Note: Descriptions are shown in the official language in which they were submitted.
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IMPROVED RELEASE OF MEDICAMENT
ACTIVE AGENTS FROM A CHEWING GUM COATING
Reference to Earlier Filed Applications
The present application claims the benefit under 35 U.S.C. ~ 119(e) of
the filing date of U.S. Provisional Patent Application No. 60/112,389, filed
December 15, 1998. The application is also a continuation-in-part of U.S.
Patent Application Serial No. 091389,211, filed September 2, 1999, a
continuation-in-part of U.S. Patent Application Serial No. 09/286,818, filed
April 6, 1999 and a continuation-in-part of U.S. Patent Application Serial No.
09/308,972, filed May 27, 1999, which is a nationalization of
PCT/US96/18977, filed November 27, 1996. Each of the foregoing
applications are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
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. Preferably, 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.
In recent years, 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 various
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. On the other hand, some ingredients have been treated so
as to increase their rate of release in chewing gum.
Besides sweeteners, other ingredients may require a controlled release
from chewing gum. In certain embodiments, it is contemplated that 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
suerl~ sH~ csum 2s~
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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.
It is of course known to provide active medicaments to individuals for
various purposes. These medicaments can be used to treat diseases and as
such are typically referred to as drugs or medicaments. Likewise, 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.
There are a great variety of such medicaments. These 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.
Typically, drugs or medicaments are administered parenterally or
enterally. Of course, 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. In either case,
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. When administered orally, 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
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acceptance. Accordingly, these capsules or tablets must be disintegrated or
dissolved before absorption can occur. There are a variety of factors capable
of varying or retarding disintegration of solid dosage forms. Further, 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.
When a drug rapidly dissolves from a drug product and readily passes
across membranes, absorption from most site administration tends to be
complete. This is not always the case for drugs given orally. Before reaching
the vena cava, the drug must move down the alimentary canal and pass
through the gut wall and liver, which are common sites of drug metabolism.
Thus, 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 GI 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.
Although 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. Typically 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.
There is therefore a need for an improved method of delivering drugs
and other active agents to an individual.
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SUMMARY OF THE INVENTION
The present invention provides improved methods for delivering a
medicament or active agent to an individual. To this end, coated chewing
gum products are provided 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.
Improved chewing gum products including medicaments and active
agents in a gum coating are also provided by the present invention.
To this end, 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.
Such 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.
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Accordingly, an advantage of an embodiment of the present invention
is to provide new methods for delivering medicaments or active agents io an
individual.
Still further, an advantage of an embodiment of the present invention is
5 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.
Further, 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.
Furthermore, 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.
Moreover, 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. .
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In one aspect, the invention provides a method of producing coated chewing
gum products containing at least one active agent in the coating so as to
modify the
release of the active agent in the mouth comprising the steps of: providing
chewing
gum product cores; providing a coating solution containing a bulk sweetener;
providing a powder material comprising an active agent; and coating the
chewing
gum product cores with the coating solution and powder material, with the
powder
material being applied as a dry charge between two or more applications of the
coating solution, to provide coated chewing gum products, the coating
including the
active agent at a level of from about 0.2% to about 5% in the gum products.
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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. Pursuant to the
present invention, 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.
Accordingly, as the chewing gum is chewed, the active agent is
released into the saliva more quickly. During continual chewing, 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 buccat cavity.
The oral mucosa favors drug absorption. In contrast to a typically oral
ingested drug, wherein the solution is in contact too briefly for absorption
to be
i5 appreciable through the oral mucosa, it is believed that during the
crewing,
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.
It is also possible that less medicament or active agent can be placed
in the chewing gum coating than is typically orally administered to an
individual to achieve an effect and the same bioequivalence can be achieved.
In some instances, for certain drugs and agents, 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,
For example, caffeine is commonly used as a stimulant to alleviate the
effects of steep deprivation. It is almost completely metabolized in the liver
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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 en~:yme activity.
Data set forth in detail in U.S. Patent Application Serial No. 09/386,818
suggests that the absorption rate constant
(Ka) is significantly increased when caffeine is administrated through chewing
gum versus a pill. This means that the caf~eine is moving into the systemic
circulation at a significantly faster rate. A similar change in the onset of
dynamic response has also been noted, e.g., alertness and performance.
When caffeine is added to stick che~Ning guru at a level of about 0.2%
to about 5%, caffeine imparts an intense bitterness to the chewing gum that
lasts throughout the chewing period. The higher the level used, the stronger
the bitterness. At about 0.2%, which is about 5 mg per 2.7 gram stick, the
bitterness is below the threshold limit and is not readily discernible. Taste
limits in stick chewing gum are generally about 0.4% (10 mg) to about 4%
(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. However, at this
level
caffeine bitterness overwhelms the flavor initially and lasts throughout the
chewing period.
For coated pellet gum, piece weight is generally about 1.5 grams per
piece. However, one coated piece of gum is about equal to ~h piece of stick
gum. Two pellets are equivalent to a stick of gum, and together weigh about
3 grams. The above-noted target level of ~!0 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 chewinc3 gum. Caffeine is 2.1 % soluble in
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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
0 min --
min 56
min 73
min 88
40 min 97
Generally, highly water soluble ingredients such as sugars in stick gum
5 are about 80-90% released after only five minutes of chewing. For 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.
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
10 its normal crystalline state and release at a rate similar to that shown
above.
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
15 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.
20 Other agents or medicaments may be included in the present
invention. By the terms "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
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that determine mood and behavior. Of course these are just examples of
what is intended by therapeutic effect. Those of skill in the art will readily
recognize that a particular agent has or is associated with a given
therapeutic
effect.
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, carnitine, vitamin C, vitamin D and its analogs, vitamin
A and the carotenoids, retinoic acid, vitamin E and vitamin K.
Examples of 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.
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.
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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,
5 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
10 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. Other useful agents may include amobartital,
aprobarbital, butabarbital, butalbital mephobarbital, methohexital,
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pentobarbital, Phenobarbital, secobarbital, thiopental, paral, chloralhydrate,
ethchlonrynol, 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.
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).
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, nardil, parnate,
eldepryl.
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,
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yohirnbine, propanolol, metoprolol, nadolol, atenolol, timolol, esmolol,
pindolol,
acebutolol, labetalol, phentofamine, carvedilol, bucindolol, verapamil,
nifedipine, amlodipine and dobutamine, or a sexual dysfunction agent like
sildenafil citrate (Viagra).
It is envisioned that depending on the active agent or medicament, the
resultant chewing gum can be used to treat inter alias coughs, colds, motion
sickness; allergies; fevers; pain; inflammation; sore throats; ccld 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. 5,8~~8,412 and U.S. Patent
No. 5,858,383. Additionally, Goodman and Gilman's "The Pharmaceutical
Basis of Therapeutics" (Eds. Hardman et al., Publ. McGraw Hill, NY) provides
comprehensive guidance of useful drugs and their mechanisms of action.
Medicated chewing gums have been particularly effective in the delivery of
agents such as nicotine as described in, for example; U.S. Patent
No. 5,866,179; and U.S. Patent No. 5,889,028. U.S. Patent No. 5,846,557
describes general chewing gum compositions containing cough suppressing
agents. These patents provide
teaching of the incorporation of medicinal a~~ents into oral chewable
formulations. 1t should be understood that the present chewing gum
formulations) and coatings are not limited to the agents listed herein above,
indeed any medicinal or other active agent l:hat lends itself to ingestion may
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be formulated into the chewing gum coatings and used in the present
invention.
Nutraceuticals and nutritional supplements may also be added to
chewing gums as well as the gum coatings as active agents. Among these
are 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. Also included are mineral supplements such as
calcium, copper, iodine, iron, magnesium, manganese, molybdenum,
phosphorous, selenium and zinc. Other 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.
Preferably, 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 picoiinate 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).
While the present invention is particularly directed to the use of active
agents in chewing gum coatings, it is also recognized that there may be a
benefit in having a part of the active agent in the chewing gum formulation.
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.
For example, when the agent is 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
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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.
For botanical agents (e.g., chamomile, kava, kola, nut, ginseng, and
Echinacea), 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. For a metabolizes, 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. If 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.
Pursuant to the present invention, depending on the agent or
medicament, the dosing regiment will change. For example, if the
medicament is an analgesic, the chewing gum product would be taken on an
"as-needed" basis. Of course, similar to the oral administration of an
analgesic, there would be restrictions on the number of pieces of chewing
gum product chewed, for example, not more often than one pellet every four
hours and not more often than four to five times a day. If 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. Referring now to the chewing gum,
pursuant to the present invention the chewing gum may be based on a variety
of different chewing gums that are known. For example, 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.
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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. These can
5 also have the effect of reducing unpleasant tastes such as bitterness.
Additional 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
10 also added to the gum center with or without encapsulation for slow
release.
If 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
15 and in the gum center for various reasons. In some cases, medicaments may
be reactive to one another and should be kept form coming in contact with
each other. In other cases, combinations of medicaments may be used for
various symptoms where multiple medicaments may be effective. For
example, 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. For sore throat, an oral anesthetic
like dyclonine hydrochloride may be used in the gurn coating and an
antibacterial agent like cetyl pyridinium chloride may be added to a gum
center. Additionally, 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.
In many instances, 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.
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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,
Philadelphia, Pennsylvania. 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. Among these,
the most preferred is sodium gluconate and sodium glycinate since they have
a low salty taste and are most effective to reduce bitterness of most active
medicaments.
Most of the sodium salts are very water soluble and are readily
released from chewing gum coating to function as bitterness inhibitors. In
most instances, the sodium salts which release readily from chewing gum
center may be modified by encapsulation to give an even faster release from
chewing gum. However, in some instances the sodium salts would be
encapsulated or entrapped to give a delayed release from gum. Generally,
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.
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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 vehicles that may be used to increase transdermal
absorption are: 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, and long chain amphipathic
molecules (molecules with polar or non-ionized groups on one end and non-
polar groups at the other end).
Tableting of chewing gum is disclosed in U.K. Patent Publication No.
1,489,832; U.S. Patent No. 4,753,805; EP Patent Publication No. 0 221 850;
and Italy Patent Publication No. 1,273,487. These patents disclose active
agents added to chewing gum which is then tableted. As an embodiment of
this invention, active agents may be encapsulated or entrapped and added to
a chewing gum formulation which is then tableted and used as a core for a
coated chewing gum pellet that is coated with a sugar, polyol or film that
includes an active agent. The chewing gum core may contain one active
agent or multiple active medicaments and the coating may contain one or a
plurality of active medicaments. This form will yield unique chewing gum
products.
In general, 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 gurn base can constitute approximately 5% to
about 95% by weight of the chewing gum, more commonly the gum base
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1$
comprises 10% to about 50% of the gum, and in some preferred
embodiments approximately 25% to about 35% by weight, of the chewing
gum.
In a particular embodiment, 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.
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Elastomer plasticizers may include, t>ut 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 parlialiy 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. The preferred elastomer plasticizers will also vary depending on
the specific application, and on the type of alastomer which is used.
70 Fillersltexturizers may include magnesium and calcium carbonate,
ground limestone, silicate types such as m;~gnesium 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 triac.etate, lecithin, mono-,.di- and
triglycerides, acetylated monogljrcerides, 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 US Patent No. 5,286,500.
In addition to a water insoluble gum base portion, 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
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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
5 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
10 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
15 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
20 and its salts, glycyrrhizinate, dihydrochalcones, thaumatin, monellin, and
the
like, alone or in combination. In order to provide longer fasting sweetness
and
flavor perception, it may be desirable to encapsulate or otherwise control the
release of at least a portion of the artificial sweetener. 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.
Examples of low caloric bulking agents include: polydextrose; Raftilose,
Raftilin; fructooligosaccharides (NutraFlora); palatinose oligosaccharide;
guar
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gum hydrolysate (Sun Fiber); or indigestible dextrin (Fibersol). However,
other
low calorie bulking agents can be used.
A variety of 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.
In general, 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.
Generally, 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.
Other optional ingredients are added to the batch in a typical fashion, well
known to those of ordinary skill in the art.
The entire mixing procedure typically takes from five to fifteen minutes,
but longer mixing times may sometimes be required. Those skilled in the art
will recognize that many variations of the above described procedure may be
followed.
1n this invention, 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
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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.
Conventional panning procedures generally coat with sucrose, but
recent advances in panning have allowed use of other carbohydrate materials
to be used in place of sucrose. Some of these components include, but are
not limited to, dextrose, maltose, palatinose, xylitol, lactitol, hydrogenated
isomaltulose, erythritol, maltitol, and other new alditols or combinations
thereof. These materials may be blended with 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.
Another type of 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
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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.
After a coating film with an active medicament is applied to a chewing
gum product, a hard shell sugar or polyol coating may then be applied over
the film coated product. In some instances 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%. When the active agent is added with the film coating and
not with the sugar/polyol coating, better control of the amount of active
agent
in the product may be obtained. In addition, the sugar/polyol overcoating may
give an improved stability to the active agent in the product.
As noted above, 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
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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
0. 1 % to about 1.0%, and preferably from about 0.3% to about 0.6% of the
agent.
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.
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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. In general, the coating process is carried out in a rotating pan.
5 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
10 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.
In a hard coating panning procedure, syrup is added to the gum center
tablets at a temperature range of from about 100°F to about
240°F. Mostly,
the syrup temperature is from about 130°F to about 200°F
throughout the
15 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.
In general, a plurality of layers is obtained by applying single coats,
allowing the layers to dry, and then repeating the process. The amount of
20 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%
25 coating. Where higher dosage of an active agent is needed, the final
product
may be higher than 75% coating.
Those skilled in the art will recognize that in order to obtain a plurality
of coated layers, 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.
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Once a coating of syrup is applied to the gum center tablets, 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
115°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.
For many years, 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.
For mint flavors such spearmint, peppermint and wintergreen, some of
the flavor components are volatilized, but sufficient flavor remains to give a
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product having a strong, high impact flavor. 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.
In an embodiment of this invention, an active agent is preblended with
a gum arabic solution to become a paste and then applied to the cores. To
reduce stickiness, 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.
Gum Formulation Examples
The following examples of the invention and comparative examples are
provided by way of explanation and illustration.
As noted earlier, 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.
Keeping this in mind, if a coating of about 25% of the total product is
added to a pellet core as sugar or polyols, the gum base in the pellet core
should also be increased by 25%. Likewise, if a 33% coating is applied, the
base levels should also be increased by 33%. As a result, 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.
Generally 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. However flavors can also be added to the coating to give increased
flavor impact and more flavor perception.
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A wide range of changes and modifications to the embodiments of the
invention described above will be apparent to persons skilled in the art.
While
the invention is described with respect to hard-coated chewing gum, it will be
appreciated that the process is applicable to coating other food products,
such
as candies, in which a coating with dyclonine hydrochloride would have
utility.
Examples
The following examples of the invention and comparative examples are
provided by way of explanation and illustration.
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.
Various 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.
Some typical sugar type gum center formulations are shown in Table 1.
Gum center formulas may or may not contain dyclonine hydrochloride.
TABLE 1
(WEIGHT PERCENT)
EX.1 EX.2 EX.3 EX.4 EX.S EX.6
SUGAR 52.0 48.7 47.55 44.0 40.7 38.55
GUM BASE 26.0 30.0 35.00 26.0 30.0 35.00
CORN SYRUP 20.0 19.0 15.00 18.0 17.0 14.00
GLYCERIN 1.0 1.0 1.00 1.0 1.0 1.00
PEPPERMINT 1.0 1.0 1.00 1.0 1.0 1.00
FLAVOR
DEXTROSE - - - 10.0 10.0 10.00
MONOHYDRATE
DYCLONINE - 0.3 0.45 - 0.3 0.45
HYDROCHLORIDE
Gum center formulations with or without active dycionine hydrochloride
can also be made similar to other formulations for low, medium, and high
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29
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. The following Table 2 shows some sugar
and dextrose type formulas:
TABLE 2
(DRY WEIGHT PERCENT)
EX.7 EX.8 EX.9 EX.10 EX.11 EX.12
SUGAR 97.0 95.2 93.5 96.8 94.9 93.0
GUM ARABIC 2.0 3.0 4.0 2.0 3.0 4.0
TITANIUM 0.5 1.0 1.0 - -
DIOXIDE
CALCIUM - - - 0.5 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.8 0.5 0.8 0.3
WAX 0.1 0.1 0.1 0.1 O.i 0.1
DYCLONINE 0.1 0.2 0.6a~ 0.1 0.2 0.6a~
HYDRO-
CHLORIDE
TABLE 2 (Cont'd)
LDRY WEIGHT PERCENT)
EX.13 EX.14 EX.15 EX.16
DEXTROSE 97.5 95.2 97.0 93.9
MONOHYDRATE
GUM ARABIC 1.5 3.0 1.5 3.0
TITANIUM 0.5 1.0 - -
DIOXIDE
CALCIUM - - 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.2 0.4
WAX 0.1 0.1 0.1 0.1
DYCLONINE 0.1 0.2 0.2 0.6a~
HYDRO-
CHLORIDE
a) All of the active agent is in the coating, which comprises 33% of the
product.
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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
5 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
10 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
15 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.
20 TABLE 3
(WEIGHT PERCENT)
EX.17 EX.18 EX.19 EX.20EX.21 EX.22 EX.23
GUM BASE 35.0 35.0 30.0 30.0 30.0 40.0 50.0
CALCIUM CARBONATE - - 5.0 10.0 15.0 - -
SORBITOL 43.3 45.0 45.9 40.3 44.5 41.4 26.1
MANNITOL 10.0 10.0 5.0 10.0 - 8.0 10.0
GLYCERIN - 8.0 2.0 - 8.0 2.0 2.0
SORBITOL LIQUID 10.0 - 10.0 8.0 - 6.Oa~ IO.Oa~
FLAVOR 1.5 1.5 1.5 1.5 2.0 2.0 1.3
HIGH INTENSITY 0.2 0.2 0.2 0.2 0.2 0.3 0.2
SWEETENER
ACTIVE DYCLONINE - 0.3 0.4 - 0.3 0.3 0.4
HYDRO-CHLORIDEb~
a) Lycasin brand hydrogenated starch hydrolyzate used instead of sorbitol
liquid
b) This material may be dissolved in water, glycerin, sorbitol liquid, or HSH.
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31
In the above center formulations, the high intensity sweetener used is
aspartame. However other 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
15
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. The
following table gives formulas for a xylitol coating:
TABLE 4
(DRY WEIGHT PERCENT)
EX.24 EX.25 EX.26 EX.27 EX.28 EX.29
XYLITOL 94.7 92.2 90.1 90.0 89.7 88.2
GUM ARABIC 4.0 6.0 7.0 8.5 8.5 10.0
FLAVOR 0.5 0.5 0.7 0.7 0.9 0.5
TITANIUM 0.5 0.9 - 0.5 0.5*' 0.5**
DIOXIDE
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
COLOR' - - 1.4 - - -
DYCLONINE 0.1 0.2 0.6a~ 0.1 0.2 0.6a~
HYDRO-
CHLORIDE
' Lake color dispersed in xylitol solution
*' Calcium carbonate used in place of titanium dioxide
a) All of the active agent is in the gum coating, which comprises 33% of the
gum
product.
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
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32
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.
For coating formulas based on sorbitol, maltitol, lactitol, and
hydrogenated isomaltulose, gum arabic can be used as a binder and film
former, and a crystallization modifier to help facilitate coating. Generally
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.
TABLE 5
(DRY WEIGHT PERCENT)
EX.30 EX.31 EX.32 EX.33 EX.34 EX.35
MALTITOL 96.7 94.7 91.5 86.7 75.9 68.9
MALTITOL - - - 10.0 20.0 25.0
POW DER
GUM ARABIC 2.0 4.0 6.0 2.0 3.0 4.0
FLAVOR 0.5 0.4 0.7 0.5 0.3 0.7
TITANIUM DIOXIDE0.5 0.5 1.0 0.5 0.4 0.6
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
DYCLONINE 0.1 0.2 0.68 0.1 0.2 0.6a~
HYDROCHLORIDE
a) All of the active agent is in the coating, which comprises 33% of the
product.
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.
In a similar manner, 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
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33
powder. Like maltitol, 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. In the later stages of the coating process, less gum arabic
could be used and a more pure polyol syrup could be used to give a smooth
surface. Also, the dry charge would only be used in the early stages of the
coating process.
In addition to dry charging with the specific polyol, other 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. Also, 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.
Some typical sugar type gum center formulations are shown in Table 6
with chiorpheniramine maleate. Chlorpheniramine maleate is an active
medicament used as an antihistamine. Gum center formulas may or may not
contain chlorpheniramine maleate.
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34
TABLE 6
WEIGHT PERCENT)
EX.36 EX.37 EX.38 EX.39 EX.40 EX.41
SUGAR 52.0 48.73 47.59 44.0 40.73 38.59
GUM BASE 26.0 30.0 35.00 26.0 30.0 35.00
CORN SYRUP 20.0 19.0 15.00 18.0 17.0 14.00
GLYCERIN 1.0 1.0 1.00 1.0 1.0 1.00
PEPPERMINT 1.0 1.0 1.00 1.0 1.0 1.00
FLAVOR
DEXTROSE - - - 10.0 10.0 10.00
MONOHYDRATE
ACTIVE -a~ 0.27 0.41 -a~ 0.27 0.41
CHLORPHENIRAMINE
MALEATE
a) All of the active agent is in the coating, which comprises 33% of the
product.
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 maieate 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:
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TABLE 7
(DRY WEIGHT PERCENT
EX.42 EX.43 EX.44 EX.45 EX.46 EX.47
SUGAR 96.83 95.13 93.29 96.63 94.83 92.79
GUM ARABIC 2.0 3.0 4.0 2.0 3.0 4.0
TITANIUM 0.5 1.0 1.0 - - -
DIOXIDE
CALCIUM - - - 0.5 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.8 0.5 0.8 0.3
WAX 0.1 0.1 0.1 0.1 0.1 0.1
CHLORPHEN- 0.27 0.27 0.81a~ 0.27 0.27 0.81a~
IRAMINE
MALEATE
5
TABLE 7 (Cont'd)
(DRY WEIGHT PERCENT)
EX.48 EX.49 EX.50 EX.51
DEXTROSE 97.33 95.13 96.93 93.69
MONOHYDRATE
GUM ARABIC 1.5 3.0 1.5 3.0
TITANIUM 0.5 1.0 - -
DIOXIDE
CALCIUM - - 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.2 0.4
WAX 0.1 0.1 0.1 0.1
CHLORPHEN- 0.27 0.27 0.27 0.81 a~
IRAMINE
MALEATE
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
10 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
15 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
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36
more coats. Chlorpheniramine maleate may be dissolved in flavar 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.
TABLE 8
(WEIGHT PERCENT)
EX.52 EX.53 EX.54 EX.55 EX.56 EX.57 EX.58
GUM BASE 35.0 35.0 30.0 30.0 30.0 40.0 50.0
CALCIUM - - 5.0 10.0 15.0 - -
CARBONATE
SORBITOL 43.3 45.03 45.89 40.3 44.53 41.29 25.96
MANNITOL 10.0 10.0 5.0 10.0 - 8.0 10.0
GLYCERIN - 8.0 2.0 - 8.0 2.0 2.0
SORBITOL 10.0 - 10.0 8.0 - 6.Oa~ IO.Oa~
LIQUID
FLAVOR 1.5 1.5 1.5 1.5 2.0 2.0 1.3
HIGH INTENSITY0.2 0.2 0.2 0.2 0.2 0.3 0.2
SW EETENER
ACTIVE -~ 0.27 0.41 ~~ 0.27 0.41 0.54
CHLORPHEN-
IRAMINE
MALEATEb~
a) Lycasin brand hydrogenated starch hydrolyzate used instead of sorbitol
liquid
b) This material may be dissolved in water, glycerin, sorbitol liquid, or HSH.
c) All of the active agent is in the coating, Which comprises 33% of the
product.
In the above center formulations, the high intensity sweetener used is
aspartame. However other 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
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37
combinations thereof may be used in any of the examples with the level
adjusted for sweetness.
L_ycasin 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. The
following table gives formulas for a xylitol coating:
TABLE 9
(DRY WEIGHT PERCENT)
EX.59 EX.60 EX.61 EX.62 EX.63 EX.64
XYLITOL 94.53 92.13 89.89 89.83 89.63 87.99
GUM ARABIC 4.0 6.0 7.0 8.5 8.5 10.0
FLAVOR 0.5 0.5 0.7 0.7 0.9 0.5
TITANIUM 0.5 0.9 - 0.5 0.5** 0.5"
DIOXIDE
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
COLOR* - - 1.4 - - -
CHLORPHEN- 0.27 0.27 0.81 0.27 0.27 0.81
a~ a~
IRAMINE
MALEATE
* Lake color dispersed in xylitol solution
** Calcium carbonate used in place of titanium dioxide
a) All of the active agent is in the coating, which comprises 33% of the
product.
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.
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38
For coating formulas based on sorbitol, maltitol, lactitol, erythritol, and
hydrogenated isomaltulose, gum arabic can be used as a binder and film
former, and a crystallization modifier to help facilitate coating. Generally
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.
TABLE 10
1 O (DRY WEIGHT PERCENT)
EX.65 EX.66 EX.67 EX.68 EX.69 EX.70
MALTITOL 96.53 94.63 91.29 86.53 75.83 68.69
MALTITOL - - - 10.0 20.0 25.0
POW DER
GUM ARABIC 2.0 4.0 6.0 2.0 3.0 4.0
FLAVOR 0.5 0.4 0.7 0.5 0.3 0.7
TITANIUM DIOXIDE0.5 0.5 1.0 0.5 0.4 0.6
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
CHLORPHEN- 0.27 0.27 0.81a~ 0.27 0.27 0.81a~
IRAMINE
MALEATE
a) All of the active agent is in the coating, which comprises 33% of the
product.
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.
In a similar manner, 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. Like maltitol, the other polyols may become sticky during the coating
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39
and drying process, so the dry powder charge may be needed to give the
proper drying. In the later stages of the coating process, less gum arabic
could be used and a more pure polyol syrup could be used to give a smooth
surface. Also, the dry charge would only be used in the early stages of the
coating process.
In addition to dry charging with the specific polyol, other 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. Also, 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.
Some typical sugar type gum center formulations are shown in
Table 11 containing pseudoephedrine hydrochloride, which is a nasal
decongestant as an active medicament.
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TABLE 11
WEIGHT PERCENT)
EX.71 EX.72 EX.73 EX.74 EX.75 EX.76
SUGAR 52.0 48.0 46.5 44.0 40.0 37.5
GUM BASE 26.0 30.0 35.0 26.0 30.0 35.0
CORN SYRUP 20.0 19.0 15.00 18.0 17.0 14.00
GLYCERIN 1.0 1.0 1.00 1.0 1.0 1.00
PEPPERMINT 1.0 1.0 1.00 1.0 1.0 1.00
FLAVOR
DEXTROSE - - - 10.0 10.0 10.00
MONOHYDRATE
ACTIVE a~ 1.0 1.5 -a~ 1.0 1.5
PSEUDOEPHEDRINE
HYDROCHLORIDE
5
a) All of the active agent is in the coating, which comprises 33% of the
product.
Formulations with or without active pseudoephedrine hydrochloride can
also be made similar to other formulations for low, medium, and high moisture
10 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
15 pseudoephedrine hydrochloride in two gum pieces, total piece must contain
1.0%.
Pseudoephedrine hydrochloride can be used in the coating formula on
the various pellet gum formulations. The following Table 12 shows some
sugar and dextrose type formulas:
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41
TABLE 12
(DRY WEIGHT PERCENT)
EX.77 EX.78 EX.79 EX.80 EX.81 EX.82
SUGAR 95.1 94.4 91.1 94.9 94.1 90.6
GUM ARABIC 2.0 3.0 4.0 2.0 3.0 4.0
TITANIUM DIOXIDE0.5 1.0 1.0 - - -
CALCIUM - - - 0.5 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.8 0.5 0.8 0.3
WAX 0.1 0.1 0.1 0.1 0.1 0.1
PSEUDO- 2.0 1.0 3.Oa~ 2.0 1.0 3.Oa~
EPHEDRINE
HYDROCHLORIDE
TABLE 12 (Cont'd)
DRY WEIGHT PERCENT
EX.83 EX.84 EX.85 EX.86
DEXTROSE 95.6 94.4 96.2 91.5
MONOHYDRATE
GUM ARABIC 1.5 3.0 1.5 3.0
TITANIUM DIOXIDE0.5 1.0 - -
CALCIUM - - 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.2 0.4
WAX 0.1 0.1 0.1 0.1
PSEUDO- 2.0 1.0 1.0 3.Oa~
EPHEDRINE
HYDROCHLORIDE
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.
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
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42
added to the coating. After the final coats are applied and dried, wax is
applied to give a smooth polish.
As shown in Table 13, some of the sugar or dextrose may be added as
a dry charge, which may also contain the active agent.
TABLE 13
(DRY WEIGHT PERCENT)
EX.87 EX.88 EX.89 EX.90 EX.91 EX.92
SUGAR 76.5 78.4 - - 86.5 -
DEXTROSE - - 76.5 83.3 - 84.1
MONOHYDRATE
POWDER 20.0 15.0 - - - -
SUGAR
POWDER - - 20.0 10.0 - -
DEXTROSE
GUM ARABIC 2.0 3.0 2.0 3.0 8.0 8.0
POWDER
GUM ARABIC - - - - 4.0 4.0
SOLUTION
FLAVOR 0.4 0.5 0.4 0.6 0.4 0.8
WAX 0.1 0.1 0.1 0.1 0.1 0.1
PSEUDO- 1.0 3.Oa~ 1.0 3.Oa~ 1.0 3.Oa~
EPHEDRINE
HYDROCHLORIDE
' Powder and/or crystalline sugar may be used.
a) All of the active agent is in the coating, which comprises 33% of the
product.
In Examples 87-90 gum arabic powder is blended in the sugar syrup.
In Examples 91 and 92, 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
CA 02355779 2001-06-14
WO 00/35296 PCT/US99/29742
43
ingredients proportionally reduced. Some typical gum formulas are in
Table 14.
TABLE 14
(W EIGHT PERCENT)
EX.93 EX.94 EX.95 EX.96 EX.97 EX.98 EX.99
GUM BASE 35.0 35.0 30.0 30.0 30.0 40.0 50.0
CALCIUM - - 5.0 10.0 15.0 - -
CARBONATE
SORBITOL 43.3 44.3 44.8 40.3 43.8 40.2 24.5
MANNITOL 10.0 10.0 5.0 10.0 - 8.0 10.0
GLYCERIN - 8.0 2.0 - 8.0 2.0 2.0
SORBITOL 10.0 - 10.0 8.0 - 6.Oa~ lO.Oa~
L1QUID
FLAVOR 1.5 1.5 1.5 1.5 2.0 2.0 1.3
HIGH INTENSITY 0.2 0.2 0.2 0.2 0.2 0.3 0.2
SWEETENER
ACTIVE -'~ 1.0 1.5 '~ 1.0 1.5 2.0
PSEUDO-
EPHEDRINE
HYDRO-
CHLORIDEb~
a) Lycasin brand hydrogenated starch hydrolyzate used instead of sorbitol
liquid
b) This material may be dissolved in water, glycerin, sorbitol liquid, or HSH.
c) All of the active agent is in the coating, which comprises 33% of the
product.
In the above center formulations, the high intensity sweetener used is
aspartame. However other 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, lactitoi 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.
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44
Pseudoephedrine hydrochloride may be used in sugarless coatings
with xylitol, sorbitol, maltitol, lactitol, hydragenated isomaltulose and
erythritol.
The following table gives formulas for a xylitol coating:
TABLE 15
(DRY WEIGHT PERCENT)
EX.100 EX.101 EX.102 EX.103EX.104 EX.105
XYLITOL 92.8 91.4 87.7 88.1 88.9 85.8
GUM ARABIC 4.0 6.0 7.0 8.5 8.5 10.0
FLAVOR 0.5 0.5 0.7 0.7 0.9 0.5
TITANIUM DIOXIDE0.5 0.9 - 0.5 0.5" 0.5'*
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
COLOR* - - 1.4 - - -
PSEUDO- 2.0 1.0 3.Oa~ 2.0 1.0 3.Oa~
EPHEDRINE
HYDROCHLORIDE
* Lake color dispersed in xylitol solution
** Calcium carbonate used in place of titanium dioxide
a) All of the active agent is in the coating, which comprises 33% of the
product.
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.
For coating formulas based on sorbitol, maltitol, lactitol, erythritol, and
hydrogenated isomaltulose, gum arable can be used as a binder and film
former, and a crystallization modifier to help facilitate coating. Generally
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.
CA 02355779 2001-06-14
WO 00/35296 PCT/US99/29742
TABLE 16
(DRY WEIGHT PERCENT)
EX.106 EX.107 EX.108 EX.109 EX.110 EX.111
MALTITOL 94.8 93.9 89.1 84.8 75.1 66.5
MALTITOL - - - 10.0 20.0 25.0
POW DER
GUM ARABIC 2.0 4.0 6.0 2.0 3.0 4.0
FLAVOR 0.5 0.4 0.7 0.5 0.3 0.7
TITANIUM DIOXIDE0.5 0.5 1.0 0.5 0.4 0.6
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
PSEUDO- 2.0 1.0 3.Oa~ 2.0 1.0 3.Oa~
EPHEDRINE
HYDROCHLORIDE
5
a) All of the active agent is in the coating, which comprises 33% of the
product.
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
10 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.
In a similar manner, coatings with sorbitol, lactitol, and hydrogenated
15 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. Like maltitol, 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. In the later stages of the coating process, less gum arabic
20 could be used and a more pure polyol syrup could be used to give a smooth
surface. Also, the dry charge would only be used in the early stages of the
coating process.
In addition to dry charging with the specific polyol, other ingredients
may be added to the dry charge to help absorb moisture. These materials
CA 02355779 2001-06-14
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46
could be inert such as talc, calcium carbonate, magnesium carbonate,
starches, gums like arabinogalactan, gum talha, gum arabic or other moisture
absorbing materials. Also, 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.
CA 02355779 2001-06-14
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47
TABLE 17
WEIGHT PERCENT)
EX.112 EX.113 EX.114 EX.115 EX.116 EX.117
SUGAR 52.0 48.67 47.5 44.0 40.67 38.5
GUM BASE 26.0 30.0 35.0 26.0 30.0 35.0
CORN SYRUP 20.0 19.0 15.0 18.0 17.0 14.0
GLYCERIN 1.0 1.0 1.0 1.0 1.0 1.0
PEPPERMINT 1.0 1.0 1.0 1.0 1.0 1.0
FLAVOR
DEXTROSE - - - 10.0 10.0 10.0
MONOHYDRATE
ACTIVE CPC a) 0.33 0.5 -.a) 0.33 0.5
a) All of the active agent is in the coating, which comprises 33% of the
product
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. The following Table 18 shows some sugar and dextrose type
formulas:
CA 02355779 2001-06-14
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48
TABLE 18
(DRY WEIGHT PERCENT)
EX.118 EX.119 EX.120 EX.121 EX.122 EX.123
SUGAR 96.6 95.07 93.1 96.4 94.77 92.6
GUM ARABIC 2.0 3.0 4.0 2.0 3.0 4.0
TITANIUM 0.5 1.0 1.0 - -
DIOXIDE
CALCIUM - - - 0.5 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.8 0.5 0.8 0.3
WAX 0.1 0.1 0.1 0.1 0.1 0.1
CPC 0.5 0.33 l.Oa~ 0.5 0.33 l.Oa~
TABLE 18 (Cont'd)
(DRY WEIGHT PERCENT)
EX.124 EX.125 EX.126 EX.127
DEXTROSE 97.1 95.07 96.87 93.5
MONOHYDRATE
GUM ARABIC 1.5 3.0 1.5 3.0
TITANIUM 0.5 1.0 - -
DIOXIDE
CALCIUM - - 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.2 0.4
WAX 0.1 0.1 0.1 0.1
CPC 0.5 0.33 0.33 l.Oa~
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. 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.
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49
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.
TABLE 19
(DRY WEIGHT PERCENT)
EX.128 EX.129 EX.130 EX.131 EX.132 EX.133
SUGAR 77.17 80.4 - - 87.17 -
DEXTROSE - - 77.17 85.3 - 86.1
MONOHYDRATE
POWDER 20.0 15.0 - - - -
SUGAR'
POWDER - - 20.0 10.0 - -
DEXTROSE'
GUM ARABIC 2.0 3.0 2.0 3.0 8.0 8.0
POW DER
GUM ARABIC - - - - 4.0 4.0
SOLUTION
FLAVOR 0.4 0.5 0.4 0.6 0.4 0.8
WAX 0.1 0.1 0.1 0.1 0.1 0.1
CPC 0.33 l.Oa) 0.33 l.Oa~ 0.33 l.Oa~
Powder and/or crystalline sugar may be used.
a) All of the active agent is in the coating, which comprises 33% of the
product.
In Examples 128-131, gum arabic is blended in the sugar syrup. In
Examples 132 and 133, 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
CA 02355779 2001-06-14
WO 00/35296 PCT/tJS99/29742
level may be increased to 30-46% with the other ingredients proportionally
reduced. Some typical gum center formulas are in Table 20.
TABLE 20
5 (WEIGHT PERCENT)
EX.134 EX.135 EX.136 EX.137 EX.138 EX.139 EX.140
GUM BASE 35.0 35.0 30.0 30.0 30.0 40.0 50.0
CALCIUM - - 5.0 10.0 15.0 - -
CARBONATE
SORBITOL 43.3 44.97 45.8 40.3 44.47 41.2 25.84
MANNITOL 10.0 70.0 5.0 10.0 - $.0 10.0
GLYCERIN - 8.0 2.0 - 8.0 2.0 2.0
SORBITOL 10.0 - 10.0 8.0 - 6.Oa~ 10.0a~
LIQUID
FLAVOR 1.5 1.5 1.5 1.5 2.0 2.0 1.3
HIGH 0.2 0.2 0.2 0.2 0.2 0.3 0.2
INTENSITY
SW EETENER
CPCb~ -'~ 0.33 0.5 ~~ 0.33 0.5 0.66
a) Lycasin brand hydrogenated starch hydrolyzate used instead of sorbitol
liquid.
b) This material may be dissolved in water, glycerin, sorbitol liquid, or HSH.
10 c) All of the active agent is in the coating, which comprises 33% of the
product.
In the above center formulations, the high intensity sweetener used is
aspartame. However other high intensity such as alitame, acesulfame K,
salts of acesulfame, cyclamate and its salts, saccharin and its salts,
neotame,
15 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
20 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. The
25 following table gives formulas for a xylitol coating:
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51
TABLE 21
(DRY WEIGHT PERCENT)
EX.141 EX.142 EX.143 EX.144 EX.145 EX.146
XYLITOL 94.3 92.07 89.7 89.6 89.57 87.8
GUM ARABIC 4.0 6.0 7.0 8.5 8.5 10.0
FLAVOR 0.5 0.5 0.7 0.7 0.9 0.5
TITANIUM 0.5 0.9 - 0.5 0.5** 0.5**
DIOXIDE
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
COLOR* - - 1.4 - - -
CPC 0.5 0.33 l.Oa~ 0.5 0.33 l.Oa~
* Lake color dispersed in xylitol solution
** Calcium carbonate used in place of titanium dioxide
a) All of the active agent is in the coating, which comprises 33% of the
product.
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. 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.
For coating formulas based on sorbitol, maltitol, lactitol, erythritol, and
hydrogenated isomaltulose, gum arabic can be used as a binder and film
former, and a crystallization modifier to help facilitate coating. Generally
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.
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52
TABLE 22
(DRY WEIGHT PERCENT)
EX.147 EX.148 EX.149 EX.150 EX.151 EX.152
MALTITOL 96.3 94.57 91.1 86.3 75.77 68.5
MALTITOL - - - 10.0 20.0 25.0
POW DER
ARABINO- 2.0 4.0 6.0 2.0 3.0 4.0
GALACTAN
FLAVOR 0.5 0.4 0.7 0.5 0.3 0.7
TITANIUM 0.5 0.5 1.0 0.5 0.4 0.6
DIOXIDE
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
CETYL 0.5 0.33 l.Oa~ 0.5 0.33 l.Oa~
PYRIDIMIUM
CHLORIDE
a) All of the active agent is in the coating, which comprises 33% of the
product.
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.
In a similar manner, 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. Like maltitol, 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. In the later stages of the coating process, less gum arabic
could be used and a more pure polyol syrup could be used to give a smooth
surface. Also, the dry charge would only be used in the early stages of the
coating process.
in addition to dry charging with the specific polyol, other ingredients
may be added to the dry charge to help absorb moisture. These materials
CA 02355779 2001-06-14
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53
could be inert such as talc, calcium carbonate, magnesium carbonate,
starches, gums like arabinogalactan, gum talha, gum arabic or other moisture
absorbing materials. Also, 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.
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54
TABLE 23
WEIGHT PERCENT)
EX.153 EX.154 EX.155 EX.156 EX.157 EX.158
SUGAR 52.0 48.17 46.75 44.0 40.17 37.75
GUM BASE 26.0 30.0 35.0 26.0 30.0 35.0
CORN SYRUP 20.0 19.0 15.0 18.0 17.0 14.0
GLYCERIN 1.0 1.0 1.0 1.0 1.0 1.0
PEPPERMINT 1.0 1.0 1.0 1.0 1.0 1.0
FLAVOR
DEXTROSE - - - 10.0 10.0 10.0
MONOHYDRATE
KETOPROFEN .a~ 0.83 1.25 .a~ 0.83 1.25
a) All of the active agent is in the coating, which comprises 33% of the
product
Formulations with or without 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. The following Table 24 shows some sugar and dextrose
type formulas:
TABLE 24
DRY WEIGHT PERCENT)
EX.159 EX.160 EX.161 EX.162 EX.163 EX.164
SUGAR 96.1 94.57 91.6 95.9 94.27 91.1
GUM ARABIC 2.0 3.0 4.0 2.0 3.0 4.0
TITANIUM 0.5 1.0 1.0 - - -
DIOXIDE
CALCIUM - - - 0.5 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.8 0.5 0.8 0.3
WAX 0.1 0.1 0.1 0.1 0.1 0.1
KETOPROFEN 1.0 0.83 2.5a~ 1.0 0.83 2.5a
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WO 00/35296 PCT/US99/29742
TABLE 24 (Cont'd)
DRY WEIGHT PERCENT
EX.165 EX.166 EX.167 EX.168
DEXTROSE 96.6 94.57 96.37 92.0
MONOHYDRATE
GUM ARABIC 1.5 3.0 1.5 3.0
TITANIUM 0.5 1.0 - -
DIOXIDE
CALCIUM - - 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.2 0.4
WAX 0.1 0.1 0.1 0.1
KETOPROFEN 1.0 0.83 0.$3 2.5a~
a) All of the active agent is in the coating, which comprises 33% of the
product.
5
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
10 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.
15 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 shelf. Table 25 gives these types of formulas.
CA 02355779 2001-06-14
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56
TABLE 25
(DRY WEIGHT PERCENT)
EX.169 EX.170 EX.171 EX.172 EX.173 EX.174
SUGAR 76.67 78.9 - - 86.67 -
DEXTROSE - - 76.67 83.8 - 84.6
MONOHYDRATE
POWDER 20.0 15.0 - - - -
SUGAR*
POWDER - - 20.0 10.0 - -
DEXTROSE'
GUM ARABIC 2.0 3.0 2.0 3.0 8.0 8.0
POW DER
GUM ARABIC - - - - 4.0 4.0
SOLUTION
FLAVOR 0.4 0.5 0.4 0.6 0.4 0.8
WAX 0.1 0.1 0.1 0.1 0.1 0.1
KETOPROFEN 0.83 2.5a) 0.83 2.58 0.83 2.5a~
* Powder and/or crystalline sugar may be used.
a) All of the active agent is in the coating, which comprises 33% of the
product.
In Examples 169-172, gum arabic is blended in the sugar syrup. In
Examples 173 and 174, 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.
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57
TABLE 26
(WEIGHT PERCENT)
EX.175 EX.176 EX.177 EX.17$ EX.179 EX.180 EX.181
G U M BAS 35.0 35.0 30.0 30.0 30.0 40.0 50.0
E
CALCIUM - - 5.0 10.0 15.0 - -
CARBONATE
SORBITOL 43.3 44.47 45.05 40.3 43.97 40.45 24.83
MANNITOL 10.0 10.0 5.0 10.0 - 8.0 10.0
GLYCERIN - 8.0 2.0 - 8.0 2.0 2.0
SORBITOL 10.0 - 10.0 8.0 - 6.Oa~ 10.0a~
LIQUID
FLAVOR 1.5 1.5 1.5 1.5 2.0 2.0 1.3
HIGH 0.2 0.2 0.2 0.2 0.2 0.3 0.2
INTENSITY
SW EETENER
KETOPROFEN~-'~ 0.83 1.25 -~ 0.83 1.25 1.67
a) Lycasin brand hydrogenated starch hydrolyzate used instead of sorbitol
liquid.
b) Ketoprofen may be dissolved in water, glycerin, sorbitol liquid, HSH, or
flavor.
c) All of the active agent is in the coating, which comprises 33% of the
product.
In the above center formulations, the high intensity sweetener used is
aspartame. However other 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 sorbitoi
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:
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TABLE 27
(DRY WEIGHT PERCENT)
EX.182 EX.183 EX.184 EX.185 EX.186 EX.187
XYLITOL 93.8 91.57 88.2 89.1 89.07 86.3
GUM ARABIC 4.0 6.0 7.0 8.5 8.5 10.0
FLAVOR 0.5 0.5 0.7 0.7 0.9 0.5
TITANIUM 0.5 0.9 - 0.5 0.5'* 0.5"
DIOXIDE
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
COLOR' - - 1.4 - - -
KETOPROFEN 1.0 0.83 2.5a~ 1.0 0.83 2.5a~
Lake color dispersed in xylitol solution.
Calcium carbonate used in place of titanium dioxide.
a) All of the active agent is in the coating, which comprises 33% of the
product.
The above formulas are used to coat pellets by applying a xylitoi/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. 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.
For coating formulas based on sorbitol, maltitol, iactitol, erythritol, and
hydrogenated isomaltulose, gum arabic can be used as a binder and film
former, and a crystallization modifier to help facilitate coating. Generally
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.
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TABLE 28
(DRY WEIGHT PERCENT)
EX.188 EX.189 EX.190 EX.191 EX.192 EX.193
MALTITOL 95.8 94.07 89.6 85.8 75.27 67.0
MALTITOL - - - i 0.0 20.0 25,0
POW DER
GUM ARABIC 2.0 4.0 6.0 2.0 3.0 4.0
FLAVOR 0.5 0.4 0.7 0.5 0.3 0.7
TITANIUM 0.5 0.5 1.0 0.5 0.4 0.6
DIOXIDE
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
KETOPROFEN 1.0 0.83 2.5a~ 1.0 0.83 2.5a~
a) All of the active agent is in the coating, which comprises 33% of the
product.
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.
In a similar manner, 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. Like maltitol, 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. In the later stages of the coating process, less gum arabic
could be used and a more pure polyol syrup could be used to give a smooth
surface. Also, the dry charge would only be used in the early stages of the
coating process.
In addition to dry charging with the specific polyol, other 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
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absorbing materials. Also, 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
5 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
10 should be used. Generally high intensity sweeteners are added with the
polyol/gum arabic solution to obtain an even distribution in the coatings.
Some typical sugar type gum center formulations are shown in
Table 29 in which dextromethorphan hydrobromide can be added as the
active medicament. This material is an antitussive for cough relief. These
15 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.
TABLE 29
20 (WEIGHT PERCENT)
EX.194 EX.195 EX.196 EX.197 EX.198 EX.199
SUGAR 52.0 48.0 46.5 44.0 40.0 37.5
GUM BASE 26.0 30.0 35.0 26.0 30.0 35.0
CORN SYRUP 20.0 19.0 15.0 18.0 17.0 14.0
GLYCERIN 1.0 1.0 1.0 1.0 1.0 1.0
PEPPERMINT 1.0 1.0 1.0 1.0 1.0 1.0
FLAVOR
DEXTROSE - - - 10.0 10.0 10.0
MONOHYDRATE
DEXTRO- a~ 1.0 1.5 - a~ 1.0 1.5
METHORPHAN
HBr
a) All of the active agent is in the coating, which comprises 33% of the
product.
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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. The following Table 30 shows
some sugar and dextrose type formulas:
TABLE 30
(DRY WEIGHT PERCENT)
EX.200 EX.201 EX.202 EX.203 EX.204 EX.205
SUGAR 95.1 94.4 91.1 94.9 94.1 90.6
GUM ARABIC 2.0 3.0 4.0 2.0 3.0 4.0
TITANIUM 0.5 1.0 1.0 - - -
DIOXIDE
CALCIUM - - - 0.5 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.8 0.5 0.8 0.3
WAX 0.1 0.1 0.1 0.1 0.1 0.1
DEXTRO- 2.0 1.0 3.Oa~ 2.0 1.0 3.Oa~
METHORPHAN
HBr
_TABLE 30 (Cont'd)
(DRY WEIGHT PERCENT)
EX.206 EX.207 EX.208EX.209
DEXTROSE 95.6 94.4 96.2 91.5
MONOHYDRATE
GUM ARABIC 1.5 3.0 1.5 3.0
TITANIUM 0.5 1.0 - -
DIOXIDE
CA>_CIUM - - 1.0 2.0
CARBONATE
FLAVOR 0.3 0.5 0.2 0.4
WAX 0.1 0.1 0.1 0.1
DEXTRO- 2.0 1.0 1.0 3.Oa~
METHORPHAN
HBr
a) All of the active agent
is in the coating, which comprises
33% of the
product.
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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.
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. Dextromethorphan
hydrobromide may also be added to the dry charge material. Table 31 gives
these types of formulas.
TABLE 31
(DRY WEIGHT PERCENT)
EX.210 EX.211 EX.212 EX.213 EX.214 EX.215
SUGAR 76.5 78.4 - - 86.5 -
DEXTROSE - - 76.5 83.3 - 84.1
MONOHYDRATE
POWDER 20.0 15.0 - - - -
SUGAR'
POWDER - - 20.0 10.0 - -
DEXTROSE'
GUM ARABIC 2.0 3.0 2.0 3.0 8.0 8.0
POWDER
GUM ARABIC - - - - 4.0 4.0
SOLUTION
FLAVOR 0.4 0.5 0.4 0.6 0.4 0.8
WAX 0.1 0.1 0.1 0.1 O.i 0.1
DEXTRO- 1.0 3.Oa~ 1.0 3.Oa~ 1.0 3.Oa~
METHORPHAN
HBr
Powder and/or crystalline sugar may be used.
a) All of the active agent is in the coating, which comprises 33% of the
product.
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In Examples 210-213 gum arabic is blended in the sugar syrup. In
Examples 214 and 215, 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. 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 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.
TABLE 32
(WEIGHT PERCENT)
EX.216 EX.217 EX.218 EX.219 EX.220 EX.221 EX.222
GUM BASE 35.0 35.0 30.0 30.0 30.0 40.0 50.0
CALCIUM - - 5.0 10.0 15.0 - -
CARBONATE
SORBITOL 43.3 44.3 43.3 40.3 43.8 38.7 24.5
MANNITOL 10.0 10.0 5.0 10.0 - 8.0 10.0
GLYCERIN - 8.0 2.0 - 8.0 2.0 2.0
SORBITOL 10.0 - 10.0 8.0 - 6.Oa~IO.Oa~
LIQUID
FLAVOR 1.5 1.5 1.5 1.5 2.0 2.0 1.3
HIGH 0.2 0.2 0.2 0.2 0.2 0.3 0.2
INTENSITY
SWEETENER
DEXTRO ~ 1.0 3.0 -'~ 1.0 3.0 2.0
METHOR-
PHAN HBrb~
a) Lycasin brand hydrogenated starch hydrolyzate used instead of sorbitol
liquid
b) Dextromethorphan HBr may be dissolved in water, glycerin, sorbitol liquid,
HSH, or
flavor
c) All of the active agent is in the coating, which comprises 33% of the
product
In the above center formulations, the high intensity sweetener used is
aspartame. However other high intensity such as alitame, acesulfame K,
salts of acesulfame, cyclamate and its salts, saccharin and its salts,
neotame,
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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.
Dextromethorphan hydrobromide 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 33
(DRY WEIGHT PERCENT)
EX.223 EX.224 EX.225 EX.226 EX.227 EX.228
XYLITOL 92.8 91.4 87.7 88.1 88.9 85.8
GUM ARABIC4.0 6.0 7.0 8.5 8.5 10.0
FLAVOR 0.5 0.5 0.7 0.7 0.9 0.5
TITANIUM 0.5 0.9 - 0.5 0.5*" 0.5"
DIOXIDE
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
COLOR" - - 1.4 - - -
DEXTRO- 2.0 1.0 3.Oa~ 2.0 1.0 3.Oa~
METHORPHAN
HBr
' Lake color dispersed in xylitol solution
'" Calcium carbonate used in place of titanium dioxide
a) All of the active agent is in the coating, which comprises 33% of the
product.
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
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with hot syrup and used in the early stages of coating or used throughout the
coating process.
For coating formulas based on sorbitol, maltitol, lactitol, erythritol, and
hydrogenated isomaltulose, gum arabic can be used as a binder and film
5 former, and a crystallization modifier to help facilitate coating. Generally
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 active may be premixed with the dry charge
10 material. The following formulations may be used.
TABLE 34
(DRY WEIGHT PERCENT)
EX.229 EX.230 EX.231 EX.232 EX.233 EX.234
MALTITOL 94.8 93.9 87.1 91.8 85.1 76.5
MALTITOL - - - 5.0 10.0 15.0
POW DER
GUM ARABIC2.0 4.0 6.0 2.0 3.0 4.0
FLAVOR 0.5 0.4 0.7 0.5 0.3 0.7
TITANIUM 0.5 0.5 1.0 0.5 0.4 0.6
DIOXIDE
TALC 0.1 0.1 0.1 0.1 0.1 0.1
WAX 0.1 0.1 0.1 0.1 0.1 0.1
DEXTRO- 2.0 1.0 3.Oa~ 2.0 1.0 3.Oa~
METHORPHAN
HBr
15 a) All of the active agent is in the coating, which comprises 33% of the
product.
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
20 xylitol examples, or added with the dry charge material.
In a similar manner, 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
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powder. Like maltitol, 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. In the later stages of the coating process, less gum arabic
could be used and a more pure polyol syrup could be used to give a smooth
surface. Also, the dry charge would only be used in the early stages of tine
coating process.
In addition to dry charging with the specific polyol, other 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. Also, powdered sweeteners or flavors could be added
with the dry charge.
Some polyols such as sorbitol, maltitol, erythritol, iactitol, 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.
The following gum center formulation was made as a gum pellet center
and coated with the gum coating formulation and procedure:
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Example 235
Gum Center
Gum Base 47.0
Sorbitol 39.52
Liquid Sorbitol 7.5
Flavors 2.36
Encapsulated Flavors 2.0
Glycerin 0.75
Encapsulated Sweeteners0.87
100.0
_ Gum Coating Coating Syrup 1. % Coating Syrup
2.
Xylitol 63.03 74.35
Water 11.14 13.15
40% Gum Tahla solution20.87 7.g6
Titanium Dioxide 0.37 0.44
whitener
Peppermint Flavor" 0.81
0.0
Caffeine 3.78 4.10
100.0 100.0
"Flavor added in 2 additions after 10th and 15th coat within coating syrup 1.
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.
Comparisons of caffeine delivery between chewing gum and the three
beverages are demonstrated by statistically significant differences in one or
more of the following parameters:
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1. 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.
2. Plasma absorption rate constant (A-rate) 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.
Data from the six subjects participating in the study were compiled,
analyzed, and graphed, with mean plasma caffeine concentrations at specific
time intervals determined. Analysis of variance (ANOVA) were performed on
the means to determine statistical significance.
Pharmacokinetic parameters were determined through Wagner's 1967
Method of Residuals using a pharmacokinetic software package. Absorption
rate constants and absorption half-life were also determined through the
analysis of the absorption phase of the plots by linear regression since the
absorption phase followed zero order kinetics.
The conclusions were as follows:
1. There was a faster uptake of caffeine in plasma during the early
time intervals post dose 10 minutes to 25 minutes (T10-T25) via gum delivery
vs. the same level of caffeine delivered via coffee and cola. For example, the
average level of plasma caffeine (at T = 10 minutes) present after gum chew
is 0.545 ~g/ml compared to 0.186 pg/ml for coffee and 0.236 ~.g/ml for cola.
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In other words, with the same level of caffeine being delivered from the three
different vehicles, at T10 there is 3 times more caffeine present in plasma
after chewing gum than from ingesting coffee and 2 times more caffeine from
gum than from cola. The results of the tea study proved to be too variable
due to instrument problems and repeat freeze/thawing of the samples. They
were not included in the calculations.
2. Classical pharmacokinetic parameters, T-max, A-rate constant,
abs. half-life, do not tell the story of faster uptake in the time interval of
interest (T10-T25) in this study. This is due in part to the calculation using
the
Method of Residuals. This method was derived using classical
pharmacokinetic curves which do not have much fluctuation in the data in that
the drug concentration (usually measured every hour) increases to a sharp T-
max, then decreases, without any fluctuation. In comparison, the data did
contain minor fluctuations, due most likely to a combination of factors:
measurement of plasma concentrations every five minutes rather than every
quarter hour to one hours, caffeine binding with plasma protein, combination
of both sublingual and gut absorption being detected. The plasma caffeine
concentration followed the same trends as in classical pharmacokinetic
curves, except that the concentration increased to a broad T-max, then
decreased, and some of the points in the curve fluctuated up and down.
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. For example, 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. An ANOVA separating subjects 1-4 from 5 and 6
indicated that for subjects 1-4 cola abs. half-life is statistically greater
than G2
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abs. half-life (p = 0.10), and the G2 A-rate is statistically greater than
both the
cola and coffee A-rate (p = 0.05).
3. It was shown that significant levels of caffeine are absorbed
sublingually directly into the bloodstream via delivery from gum This was
5 demonstrated through the testing of caffeinated gum where the saliva was
expectorated. Even though the saliva was expectorated, 20-50% of the
caffeine was absorbed through the oral cavity. This accounts for the early
uptake into the bloodstream.
Example 236
Gum Center
Gum Base 33.0
Calcium Carbonate 13.0
Sorbitol 44.23
Glycerin 4.0
Flavors 2.32
Encapsulated Caffeine' 1.5
Free Caffeine 0.45
Lecithin 0.6
Encapsulated Sweeteners 0.9
100.0
Gum Coating (dry) Coating Syrup 3 % Coating Syrup 4
Xylitol 64.14 76.23
Water 11.14 13.15
40% Gum Tahla solution 20.87 7.96
Titanium Dioxide whitener 0.4 0.4
Peppermint Flavor** 1.4 0.0
Sweeteners 0.27 0.27
Carnauba Wax/Talc polishing 0.0 0.27***
agents
Caffeine 1.78 1.72
100.0 100.0
* Spray dried maltodextrin/caffeine at 50% active caffeine.
** Flavor added in 3 additions after 3 separate syrup addition within coating
syrup 1.
*** polished after completion of coating.
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.
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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.
Data from the six subjects participating in each study were compiled,
analyzed, and graphed, with mean plasma caffeine concentrations at specific
time intervals determined. Analysis of variance (ANOVA) and Student t-Tests
were performed on the means to determine statistical significance.
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-PIusT"" pill, containing
approximately 50 mg caffeine in one pill (designated as Pill 1, Pill 2, or 50
mg
pill). Pro-PIusT"" 50 mg tablet is manufactured by the product license holder:
PP Products, 40 Broadwater Road, Welayn Garden City, Harts, AL7 Bay, UK.
Caffeine analysis were analyzed at 48.3 mg ~ 1.4 mg caffeine per pill (avg. of
n=5).
It was concluded that caffeine uptake in the bloodstream was faster for
gum than a piH, based on the following:
1. Faster uptake of plasma caffeine via gum delivery was found
during the early time intervals post dose 5 minutes to 50 minutes (T5-T50)
when compared to the same level of caffeine delivered via a pill (50 mg). For
example, with the same level of caffeine being delivered from the two
different
vehicles, on average, at T5 there is 30 times more caffeine detected in
plasma after chewing gum (0.205~g/ml) than after ingesting a pill (0.006
p.g/ml). At T10 there is 16 times more caffeine detected in plasma after
chewing gum (0.546 ~g/ml) than after ingesting a pill (0.034 pg/ml). Average
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plasma caffeine levels significantly greater than the pill at a=0.01 for T5,
and
a=0.005 for T10.
2. Classical pharmacokinetic parameters, T-Max (time for peak
plasma caffeine concentration) and Abs.'/2 Life (absorbance'h life, time for
caffeine concentration to be'h of peak) were significantly different for
caffeine
delivered via 50 mg pellet gum (Example 235) than via a 50 mg pill. Faster
uptake of plasma caffeine was demonstrated via delivery from gum compared
to a pill due to the average plasma Abs. '/2 Life and average plasma T-Max
being significantly smaller for gum than the pill. For the 50 mg pellet gum,
the
average Abs. '/2 Life = 12.84 min and the average T-Max-36.5 min. compared
to the 50 mg pill with an average Abs. '/2 Life = 24.47 min (pill
significantly
greater than gum, a=0.0075, and an average T-Max = 73.67 min (pill
significantly greater than gum, a=0.0075), and an average T-Max = 73.67 min
(pill significantly greater than gum, a=0.005). In other words, after
ingesting a
pill, it takes a longer amount of time to reach'/2 of the peak plasma caffeine
concentration and the peak plasma caffeine concentration than after chewing
gum delivering the same level of caffeine.
3. 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. For the 50 mg pellet gum, the average Abs. Rate
Const. = 0.060 compared to the 50 mg pill with an average Abs. Rate
Const. = 0.031 (gum significantly greater than pill, a=0.005).
4. The test also demonstrated faster uptake of plasma caffeine via
Example 236, 40 mg pellet gum, delivery during the early time intervals post
dose 10 minutes to 30 minutes (T10-T30} when compared to 50 mg of
caffeine delivered via a pill. Significance levels ranged from a=0.05 to
a=0.20.
For example, the average level of plasma caffeine (at T=10 minutes) present
after 40 mg pellet gum is chewed is 0.228 ~g/ml compared to 0.034 ~g/ml for
pill (difference was slightly significant, a=0.2). In other words, with
caffeine
being delivered from the two different vehicles at T10 there is 6.7 times more
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caffeine detected in plasma after chewing Example 236 gum caffeine than
after ingesting a pill, even though the pill delivered approximately 50 mg
caffeine, and Example 236 delivered approximately 40 mg. At T5, on average
there was 13 times more caffeine detected in plasma after chewing
Example 236 gum than after ingesting a pill.
5. Classical pharmacokinetic parameters, T-Max and Abs. '/z Life
were significantly different for caffeine delivered via Example 236 40 mg
pellet
gum than via a 50 mg pill. Faster uptake of plasma caffeine was
demonstrated via delivery from Example 236 gum compared to a pill due to
the average plasma Abs. '/z Life and average plasma T-Max being
significantly smaller for gum than the pill. For the 50 mg Example 235 gum,
the average Abs. '/z Life = 18.33 min and the average T-Max = 45 min
compared to the 50 mg pill with an average Abs. '/z Life = 24.47 min (pill
significantly greater than gum, a=0.05), and an average T-Max = 73.67 min
(pill significantly greater than gum, a=0.15). Even though the Example 236
delivered 40 mg caffeine compared to delivery of 50 mg via a pill, it still
took a
longer amount of time to reach'/2 of the peak plasma caffeine concentration
the peak plasma caffeine concentration for the pill than for the gum.
6. It was concluded that 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:
Classical pharmacokinetic parameters T-Max and Abs. '/z Life were
greater than pill for both 50 mg pellet and Example 235, though the level of
significant difference was much greater for the 50 mg pellet (Example 235)
(a=0.0075 and a=0.005 respectively) than Example 236 (a=0.05, a=0.15).
The Abs. Rate Const. was significantly lower for the pill than for either the
50 mg pellet or the Example 236. Again, the level of significant difference
was greater for the 50 mg pellet (Example 235), a=0.005 compared to 0.20 for
Example 236.
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7. Combining the conclusions from the two completed caffeine
studies, it appears that rate of caffeine uptake in plasma via the various
delivery vehicles tested follow this pattern:
Pellet with caffeine all in coating > Pellet with caffeine split between
coating and center = Beverages coffee/cola > Pill
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.
It should be appreciated that the 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.
