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WO2025128724A1 - Sels inorganiques revêtus et leurs utilisations - Google Patents

Sels inorganiques revêtus et leurs utilisations Download PDF

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Publication number
WO2025128724A1
WO2025128724A1 PCT/US2024/059606 US2024059606W WO2025128724A1 WO 2025128724 A1 WO2025128724 A1 WO 2025128724A1 US 2024059606 W US2024059606 W US 2024059606W WO 2025128724 A1 WO2025128724 A1 WO 2025128724A1
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WIPO (PCT)
Prior art keywords
salt
inorganic salt
coated
composition
granules
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English (en)
Inventor
Hemant N. Joshi
Craig ARONCHICK
Gerald BERTIGER
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Arbert LLC
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Arbert LLC
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin

Definitions

  • This patent document relates to coated salts. Also disclosed herein are methods of coating the inorganic salt(s), masking the taste of the salts and controlling the release of the salts. Also disclosed are compositions and kits of the salts for various indications.
  • Sodium chloride and potassium chloride are key inorganic salts (i.e. electrolytes) in our body.
  • Many other minerals such as calcium, zinc, copper, chromium, molybdenum, and manganese are also present in the human body.
  • electrolytes e.g. hyponatremia and hypokalemia.
  • hyponatremia dilutional hyponatremia
  • Adding a quantity of tasteless salts to free fluid will reduce the chances of dilutional hyponatremia during rehydration during exercise maintaining iso-osmolarity.
  • the preparation is a thickened liquid that is easy to swallow, especially for people suffering from dysphagia.
  • the preparation uses ingredients which do not produce any insoluble matter in the GI tract, which can impede the colon examination. Similar side effects may be obsen ed when people consume laxatives to treat chronic constipation, or have diseases causing nausea, vomiting, and/or diarrhea.
  • Acceptability' of oral formulations depends upon four factors - appearance (eyes), odor (nose), taste (tongue) and texture to ensure patient compliance.
  • Taste-masking is a more difficult task in many drug formulations. Addition of a flavor and a sweetener/sugar are normally and frequently tried first to mask the unpleasant taste of drugs. Taste receptors in the mouth are blocked sometimes to mask the unpleasant taste of the drug. Thresholds concentrations of primary taste sensation are - sweet (0.5%), sour (0.25%), salt (0.007%) and bitter (0.00005%). Clearly, one can taste even very small amounts of salts and bitter compounds.
  • Taste masking can be achieved by inclusion-complexes with cyclodextrins.
  • the masking can also be achieved by ion-pairing the drug with ion-exchange resins.
  • ion-pairing the drug with ion-exchange resins.
  • the present disclosure provides a coating configuration for inorganic salt(s), which not only masks the taste of the salt but also provides a delayed release and/or sustained release in the GI tract.
  • the present disclosure provides coated inorganic salt(s), compositions, kits and methods of preparation for a colonoscopy product that provides a delayed release and/or sustained release of electrolytes in the GI tract.
  • the present disclosure also provides balanced electrolyte compositions (i.e. sports drinks) comprising taste-masked electrolytes.
  • An aspect of the patent document provides a coated inorganic salt(s) comprising:
  • a first polymer coating layer enclosing the core; wherein the first polymer coating is an enteric or a reverse enteric coating, wherein the enteric coating dissolves in the small intestine and the reverse enteric coating dissolves in the stomach, wherein the concentration of salt ranges from about 5% to about 95% by weight in the composition.
  • the one or more inorganic salt(s) are admixed with a diluent and/or a gelling agent in the core, wherein the diluent or the gelling agent comprises one or more of polyethylene glycol, gellan gum, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, mannitol, sorbitol, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, Kollidon (povidone), com starch, and carboxy methylcellulose, wherein the gelling agent is present in the core and swells upon contact with water thereby releasing the inorganic salt(s).
  • the diluent or the gelling agent comprises one or more of polyethylene glycol, gellan gum, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, mannitol,
  • the inorganic salt(s) is in the form of a plurality of granules in the core.
  • the granules have an average particle size smaller than 3000 microns.
  • the coated inorganic salt(s) further comprise an undercoat between the core and the first polymer coating layer, wherein the undercoat prevents interaction between the inorganic salt(s) and the first polymer coating layer.
  • the coated inorganic salt(s) further comprise a second polymer coating enclosing the core and the first polymer coating, wherein the second polymer coating delays the release of the inorganic salt(s), preferably wherein the second polymer comprises wax, PEG stearate coating, and any combination thereof.
  • the core further comprises an inner core free from the inorganic salt(s), wherein the inorganic salt(s) are coated on the inner core.
  • the coated inorganic salt(s) further comprise an extended- release layer between the core and the first polymer coating layer, wherein the coated inorganic salt(s) is configured so that, when tested with a USP type 2 dissolution system (Paddle Apparatus) at 50 rpm and a temperature of 37 ⁇ 0.5 °C in 125 mL 0.1 N HC1, at a pH of about 1.2 less than 20%-of the salt is released within 90 minutes.
  • a USP type 2 dissolution system Paddle Apparatus
  • the coated inorganic salt(s) further comprise an extended- release layer between the core and the first polymer coating layer, wherein the coated inorganic salt(s) is configured so that, tested with a USP type 2 dissolution system (Paddle Apparatus) at 50 rpm and a temperature of 37 ⁇ 0.5 °C in 125 mL of 0.05 M phosphate buffer, at a pH of about 6.8 or a pH of about 7.4,
  • a USP type 2 dissolution system Paddle Apparatus
  • the extended-release layer comprises one or more of ethyl cellulose, sodium polyacrylate, polyacrylamide copolymer, ethylene maleic anhydride copolymer, crosslinked carboxymethyl cellulose, polyvinyl alcohol copolymer, and crosslinked polyethylene oxide.
  • composition comprising the aforementioned coated inorganic salt.
  • the composition is in the form of a powder. In some embodiments, the composition is in the form of a tablet. In some embodiments, the composition further comprises a suspending agent, wherein the composition is in a liquid form. In some embodiments, the liquid form is a gel or a semi-solid.
  • kits comprising:
  • the liquid medium comprises a polyethylene glycol and/or water, wherein the polyethylene glycol is a colon cleansing agent.
  • the polyethylene glycol has a molecular weight ranging from 2000 daltons to 8000 daltons.
  • the wherein the liquid medium comprises a suspending agent and/or water.
  • suspending agents include xanthan gum, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, agar, bentonite, carbomers, polyvinylpyrrolidone K30, and any combination thereof.
  • Another aspect provides a method of providing coated inorganic salt(s) to a subject in need thereof, the method comprising administering to the subject any of the aforementioned coated inorganic salt(s), compositions, or kits.
  • the wherein the method provides balanced electrolytes. In some embodiments, wherein the subject is electrolyte deficient. In some embodiments, the method reduces the taste of the inorganic salt(s). In some embodiments, the coated inorganic salt(s) is delivered to a subject prior to a colonoscopy procedure.
  • FIGURE 1 shows a pictorial diagram of a granule or a bead with various coatings, including (1) a coat (e.g. wax coating), (2) an enteric coating, (3) an coat (e.g. HPMC), (4) a diluent or gelling agent, and (5) the inorganic salt(s) (i.e. electrolytes).
  • the core contains an electrolyte with a diluent and a gelling agent.
  • the gelling agent provides a modified release of the electrolyte.
  • the core is coated with a sub-coat, an enteric coat and a super-coat (wax coat).
  • FIGURE 2 is a pictorial diagram of the release of electrolyte from the core. Once the enteric coat dissolves (1), water is absorbed in the core (2). The gelling polymer swells slowing down the release of the inorganic salt(s) (3). Over time, the inorganic salt(s) diffuse out of the core (4).
  • FIGURE 3 is a pictorial diagram of particles for non-colonoscopy preparations.
  • the core contains an electrolyte (6) with a diluent and a gelling agent (5).
  • the core is coated with a sub-coat (4).
  • the last coat is a wax coat (2).
  • FIGURE 4 is a pictorial diagram of a sugar bead or suglet (2) coated with electrolyte powder and gelling polymer (3). This is further coated with a sub-coat (1), enteric coat or a reverse enteric coat (4).
  • the beads can be coated with water-insoluble but water swellable polymer and a wax coat.
  • FIGURE 5 is a depiction of various release profdes, such as immediate release (1), sustained release (2), delayed release followed by an extended/partial immediate release, (3) and delayed release followed by sustained release profile (4).
  • FIGURE 6 is a table listing commercially available laxative MoviPrep, Plenvu, Gavilyte, Trilyte, CoLyte, Golytely, Nulytely, Halflytely, Suflave, and Suclear and respective ingredients.
  • Various embodiments herein disclose a composition of a coated salt.
  • the coated salt disclosed herein can not only mask the taste but also provide the advantage of a delayed and/or extended release of the salt at a desired location for a suitable period of time. Meanwhile, incidences of adverse events such as nausea and vomiting can be eliminated or reduced.
  • the coating approach can be adopted to various types of salts, in particular inorganic salt(s).
  • extended release refers to continuous release of a salt over a period of at least 30 minutes upon contact with a test medium or after being administered to the subject.
  • the penod of continous release is at least 1 hour, at least 2 hours, at least 3 hour, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 15 hours, at least 20 hours, or at least 24 hours.
  • the amount of a salt released from the composition or dosage form is measured by dissolution testing in aqueous medium as described herein. The results of the dissolution testing are reported in terms of percentage content (w/w) released within the release time.
  • the dissolution can be determined, for example, using a USP type 2 dissolution system (Paddle Apparatus) at 50 rpm and a temperature of 37 ⁇ 0.5 °C in a dissolution medium of 125 mL 0. 1 N HC1.
  • the dissolution profile is determined using a USP type 2 dissolution system (Paddle Apparatus) at 50 rpm and a temperature of 37 ⁇ 0.5 °C in 125 mL of 0.05 M phosphate buffer, pH 6.8 or 7.4.
  • immediate release refers to release of more than or equal to about 80% of a salt in less than or equal to about 30 minutes upon contact with a test medium or after being administered to the subj ect. In some embodiments, more than or equal to about 80% or more than or equal to about 90% or more than or equal to about 95% of the salt in an immediate release dosage form is released in less than or equal to about 30 minutes. Unless otherwise indicated, the amount of a salt released from the composition or dosage form is measured by dissolution testing in aqueous medium as described herein. The results of the dissolution testing are reported in terms of percentage content (w/w) released within the release time.
  • the dissolution can be determined, for example, using a USP type 2 dissolution system (Paddle Apparatus) at 50 rpm and a temperature of 37 ⁇ 0.5 °C in a dissolution medium of 125 mL 0.1 N HC1.
  • the dissolution profile is determined using a USP type 2 dissolution system (Paddle Apparatus) at 50 rpm and a temperature of 37 ⁇ 0.5 °C in 125 mL of 0.05 M phosphate buffer. pH 6.8 or 7.4.
  • coat refers a continuous and enclosing layer.
  • the coating can serve various goals including masking the taste of a salt, controlling the release profde of the salt, and maintaining the quality or stability of the salt.
  • the term “functional coat” refers to a coating applied to an inorganic salt(s), which is designed to provide specific and desired release rate for the inorganic salt(s) including an immediate, delayed, extended-release properties and/or protective properties from various pH environments.
  • Such coats include, but are not limited to, enteric coatings, reverse enteric coatings, and undercoating.
  • the enteric coating functions to minimize the dissolution of inorganic salt(s) in the stomach and dissolve the inorganic salt(s) in the intestine.
  • the reverse enteric coating functions to dissolve the inorganic salt(s) in the stomach,
  • the undercoat functions to prevent interaction between the inorganic salts and the first polymer coating layer.
  • each coat serves a distinct function in achieving the desired delayed, extended release and/or protective properties.
  • the term “delayed release” means that the release of a salt does not initate immediately once ingested and the composition does not initiate the release of active until it reaches an environment of a predetermined pH range. Therefore, after being administered, the salt may not be released immediately and to reach the desired pH environment, it will take the salt composition a period of time, which may for example ranges from 5 minutes to 60 minutes, from 10 minutes to 60 minutes, or from 20 minutes to 60 minutes, or from 30 minutes to 60 minutes.
  • the delayed release can prevent dumping of salts in the stomach.
  • electrolyte refers to a mineral that becomes ionized when dissolved in solvents like water, thus capable of conducting electricity.
  • the terms salts and electrolytes can be used interchangeably.
  • the salt is an inorganic salt.
  • coloring agent refers to an agent generates a desired color.
  • flavors refers to an agent, which when added to the dosage form, provides a pleasing smell or odor.
  • sweeteners refers to an agent, which when added to the dosage form, incorporates a desired sweetness.
  • taste enhancing agent refers to an agent, which stimulates taste sensation and provides a pleasing taste in the mouth cavity.
  • the term "subject" as used herein is intended to include human and non-human animals.
  • Non-human animals include all vertebrates, e.g. mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows and horses.
  • the subject is a colonoscopy patient. In some embodiments, the colonoscopy patient suffers from dysphagia. In another embodiment, the subject has a lower- than-normal level of electrolytes. In some embodiments, the subject is a person who is electrolyte deficient as a result of physical exercise. In some embodiments, the subject is an athlete or a sportsperson.
  • electrolyte deficient refers to the subject lacking one or more inorganic salt(s), such as sodium chloride, potassium chloride, calcium chloride, or other inorganic salt(s) commonly used in electrolyte formulations.
  • electrolyte deficient means the subject has a lower-than-normal level of electrolytes.
  • a "normal level" of electrolytes is an average level of electrolytes measured from a group of healthy individuals.
  • a lower-than-normal level of electrolytes i.e. , an electrolyte imbalance
  • electrolytes can result from a decrease in electrolytes of least 1%, 5%, at least 10%, or at least 15% in electrolytes compared to a normal level.
  • the term “configured” means that the coated inorganic salt, or compositions thereof, have been intentionally designed to achieve a specific function.
  • the coated inorganic salt(s) have been deliberately designed to produce particular release profiles (extended and delayed release), controlling release timing, and/or masking the taste of the inorganic salt(s).
  • An aspect of the patent document provides a coated inorganic salt comprising (a) one or more inorganic salt; (b) a core comprising the one or more inorganic salt; and (c) a first polymer coating layer enclosing the core; wherein the concentration of salt ranges from about 5% to about 95% by weight in the composition.
  • Various inorganic salt(s) can be incorporated into the coated inorganic salt.
  • Nonlimiting examples include sodium salt (e.g. sodium chloride, sodium bicarbonate, sodium carbonate, sodium sulfate, sodium phosphate), potassium salt (e.g. potassium chloride, potassium carbonate, potassium bicarbonate, potassium sulfate, potassium phosphate), calcium salt, iron salt, copper salt, zinc salt, manganese salt, magnesium slat, molybdenum salt, cobalt salt, chromium salt, salts of halide (F, Br, Cl, or I).
  • sodium salt e.g. sodium chloride, sodium bicarbonate, sodium carbonate, sodium sulfate, sodium phosphate
  • potassium salt e.g. potassium chloride, potassium carbonate, potassium bicarbonate, potassium sulfate, potassium phosphate
  • calcium salt iron salt, copper salt, zinc salt, manganese salt, magnesium slat, molybdenum salt, cobalt salt, chromium
  • the amount of the salt in the coated inorganic salt ranges from about 10% to about 95%, from about 20% to about 80%, from about 30% to about 95%, from about 40% to about 80%, or from about 40% to about 60% by weight in the coated inorganic salt.
  • Nonlimiting examples of the amount include about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 80%, about 90%, about 95%, and any range between any two of the aforementioned values.
  • a mixture of salts can be coated using the same methods disclosed herein. Benefit of coating a mixture includes saving of time of coating, saving of cost, ease of handling materials during packaging etc.
  • the mixture may include for example sodium chloride + potassium chloride, sodium chloride + sodium sulfate, sodium chloride + sodium bicarbonate, sodium chloride + potassium chloride + sodium sulfate, sodium chloride + potassium chloride + sodium sulfate + sodium bicarbonate, etc.
  • the salt mixture can be in the form of particles or granules prior to coating.
  • the first polymer coating layer serves a role of a reverse enteric coat. In some embodiments, this coating does not dissolve in neutral/basic pH, for example, above pH 4.5, above pH 5, above pH 5.5 or above pH 6.
  • suitable polymers include basic butylated methacrylate copolymer, amino methacry late copolymer, and aminoalkyl methacrylate copolymer E.
  • the first polymer coating layer may contain one or both of the enteric coat and the reverse enteric coat.
  • the core is coated with a reverse enteric coat followed by an enteric coat.
  • the core is coated with a mixture of enteric coat polymer(s) and reverse enteric coat polymer(s) to obtain a desire dissolution profile in the stomach.
  • the core may also contain an excipient such as a diluent and a gelling agent admixed with the salt.
  • the gelling agent can swell upon contact with water thereby releasing over a period of time the inorganic salt from the porosity resulting from gel swelling.
  • the diluent or filler materials include lactose, sucrose, sorbitol, mannitol, and xylitol, .
  • Nonlimiting examples of the gelling agent include hydroxypropyl methyl cellulose (HPMC), methyl cellulose (MC), hydroxy propyl cellulose (HPC), carboxy methyl cellulose (CMC), sodium carboxymethyl cellulose, xanthan gum, gellan gum, alginic acid, sodium alginate, hyaluronic acid, sodium hyaluronate, povidone, and Chitosan.
  • HPMC hydroxypropyl methyl cellulose
  • MC methyl cellulose
  • HPC hydroxy propyl cellulose
  • CMC carboxy methyl cellulose
  • sodium carboxymethyl cellulose xanthan gum
  • Some agents can play the role of both a diluent and a gelling agent.
  • the amount of the diluent or gelling agent may vary depending on the specific salt and the rate of delayed or controlled release.
  • the amount of the diluent or gelling agent independently ranges from about 2% to about 80%, from about 5% to about 70%, from about 10% to about 60%, from about 20% to about 50%, or from about 20% to about 40% in the coated inorganic salt.
  • Nonlimiting examples of the amount include about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, and any range between any two of the aforementioned values.
  • the core may also contain an inner core, where the salt is coated on the inner core.
  • the inner core is inert and free from the inorganic salt.
  • a mixture of powdered salt and a sustained release polymer can be coated on sugar beads or suglets or glucose beads, which can be further coated with one or more layers of functional coatings.
  • the D90 value (it is the value of the particle size below which 90% of particles reside) of the uncoated suglets particles is less than 700 pm. D90 of less than 700 pm means 90% of the particles are less than 700 pm.
  • the salt in the coated inorganic salt may exist in its natural form such as granules or crystals.
  • the salt may also be granulated using a binding agent before being coated or admixed with an excipient.
  • the salt to be coated can be first granulated with excipients to form granules or beads or microspheres, which optionally provide an additional level of control over sustained release of salts in the GI tract.
  • the salt is first granulated with a polymer to provide an extended or sustained release profile because of the swelling of polymer, and the granules are then enteric-coated or reverse enteric coated and/or wax coated.
  • the binding agent may also play little or no role in extended release depending on the selection of the agent and its amount.
  • Nonlimiting examples of the binding agent include HPMC, HPC, lactose, mannitol, sorbitol, xanthan gum, Sodium CMC, and any combination thereof.
  • the particle size of electrolytes or salts is very important.
  • Sodium chloride is available in the granular form.
  • Potassium chloride is available in the granular form, but the particle size is smaller than the granules of sodium chloride.
  • Sodium bicarbonate is available mostly as a fine powder. It is available as granules, but the particle size is significantly smaller than sodium chloride granules.
  • Sodium sulfate and magnesium sulfate are available as fine powders.
  • the binding agent and its amount are selected so that the granules have an average particle size (or D90) ranging from about 20 to about 5000 microns, from about 20 to about 5000 microns, from about 100 to about 3000 microns, from about 20 to about 2000 microns, from about 50 to about 1500 microns, from about 100 to about 1500 microns, from about 200 to about 1000 microns, or from about 500 to about 1000 microns.
  • Nonlimiting examples of the average size include about 20 microns, about 50 microns, about 100 microns, about 150 microns, about 200 microns, about 250 microns, about 300 microns, about 300 microns, about 400 microns, about 500 microns, about 600 microns, about 800 microns, about 1000 microns, about 1200 microns, about 1500 microns, about 2000 microns, about 2500 microns, about 3000 microns, about 3500 microns, about 4000 microns, about 5000 microns, about 6000 microns, about 8000 microns, and any range between any two of the aforementioned values.
  • the core may be further coated with an extended or modified release layer between the core and the first polymer coating layer. This layer is different from the undercoat.
  • the salt is coated with water-insoluble, but water-swellable polymer such as ethyl cellulose to obtain a modified release of the salt.
  • the coating can be a mixture of water-insoluble/water-swellable polymer and water-soluble polymer to alter the porosity of the coating.
  • the extended or modified release coat ranges from about 2% to about 80%, from about 5% to about 70%, from about 10% to about 60%, from about 2% to about 40%, from about 50% to about 30%, or from about 10% to about 20% by weight in the coated inorganic salt.
  • Nonlimiting examples of the amount include about 2%, about 5%, about 8%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, and any range between any two of the aforementioned values.
  • Nonlimiting examples of the excipient in the extended-release layer include ethyl cellulose, sodium polyacrylate, polyacrylamide copolymer, ethylene maleic anhydride copolymer, crosslinked carboxymethyl cellulose, polyvinyl alcohol copolymer, cross-linked polyethylene oxide, and any combination thereof.
  • the coated inorganic salt further includes an undercoat between the core and the first polymer coating layer.
  • This undercoat can prevent interaction between the electrolyte and the polymer used for enteric coating.
  • the undercoat is soluble in water.
  • excipients suitable for the undercoat include methyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and polyvinyl alcohol.
  • the undercoat does not delay or extend the release but instead serves as an immediate release layer.
  • the salt core is coated with an immediate release polymer (undercoat) followed by an enteric coating.
  • the salt core is coated with an immediate release polymer (undercoat) followed by a wax coating.
  • the undercoat may range from about 0.1% to about 20%, from about 0.1% to about 15%, from about 0.1% to about 10%, from about 1% to about 10%, from about 5% to about 10%, or from about 10% to about 20% in the coated inorganic salt.
  • the amount include about 0.1%, about 0.5%, about 1%, about 2%, about 4%, about 6%, about 8%, about 10%, and any range between any two of the aforementioned values.
  • the coated inorganic salt further includes a second polymer coating enclosing the core and the first polymer coating.
  • the second polymer coating dissolves slowly in water delaying/slowing the release of electrolytes.
  • Nonlimiting examples of the second polymer include wax, PEG stearate, carnauba wax, bees wax, shellac, a high molecular weight polymer or combination thereof.
  • each coating of the coated inorganic salt is water-soluble.
  • all the ingredients in the coated inorganic salt or dosage form must be water-soluble so that none of the colonic mucosa is obscured by the insoluble residue.
  • one or more coating of the coated inorganic salt is water insoluble. In some embodiments for the non-colonoscopy preparation, some of the ingredients for coatings may not be water-soluble.
  • excipients can also be included in the coated inorganic salt disclosed herein, including for example plasticizer, flavor, taste enhancer, stabilizer.
  • plasticizers include diethyl phthalate, tnbutyl citrate, triethyl citrate, glycerin, propylene glycol, polyethylene glycol, tributyrin.
  • PEG 3350 at 10% of the enteric coating polymer level can be used.
  • a solvent mixture containing ethanol, acetone and water at 50%, 20% and 30%, respectively can be used to facilitate the process. In some embodiments, other ratios of these solvents are used. In some embodiments, other solvents, such as isopropyl alcohol, can be used in the solvent mixture.
  • the coated inorganic salt is configured, and the excipients or polymers and their amounts are selected so that the inorganic salt of the coated inorganic salt is controlled via delayed release, immediate release, and/or extended release in an environment of a predetermined pH or a predetermined pH range.
  • a super coated (e.g. wax coating) particle or tablet dissolves slowly in intestine thereby delaying the release of the salt.
  • an inner extended-release layer e.g., ethyl cellulose coating
  • the coating layers e.g.
  • super-coat, first polymer coating, and/or second polymer coating) of the coated inorganic salt are configured to dissolve only under a predetermined pH, including for example, 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0, or at a range between any two of the aforementioned values.
  • the salts should be released slowly from the coated inorganic salt (sustained or slow-release system or dosage form) but the AUC (area under the drug absorption curve) needs to be satisfactory.
  • the coated inorganic salt is configured, and the excipients or polymers and their amounts are selected so that the inorganic salt of the coated inorganic salt has one or more or all of the following in vitro dissolution characteristics in the dissolution media having pH of about 6.5 to 7.5.
  • the released salt accounts for about 0.01% to about 5%, about 0.01% to about 4%, about 0.01% to about 3%, about 0.01% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.1%, about 0.01% to about 0.05%, about 0.05% to about 5%, about 0.05% to about 4%, about 0.05% to about 3%, about 0.05% to about 2%, about 0.05% to about 1 %, about 0.1 % to about 5%, about 0. 1 % to about 4%, about 0. 1 % to about 3%, about 0.1% to about 2%, about 0.1% to about 1% of the total amount of the salt (w/w);
  • the released salt accounts for about 0.1% to about 20%, about 0.1% to about 18%, about 0.1% to about 16%, about 0.1% to about 14%, about 0.1% to about 12%, about 0.1% to about 10%, about 0.1% to about 8%, about 0.1% to about 6%, about 0.1% to about 6%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.5% to about 10%, about 0.5% to about 8%, about 0.5% to about 6%, about 0.5% to about 6%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 0.5% to about 1%, about 1% to about 10%, about 1% to about 8%, about 1% to about 6%, about 1% to about 6%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, about 1% to about 1% of the total amount of the salt (w/w);
  • the released salt accounts for about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, about 2% to about 8%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 8% to about 30%, about 8% to about 25%, about 8% to about 20%, about 8% to about 15%, or about 8% to about 12% of the total amount (w/w);
  • the released salt accounts for about 2% to about 40%, about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, about 2% to about 8%, about 5% to about 40%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 8% to about 40%, about 8% to about 30%, about 8% to about 25%, about 8% to about 20%, about 8% to about 15%, or about 8% to about 12% of the total amount (w/w); and/or
  • the released salt accounts for about 50% to about 100%, about 70% to about 100%, about 60% to about 100%, about 50% to about 95%, about 70% to about 95%, or about 80% to about 100% of the total amount (w/w).
  • the coated inorganic salt has one, two, three or four of the above dissolution characteristics.
  • the coated inorganic salt provides the dissolution of the active ingredient having the above (a).
  • the coated inorganic salt provides the dissolution of the active ingredient having the above (a) and (b).
  • the coated inorganic salt provides the dissolution of the salt having the above (a), (b) and (c).
  • the coated inorganic salt provides the dissolution of the salt having the above (a), (b), (c) and (d). In some embodiments, the coated inorganic salt provides the dissolution of the salt having the above (a), (b), (c), (d), and (e).
  • the coated inorganic salt is configured to provide a delayed- release profile wherein no more than 25%, and preferably, no more than 10% of electrolytes dissolve in stomach. Further, in some embodiments, the coated inorganic salt is configured to provide an extended release in the intestine over a time frame of about 30 minutes to about 60 minutes.
  • the coated inorganic salt has the following in-vitro dissolution for the release of the salt: less than 40% is released in 2 hours, preferably less than 30% is released within 2 hours, more preferably less than 30% is released in 2 hours, more preferably less than 20% is released in 2 hours, more preferably, less than 10% is released in 2 hours, most preferably no salt is released in 2 hours.
  • the coated inorganic salt has the following in-vitro dissolution for the release of the salt in pH 1.2: less than 40%, preferably less than 30%, more preferably less than 20%, more preferably, less than 9%, more preferably, less than 8%, more preferably, less than 7%, more preferably, less than 6%, more preferably, less than 5%, more preferably, less than 4%, more preferably, less than 3%, more preferably, less than 2%, more preferably, less than 1%, more preferably, less than 0.1% is released, and most preferably no salt is released within 30 minutes, within 60 minutes, within 90 minutes, or within 120 minutes.
  • the composition may be in any suitable form.
  • the composition may be in the form of a powder, a granule, tablets, capsules, a particle, a gel, or a suspension.
  • the composition is in the form of a liquid, further comprising a suspending agent selected from, but not limited to xanthan gum, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, agar, bentonite, carbomers, polyvinylpyrrolidone K30, and any combination thereof, wherein the polymer-coated core is suspended in the liquid.
  • a suspending agent selected from, but not limited to xanthan gum, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, agar, bentonite, carbomers, polyvinyl
  • the composition is in the form of tablets, minitablets, beads, mini -capsules, powder, granules, or liquid. In some embodiments, the composition is loaded into a capsule. In some embodiments, the composition is a powder of a plurality of particles, wherein each of the particles comprises the core and the first polymer coating. In some embodiments, the composition is a plurality of mini-tablets or beads or mini-capsules.
  • the composition provides a certain amount of acid, ranging from about 0.001% to about 2%.
  • the amount of acid in the composition ranges from about 0.001% to about 0.01%, about 0.01% to about 0.1%, about 0.1% to about 1.0%, or from about 1% to about 2% in the composition.
  • Nonlimiting examples of the amount include about 0.001%, about 0.005%, about 0.01%, about 0.05%, about 0.1%, about 0.5%, about 1%, about 1.5%, about 2%, and any range between any two of the aforementioned values.
  • the acid can be citnc acid, ascorbic acid tartaric acid, succinic acid, maleic acid, malic acid, or other poly-carboxylic acid.
  • the composition has a pH of between about 2 to about 8. In some embodiments, the composition has a pH of between ranges from about 2 to about 3.5, about 2.5 to about 4, about 3 to about 4.5, about 3.5 to about 5, about 4 to about 5.5, about 4.5 to about 6, about 5 to about 6.5, about 5.5 to about 7, about 6 to about 7.5, or about 6.5 to about 8.
  • Nonlimiting examples of the amount include about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, and about 8, and any range between any two of the aforementioned values.
  • the composition comprises additionally an effervescence agent.
  • the effervescence agent is a carbon dioxide (CO2) producing agent which, when present in the stomach or an acidic environment, will release CO2.
  • CO2 carbon dioxide
  • the effervescence agent can be a combination of sodium bicarbonate and citric acid.
  • the effervescence agent can be a combination of sodium carbonate and citric acid.
  • plasticizer examples include diethyl phthalate, tributyl citrate, triethyl citrate, glycerin, propylene glycol, polyethylene glycol, tributyrin.
  • PEG 3350 at 10% of the enteric coating polymer level can be used.
  • a solvent mixture containing ethanol, acetone and water at 50%, 20% and 30%, respectively can be used to facilitate the process of coating.
  • compositions in the form of a combination comprising the coated inorganic salt(s) and a polyethylene glycol.
  • Polyethylene glycol acts as a colon cleanser.
  • the molecular weight of the polyethylene glycol may be for example, 100, 200, 400, 800, 1000, 1200, 1500, 1800, 2000, 2200, 2500, 2800, 3000, 3200, 3350, 3500, 3800, 4000, 4200, 4500, 4800, 5000, 5200, 5500, 5800, 6000, 6500, 7000, 8000, 10,000 daltons or any range between any two the aforementioned values.
  • the polyethylene glycol polymer has a molecular weight ranging from 2000 daltons to 8000 daltons.
  • the polyethylene glycol polymer is PEG 3350 or PEG 8000.
  • the combination may also comprise a flavoring agent.
  • flavoring agent include limited to peppermint oil, lemon, and fruit punch.
  • the combination may also comprise a suspending agent selected from, but not limited to xanthan gum, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, agar, bentonite, carbomers, polyvinylpyrrolidone K30,and any combination thereof.
  • the combination may also comprise a commercially available laxative.
  • the laxatives may be synthetic or derived from natural products, i.e., herbs and fibers.
  • the laxatives may be used together with the combination or sequentially.
  • Preferred examples of commercially available laxatives are selected from Gavilyte, Golytely, CoLyte, Nulytely, Trilyte, Halflytely, MoviPrep, Plenvu, Suflave, and Suclear. These laxatives and their respective ingredients are detailed in FIGURE 6.
  • the coated inorganic salt(s) is admixed with a laxative, with non-coated salts present in the formulation. In some embodiments, the coated inorganic salt(s) is used in place of the non-coated salts present in the laxative.
  • compositions in the form of a liquid system comprising the coated inorganic salt(s) disclosed herein and a liquid medium admixed with the coated inorganic salt(s).
  • the liquid system can be in a suspension, a viscous mixture or a gel, wherein the composition remains undissolved as a solid form.
  • the liquid medium is pure water.
  • the liquid medium is polyethylene glycol.
  • the liquid medium is a combination of polyethylene glycol and water.
  • the molecular weight of the polyethylene glycol may be for example, 100, 200, 400, 800, 1000, 1200, 1500, 1800, 2000, 2200, 2500, 2800, 3000, 3200, 3350, 3500, 3800, 4000, 4200, 4500, 4800, 5000, 5200, 5500, 5800, 6000, 6500, 7000, 8000, 10,000 daltons or any range between any two the aforementioned values.
  • the liquid medium comprises a suspending agent.
  • suspending agents include xanthan gum, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, agar, bentonite, carbomers, polyvinylpyrrolidone K30, and alike.
  • the suspending agent is selected from xanthan gum or sodium carboxy methyl cellulose.
  • the liquid system may further include water for adjusting the viscosity of the system.
  • the liquid system can be prepared by mixing the coated inorganic salt(s) with a suspending agent and diluent(s) in suitable proportions. Water may be added for viscosity adjustment or composition of a suspension or a gel. The kinematic viscosity was measured by the Canon viscometer. In some embodiments, the viscosity of the liquid system ranges from 10 cps to 2000 cps, from 50 cps to 1000 cps, 50 cps to 100 cps, 100 cps to 500 cps or 500 cps to 1000 cps.
  • Nonlimiting examples of the viscosity include about 10, about 20, about 50, about 100, about 200, about 300, about 500, about 800, about 1000, about 1200, about 1500, about 2000 cps and an any range between any two of the aforementioned values.
  • the ratio by weight between the suspending agent and water ranges from 1 : 10 to 1: 10000, from 1:50 to 1 :5000, from 1 :100 to 1: 1000, from 1:200 to 1 :500.
  • the ratio by weight between the suspending agent and water is 1: 10, 1:20, 1 :30, 1:40, 1 :50, 1:60, 1:70, 1:80, 1:90, 1: 100, 1:200, 1:300, 1:400, 1:500, 1 :600, 1:700, 1:800, 1:900 1: 1000, 1:2000, 1:3000, 1:4000, 1:5000, 1:6000, 1:7000, 1 :8000, 1:9000, 1: 10000 or any range between any two of the aforementioned values.
  • the ratio by weight between the suspending agent and water is between about 1:200 to about 1 :500.
  • the suspending agent is present in an amount of about 0.01% to about 10% of the total composition. In a preferred embodiment, the suspending agent is present in an amount of about 0.2% to about 1.0% in the final gel formed.
  • the liquid system is configured to reduce the volume of liquid to be administered to a subject.
  • the liquid system can be a gel or a semisolid.
  • the volume of the liquid system ranges from about 0. 1 liters to about 8.0 liters, about 0.1 liters to about 7.0 liters, about 0.1 to about 6.0 liters, about 0.1 to about 5.0 liters, about 0.1 to about 4.0 liters, about 0.1 to about 3.0 liters, about 0.1 to about 2.0 liters, about 0.1 to about 1.0 liters.
  • the liquid system has a total volume of about 1.0 liters, or any range between any two of the aforementioned values. 3. Kit
  • the liquid medium comprises a polyethylene glycol and/or water, wherein the polyethylene glycol is a colon cleansing agent.
  • the liquid medium is pure water.
  • the liquid medium is polyethylene glycol.
  • the liquid medium is a combination of polyethylene glycol and water. Polyethylene glycol acts as a colon cleansing agent.
  • the molecular weight of the polyethylene glycol may be for example, 100, 200, 400, 800, 1000, 1200, 1500, 1800, 2000, 2200, 2500, 2800, 3000, 3200, 3350, 3500, 3800, 4000, 4200, 4500, 4800, 5000, 5200, 5500, 5800, 6000, 6500, 7000, 8000, 10,000 daltons or any range between any two the aforementioned values.
  • the polyethylene glycol polymer has a molecular weight ranging from 2000 daltons to 8000 daltons.
  • the polyethylene glycol polymer is PEG 3350 or PEG 8000.
  • the kit also comprises a flavoring agent, which may be added to any of the aforementioned components (i) or (ii), or as an additional component.
  • a flavoring agent include limited to peppermint oil, lemon, and fruit punch.
  • no gelling agent is added.
  • the contents will be dissolved in water and coated electrolytes are swallowed along with the PEG solution.
  • a gelling agent is added in (ii) along with other excipients.
  • the contents when mixed with water form a nice gel. Coated electrolytes are swallowed along with the second gel.
  • a gelling agent is added in (ii) along with other excipients.
  • the contents when mixed with water form a nice gel.
  • Coated electrolytes are suspended in the PEG gel. The mixture is swallowed within 15 to 20 minutes.
  • Sodium sulfate and/or magnesium sulfate/citrate beads/granules are mixed with electrolytes.
  • a marketed purgative product is administered along with PEG and electrolytes.
  • the kit may also comprise a commercially available laxative, which may be added to any of the aforementioned components (i) or (ii) or as an additional pouch.
  • the laxatives may be synthetic or derived from natural products, i.e., herbs and fibers.
  • Non-limiting examples of laxatives include bisacodyl, picosulfate sodium, senna extract, Isabgol, psyllium, docusate sodium, castor oil, and polycarbophil.
  • the laxatives may be used together with the colonoscopy kit or sequentially.
  • laxatives containing polyethylene glycol are selected from Gavilyte, Golytely, CoLyte, Nulytely, Trilyte, Halflytely, MoviPrep, Plenvu, Suflave, and Suclear. These laxatives and their respective ingredients are detailed in FIGURE 6.
  • the coated inorganic salt(s) is admixed with a laxative, with non-coated salts present in the formulation. In some embodiments, the coated inorganic salt(s) is used in place of the non-coated salts present in the laxative.
  • the method may include a step of preparing the salt core by mixing a salt or granule thereof with a diluent and a gelling agent.
  • the salt core can include an inner core.
  • Subsequent steps include coating with an enteric coat or a reverse enteric coat and optionally applying an outer coat.
  • the disclosure provides a method of making the coated inorganic salt(s) comprising sugar beads or suglets.
  • the method comprises: (a) an extrusion step; (b) a spherization step; and (c) loading electrolytes on sugar beads.
  • the coated salts comprise a sugar bead or suglets.
  • the method comprises (a) loading sugar beads into a coating pan, (b) admixing inorganic salt(s) and a diluent or gelling agent with the sugar beads; (c) spraying a binder to adhere the inorganic salt(s) and diluent or gelling agent to the sugar beads.
  • the method further comprises drying the coated inorganic salt(s) at about 40 °C to 50 °C for 4 to 6 hours. In some embodiments, the method further comprises admixing the coated inorganic salt(s) with an undercoat, enteric coat, and/or reverse enteric coat. In some embodiments, the binder is Povidone K30.
  • fluid bed dryer is used to coat the salts.
  • a top spray gun is used in the fluid bed process.
  • a bottom spray gun was used in the fluid bed process.
  • a pan coater is used in the process.
  • the coating is performed using a solution of polymer or a dispersion of polymer in water.
  • the process further includes color coating the coated inorganic salt(s).
  • sweeteners are included in the coating matrix.
  • Another aspect of the patent document relates to a method of providing an inorganic salt(s) to a subject in need thereof.
  • the method includes administering to the subject the coated inorganic salt(s), compositions, and/or kits disclosed herein.
  • the method reduces or eliminates the taste of the inorganic salt(s).
  • the subject has a lower-than-normal level of the inorganic salt(s).
  • the subject is electrolyte deficient.
  • electrolyte deficient refers to a deficiency in one or more inorganic salt(s).
  • the compositions and/or kits to be administered comprise polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • water is a necessary component for colonoscopy preparations since the major cleansing effect is osmotic in nature.
  • water may be consumed by the patient as part of the compositions and/or kits or in addition to the compositions and/or kits.
  • water is administered to the colonoscopy patient prior to administering the compositions and/or kits.
  • water is administered to the colonoscopy patient after administering the compositions and/or kits.
  • water is administered simultaneously with the compositions and/or kits to the patient.
  • the salt administered to the subject may range from about 0.01 mg to about 100 g, from about 10 mg to 100 g, about 100 mg to about 50 g, about 100 mg to about 10 g, about 500 mg to about 5 g, or as determined by a medical professional.
  • inorganic salt(s) electrolytes
  • salt is necessary in our food products and it provides a good taste. But excess salt makes the food salty. In fact, one may vomit if he/she consumes too much salt at a time.
  • Different salts or electrolytes taste different. For example, potassium chloride is less salty but imparts a bitter taste.
  • Sodium bicarbonate has an unpleasant taste, and it has a slightly acidic in taste. The coated inorganic salt(s) and methods disclosed address this effectively.
  • the coated inorganic salt(s) disclosed herein can be configured such that delivery to certain segments of the gastrointestinal tract can be achieved for a variety of purposes and the profile and rate of release of salts for absorption can be controlled. These are commonly termed as “functional” coats.
  • functional coats By way of example, if large quantities of sodium chloride are ingested in the commercially available tablet preparations, there will be an extremely high percentage of individuals that will have a noxious reaction to the ingestion. This is principally due to the high local concentrations of salt within the lumen of the stomach, which can activate a variety of neurohumoral mechanisms inducing very severe nausea and repetitive vomiting.
  • the coated inorganic salt(s) and methods disclosed herein speak to the administration of very high quantities of sodium chloride and many other inorganic salt(s), which can be released after the stomach and into the more capacious small intestine allowing for a variety of therapeutic advantages.
  • the enteric coated salts provide a delayed release profile in the GI tract. In some embodiments, the enteric coated salts provide a delayed and sustained release profile in the GI tract.
  • the coated inorganic salt(s) is configured to provide an immediate release, delayed release, sustained release or any combination thereof. In some embodiments, the coated inorganic salt(s) is configured to provide an immediate release of the inorganic salt(s). In some embodiments, the coated inorganic salt(s) is configured to provide an extended or sustained release of the inorganic salt(s). In some embodiments, the coated inorganic salt(s) is configured to provide a delayed release followed by an extended or sustained release of the inorganic salt(s). In some embodiments, the coated inorganic salt(s) is configured to provide a delayed release followed by an immediate release of the inorganic salt(s).
  • Embodiment 1 A composition of one or more inorganic salt(s), comprising (a) a core comprising the one or more inorganic salt(s); (b) a first polymer coating layer enclosing the core; wherein the inorganic salt(s) range from about 5% to about 95% by weight in the composition.
  • Embodiment 2 The composition of Embodiment 1, wherein the one or more inorganic salt(s) are admixed with a diluent or a gelling agent in the core; (c) the blend of an inorganic salt(s), diluent and a gelling agent is converted to form granules or beads.
  • Embodiment 3 The composition of Embodiment 1, wherein the inorganic salt(s) is in the form of a plurality of granules in the core.
  • Embodiment 4 The composition of Embodiment 3, wherein the inorganic salt(s) granules have an average particle size smaller than 2000 microns.
  • Embodiment 5 The composition of Embodiment 2, wherein the diluent or the gelling agent comprises one or more of polyethylene glycol, gellan gum, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, mannitol, sorbitol, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, Kollidon (povidone), com starch, and carboxy methylcellulose, preferably the gelling agent is present in the core and swells upon contact with water thereby releasing the inorganic salt(s).
  • Embodiment 6 The composition of Embodiment 2, wherein the gelling agent is present in the core and swells upon contact with water thereby slowly releasing the inorganic salt(s).
  • Embodiment 7 The composition of Embodiment 1, wherein the core further comprises an inner core free from the inorganic salt(s), wherein the inorganic salt(s) are coated on the inner core.
  • Embodiment 9 The composition of Embodiment 8, wherein the extended-release layer comprises one or more of ethyl cellulose, sodium polyacrylate, polyacrylamide copolymer, ethylene maleic anhydride copolymer, crosslinked carboxymethyl cellulose, polyvinyl alcohol copolymer, cross-linked polyethylene oxide, gellan gum, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, mannitol, sorbitol, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, Kollidon (povidone), com starch, and carboxy methylcellulose.
  • the extended-release layer comprises one or more of ethyl cellulose, sodium polyacrylate, polyacrylamide copolymer, ethylene maleic anhydride copolymer, crosslinked carboxymethyl cellulose, polyvinyl alcohol copolymer, cross-linked polyethylene oxide, gellan gum, xanthan gum
  • Embodiment 10 The composition of Embodiment 1, wherein the first polymer coating is an enteric coating.
  • Embodiment 11 The composition of Embodiment 1, wherein the first polymer coating is a reverse enteric coating.
  • Embodiment 12 The composition of Embodiment 1, further comprising an undercoat between the core and the first polymer coating layer.
  • Embodiment 13 The composition of Embodiment 1, wherein the composition is free from water-insoluble polymers.
  • Embodiment 14 The composition of Embodiment 1, further comprising a second polymer coating enclosing the core and the first polymer coating.
  • Embodiment 15 The composition of Embodiment 1, wherein the second polymer comprises wax, PEG stearate coating, and any combination thereof.
  • Embodiment 16 The composition of Embodiment 1, which is in the form of a tablet.
  • Embodiment 17 The composition of Embodiment 1, which is in the form of a plurality of particles, wherein each of the particles comprises the core and the first polymer coating.
  • Embodiment 18 The composition of Embodiment 1, wherein the one or more inorganic salt(s) are selected from the group consisting of sodium salt, potassium salt, calcium salt, iron salt, copper salt, zinc salt, manganese salt, magnesium slat, molybdenum salt, cobalt salt, and chromium salt.
  • Embodiment 19 The composition of Embodiment 1, wherein the one or more inorganic salt(s) comprise one or more anions selected from the group consisting of chloride, fluoride, sulfate, bisulfate, carbonate, bicarbonate, and phosphate.
  • Embodiment 20 The composition of Embodiment 1, wherein the first polymer coating is configured to mask the taste of the inorganic salt(s).
  • Embodiment 21 The composition of Embodiment 1, which is configured to provide a delayed and/or extended release of the inorganic salt(s).
  • Embodiment 22 The composition of Embodiment 1, which is color coated.
  • Embodiment 23 A liquid system comprising the composition of Embodiment 1 and a suspending agent admixed with the composition.
  • Embodiment 24 The liquid system of Embodiment 23, wherein the suspending agent is selected from xanthan gum, polyethylene glycol, sodium alginate, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose.
  • Embodiment 25 The liquid system of Embodiment 23, which is a gel.
  • Embodiment 26 A method of providing an inorganic salt(s) to a subject in need thereof, comprising administering to the subject the composition of Embodiment 1.
  • Embodiment 27 The method of Embodiment 26, which reduces or eliminates the taste of the inorganic salt(s).
  • Embodiment 28 The method of Embodiment 26, wherein the subject has a lower- than-normal level of the inorganic salt(s).
  • Embodiment 29 A method of preparing a subject for colonoscopy, comprising administering to the subject the liquid system of Embodiment 23.
  • Embodiment 30 A colonoscopy composition comprising:
  • Embodiment 31 The colonoscopy composition of Embodiment 30, wherein the colonoscopy composition is in the form of a plurality of granules, wherein each of the granules comprises the core and the first polymer coating.
  • Embodiment 32 The colonoscopy composition of any one of Embodiments 30 to 31, wherein the granules have an average particle size smaller than 3000 microns.
  • Embodiment 33 The colonoscopy composition of any one of Embodiments 30 to 32, wherein the first polymer coating is either an enteric coating or a reverse enteric coating.
  • Embodiment 34 The colonoscopy composition of any one of Embodiments 30 to 33, further compnsing an undercoat between the core and the first polymer coating layer.
  • Embodiment 35 The colonoscopy composition of any one of Embodiments 30 to 34, wherein the colonoscopy composition is free from insoluble polymers.
  • Embodiment 36 The colonoscopy composition of any one of Embodiments 30 to 35, further compnsing a second polymer coating enclosing the core and the first polymer coating, wherein the second polymer comprises wax, PEG stearate coating, and any combination thereof.
  • Embodiment 37 The colonoscopy composition of any one of Embodiments 30 and 32 to 36, which is in the form of a powder.
  • Embodiment 38 The colonoscopy composition of any one of Embodiments 30 to 37, wherein the one or more electrolytes are inorganic salt(s) selected from the group consisting of sodium salt, potassium salt, calcium salt, iron salt, copper salt, zinc salt, manganese salt, magnesium slat, molybdenum salt, cobalt salt, and chromium salt, and/or the inorganic salt(s) comprise one or more anions selected from the group consisting of chloride, fluoride, sulfate, bisulfate, carbonate, bicarbonate, phosphate, citrate.
  • Embodiment 39 Embodiment 39.
  • a diluent or a gelling agent comprises one or more of polyethylene glycol, gellan gum, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, mannitol, sorbitol, methyl cellulose, carboxymethyl cellulose,
  • Embodiment 40 The colonoscopy composition of any one of Embodiments 30 to 39, wherein the diluent or the gelling agent is present in the core and swells upon contact with water thereby releasing the inorganic salt(s).
  • Embodiment 41 The colonoscopy composition of any one of Embodiments 30 to 40, further comprising an extended-release layer between the core and the first polymer coating layer, wherein the colonoscopy composition is configured so that, when tested with a USP type 2 dissolution system (Paddle Apparatus) at 50 rpm and a temperature of 37 ⁇ 0.5 °C in 125 mL 0. 1 N HC1, at a pH of about 1.2, less than 1 %, less than 5%, less than 10%, less than 20%, less than 30%, or less than 40% of the salt is released within 30 minutes, within 60 minutes, within 90 minutes, or within 120 minutes.
  • a USP type 2 dissolution system Paddle Apparatus
  • Embodiment 42 The colonoscopy composition of any one of Embodiments 30 to 40, further comprising an extended-release layer between the core and the first polymer coating layer, wherein the colonoscopy composition is configured so that, tested with a USP type 2 dissolution system (Paddle Apparatus) at 50 rpm and a temperature of 37 ⁇ 0.5 °C in 125 mL of 0.05 M phosphate buffer, at a pH of about 6.8 or a pH of about 7.4,
  • a USP type 2 dissolution system Paddle Apparatus
  • Embodiment 43 The colonoscopy composition of Embodiments 41 or 42, wherein the extended-release layer comprises one or more of ethyl cellulose, sodium polyacrylate, polyacrylamide copolymer, ethylene maleic anhydride copolymer, crosslinked carboxymethyl cellulose, polyvinyl alcohol copolymer, and cross-linked polyethylene oxide.
  • Embodiment 44 The colonoscopy composition of any one of Embodiments 30 to 42, which is configured to reduce or eliminate the taste of the electrolytes.
  • Embodiment 45 The colonoscopy composition of any one of Embodiments 39 to 44, wherein:
  • the one or more electrolytes comprise one or more salts selected from the group consisting of sodium chloride, potassium chloride, sodium bicarbonate, sodium sulfate and magnesium sulfate;
  • the first polymer coating layer enclosing the core is a methacrylic acid copolymer; wherein the electrolytes range from about 5% to about 25% by weight in the composition;
  • the gelling agent is carboxymethyl cellulose.
  • Embodiment 46 The colonoscopy composition of any one of Embodiments 30 to 45, further comprising a polyethylene glycol, and optionally a suspending agent admixed with the composition.
  • Embodiment 47 The colonoscopy composition of Embodiment 46, wherein the composition is in the form of a liquid, wherein the suspending agent selected from, but not limited to xanthan gum, polyethylene glycol, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, agar, bentonite, carbomers, polyvinylpyrrolidone K30, and any combination thereof, wherein the polymer-coated core is suspended in the liquid.
  • Embodiment 48 The colonoscopy composition of Embodiment 47, which is in the form of a gel.
  • Embodiment 49 A kit comprising two pouches, wherein:
  • Embodiment 50 The kit of Embodiment 49, wherein the polyethylene glycol polymer has a molecular weight ranging from 2000 daltons to 8000 daltons.
  • Embodiment 51 The kit of Embodiment 49 or 50, further comprising a flavoring agent.
  • Embodiment 52 The kit of any one of Embodiment 49 to 51, further comprising a suspending agent selected from, but not limited to xanthan gum, polyethylene glycol, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and any combination thereof.
  • Embodiment 53 The kit of any one of Embodiments 49 to 52, wherein the kit further comprises a laxative, or mixtures thereof.
  • Embodiment 54 The kit of Embodiment 53, wherein the laxative contains additional salts that are not coated.
  • Embodiment 55 The colonoscopy composition of any one of Embodiments 46 to 48, wherein the polyethylene glycol polymer has a molecular weight ranging from 2000 daltons to 8000 daltons.
  • Embodiment 56 The colonoscopy composition of any one of Embodiments 46 to 48 and 55, wherein the combination comprises a flavoring agent(s).
  • Embodiment 57 The colonoscopy composition of any one of Embodiments 45 to 47, 55 and 56, wherein the combination further comprises a laxative(s).
  • Embodiment 58 The colonoscopy composition of Embodiment 57, wherein the laxative contains additional salts that are not coated.
  • Embodiment 59 A method of providing electrolytes to a subject in need thereof, comprising administering to the subject the colonoscopy composition of any one of Embodiments 30 to 48 and 55 to 58, or administering to the subject the kit of any one of
  • Embodiment 60 The method of Embodiment 59, wherein the subject has an electrolyte imbalance.
  • Embodiment 61 The method of Embodiment 59 or 60, wherein the subject has a lower-than-normal level of electrolytes.
  • Embodiment 62 A balanced electrolyte composition comprising:
  • Embodiment 63 The electrolyte composition of Embodiment 62, wherein the one or more electrolytes are admixed with a diluent or a gelling agent in the core.
  • Embodiment 64 The electrolyte composition of Embodiment 63, wherein the electrolytes are in the form of a plurality of granules in the core.
  • Embodiment 65 The electrolyte composition of Embodiment 64, wherein the granules have an average particle size smaller than 2000 microns.
  • Embodiment 66 The electrolyte composition of Embodiment 63, wherein the diluent or the gelling agent comprises one or more of polyethylene glycol, gellan gum, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, mannitol, sorbitol, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, Kollidon (povidone), com starch, and carboxy methylcellulose.
  • the diluent or the gelling agent comprises one or more of polyethylene glycol, gellan gum, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, mannitol, sorbitol, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, Kollidon (povidone), com starch, and carboxy methylcellulose.
  • Embodiment 67 The electrolyte composition of Embodiment 63, wherein the gelling agent is present in the core and swells upon contact with water thereby slowly releasing the electrolytes.
  • Embodiment 68 The electrolyte composition of Embodiment 62, wherein the core further comprises an inner core free from the inorganic salt(s), wherein the electrolytes are coated on the inner core.
  • Embodiment 69 The electrolyte composition of Embodiment 62, further comprising an extended-release layer between the core and the first polymer coating layer, wherein the electrolyte composition is configured to provide an extended release of the electrolytes over at least 1 hour.
  • Embodiment 70 The electrolyte composition of Embodiment 69, wherein the extended-release layer comprises one or more of ethyl cellulose, sodium polyacrylate, polyacrylamide copolymer, ethylene maleic anhydride copolymer, crosslinked carboxymethyl cellulose, polyvinyl alcohol copolymer, and cross-linked polyethylene oxide.
  • Embodiment 71 The electrolyte composition of Embodiment 62, wherein the first polymer coating is an enteric coating.
  • Embodiment 72 The electrolyte composition of Embodiment 62, wherein the first polymer coating is a reverse enteric coating.
  • Embodiment 73 The electrolyte composition of Embodiment 62, further comprising an undercoat between the core and the first polymer coating layer.
  • Embodiment 74 The electrolyte composition of Embodiment 62, further comprising a second polymer coating enclosing the core and the first polymer coating.
  • Embodiment 75 The electrolyte composition of Embodiment 62, wherein the second polymer comprises wax, PEG stearate coating, and any combination thereof.
  • Embodiment 76 The electrolyte composition of Embodiment 62, which is in the form of a tablet or capsule.
  • Embodiment 77 The electrolyte composition of Embodiment 62, which is in the form of a powder.
  • Embodiment 78 The electrolyte composition of Embodiment 77, wherein the powder is dissolved in a liquid.
  • Embodiment 79 The electrolyte composition of Embodiment 62, which is in the form of a plurality of particles, wherein each of the particles comprises the core and the first polymer coating.
  • Embodiment 80 The electrolyte composition of Embodiment 62, wherein the one or more electrolytes are inorganic salt(s) selected from the group consisting of sodium salt, potassium salt, calcium salt, iron salt, copper salt, zinc salt, manganese salt, magnesium slat, molybdenum salt, cobalt salt, and chromium salt.
  • the one or more electrolytes are inorganic salt(s) selected from the group consisting of sodium salt, potassium salt, calcium salt, iron salt, copper salt, zinc salt, manganese salt, magnesium slat, molybdenum salt, cobalt salt, and chromium salt.
  • Embodiment 81 The electrolyte composition of Embodiment 62, wherein the one or more electrolytes are inorganic salt(s) comprise one or more anions selected from the group consisting of chloride, fluoride, sulfate, bisulfate, carbonate, bicarbonate, phosphate.
  • Embodiment 82 The electrolyte composition of Embodiment 62, wherein the first polymer coating is configured to mask the taste of the electrolytes.
  • Embodiment 83 The electrolyte composition of Embodiment 62, further comprising a suspending agent or gelling agent, wherein the suspending agent or gelling agent is gellan gum, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, mannitol, sorbitol, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, Kollidon (povidone), com starch, and carboxy methylcellulose.
  • the suspending agent or gelling agent is gellan gum, xanthan gum, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, lactose, mannitol, sorbitol, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, Kollidon (povidone), com starch, and carboxy methylcellulose.
  • Embodiment 84 The electrolyte composition of Embodiment 62, further comprising an effervescent agent.
  • Embodiment 85 A liquid system comprising the electrolyte composition of Embodiment 62 and a suspending agent admixed with the composition.
  • Embodiment 86 The liquid system of Embodiment 85, wherein the suspending agent is selected from, but not limited to xanthan gum, polyethylene glycol, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, agar, bentonite, carbomers, polyvinylpyrrolidone K30, and any combination thereof.
  • the suspending agent is selected from, but not limited to xanthan gum, polyethylene glycol, sodium alginate, sodium carboxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, agar, bentonite, carbomers, polyvinylpyrrolidone K30, and any combination thereof.
  • Embodiment 87 The liquid system of Embodiment 85, which is a gel.
  • Embodiment 88 The liquid system of Embodiment 85, wherein total volume is about 0.5 liter to about 1 liter.
  • Embodiment 89 The method of Embodiment 85, wherein the electrolyte composition is effective in suppressing the taste of the electrolytes.
  • Embodiment 90 A method of providing electrolytes to a subject, the method comprising administering to the subject the balanced electrolyte composition of Embodiment 62.
  • Embodiment 91 The method of Embodiment 90, wherein the balanced electrolyte composition is in the form of a gelling tablet.
  • Embodiment 92 The method of Embodiment 90, wherein the balanced electrolyte composition is in the form of effervescent electroly te tablets.
  • Embodiment 93 The method of Embodiment 90, wherein the balanced electrolyte composition is a sprinkle formulation.
  • Embodiment 94 The method of Embodiment 90, wherein the balanced electrolyte composition is effective in suppressing the taste of the electrolytes.
  • Embodiment 95 The method of Embodiment 90, wherein the subject has an electrolyte imbalance.
  • Embodiment 96 The method of Embodiment 90, wherein the subject patient suffers from dysphagia.
  • Embodiment 97 The method of Embodiment 90, wherein the balanced electrolyte composition is a delayed-release formulation.
  • Triethyl citrate was added as a plasticizer. PEG 3350 or Glyceryl monostearate make the coating softer. In batch 3, only PEG 3350 at 10% of the enteric coating polymer level was used. A solvent mixture containing ethanol, acetone and water at 50%, 20% and 30%, respectively was used in batch 4. Sodium chloride granules were coated with 10% Eudragit L100-55 and used blue color to identify the electrolyte. Sodium chloride was passed through 20 mesh before using in the batch. The volume of coating solution was thicker than desired. In batch 5, Eudragit concentration in the coating solution was reduced from 10% to 5%. The spraying process improved significantly. [0215] Baking soda was in a fine powder form, which was very hard to coat.
  • a solution of 2.03 g HPMC E5 in 15.31 g water was prepared. It was used to granulate 100 grams of baking soda (batch 7). The dough was passed through a 14-mesh sieve. The granules were dried in an oven at 40°C and then transferred to Fluid Bed dryer for full drying and coating. 5% Eudragit was used to coat and the concentration of Eudragit in the coating solution was 4%.
  • baking soda was granulated with Eudragit L100-55. The granules turned out to be satisfactory.
  • sodium bicarbonate was first granulated with Eudragit LI 00-55 dissolved in ethanol and acetone (70:30). The granules were passed through a 14-mesh sieve and dried in oven at 40°C. The granules with coated with Eudragit LI 00-55. Bigger granules were less colored suggesting lower coating. It is important to have a uniform particle size. Smaller particles were observed to be get coated better, but there was higher % loss of smaller particles to the filter of fluid bed dryer. Table 1 lists the result of sieve analysis of coated sodium bicarbonate.
  • KC1 Potassium chloride
  • batch 10 KC1 granules were coated as is. The color yellow was used to differentiate from other coated granules. A10% coating was used and the granules showed nice uniform yellow color.
  • Batch 15 coating of sodium bicarbonate.
  • the granulation solution was prepared using 1040 mg xanthan gum in 25 mL water.
  • Sodium bicarbonate (151.2 g) was mixed with 48.63 g mannitol. Powders were mixed well and passed through 20 mesh sieves. The powder mixture was granulated with the xanthan gum gel. The wet mass was passed through a 14-mesh sieve and dried at 50°C. The coated granules had satisfactory properties.
  • Batch 16 Coating of potassium chloride. Weighed 109.75 gm of KC1, passed through a 20-mesh sieve, then passed through a 80-mesh sieve. Granules on the top of 80 mesh sieve (100.27 gm) were used for coating. The coating process was excellent and no lumps were observed in the granules. The granules were slightly salty, but could feel a slight bitter taste of potassium chloride.
  • a stack of sieves was prepared in the order listed in Table 3 above.
  • Sodium sulfate powder 50.03 g, was placed on 14 mesh. The stack was vibrated to let the powder pass through sieves gently. Nearly all the powder passed through 14 and 20 mesh. It means, all the particles were smaller than 841 microns. Only about 5% stayed on 30 mesh, which suggested that most particles were smaller than 595 microns. About 42% powder passed through 60 mesh (250 microns) and 58% remained on the top. In general, most of the sodium sulfate particles were less than 500 microns.
  • Table 5 Enteric Coating of FB Batch #20, NaHCO3 granules with HPC
  • Ethyl cellulose is not soluble in water, but dissolves in methanol, ethanol etc. organic solvents. For 10% coating on 100 g sodium chloride, 10 grams of ethyl cellulose was needed. Ten grams of ethyl cellulose did not dissolve easily in 200 mL of 200 proof ethanol. The effect of % water in ethanol on the solubility of ethyl cellulose was studied. Prepared the coating solution using - 10 g ethyl cellulose, 1-gram tri ethyl citrate, FD&C Blue color 30 mg in 20% water in ethanol solution. The coating process was smooth and the % yield was 87.3%. [0252] Example 11
  • KC1 granules were smaller than NaCl granules.
  • KC1 was granulated first.
  • KC1 100 grams was mixed with 11 g HPC Klucel EXF in a ziplock bag.
  • Granulating solution contained- Sodium CMC 7LF - 2 grams and PEG 400 - 202.2 mg in Water.
  • KC1 with HPC mixture was granulated with the granulating solution. The mass was passed through 12-mesh sieve and then dried at 40°C overnight. Table 6 lists the composition of the coating solution.
  • Table 7 Composition for the Granulation of Na2SO4
  • Table 8 lists the ingredients used in the composition of the coating solution
  • Batch 25 Coating of sodium chloride with ethyl cellulose with HPMC undercoat.
  • Table 10 Granulating solution with Sodium CMC used in sodium chloride granules
  • HPMC coating solution - 9.53 g of HPMC was dissolved in 151.53 mL water. The coating process was completed in 2 hours and the coating was satisfactory.
  • Table 11 Composition of ethyl cellulose coating solution. 4 gm
  • Weight of coated NaCl 208.14 gm; %Yield: 100 %.
  • Table 12 Composition used in the Granulation of NaHCO3
  • PEG 400 was added to hot water. CMC was added slowly to get a slightly thick gel.
  • PEG Stearate Coating Prepared a PEG Stearate solution in water-ethanol mixture (Table 14) It was used to coat enteric-coated granules of sodium bicarbonate.
  • the granulation step was similar to the granulation performed earlier. The key was to bind the materials but should not be too sticky.
  • the core contained a diluent, an electrolyte and a gelling agent.
  • the bead size after spheronization was between 1 to 4 mm. These beads were coated with HPMC E5 as an undercoat. The beads were then enteric coated and then coated with PEG Stearate.
  • USP Apparatus II (paddle) is used to conduct dissolution studies of coated electrolytes.
  • Three media are used - distilled water, 0. 1 N HC1, and 0.05 M phosphate buffer, pH 6.8.
  • the volume of each medium to be used is 125 to 900 mL.
  • the paddle speed of 50 rpm is used.
  • the sampling times for the dissolution studies in HC1 are - 10, 20, 30, 45 and 60 minutes.
  • the sampling times for the dissolution studies in water and phosphate buffer are - 15, 30, 60, 90, 120 and 180 minutes.
  • One coated electrolyte is tested in each dissolution testing.
  • Sodium is a common ion in sodium chloride, sodium sulfate and sodium bicarbonate.
  • the other two cations are - potassium and Magnesium.
  • ICP-MS technique is used to determine the levels of cations in the dissolution media.
  • the salts are taste tested by the volunteers. About 1 to 2 grams of coated electrolytes are administered to the subjects. They keep the salts in the mouth for 3 to 5 minutes and the taste is recorded. The salts are spit out and the mouth is rinsed with water. The taste of salt in the mouth is examined again after 3 to 5 minutes.
  • a mixture of salts can be coated.
  • Benefit of coating a mixture includes saving of time of coating, saving of cost, ease of handling materials during packaging etc.
  • the mixture may include for example sodium chloride + potassium chloride, sodium chloride + sodium sulfate, sodium chloride + sodium bicarbonate, sodium chloride + potassium chloride + sodium sulfate, sodium chloride + potassium chloride + sodium sulfate + sodium bicarbonate, etc.
  • Sodium sulfate and sodium bicarbonate are commercially available in a fine powder form. Sodium sulfate, 170 grams, was mixed with 30 grams of sodium bicarbonate. It was mixed with 22 grams of HPC and granulated with the sodium CMC solution. The granules were dried in the oven at 40°C. The granules were coated with HPMC E5 (undercoat), Eudragit LI 00-55 (enteric coating) and PEG stearate.
  • New batches were prepared using only PEG 3350 and different gelling agents - xanthan gum, kappa Carrageenan and gelatin. Gelatin needed heating at about 80 °C to dissolve fully. All formed satisfactory gels. In order to make a stable gel and also, to block salty taste, it was deemed necessary to coat the salts. Enteric (Eudragit L 100/55 , batch 8) and reverse entering (Eudragit EPO, batch 9) coatings were compared on sodium chloride granules. One gram of polymers dissolved in 10 mL of 200 proof ethanol. Yellow and blue colors were added for enteric and reverse entering coatings, respectively.
  • Example 23 Ten grams of sodium chloride granules were coated in a beaker under low heat and adding the coating solutions drop wise. The coated granules produced results as expected when the granules were added to 0. 1 N HC1, water or pH 10 sodium hydroxide solution. The granules were tasted as is and showed slight salty taste. It means the coating were found to be effective. [0317] Example 23
  • Table 16 Colonoscopy Batch #10, #11 and #12
  • Plenvu® is one of the leading colonoscopy composition available in the market. It contains Dose 1 and Dose 2. Dose 1 contains one pouch, whereas Dose 2 has Pouches A and B. The total weight of pouch in Dose 1 is 115.96 grams, which contains - PEG 3350- 100 g, Sodium sulfate - 9 g, Sodium chloride - 2 g, Potassium chloride - 1 g. Dose 1 is dissolved in 16 oz (480 mL) of water. A 30-mL solution of Dose 1 of Plenvu was prepared. Various batches, which contained different amounts of aspartame was also prepared (Table 17).
  • Plenvu Dose 2 pouch A contains PEG 3350 - 40 grams, sodium chloride - 3.2 grams and potassium chloride - 1.2 g and unknown excipients - 1.86 g (total weight - 46.26 g).
  • Plenvu Dose 2 Pouch B contains sodium ascorbate - 48. 11 g and ascorbic acid - 7.54 g (total weight - 55.65 g).
  • a 30 mL solution of Dose 2 was prepared by mixing appropriate amounts of powders from Pouch A and Pouch B. The solution had a slight saltiness, and it was moderately sweet.
  • a 30 mL salt solution with 750.4 mg sodium chloride, 2.25 g sodium sulfate and 75 mg of citric acid was prepared. 0.25% or less quantity of aspartame was added in the samples and their taste was checked. Similar to results for Plenvu Dose 1, the saltiness decreased as the amount of aspartame was increased. The sample was very salty without aspartame. In this study, a small percentage of aspartame was added so that the sweetness could be controlled (Table 18). More citric acid buffer was added to samples 18 and 19. In general, citric acid and aspartame addition to the formulation was observed to have a beneficial effect on taste of the formulation.
  • Table 21 lists the composition of batch 32 and its observations. Sodium CMC showed a potential of being used in the colonoscopy formulations.
  • a typical colonoscopy composition was used and the effects of xanthan gum and sodium carboxymethyl cellulose as the gelling agents were examined (batches 35 to 37, Table 22).
  • Batch #35 formed a thin gel and has a sweet and salty taste.
  • a batch of colonoscopy composition without xanthan gum was prepared (Table 24).
  • PEG 3350, ascorbic acid, citric acid, acesulfame and fruit punch flavor were dissolved in water. The taste of product was satisfactory.
  • Table 24 Composition of colonoscopy composition without xanthan gum.
  • Xanthan gum and gellan gum at 5 mg/mL were added to water and added citric acid at 1.2 mg/mL. Both did not form gel.
  • Various gelling agents (MC, CMC, Sodium CMC, Gellan gum, Xanthan gum, HPMC E5, HPMC E50) were used to attempt to form a gel in the presence of citric acid. 62.5 mL water, 325 mg gelling agent and 62.5 mg of citric acid. pH was maintained at 4.0.
  • Table 27 Composition of colonoscopy composition, batch 41
  • Table 28 lists the compositions of Batches # 42 to #45. We wanted to study the effect of various polymers on the gel formation. [0363] Table 28: Composition of colonoscopy compositions, batch 42 to 45.
  • Batch #43 Transferred the powder mixture to a zip lock bag. Mixed well and added to water, shook for a minute. Uniformly distributed. No lumps, hazier than batch #42. Good sweetness and flavor, not very salty. pH 3.19. Slightly more viscous than batch #42. [0366] Batch #44: same as batch #43. Hazy and slightly viscous than batch #42.
  • Batch #45 Same viscosity as batch #43 and #44. Hazy, this batch was more clear than other three formulations.
  • citric acid instead of citric acid, 0.1 M and 0.25 M citrate buffers were used to prevent fluctuations in the pH with sodium bicarbonate.
  • the pH is stable with 0.25 M citrate buffer, but the solution becomes too sour, and this concentration cannot be used.
  • Table 29 Colonoscopy Compositions, Batches #46 and #47
  • #47- dissolved easily but formed a turbid solution. Not sweet, lemon flavor is not so good. It was too strong. Some acidic touch.
  • Batch #48 did not contain citric acid, a coloring agent and a flavoring agent. [0376] Table 30: Colonoscopy composition batch #48.
  • Blanose CMC 7HCF was used as the gelling agent (Table 31). It is a neutral molecule.
  • pH of batch #49 with granules after 10 min was 6.36. That means, NaHCO3 granules reacted mostly with acid.
  • the granules were coated with PEG stearate and MCT (medium chain triglyceride).
  • PEG stearate 604.8 mg was mixed with MCT (1.073 g, 36. 1% PEG Stearate in the solution) and heated to produce a solution.
  • Enteric coated sodium chloride, potassium chloride, sodium bicarbonate and sodium sulfate granules were weighed and mixed.
  • the mixture was coated with 3 drops of PEG Stearate-MCT solution. The effect of oil coating on the dissolution rate of these electrolytes was observed. Colonoscopy batch #50 did not have any citric acid (Table 32).
  • Acesulfame Added 50 mL water. Mixed with spatula. No lumps formed, thick gel. Good taste. It was sweeter. Therefore, need to reduce acesulfame 40 mg. No salty taste. All granules settled down. The solution was turbid. After half hour, the granules dissolved partially.
  • Table 34 Colonoscopy Composition, Batches #52 to #54
  • xanthan gum can be used in the formulation instead of Blanose.
  • Table 36 Colonoscopy Composition, Batch # 57 [0400] Similar to previous batches, all electrolytes were weighed and added to the MCT-PEG Stearate solution. The salts were mixed well to get coated with the solution. Weighed PEG 3350 and added to the salt mixture. Xanthan gum and acesulfame were added to the above mixture and mixed well. Added water and stirred to dissolve the mixture.
  • Table 40 lists the composition of the colonoscopy preparation, Batch 61 containing magnesium citrate and sodium picosulfate.
  • Table 40 Colonoscopy composition, Batch 61
  • Table 41 lists the composition of the colonoscopy preparation, Batch 62.
  • Coated granules of four salts listed in Table 41 were prepared using the aforementioned process. The granules were color coded as described in the table. The mixture of coated granules was placed in a pouch. PEG 3350 along with sorbitol, gelling agent, an artificial sweetener and a flavoring agent were placed in another pouch. The patient adds the ingredients from the PEG 3350 pouch to 500 ml water and will stir well. It forms a thick gel. The mixture of coated granules was suspended in the gel and the suspension is administered to the patient. The empty bottle of gel is rinsed with more water and the rinsate is consumed. [0418] In batch 63, instead of granules of salts, beads of various salts in the formulation were used.
  • Table 42 lists the colonoscopy formulation composition of batch 64.
  • Table 42 Colonoscopy composition, batch # 64 [0421] Coated bead of three salts listed in Table 42 were prepared using the method described before. The beads were color coded. The beads were mixed with sorbitol, gelling agent and a flavoring agent. The mixture was filled in a pouch. The mixture is added to 500 mL water and stir well. It forms a thick gel. The gel contains suspended salt beads. The gel is consumed. The contained is rinsed with water, which is then consumed.
  • Pouch 1 contains PEG 3350, ascorbic acid, and sodium ascorbate.
  • Pouch 2 contains three salts and one biscodyl enteric coated tablet. Contents of pouch 1 are dissolved in 500 mL water. Contents of pouch 2 are swallowed using the solution of PEG 3350 followed by water. The second dose is taken on the day of colonoscopy.
  • non-colonoscopy compositions which includes but is not limited to sports drinks, formulations containing a mixture of various key salts to patients suffering from diarrhea, vomiting etc., formulations with specific single electrolytes such as sodium chloride, potassium chloride or sodium bicarbonate.
  • all the formulations must have only water-soluble components including polymers used in the coating of granules, spheres etc.
  • water-insoluble polymers such ethyl cellulose can be used.
  • Table 44 Composition of a gel formulation
  • the volume of 000 capsule is 1.37 mL.
  • the density of KC1 granules was observed to be 0.929 g/mL and 0.821 g/mL.
  • the amount of KC1 in each capsule will be 0.699 g and 0.617 g, respectively.
  • Average human beings cannot ingest this capsule. Thus, it is recommended to open the capsule and transfer the contents in a spoon or in a small glass.
  • the granules can be administered with water.
  • the granules were tasteless and there was no need to add any excipients. For higher doses, more than one capsule can be used.
  • the granules can be sprinkled over edible semisolids, such as Jello, Jelly, Apple sauce etc.
  • the density values of EC-coated NaCl granules were observed to be 0.996 g/mL and 0.809 g/mL for small and large granules.
  • 1.36 g and 1.11 g granules can fill one capsule.
  • Pouches or stick-packs can be filled with 3-4-gram granules.
  • the granules can be administered “as is” or it can be sprinkled over edible semi-solids, such as Jello, Jelly, Apple sauce etc.
  • the coated electrolytes tend to sink when added to water. However, if these electrolytes are added to a gel, the electrolytes remain suspended. Table 48 lists the composition of a formulation, which forms a gel when added to water.
  • Orally disintegrating tablets can be orally administered allowing them to disintegrate. Some elderly people with dry mouth issue do not like this approach as the tablet may further dry their mouth.
  • the ODT can be administered by presoaking it with water in a spoon.
  • the tablet was placed in a spoon and water was added.
  • the tablet absorbed water immediately, resulting in disintegration and swelling of the tablet.
  • This soft mass can be eaten easily by children or elderly patients.
  • Table 49 lists a typical composition of the ODT product. The composition can be easily modified to meet new requirements, if any.
  • Table 50 lists the composition of an effervescent tablet to be placed in a spoon. The effervescent tablet was placed in a spoon and water is added. Tablet disintegrated producing some fuzz. The effervescence helped disintegration of tablets and it disintegrated in a short time.
  • Table 50 Composition of effervescent disintegrating tablets in spoon.
  • Table 51 Composition of effervescent disintegrating tablets in a glass of water
  • Table 52 Composition of a gelling tablets with coated electrolytes
  • the gelling tablet is placed in a tablespoon and water is added.
  • the tablet absorbs water and starts swelling. Add sufficient water so that the tablet swells fully and forms a gel.
  • the soft mass is eaten like an apple sauce. This is good mainly for elderly patients or kids.
  • Athletes or long-distance runners sweat a lot. It is commonly known that electrolytes are lost in the sweat and it can affect the performance. Thus, it is important to replenish electrolytes during the activity.
  • the “On the Run Six-Pack” contains three essential electrolytes and three vitamins. Table 53 lists the composition of this formulations. It also contains a gelling agent, a sweetener and a flavor of one’s choice. The key aspect is formation of a gel by just mixing with 12-16 Oz of water in a “trainer’s bottle”.

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Abstract

L'invention concerne des compositions de sels revêtus. L'invention concerne également des procédés de revêtement du ou des sels inorganiques, de masquage du goût des sels et de régulation de la libération des sels dans le tractus gastro-intestinal. Les sels granulaires peuvent être revêtus tels quels. Les sels en poudre peuvent être granulés en premier ou sphéronisés ou formés en minicomprimés ou capsules avant revêtement. Les sels enrobés de granulés sont utilisés dans des préparations de coloscopie et des préparations non de coloscopie.
PCT/US2024/059606 2023-12-12 2024-12-11 Sels inorganiques revêtus et leurs utilisations Pending WO2025128724A1 (fr)

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US4574080A (en) * 1982-08-13 1986-03-04 A/S Alfred Benzon Combination formulation
US4822619A (en) * 1987-02-18 1989-04-18 Ionor, Inc. Controlled release pharmaceutical preparation containing a gastrointestinal irritant drug
US5674529A (en) * 1995-06-06 1997-10-07 Church & Dwight Co., Inc. Alkalinizing potassium salt controlled release preparations
US20130195974A1 (en) * 2010-07-30 2013-08-01 Péter Hajnal Ph-dependent gradual release pharmaceutical composition
WO2024246566A1 (fr) * 2023-05-31 2024-12-05 Meditop Gyógyszeripari Kft. Pastille enrobée gastro-résistante contenant du bicarbonate de sodium, production associée, préparation pharmaceutique et complément alimentaire contenant celle-ci, et leur utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4574080A (en) * 1982-08-13 1986-03-04 A/S Alfred Benzon Combination formulation
US4822619A (en) * 1987-02-18 1989-04-18 Ionor, Inc. Controlled release pharmaceutical preparation containing a gastrointestinal irritant drug
US5674529A (en) * 1995-06-06 1997-10-07 Church & Dwight Co., Inc. Alkalinizing potassium salt controlled release preparations
US20130195974A1 (en) * 2010-07-30 2013-08-01 Péter Hajnal Ph-dependent gradual release pharmaceutical composition
WO2024246566A1 (fr) * 2023-05-31 2024-12-05 Meditop Gyógyszeripari Kft. Pastille enrobée gastro-résistante contenant du bicarbonate de sodium, production associée, préparation pharmaceutique et complément alimentaire contenant celle-ci, et leur utilisation

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