U.S. patent application number 09/759838 was filed with the patent office on 2001-06-07 for over-coated chewing gum formulations including tableted center.
Invention is credited to Corriveau, Christine L., Graff, Gwendolyn, Matulewicz, Leonard, Ream, Ronald L..
Application Number | 20010002998 09/759838 |
Document ID | / |
Family ID | 24479223 |
Filed Date | 2001-06-07 |
United States Patent
Application |
20010002998 |
Kind Code |
A1 |
Ream, Ronald L. ; et
al. |
June 7, 2001 |
Over-coated chewing gum formulations including tableted center
Abstract
Methods and products for delivering a medicament or agent to an
individual are provided as well as methods for producing the
product. The product includes a coating having a medicament or
agent. The medicament or agent is present within the coating that
surrounds a tableted gum center (the water soluble portion and a
water insoluble base portion). By chewing the gum, the medicament
or agent is released from the product. Continuing to chew the
chewing gum creates a pressure within the buccal cavity forcing the
agent or medicament directly into the systemic system of the
individual through the oral mucosa contained in the buccal cavity.
This greatly enhances the absorption of the drug into the systemic
system as well as the bioavailability of the drug within the
system.
Inventors: |
Ream, Ronald L.; (Plano,
IL) ; Corriveau, Christine L.; (Orland Park, IL)
; Graff, Gwendolyn; (DeKalb, IL) ; Matulewicz,
Leonard; (Oswego, IL) |
Correspondence
Address: |
Robert M. Barrett, Esq.
BELL BOYD & LLOYD LLC
P.O. Box 1135
Chicago
IL
60690-1135
US
|
Family ID: |
24479223 |
Appl. No.: |
09/759838 |
Filed: |
January 11, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09759838 |
Jan 11, 2001 |
|
|
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09618808 |
Jul 18, 2000 |
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Current U.S.
Class: |
424/441 ;
424/474; 424/479; 424/481 |
Current CPC
Class: |
A23G 2200/04 20130101;
A61K 9/2086 20130101; A61P 21/02 20180101; A61P 25/18 20180101;
A61P 9/00 20180101; A61P 3/10 20180101; A23G 4/08 20130101; A23G
3/343 20130101; A61P 3/02 20180101; A61P 29/00 20180101; A23G
2200/04 20130101; A23G 3/343 20130101; A23G 4/20 20130101; A61P
31/12 20180101; A61K 9/0058 20130101; A61K 9/209 20130101; A61P
1/04 20180101; A61P 31/04 20180101; A61P 43/00 20180101 |
Class at
Publication: |
424/441 ;
424/474; 424/479; 424/481 |
International
Class: |
A61K 009/68; A61K
009/36 |
Claims
We claim:
1. A method for delivering a medicament to an individual comprising
the steps of: providing a chewing gum that includes a tableted gum
center and a coating that substantially surrounds the tableted gum
center, the coating comprising at least 50% by weight of the
chewing gum, the coating including a medicament; chewing the
chewing gum to cause the medicament to be released from the chewing
gum composition into the buccal cavity of the individual; and
continuing to chew the chewing gum thereby creating a fluid
pressure causing the medicament to enter the systemic system of the
individual through an oral mucosa of the individual.
2. The method of claim 1 wherein the coating includes a
high-intensity sweetener.
3. The method of claim 1 wherein the high-intensity sweetener is
chosen from the group consisting of aspartame, sucralose,
saccharin, and acesulfame-k.
4. The method of claim 1 wherein the coating is produced by
alternating layers of a powder and a syrup onto the tableted gum
center.
5. The method of claim 1 wherein the tableted gum center includes
at least 50% by weight water-insoluble gum base.
6. The method of claim 1 wherein the medicament is chosen from the
group consisting of: analgesics; muscle relaxants; antibiotics;
antivirals; antihistamines; decongestants; anti-inflammatories;
antacids; psychotherapeutic agents; insulin; vitamins; minerals;
and cardiovascular agents.
7. The method of claim 1 wherein the coating has a matte
finish.
8. The method of claim 1 wherein the coating does not include a
shellac layer.
9. A chewing gum comprising: a tableted gum center including a
water soluble portion and a water insoluble portion; and a coating
including a medicament that surrounds the tableted gum center, the
coating comprising at least 50% by weight of the chewing gum
product.
10. The chewing gum of claim 9 wherein the medicament is chosen
from the group consisting of: analgesics; muscle relaxants;
antibiotics; antivirals; stimulants; antihistamines; decongestants;
anti-inflammatories; antacids; psychotherapeutic agents; insulin;
vitamins; minerals; and cardiovascular agents.
11. The chewing gum of claim 9 wherein the coating includes a
sufficient amount of taste masking agent to provide acceptable
organoleptic properties.
12. The chewing gum of claim 1 wherein the taste masking agent is
chosen from the group consisting of: zinc gluconate, ethyl maltol,
glycine, acesulfame-k, aspartame; saccharin; fructose; xylitol;
isomalt; maltitol; spray dried licorice root; glycerrhizine; sodium
gluconate; glucono delta-lactone; ethyl vanillin; dextrose;
sucralose; vanillin; and ethyl maltol.
13. The chewing gum of claim 11 wherein the taste masking agent
comprises approximately 30% to about 99% by weight of the
coating.
14. The chewing gum of claim 9 wherein the coating includes
approximately 0.5% to about 5% by weight of a high-intensity
sweetener chosen from the group consisting of aspartame, sucralose,
saccharine, and acesulfame-k.
15. The chewing gum of claim 9 wherein the tableted gum center
includes at least 50% by weight water-insoluble gum base.
16. The chewing gum of claim 9 wherein the coating does not have a
shellac layer.
17. The chewing gum of claim 9 wherein the tableted gum center and
coating are sugar-free.
18. A product including a medicament comprising: a tableted gum
center including a water soluble portion and a water insoluble
portion, the water insoluble portion comprising at least 30% by
weight of the tableted gum center; and a coating that at least
substantially surrounds the tableted gum center and includes a
medicament and a high-intensity sweetener, the coating comprising
at least 50% by weight of the product.
19. The product of claim 18 wherein the medicament is chosen from
the group consisting of: analgesics; muscle relaxants; antibiotics;
antivirals; stimulants; antihistamines; decongestants;
anti-inflammatories; antacids; psychotherapeutic agents; insulin;
vitamins; minerals; and cardiovascular agents.
20. The product of claim 18 wherein the coating includes a
sufficient amount of taste masking agent to provide acceptable
organoleptic properties.
21. The product of claim 18 wherein the taste masking agent is
chosen from the group consisting of: zinc gluconate, ethyl maltol,
glycine, acesulfame-k, aspartame; saccharin; fructose; xylitol;
isomalt; maltitol; spray dried licorice root; glycerrhizine; sodium
gluconate; glucono delta-lactone; ethyl vanillin; dextrose;
sucralose; vanillin; and ethyl maltol.
22. The product of claim 18 wherein the taste masking agent
comprises approximately 30% to about 99% by weight of the
coating.
23. The product of claim 18 wherein the coating includes
approximately 0.5% to about 5% by weight of a high-intensity
sweetener chosen from the group consisting of aspartame, sucralose,
saccharine, and acesulfame-k.
24. The product of claim 18 wherein the coating comprises at least
70% by weight powder when it is applied to the tableted gum
center.
25. The product of claim 18 wherein the product is sugar-free.
26. The chewing gum of claim 18 wherein the coating does not have a
shellac layer.
27. A method of delivering a medicament comprising the steps of:
providing a chewing gum having a tableted gum center and a coating
that substantially surrounds the center, the coating comprising at
least 50% by weight of the chewing gum, the coating including a
medicament and not including a shellac layer; and chewing the
chewing gum for at least 2 minutes in a buccal cavity of an
individual chewing the chewing gum.
28. The method of claim 27 wherein the medicament is chosen from
the group consisting of: analgesics; muscle relaxants; antibiotics;
antivirals; antihistamines; decongestants; anti-inflammatories;
antacids; psychotherapeutic agents; and cardiovascular agents.
29. The method of claim 27 wherein the tableted gum center
comprises approximately 30% to about 90% by weight insoluble gum
base.
30. A method for delivering a medicament to an individual
comprising the steps of: providing a chewing gum product that
includes a tableted gum center that is substantially coated by a
formulation that includes a medicament and a sufficient amount of a
masking agent to provide acceptable organoleptic properties, the
formulation comprising at least 50% by weight of the chewing gum
product; and chewing the chewing gum product to cause the
medicament to be released from the formulation into a buccal cavity
of the individual.
31. The method of claim 30 wherein the formulation includes a
high-intensity sweetener.
32. The method of claim 30 wherein the medicament is chosen from
the group consisting of: analgesics; muscle relaxants; antibiotics;
antivirals; stimulants; antihistamines; decongestants;
anti-inflammatories; antacids; psychotherapeutic agents; insulin;
vitamins; minerals; and cardiovascular agents.
33. The method of claim 30 wherein the taste masking agent is
chosen from the group consisting of: zinc gluconate, ethyl maltol,
glycine, acesulfame-k, aspartame; saccharin; fructose; xylitol;
isomalt; maltitol; spray dried licorice root; glycerrhizine; sodium
gluconate; glucono delta-lactone; vanillin; dextrose; sucralose;
and ethyl maltol.
34. The method of claim 30 wherein the masking agent comprises
approximately 30% to about 99% by weight of the coating.
35. A method of manufacturing a product containing an agent
comprising the steps of: preparing a gum center having water
soluble portion and a water insoluble by tableting the
water-soluble portion and water-insoluble portion to produce a
tableted gum center; and coating the center by placing alternating
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 one agent.
36. The method of claim 35 wherein the coated product comprises at
least 50% by weight syrup and powder coating.
37. The method of claim 35 wherein the tableted gum center includes
at least 50% by weight water-insoluble gum base.
38. The method of claim 35 wherein the coating includes a
high-intensity sweetener.
39. The method of claim 35 wherein the agent is a medicament.
40. The method of claim 38 wherein the medicament is chosen from
the group consisting of: analgesics; muscle relaxants; antibiotics;
antivirals; antihistamines; decongestants; anti-inflammatories;
antacids; psychotherapeutic agents; insulin; vitamins; minerals;
and cardiovascular agents.
41. The method of claim 35 wherein at least two alternating layers
are coated on to the center.
42. The method of claim 35 wherein the powder comprises at least
70% by weight of the coating.
43. The method of claim 35 wherein the coating does not include a
shellac layer.
44. A method of providing chewing gum that includes a medicament
comprising the steps of: preparing a gum center having a
water-soluble portion and a water-insoluble portion by tableting
the water-soluble and water-insoluble portions into a predefined
shape; and coating the predefined shape with at least one layer
including a medicament.
45. The method of claim 44 wherein the coated product comprises at
least 50% by weight syrup and powder coating.
46. The method of claim 44 wherein the medicament is chosen from
the group consisting of: analgesics; muscle relaxants; antibiotics;
antivirals; antihistamines; decongestants; anti-inflammatories;
antacids; psychotherapeutic agents; insulin; vitamins; minerals;
and cardiovascular agents.
47. The method of claim 44 wherein the coating includes a
high-intensity sweetener.
Description
[0001] This is a divisional of U.S. patent application Ser. No.
09/618,808, filed on Jul. 18, 2000, which is a continuation-in-part
of U.S. patent application Ser. No. 09/510,878, filed on Feb. 23,
2000, which is a continuation-in-part of U.S. patent application
Ser. No. 09/286,818, filed on Apr. 6, 1999 and PCT Patent
Application No. PCT/US99/29742 filed on Dec. 14, 1999.
BACKGROUND OF THE INVENTION
[0002] 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
chewing gum formulations and methods for producing such
products.
[0003] 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 run 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.
[0004] 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.
[0005] 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.
[0006] 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 the 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. Merck Manual, 16th Edition, pp.
2598-2599.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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 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.
[0011] 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.
[0012] 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 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.
[0013] Bioavailability considerations are most often encountered
for orally administered drugs. Differences in bioavailability can
have profound clinical significance.
[0014] 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 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.
[0015] Thus, there is a need for an improved method of delivering
drugs and agents to an individual.
[0016] 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 OF THE INVENTION
[0017] 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 gum center is
tableted and then coated to produce a coated chewing gum product
including a medicament or agent. The medicament or agent is present
within the coating or shell that substantially encloses the
tableted gum center (the water soluble portion and insoluble base
portion). It has been found that by tableting the gum center that a
specifically defined coating can be provided, providing a
predetermined and controllable level of medicament or agent.
[0018] Improved formulations including medicaments or agents are
also provided by the present invention.
[0019] To this end, the present invention provides a coated chewing
gum composition including a tableted gum center. The tableted gum
center includes a water soluble portion and a water insoluble
portion. The coating substantially surrounds the tableted gum
center, the coating comprises at least 50% by weight of the chewing
gum product. The coating includes a medicament or agent.
[0020] In an embodiment, the coating includes a sufficient amount
of a masking agent to improve 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.
[0021] 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.
[0022] In an embodiment, the tableted gum center comprises
approximately 15% to about 90% by weight water insoluble gum
base.
[0023] In an embodiment, the coating comprises up to 75% by weight
of the chewing gum composition.
[0024] In an embodiment, the coating is a recrystallized granular
coating.
[0025] In an embodiment, the coating is an amorphous coating.
[0026] In an embodiment, the coating is a powder coating.
[0027] 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; and cardiovascular
agents.
[0028] In another embodiment of the present invention a method of
drug delivery is provided. The method comprising the steps of:
providing a chewing gum that includes a coating that comprises at
least 50% by weight of the chewing gum, the coating including a
medicament that substantially surrounds a tableted gum center;
chewing the chewing gum to cause the medicament to be released from
the chewing gum composition into the buccal cavity of the chewer;
and continuing to chew the chewing gum 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 a further embodiment of the present invention, a method
for reducing the amount of agent necessary to achieve an effect in
an individual as compared to a typical agent that is swallowed is
provided. The method comprises the steps of: providing a chewing
gum including a coating that surrounds a tableted gum center, the
coating comprising at least 50% by weight of the total chewing gum,
the coating including an agent that is typically swallowed by an
individual to achieve a specific effect. However, the coating
includes less than the typical amount of agent that is swallowed by
the individual to achieve the effect; chewing the chewing gum and
thereby causing the agent to be released into the salvia of the
individual; and continuing to chew the chewing gum forcing the
agent through the mucous membranes in a buccal cavity of the
individual.
[0030] 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; and cardiovascular
agents.
[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 chewing gum including a coating that
comprises at least 50% by weight of the chewing gum and surrounds a
tableted gum center and includes a medicament; and chewing the
chewing gum for at least 2 minutes.
[0032] In a still further embodiment of the present invention a
chewing gum composition is provided. The chewing gum includes a
tableted gum center including a water soluble portion and a water
insoluble portion, the water insoluble portion comprising at least
15% by weight of the gum center. The coating surrounds the tableted
gum center and includes a medicament and comprising at least 50% by
weight of the chewing gum. The coating includes a
macrosweetener.
[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
tableted gum center having water-soluble portion and a
water-insoluble; coating the tableted 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; and the coated
product comprising at least 50% by weight syrup and powder
coating.
[0034] In an embodiment the powder and syrup are coated on the gum
center in alternating steps until a sufficient coating has been
built up.
[0035] In an embodiment the coating is not covered with a shellac
or other finishing 10 layer but rather maintains a matte
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] 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.
[0039] 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.
[0040] 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.
[0041] Additionally, an advantage of the present invention is to
provide a method for administering medicaments that is more
palatable than current methods.
[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.
[0044] Still, 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.
[0045] An advantage of the present invention is that a coated
product is provided wherein the coating can absorb or lose moisture
without apparent degradation.
[0046] Further, an advantage of the present invention is that a
coated chewing gum product including medicament is provided having
an extended shelf-life.
[0047] Furthermore, an advantage of the present invention is that
it can produce medicament-containing products having precise sizes
and shapes.
[0048] 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 chewing gum product.
[0049] Additional features and advantages of the present invention
will be described in and apparent from the detailed description of
the presently preferred embodiments and the figures.
BRIEF DESCRIPTION OF THE FIGURES
[0050] FIG. 1 illustrates generally an embodiment of the chewing
gum of the present invention.
[0051] FIG. 2 illustrates graphically the results of Experiment No.
1 that is discussed supra.
[0052] FIG. 3 illustrates graphically the results of Experiment No.
2 that is discussed supra.
[0053] FIG. 4 illustrates graphically the results of Experiment No.
3 that is discussed supra.
DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
[0054] 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.
[0055] Pursuant to the present invention, a medicament or agent is
contained in a coating that surrounds a tableted gum center
formulation. As used herein "tableted" means that a gum center is
provided that has a precise size (within an acceptable range)
depending on the medicament or agent and shape. Thus allows an
accurate control of the coating as well as allows one to create
products having specific sizes and shapes. The coating comprises at
least 50% by weight of the entire chewing gum product.
[0056] As the chewing gum is chewed, the medicament or agent is
released into the saliva. During continual chewing, 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 bioavailability is also much greater
than oral administration.
[0057] Referring to FIG. 1, an embodiment of the chewing gum
composition 10 of the present invention is illustrated. As
illustrated, the chewing gum composition 10 includes a tableted gum
center 12. The tableted gum center can be any chewing gum
formulation known in the art, though as noted below preferably the
tableted gum center has a higher level of water insoluble gum base
than is typically used. Pursuant to the present invention,
surrounding the tableted gum center 12 is a coating 14. The coating
14 includes a medicament or other active agent.
[0058] As noted above, the tableted gum center 12 can be any size
or shape. However, the key is that by tableting the gum center, one
can control to a precise relative standard deviation, the size of
the gum center 12. This allows one to accurately control the amount
of coating 14 that is placed around the gum center 12 to create the
resultant product. In this regard, if the gum center is too large
or too small, the resultant coating will either be greater or less
than desired. Because the coating, as noted below, contains a
medicament, if the size of the gum 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 gum center, through the tableting process, one is ensured that
a precise level of coating, and therefore medicament, can be
provided and thereby delivered.
[0059] Additionally, by using the tableting process one can vary
the size and shape of the resultant product. For example, for a
chewing gum product including an analgesic, the product can have an
aspirin shape. In a similar vein, for proprietary designs that are
used for certain drugs, one can create the gum center in the
proprietary design allowing the resultant product to have the
proprietary shape or design.
[0060] A variety of different tableting processes can be used. What
is important is that a process is used that allows one to create a
uniform gum center. 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..
[0061] Referring now to the coating 14, the coating 14 comprises at
least 50% by weight of the chewing gum composition. Preferably, the
coating 14 comprises approximately 50% to about 75% by weight of
the chewing gum composition and in a preferred embodiment, the
coating 14 comprises approximately 67% by weight of the product. 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.
[0062] Preferably, the coating 14 will include masking agents. In
this regard, high-intensity sweeteners and appropriate flavors can
be used to mask 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 have an offensive taste, the matrix
used as the coating of the present invention, including the masking
agent, will 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 based on the bad or off taste produced by
the medicament, one can provide a palatable formulation.
[0063] 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.
[0064] 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.
[0065] In an embodiment of the invention, sufficient masking agent
will be used in the coating to improve and provide acceptable
organoleptic properties to the chewing gum product. As used herein
to provide "acceptable organoleptic properties" means that the
chewing gum formulation will have a sufficiently pleasant, or at
least non-offensive taste, to allow the consumer to chew the
chewing gum for at least two minutes. Whether a masking agent is
necessary and/or the amount of masking agent will vary depending on
medicament or agent. Of course, if desired, more than one masking
agent can be used, e.g., zinc gluconate and a sweetener or flavor.
In an embodiment, the masking agent may comprise approximately 30%
to about 99% by weight of the coating formulation.
[0066] 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 0.5% to about 5% by weight of the coating.
[0067] As noted above, the coating will include a medicament or
agent. It has also been surprisingly found that less medicament or
agent can be placed in the chewing gum than is typically orally
administered to an individual to achieve an effect and the same
bioequivalence can be achieved. In fact, it has been surprisingly
found that in certain instances, for at least certain drugs and
agents, the administration of the medicament or agent using chewing
gum through the buccal cavity can provide an increase effect even
as compared to parenteral administration.
[0068] For example, caffeine is commonly used as a stimulant to
alleviate the effects of sleep deprivation. It is almost completely
metabolized in the liver and therefore classified as a low
clearance, flow independent drug. This means its rate of
inactivation is unaffected by delivery to the liver and can only be
modified by a change in the hepatic enzyme activity.
[0069] The pharmacokinetics of caffeine have been well documented
and there is no significant difference between oral and intravenous
administration. However, data set forth in detail below, suggests
that the absorption rate constant (Ka) is significantly increased
when caffeine is administered through chewing gum. This means that
the caffeine 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.
[0070] It has additionally been surprisingly found that for at
least certain agents that placing the agent in the chewing gum can
have a triggering effect on the agent that may be in the systemic
circulation. For example, it has been found that with respect to
caffeine that is ingested orally, that after the ingestion of a
certain amount of caffeine, and the elapse of a certain period of
time, that further ingestion of caffeine has a negligible effect on
the individual. However, upon chewing gum with caffeine there has
been observed a triggering effect that appears to create a
synergistic effect with the caffeine that is in the systemic
circulation. It is believed that this triggering effect will also
be present with other agents, e.g., analgesics.
[0071] 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. Generally, such
medicaments include, inter alia, analgesics, antibiotics,
antivirals, antihistamines, anti-inflammatories, decongestants,
antacids, muscle relaxants, psychotherapeutic agents, insulin, and
cardiovascular agents. It is envisioned, that depending on the
medicament, the resultant chewing gum can be used to treat, inter
alia: coughs; colds; motion sickness; allergies; fevers; pain;
inflammation; sore throats; cold sores; sinus problems; diarrhea;
diabetics; depression; anxiety; and other maladies and symptoms.
Specific agents/medicaments include, by way of example and not
limitation: caffeine; aspirin; acetaminophen; ibuprofen;
hydroxycitric acid; chromium picolinate; phosphatidylserine;
nicotine; insulin; Echinacea purpurea; zinc; vitamin C; ginseng;
kola nut; kaua kaua; and chamomile.
[0072] Preferably, the agents or medicaments are contained in the
coating of the chewing gum formulation 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 per serving (2.8 grams of coated chewing gum);
aspirin would be preset at a level of 325 milligrams per 2.8/gram
serving. The level of medicament or agent in the coating of the
chewing gum formulation is selected so as to create, when the gum
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 nicotine
or caffeine, the level of the stimulant in the coating of the
chewing gum should be such that it creates a saliva content of
stimulant of approximately 15 to 440 ppm when the chewing gum is
chewed for 2 minutes. At this level, a sufficient amount of
stimulant will be delivered to the chewer to create 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 coating of the chewing gum to create a salvia
content of approximately 1700 to approximately 4400 ppm after the
chewing gum has been chewed for 2 minutes. 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 when the chewing gum is chewed for
2 minutes. 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 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.
[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 chewing gum 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, chewed, for example, not more often than one stick
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 chewing gum would be chewed, in a
preferred embodiment ten minutes or less before the performance. As
set forth below in the experiment, it has been surprisingly found
that for a chewing gum stick including caffeine, with another 5
minutes of chewing a high level of alertness is achieved.
[0076] A variety of methods can be used for constructing the
coating of the chewing gum. Typically coatings are applied to
chewing gum 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.
[0077] As noted above, in contrast to typical coated chewing gum
products, the products of the present invention include at least
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.
[0078] 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.
[0079] In an embodiment of constructing the coated chewing gum,
first the syrup is distributed on the gum 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 chewing gum, e.g., 10 to 20 coating
layers or more are applied. The coating which plays an important
role as the masking agent, can include a combination of sugar, corn
syrups, or in the case of a sugar-free product, various
combinations of sugar alcohols, monomers, and polymers.
[0080] 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.
[0081] 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.
[0082] 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.
[0083] 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 0.5 to about 5% of the coating. As noted above, these
high-intensity sweeteners are excellent masking agents.
[0084] The coating including medicament or agent can surround a
variety of different gum center compositions. Referring now to the
chewing gum center, pursuant to the present invention, the gum
center may be based on a variety of different chewing gums that are
known. For example, the gum center 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.
[0085] Chewing gum generally consists of a water insoluble gum
base, a water soluble portion, and flavor. The water soluble
portion dissipates with a portion of the flavor of the gum over a
period of time during chewing. The gum base portion is retained in
the mouth throughout the chew.
[0086] The insoluble gum base generally comprises elastomers,
resins, fats and oils, softeners and inorganic fillers. The gum
base may or may not include wax. Typically, gum base comprises
approximately 20 to about 40% of the gum product. However, because
in the present invention such a high level of coating is used, the
gum center is unusually small; otherwise the entire coating chewing
gum piece would be too large for consumption. If a typical amount
of gum base was used in the small gum center, it would result in an
inadequate cud to masticate. Consequently, in the present
invention, the base level is higher than normal. The insoluble gum
base can constitute approximately 30% to about 90% by weight of the
chewing gum, in an embodiment, the gum base comprises at least 50%
of the chewing gum.
[0087] In an 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.
[0088] 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.
[0089] 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%.
[0090] 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.
[0091] Elastomer plasticizers may include, but are not limited to,
natural rosin esters such as glycerol esters or partially
hydrogenated rosin, glycerol esters of polymerized rosin, glycerol
esters of partially dimerized rosin, glycerol esters of rosin,
pentaerythritol esters of partially hydrogenated rosin, methyl and
partially hydrogenated methyl esters of rosin, pentaerythritol
esters of rosin; synthetics such as terpene resins derived from
alpha-pinene, beta-pinene, and/or d-limonene; and any suitable
combinations of the foregoing. The preferred elastomer plasticizers
will also vary depending on the specific application, and on the
type of elastomer which is used.
[0092] Fillers/texturizers may include magnesium and calcium
carbonate, ground limestone, silicate types such as magnesium and
aluminum silicate, clay, alumina, talc, titanium oxide, mono-, di-
and tri-calcium phosphate, cellulose polymers, such as wood, and
combinations thereof.
[0093] Softeners/emulsifiers may include tallow, hydrogenated
tallow, hydrogenated and partially hydrogenated vegetable oils,
cocoa butter, glycerol monostearate, glycerol triacetate, lecithin,
mono-, di- and triglycerides, acetylated monoglycerides, fatty
acids (e.g. stearic, palmitic, oleic and linoleic acids), and
combinations thereof.
[0094] Colorants and whiteners may include FD&C-type dyes and
lakes, fruit and vegetable extracts, titanium dioxide, and
combinations thereof.
[0095] The base may or may not include wax. An example of a
wax-free gum base is disclosed in U.S. Pat. No. 5,286,500, the
disclosure of which is incorporated herein by reference.
[0096] 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.
[0097] Softeners are added to the chewing gum in order to optimize
the chewability and mouth feel of the gum. The softeners, which are
also known as plasticizers and plasticizing agents, generally
constitute between approximately 0.5% to about 15% by weight of the
chewing gum. The softeners may include glycerin, lecithin, and
combinations thereof. Aqueous sweetener solutions such as those
containing sorbitol, hydrogenated starch hydrolysates, corn syrup
and combinations thereof, may also be used as softeners and binding
agents in chewing gum.
[0098] Bulk sweeteners include both sugar and sugarless components.
Bulk sweeteners typically constitute about 5% to about 95% by
weight of the chewing gum, more typically, about 20% to about 80%
by weight, and more commonly, about 30% to about 60% by weight of
the gum. Sugar sweeteners generally include saccharide-containing
components commonly known in the chewing gum art, including but not
limited to, sucrose, dextrose, maltose, dextrin, dried invert
sugar, fructose, levulose, glactose, corn syrup solids, and the
like, alone or in combination. Sugarless sweeteners include, but
are not limited to, sugar alcohols such as sorbitol, mannitol,
xylitol, hydrogenated starch hydrolysates, maltitol, and the like,
alone or in combination.
[0099] 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, 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.
[0100] 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.
[0101] 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 Gum Hydrolysate (Sun
Fiber); or indigestible dextrin (Fibersol). However, other low
calorie bulking agents can be used.
[0102] 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.
[0103] A process for preparing the tableted gum center is as
follows: to an unheated gum mixer, preferably a double sigma blade,
shredded gum base is added. Along with the gum base is added
powdered color and one-third of the portion of sugar that will be
used. Mixing is begun in the gum mixer. After the sugar
incorporates into the gum base, approximately 5-7 minutes, the
second one-third portion of the sugar is added thereto. Once the
mixture appears to be homogenous the remaining sugar portion (last
third) is added. The total mixing time is approximately 25 minutes.
The powder is removed from the mixer. The powder is shifted to
desired mesh size. An appropriate amount of spray dried flavor,
acid, tableting agents (magnesium stearate) and flow agents
(silicone dioxide) are added. This is then mixed until the powder
is homogenous. The resulting powder is then pressed on a tableting
machine, for example, a Stokes machine.
[0104] By way of example, and not limitation, examples of some
coated chewing gum formulations including a medicament or agent are
as follows:
1 TABLETED COATED PRODUCT The tableted gum will include a gum
center and a coating. In an embodiment, the gum center will include
the following ingredients in the following ranges: Gum Base
(powdered gum) 15 to 90% Powdered Sugar 5 to 95% Color (Lake) 0 to
1% S.D. Flavor 0.1 to 10% Magnesium Stearate 0.1 to 5% Silicon
Dioxide 0.1 to 5% Macro-sweetener 0.1 to 5%
[0105] An embodiment of the tableted coated product is as
follows:
2 Tableted Gum Center Coating Wt. Ingredient Percent Ingredient
Grams Gum Base (powdered 18.04 Acetaminophen 0.3490 gum) Powdered
Sugar 76.99 Peppermint Flavor (dry) 0.0072 Color (Lake) 0.01
Menthol Flavor (dry) 0.0062 S.D. Flavor 1.46 Dextrose 1.4200
Magnesium Stearate 1.50 Sucrolose 0.0030 Silicon Dioxide 1.00
Aspartame 0.0062 Macro-sweetener 1.00 Glucose 0.2080 100.00% 2.0000
g
[0106]
3 ACETAMINOPHEN COATED BUBBLE GUM Gum Center (1 gram) Coating (1
gram) Ingredient Grams Ingredient Grams Gum Base 400.0
Acetaminophen 80.0 Corn Syrup 91.0 Encapsulated Aspartame 20.0
Glycerine 49.0 Aspartame 50.0 Sugar 829.9 Salt Flour 2.5 Red Dye
0.7 Dextrose 643.5 Aspartame 14.0 Bubble Gum Flavor 4.0 Bubble Gum
Flavor 15.4 800.0 1400.0
[0107]
4 ACETAMINOPHEN COATED CHEWING GUM Gum Center (1 gram) Coating (2
grams) Ingredient Grams Ingredient Grams Xylitol 56.0 Acetaminophen
335.0 Natural Peppermint Flavor 27.0 Natural Peppermint 7.0 Natural
Peppermint Flavor 25.0 S.D. Menthol 6.0 Natural Menthol 9.0
Dextrose 1,221.0 Natural Peppermint Flavor 26.0 Aspartame 32.0
Glycerine 96% USP 14.0 1,601.0 Bubble Gum 480.0 Firm Modifier 90.0
Aspartame 6.0 Ace-K 9.0 Gum Base 620.0 Corn Syrup 112.0 Powdered
Sugar 406.0 1400.0
[0108]
5 PSEUDOEPHEDRIN COATED GUM Gum Center (1 gram) Coating (2 grams)
Ingredient Grams Ingredient Grams Xylitol 56.0 Dextrose 1,476.00
Natural Peppermint Flavor 27.0 Eucalyptus* 2.00 Natural Peppermint
Flavor 25.0 Menthol* 30.00 Natural Menthol 9.0 Aspartame 32.00
Natural Peppermint Flavor 26.0 Pseudoephedrin 60.00 Glycerine 96%
USP 14.0 1,600.00 Gum Base 670.0 Firm Modifier 90.0 Aspartame 6.0
Ace-K 9.0 Gum Base 140.0 Corn Syrup 112.0 Powdered Sugar 406.0
1,400.0 *sprayed dried
[0109]
6 PEPPERMINT CAFFEINE COATED CHEWING GUM Gum Center (1 gram)
Coating (2 grams) Ingredient Grams Ingredient Grams Xylitol 56.0
Caffeine 100.0 Natural Peppermint Flavor 27.0 Peppermint 13.0
Natural Peppermint Flavor 25.0 Dextrose 1,455.0 Natural Menthol 9.0
Aspartame 32.0 Natural Peppermint Flavor 26.0 1,600.0 Glycerine 96%
USP 14.0 Gum Base 620.0 Firm Modifier 90.0 Aspartame 6.0 Ace-K 9.0
Gum Base 140.0 Corn Syrup 112.0 Powdered Sugar 406.0 1,400.0
[0110] By way of example, and not limitation, experiments and
examples testing chewing gum including a medicament or agent in the
gum body or coating are as follows:
Experiment No. 1
[0111] Single dose, placebo controlled, randomized, two-way
crossover study in 20 subjects to evaluate the effect of 50 mg
caffeine gum compared to placebo gum-on positive and negative mood
affects. Healthy subjects 18-65. Screening questionnaire to
evaluate average caffeine consumption, tobacco drug and alcohol
status. Any subjects taking medications with a CNS affect were
excluded from the study. Approximately 2 hours on two occasions
separated by at least 24 hours.
[0112] Dosing: 1.times.stick of caffeine gum to be chewed for 30
minutes. The chewing gum had the formulation set forth above in the
table entitled caffeine gum.
[0113] The subjects were instructed that they were to have
caffeine, alcohol or other drug use for at least 8 hours prior to
test. No tobacco products for at least 2 hours prior to test.
Subjects must have been awake and active for at least 8 but no more
than 16 hours prior to starting the test. Subjects will be required
to complete a 10 part questionnaire at the following time points
(-20, -10, -5 and at 2, 5, 10, 15, 20, 30, 40 and 1 hour after
starting to chew the gum. Appropriate analysis of comparison of
each individual item of the test and grouped analysis for both
positive and negative affect.
[0114] Data was corrected for baseline data (-5 minute reading) at
each time point. Means and standard deviations for both active and
placebo groups were evaluated for all time points.
[0115] The results of the analysis are set forth in FIG. 2. FIG. 2
graphically illustrates alertness versus time. These results
demonstrate that by 5 minutes the subject reported that they were
quite a bit alert. The alertness response was based on reference
Panas feeling and emotion scale.
Experiment No. 2
[0116] A randomized, single-dose, two-way crossover study was
conducted with six (6) healthy, adult, non-tobacco-using male
subjects. A single 100 mg does of caffeine was administered in each
study period after an overnight fast. The test treatment was two 50
mg caffeine chewing gum pieces (sticks), which were chewed for 15
minutes and removed. The reference treatment was one 100 mg
chewable No-Doz.RTM. tablet, which was chewed and swallowed. One of
the treatments was given in each period; the order of
administration was according to the dosing randomization schedule.
There was a 7-day washout between treatments.
[0117] Blood samples were collected pre-dose and over 15 hours
after each dose. Plasma concentrations of caffeine were measured by
a fully validated chromatographic procedure. Samples from subject
with measurable pre-dose levels of caffeine were corrected for
these levels. Pharmacokinetic parameters were calculated from the
adjusted data and statistical analyses were performed to compare
the test and reference treatments.
[0118] Clinical Procedures
[0119] A. Subject Selection
[0120] The 6 subjects who participated in this study were healthy
males, in the age range of 25 to 35 years, and within 15% of their
ideal weight as specified in the protocol.
[0121] All subjects were selected based on the absence of any
clinically significant findings on the medical history, physical
examination, and clinical laboratory evaluations. Any laboratory
value or vital sign measurement more than 10% outside the normal
range was evaluated individually by the investigator. All were
determined to be not clinically significant for those subjects
enrolled in the study. All screening evaluations were performed
within 28 days of initial dosing.
[0122] B. Drug Supplies
[0123] Formulations:
[0124] Test (A)--Two 50 mg chewing gum sticks, Amurol Confections
Co. (Lot #ALRT7/9/19/96, No exp. Date)
[0125] Reference (B)--One 100 mg No-Doz.RTM. chewable table,
Bristo-Myers Products (Lot #601041, Exp. date 10/98).
[0126] Administration: The subjects received the test and reference
after an overnight fast. The subjects randomized to the test first
drank 240 ml of room temperature tap water. The chewing gum pieces
were then chewed for 15 minutes and deposited into a labeled vial.
The subjects randomized to the reference chewed the No-Doz.RTM.
tablets and then drank 240 ml of room temperature tap water. The
order of treatment administration was according to the
randomization schedule.
[0127] All doses were administered at one-minute intervals
beginning at 0700 hours. A thorough mouth check was performed to
ensure that the chewable tablet was swallowed. A schedule of the
actual dosing times, dates and treatment assignments is included in
Table C2. All subjects remained under observation sitting upright
or standing for at least two hours after each dosing. Six subjects
were dosed in both Period I and Period II.
[0128] C. Study Conduct
[0129] Confinement, Meals: During the confinement periods of this
study, the subjects were housed and fed at the clinical
facility.
[0130] In each period, the subjects reported for check-in (Day -1)
at least 12 hours before dosing. Meals were provided on check-in
day and completed at least 10 hours prior to scheduled dosing time.
No food or beverages (except water) were permitted after 2100 hours
on Day -1.
[0131] During confinement (Day 1), standardized, caffeine-free
meals or snacks were served at 4, 10 and 14 hours after dosing, as
specified on the Activity Schedule and Menu found in Section 3. The
same menu was used during each study period. The subjects consumed
at least 95% all food and beverages that were required. The
subjects were released from the clinical facility approximately
2200 hours after dosing in each study period. A 7-day washout
separated the dosings.
[0132] Restrictions: Prior to check-in for the study, the subjects
were instructed to take no prescribed medications for at least 14
days prior to the initial dosing and throughout the study. No
over-the-counter medications were permitted for 72 hours before
dosing in each study period. No medications were permitted during
confinement except those administered. Subjects were also
instructed to abstain from any products containing alcohol or
caffeine for 48 hours prior to dosing and throughout each
confinement. None of the subjects reported taking any restricted
substance within the time frame indicated.
[0133] During the confinement periods of the study, water was
restricted from one hour before until one hour after dosing except
for water (240 ml) administered with the dose. Water was permitted
ad lib at all other times. Subjects remained sitting upright or
standing for 2 hours after each dosing, except as required for
study procedures. No strenuous physical exercise was permitted
during confinement.
[0134] Safety: Urine drug screens were performed at each check-in
to test for alcohol, marijuana and cocaine metabolites.
[0135] Blood pressure (sitting), pulse rate, respiratory rate and
oral temperature were measured before each dosing. The investigator
considered the measurements of all subjects as clinically
acceptable for dosing.
[0136] Blood pressure and pulse rate measurements (sitting) were
obtained approximately one hour after each dose and prior to
release in each study period to monitor the health of the subjects.
Measurements were repeated if clinically warranted.
[0137] A blood sample was collected at the time of the last sample
of the study for a hematocrit determination. All hematocrit values
were within 10% of the normal range (41-50%).
[0138] Adverse Events: The subjects were monitored throughout the
study for any adverse experiences. They were encouraged to report
signs, symptoms, and any changes in health to the study nurse. None
of the subject reported any adverse events during this study.
[0139] Pharmacokinetic Samples: In each period, blood samples were
collected prior to dosing and at the following nominal times after
dosing: 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 15 hours.
The samples were labeled at the time of collection with a unique
6-digit code number. Pre-dose samples were collected within 30
minutes before dosing. All plasma samples were stored frozen
between -18.degree. C. and -20.degree. C. until transfer to the
laboratory for analysis, with the exception of one day.
[0140] Subject Completion: A total of 6 subjects were entered into
the study and all subjects completed one study.
[0141] Analytical Procedures
[0142] A. Quality Control
[0143] Standards and Controls: Calibration standards were prepared
spiking a pool of human, interference-free, heparinized plasma with
caffeine (USP Reference, Lot I). The plasma was obtained from
Interstate Blood Bank (Memphis, Tenn.). The standards were prepared
to contain 0.050, 0.100, 0.200, 0.500, 1.00, 2.00 and 5.00 .mu.g/ml
of caffeine.
[0144] The caffeine standards and controls were divided into 2.5 ml
aliquots and stored in the laboratory in polypropylene snap-cap
tubes frozen to at least -19.degree. C.
[0145] The pre-study within-run coefficient of variation ranged
from 0.915% to 2.54%. The relative accuracy of the procedure was
estimated, through comparison of the measured concentration means
of the control samples against their theoretical concentrations,
and was found to average 99.5% for caffeine.
[0146] Run Acceptance Criteria: Chromatographic peak responses and
peak response ratios were monitored using an electronic integrator.
Each chromatographic tracing was inspected for acceptable retention
times, peak shapes, resolution and integration before the peak
response ratios (analyte-to-internal standard) were entered into
the computer.
[0147] The acceptable limit of quantization for the run was
evaluated through comparison of the mean response of the lowest
concentration standards (0.050 .mu.g/ml) with the responses of any
interferences observed in the water blank, matrix blank and zero
standard. The limit of quantization for the run was defined as the
concentration at which the signal-to-noise ratio was at least
2.
[0148] Samples, standards and controls with an internal standard
peak response which deviated more than .+-.25% from the mean
within-run peak response of the internal standard (calculated for
all standards and controls) were rejected.
[0149] The response ratio for each remaining non-zero standard was
plotted as a function of concentration. A linear regression was
calculated (R/S 1, version 4.3) by the method of least-squares
using (1/CONC).sup.2 as a weighting factor. With this calibration
line, a calculated concentration was determined for each standard
sample. Any standard differing by more than .+-.25% from its
theoretical value was excluded from the regression and the
regression was recalculated. The analyte concentrations in the
samples and the controls were estimated from the calibration line
by use of the equation: (RATIO-INTERCEPT)/SLOPE.
[0150] The analytical run was considered acceptable if 4 of 6
controls passed established acceptance criteria and that at least
one control sample was acceptable within each concentration range.
Controls within an analytical run were considered acceptable if the
low control values differed by no more than .+-.20% and the middle
and high controls differed by no more than .+-.15% from their
theoretical values. The concentrations o the controls were
graphically displayed to permit visual confirmation of
acceptability and identification of trends.
[0151] B. Sample Analysis
[0152] Sample Storage and Stability: The plasma samples, which were
collected in the clinic were transferred to the laboratory and
stored frozen to at least -19.degree. C. until analyzed. Samples
were not identified to the analysts by treatment group. All
subjects' samples were analyzed within 19 days of the initial
sampling. The frozen stability of caffeine in plasma has been
confirmed for 138 days.
[0153] Peak Identification: The retention times of the analyte and
the internal standard were identified, in any given analytical run,
by comparison to stock standards chromatographed at the beginning
of the run and to processed standards chromatographed through the
run.
[0154] Pharmacokinetic and Statistical Procedures
[0155] A. Pharmacokinetic Data
[0156] All the available data from 6 subjects with reported
caffeine concentrations were used in the pharmacokinetic analyses.
Several subjects had pre-dose samples which contained measurable
concentrations of caffeine. For each of these subject's data, the
measured concentration at each sampling time was corrected by
subtracting the level of caffeine at that time predicted from the
decay of the pre-dose level. The decay curve was constructed using
the elimination rate observed in the same period as the decay
constant. After adjustment, each pre-dose level was 0.0 .mu.g/ml,
and each post-dose concentration was reduced accordingly.
[0157] Pharmacokinetic parameters (areas, times to peak, and
elimination rates and half-lives) were calculated using the actual
rather than the scheduled time of sample collection. Graphical
presentations of individual subject results also used the exact
times of sample collection. Graphical presentations of mean results
used the scheduled times of sample collection.
[0158] Peak concentration (Cmax) was the observed maximum value
(corrected for pre- dose levels, if necessary) during the
collection period of 0 to 15 hours. The time to peak concentration
(Tmax) was the time at which Cmax was observed (or first observed,
if more than one peak was present).
[0159] The apparent first-order elimination rate (Ke) was estimated
as the absolute value of the slope of the regression line for the
terminal log-linear concentration-time values. The values included
in the regression analyses were determined by examination of the
individual subject plots of natural logarithm of concentration
against time. Elimination half-life (t-1/2) was calculated as
0.693/Ke.
[0160] Area under the curve (AUC) to the time of the last non-zero
concentration (C.sub.t) was calculated by the linear trapezoidal
method. Area to infinite time (AUCinf) was calculated by
extrapolating AUC by the addition of the quantity: C.sub.t/Ke.
[0161] B. Statistical Analyses
[0162] Statistical analyses were performed using the General Linear
Models (GLM) procedures of the SAS statistical program. Hypothesis
testing for treatment effects was conducted at .alpha.=0.05. The
statistical model contained main effects of sequence, subject
within sequence, period, and treatment. Sequence effects were
tested against the type III mean square term for subjects within
sequence. All other main effects were tested against the mean
square error term.
[0163] The observed and calculated pharmacokinetic parameters as
well as the caffeine concentrations at each of the individual
collection times were compared statistically.
[0164] Power for the pair-wise pharmacokinetic comparisons was
calculated as the probability (.alpha.=0.05) of detecting a
difference equal to 20% of the mean for the reference treatment in
the comparison, or a ratio of 1.25 for In-transformed results.
[Winer, B J. Statistical Principles In Experimental Design. NEW
YORK: McGraw-Hill Book Company (1962) 21-26.]
[0165] Confidence Intervals (90%) for pair-wise area and peak
concentrations comparisons were calculated by the t-test approach
(2,1-sided) at .alpha.=0.05 each side. The intervals were computed
for the "true" mean test-to-reference treatment ratio (or geometric
mean ratio for In-transformed results).
[0166] Discussion and Results
[0167] Statistical analyses were performed on the caffeine data in
order to compare the test chewing gum to the chewable reference
tables. Natural log-transformation of the area and Cmax parameters
was also performed and analyzed statistically. Table 1, which
follows, summarizes the results (n=6) of the statistical analyses
of the major bioavailability parameters.
[0168] Statistical comparisons of the test and reference
formulations at each sampling time are summarized in Table 2.
[0169] Conclusion
[0170] The caffeine chewing gum pieces appear to have a much faster
rate of absorption that the No-Doz.RTM. chewable tablets. The areas
and peak concentrations of the chewing gum were less than half that
of No-Doz.RTM. even though the gum base released one-half the
caffeine that the tablet did. And the time to reach a peak for the
gum was 30 minutes earlier than for the tablet.
7TABLE 1 Comparisons of caffeine results for 50 mg chewing gum
pieces (Test) vs. 100 mg No-Doz .RTM. chewable tablets (Reference)
administered as a single 100 mg dose under fasting conditions to 6
subjects. Least 90% Confidence Squares Means.sup.1 Test/Ref.
Interval.sup.4 Parameter Test Reference Ratio.sup.2 Power.sup.3
Lower Upper AUC 0-t 7.26 17.65 0.412* 0.50 0.246 0.577
(.mu.g-hr/ml) AUCinf 9.60 23.72 0.405* 0.39 0.211 0.598
(.mu.g-hr/m1) Cmax 0.92 2.15 0.429* 0.76 0.309 0.548 (.mu.g/ml)
Tmax 1.08 1.58 0.684 0.22 -- -- (hour) Ke 0.1241 0.1058 1.173* 0.86
-- -- (1/hour) Elimhalf 5.97 6.97 0.857* 0.86 -- -- (hour)
Ln-Transformed Data AUC 0-t 6.22 17.44 0.357* 0.15 0.239 0.532
(.mu.g-hr/ml) AUCinf 7.66 23.00 0.333* 0.13 0.212 0.524
(.mu.g-hr/ml) Cmax 0.84 2.14 0.391* 0.17 0.272 0.562 (.mu.g/ml)
.sup.1Least squares geometric means for In-transformed data.
.sup.2Test/Ref Ratio calculated as Test mean divided by Reference
mean. .sup.3Power to detect a difference of 20% (original data) or
a ratio of 1.25 (Intransformed data). .sup.4Confidence interval on
the ratio. *Detected as statistically significant by ANOVA
(.alpha.= 0.05).
[0171]
8TABLE 2 Summary of caffeine statistical comparisons at each
sampling time comparing 50 mg chewing gum pieces (Test) vs. 100 mg
No-Doz .RTM. chewable tablets (Reference) administered as a single
100 mg dose under fasting conditions to 6 subjects. Sample
Collection Least Squares Means (.mu.g/ml) Time (Hour) Test
Reference Significance* 1 Pre-dose 0.00 0.00 -- 2 0.25 0.23 0.36
0.0269 3 0.50 0.79 1.18 None 4 1.00 0.83 1.91 0.0008 5 1.50 0.84
2.05 0.0006 6 2.00 0.75 2.01 0.0004 7 2.50 0.72 1.92 0.0001 8 3.00
0.68 1.78 0.0006 9 4.00 0.66 1.64 0.0006 10 6.00 0.57 1.33 0.0046
11 8.00 0.47 1.10 0.0088 12 10.00 0.37 0.90 0.0052 13 12.00 0.28
0.75 0.0021 14 15.00 0.22 0.56 0.0068 *Statistical comparisons to
test for the equivalence of treatment effects were performed at an
a level of 0.05. The actual p-value is indicated at the time where
statistically significant differences (p < 0.05) were detected;
"None" indicates that no significance was detected (p <0.05) at
that time.
[0172] FIG. 3 illustrates graphically least squares mean plasma
concentration (.about.=6). Concentration of caffeine in (reg/ml)
versus hours of the dose is illustrated graphically; chewing gum
provided 50 mg of caffeine versus 100 mg of No-Doz.RTM. tablet. It
should be noted that although in FIG. 2 the blood concentration
level of caffeine is approximately 50% that of No-Doz.RTM., the
amount of caffeine delivered by the chewing gum was 50% that of the
No-Doz.RTM..
Experiment No. 3
[0173] The following protocol was followed. The chewing gum formula
set forth on page 15 under the heading caffeine gum was used.
Subjects chewed gum for 5 minutes. Then, the gum cuds were then
collected and analyzed for caffeine. At T-10 minutes, the gum was
collected after chewing for 10 minutes and then had the caffeine
analyzed. This was repeated for all the time figures up to time 60
minutes. "Times 0" refers to non-chewed gum product. All these T-0
to T-60 minute gum samples were from the same lot of chewing
gum.
[0174] The results are as follows:
9TABLE 3 Actual Relative Timed Chewed Mg Caffeine % Caffeine %
Caffeine Minutes remaining in gum remaining in gum remaining in gum
T.sub.0 57.96 2.07 100.00 T.sub.5 16.80 0.60 28.70 T.sub.10 7.56
0.27 12.98 T.sub.20 1.68 0.06 3.01 T.sub.30 0.84 0.03 1.32 T.sub.40
0.00 0.00 0.00 T.sub.60 0.00 0.00 0.00
[0175] FIG. 3 illustrates graphically % caffeine remaining over
chew-out time in minutes.
Experiment No. 4
[0176] To detect absorption in the oral cavity, the following
experiment was carried out.
[0177] Samples of Stay-Alert Cinnamon flavored caffeine gum (Lot
713176) were analyzed for caffeine and found to contain
53.44.+-.0.52 mg per stick. Two subject (S1 and S2) were recruited
to chew the gum. Each subject chewed one stick of gum for 20
minutes, expectorating all saliva into a container. After chewing,
each rinsed twice with 10 ml of water (20 ml total) and added the
rinse water to the collected saliva. The volume of this solution
was brought up to 75 ml with distilled water. S2 repeated the
extraction process with a new stick of gum.
[0178] The chewed gum cuds and the saliva solutions were analyzed
for caffeine by gas chromatography. (A spiking study was also
conducted which showed recovery of caffeine from gum cuds and
saliva solutions to be 99.25% and 103.50% respectively. Measured
caffeine levels were not corrected for these recoveries as they
were not deemed significantly different from 100%,) The results of
the experiment are reported in Table
10 TABLE 4 S1 S2a S2b Volume of Saliva (ml) 50 30 30 Initial
caffeine level (mg) 53.44 53.44 53.44 Caffeine remaining in cud
(mg) 2.00 13.09 15.12 Caffeine in Saliva (mg) 45.69 30.26 28.97
Total Caffeine recovered (mg) 47.69 43.35 44.09 Unrecovered
caffeine (mg) 5.75 10.09 9.35 Percent of released unrecovered 11.2
25.0 24.4
[0179] It is believed that the unrecovered caffeine was adsorbed
through mucous membranes in the oral cavity. Thus between 11 and
25% of the released caffeine was adsorbed orally. Note that the
higher concentration of caffeine in saliva for S2 may have
contributed to the higher adsorption in that subject.
Experiment No. 5
[0180] The following gum center formulation was made as a gum
pellet center:
11 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
[0181] The gum pellet was coated with the following gum coating
formulation:
12 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.sup.1 0.81 0.00 Caffeine 3.78
4.10 100.00 100.00 .sup.1Flavor added in 2 additions after 10th and
15th within coating syrup 1.
[0182] 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.
[0183] 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.
[0184] 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:
[0185] 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.
[0186] 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.
[0187] 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.
[0188] 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.
[0189] 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.
[0190] The conclusions were as follows:
[0191] 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 .mu.g/ml
compared to 0.186 .mu.g/ml for coffee and 0.236 .mu.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 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.
[0192] 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.
[0193] 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).
[0194] 3. It was shown that significant levels of caffeine are
absorbed sublingually directly into the bloodstream via delivery
from gum. 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. 6
[0195] The following formulation was made:
13 Gum Center % Gum Base 33.00 Calcium Carbonate 13.00 Sorbitol
44.23 Glycerin 4.00 Flavors 2.32 Encapsulated Caffeine.sup.2 1.50
Free Caffeine 0.45 Lecithin 0.60 Encapsulated Sweeteners 0.90
100.00 .sup.2Spray dried maltodextrin/caffeine at 50% active
caffeine.
[0196]
14 Gum Coating 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 0.40 0.40 Peppermint Flavor.sup.3 1.40 0.00
Sweeteners 0.27 0.27 Carnauba Wax/ 0.00 0.27.sup.4 Talc Polishing
Agents Caffeine 1.78 1.72 100.00 100.00 .sup.3Flavor added in 3
additions after 3 separate syrup addition within coating syrup 1.
.sup.4Polished after completion of coating.
[0197] 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.
[0198] 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.
[0199] 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-Plus.TM. 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).
[0200] It was concluded that caffeine uptake in the bloodstream was
faster for gum than a pill, based on the following:
[0201] 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 .mu.g/ml). Average plasma caffeine levels
significantly greater than the pill at a=0.01 for T5, and a=0.005
for T10.
[0202] 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.
[0203] 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).
[0204] 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 .mu.g/ml compared
to 0.034 .mu.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 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.
[0205] 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.
[0206] 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:
[0207] 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 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.
[0208] 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:
[0209] Pellet with caffeine all in coating>Pellet with caffeine
split between coating and center=Beverages coffee/cola>Pill
[0210] 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.
[0211] 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 invention and without diminishing its intended
advantages. It is therefore intended that such changes and
modifications be covered by the appended claims.
* * * * *