Note: Descriptions are shown in the official language in which they were submitted.
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TABLETS COMPRISING A CORE AND A MEDICAMENT-CONTAINING COATING FOR BUCCAL
RELEASE
BACKGROUND
[0001] The present invention generally relates to the delivery of medicaments
and other agents. More specifically, the present invention relates to the
delivery of
medicaments and agents using chewable products and methods for producing such
products.
[0002] It is of course known to provide agents to individuals for various
purposes. These agents 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
prophylactic purposes. Still, it is known to provide agents to an individual
for a
variety of non-medical purposes including enhancing performance or maintaining
or
initiating alertness. There are a great variety of such agents. These agents
ran the
gamut from stimulants such as caffeine to drugs such as analgesics,
tranquilizers,
cardiovascular products, insulin, etc. Some such agents are taken on an as
needed
basis while other agents must be taken at regular intervals by the individual.
[0003] Typically, drugs (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.
[0004] Except when given intravenously, a drug must traverse several
semipermeable cell membranes before reaching general circulation. These
membranes
act as a biological barrier that inhibits the passage of drug molecules. There
are
believed to be four processes by which drugs move across a biological barrier:
passive
diffusion; facilitated diffusion; active transport; and pinocytosis.
[0005] Passive diffusion is the transport across the cell membrane wherein the
driving force for the movement is the concentration gradient of the solute. In
orally
administered drugs, this absorption occurs in the small intestines.
Facilitated diffusion
is believed to be based on a carrier component that combines reversibly with
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substrate molecule at the cell membrane exterior. The carrier substrate
complex
diffuses rapidly across the membrane with release of the substrate at the
interior
surface. Active transport requires an energy expenditure by the cell and
appears to be
limited to agents with structural similarities to normal body constituents.
These agents
are usually absorbed from specific sites in the small intestines. Pinocytosis
refers to
the engulfing of particulars or fluid by a cell. It is believed to play a
minor role in drug
transport. MerckManual, 16th Edition, pp. 2598-2599.
[0006] In determining the efficacy of a drug and the effectiveness of the use
of
a drug to treat a disease, drug absorption is a critical concern. Drug
absorption refers
to the process of drug movement from the site of administration toward the
systemic
circulation.
[0007] Oral administration of drugs is by far the most common method. 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 canal 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.
[0008] A further issue effecting the absorption of orally administered drugs
is
the form of the drug. Most orally administered drugs are in the form of
tablets or
capsules. This is primarily for convenience, economy, stability, and patient
acceptance. 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 effect the dissolution rate and therefore determine the availability of
the drug for
absorption. See Merck Manual at page 2600.
[0009] Parenteral administration allows for the direct placement of the drug
into the blood stream. This usually insures complete delivery of the dose to
the
general circulation. However, administration by a route that requires drug
transfer
through one or more biologic membranes to reach the blood stream precludes a
guarantee that all of the drug will eventually be absorbed. Even with
parenteral
administration, because capillaries tend to be highly porous, the perfusion
(blood
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flow/gram of tissue) is a major factor in the rate of absorption. Thus, the
injection site
can markedly influence a drugs' absorption rate; e.g., the absorption rate of
diazepam
injected IM into a site with poor blood flow can be much slower than following
an oral
dose. See Merck Manual at page 2601.
[0010] Not only is drug absorption an issue in drug delivery but also the
bioavailability of the drug is also critical. Bioavailability is defined as
the rate at
which and the extent to which the active moiety (drug or metabolite) enters
the general
circulation, thereby gaining access to the site of action. Bioavailability
depends upon a
number of factors, including how a drug product is designed and manufactured,
its
physicochemical properties, and factors that relate to the physiology and
pathology of
the patient. See Merck Manual at page 2602.
[0011] 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 drags show low bioavailability
owing 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.
[0012] Bioavailability considerations are most often encountered for orally
administered drugs. Differences in bioavailability can have profound clinical
significance.
[0013] 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 not preferred due to patient concerns
including
comfort, infection, etc., as well as the equipment and costs involved.
However, despite
best efforts certain therapies require parenterally injected drugs. For
example, research
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for decades has focused on an attempt to deliver insulin to an individual
through a non-
parenteral means. Despite such efforts, today insulin is still only
administered
intravenously.
[0014] In producing products for delivering medicaments and other agents to
an individual, it may be critical that a predefined amount of medicament or
agent is
delivered per dose of the product. This allows the physician and/or patient to
determine the amount of product to ingest and insure that a safe and effective
level of
medicament or agent is delivered. If the medicament or agent is located in a
coating of
the product it is necessary to ensure that definite levels of coating are
present in each
product. This requires a manufacturing process that allows for the accurate
production
of coated products.
SUMMARY
[0015] The present invention provides improved methods for manufacturing
products for delivering a medicament or agent to an individual as well as such
products. To this end, a chewable consumable center is initially coated to
produce a
coated product including one or more medicaments or agents. The medicament or
agent can be present within the coating that substantially encloses the
consumable
center. If desired, the consumable center can be tableted so that a
specifically defined
coating can be provided, providing a predetermined and controllable level of
medicament or agent.
[0016] The chewable consumable center can be, by way of example and not
limitation, a gummi candy, confectionary starch, hard candy, licorice-type
candy or
tableted excipient such as dextrose, sucrose, or other saccharides, sorbitol,
mannitol,
iso-malitol, other sugar alcohols, or combinations thereof.
[0017] Improved formulations including medicaments or agents are also
provided by the present invention.
[0018] To this end, the present invention provides a product including a
consumable center. The consumable center can be partially, substantially or
entirely
surrounded by one or more coatings. The coating includes a medicament or agent
and
comprises at least 50% by weight of the product. The consumable center can
have a
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hardness of about 4-6 KPA, which provides the consumable center with a soft
chew
characteristic.
[0019] In an embodiment, the coating includes a masking agent to assist in
improving the organoleptic properties of the coating containing the
medicament. The
masking agent may be chosen from the group consisting of. sucralose; zinc
gluconate;
ethyl maltol; glycine; acesulfame-K; aspartame; saccharin; fructose; xylitol;
spray
dried licorice root; glycerrhizine; dextrose; sodium gluconate; glucono delta-
lactone;
ethyl vanillin; vanillin; normal and high-potency sweeteners; and a variety of
appropriate flavors.
[0020] In an embodiment, the coating includes a high-intensity sweetener. In a
further embodiment, the high-intensity sweetener is chosen from the group
consisting
of aspartame, sucralose, and acesulfame-K.
[0021] In an embodiment, the consumable center is chosen from the group
consisting of gummi candy, hard candy, confectionary starch, or compressed
excipient.
[0022] In an embodiment, the coating comprises 50% to 75% by weight of the
product.
[0023] In an embodiment, the coating is a recrystallized granular coating.
[0024] In an embodiment, the coating is an amorphous coating.
[0025] In an embodiment, the coating is a powder coating.
[0026] In an embodiment, the medicament is chosen from the group consisting
of. analgesics; muscle relaxants; antacids; antihistamines; decongestants;
anti-
inflammatories; antibiotics; antivirals; psychotherapeutic agents; insulin;
nutraceuticals; nutritional supplements; diuretics; vitamins; minerals;
anesthetics;
antitussives; bioengineered pharmaceuticals; and cardiovascular agents.
[0027] In an alternative embodiment, the present invention provides one or
more coatings comprising a fat-based confectionery surrounding the consumable
center to provide the consumable center a more aesthetic and taste appeal. For
example, the fat-based confectionery can comprise an ingredient such as white
chocolate, dark chocolate, milk chocolate and combinations thereof. The fat-
based
confectionery can also comprise one or more flavors such as, for example,
chocolate,
strawberry cream, orange, peach and mint and combinations thereof. The fat-
based
confectionery can be a component of the initial or first medicament/active
agent
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coating. In another embodiment, the fat-based confectionery can comprise a
second
coating that surrounds the medicament coated consumable center.
[0028] In another embodiment of the present invention a method of drug
delivery is provided. The method comprising the steps of: providing a product
that
includes a consumable center that is substantially surrounded by one or more
coatings.
For example, the coating includes a medicament; chewing the product to cause
the
medicament to be released from the product into the buccal cavity of the
chewer; and
continuing to chew the product thereby creating a fluid pressure causing the
medicament to enter the systemic system of the chewer through the oral mucosa
contained in the buccal cavity.
[0029] In an embodiment of the method, the agent is a medicament. In an
embodiment of the method, the medicament is chosen from the group consisting
of:
analgesics; muscle relaxants; antihistamines; decongestants; antacids; anti-
inflammatories; antibiotics; antivirals; psychotherapeutic agents; insulin;
nutraceuticals; nutritional supplements; diuretics; vitamins; minerals;
anesthetics;
antitussives; bioengineered pharmaceuticals; and cardiovascular agents.
[0030] In an embodiment of the method, one or more coatings comprising a
fat-based confectionery surround the consumable center to provide the
consumable
center a more aesthetic and taste appeal. For example, the fat-based
confectionery can
comprise an ingredient such as white chocolate, dark chocolate, milk chocolate
and
combinations thereof. The fat-based confectionery can also comprise one or
more
flavors such as, for example, chocolate, strawberry cream, orange, peach and
mint and
combinations thereof. The fat-based confectionery can be a component of the
initial
medicament/active agent coating or comprise a second coating that surrounds
the
medicament coated consumable center.
[0031 ] In yet another embodiment of the present invention a method of
delivering a medicament is provided. The method comprising the steps of.
providing a
product including a coating that comprises at least 50% by weight of the
product and
surrounds a consumable center, the coating includes a medicament; and chewing
'the
product.
[0032] In a still further embodiment of the present invention a product
containing a medicament or agent is provided. The product includes a
consumable
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center. A coating surrounds the consumable center and includes a medicament.
The
coating comprises at least 50% by weight of the product and includes taste
masking
agents.
[0033] Moreover, in an embodiment of the present invention, a method of
manufacturing a product containing a medicament or agent is provided. The
method
comprising the steps of. preparing a consumable center; and coating the
consumable
center with a powder and a syrup to create a coated product, at least one of
the powder
or syrup portion including a medicament or agent.
[0034] In an embodiment the powder and syrup are coated on the compressed
excipient in alternating steps until a sufficient coating has been built up.
[0035] In an embodiment the coating has a polished finish.
[0036] Accordingly, an advantage of the present invention is to provide new
methods for manufacturing products for delivering medicaments or agents to an
individual.
[0037] Furthermore, an advantage of the present invention is to provide an
improved product containing a medicament.
[0038] Additionally, an advantage of the present invention is to provide a
method for administering medicaments that is more palatable than current
methods.
[0039] Still further, an advantage of the present invention is to provide a
method of delivering medicaments to an individual that provides for increase
absorption and bioavailability as compared to medicaments that are designed to
be
absorbed in the GI tract.
[0040] Further, an advantage 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.
[0041] Furthermore, an advantage of the present invention is to provide a
method for administering medicaments or agents to an individual that
heretofore were
administered parenterally.
[0042] Another advantage of the present invention is to provide a method for
manufacturing products including medicaments or agents in the coating.
[0043] Moreover, an advantage of the present invention is to provide an
improved method for drug delivery.
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[0044] Further, an advantage of the present invention is to provide a chewable
product that contains an agent that heretofore could not be provided in a
chewable form
that was palatable.
[0045] Still further, an advantage of the present invention is to provide a
method
for ensuring that a coated product that includes a medicament has a precise
level of
medicament.
[0046] An advantage of the present invention is that a coated product is
provided
wherein the coating can absorb or lose moisture without apparent degradation.
[0047] Further, an advantage of the present invention is that a coated
chewable
product including medicament is provided having an extended shelf-life.
[0048] Furthermore, an advantage of the present invention is that it provides
methods of producing medicament-containing products having precise sizes and
shapes.
[0049] Another advantage of the present invention is to provide a method of
controlling the amount of agent containing coating that is used on a coated
product.
[0049a] In summary, a product including a medicament is provided, the product
comprising:
(a) a consumable center having a hardness of about 4-6 KPA; and
(b) a coating including a medicament that surrounds the consumable center,
wherein the coating comprises a powder, a syrup or both a syrup and a powder.
[0049b] Also provided is a method of manufacturing the product, the method
comprising:
(a) preparing a tableted consumable center having a hardness of about 4-6
KPA; and
(b) coating the tableted consumable center by placing layers of a powder and
a syrup on the center to create a coated product, at least one of the powder
or syrup layers
including at least a medicament.
[0050] Additional features and advantages are described herein, and will be
apparent from, the following Detailed Description and the figures.
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BRIEF DESCRIPTION OF THE FIGURES
[0051] Figure 1 illustrates generally the product having a coating in one
embodiment of the present invention.
[0052] Figure 2 illustrates generally the product having a fat-based
confectionery
coating in an alternative embodiment of the present invention.
DETAILED DESCRIPTION
[0053] The present invention provides improved methods for delivering
medicaments and other agents to an individual as well as improved products
including
such medicaments or agents and methods for producing same.
[0054] Pursuant to the present invention, a medicament or agent is contained
in
one or more coatings that surrounds a consumable center. As used herein
"consumable
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center" means that a center is provided that can be ingested by the consumer.
Preferably, the center can be chewed by the consumer. Unlike chewing gum, the
consumable center is designed to dissolve in the mouth of the consumer and/or
to be
swallowed. If desired, the center can be tableted so that it has a precise
size (within an
acceptable range) depending on the medicament or agent and shape. This allows
an
accurate control of the coating as well as allows one to produce products
having
specific sizes and shapes. In a preferred embodiment, the coating comprises at
least
50% by weight of the entire product.
[0055] In another embodiment, the present invention provides one or more
coatings comprising a fat-based confectionery surrounding a consumable center
to
provide the consumable center a more aesthetic and taste appeal. For example,
the fat-
based confectionery coatings can give the consumable center a smoother surface
and a
better taste and texture when consumed. The fat-based confectionery can be
included
as a component of the initial or first medicament/active agent coating. In an
alternative embodiment, the fat-based confectionery can comprise a second or
additional coating that surrounds the medicament coated consumable center. In
alternative embodiments, the fat-based confectionery can partially,
substantially or
completely surround the consumable center
[0056] As the product of the present invention is chewed, the medicament or
agent is released into the saliva. During continual chewing or crunching of
the product
between the teeth, the medicament or agent in the saliva is then forced
through the oral
mucosa in the buccal cavity due to the pressure created by the chewing. The
oral
mucosa has a thin epithelium and a rich vascularity. Thus, the oral mucosa
favors drug
absorption. In contrast to a typically orally ingested drug, wherein the
solution is in
contact too briefly for absorption to be appreciable through the oral mucosa,
it is
believed that during chewing, the agent and/or medicament remains in the
buccal
cavity and is forced through the oral mucosa. Also it has been surprisingly
found that
an increase in the absorption of the drug is achieved as well as an increase
in the
bioavailability of the drug as compared to typical oral administration. It has
been
found that the drug or agent is absorbed much quicker than if it was swallowed
as in a
typical oral administration. Indeed, the absorption approaches that of a
parenteral
administration, and the bioavailability is also much greater than oral
administration.
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[0057] Referring to Figure 1, an embodiment of the coated product 10 of the
present invention is presented. As illustrated, the coated product 10 includes
a
consumable center 12. It should be appreciated that the consumable center 12
can be
any of a variety of confectionary products or compressed excipients known in
the art.
For example, such confectionery products that are consumable include, without
limitation, gummi candies, hard candies, confectionary starches, and licorice-
based
candies. Examples of compressible excipients include, without limitation,
saccharides
such as dextrose and sucrose, and sugar alcohols such as sorbitol and
mannitol, and
combinations of same. The consumable center 12 can have a hardness of about 4-
6
KPA.
[0058] Pursuant to the present invention, surrounding the consumable center
12 is a coating 14. The coating 14 includes a medicament or other active
agent. The
coating 14 can also comprise a fat-based confectionery such as, for example,
white
chocolate, dark chocolate, milk chocolate and combinations thereof. The fat-
based
confectionery can also comprise one or more flavors such as, for example,
chocolate,
strawberry cream, orange, peach and mint and combinations thereof. The coating
14
can be any suitable thickness.
[0059] Referring to Figure 2, an alternative embodiment of a coated product 20
of the present invention is presented. As illustrated, the coated product 20
includes the
consumable center 12. Surrounding the consumable center 12 is the first
coating 14.
The first coating 14 includes a medicament or other active agent. Surrounding
the first
coating 14 is a second fat-based confectionery coating 22. For example, the
second
fat-based confectionery coating 22 can comprise an ingredient such as white
chocolate,
dark chocolate, milk chocolate and combinations thereof. The fat-based
confectionery
coating 22 can also comprise one or more flavors such as, for example,
chocolate,
strawberry cream, orange, peach and mint and combinations thereof. The fat-
based
confectionery coating 22 can be any suitable thickness. It should be
appreciated that
the second fat-based confectionery coating 22 may not include any medicaments
or
active agents.
[0060] It should be appreciated that the coated products 10 and 20 can
comprise any suitable shape. As noted above, the consumable center 12 can be
of any
size or shape, although in a preferred embodiment the consumable center has a
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shape. As also noted above, if desired, by tableting the consumable center 12,
one can
control to a precise relative standard deviation, the size of the consumable
center 12.
This allows one to accurately control the amount of coating 14 that is placed
around
the consumable center 12 to create the resultant product. In this regard, if
the
consumable center is too large or too small, the resultant coating 14 will
either be
greater or less than desired. Because the coating 14 contains a medicament, if
the size
of the consumable center 12 is not the predetermined size, the level of
medicament
present in the resultant product could vary. By precisely controlling the size
of the
consumable center, through the tableting process, one is ensured that a
precise level of
coating 14, and therefore medicament, can be provided and thereby delivered.
[0061] Additionally, by using a tableting process one can vary the size and
shape of the resultant product 10. For example, for a product including an
analgesic,
the product can have a traditional aspirin shape. In a similar vein, for
proprietary
designs that are used for certain drugs, one can create the consumable center
in the
proprietary design allowing the resultant product to have the proprietary
shape or
design.
[0062] If desired, a variety of different tableting processes can be used. For
example, conventional drug tableting equipment or confectionary tableting
product
equipment can be utilized. An example of such equipment is the Stokes
tableting
machine available from Stokes Manufacturing Inc.
[0063] Referring now to the coating 14, preferably, the coating 14 comprises
approximately 50% to about 75% by weight of the product 10. A variety of
coatings
can be utilized. For example, the coating can be a soft amorphous coating. Or,
the
coating can be a recrystallized granular coating. As discussed below, in a
preferred
embodiment, the coating is applied as a syrup/powder composition.
[0064] Preferably, the coating 14 will include masking agents. In this regard,
high-intensity sweeteners and appropriate flavors can be used to help mask,
along with
the tableted center, any off notes that are present due to the medicament or
agent. It
has been found that with respect to certain medicaments or agents that may
have an
astringent or bitter taste that by adding a masking agent to the formulation,
that a
much more palatable formulation, including the medicament, can be provided. In
this
regard, even though the medicament in for example, its powder form may be
bitter or
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have an offensive taste, the matrix used as the coating of the present
invention,
including the masking agent, will help, along with the tableted center, to
afford a
product having acceptable organoleptic properties. For example, it has been
surprisingly found that by solubilizing a powdered matrix of medicament and
masking
agent, this increases the ability of the masking agent to cover up bitter and
bad flavors
produced by the medicament or agent. By selecting specific masking agents in
combination with the compressed excipients, based on the bad or off taste
produced by
the medicament, one can provide a palatable formulation.
[0065] For example, if one is attempting to cover an astringent flavor such as
aspirin, one could use masking agents found to be effective against
astringency such
as fructose and high-intensity sweeteners, e.g. saccharin, aspartame,
sucralose, and
acesulfame-k. In the case of a moderately bitter active ingredient, such as
caffeine,
one would use ingredients such as glycine, ethyl maltol, zinc gluconate,
licorice root
powder, high-intensity sweeteners, etc. In the case of a very bad tasking
active
ingredient such as acetaminophen it has been found that peppermint functions
very
well, but, may need to be augmented with a high-intensity sweetener, such as,
for
example, aspartame.
[0066] The masking agents, in an embodiment, are selected from the group
consisting of: sucralose; zinc gluconate; ethyl maltol; glycine; acesulfame-k;
aspartame; saccharin; fructose; xylitol; maltitol; isomalt; salt; spray dried
licorice root;
glycyrrhizin; dextrose; sodium gluconate; sucrose; glucono delta-lactone;
ethyl
vanillin; and vanillin.
[0067] In an embodiment of the invention, sufficient masking agent and/or
tableted excipient will be used to improve and provide acceptable organoleptic
properties to the product. As used herein to provide "acceptable organoleptic
properties" means that the product will have a sufficiently pleasant, or at
least non-
offensive taste, to allow the consumer to chew the product allowing at least a
portion
of the medicament to be absorbed through the buccal cavity of the consumer.
Whether
a masking agent is necessary and/or the amount of masking agent will vary
depending
on medicament or agent and compressed excipient. Of course, if desired, more
than
one masking agent can be used, e.g., zinc gluconate and a sweetener or flavor.
In an
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embodiment, the masking agent may comprise approximately 30% to about 99% by
weight of the coating formulation.
[0068] In a preferred embodiment, the coating includes a high-intensity
sweetener such as aspartame, sucralose, and acesulfame-k. Preferably, the high-
intensity sweetener comprises approximately 0.1% to about 5% by weight of the
coating. As noted above, the coating will include a medicament or agent. It is
envisioned, that a variety of different medicaments and agents can be placed
in the
coating. For example, such agents include, inter alia, stimulants such as
caffeine and
nicotine. Generally, such medicaments include, inter alia, analgesics,
antibiotics,
antivirals, antihistamines, anti-inflammatories, decongestants, antacids,
muscle
relaxants, psychotherapeutic agents, insulin, diuretics, vitamins, minerals,
anesthetics,
antitussives, anti-diabetic agents, bioengineered pharmaceuticals,
nutraceuticals,
nutritional supplements, and cardiovascular agents. It is envisioned, that
depending on
the medicament, the resultant product can be used to treat, inter alia:
coughs; colds;
motion sickness; allergies; fevers; pain; inflammation; sore throats; cold
sores; sinus
problems; diarrhea; diabetics; gastritis; depression; anxiety; hypertension;
angina; and
other maladies and symptoms. Specific agents/medicaments include, by way of
example and not limitation: caffeine; aspirin; acetaminophen; ibuprofen;
ketoprofen;
cimetodine; ranitidine; famotidine; dramamine; omeprazole; dyclonine;
chlorpheniramine maleate; pseudoephedrine; hydrochloride; dextromethorphan
hydrobromide; benzocanine; sodium naproxen; nicotine; hydroxycitric acid;
chromium
picolinate; phosphatidylserine; nicotine; insulin; echinacea purpurea; zinc;
vitamin C;
ginseng; kola nut; capsicum; nettle; passion flower; St. Johns Wort; valerian;
Ma
Huang/guarana; kava kava; and chamomile.
[0069] It is believed that the product of the present invention will allow
chewable products including a medicament to be provided that heretofore were
not
provided due to offensive taste. Such products include, by way of example and
not
limitation, excedrin, pseudoephedrin, and Ma Huang/guarana diet pills.
[0070] Preferably, the agents or medicaments are contained in the coating of
the product at levels of approximately 50 micrograms to 500 milligrams. The
specific
levels will depend on the active ingredient. For example, if chromium
picolinate is the
active ingredient in an embodiment, it would be present at a level of 50
micrograms
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per serving (3.0 grams of coated product); aspirin would be preset at a level
of 325
milligrams per 3.0/gram serving. The level of medicament or agent in the
coating of
the product is selected so as to create, when the product is chewed, a
sufficiently high
concentration of the medicament or agent in the saliva.
[0071] For example, when the agent is a stimulant such as nicotine or
caffeine,
the level of the stimulant in the coating of the product should be such that
it creates a
saliva content of stimulant of approximately 15 to 440 ppm after the product
is
chewed. At this level, a sufficient amount of stimulant will be delivered to
the chewer
to create the effects set forth in the application. For a botanicals (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 after the
product is
chewed. For a metabolizer, for example, chromium picolineate 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 after the product is chewed. 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 after the product is chewed.
[0072] The level of medicament or agent in the coating is selected so as to
create, when the product is chewed, a sufficiently high concentration of the
medicament or agent in the saliva.
[0073] For example, when the agent is a stimulant such as caffeine, the level
of
the stimulant in the compacted powder formulation should be such that it
creates a
saliva content of stimulant of approximately 1% to about 66% after the
formulation is
placed in the mouth. At this level, a sufficient amount of stimulant will be
delivered to
the user to create the effects set forth in the application. If a medicament
is used such
as a medicinal (e.g., analgesics), sufficient medicinal should be present in
the
compacted powder formulation to create a salvia content of approximately 1 %
to about
66%. For botanicals (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 1% to about 66%. For a metabolizer, for example, chromium
picolineate and hydroxi-chitic acid, the agents should be present in an amount
to create
a saliva content of approximately 1 % to about 66%. If the agent is a vitamin
or
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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 2% to
about 30%.
[0074] 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 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 doses
taken, for
example, not more often than one product every four hours and not more often
than
four to five times a day.
[0075] If the agent is a stimulant, such as caffeine, to be used to enhance
performance than the product would be ingested, in a preferred embodiment ten
minutes or less before the performance.
[0076] A variety of methods can be used for constructing the coatings of the
product. Typically coatings are applied to products in a three-phase
operation. In this
regard, the first phase is to add a crude coating of an alternate application
of syrup and
powder is applied. This is followed by a second phase called the finishing
coating in
which finer powder and longer tumbling is used to produce a smooth finish.
Finally a
shellacking and polishing third phase is performed to provide a high-sheen
smooth
finish. In a preferred embodiment, the second phase is not used and the third
phase is
optional. As noted above, in an embodiment, the products of the present
invention can
include 50% to 75% by weight coating. Using only the first phase of the
method, this
large percent of coating can be applied to the product in a realistic time-
frame.
[0077] In an embodiment, the coating comprises approximately 10 to about 30
% by weight syrup and approximately 70% to about 90 % by weight powder. For
example, in a preferred embodiment, the coating comprises 20% syrup and 80%
powder.
[0078] In an embodiment of constructing the coated product, first the syrup is
distributed on the center. Then a portion of the powder is sprinkled on top to
dry up
the syrup. A further amount of syrup is added and powder supplied. This
process is
continued until the necessary amount of syrup and powder have been applied to
the
exterior of the center, e.g., 10 to 20 coating layers or more are applied. The
coating
which can play an important role as the masking agent, can include a
combination of
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sugar, corn syrups, or in the case of a sugar-free product, various
combinations of
sugar alcohols, monomers, and polymers.
[0079] It has been found that by using this type of gross up coating process
that
advantages are achieved for the product containing medicament of the present
invention. This is true whether or not the medicament is contained in the
powder or in
the syrup. Accordingly, if desired, the medicament can be contained in the
syrup
rather than in the powder.
[0080] Pursuant to the present invention, the coated product may not include a
shellac or other finishing or shiny layer. It has been found, that the coating
can
comprise merely a matte finish and still function, not only satisfactorily,
but has some
advantages. In this regard, typically coated products that retain moisture on
the
coating along with a shellac layer may degrade due to moisture in the coating
and
therefore do not have an extended shelf-life. This is especially true with the
thick
coatings of the present invention. Such thick coatings absorb more moisture
than
thinner coatings. If a matte finish is utilized, although the thick coating
layer can
absorb the moisture, the matte finish allows the moisture to move into and out
of the
coating layer. This thereby prevents degradation of the product. Thus, the
present
invention provides a product having a thick coating with increased shelf-life.
[0081] The matte finish additionally not only allows a thick coating to be
used
but also ingredients that have high moisture absorption. Due to the matte
finish, high
moisture absorbing medicaments can be used without undue product degradation.
[0082] In an embodiment of the coating, dextrose or sucrose or combinations
thereof function as the main ingredient. In a preferred embodiment, dextrose
is
utilized and the dextrose comprises approximately 50 to about 90% of the
coating.
The active ingredients or medicaments in the coating may comprise as much as
30% of
the coating down to very small amounts as long as the medication is
efficacious. In a
preferred embodiment, the flavors are powdered flavors and can range from 0.1%
to
approximately 5%. High-intensity sweeteners such as aspartame, sucralose, and
acesulfame-k can also be used in the coating and range from approximately 0.1
to
about 5% of the coating. As noted above, these high-intensity sweeteners are
excellent
masking agents.
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[0083] Preferred sweeteners include, but are not limited to, sucralose,
aspartame, salts of acesulfame, altitame, saccharin and its salts, cyclamic
acid and its
salts, glycerrhizinate, dihydrochalcones, thaumatin, monellin, and the like,
alone or in
combination. In order to provide longer lasting 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.
[0084] 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.
[0085] By way of example and not limitation, examples of products and
methods of the present invention are as follows:
PRODUCTS
[0086] Embodiments of the products will include a center and a coating. By
way of example, embodiments of the center are as follows:
Center Formulations
Formulation No. I
WEIGHT USED DRY WEIGHT % FINISHED
INGREDIENTS LBS LBS PRODUCT
Dry Sugar 6.00 6.00 59.23
Water 3.00
Corn Syrup 42DE, 43BE 5.00 4.00 39.52
Yellow Color TO SUIT -------
Citric Acid 56 gr 0.12 1.25
Lemon Flavor ---- 5 ml. ------- -------
TOTAL 14.12 10.12 100.00
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Manufacturing Procedure:
[0087] Weigh the ingredients. Place the sugar, water, corn syrup, and color in
an open fire pan and wash the sides down with the water. Cook the batch to 280
F.
Transfer the batch to the vacuum cooker. Turn on the vacuum pump and draw 27"
of
vacuum. Hold the vacuum at 27" for four minutes. Vent the vacuum kettle and
open
the pan to empty the unit. Scrape the batch into a transfer pan and place it
on the
cooling slab. Cool and temper the batch while mixing in the flavor and acid.
Hand
spin and cut into bite sized pieces using the wafer cutter. Cool the candy and
pack.
Formulation No. 2
Weight for 1500 gm
Ingredients finished product
Rousselot 250A, gelatin 30 mesh 90 gm
Corn syrup 42 DE 675 gm
Granulated sugar 555 gm
Water (for gelatin solution) 180 gm
Water (for sugar solution) 210 gm
Citric Acid solution (50%) 30 gm
Manufacturing Procedure:
[0088] Depending on mesh size of the Rousselot gelatin, allow it to swell in
cold water or dissolve directly in water heated to 80-90 C (176-194 F). Boil
granulated sugar, corn syrup and remainder of water to 116 C (241 F). Cool
to 100
C (212 F). Add gelatin solution either swollen or as a solution. Stir slowly
(until
swollen gelatin has completely dissolved) in order to produce a homogeneous
mixture.
Use deaerating equipment to remove air bubbles from the mixture or allow
mixture to
stand at 80 C (176 F) until a thin film forms at the surface. Remove film
prior to
depositing. Add citric acid, flavor and color. Deposit in cool, dry starch
(maximum
30-35 C or 86-95 F and 6-8% moisture). Sprinkle some starch on top of the
candies.
Depositing solids should be 77-78 brix. Depositing temperature should be 70-75
C
(158-167 F). Store starch trays overnight at room temperature. After removal
from
starch, either oil or sugar sand candies. The texture of the finished candies
can be
modified by adjusting gelatin usage level or bloom strength.
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FORMULATION NO. 3 (Sweetose 64 D.E. Syrup)
SWEETOSE 4300 143.0 lb
Granulated Sugar 100.0
MIRA-QUIK MGL Starch 11.5
Confectioners G Starch 20.0
Water 215.0
489.5
FORMULATION NO. 4 (42 D.E. Syrup)
Staley 1300 Corn Syrup 107.0 lb
Crystalline Dextrose 36.0
Granulated Sugar 100.0
MIRA-QUIK MGL Starch 11.5
Confectioners G Starch 20.0
Water 215.0
489.5
Procedure (either Formulation Nos. 3 or 4):
[0089] Mix the starch into 125 lbs of water and set aside. Add the remaining
water and sweeteners to the cooking kettle and heat to boiling. Then slowly
add the
starch slurry and cook to about 226 F (or 78% solids). Add color and flavor
and
deposit into moulding starch. Dry to a minimum 80% solids (24 hours at 120-140
F).
Shake out and sugar sand.
Formulation No. 5
Ingredient Percent of Uncooked Mix
Corn Syrup - 63 D.E. 47.00
Flour - Wheat 25.00
Sugar 12.50
Water 7.00
Corn Starch 6.00
Partially Hydrogenated Vegetable Oil 1.30
Flavor 0.40
Salt 0.30
Citric Acid 0.30
Titanium Dioxide 0.10
Red #40 Dye 0.07
Vanillin 0.03
100.00
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[0090] The above formula is for a continuous cooking system. The mix
moisture is approximately 20.0%. The finished candy would contain between 15%
and 16% moisture. If the formula were to be kettle cooked, the mix moisture
would be
increased to approximately 40%. Also, for kettle cooked licorice, a mold
suppressing
preservative such as potassium sorbate would usually be added at approximately
0.02%.
COATING
An embodiment of the coating for the product is as follows:
Ingredient Grams
Acetaminophen 0.3490
Peppermint Flavor (dry) 0.0072
Menthol Flavor (dry) 0.0062
Dextrose 1.4200
Sucrolose 0.0030
Aspartame 0.0062
Glucose 0.2080
2.0000 g
[0091] The coating can be used to coat a consumable center, e.g., Formulations
1-4 using the processes described earlier.
COATED PRODUCTS
Example No. 1
ACETAMINOPHEN COATED PRODUCT
Center (1 gram) Coating (1 gram)
Ingredient Percent Ingredient Grams
Acetaminophen 80.0
Any of Above 100.00% Encapsulated
Formulations 1-4 Aspartame 20.0
Aspartame 50.0
Salt Flour 2.5
Dextrose 643.5
Flavor 4.0
800.0
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Example No. 2
ACETAMINOPHEN COATED PRODUCT
Center (1 gram) Coating (2 grams)
Ingredient Percent In reg, dient Grams
Acetaminophen 335.0
Any of Above 100.00% Natural Peppermint 7.0
Formulations 1-4 S.D. Menthol 6.0
Dextrose 1,221.0
Aspartame 32.0
1,601.Og
Example No. 3
PSEUDOEPHEDRIN COATED PRODUCT
Center (1 gram) Coating (2 grams)
Ingredient Grams Ingredient Grams
Dextrose 1,476.00
Any of Above 100.00% Eucalyptus* 2.00
Formulations 1-4 Menthol* 30.00
Aspartame 32.00
Pseudoephedrin 60.00
1,600.00
* sprayed dried
Example No. 4
PEPPERMINT CAFFEINE COATED PRODUCT
Gum Center (1 gram) Coating (2 grams)
In reg dient Grams Ingredient Grams
Caffeine 100.0
Any of Above 100.00% Peppermint 13.0
Formulations 1-4 Dextrose 1,455.0
Aspartame 32.0
1,600.0
CHOCOLATE COATINGS AND PANNING METHOD
[0092] In an embodiment, chocolate or other suitable fat-based confectioneries
can be applied as a confectionery coating to the medicament coated centers by
any
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suitable coating methods such as, for example, a panning method. In this
method, for
example, the chocolate is melted to approximately 120 F. The centers to be
coated
with chocolate are introduced into a revolving pan. The melted chocolate is
sprayed or
pour melted onto the centers. In an embodiment, molten chocolate is applied
until a
thin, even coating covers the surface of the centers. Air flow is introduced
into the pan
mouth to enhance solidification of the chocolate coating. The air flow should
be
carefully monitored to achieve an smooth and aesthetically pleasing chocolate
coated
product. For example, excessive air flow may cause a bumpy chocolate coating
surface. This chocolate coating process is repeated until the desired amount
of
chocolate is coating the centers. It should be appreciated any other suitable
coating
methods may be used to apply the chocolate or fat-based coating to the
medicament
coated centers.
[0093] Any suitable formulations for the chocolate or fat-based coating can be
used. For example, the fat-based coating can comprise white chocolate, dark
chocolate, milk chocolate and other chocolate compounds. Various flavors or
ingredients such as strawberry cream, orange, peach and mint can also be used
in the
fat-based coating. By way of example and not limitation, examples of chocolate
formulations for the fat-based coatings in embodiments of the present
invention are as
follows:
CHOCOLATE COMPOUND COATING FORMULATION
Ingredient Percent
Sugar [Sucrose] 50%+/- 5%
Cocoa Powder 10%+/-2%
Vegetable Oil/Fat 30%+/-3%
Milk Solids 10%+/-2%
REAL CHOCOLATE COATING FORMULA
Ingredients Percent
Sugar [Sucrose] 55%+/-5%
Chocolate Liquor 12%+/-2%
Milk Solids 13%+/-2%
Cocoa Butter 20%+/-2%
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SOFT TABLETED CENTERS
[0094] Conventional tablets have a hardness of 16-20 KPA [Kilopascal Units].
In an embodiment, soft tableted centers can be achieved by setting the
hardness
adjustment on the tableting machine to achieve a hardness in the range of
about 4-6
KPA. As a result, it was surprisingly found that using a reduced compression
resulted
in a softer, more tooth friendly tablet. For example, being within these
compression
specifications allows the coated tablet product to be perceived as a
contiguous soft and
comfortable bite through or chew.
PANNING METHOD FOR LONG TERM SOFT CHEWABLE COATING
[0095] In an embodiment, the following panning technique resulted in a
product that has a coating that remains soft for a range of 24 to 48 months
(compared
to a limited shelf life) using normal packaging protection.
PREPARATION OF COATING SYRUP
[0096] All of the syrup ingredients used for the initial coating are mixed in
a
kettle and heated to 195 F with agitation. The temperature is maintained at
approximately 195 F for 10 minutes. The syrup is cooled to approximately 110
to
120 F before adding flavors. Once the desired temperature is reached, flavors
are
added and the syrup is further mixed. A temperature of approximately 105-115
F is
maintained throughout process.
PANNING
[0097] In an embodiment, the confectionery or gum centers are added to a pan.
Conventionally, the centers are tumbled in the pan at a rotation speed of 28
rpms.
However, in the improved method, the centers are tumbled in the pan at a
rotation
speed of about 6-10 rpms as the coating is applied. For example, syrup is
added to the
centers and allowed to coat all pieces evenly. This usually is done for
approximately
1.0-1.5. A suitable dry charge is added until pieces are no longer sticky and
will not
take up any additional powder. Over adding dry charge should not be done. For
example, there should be no powder in the back of the pan. The pieces are
tumbled
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until almost dry for approximately 7-8 minutes. When dry, 12 oz of syrup is
again
added and allowed to coat all pieces evenly (approx. 1.0-1.5 min). A very
small
amount of coarse dextrose may be sprinkled in to prevent the pieces from
sticking/doubling.
[0098] Additional rounds of the process steps of adding syrup to coat the
pieces, adding dry charge and tumbling the pieces until the pieces are almost
dry can
be repeated as many times as necessary until a sufficient amount of coating
has
surrounded the confectionery or gum center. It should be appreciated that the
amount
of syrup and dry charge added in each round can vary accordingly. For example,
the
amount of syrup added in subsequent rounds can be increased to provide a
sufficient
coating layer to the centers. One or more dry charges may be used. Once almost
all of
the dry charge is used and coated pieces are within desired specification, the
pieces
should be allowed to tumble until almost dry. The coated pieces are then
removed
from the coating pan and place in trays to further dry for 24 hours. It was
surprisingly
found that slowing the panning revolutions from conventional 28 rpms to
approximately 6-10 rpms provided a stable and long-term, soft-finished coated
product.
EXPERIMENTAL RESULTS FOR MODIFIED PANNING PROCEDURE
[0099] A pilot batch of tableted centers with calcium carbonate coating having
a chocolate flavor were tested. The conventional panning procedure for coating
was
used with a rotation speed of 28 rpms. The product samples were found to be
too firm
due to the processing method. The calcium and vitamin D were stable in 4 month
accelerated stability tests
[00100] Pilot batches of tableted centers with calcium carbonate coatings
having a chocolate flavor (slight flavor increase) were made using
modifications in the
panning process to soften the product sample texture. During the modified
coating
process, the centers were tumbled in the pan at a reduced rotation speed of 6-
10 rpms.
Optimal formulation and soft texture were achieved for the coated calcium
supplement
product samples using the modified panning process.
[00101] In additional batches of the coated tableted centers, one month
of accelerated stability tests were successfully performed on the coated
products
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manufactured during pilot production using the modified coating process. Also,
no
significant change in coating texture was found during real-time shelf life
experience
of 3 years (stored at 72 F / 50% RH).
[00102] In laboratory studies, tableted centers with calcium carbonate
coating having a chocolate flavor (slight flavor increase) plus an additional
chocolate
flavored compound coating (second coating) using the modified coating process
were
prepared. The chocolate flavored compound coating was deemed to have no impact
on the calcium and vitamin D stability performance. In addition, the chocolate
flavored compound coating provided (i) more of a conventional chocolate
texture, (ii)
better appearance (shine), and (iii) in general, all the feelings of biting
into chocolate.
BENEFITS OF MEDICAMENT IN COATING
[00103] By way of example, and not limitation, experiments
demonstrating the benefits of placing a medicament in a coating surrounding a
chewable confectionary, chewing gum, will now be provided.
Experiment No. 1
The following gum center formulation was made as a gum pellet center:
Gum Center %
Gum Base 47.00
Sorbitol 39.52
Liquid Sorbitol 7.50
Flavors 2.36
Encapsulated Flavors 2.00
Glycerin 0.75
Encapsulated Sweeteners 0.87
100.00
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[00104] The gum pellet was coated with the following gum coating
formulation:
Gum Coating % of Syrup 1 % of Syrup 2
Xylitol 63.03 74.35
Water 11.14 13.15
40% Gum Tahla Solution 20.87 7.96
Titanium Dioxide Whitener 0.37 0.44
Peppermint Flavor' 0.81 0.00
Caffeine 3.78 4.10
100.00 100.00
[00105] 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 I
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.
[00106] 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.
[00107] 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:
[00108] 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.
Flavor added in 2 additions after 10th and 15th within coating syrup 1.
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[00109] 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.
[00110] 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 present 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.
[00111] 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.
[00112] Phamacokinetic 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.
[00113] The conclusions were as follows:
[00114] 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 [tg/ml for coffee and 0.236
g/ml for cola. 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
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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.
[00115] 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.
[00116] 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 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 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).
[00117] 3. It was shown that significant levels of caffeine
are absorbed sublingually directly into the bloodstream via delivery from gum.
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WO 2007/058645 PCT/US2005/041236
This was 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.
Experiment No. 2
The following formulation was made:
Gum Center %
Gum Base 33.00
Calcium Carbonate 13.00
Sorbitol 44.23
Glycerin 4.00
Flavors 2.32
Encapsulated Caffeine2 1.50
Free Caffeine 0.45
Lecithin 0.60
Encapsulated Sweeteners 0.90
100.00
Gum Coating Coating Syrup 3.0 % Coating Syrup 4.0 %
Xylitol 64.14 76.23
Water 11.14 13.15
40% Gum Tahla Solution 20.87 7.96
Titanium Dioxide Whitener 0.40 0.40
Peppermint Flavor3 1.40 0.00
Sweeteners 0.27 0.27
Carnauba Wax/
Talc Polishing Agents 0.00 0.274
Caffeine 1.78 1.72
100.00 100.00
[00118] 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
2 Spray dried maltodextrin/caffeine at 50% active caffeine.
3 Flavor added in 3 additions after 3 separate syrup addition within coating
syrup 1.
4 Polished after completion of coating.
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WO 2007/058645 PCT/US2005/041236
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.
[00119] This gum product was used in a caffeine absorption study to
compare release and absorption uptake of caffeine from gum versus 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 delivery via gum than after delivery
of same
caffeine dose via a pill.
[00120] 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 from Experiment No. 5, 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 Experiment No. 6, 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-PIusTM 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).
[00121] It was concluded that caffeine uptake in the bloodstream was
faster for gum than a pill, based on the following:
[00122] 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). Average plasma
caffeine levels significantly greater than the pill at a=0.01 for T5, and
a=0.005
for T10.
CA 02629957 2008-05-15
WO 2007/058645 PCT/US2005/041236
[00123] 2. Classical pharmacokinetic parameters, T-Max
(time for peak plasma caffeine concentration) and Abs. half-life (absorbence
half-life, time for caffeine concentration to be half of peak) were
significantly
different for caffeine delivered via 50 mg pellet gum (Experiment No. 5) 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. half-life
and average plasma T-Max being significantly smaller for gum than the pill.
For the 50 mg pellet gum, the average Abs. half-life = 12.84 min. and the
average T-Max = 36.5 min. compared to the 50 mg pill with an average Abs.
half-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 half of the peak plasma caffeine concentration and the peak plasma
caffeine concentration than after chewing gum delivering the same level of
caffeine.
[00124] 3. The Abs. Rate Const. (absorption rate constant,
rate at which caffeine absorbs into the bloodstream) was significantly greater
for 50 mg pellet gum (Experiment No. 5) 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).
[00125] 4. The test also demonstrated faster uptake of
plasma caffeine via the product of Experiment No. 6, 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 caffeine detected in
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WO 2007/058645 PCT/US2005/041236
plasma after chewing the product of Experiment No. 6 gum caffeine than after
ingesting a pill, even though the pill delivered approximately 50 mg caffeine,
and the product of Experiment No. 6 delivered approximately 40 mg. At T5,
on average there was 13 times more caffeine detected in plasma after chewing
Experiment No. 6 gum than after ingesting a pill.
[00126] 5. Classical pharmacokinetic parameters, T-Max
and Abs. half-life were significantly different for caffeine delivered via the
product of Experiment No. 6 40 mg pellet gum than via a 50 mg pill. Faster
uptake of plasma caffeine was demonstrated via delivery from the product of
Experiment No. 6 gum compared to a pill due to the average plasma Abs. half-
life and average plasma T-Max being significantly smaller for gum than the
pill. For the 50 mg Experiment No. 5 gum, the average Abs. half-life = 18.33
min. and the average T-Max = 45 min compared to the 50 mg pill with an
average Abs. half-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 product of Experiment No. 6 delivered 40 mg
caffeine compared to delivery of 50 mg via a pill, it still took a longer
amount
of time to reach half of the peak plasma caffeine concentration for the pill
than
for the gum.
[00127] 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:
[00128] Classical pharmacokinetic parameters T-Max and Abs.
half-life were greater than pill for both 50 mg pellet and Experiment No. 5
though the level of significant different was much greater for the 50 mg
pellet
(Experiment No. 5) (a=0.0075 and a=0.005 respectively) than the product of
Experiment No. 6 (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 product of
Experiment
No. 6. Again, the level of significant difference was greater for the 50 mg
pellet (Experiment No. 5), a=0.005 compared to 0.20 for the product of
Experiment No. 6.
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[00129] 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:
[00130] Pellet with caffeine all in coating > Pellet with caffeine
split between coating and center = Beverages coffee/cola >Pill
[00131] 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 gums
could
behave.
[00132] It should be understood that various changes and modifications
to the presently preferred embodiments described herein will be apparent to
those
skilled in the art. Such changes and modifications can be made without
departing from
the spirit and scope of the present subject matter and without diminishing its
intended
advantages. It is therefore intended that such changes and modifications be
covered by
the appended claims.
33
