidity
  • the storage stability of the liquid formulations provided herein may be characterized by the bioadhesiveness or mucoadhesiveness of the liquid formulations after storage.
  • the liquid formulation has a bioadhesion of at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9% or at least about 10% as determined by the in vitro bioadhesion test using a texture analyzer as described herein after 1 month of storage at 40°C. In some embodiments, the liquid formulation has bioadhesion of at least about 4% as determined by the in vitro bioadhesion test using a texture analyzer described herein after 1 month of storage at 40°C.
  • the liquid formulation has a bioadhesion of less than or equal to about 20%, less than or equal to about 17%, less than or equal to about 15%, less than or equal to about 12%, or less than or equal to about 10% as determined by the in vitro bioadhesion test using a texture analyzer described herein after 1 month of storage at 40°C.
  • the liquid formulation has a bioadhesion of between about 4% and about 20%, between about 4% and about 17%, between about 4% and about 15%, between about 4% and about 12%, between about 4% and about 10%, between about 5% and about 20%, between about 5% and about 17%, between about 5% and about 15%, between about 5% and about 12%, between about 5% and about 10%, between about 7% and about 20%, between about 7% and about 17%, between about 7% and about 15%, between about 7% and about 12%, between about 7% and about 10%, between about 10% and about 20%, between about 10% and about 17%, between about 10% and about 15%, or between about 10% and about 12% as determined by the in vitro bioadhesion test using a texture analyzer described herein after 1 month of storage at 40°C.
  • the storage stability of the liquid formulations provided herein may be characterized by the viscosities of the liquid formulations after storage.
  • the storage stability of the liquid formulations may be evaluated by the three-interval thixotropy test as described above.
  • the viscosities of the liquid formulations may be evaluated after 1 month of storage at 40°C and at 75% relative humidity.
  • the liquid formulation has an initial viscosity of at least about 1000 centipoise (cP), at least about 2500 cP, at least about 5000 cP, or at least about 10000 cP as determined by the three-interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity. In certain embodiments, the liquid formulation has an initial viscosity of at least about 1000 centipoise (cP) as determined by the three- interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity.
  • cP centipoise
  • the liquid formulation has an initial viscosity of less than or equal to about 30000 cP, less than or equal to about 27000 cP, less than or equal to about 25000 cP, less than or equal to about 20000 cP, less than or equal to about 15000 cP, or less than or equal to about 10000 cP as determined by the three-interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity. In certain embodiments, the liquid formulation has an initial viscosity of less than or equal to about 20000 cP as determined by the three-interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity.
  • the liquid formulation has an initial viscosity of between about 1000 cP and about 30000 cP, between about 1000 cP and about 27000 cP, between about 1000 cP and about 25000 cP, between about 1000 cP and about 20000 cP, between about 1000 cP and about 15000 cP, between about 1000 cP and about 10000 cP, between about 2500 cP and about 25000 cP, between about 2500 cP and about 20000 cP, between about 2500 cP and about 15000 cP, between about 2500 cP and about 10000 cP, between about 5000 cP and about 25000 cP, between about 5000 cP and about 20000 cP, between about 5000 cP and about 15000 cP, between about 5000 cP and about 10000 cP, between about 10000 cP and about 25000 cP, between about 10000 cP and about 20000 cP, or between about 10
  • the liquid formulation has a recovery viscosity of at least about 1000 centipoise (cP), at least about 2000 cP, at least about 5000 cP, or at least about 7500 cP as determined by the three-interval thixotropy test described herein. In certain embodiments, the liquid formulation has a recovery viscosity of at least about 1000 centipoise (cP) as determined by the three-interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity.
  • cP centipoise
  • the liquid formulation has a recovery viscosity of less than or equal to about 15000 cP, less than or equal to about 12000 cP, less than or equal to about 10000 cP, or less than or equal to about 7500 cP as determined by the three-interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity. In certain embodiments, the liquid formulation has a recovery viscosity of less than or equal to about 15000 cP as determined by the three- interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity.
  • the liquid formulation has a recovery viscosity of between about 1000 cP and about 15000 cP, between about 1000 cP and about 12000 cP, between about 1000 cP and about 10000 cP, between about 1000 cP and about 7500 cP, between about 2000 cP and about 15000 cP, between about 2000 cP and about 12000 cP, between about 2000 cP and about 10000 cP, between about 2000 cP and about 7500 cP, between about 5000 cP and about 15000 cP, between about 5000 cP and about 15000 cP, between about 5000 cP and about 10000 cP, between about 5000 cP and about 7500 cP, between about 7500 cP and about 15000 cP, between about 7500 cP and about 12000 cP, or between about 7500 cP and about 10000 cP as determined by the three-interval thixotropy test described herein after 1
  • the viscosity of the liquid formulation may be described as having an initial viscosity and a recovery viscosity.
  • the liquid formulation has an initial viscosity of between about 1000 cP and about 30000 cP, between about 1000 cP and about 27000 cP, between about 1000 cP and about 25000 cP, between about 1000 cP and about 20000 cP, between about 1000 cP and about 15000 cP, between about 1000 cP and about 10000 cP, between about 2500 cP and about 25000 cP, between about 2500 cP and about 20000 cP, between about 2500 cP and about 15000 cP, between about 2500 cP and about 10000 cP, between about 5000 cP and about 25000 cP, between about 5000 cP and about 20000 cP, between about 5000 cP and about 15000 cP, between about 5000 cP and
  • liquid formulations described herein may be characterized by viscosity range, for example, as set by the initial viscosity and recovery viscosity as measured by the three-interval thixotropy test after storage.
  • the liquid formulation has a viscosity of between about 1000 cP and about 30000 cP, between about 1000 cP and about 27000 cP, between about 1000 cP and about 25000 cP, between about 1000 cP and about 20000 cP, between about 1000 cP and about 15000 cP, between about 1000 cP and about 10000 cP, between about 2500 cP and about 25000 cP, between about 2500 cP and about 20000 cP, between about 2500 cP and about 15000 cP, between about 2500 cP and about 10000 cP, between about 5000 cP and about 25000 cP, between about 5000 cP and about 20000 cP, between about 5000 cP and about 15000 cP, between about 5000 cP and about 10000 cP, between about 10000 cP and about 25000 cP, between about 10000 cP and about 20000 cP, or between about 10000
  • the liquid formulation has a viscosity of between about 1000 centipoise (cP) and about 30000 cP as determined by the three-interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity. In some embodiments, the liquid formulation has a viscosity of between 1000 cP and 27000 cP as measured by the controlled shear rate three- interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity.
  • cP centipoise
  • the liquid formulation has a viscosity of between 1000 cP and 27000 cP as measured by the controlled shear rate three- interval thixotropy test described herein after 1 month of storage at 40°C and at 75% relative humidity.
  • the liquid formulations of the present disclosure may be suspensions.
  • a suspension is a biphasic preparation consisting of solid particles dispersed throughout a liquid phase.
  • a common type of suspension contains solid particles of one or more active pharmaceutical ingredients and/or excipients suspended throughout a liquid medium of one or more solvents. It should be recognized when an ingredient is indicated as “in suspension” or “suspended”, at least a portion of the ingredient is undissolved in the primary liquid medium.
  • liquid formulations provided herein may be characterized by observations of their formulation stability or lack thereof following exposure to particular temperature and humidity conditions, such as set forth in a freeze-thaw cycling procedure according to the Handbook of Stability Testing in Pharmaceutical Development: Regulation, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer, November 2008, Chapter 2 (e.g., three cycles of (1) storage at -20°C for four days followed by (2) storage at 25°C, and 60% relative humidity (RH) for three days).
  • Formulation stability may be visually assessed, for example, by observation for any phase separation.
  • the liquid formulations provided herein do not exhibit phase separation after being subjected to freeze-thaw cycling. In other embodiments, the liquid formulations provided herein exhibit phase separation after being subjected to a freezethaw cycling. In certain embodiments wherein the liquid formulations exhibit phase separation after being subjected to a freeze-thaw cycling, the liquid formulations may be resuspended or re-dispersed by shaking.
  • the method comprises: (a) combining at least one active pharmaceutical ingredient, alginic acid or a pharmaceutically acceptable salt thereof, at least one of pectin and carrageenan; and water to provide a mixture; (b) optionally adding one or more additional pharmaceutically acceptable excipients to the mixture of step (a); and (c) stirring the mixture to provide the liquid formulation.
  • the active pharmaceutical ingredients, excipients, or any mixtures thereof used to prepare the suspensions can be subjected to heating, stirring, or homogenization in order to improve dispersion and/or reduce particle size.
  • the active pharmaceutical ingredient(s) and/or excipients may be homogenized using a 20 mesh sieve, e.g., to a particle size less than or equal to about 850 pm.
  • the processing conditions of the methods and steps as described herein including, but not limited to, temperature, mixing times, and stir rates (rpm) may adjusted.
  • the step (a) of combining comprises homogenizing the at least one active pharmaceutical ingredient, alginic acid or a pharmaceutically acceptable salt thereof, at least one of pectin and carrageenan; and water to reduce the particle size of the at least one active pharmaceutical ingredient, alginic acid or a pharmaceutically acceptable salt thereof, at least one of pectin and carrageenan.
  • the step (b) of optionally adding one or more additional pharmaceutically acceptable excipients comprises adding one or more flavorants to the mixture of step (a).
  • any of the steps of the present methods are preferably performed under agitation to ensure uniformity and even distribution of the mixtures and suspensions generated.
  • agitation includes mixing or stirring.
  • the agitation is continuous or intermittent.
  • the steps of the present methods are performed in one or more reactors capable of agitating the mixtures and suspensions described herein.
  • active ingredients and excipients in the suspension may be combined in, added to, heated in, cooled in, or stored in such a reactor or reactors.
  • Exemplary disorders of the present disclosure may include but are not limited to cough or barking cough (croup or laryngotracheobronchitis), itchy throat, throat pain, irritation of the throat, swelling of the throat, redness of the throat, dysphagia (difficulty swallowing), xerostomia (dry mouth and/or throat), paroxysmal pertussis, etc.
  • the present disclosure provides a method for treating cough, comprising administering to a human in need thereof a liquid formulation as described herein.
  • the present disclosure provides a method for treating barking cough (croup or laryngotracheobronchitis), comprising administering to a human in need thereof a liquid formulation as described herein.
  • the liquid formulation is administered once, twice, three times or four times daily. In certain embodiments, the liquid formulation is administered once or twice daily. It should be recognized that the number of times the liquid formulation is administered daily may depend upon the amount to be administered per dose. In some embodiments, the liquid formulation is administered at a dosage of about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, or about 30 mL.
  • the liquid formulation is administered at a dosage of between about 5 mL and about 30 mL, between about 5 mL and about 25 mL, between about 5 mL and about 20 mL, between about 5 mL and about 15 mL, between about 5 mL and about 10 mL, between about 10 mL and about 30 mL, between about 10 mL and about 25 mL, between about 10 mL and about 20 mL, between about 10 mL and about 15 mL, between about 15 mL and about 30 mL, between about 15 mL and about 25 mL, or between about 15 mL and about 20 mL.
  • a method for treating cold symptoms comprising administering to a human in need thereof a liquid formulation as described herein.
  • an article of manufacture such as a container comprising the liquid formulations as described herein, and a label containing instructions for use of the liquid formulations.
  • the container is a bottle.
  • kits comprising the liquid formulations as described herein; and a package insert containing instructions for use of such liquid formulations.
  • the instructions for use of the liquid formulations may include instructions for dosage amount and/or frequency of administration, for treating various cold and cough-related disorders.
  • the instructions for use of the liquid formulations comprise instructions for dosage amount and/or frequency for the treatment of cold or cough, such as barking cough.
  • the present example details the preparation of an exemplary liquid oral formulation according to the present disclosure.
  • Table 1 details ingredients and theoretical amounts to be combined for an exemplary formulation.
  • the present example describes the composition of various formulations prepared in accordance with the present disclosure as compared to four comparable commercially available suspension formulations.
  • liquid formulations evaluated in the present example included four commercially available products — Comparative Formulations #1-4 — and four formulations as provided in the present disclosure — Formulations #1-4.
  • the compositions of the liquid formulations are shown in Tables 2-5.
  • Comparative Formulation #1 contained alginate but no pectin or carrageenan. Comparative Formulation #3 similarly contained alginate but did not contain any pectin and carrageenan. Comparative Formulation #2 contained alginate at a level of lOOOmg per dose, and a carbomer at an unknown level.
  • the present example describes two in vitro bioadhesion tests of formulations as provided herein to evaluate their ability to adhere to surfaces and, more specifically, to mucous membranes.
  • the liquid formulations evaluated in the present example Comparative Formulation #2, Comparative Formulation #3, Formulation #1 and Formulation #2 — were the same as the liquid formulations evaluated in Example 2 above.
  • the adhesive properties of the liquid formulations were assessed with respect to their ability adhere to a polyethylene probe.
  • the liquid formulations were assessed with respect to their abilities to adhere to a biological membrane (tripe).
  • formulations were evaluated for their ability to an angled surface under the force of gravity.
  • FIG. 1A depicts an exemplary apparatus for conducting the bioadhesion test of the present example.
  • FIG. IB shows an photograph of the polyethylene attachment. The polyethylene attachment was mechanically dipped into the beaker containing the sample and allowed to remain stationary for 10 seconds. After 10 seconds had elapsed, the texture analyzer arm was adjusted so that the polyethylene attachment was removed from contact with the sample.
  • the polyethylene attachment was allowed to remain stationary for an additional period of 10-15 seconds to allow for any excess sample to drop.
  • the polyethylene attachment was then removed from the texture analyzer arm and weighed to determine the combined final weight of the polyethylene attachment and sample adhered to attachment.
  • Each sample beaker was subjected to a total of five trials (dips). After five trials, the final weight of the sample remaining in the beaker was measured, and the percentage of sample retained by the polyethylene attachment (that is, removed from the sample beaker) was calculated.
  • Table 6, Table 7, and Table 8 show the bioadhesion results for the four formulations tested, as represented by the amount of sample retained on the texture analyzer polyethylene attachment after each trial (Table 6 and Table 7) and by the total amount of sample retained (removed from the sample container by the attachment) after the five trials (Table 8).
  • bovine stomach reticulum region, commercially sourced
  • the bovine reticulum, or tripe was employed as a surrogate mucous membrane for a human stomach.
  • tripe samples 2” by 2” squares of tripe were excised from the initial reticulum stock. Each square section was thawed in commercially available artificial human saliva (potassium salt (e.g., potassium chloride or potassium hydrogen phosphate), sodium chloride, calcium chloride, sodium hydroxide (for pH adjustment)) for 1 hour prior to use.
  • the tripe samples were gently pat dried to remove excess saliva solution and weighed in a tared polyethylene bottle with a cap to record the initial sample weights (uncoated tripe).
  • the present example describes tests to determine the thixotropic behavior of the liquid formulations provided herein.
  • the viscosity and thixotropy measurements were carried out on a cone-plate rotational rheometer (Anton Paar MCR 302; Position length (mm) 100; Trim Position (pm) 25; Torsional Com (rad.Nm) 0.001025). Each formulation was subjected to a controlled shear rate three-interval thixotropy measurement as described herein to measure initial and recovery viscosity values (in centipoise).
  • each sample was subjected to three-intervals of controlled shear rate, including a first interval at a low shear rate (1/s), a second interval at a high shear rate (1000/s) and a third interval at the same low shear rate as the first interval (1/s).
  • the shear rate was held for each interval for a duration of 2 minutes (120 seconds).
  • the viscosity was recorded at the start of the first interval (initial) and at the end of the third interval (recovery).
  • the liquid formulations were evaluated both after initial preparation and after storage at 40°C for 1 month to observe changes in thixotropic behavior. The results from the three-interval thixotropy test are shown in Table 14 below.
  • Comparative Formulation #2 demonstrated a similar initial viscosity to that of Formulation #4 but did not recover to its initial viscosity, whereas Formulation #4 did.
  • Formulations #1-3 increased in initial and recovery viscosities measured as compared to their initial and recovery viscosities observed immediately after preparation.
  • Comparative Formulation #3 and Comparative Formulation #2 exhibited a reduction in their initial and recovery viscosities after storage relative to the viscosities observed before storage.
  • Example 2 for physical stability after storage at 40°C and 7% relative humidity for 1 month and after freeze-thaw cycling to assess each formulation s stability to extreme temperature conditions.
  • FIGS. 3A and 3C Samples of the liquid formulations to be tested were placed in clear glass wide- mouth jars and sealed, as shown in FIGS. 3A and 3C.
  • the sealed jars were stored at 40°C, 75% relative humidity, for 1 month, undisturbed. After 1 month, the samples in the jars were visually assessed for any apparent phase separation, in FIGS. 3B and 3D. As shown in FIGS. 3B and 3D, phase separation was observed in Formulations #2-4 after storage. However, the liquid formulations were readily re-dispersed to form suspensions upon shaking.
  • FIG. 4A shows the four samples prior to undergoing freeze-thaw cycling. Each sample was subjected to three freeze-thaw cycles, in which each cycle involved storage at -20°C for 4 days followed by storage at 20°C and 60% relative humidity (%RH) for 3 days, for a total duration of 21 days (three cycles). After the three freeze-thaw cycles, each sample formulation was visually assessed in the sealed scintillation vial for any sign of phase separation. None of the tested formulations (Formulations #1-4) exhibited any phase separation after freeze-thaw cycling as shown in FIG. 4B.
  • the present example details the evaluation of various liquid oral antacid formulations prepared in accordance with the disclosure herein.
  • the quantities of sodium alginate, pectin, and carrageenan were varied in each formulation to assess and compare any changes in pH and bioadhesion as a result of the differing quantities of these three components.
  • the compositions for various formulations evaluated in this example are described in Table 15, Table 16 and Table 17 below. Comparative Formulations #1-3, Formulations #1-2 and Formulation#4 (as detailed in Example 2) were included in the comparison.
  • Formulations#8-10 were prepared with alginate levels ranging from 300 mg per dose to 500 mg per dose, and a 1-to-l ratio of pectin-to-carrageenan (90 mg or 225 mg).
  • Formulations #4, #11, #12 and #13 were prepared with a fixed alginate content of 300 mg per dose and either no pectin (Formulation #4) or varied ratios of pectin-to-carrageenan (approximately l-to-5, 5-to-l and 1-to-l) (Formulations #11-13). With a decrease in carrageenan (at the 5-to-l ratio, Formulation #12), the bioadhesiveness was observed to be slightly higher than that of the l-to-5 ratio formulation (Formulation #11).
  • the present example details the preparation of an exemplary liquid oral formulation according to the present disclosure.
  • Tables 19-21 detail ingredients and theoretical amounts to be combined for exemplary formulations comprising dextromethorphan.

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Abstract

La présente invention concerne de manière générale des formulations liquides en tant que plateforme d'administration générale pour des ingrédients pharmaceutiques actifs, et plus spécifiquement des formulations liquides orales comprenant de l'acide alginique ou des sels pharmaceutiquement acceptables de celui-ci, de la pectine et/ou du carraghénane pour le traitement de la toux et du rhume. La présente invention concerne également des procédés d'utilisation des formulations décrites dans la description pour le traitement de la toux et du rhume.
PCT/US2022/039721 2021-08-10 2022-08-08 Formulations liquides comprenant de l'acide alginique, de la pectine et du carraghénane et leurs procédés d'utilisation WO2023018661A1 (fr)

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