WO2000035296A1 - Liberation amelioree d'agents medicamenteux actifs par un enrobage de chewing-gum - Google Patents

Liberation amelioree d'agents medicamenteux actifs par un enrobage de chewing-gum Download PDF

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Publication number
WO2000035296A1
WO2000035296A1 PCT/US1999/029742 US9929742W WO0035296A1 WO 2000035296 A1 WO2000035296 A1 WO 2000035296A1 US 9929742 W US9929742 W US 9929742W WO 0035296 A1 WO0035296 A1 WO 0035296A1
Authority
WO
WIPO (PCT)
Prior art keywords
coating
active agent
gum
chewing gum
chewing
Prior art date
Application number
PCT/US1999/029742
Other languages
English (en)
Inventor
Sonya S. Johnson
David W. Record
Michael J. Greenberg
Michael A. Reed
Victor V. Gudas
Philip G. Schnell
Donald A. Seielstad
Henry T. Typrin
Michael P. Russell
David L. Witkewitz
Joo H. Song
Donald J. Townsend
Robert J. Yatka
Ronald L. Ream
Christine L. Corriveau
William J. Wokas
Original Assignee
Wm. Wrigley Jr. Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US1996/018977 external-priority patent/WO1998023165A1/fr
Priority claimed from US09/308,972 external-priority patent/US6165516A/en
Priority to AU21843/00A priority Critical patent/AU765999B2/en
Priority to EP99966257A priority patent/EP1139774A4/fr
Priority to CA002355779A priority patent/CA2355779C/fr
Priority to BR9916303-9A priority patent/BR9916303A/pt
Application filed by Wm. Wrigley Jr. Company filed Critical Wm. Wrigley Jr. Company
Priority to US09/510,878 priority patent/US6355265B1/en
Publication of WO2000035296A1 publication Critical patent/WO2000035296A1/fr
Priority to US09/618,808 priority patent/US6322806B1/en
Priority to US09/621,643 priority patent/US6627234B1/en
Priority to US09/748,699 priority patent/US6541048B2/en
Priority to US09/759,561 priority patent/US6558692B2/en
Priority to US09/759,838 priority patent/US6290985B2/en
Priority to US09/924,914 priority patent/US6465003B2/en
Priority to US09/955,870 priority patent/US6426090B1/en
Priority to US09/956,445 priority patent/US6592850B2/en
Priority to US09/992,122 priority patent/US6773716B2/en
Priority to US09/990,628 priority patent/US20020159956A1/en
Priority to US10/024,631 priority patent/US7163705B2/en
Priority to US11/269,980 priority patent/US7935362B2/en
Priority to US12/651,873 priority patent/US20100104620A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/02—Apparatus specially adapted for manufacture or treatment of chewing gum
    • A23G4/025—Apparatus specially adapted for manufacture or treatment of chewing gum for coating or surface-finishing
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A23G4/064—Chewing gum characterised by the composition containing organic or inorganic compounds containing inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A23G4/068—Chewing gum characterised by the composition containing organic or inorganic compounds containing plants or parts thereof, e.g. fruits, seeds, extracts
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A23G4/10—Chewing gum characterised by the composition containing organic or inorganic compounds characterised by the carbohydrates used, e.g. polysaccharides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/06—Chewing gum characterised by the composition containing organic or inorganic compounds
    • A23G4/12—Chewing gum characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins
    • A23G4/126—Chewing gum characterised by the composition containing organic or inorganic compounds containing microorganisms or enzymes; containing paramedical or dietetical agents, e.g. vitamins containing vitamins, antibiotics
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
    • A23G4/00—Chewing gum
    • A23G4/18—Chewing gum characterised by shape, structure or physical form, e.g. aerated products
    • A23G4/20—Composite products, e.g. centre-filled, multi-layer, laminated
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/86—Addition of bitterness inhibitors
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to methods for producing chewing gum. More particularly, the invention relates to producing chewing gum containing an effective amount of an active medicament.
  • the active medicament is added to the chewing gum coating to control its rate of release from chewing gum and control the release of medicament for maximum effectiveness.
  • efforts have been devoted to controlling release characteristics of various ingredients in chewing gum. Most notably, attempts have been made to delay the release of sweeteners and flavors in va ⁇ ous chewing gum formulations to thereby lengthen the satisfactory chewing time of the gum. Delaying the release of sweeteners and flavors can also avoid an undesirable overpowering burst of sweetness or flavor during the initial chewing period.
  • some ingredients have been treated so as to increase their rate of release in chewing gum.
  • the active medicament that is added to the gum coating is generally released very readily.
  • An active medicament may be added to the gum coating which is a water soluble matrix such that, during the chewing period, the medicament may be released quickly, resulting in a fast release. This would allow a chewing gum coating to be a carrier for an active medicament with these fast release characteristics.
  • active medicaments can be used to treat diseases and as such are typically referred to as drugs or medicaments.
  • the drugs or medicaments can be used for preventive purposes. Still, it is known to provide medicaments to an individual for a variety of non-medical purposes including enhancing performance or maintaining health.
  • medicaments run the gamut from stimulants such as caffeine to drugs such as analgesics, tranquilizers, cardiovascular products, as well as vitamins, minerals, and supplements. Some such medicaments are taken on an "as-needed" basis while other medicaments must be taken at regular intervals by the individual.
  • parenteral administration is the administration of the drug intravenously directly into the blood stream.
  • Enteral refers to the administration of the drug into the gastrointestinal tract.
  • the goal of the drug administration is to move the drug from the site of administration towards the systemic circulation.
  • Oral administration of drugs is by far the most common method of moving drugs towards systemic circulation.
  • drug absorption usually occurs due to the transport of cells across the membranes of the epithelial cells within the gastrointestinal tract.
  • Absorption after oral administration is confounded by numerous factors. These factors include differences down the alimentary cannel in: the luminal pH; surface area per luminal volume; perfusion of tissue, bile, and mucus flow; and the epithelial membranes. See Merck Manual at page 2599.
  • a further issue affecting the absorption or orally administered drugs is the form of the drug. Most orally administered drugs are in the form of tablets or capsules. This is primarily for convenience, economy, stability, and patient acceptance.
  • these capsules or tablets must be disintegrated or dissolved before absorption can occur.
  • factors capable of varying or retarding disintegration of solid dosage forms there are a variety of factors that affect the dissolution rate and therefore determine the availability of the drug for absorption. See Merck Manual at page 2600.
  • the drug may be metabolized before it can be measured in the general circulation.
  • This cause of a decrease in drug input is called the first pass effect.
  • a large number of drugs show low bioavailabilities owning to an extensive first pass metabolism.
  • the two other most frequent causes of low bioavailability are insufficient time in the Gl tract and the presence of competing reactions. See Merck Manual at page 2602.
  • Bioavailability considerations are most often encountered for orally administered drugs. Differences in bioavailability can have profound clinical significance.
  • parenteral administration does provide a method for eliminating a number of the variables that are present with oral administration, parenteral administration is not a preferable route.
  • parenteral administration requires the use of medical personnel and is just not warranted nor practical for the administration of most agents and drugs, e.g., analgesics. Even when required, parenteral administration is objectionable due to patient concerns including comfort, infection, etc., as well as the equipment and costs involved.
  • coated chewing gum products including a medicament or active agent.
  • the medicament or active agent is present within the coating of a chewing gum composition. It has been found that by adding the active agent to a gum coating, the medicament or active agent is quickly released from the chewing gum into saliva. Possibly, saliva coats the oral tissues under the tongue (sublingual) and the sides of the mouth where the drug may partition from the saliva into the oral mucosa. Continuing to chew the chewing gum may create a pressure within the buccal cavity and may force the medicament or active agent or medicament directly into the systemic system of the individual through the oral mucosa contained in the buccal cavity. This may greatly enhance the transmucosal absorption of the drug into the systemic system as well as the bioavailability of the drug within the system.
  • the present invention provides a method of drug delivery comprising the steps of: providing a chewing gum with a coating that includes a medicament in the chewing gum coating; chewing the chewing gum to cause the medicament to be released from the chewing gum coating into the buccal cavity of the chewer.
  • the active medicament may be any agent that is traditionally used as a medicament and lends itself to being administered through the oral cavity.
  • active agents may be vitamins, cancer chemotherapeutics; antimycotics; oral contraceptives, nicotine or nicotine replacement agents, minerals, analgesics, antacids, muscle relaxants, antihistamines, decongestants, antibacterial agents, anesthetics, antitussives, diuretics, anti-inflammatories, antibiotics, AIDS medication, neurological drugs, antivirals, psychotherapeutic agents, anti-diabetic agents and cardiovascular agents, nutraceuticals and nutritional supplements. Accordingly, an advantage of an embodiment of the present invention is to provide new methods for delivering medicaments or active agents to an individual.
  • an advantage of an embodiment of the present invention is to provide a method of delivering medicaments to an individual that provides for increase absorption and bioavailability as compared to medicaments that are designed to be absorbed in the Gl tract.
  • an advantage of an embodiment of the present invention is to provide a method of administering a medicament or agent to an individual at a lower level than is typically administered orally while still achieving the same effect.
  • an advantage of an embodiment of the present invention is to provide a method for administering drugs or agents to an individual that heretofore were administered parenterally. Additionally, an advantage of an embodiment of the present invention is to provide a method of administering drugs that is more palatable than current methods.
  • an advantage of an embodiment of the present invention is to provide an improved method for drug delivery.
  • the present invention also provides a method of producing chewing gum with active medicaments to control their release. Such active medicaments are added to a gum coating to deliver the active medicaments systemically.
  • the present invention also relates to the chewing gum products so produced.
  • Active medicaments may be added to sucrose-type gum formulations and sucrose-type coatings.
  • the formulation may be a low or high moisture formulation containing low or high amounts of moisture containing syrup.
  • Active medicaments may also be used in low or non-sugar gum formulations and coatings that use sorbitol, mannitol, other polyols or carbohydrates.
  • Non-sugar formulations may include low or high moisture sugar-free chewing gums. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • the present invention provides improved methods for delivering medicaments and other active agents to an individual, as well as improved formulations including such medicaments and agents.
  • a medicament or active agent is contained in the coating of a chewing gum formulation, in contrast to some prior such formulations where the medicament or active agent is contained directly in the chewing gum composition.
  • the active agent is released into the saliva more quickly.
  • the medicament or active in the saliva may be then forced due to the pressure created by the chewing gum through the oral mucosa in the buccal cavity.
  • the oral mucosa favors drug absorption.
  • the active agent and/or medicament remains in the buccal cavity and may be forced or partitioned through the oral mucosa.
  • An increase in the transmucosal absorption of the drug may be achieved as well as an increase in the bioavailability of the drug as compared to typical oral administration.
  • the drug or active agent may be absorbed much quicker than if it was swallowed as in a typical oral administration. Indeed, the absorption approaches that of a parental administration and bioavailability may be also much greater than oral administration.
  • the administration of the medicament or agent using chewing gum through the buccal activity may provide an increase in therapeutic effect even as compared to parenteral administration.
  • caffeine is commonly used as a stimulant to alleviate the effects of sleep deprivation. It is almost completely metabolized in the liver and therefore classified as a low clearance, flow independent drug. This means its rate of inactivation is unaffected by delivery to the liver and can only be modified by a change in the hepatic enzyme activity.
  • caffeine in a stick of gum (100 mg) of caffeine in a stick of gum.
  • the 60-80 mg level of caffeine is about the level of caffeine found in a conventional cup of coffee.
  • the target level of caffeine in stick gum is about 40 mg per stick, with a range of about 25-60 mg, so that a five stick package of gum would contain about 200 mg of caffeine, or the equivalent of caffeine in two strong cups of coffee.
  • caffeine bitterness overwhelms the flavor initially and lasts throughout the chewing period.
  • piece weight is generally about 1.5 grams per piece. However, one coated piece of gum is about equal to V ⁇ piece of stick gum. Two pellets are equivalent to a stick of gum, and together weigh about
  • the above-noted target level of 40 mg per stick is equivalent to 20 mg per coated piece, or a range of about 12 to 30 mg caffeine per piece. This is about 0.8% to about 2% caffeine in a piece of coated gum, or a target level of 1.3%.
  • Caffeine is a slightly water soluble substance and, therefore, has a moderately slow release from stick chewing gum. Caffeine is 2.1 % soluble in water at room temperature, 15% soluble in water at 80°C and 40% soluble in boiling water. This gives caffeine a moderately slow release as shown below: Chewing Time % Caffeine Release
  • highly water soluble ingredients such as sugars in stick gum are about 80-90% released after only five minutes of chewing.
  • caffeine only about 50% is released, while the other 50% remains in the gum after five minutes of chewing. After 20 minutes almost 90% of caffeine is released.
  • caffeine Even if caffeine is dissolved in hot water and mixed in the stick gum, when the gum is cooled or kept at room temperature, caffeine may return to its normal crystalline state and release at a rate similar to that shown above.
  • the active agent When an active such as caffeine is added to a gum coating, the active agent will have an increased water solubility, and release quickly into the mouth from the gum coating. Depending on the active agent, which may generally be non-water soluble, adding the active agent to a gum coating will increase the release of the active agent from chewing gum. Most water soluble active agents can be easily added to a gum coating to give a more uniform release from chewing gum. Depending on the active agent, the level released from the gum into the mouth can be adjusted for maximum effectiveness. Other agents or medicaments may be included in the present invention.
  • active agent the present invention refers to a compound that has a desired therapeutic or physiological effect once ingested and/or metabolized.
  • the therapeutic effect may be one which decreases the growth of a xenobiotic or other gut flora or fauna, alters the activity of an enzyme, provides the physical relief from a malady (e.g., diminishes pain, acid reflux or other discomfort), has an effect on the brain chemistry of molecules that determine mood and behavior.
  • a malady e.g., diminishes pain, acid reflux or other discomfort
  • the active agent may be any agent that is traditionally used as a medicament and lends itself to being administered through the oral cavity.
  • Such active agents may be vitamins, cancer chemotherapeutics, antimycotics, oral contraceptives, nicotine or nicotine replacement agents, minerals, analgesics, antacids, muscle relaxants, antihistamines, decongestants, anesthetics, antitussives, diuretics, anti-inflammatories, antibiotics, antivirals, psychotherapeutic agents, anti-diabetic agents, cardiovascular agents, bioengineered pharmaceuticals, nutraceuticals and nutritional supplements.
  • Vitamins and co-enzymes that may be delivered using this invention include but are not limited to water or fat soluble vitamins such as thiamin, riboflavin, nicotinic acid, pyridoxine, pantothenic acid, biotin, flavin, choline, inositol and paraminobenzoic acid, camitine, vitamin C, vitamin D and its analogs, vitamin A and the carotenoids, retinoic acid, vitamin E and vitamin K.
  • water or fat soluble vitamins such as thiamin, riboflavin, nicotinic acid, pyridoxine, pantothenic acid, biotin, flavin, choline, inositol and paraminobenzoic acid, camitine, vitamin C, vitamin D and its analogs, vitamin A and the carotenoids, retinoic acid, vitamin E and vitamin K.
  • cancer chemotherapeutics agents include but are not limited to cisplatin (CDDP), procarbazine, mechlorethamine, cyclophosphamide, ,camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, dactinomycin: daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, taxol, transplatinum, 5-fluorouracil, vincristin, vinblastin and methotrexate or any analog or derivative variant thereof.
  • CDDP cisplatin
  • procarbazine mechlorethamine
  • cyclophosphamide cyclophosphamide
  • camptothecin ifosfamide
  • melphalan chlorambucil
  • bisulfan nitrosurea
  • dactinomycin daunorubi
  • Antimicrobial agents that may be used include but are not limited to naficillin, oxacillin, vancomycin, clindamycin, erythromycin, trimethoprim-sulphamethoxazole, rifampin, ciprofloxacin, broad spectrum penicillin, amoxicillin, gentamicin, ceftriazoxone, cefotaxime, chloramphenicol, clavunate, sulbactam, probenecid, doxycycline, spectinomycin, cefixime, penicillin G, minocycline, P-lactamase inhibitors; meziocillin, piperacillin, aztreonam, norfloxacin, trimethoprim, ceftazidime, dapsone.
  • Antifungal agents that may be delivered include but are not limited to ketoconazole, fluconazole, nystatin, itraconazole, clomitrazole, and amphotericin B.
  • Antiviral agents that may be used include but are not limited to acyclovir, trifluridine, idoxorudine, foscamet, ganciclovir, zidovudine, dideoxycytosine, dideoxyinosine, stavudine, famciclovir, didanosine, zalcitabine, rifimantadine, and cytokines.
  • Antacids include cimetidine, ranitidine, nizatidine, famotidine, omeprazole, bismuth antacids, metronidazole antacids, tetracylcine antacids, clarthromycin antacids, hydroxides of aluminum, magnesium, sodium bicarbonates, calcium bicarbonate and other carbonates, silicates, and phosphates.
  • Antihistamines are represented by but are not limited to cimetidine, ranitidine, diphenydramine, prylamine, promethazine, chlorpheniramine, chlorcyclizine, terfenadine, carbinoxamine maleate, clemastine fumarate, diphenhydramine hydrochloride, dimenhydrinate, prilamine maleate, tripelennamine hydrochloride, tripelennamine citrate, chlorpheniramine maleate, brompheniramine maleate, hydroxyzine pamoate, hydroxyzine hydrochloride, cyclizine lactate, cyclizine hydrochloride, meclizine hydrochloride, acrivastine, cetirizine hydrochloride, astemizole, levocabastine hydrochloride, and loratadine.
  • Decongestants and antitussives include agents such as dextromethorphan hydrobromide, levopropoxyphene napsylate, noscapine, carbetapentane, caramiphen, chlophedianol, pseudoephedrine hydrochloride, pseudoephedrine sulfate, phenylephidrine, diphenhydramine, glaucine, pholcodine, and benzonatate.
  • Anesthetics include etomidate, ketamine, propofol, and benodiazapines (e.g., chlordiazepoxide, diazepame, clorezepate, halazepam, flurazepam, quazepam, estazolam, triazolam, alprozolm, midazolam, temazepam, oxazepam, lorazepam), benzocaine, dyclonine, bupivacaine, etidocaine, lidocaine, mepivacaine, promoxine, prilocaine, procaine, proparcaine, ropivacaine, tetracaine.
  • benodiazapines e.g., chlordiazepoxide, diazepame, clorezepate, halazepam, flurazepam, quazepam, estazolam, triazolam, alprozolm, mida
  • Other useful agents may include amobartital, aprobarbital, butabarbital, butalbital mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, thiopental, paral, chloralhydrate, ethchlorvynol, clutethimide, methprylon, ethinamate, and meprobarnate.
  • Analgesics include opioids and other medicaments such as morphine, mepidine, dentanyl, sufentranil, alfentanil, aspirin, acetaminophen, ibuprofen, indomethacine, naproxen, atrin, isocome, midrin, axotal, firinal, phrenilin, ergot, and ergot derivatives (wigraine, cafergot, ergostat, ergomar, dihydroergotamine), imitrex, and ketoprofen.
  • opioids include opioids and other medicaments such as morphine, mepidine, dentanyl, sufentranil, alfentanil, aspirin, acetaminophen, ibuprofen, indomethacine, naproxen, atrin, isocome, midrin, axotal, firinal, phrenilin, ergot, and ergot derivatives (wigraine,
  • Diuretics include but are not limited to acetazolamide, dichlorphenamide, methazolamide, furosemide, bumetanide, ethacrynic acid torseimde, azosemide, muzolimine, piretanide, tripamide, bendroflumethiazide, benzthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, indapamide, metolazone, quinethazone, amiloride, triamterene, sprion olactone, canrenone, and potassium canrenoate.
  • Anti-inflammatories include but are not limited to salicylic acid derivatives (e.g. aspirin), indole and indene acetic acids (indomethacin, sulindac and etodalac) heteroaryl acetic acids (tolmetin diclofenac and ketorolac) aryl propionic acid derivatives (ibuprofen, naproxen, ketoprofen, fenopren, oxaprozine), anthranilic acids (mefenamic acid, meclofenamic acid) enolic acids (piroxicam, tenoxicam, phenylbutazone and oxyphenthatrazone).
  • salicylic acid derivatives e.g. aspirin
  • indole and indene acetic acids indomethacin, sulindac and etodalac
  • heteroaryl acetic acids tolmetin diclofenac and ketorolac
  • Psychotherapeutic agents include thorazine, serentil, mellaril, millazinetindal, permitil, prolixin, trilafon, stelazine, suprazine, taractan, navan, clozaril, haldol, halperon, loxitane, moban, orap, risperdal, alprazolam, chordiaepoxide, clonezepam, clorezepate, diazepam, halazepam, lorazepam, oxazepam, prazepam, buspirone, elvavil, anafranil, adapin, sinequan, tofranil, surmontil, asendin, norpramin, pertofrane, ludiomil, pamelor, vivactil, prozac, luvox, paxil, zoloft, effexor, wellbutrin, serzone, desyrel
  • Cardiovascular agents include but are not limited to nitroglycerin, isosorbide dinitrate, sodium nitroprisside, captopril, enalaprill, enalaprilat, quinapril, lisinopril, ramipril, losartan, amrinone, linnone, vesnerinone, hydralazine, nicorandil, prozasin, doxazosin, bunazosin, tamulosin, yohimbine, propanolol, metoprolol, nadolol, atenolol, timolol, esmolol, pindolol, acebutolol, labetalol, phentolamine, carvedilol, bucindolol, verapamil, nifedipine, amlodipine and dobutamine, or a sexual dysfunction agent like sildenafil citrate (
  • the resultant chewing gum can be used to treat inter alia: coughs, colds, motion sickness; allergies; fevers; pain; inflammation; sore throats; cold sores; migraines; sinus problems; diarrhea; diabetes, gastritis; depression; anxiety, hypertension; angina and other maladies and symptoms. Also these gums may be useful in ameliorating cravings in substance abuse withdrawal or for appetite suppression.
  • Specific active agents or medicaments include by way of example and limitation: caffeine, aspirin, acetaminophen; ibuprofen; ketoprofen; cimetidine, ranitidine, famotidine, dramamine, omeprazole, dyclonine hydrochloride, chlorpheniramine maleate, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, benzocaine, sodium naproxen, and nicotine.
  • compositions that may be formulated into a suitable chewing gum formulation are described in, for examples, U.S. Patent No. 5,858,423; U.S. Patent No. 5,858,413; U.S. Patent No. 5,858,412 and U.S. Patent No. 5,858,383. Additionally, Goodman and Gilman's "The Pharmaceutical
  • Nutraceuticals and nutritional supplements may also be added to chewing gums as well as the gum coatings as active agents.
  • herbs and botanicals that include, but are not limited to capsicum, chamomile, cat's claw, echinacea, garlic, ginger, ginko, various ginseng, green tea, golden seal, kava kava, nettle, passion flower, saw palmetto, St. John's wort, and valerian.
  • mineral supplements such as calcium, copper, iodine, iron, magnesium, manganese, molybdenum, phosphorous, selenium and zinc.
  • nutraceuticals that also can be added to chewing gum as active agents are benzoin, fructo-oligosaccharides, glucosamine, grapeseed extract, guarana, inulin, phosphotidylserine, phytosterols, phytochemicals, isoflavones, lecithin, lycopene, oligofructose, polyphenol and psyllium as well as weight loss agents such as chromium picolinate and phenylpropanolamine.
  • the agents or medicaments are contained in the chewing gum coating at levels of approximately 12 micrograms to 250 milligrams per gram of gum product (core plus coating weight).
  • the specific levels will depend on the active ingredient. For example, if chromium picolinate is the active ingredient in an embodiment, it would be present at a level of 50 micrograms per serving (1.5 grams per pellet of gum); aspirin would be preset at a level of 325 milligrams per 1.5/gram serving (pellet).
  • the level of medicament or agent in the chewing gum formulation and in the coating is selected so as to create, when the gum is chewed, a sufficiently high concentration of the medicament or agent in the saliva.
  • the level of the stimulant in the chewing gum and coating should be such that it creates a saliva content of stimulant of approximately 15 to 440 ppm when the chewing gum is chewed for 2 minutes. At this level, a sufficient amount of stimulant will be delivered to the chewer to create desired therapeutic effects. If a medicament is used such as a medicinal agent (e.g., analgesics), sufficient medicinal agent should be present in the chewing gum and coating to create a saliva content of approximately 1700 to approximately 4400 ppm after the chewing gum product has been chewed for 2 minutes.
  • a stimulant such as nicotine or caffeine
  • the level of the stimulant in the chewing gum and coating should be such that it creates a saliva content of stimulant of approximately 15 to 440 ppm when the chewing gum is chewed for 2 minutes. At this level, a sufficient amount of stimulant will be delivered to the chewer to create desired therapeutic effects.
  • a medicament such as a medicinal agent (e.g., analgesics)
  • the agent should be present in a sufficient amount to create a saliva content of approximately 85 to 1100 ppm when the chewing gum product is chewed for 2 minutes.
  • a metabolizer for example, chromium picolinate and hydroxi-chitic acid
  • the agents should be present in an amount to create a saliva content of approximately 0.5 to about 900 ppm when chewed for at least two minutes.
  • the agent is a vitamin or mineral (e.g., phosphatidy serine, vitamin C, and zinc)
  • the agent should be present in the amount to create a saliva content of the vitamin or mineral of approximately 10 to about 250 ppm when chewed for 2 minutes.
  • the dosing regiment will change.
  • the medicament is an analgesic
  • the chewing gum product would be taken on an "as-needed" basis.
  • the agent is a stimulant such as caffeine to be used to enhance performance than the chewing gum product would be chewed, in a preferred embodiment ten minutes or less before the performance.
  • the medicament or agent can be contained in coatings on a variety of different chewing gum compositions.
  • the chewing gum may be based on a variety of different chewing gums that are known.
  • the chewing gums can be low or high moisture, sugar or sugarless, wax containing or wax free, low calorie (via high base or low calorie bulking agents), and/or may contain dental agents.
  • Active agents may be added to the gum coating along with sweeteners, more specifically high-intensity sweeteners such as thaumatin, dihydrochalcones, acesulfame K, aspartame, N-substituted APM derivatives such as neotame, sucralose, alitame, saccharin and cyclamates.
  • sweeteners more specifically high-intensity sweeteners such as thaumatin, dihydrochalcones, acesulfame K, aspartame, N-substituted APM derivatives such as neotame, sucralose, alitame, saccharin and cyclamates.
  • sweeteners more specifically high-intensity sweeteners such as thaumatin, dihydrochalcones, acesulfame K, aspartame, N-substituted APM derivatives such as neotame, sucralose, alitam
  • bitterness inhibitors or taste maskers can also be combined with active agents and sweeteners to give a reduced unpleasant taste.
  • Medicament actives may also be combined in a coated chewing gum product.
  • a single active may be added to a gum coating for fast release and also added to the gum center with or without encapsulation for slow release.
  • the active has an affinity for the gum base, it may naturally give a slow release without encapsulation. If the active is fast release, it would have to be encapsulated or entrapped for the desired time release.
  • a combination of medicament actives may be used in the gum coating and in the gum center for various reasons.
  • medicaments may be reactive to one another and should be kept form coming in contact with each other.
  • combinations of medicaments may be used for various symptoms where multiple medicaments may be effective.
  • a decongestant such as pseudoephedrine may be added to a gum coating and an antihistamine such as chloropheniramine may be added to a gum center to treat cold/allergy symptoms.
  • an oral anesthetic like dyclonine hydrochloride may be used in the gum coating and an antibacterial agent like cetyl pyridinium chloride may be added to a gum center.
  • any other materials like dextromethorphan hydrobromide for cough relief or an analgesic like ketoprofen may be added to either a gum coating and a gum center for cold symptoms.
  • Other combinations of medicament active agents for other types of ailments are also within the scope of this invention.
  • active medicaments may have a low quality off- taste or bitterness, if added to a chewing gum coating. In most cases, this off taste may be masked with high intensity sweeteners, but in other instances, a bitterness inhibitor may be needed to reduce a bitter taste of a medicament.
  • bitterness inhibitors There are a wide variety of bitterness inhibitors that can be used in food products as well as with active agents. Some of the preferred bitterness inhibitors are the sodium salts which are discussed in the article Suppression of Bitterness by Sodium: Variations Among Bitter Taste Stimuli, by R.A.S. Breslin and G.K. Beceuchenp from Monell Chemical Senses Center,
  • Sodium salts discussed are sodium acetate and sodium gluconate.
  • Other sodium salts that may also be effective are sodium glycinate, sodium ascorbate and sodium glycerolphosphate.
  • sodium gluconate and sodium glycinate since they have a low salty taste and are most effective to reduce bitterness of most active medicaments.
  • the sodium salts are very water soluble and are readily released from chewing gum coating to function as bitterness inhibitors.
  • the sodium salts which release readily from chewing gum center may be modified by encapsulation to give an even faster release from chewing gum.
  • the sodium salts would be encapsulated or entrapped to give a delayed release from gum.
  • the bitterness inhibitor should release with the active medicament for maximum effectiveness. Release of the medicament from gum coating may also be effected by particle size of the medicament. Small particles release more quickly whereas large particles more slowly. Fast release can also be accomplished by dissolving medicament in a liquid and used in a gum coating.
  • Medicaments may be dissolved in solvents, flavors, or other transdermal vehicles used as absorption enhancing agents and added to gum or to a gum coating. These absorption enhancing agents may also be added to the gum or gum coating separately from the active ingredient. Their presence may help volatilize medicaments or allow increased transmucosal absorption of the active agent through the nasal mucosa or the lungs. These solvents, flavors, or transdermal vehicles may transport medicaments faster through the oral mucosa.
  • Faster absorption may be affected by increasing flavor levels as well as the addition of other flavor components, such as menthol and menthol derivatives, limonene, carvone, isomenthol, eucalyptol, menthone, pynene, camphor and camphor derivatives, as well as monoterpene natural products, monoterpene derivatives, and sesquaterpenes, including caryophyllene and copaene.
  • other flavor components such as menthol and menthol derivatives, limonene, carvone, isomenthol, eucalyptol, menthone, pynene, camphor and camphor derivatives, as well as monoterpene natural products, monoterpene derivatives, and sesquaterpenes, including caryophyllene and copaene.
  • ethanol polyethylene glycol
  • 2-pyrrolidones myristic acid
  • Brij-35 surfactant
  • p-phenyl phenol nitrobenzene
  • stearyl alcohol cetyl alcohol
  • croton oil liquid paraffin
  • dimethyl sulfoxide (DMSO) non-ionic surfactants
  • liposomes lecithin fractions
  • long chain amphipathic molecules molecules with polar or non-ionized groups on one end and non- polar groups at the other end.
  • a chewing gum composition typically comprises a water-soluble bulk portion, a water-insoluble chewable grams base portion and typically water-insoluble flavoring agents.
  • the water-soluble portion dissipates with a portion of the flavoring agent over a period of time during chewing.
  • the gum base portion is retained in the mouth throughout the chew.
  • the insoluble gum base generally comprises elastomers, resins, fats and oils, softeners and inorganic fillers.
  • the gum base may or may not include wax.
  • the insoluble gum base can constitute approximately 5% to about 95% by weight of the chewing gum, more commonly the gum base comprises 10% to about 50% of the gum, and in some preferred embodiments approximately 25% to about 35% by weight, of the chewing gum.
  • the chewing gum base of the present invention contains about 20% to about 60% by weight synthetic elastomer, about 0% to about 30% by weight natural elastomer, about 5% to about 55% by weight elastomer plasticizer, about 4% to about 35% by weight filler, about 5% to about 35% by weight softener, and optional minor amounts (about 1 % or less by weight) of miscellaneous ingredients such as colorants, antioxidants, etc.
  • Synthetic elastomers may include, but are not limited to, polyisobutylene with GPC weight average molecular weight of about 10,000 to about 95,000, isobutylene-isoprene copolymer (butyl elastomer), styrene-butadiene, copolymers having styrene-butadiene ratios of about 1 :3 to about 3: 1 , polyvinyl acetate having GPC weight average molecular weight of about 2,000 to about 90,000, polyisoprene, polyethylene, vinyl acetate - vinyl laurate copolymer having vinyl laurate content of about 5% to about 50% by weight of the copolymer, and combinations thereof.
  • Preferred ranges for polyisobutylene are 50,000 to 80,000 GPC weight average molecular weight and for styrene-butadiene are 1 : 1 to 1 :3 bound styrene-butadiene, for polyvinyl acetate are 10,000 to 65,000 GBC weight average molecular weight with the higher molecular weight polyvinyl acetates typically used in bubble gum base, and for vinyl acetate-vinyl laurate, vinyl laurate content of 10-45%.
  • Natural elastomers may include natural rubber such as smoked or liquid latex and guayule as well as natural gums such as jelutong, lechi caspi, perillo, sorva, massaranduba balata, massaranduba chocolate, nispero, rosindinha, chicle, gutta hang kang, and combinations thereof.
  • the preferred synthetic elastomer and natural elastomer concentrations vary depending on whether the chewing gum in which the base is used is adhesive or conventional, bubble gum or regular gum, as discussed below.
  • Preferred natural elastomers include jelutong, chicle, sorva and massaranduba balata.
  • Elastomer plasticizers may include, but are not limited to, natural rosin esters such as glycerol esters or partially hydrogenated rosin, glycerol esters of polymerized rosin, glycerol esters of partially dimerized rosin, glycerol esters of rosin, pentaerythritol esters of partially hydrogenated rosin, methyl and partially hydrogenated methyl esters of rosin, pentaerythritol esters of rosin; synthetics such as terpene resins derived from alpha-pinene, beta-pinene, and/or d-limonene; and any suitable combinations of the foregoing.
  • natural rosin esters such as glycerol esters or partially hydrogenated rosin, glycerol esters of polymerized rosin, glycerol esters of partially dimerized rosin, glycerol esters of rosin, pentaerythri
  • the preferred elastomer plasticizers will also vary depending on the specific application, and on the type of elastomer which is used.
  • Fillers/texturizers may include magnesium and calcium carbonate, ground limestone, silicate types such as magnesium and aluminum silicate, clay, alumina, talc, titanium oxide, mono-, di- and tri-calcium phosphate, cellulose polymers, such as wood, and combinations thereof.
  • Softeners/emulsifiers may include tallow, hydrogenated tallow, hydrogenated and partially hydrogenated vegetable oils, cocoa butter, glycerol monostearate, glycerol triacetate, lecithin, mono-,.di- and triglycerides, acetylated monoglycerides, fatty acids (e.g. stearic, palmitic, oleic and linoleic acids), and combinations thereof
  • Colorants and whiteners may include FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide, and combinations thereof.
  • the base may or may not include wax.
  • An example of a wax-free gum base is disclosed in U.S. Patent No. 5,286,500, the disclosure of which is incorporated herein by reference.
  • a typical chewing gum composition includes a water soluble bulk portion and one or more flavoring agents.
  • the water soluble portion can include bulk sweeteners, high intensity sweeteners, flavoring agents, softeners, emulsifiers, colors, acidulants, fillers, antioxidants, and other components that provide desired attributes.
  • Softeners are added to the chewing gum in order to optimize the chewability and mouth feel of the gum.
  • the softeners which are also known as plasticizers and plasticizing agents, generally constitute between approximately 0.5% to about 15% by weight of the chewing gum.
  • the softeners may include glycerin, lecithin, and combinations thereof.
  • Aqueous sweetener solutions such as those containing sorbitol, hydrogenated starch hydrolysates, corn syrup and combinations thereof, may also be used as softeners and binding agents in chewing gum.
  • Bulk sweeteners include both sugar and sugarless components. Bulk sweeteners typically constitute about 5% to about 95% by weight of the chewing gum, more typically, about 20% to about 80% by weight, and more commonly, about 30% to about 60% by weight of the gum. Sugar sweeteners generally include saccharide-containing components commonly known in the chewing gum art, including but not limited to, sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose, levulose, glactose, corn syrup solids, and the like, alone or in combination. Sugarless sweeteners include, but are not limited to, sugar alcohols such as sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates, maltitol, and the like, alone or in combination.
  • High intensity artificial sweeteners can also be used, alone or in combination, with the above.
  • Preferred sweeteners include, but are not limited to, sucralose, aspartame, N-substituted APM derivatives such as neotame, salts of acesulfame, altitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizinate, dihydrochalcones, thaumatin, monellin, and the like, alone or in combination.
  • Such techniques as wet granulation, wax granulation, spray drying, spray chilling, fluid bed coating, coacervation, and fiber extension may be used to achieve the desired release characteristics.
  • Combinations of sugar and/or sugarless sweeteners may be used in chewing gum. Additionally, the softener may also provide additional sweetness such as with aqueous sugar or alditol solutions. If a low calorie gum is desired, a low caloric bulking agent can be used.
  • low caloric bulking agents examples include: polydextrose; Raftilose, Raftilin; fructooligosaccharides (NutraFlora); palatinose oligosaccharide; guar gum hydrolysate (Sun Fiber); or indigestible dextrin (Fibersol).
  • polydextrose Raftilose, Raftilin
  • fructooligosaccharides NutraFlora
  • palatinose oligosaccharide guar gum hydrolysate (Sun Fiber); or indigestible dextrin (Fibersol).
  • Other low calorie bulking agents can be used.
  • flavoring agents can also be used, if desired.
  • the flavor can be used in amounts of about 0. 1 to about 15 weight percent of the gum, and preferably, about 0.2% to about 5% by weight.
  • Flavoring agents may include essential oils, synthetic flavors or mixtures thereof including, but not limited to, oils derived from plants and fruits such as citrus oils, fruit essences, peppermint oil, spearmint oil, other mint oils, clove oil, oil of wintergreen, anise and the like.
  • Artificial flavoring agents and components may also be used. Natural and artificial flavoring agents may be combined in any sensorially acceptable fashion.
  • chewing gum is manufactured by sequentially adding the various chewing gum ingredients to a commercially available mixer known in the art. After the ingredients have been thoroughly mixed, the gum mass is discharged from the mixer and shaped into the desired form such as rolling sheets and cutting into sticks, extruding into chunks or casting into pellets, which are then coated or panned.
  • the ingredients are mixed by first melting the gum base and adding it to the running mixer.
  • the base may also be melted in the mixer itself.
  • Color or emulsifiers may also be added at this time.
  • a softener such as glycerin may also be added at this time, along with syrup and a portion of the bulking agent. Further parts of the bulking agent are added to the mixer.
  • Flavoring agents are typically added with the final portion of the bulking agent.
  • medicaments or actives are used in the coating/ panning of a pellet chewing gum.
  • Pellet or ball gum is prepared as conventional chewing gum but formed into pellets that are pillow shaped, or into balls.
  • the pellets/balls can be then sugar coated or panned by conventional panning techniques to make a unique coated pellet gum.
  • the active agent may be soluble in flavor or can be blended with other powders often used in some types of conventional panning procedures.
  • Active agents are isolated from other gum ingredients which modifies its release rate from chewing gum. Levels of actives may be about 10 ppm to 30% by weight of chewing gum coating.
  • the weight of the coating may be about 20% to about 50% of the weight of the finished product, but may be as much as 75% of the total gum product.
  • the active level will be based on the dosage for one or two pellets.
  • panning modifiers including, but not limited to, gum arabic, maltodextrins, corn syrup, gelatin, cellulose type materials like carboxymethyl cellulose or hydroxymethyl cellulose, starch and modified starches, vegetables gums like alginates, locust bean gum, guar gum, and gum tragacanth, insoluble carbonates like calcium carbonate or magnesium carbonate and talc.
  • Antitack agents may also be added as panning modifiers, which allow the use of a variety of carbohydrates and sugar alcohols to be used in the development of new panned or coated gum products. Flavors may also be added with the sugar or sugarless coating and with the active to yield unique product characteristics.
  • pan coating could also isolate the active agent from the chewing gum ingredients.
  • This technique is referred to as a film coating and is more common for pharmaceuticals than in chewing gum, but procedures are similar.
  • a film like shellac, zein, or cellulose type material is applied onto a pellet-type product forming a thin film on the surface of the product.
  • the film is applied by mixing the polymer, plasticizer and a solvent (pigments are optional) and spraying the mixture onto the pellet surface. This is done in conventional type panning equipment, or in more advanced side-vended coating pans. Since most active agents may be alcohol soluble, they may be readily added with this type of film. When a solvent like an alcohol is used, extra precautions are needed to prevent fires and explosions, and specialized equipment must be used.
  • Some film polymers can use water as the solvent in film coating. Recent advances in polymer research and in film coating technology eliminates the problem associated with the use of solvents in coating. These advances make it possible to apply aqueous films to a pellet or chewing gum product.
  • Some active agents can be added to this aqueous film or even the alcohol solvent film, in which an active agent is highly soluble. This film may also contain a flavor along with a polymer and plasticizer.
  • the active agent can also be dissolved in the aqueous or non-aqueous solvent and coated on the surface with the aqueous film. In some instances a combination of film and sugar or polyol coating may be useful, especially if the active is added with the film coating material. Also the film coating may be applied early, middle, or late in the coating process. This will give a unique release of active agent from a film-coated product.
  • a hard shell sugar or polyol coating may then be applied over the film coated product.
  • a soft shell sugar or polyol coating may also be used over the film coated product.
  • the level of film coating applied to a pellet gum may be generally from about 0.5% to about 3% of the gum product.
  • the level of overcoating of the hard or soft shell may be about 20% to about 75%.
  • the coating may contain ingredients such as flavoring agents, as well as artificial sweeteners and dispersing agents, coloring agents, film formers and binding agents.
  • Flavoring agents contemplated by the present invention include those commonly known in the art such as essential oils, synthetic flavors or mixtures thereof, including but not limited to oils derived from plants and fruits such as citrus oils, fruit essences, peppermint oil, spearmint oil, other mint oils, clove oil, oil of wintergreen, anise and the like.
  • the flavoring agents may be used in an amount such that the coating will contain from about 0.2% to about 3% flavoring agent, and preferably from about 0.7% to about 2.0% flavoring agent. Active agents may be preblended with the flavor used in coating.
  • Artificial sweeteners contemplated for use in the coating include but are not limited to synthetic substances, saccharin, thaumatin, alitame, saccharin salts, aspartame, N-substituted APM derivatives such as neotame, sucralose and acesulfame-K.
  • the artificial sweetener may be added to the coating syrup in an amount such that the coating will contain from about 0.01 % to about 0.5%, and preferably from about 0.1 % to about 0.3% artificial sweetener.
  • Dispersing agents are often added to syrup coatings for the purpose of whitening and tack reduction.
  • Dispersing agents contemplated by the present invention to be employed in the coating syrup include titanium dioxide, talc, or any other antistick compound. Titanium dioxide is a presently preferred dispersing agent of the present invention.
  • the dispersing agent may be added to the coating syrup in amounts such that the coating will contain from about
  • Coloring agents are preferably added directly to the syrup in the dye or lake form.
  • Coloring agents contemplated by the present invention include food quality dyes.
  • Film formers preferably added to the syrup include methyl cellulose, gelatins, hydroxypropyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like and combinations thereof.
  • Binding agents may be added either as an initial coating on the chewing gum center or may be added directly into the syrup.
  • Binding agents contemplated by the present invention include gum arabic, gum talha (another type of acacia), alginate, cellulosics, vegetable gums and the like.
  • the coating is initially present as a liquid syrup which contains from about 30% to about 80% or 85% of the coating ingredients previously described herein, and from about 15% or 20% to about 70% of a solvent such as water.
  • a solvent such as water.
  • the coating process is carried out in a rotating pan. Sugar or sugarless gum center tablets to be coated are placed into the rotating pan to form a moving mass.
  • the material or syrup which will eventually form the coating is applied or distributed over the gum center tablets. Flavoring agents may be added before, during and after applying the syrup to the gum centers. Once the coating has dried to form a hard surface, additional syrup additions can be made to produce a plurality of coatings or multiple layers of hard coating.
  • syrup is added to the gum center tablets at a temperature range of from about 100°F to about 240°F. Usually, the syrup temperature is from about 130°F to about 200°F throughout the process in order to prevent the polyol or sugar in the syrup from crystallizing.
  • the syrup may be mixed with, sprayed upon, poured over, or added to the gum center tablets in any way known to those skilled in the art.
  • a plurality of layers is obtained by applying single coats, allowing the layers to dry, and then repeating the process.
  • the amount of solids added by each coating step depends chiefly on the concentration of the coating syrup. Any number of coats may be applied to the gum center tablet. Generally, no more than about 75-100 coats are applied to the gum center tablets.
  • the present invention contemplates applying an amount of syrup sufficient to yield a coated comestible containing about 10% to about 75% coating. Where higher dosage of an active agent is needed, the final product may be higher than 75% coating.
  • a plurality of premeasured aliquots of coating syrup may be applied to the gum center tablets. It is contemplated, however, that the volume of aliquots of syrup applied to the gum center tablets may vary throughout the coating procedure.
  • the present invention contemplates drying the wet syrup in an inert medium.
  • a preferred drying medium comprises air. Forced drying air contacts the wet syrup coating in a temperature range of from about 70° to about 1 15°F. Generally, the drying air is in the temperature range of from about 80° to about 100°F.
  • the invention also contemplates that the drying air possess a relative humidity of less than about 15 percent. Preferably, the relative humidity of the drying air is less than about 8 percent.
  • the drying air may be passed over and admixed with the syrup coated gum centers in any way commonly known in the art. Generally, the drying air is blown over and around or through the bed of the syrup coated gum centers at a flow rate, for large scale operations, of about 2800 cubic feet per minute. If lower quantities of material are being processed, or if smaller equipment is used, lower flow rates would be used.
  • flavors have been added to a sugar coating of pellet gum to enhance the overall flavor of gum. These flavors include spearmint flavor, peppermint flavor, wintergreen flavor, and fruit flavors. These flavors are generally preblended with the coating syrup just prior to applying it to the core or added together to the core in one or more coating applications in a revolving pan containing the cores. Generally, the coating syrup is very hot, about 130° to 200°F, and the flavor may volatilize if preblended with the coating syrup too early.
  • the concentrated coating syrup is applied to the gum cores as a hot liquid, the sugar or polyol allowed to crystallize, and the coating then dried with warm, dry air. This is repeated in about 30 to 100 applications to obtain a hard shell coated product having an increased weight gain of about 40% to 75%.
  • a flavor is applied with one, two, three or even four or more of these coating applications. Each time flavor is added, several non-flavored coatings are applied to cover the flavor before the next flavor coat is applied. This reduces volatilization of the flavor during the coating process.
  • fruit flavors that may contain esters, are more easily volatilized and may be flammable and/or explosive and therefore, generally these type of fruit flavors may be pretreated in order to be able to add them to a gum coating.
  • an active agent is preblended with a gum arabic solution to become a paste and then applied to the cores.
  • the preblend may be mixed with a small amount of coating syrup before being applied. Forced air drying is then continued as the gum arabic binds the active agent to the cores. Then additional coatings are applied to cover the active agent and imbed the treated active agent in the coatings.
  • the gum formulas can be prepared as sugar or sugarless type formulations. These formulas are made in a pellet or pillow shape pellet or a round ball or any other shape of product for coating/panning. However, gum formulas for pellet centers are generally adjusted to a higher level of gum base than stick gum to give a more consumer acceptable size of gum bolus.
  • the gum base in the pellet core should also be increased by 25%.
  • the base levels should also be increased by 33%.
  • gum centers are usually formulated with about 25% to about 40% gum base with a corresponding decrease in the other ingredients except flavor.
  • Even higher levels of base may be used when an active is added to a pellet coating.
  • flavors increase with the level of gum base as the base tends to bind flavors into the gum and more flavor is needed to give a good flavorful product.
  • flavors can also be added to the coating to give increased flavor impact and more flavor perception.
  • the formulas listed in Table 1 comprise various sugar-type formulas in which active medicament can be added to gum coating after it is dissolved in water or mixed with various aqueous solvents.
  • Dyclonine hydrochloride is an active medicament used as an oral anesthetic for sore throat.
  • gum formulas may be made in a pellet or pillow shape pellet or a round ball or any other shape of product for coating/panning. As noted earlier, gum formulas are generally adjusted to a higher level of gum base to give a more consumer acceptable size of gum bolus.
  • Gum center formulas may or may not contain dyclonine hydrochloride.
  • Gum center formulations with or without active dyclonine hydrochloride can also be made similar to other formulations for low, medium, and high moisture formulas. Higher levels of base may be used with a corresponding decrease in other ingredients. Also, other sugars and polyols may be used in the gum centers.
  • Dyclonine hydrochloride may be added to a gum center only, or to a gum coating with none in the center, or to both center and coating. Coated gum pieces are about 1.5 grams, so to obtain 3 mg of dyclonine hydrochloride total piece must contain 0.2%.
  • Dyclonine hydrochloride can then be used in the coating formula on the various pellet gum formulations.
  • Table 2 shows some sugar and dextrose type formulas:
  • CHLORIDE a All of the active agent is in the coating, which comprises 33% of the product.
  • the above formulations are made by making a syrup by dissolving the sugar and gum arabic in solution at about 75% solids at boiling, and suspending titanium dioxide or calcium carbonate in this syrup. Some of the dextrose may be added as a dry charge which may also contain the active agent.
  • Dyclonine hydrochloride may be dissolved in water, not mixed with hot syrup, but added between coatings, or it may be added to the hot syrup and used in the early stages of coating or used throughout the coating process. Flavor is not mixed with the hot syrup, but added at low levels with one or more coats.
  • Dyclonine hydrochloride may be dissolved in flavor and added to the coating. After the final coats are applied and dried, wax is applied to give a smooth polish.
  • Dyclonine hydrochloride may also be used in coating of sugarless gum centers. Like sugar gum centers, the base formulation can be increased in proportion to the amount of coating applied to the center. Formulations with and without dyclonine hydrochloride for low and high moisture gum can be used to make gum centers. Generally, the base level may be increased to 30-46% with the other ingredients proportionally reduced. Some typical gum formulas are in Table 3.
  • Lycasin and other polyols such as maltitol, xylitol, lactitol and hydrogenated isomaltulose may also be used in the gum center formulations at various levels.
  • the texture may be adjusted by varying glycerin or sorbitol liquid.
  • Sweetness of the center formulation can also be adjusted by varying the level of high intensity sweetener.
  • Dyclonine hydrochloride may be used in sugarless coatings with xylitol, sorbitol, maltitol, lactitol, hydrogenated isomaltulose and erythritol.
  • xylitol sorbitol, maltitol, lactitol, hydrogenated isomaltulose and erythritol.
  • the above formulas are used to coat pellets by applying a xylitol/gum arabic solution in multiple coats and air drying. Color or whitener is also mixed in the solution.
  • Dyclonine hydrochloride may be dissolved in water and added between coating applications or mixed with the hot syrup and used in the early stages of coating or used throughout the coating process. After pellets have been coated and dried, talc and wax are added to give a polish.
  • gum arabic can be used as a binder and film former, and a crystallization modifier to help facilitate coating.
  • these polyols are more difficult to coat using only a straight syrup, but with proper technique a good smooth hard shell can be made. However, it may be preferable to add a dry charge to quicken the drying process before the pellets get too sticky.
  • the following formulations may be used.
  • Maltitol powder is used to dry charge in the early stages of coating. Maltitol, gum arabic, and whitener are blended into a syrup and applied to pellets. Dyclonine hydrochloride may be applied in a similar manner as in the previous xylitol coating or may be preblended with the dry charge material. After all coating is applied and dried, talc and wax are added to give a polish.
  • coatings with sorbitol, lactitol, and hydrogenated isomaltulose may be made in the coating formulas in Table 5 by replacing maltitol with any one of the other polyols and maltitol powder with the polyol powder.
  • the other polyols may become sticky during the coating and drying process, so the dry powder charge may be needed to give the proper drying.
  • less gum arabic could be used and a more pure polyol syrup could be used to give a smooth surface.
  • the dry charge would only be used in the early stages of the coating process.
  • ingredients may be added to the dry charge to help absorb moisture.
  • These materials could be inert such as talc, calcium carbonate, magnesium carbonate, starches, gums like arabinogalactan, gum talha, gum arabic or other moisture absorbing materials.
  • powdered sweeteners or flavors could be added with the dry charge, along with the active medicament.
  • Some polyols such as sorbitol, maltitol, lactitol, erythritol, or hydrogenated isomaltulose are not sufficiently sweet compared to sugar or xylitol, so high intensity sweeteners may be added to the coating, such as aspartame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, alitame, sucralose, thaumatin, monellin, dihydrochalcone, glycyrrhizin, neotame, and combinations thereof. If a hot syrup is applied, heat may degrade the sweetener so only stable sweeteners should be used. Generally high intensity sweeteners are added with the polyol/gum arabic solution to obtain an even distribution in the coatings.
  • Chlorpheniramine maleate is an active medicament used as an antihistamine. Gum center formulas may or may not contain chlorpheniramine maleate. TABLE 6 (WEIGHT PERCENT)
  • Gum center formulations with or without active chlorpheniramine maleate can also be made similar to other formulations for low, medium, and high moisture formulas. Higher levels of base may be used with a corresponding decrease in other ingredients. Also, other sugars are polyols may be used in the gum centers. Chlorpheniramine maleate may be added to a gum center only, or to a gum coating with none in the center, or to both center and coating. Coated gum pieces are about 1.5 grams, so to obtain 4 mg of chlorpheniramine maleate total piece must contain 0.27%. Chlorpheniramine maleate can be used in the coating formula on the various pellet gum formulations. The following Table 7 shows some sugar and dextrose type formulas:
  • the above formulations are made by making a syrup by dissolving the sugar and gum arabic in solution at about 75% solids at boiling, and suspending titanium dioxide or calcium carbonate in this syrup. Some of the dextrose may be added as a dry charge, which may also contain the active. Chlorpheniramine maleate may be dissolved in water, not mixed with hot syrup, but applied between coatings, or it may be added to the hot syrup and used in the early stages of coating or used throughout the coating process. Flavor is not mixed with the hot syrup, but added at low levels with one or more coats. Chlorpheniramine maleate may be dissolved in flavor and added to the coating. After the final coats are applied and dried, wax is applied to give a smooth polish.
  • Chlorpheniramine maleate may also be used in coating of sugarless gum centers. Like sugar gum centers, the base formulation can be increased in proportion to the amount of coating applied to the center. Formulations with and without chlorpheniramine maleate for low and high moisture gum can be used to make gum centers. Generally, the base level may be increased to 30-46% with the other ingredients proportionally reduced. Some typical gum formulas are in Table 8.
  • EX. 52 EX. 53 EX. 54 EX. 55 EX. 56 EX. 57 EX. 58
  • the high intensity sweetener used is aspartame.
  • high intensity such as alitame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, neotame, sucralose, thaumatin, monellin, dihydrochalcone, stevioside, glycyrrhizin and combinations thereof may be used in any of the examples with the level adjusted for sweetness.
  • Lycasin and other polyols such as maltitol, xylitol, lactitol and hydrogenated isomaltulose may also be used in the gum center formulations at various levels.
  • the texture may be adjusted by varying glycerin or sorbitol liquid.
  • Sweetness of the center formulation can also be adjusted by varying the level of high intensity sweetener.
  • Chlorpheniramine maleate may be used in sugarless coatings with xylitol, sorbitol, maltitol, lactitol, hydrogenated isomaltulose and erythritol.
  • xylitol sorbitol, maltitol, lactitol, hydrogenated isomaltulose and erythritol.
  • EX. 59 EX. 60
  • EX. 61 EX. 62
  • EX. 63 EX. 64
  • the above formulas are used to coat pellets by applying a xylitol/gum arabic solution in multiple coats and air drying. Color or whitener is also mixed in the solution. Chlorpheniramine maleate may be dissolved in water or flavor and added between coating applications or mixed with the hot syrup and used in the early stages of coating or used throughout the coating process. After pellets have been coated and dried, talc and wax are added to give a polish.
  • gum arabic can be used as a binder and film former, and a crystallization modifier to help facilitate coating.
  • these polyols are more difficult to coat using only a straight syrup, but with proper technique a good smooth hard shell can be made. However, it may be preferable to add a dry charge to quicken the drying process before the pellets get too sticky.
  • the following formulations may be used.
  • EX. 65 EX. 66 EX. 67 EX. 68 EX. 69 EX. 70
  • Maltitol powder is used to dry charge in the early stages of coating. Maltitol, gum arabic, and whitener are blended into a syrup and applied to pellets. After all coating is applied and dried, talc and wax are added to give a polish. Chlorpheniramine maleate may be applied in a similar manner as in the previous xylitol coating, or may be preblended with the dry charge material.
  • coatings with sorbitol, lactitol, and hydrogenated isomaltulose may be made in the coating formulas in Table 10 by replacing maltitol with any one of the other polyols and maltitol powder with the polyol powder.
  • the other polyols may become sticky during the coating and drying process, so the dry powder charge may be needed to give the proper drying.
  • less gum arabic could be used and a more pure polyol syrup could be used to give a smooth surface.
  • the dry charge would only be used in the early stages of the coating process.
  • ingredients may be added to the dry charge to help absorb moisture.
  • These materials could be inert such as talc, calcium carbonate, magnesium carbonate, starches, gums like arabinogalactan, gum talha, gum arabic or other moisture absorbing materials.
  • powdered sweeteners or flavors could be added with the dry charge.
  • Some polyols such as sorbitol, maltitol, lactitol, erythritol, or hydrogenated isomaltulose are not sufficiently sweet compared to sugar or xylitol, so high intensity sweeteners may be added to the coating, such as aspartame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, alitame, sucralose, thaumatin, monellin, dihydrochalcone, glycyrrhizin, neotame, and combinations thereof. If a hot syrup is applied, heat may degrade the sweetener so only stable sweeteners should be used. Generally high intensity sweeteners are added with the polyol/gum arabic solution to obtain an even distribution in the coatings.
  • Formulations with or without active pseudoephedrine hydrochloride can also be made similar to other formulations for low, medium, and high moisture formulas. Higher levels of base may be used with a corresponding decrease in other ingredients. Also, other sugars are polyols may be used in the gum center. Pseudoephedrine hydrochloride may be added to a gum center only, or to a gum coating with none in the center, or to both center and coating. Coated gum pieces are about 1.5 grams per piece, so to obtain 30 mg of pseudoephedrine hydrochloride in two gum pieces, total piece must contain
  • Pseudoephedrine hydrochloride can be used in the coating formula on the various pellet gum formulations.
  • Table 12 shows some sugar and dextrose type formulas: TABLE 12 (DRY WEIGHT PERCENT)
  • the above formulations are made by making a syrup by dissolving the sugar and gum arabic in solution at about 75% solids at boiling, and suspending titanium dioxide or calcium carbonate in this syrup.
  • Pseudoephedrine hydrochloride may be dissolved in water, not mixed with hot syrup, but applied between coatings, or it may be added to the hot syrup and used in the early stages of coating or used throughout the coating process. Flavor is not mixed with the hot syrup, but added at low levels with one or more coats. Pseudoephedrine hydrochloride may be dissolved in flavor and added to the coating. After the final coats are applied and dried, wax is applied to give a smooth polish.
  • some of the sugar or dextrose may be added as a dry charge, which may also contain the active agent.
  • Powder and/or crystalline sugar may be used. a) All of the active agent is in the coating, which comprises 33% of the product.
  • gum arabic powder is blended in the sugar syrup.
  • gum arabic powder is dry charged after a gum arabic solution is applied in the first stages of coating, then this is followed by a hard shell coating of sugar solution or dextrose solution.
  • Pseudoephedrine hydrochloride may also be used in coating of sugarless gum centers. Like sugar gum centers, the base formulation can be increased in proportion to the amount of coating applied to the center. Formulations with and without pseudoephedrine hydrochloride similar to other formulations for low and high moisture gum can be used to make gum centers. Generally, the base level may be increased to 30-46% with the other ingredients proportionally reduced. Some typical gum formulas are in Table 14.
  • Lycasin brand hydrogenated starch hydrolyzate used instead of sorbitol liquid
  • This material may be dissolved in water, glycerin, sorbitol liquid, or HSH.
  • All of the active agent is in the coating, which comprises 33% of the product.
  • the high intensity sweetener used is aspartame.
  • high intensity such as alitame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, neotame, sucralose, thaumatin, monellin, dihydrochalcone, stevioside, glycyrrhizin and combinations thereof may be used in any of the examples with the level adjusted for sweetness.
  • Lycasin and other polyols such as maltitol, erythritol, xylitol, lactitol and hydrogenated isomaltulose may also be used in the gum center formulations.
  • the texture may be adjusted by varying glycerin or sorbitol liquid.
  • Sweetness of the center formulation can also be adjusted by varying the level of high intensity sweetener.
  • Pseudoephedrine hydrochloride may be used in sugarless coatings with xylitol, sorbitol, maltitol, lactitol, hydrogenated isomaltulose and erythritol. The following table gives formulas for a xylitol coating:
  • EX. 100 EX . 101 EX . 102 EX. 103 EX. 104 EX. 105
  • the above formulas are used to coat pellets by applying a xylitol/gum arabic solution in multiple coats and air drying. Color or whitener is also mixed in the solution.
  • Pseudoephedrine hydrochloride may be dissolved in water or flavor and added between coating applications or mixed with the hot syrup and used in the early stages of coating or used throughout the coating process. After pellets have been coated and dried, talc and wax are added to give a polish.
  • gum arabic can be used as a binder and film former, and a crystallization modifier to help facilitate coating.
  • these polyols are more difficult to coat using only a straight syrup, but with proper technique a good smooth hard shell can be made.
  • the following formulations may be used. TABLE 16 (DRY WEIGHT PERCENT)
  • EX. 106 EX. 107 EX . 108 EX. 109 EX. 110 EX. 11 1
  • Maltitol powder is used to dry charge in the early stages of coating. Maltitol, gum arabic, and whitener are blended into a syrup and applied to pellets. After all coating is applied and dried, talc and wax are added to give a polish. Pseudoephedrine hydrochloride may be applied in a similar manner as in the previous xylitol coating examples, or may be preblended with the dry charge material.
  • coatings with sorbitol, lactitol, and hydrogenated isomaltulose may be made in the coating formulas in Table 16 by replacing maltitol with any one of the other polyols and maltitol powder with the polyol powder.
  • the other polyols may become sticky during the coating and drying process, so the dry powder charge may be needed to give the proper drying.
  • less gum arabic could be used and a more pure polyol syrup could be used to give a smooth surface.
  • the dry charge would only be used in the early stages of the coating process.
  • ingredients may be added to the dry charge to help absorb moisture.
  • These materials could be inert such as talc, calcium carbonate, magnesium carbonate, starches, gums like arabinogalactan, gum talha, gum arabic or other moisture absorbing materials.
  • powdered sweeteners or flavors could be added with the dry charge.
  • Some polyols such as sorbitol, maltitol, lactitol, erythritol, or hydrogenated isomaltulose are not sufficiently sweet compared to sugar or xylitol, so high intensity sweeteners may be added to the coating, such as aspartame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, alitame, sucralose, thaumatin, monellin, dihydrochalcone, glycyrrhizin, neotame, and combinations thereof. If a hot syrup is applied, heat may degrade the sweetener so only stable sweeteners should be used.
  • Generally high intensity sweeteners are added with the polyol/gum arabic solution to obtain an even distribution in the coatings.
  • Liquid flavors generally are not added throughout the coating but at specific points throughout the process. When flavor is added, less air is used for drying until the flavor coating is covered by the next coatings and dried.
  • Flavors may be various spearmint, peppermint, wintergreen, cinnamon, and fruit flavors to yield a wide variety of flavored chewing gum products.
  • Some typical sugar type gum center formulations are shown in Table 17 in which cetyl pyridimium chloride (CPC) can be added as the active medicament. This medicament can be used as an oral antimicrobial to reduce oral malodor and reduce oral bacteria. These formulas give a 1.5 gram piece containing 5 mg of CPC or 0.33%. Gum center formulas may or may not contain CPC, which has been encapsulated for controlled release.
  • CPC cetyl pyridimium chloride
  • EX. 112 EX. 113 EX. 1 14 EX. 115 EX. 1 16 EX. 117
  • Formulations with or without CPC can also be made similar to other formulations for low, medium, and high moisture formulas. Higher levels of base may be used with a corresponding decrease in other ingredients. Also, other sugars and polyols may be used in the gum center. Cetyl pyridimium chloride may be added to a gum center only, into a gum coating with more in the center or to both center and coating.
  • CPC can be used in the coating formula on the various pellet gum formulations.
  • Table 18 shows some sugar and dextrose type formulas:
  • the above formulations are made by making a syrup by dissolving the sugar and gum arabic in solution at about 75% solids at boiling, and suspending titanium dioxide or calcium carbonate in this syrup.
  • CPC may be dissolved in water, not mixed with hot syrup, but applied between coatings, or it may be added to the hot syrup and used in the early stages of coating or used throughout the coating process. Flavor is not mixed with the hot syrup, but added at low levels with one or more coats. CPC may also be premixed with the flavor. After the final coats are applied and dried, wax is applied to give a smooth polish.
  • the above process gives a hard shell coating. Often a dry charge of powdered sugar or dextrose monohydrate may be used. This gives a somewhat softer coating. A dry charge may be used to build up a coating, but then finished with a straight syrup to obtain a hard shell. CPC may be added dry to the coating with the dry charge material. Table 19 gives these types of formulas.
  • Powder and/or crystalline sugar may be used, a) All of the active agent is in the coating, which comprises 33% of the product.
  • gum arabic is blended in the sugar syrup.
  • gum arabic powder is dry charged after gum arabic solution is applied in the first stages of coating, then this is followed by a hard shell coating of sugar solution or dextrose solution.
  • Cetyl pyridimium chloride may also be used in coating of sugarless gum centers. Like sugar gum centers, the base formulation can be increased in proportion to the amount of coating applied to the center. Formulations with and without cetyl pyridimium chloride similar to other formulations for low and high moisture gum can be used to make gum centers. Generally, the base level may be increased to 30-46% with the other ingredients proportionally reduced. Some typical gum center formulas are in Table 20.
  • EX. 134 EX. 135 EX. 136 EX ;. 137 EX. 138 EX. 139 EX. 140
  • the high intensity sweetener used is aspartame.
  • high intensity such as alitame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, neotame, sucralose, thaumatin, monellin, dihydrochalcone, stevioside, glycyrrhizin and combinations thereof may be used in any of the examples with the level adjusted for sweetness.
  • Lycasin and other polyols such as maltitol, xylitol, erythritol, lactitol and hydrogenated isomaltulose may also be used in the gum center formulations at various levels.
  • the texture may be adjusted by varying glycerin or sorbitol liquid.
  • Sweetness of the center formulation can also be adjusted by varying the level of high intensity sweetener.
  • Cetyl pyridimium chloride may be used in sugarless coatings with xylitol, sorbitol, maltitol, lactitol, hydrogenated isomaltulose and erythritol.
  • xylitol sorbitol, maltitol, lactitol, hydrogenated isomaltulose and erythritol.
  • the following table gives formulas for a xylitol coating: TABLE 21
  • CPC may be dissolved in water or flavor and added between coating applications, or mixed with the hot syrup and used in the early stages of coating or used throughout the coating process. CPC may also be blended with the flavor used for coating. After pellets have been coated and dried, talc and wax are added to give a polish.
  • gum arabic can be used as a binder and film former, and a crystallization modifier to help facilitate coating.
  • these polyols are more difficult to coat using only a straight syrup, but with proper technique a good smooth hard shell can be made.
  • the following formulations may be used.
  • Maltitol powder is used to dry charge in the early stages of coating. Maltitol, gum arabic, and whitener are blended into a syrup and applied to pellets. After all coating is applied and dried, talc and wax are added to give a polish. Cetyl pyridimium chloride may be applied in a similar manner as in the previous xylitol coating examples, or preblended with the dry charge materials.
  • coatings with sorbitol, lactitol, and hydrogenated isomaltulose may be made in the coating formulas in Table 22 by replacing maltitol with any one of the other polyols and maltitol powder with the polyol powder.
  • the other polyols may become sticky during the coating and drying process, so the dry powder charge may be needed to give the proper drying.
  • less gum arabic could be used and a more pure polyol syrup could be used to give a smooth surface.
  • the dry charge would only be used in the early stages of the coating process.
  • ingredients may be added to the dry charge to help absorb moisture.
  • These materials could be inert such as talc, calcium carbonate, magnesium carbonate, starches, gums like arabinogalactan, gum talha, gum arabic or other moisture absorbing materials.
  • powdered sweeteners or flavors could be added with the dry charge.
  • Some polyols such as sorbitol, maltitol, erythritol, lactitol, or hydrogenated isomaltulose are not sufficiently sweet compared to sugar or xylitol, so high intensity sweeteners may be added to the coating, such as aspartame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, alitame, sucralose, thaumatin, monellin, dihydrochalcone, glycyrrhizin, neotame, and combinations thereof. If a hot syrup is applied, heat may degrade the sweetener so only stable sweeteners should be used.
  • Generally high intensity sweeteners are added with the polyol/gum arabic solution to obtain an even distribution in the coatings.
  • Liquid flavors generally are not added throughout the coating but at specific points throughout the process. When flavor is added, less air is used for drying until the flavor coating is covered by the next coatings and dried.
  • Flavors may be various spearmint, peppermint, wintergreen, cinnamon, and fruit flavors to yield a wide variety of flavored chewing gum products.
  • Some typical sugar type gum center formulations are shown in Table 23, in which ketoprofen can be added as the active medicament.
  • Ketoprofen is an analgesic to reduce inflammation and pain. These formulas give a 1.5 gram piece containing 12.5 mg of ketoprofen or 0.83% of the total gum product. Gum center formulas may or may not contain encapsulated or controlled release ketoprofen.
  • ketoprofen can also be made similar to other formulations for low, medium, and high moisture formulas. Higher levels of base may be used with a corresponding decrease in other ingredients. Also, other sugars and polyols may be used in the gum center. Ketoprofen may be added to a gum center only, into a gum coating with none in the center, or to both center and coating.
  • Ketoprofen can be used in the coating formula on the various pellet gum formulations.
  • Table 24 shows some sugar and dextrose type formulas:
  • the above formulations are made by making a syrup by dissolving the sugar and gum arabic in solution at about 75% solids at boiling, and suspending titanium dioxide or calcium carbonate in this syrup.
  • Ketoprofen may be dissolved in water, not mixed with hot syrup, but applied between coatings, or it may be added to the hot syrup and used in the early stages of coating or used throughout the coating process. Flavor is not mixed with the hot syrup, but added at low levels with one or more coats. Ketoprofen may also be premixed with the flavor. After the final coats are applied and dried, wax is applied to give a smooth polish. The above process gives a hard shell coating. Often a dry charge of powdered sugar or dextrose monohydrate may be used. This gives a somewhat softer coating. A dry charge, which also may contain the active, may be used to build up a coating, but then finished with a straight syrup to obtain a hard shell. Table 25 gives these types of formulas. TABLE 25
  • gum arabic is blended in the sugar syrup.
  • gum arabic powder is dry charged after gum arabic solution is applied in the first stages of coating, then this is followed by a hard shell coating of sugar solution or dextrose solution.
  • Ketoprofen may also be used in coating of sugarless gum centers. Like sugar gum centers, the base formulation can be increased in proportion to the amount of coating applied to the center. Formulations with and without ketoprofen for low and high moisture gum can be used to make gum centers. Generally, the base level may be increased to 30-46% with the other ingredients proportionally reduced. Some typical gum formulas are in Table 26. TABLE 26
  • EX. 175 EX. 176 EX. 177 EX . 178 EX. 179 EX. 180 EX. 181
  • the high intensity sweetener used is aspartame.
  • high intensity such as alitame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, neotame, sucralose, thaumatin, monellin, dihydrochalcone, stevioside, glycyrrhizin and combinations thereof may be used in any of the examples with the level adjusted for sweetness.
  • Lycasin and other polyols such as maltitol, xylitol, erythritol, lactitol and hydrogenated isomaltulose may also be used in the gum center formulations at various levels.
  • the texture may be adjusted by varying glycerin or sorbitol liquid.
  • Sweetness of the center formulation can also be adjusted by varying the level of high intensity sweetener.
  • Ketoprofen may be used in sugarless coatings with xylitol, sorbitol, maltitol, lactitol, hydrogenated isomaltulose and erythritol. The following table gives formulas for a xylitol coating: TABLE 27
  • EX. 182 EX. 183 EX. 184 EX . 185 EX. 186 EX. 187
  • Ketoprofen may be dissolved in water or flavor and added between coating applications, or mixed with the hot syrup and used in the early stages of coating or used throughout the coating process.
  • gum arabic can be used as a binder and film former, and a crystallization modifier to help facilitate coating.
  • these polyols are more difficult to coat using only a straight syrup, but with proper technique a good smooth hard shell can be made.
  • the following formulations may be used.
  • Maltitol powder is used to dry charge in the early stages of coating. Maltitol, gum arabic, and whitener are blended into a syrup and applied to pellets. After all coating is applied and dried, talc and wax are added to give a polish. Ketoprofen may be applied in a similar manner as in the previous xylitol coating examples, or preblended with the dry charge material and added to the coating.
  • coatings with sorbitol, lactitol, and hydrogenated isomaltulose may be made in the coating formulas in Table 28 by replacing maltitol with any one of the other polyols and maltitol powder with the polyol powder.
  • the other polyols may become sticky during the coating and drying process, so the dry powder charge may be needed to give the proper drying.
  • less gum arabic could be used and a more pure polyol syrup could be used to give a smooth surface.
  • the dry charge would only be used in the early stages of the coating process.
  • ingredients may be added to the dry charge to help absorb moisture.
  • These materials could be inert such as talc, calcium carbonate, magnesium carbonate, starches, gums like arabinogalactan, gum talha, gum arabic or other moisture absorbing materials.
  • powdered sweeteners or flavors could be added with the dry charge.
  • Some polyols such as sorbitol, maltitol, erythritol, lactitol, or hydrogenated isomaltulose are not sufficiently sweet compared to sugar or xylitol, so high intensity sweeteners may be added to the coating, such as aspartame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, alitame, sucralose, thaumatin, monellin, dihydrochalcone, glycyrrhizin, neotame, and combinations thereof. If a hot syrup is applied, heat may degrade the sweetener so only stable sweeteners should be used. Generally high intensity sweeteners are added with the polyol/gum arabic solution to obtain an even distribution in the coatings.
  • dextromethorphan hydrobromide can be added as the active medicament. This material is an antitussive for cough relief. These formulas give a 1.5 gram piece containing 15 mg of dextromethorphan hydrobromide or 1.0% of gum product. Gum centers may or may not contain dextromethorphan hydrobromide.
  • a) All of the active agent is in the coating, which comprises 33% of the product.
  • Formulations with or without dextromethorphan hydrobromide can also be made for low, medium, and high moisture formulas. Higher levels of base may be used with a corresponding decrease in other ingredients. Also, other sugars and polyols may be used in the gum center. Dextromethorphan hydrobromide may be added to the gum center only, into a gum coating with none in the center, or both center and coating.
  • Dextromethorphan hydrobromide can then be used in the coating formula on the various pellet gum formulations.
  • Table 30 shows some sugar and dextrose type formulas:
  • EX. 200 EX . 201 EX. 202 EX . 203 EX. 204 EX. 205
  • HBr a All of the active agent is in the coating, which comprises 33% of the product.
  • the above formulations are made by making a syrup by dissolving the sugar and gum arabic in solution at about 75% solids at boiling, and suspending titanium dioxide or calcium carbonate in this syrup.
  • Dextromethorphan hydrobromide may be dissolved in water, not mixed with hot syrup, but applied between coatings, or it may be added to the hot syrup and used in the early stages of coating or used throughout the coating process. Flavor is not mixed with the hot syrup, but added at low levels with one or more coats. Dextromethorphan HBr may also be premixed with the flavor. After the final coats are applied and dried, wax is applied to give a smooth polish.
  • EX. 210 EX. 211 EX. 212 EX. 213 EX. 214 EX. 215
  • Powder and/or crystalline sugar may be used, a) All of the active agent is in the coating, which comprises 33% of the product.
  • gum arabic is blended in the sugar syrup.
  • gum arabic powder is dry charged after a gum arabic solution is applied in the first stages of coating, then this is followed by a hard shell coating of sugar solution or dextrose solution.
  • Dextromethorphan hydrobromide may also be used in coating of sugarless gum centers.
  • the base formulation can be increased in proportion to the amount of coating applied to the center. Formulations with and without dextromethorphan hydrobromide for low and high moisture gum can be used to make gum centers. Generally, the base level may be increased to 30-46% with the other ingredients proportionally reduced. Some typical gum center formulas are in Table 32.
  • Lycasin and other polyols such as maltitol, xylitol, erythritol, lactitol and hydrogenated isomaltulose may also be used in the gum center formulations at various levels.
  • the texture may be adjusted by varying glycerin or sorbitol liquid.
  • Sweetness of the center formulation can also be adjusted by varying the level of high intensity sweetener.
  • Dextromethorphan hydrobromide may be used in sugarless coatings with xylitol, sorbitol, maltitol, lactitol, hydrogenated isomaltulose and erythritol.
  • the above formulas are used to coat pellets by applying a xylitol/gum arabic solution in multiple coats and air drying. Color or whitener is also mixed in the solution. After pellets have been coated and dried, talc and wax are added to give a polish. Dextromethorphan hydrobromide may be dissolved in water or flavor and added between coating applications, or mixed with hot syrup and used in the early stages of coating or used throughout the coating process.
  • gum arabic can be used as a binder and film former, and a crystallization modifier to help facilitate coating.
  • these polyols are more difficult to coat using only a straight syrup, but with proper technique a good smooth hard shell can be made.
  • the active may be premixed with the dry charge material. The following formulations may be used.
  • Maltitol powder is used to dry charge in the early stages of coating. Maltitol, gum arabic, and whitener is blended into a syrup and applied to pellets. After all coating is applied and dried, talc and wax are added to give a polish. Dextromethorphan may be applied in a similar manner as the previous xylitol examples, or added with the dry charge material.
  • coatings with sorbitol, lactitol, and hydrogenated isomaltulose may be made in the coating formulas in Table 34 by replacing maltitol with any one of the other polyols and maltitol powder with the polyol powder.
  • the other polyols may become sticky during the coating and drying process, so the dry powder charge may be needed to give the proper drying.
  • less gum arabic could be used and a more pure polyol syrup could be used to give a smooth surface.
  • the dry charge would only be used in the early stages of the coating process.
  • ingredients may be added to the dry charge to help absorb moisture.
  • These materials could be inert such as talc, calcium carbonate, magnesium carbonate, starches, gums like arabinogalactan, gum talha, gum arabic or other moisture absorbing materials.
  • powdered sweeteners or flavors could be added with the dry charge.
  • Some polyols such as sorbitol, maltitol, erythritol, lactitol, or hydrogenated isomaltulose are not sufficiently sweet compared to sugar or xylitol, so high intensity sweeteners may be added to the coating, such as aspartame, acesulfame K, salts of acesulfame, cyclamate and its salts, saccharin and its salts, alitame, sucralose, thaumatin, monellin, dihydrochalcone, glycyrrhizin, neotame, and combinations thereof. If a hot syrup is applied, heat may degrade the sweetener so only stable sweeteners should be used. Generally high intensity sweeteners are added with the polyol/gum arabic solution to obtain an even distribution in the coatings.
  • Liquid flavors generally are not added throughout the coating but at specific points throughout the process. When flavor is added, less air is used for drying until the flavor coating is covered by the next coatings and dried. Flavors may be various spearmint, peppermint, wintergreen, cinnamon, and fruit flavors to yield a wide variety of flavored chewing gum products.
  • Initial center piece weight was 0.956 grams. Gum was coated to a finished piece weight of 1.46 grams to give a 34.5% coating. Coating syrup 1 was used to coat the first 60% of the coating to a piece weight of 1.26 grams. Coating syrup 2 was used to coat to the final piece weight. Individual piece analysis of 5 pieces yielded a level of 26.1 mg of caffeine per piece. For a 2 piece dosage, caffeine level is 52.2 mg.
  • This gum product was used in a caffeine absorption study to compare release and absorption uptake of caffeine from gum and beverages.
  • the test results showed that gum is a faster delivery vehicle for caffeine when compared to the same level in beverages as measured by blood plasma caffeine.
  • Caffeine was taken up faster in the test subject's plasma after delivery via gum than after delivery of same caffeine dose via coffee, cola and tea.
  • Plasma caffeine concentration is significantly greater for gum vs. beverages within the first 10 to 30 minutes after caffeine delivery. This correlates to faster uptake.
  • Plasma absorption rate constant larger for gum vs. one or more beverages (2).
  • Plasma absorption half life (abs. half-life) smaller for gum vs. one or more beverages (2).
  • Time of peak caffeine plasma concentration T-max) smaller for gum than one or more of the beverages (2).
  • a clinical trial study was performed where six subjects participated in the test, blood was drawn and plasma separated. Blood sampling occurred prior to, and at preset time intervals following a caffeine level of 50-55 mg released through the test delivery vehicle. Five different studies were completed: gum (with saliva swallowed, G2), gum (with saliva expectorated, G3), coffee (ingested COF), cola (ingested COK) and tea (ingested T). Blood samples of 5 ml were collected and the plasma portion separated, stored, and extracted and analyzed. A method was developed for the extraction and analysis of caffeine in fluids, which reports results as the concentration of caffeine in the plasma.
  • A-rate constant and abs. half-life determinations were also made through linear regression. No significant differences were noted in the means, though a trend was noted: the A-rate for the gum study (G2) was greater than that for coffee and cola for subjects 1 -4 and the abs. half-life for the G2 study was less than that for coffee and cola for subjects 1 -4.
  • the G2 abs. half-life averaged 13 ⁇ 4 minutes for subjects 1 -4, 28 ⁇ 2 minutes for subjects 5 and 6, indicating faster absorption for subjects 1-4. This is due to the different rates of sublingual absorption between the subjects.
  • the amount of caffeine absorbed sublingually was 21 ⁇ 7 mg for subjects 1-4, and 10 ⁇ 1 mg for subjects 5 and 6, accounting for the increased A-rate and decreased abs. half-life in subjects 1-4.
  • Initial center piece weight was 0.995 grams. Gum was coated to a finished piece weight of 1.52 grams to give a 34.5% coating. Coating syrup 3 was used to coat the first 60% of the coating to a piece weight of 1.30 grams. Coating syrup 4 was used to coat to the final piece weight. Individual piece analysis of 5 pieces yielded a level of 20.0 ⁇ 0.8 mg of caffeine per piece. For a two piece dosage, caffeine level is 40.0 mg. This gum product was used in a caffeine absorption study to compare release and absorption uptake of caffeine from gum verses pills. The test results showed that gum is a faster delivery vehicle for caffeine when compared to a similar level in a pill as measured by blood plasma caffeine. Caffeine was taken up faster in the test subject's plasma after deliver, via gum than after delivery of same caffeine dose via a pill.
  • Pharmacokinetic parameters were done using a pharmacokinetic software package.
  • the gums tested were pellet Example 235, containing all the caffeine in the coating and delivering approximately 50 mg caffeine after chewing two pellets (designated as G2, G4, or 50 mg pellet), and Example 236, containing caffeine in the coating and center, and delivering approximately 40 mg caffeine after chewing two pellets (designated G5 or 40 mg pellet). Both pellets were compared to Pro-PlusTM pill, containing approximately 50 mg caffeine in one pill (designated as Pill 1 , Pill 2, or 50 mg pill).
  • Pro-PlusTM 50 mg tablet is manufactured by the product license holder: PP Products, 40 Broadwater Road, Welayn Garden City, Harts, AL7 Bay, UK.
  • the Abs. Rate Const (absorption rate constant, rate at which caffeine absorbs into the bloodstream) was significantly greater for 50 mg pellet gum (Example 235) than for the 50 mg pill, indicating that caffeine is absorbed at a greater rate after gum delivery than after delivery of the same dosage via a pill.
  • the test also demonstrated faster uptake of plasma caffeine via
  • gums formulated with all the caffeine in the pellet coating delivered caffeine more quickly to the plasma than gums formulated with the caffeine split between the coating and the center based upon the following:
  • Caffeine was chosen as a model for drug delivery tests because it is a food approved, pharmacologically active agent that is readily detected in plasma at a wide range of dosage levels. It is widely consumed via a number of delivery vehicles, including liquids (coffee, cola, and pills). Drugs are administered through different delivery vehicles, two oral delivery vehicles being liquid syrups and pills. Testing caffeinated beverages and pills vs. caffeinated gums should give an indication of how similar drugs administered as liquids or coated pills vs. coated gum could behave.
  • compositions and methods of the present invention are capable of being incorporated in the form of a variety of embodiments, only a few of which have been illustrated and described above.
  • the invention may be embodied in other forms without departing from its spirit or essential characteristics.
  • the described embodiments are to be considered in all respects only as illustrative and not restrictive, and the scope of the invention, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Abstract

La présente invention un procédé de production d'un chewing-gum permettant de mieux libérer un agent actif, et concerne également le chewing-gum ainsi produit. On obtient ce chewing-gum en ajoutant un agent actif à l'enrobage d'un chewing-gum. On ajoute l'agent actif à l'enrobage dans une solution d'enrobage, ou en le prémélange avec un arôme ou un solvant. La solution d'enrobage peut contenir un édulcorant ou d'autres agents stimulateurs transdermiques pour augmenter l'absorption transmuqueuse. Par ailleurs, on peut utiliser un agent actif dans la partie centrale du chewing-gum.
PCT/US1999/029742 1996-11-27 1999-12-14 Liberation amelioree d'agents medicamenteux actifs par un enrobage de chewing-gum WO2000035296A1 (fr)

Priority Applications (18)

Application Number Priority Date Filing Date Title
AU21843/00A AU765999B2 (en) 1998-12-15 1999-12-14 Improved release of medicament active agents from a chewing gum coating
EP99966257A EP1139774A4 (fr) 1998-12-15 1999-12-14 Liberation amelioree d'agents medicamenteux actifs par un enrobage de chewing-gum
CA002355779A CA2355779C (fr) 1998-12-15 1999-12-14 Liberation amelioree d'agents medicamenteux actifs par un enrobage de chewing-gum
BR9916303-9A BR9916303A (pt) 1998-12-15 1999-12-14 Liberação melhorada de agentes ativos de medicamentos a partir de um revestimento de goma de mascar
US09/510,878 US6355265B1 (en) 1999-04-06 2000-02-23 Over-coated chewing gum formulations
US09/618,808 US6322806B1 (en) 1999-04-06 2000-07-18 Over-coated chewing gum formulations including tableted center
US09/621,643 US6627234B1 (en) 1998-12-15 2000-07-21 Method of producing active agent coated chewing gum products
US09/748,699 US6541048B2 (en) 1999-09-02 2000-12-22 Coated chewing gum products containing an acid blocker and process of preparing
US09/759,838 US6290985B2 (en) 1999-04-06 2001-01-11 Over-coated chewing gum formulations including tableted center
US09/759,561 US6558692B2 (en) 1999-04-06 2001-01-11 Over-coated chewing gum formulations
US09/924,914 US6465003B2 (en) 1999-04-06 2001-08-08 Over-coated chewing gum formulations
US09/956,445 US6592850B2 (en) 1998-12-15 2001-09-19 Sildenafil citrate chewing gum formulations and methods of using the same
US09/955,870 US6426090B1 (en) 1999-04-06 2001-09-19 Over-coated product including tableted center and medicament
US09/992,122 US6773716B2 (en) 1999-04-06 2001-11-13 Over-coated chewing gum formulations
US09/990,628 US20020159956A1 (en) 1999-04-06 2001-11-13 Over-coated chewing gum formulations
US10/024,631 US7163705B2 (en) 1998-12-15 2001-12-17 Coated chewing gum product and method of making
US11/269,980 US7935362B2 (en) 1999-04-06 2005-11-09 Over-coated product including consumable center and medicament
US12/651,873 US20100104620A1 (en) 1999-04-06 2010-01-04 Over-coated product including tableted center and medicament

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US09/308,972 US6165516A (en) 1996-11-27 1996-11-27 Method of controlling release of caffeine in chewing gum
PCT/US1996/018977 WO1998023165A1 (fr) 1996-11-27 1996-11-27 Procede permettant de reguler la liberation de cafeine dans de la gomme a macher et gomme ainsi produite
US60/112,389 1998-12-15
US09/286,818 1999-04-06
US38921199A 1999-09-02 1999-09-02
US09/389,211 1999-09-02

Related Parent Applications (5)

Application Number Title Priority Date Filing Date
US09/308,972 Continuation-In-Part US6165516A (en) 1996-11-27 1996-11-27 Method of controlling release of caffeine in chewing gum
PCT/US1996/018977 Continuation-In-Part WO1998023165A1 (fr) 1996-11-27 1996-11-27 Procede permettant de reguler la liberation de cafeine dans de la gomme a macher et gomme ainsi produite
US28681899A Continuation-In-Part 1996-11-27 1999-04-06
US38921199A Continuation-In-Part 1996-11-27 1999-09-02
PCT/US1999/029792 Continuation-In-Part WO2000035298A1 (fr) 1996-11-27 1999-12-14 Chewing-gum contenant des agents medicamenteux actifs

Related Child Applications (4)

Application Number Title Priority Date Filing Date
US28681899A Continuation-In-Part 1996-11-27 1999-04-06
US09/510,878 Continuation-In-Part US6355265B1 (en) 1999-04-06 2000-02-23 Over-coated chewing gum formulations
US09/621,643 Continuation US6627234B1 (en) 1998-12-15 2000-07-21 Method of producing active agent coated chewing gum products
US09/654,464 Continuation US6569472B1 (en) 1999-09-02 2000-09-01 Coated chewing gum products containing antacid and method of making

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PCT/US1999/029792 WO2000035298A1 (fr) 1996-11-27 1999-12-14 Chewing-gum contenant des agents medicamenteux actifs

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US6696044B2 (en) 2000-03-10 2004-02-24 Cadbury Adams Usa Llc Stain removing chewing gum and confectionery compositions, and methods of making and using the same
EP1136487A1 (fr) * 2000-03-20 2001-09-26 Nutrinova Nutrition Specialties & Food Ingredients GmbH Sels de la nicotine, procédé pour leur préparation et leur utilisation comme agents pour la cessation de fumer
EP1347746A1 (fr) * 2000-07-18 2003-10-01 Wm. Wrigley Jr. Company Formulations de gomme a macher enrobees comprenant un centre de tablette
EP1347746A4 (fr) * 2000-07-18 2009-12-16 Wrigley W M Jun Co Formulations de gomme a macher enrobees comprenant un centre de tablette
WO2002013781A1 (fr) * 2000-08-14 2002-02-21 Fertin Pharma A/S Procede de preparation d'une gomme a macher ayant un gout agreable pour le consommateur
WO2002017731A1 (fr) * 2000-09-01 2002-03-07 Wm. Wrigley Jr. Company Produits de gomme a macher enrobes contenant des antiacides
US6663849B1 (en) 2000-09-01 2003-12-16 Wm. Wrigley Jr. Company Antacid chewing gum products coated with high viscosity materials
EP1408933A4 (fr) * 2000-11-16 2005-08-31 Wrigley W M Jun Co Formulations de gomme a macher au citrate de sildenafil et procedes d'utilisation
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WO2002051260A1 (fr) * 2000-12-22 2002-07-04 Wm. Wrigley Jr. Company Produits a base de gomme a macher enrobes contenant un agent antigaz
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WO2002051259A1 (fr) * 2000-12-22 2002-07-04 Wm. Wrigley Jr. Company Produits a macher enrobes contenant divers antiacides
US7087255B2 (en) 2000-12-27 2006-08-08 Wm. Wrigley Jr. Company Chewing gums that provide breath freshening characteristics
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US7507427B2 (en) 2001-03-23 2009-03-24 Gumlink A/S Coated degradable chewing gum with improved shelf life and process for preparing same
EP1922937A3 (fr) * 2001-03-23 2008-06-04 Gumlink A/S Gomme à mâcher enrobée dégradable dotée d'une durée de vie améliorée et son procédé de fabrication.
EP1260216A1 (fr) * 2001-05-15 2002-11-27 Peirce Management, LLC Composition pharmaceutique multicouche destinee a une administration a la fois orale et intraorale
JP2005500296A (ja) * 2001-06-20 2005-01-06 ファイザー・ヘルス・アクチボラグ コーティングしたニコチン含有チューインガム、その製造および使用
WO2002102357A1 (fr) 2001-06-20 2002-12-27 Pharmacia Ab Gomme a macher enrobee contenant de la nicotine, sa fabrication et son utilisation
JP2010070564A (ja) * 2001-06-20 2010-04-02 Mcneil Ab コーティングしたニコチン含有チューインガム、その製造および使用
US6863901B2 (en) 2001-11-30 2005-03-08 Collegium Pharmaceutical, Inc. Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration
US7387792B2 (en) 2001-11-30 2008-06-17 Collegium Pharmaceutical, Inc. Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration
US7585520B2 (en) 2001-12-05 2009-09-08 Collegium Pharmaceutical, Inc. Compositions containing both sedative and non-sedative antihistamines and sleep aids
WO2003082240A1 (fr) * 2002-03-30 2003-10-09 Beisel Guenther Preparation contenant un acide gras pour la diminution d'appetit, le rassasiement ou la reduction de poids
US8642627B2 (en) 2002-06-03 2014-02-04 Mcneil Ab Formulation and use thereof
US7767698B2 (en) 2002-06-03 2010-08-03 Mcneil Ab Formulation and use thereof
US8591967B2 (en) 2002-09-24 2013-11-26 Gumlink A/S Biodegradable chewing gum comprising at least one high molecular weight biodegradable polymer
US7833555B2 (en) 2002-09-24 2010-11-16 Gumlink A/S Chewing gum comprising at least two different biodegradable polymers
US8293295B2 (en) 2002-09-24 2012-10-23 Gumlink A/S Chewing gum comprising at least two different biodegradable polymers
WO2004062639A1 (fr) * 2003-01-08 2004-07-29 Cognis Ip Management Gmbh Compositions pour pates a macher a additifs vegetaux
JP2006514061A (ja) * 2003-01-08 2006-04-27 コグニス・アイピー・マネージメント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 植物添加物を有するチューインガム組成物
US9271904B2 (en) 2003-11-21 2016-03-01 Intercontinental Great Brands Llc Controlled release oral delivery systems
US9445612B2 (en) 2004-07-06 2016-09-20 Gumlink A/S Compressed chewing gum tablet
US8734763B2 (en) 2004-07-06 2014-05-27 Gumlink A/S Compressed chewing gum tablet
US7727565B2 (en) 2004-08-25 2010-06-01 Cadbury Adams Usa Llc Liquid-filled chewing gum composition
US9198448B2 (en) 2005-02-07 2015-12-01 Intercontinental Great Brands Llc Stable tooth whitening gum with reactive ingredients
US9011946B2 (en) 2011-04-29 2015-04-21 Intercontinental Great Brands Llc Encapsulated acid, method for the preparation thereof, and chewing gum comprising same
US9737082B2 (en) 2011-04-29 2017-08-22 Intercontinental Great Brands Llc Chewing gum composition comprising encapsulated acid
KR102060738B1 (ko) * 2012-12-13 2019-12-30 한미약품 주식회사 에스오메프라졸 유리염기 또는 그의 알칼리염을 포함하는 고미가 차폐된 약학 제제 및 이의 제조방법
EP4256969A3 (fr) * 2017-08-18 2024-03-06 Perfetti Van Melle Benelux B.V. Compositions de chewing-gum et procédés de fabrication associés

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