U.S. patent application number 10/934638 was filed with the patent office on 2006-03-09 for aspartame and citrate flavored phosphate salt laxative.
Invention is credited to Nelson Ayala, Michael L. Caswell, Sarah S. Post, Sherrie Scott.
Application Number | 20060051428 10/934638 |
Document ID | / |
Family ID | 35427494 |
Filed Date | 2006-03-09 |
United States Patent
Application |
20060051428 |
Kind Code |
A1 |
Ayala; Nelson ; et
al. |
March 9, 2006 |
Aspartame and citrate flavored phosphate salt laxative
Abstract
The present invention provides compositions, kits, and methods
suitable for cleansing the colon before colonoscopy. The
compositions include a phosphate salt and a flavorant that includes
aspartame and a citrate. The kits include the previously mentioned
compositions and also may include suitable containers, packaging,
relief wipes, and instructions for use. The methods may include
administering orally to a subject an aqueous preparation including
monobasic sodium phosphate, dibasic sodium phosphate, aspartame,
and citric acid.
Inventors: |
Ayala; Nelson; (Lynchburg,
VA) ; Caswell; Michael L.; (Lynchburg, VA) ;
Post; Sarah S.; (Forest, VA) ; Scott; Sherrie;
(Lynchburg, VA) |
Correspondence
Address: |
EVAN LAW GROUP LLC
566 WEST ADAMS, SUITE 350
CHICAGO
IL
60661
US
|
Family ID: |
35427494 |
Appl. No.: |
10/934638 |
Filed: |
September 3, 2004 |
Current U.S.
Class: |
424/601 |
Current CPC
Class: |
A61K 47/12 20130101;
A61K 33/42 20130101; A61K 47/183 20130101; A61K 2300/00 20130101;
A61P 1/10 20180101; A61K 33/42 20130101; A61K 9/0095 20130101 |
Class at
Publication: |
424/601 |
International
Class: |
A61K 33/42 20060101
A61K033/42 |
Claims
1. A composition for colonic cleansing comprising: a flavorant
comprising aspartame and a citrate; and a phosphate salt.
2. The composition of claim 1, where the composition further
comprises a flavoring selected from the group consisting of natural
fruit flavors, artificial fruit flavors, and combinations
thereof.
3. The composition of claim 1, where the citrate comprises citric
acid and potassium citrate and the composition further comprises
maltodextrin, natural flavor, acesulfame potassium, lemon juice
solids, and artificial color.
4. The composition of claim 1, where the phosphate salt comprises
at least one salt selected from the group consisting of monobasic
sodium phosphate, dibasic sodium phosphate, and combinations
thereof.
5. The composition of claim 1, where the phosphate salt is present
as a liquid comprising water and from 0.05 to 1.5 gram/mL of
monobasic sodium phosphate and from 0.02 to 0.6 gram/mL of dibasic
sodium phosphate.
6. The composition of claim 1, where the phosphate salt is present
as a liquid comprising water and from 0.4 to 1 gram/mL of monobasic
sodium phosphate and from 0.13 to 0.25 gram/mL of dibasic sodium
phosphate.
7. The composition of claim 1, where the phosphate salt is present
as a liquid comprising water and 0.48 gram/mL of monobasic sodium
phosphate and 0.18 gram/mL of dibasic sodium phosphate.
8. The composition of claim 5, where from 15 to 75 mL of the liquid
is combined with from 1 to 10 grams of the flavorant.
9. The composition of claim 5, where from 40 to 50 mL of the liquid
is combined with from 4 to 5 grams of the flavorant, where the
citrate comprises citric acid.
10. The composition of claim 5, where from 40 to 50 mL of the
liquid is combined with from 1 to 3 grams of the flavorant, and the
flavorant comprises aspartame, citrates, and artificial lemon
flavoring.
11. The composition of claim 5, where about 45 mL of the liquid is
combined with 2.0 g+/-10% by weight of the flavorant, and the
flavorant comprises aspartame, citrates, and artificial lemon
flavoring.
12. The composition of claim 1, further comprising ascorbic acid or
a salt thereof.
13. The composition of claim 1, where the flavorant further
comprises ascorbic acid or a salt thereof.
14. The composition of claim 5, further comprising from 0.25 g/L to
50 g/L of ascorbic acid or a salt thereof.
15. The composition of claim 1, further comprising a gelling
agent.
16. A kit for colonic cleansing, comprising: monobasic sodium
phosphate, dibasic sodium phosphate, and a flavorant comprising
aspartame and a citrate.
17. The kit of claim 16, where the monobasic sodium phosphate and
the dibasic sodium phosphate are present as at least one aqueous
solution.
18. The kit of claim 16, where the monobasic sodium phosphate and
the dibasic sodium phosphate are present as an aqueous solution
present in at least one plastic bottle.
19. The kit of claim 16, where the flavorant further comprises a
flavoring selected from the group consisting of natural fruit
flavors, artificial fruit flavors, and combinations thereof.
20. The kit of claim 16, where the aspartame and the citric acid
are in a powdered form.
21. The kit of claim 16, where the aspartame and the citric acid
are in a powdered form and are present in a container formed from
at least one material selected from the group consisting of
plastic, foil, paper, and combinations thereof.
22. The kit of claim 16, further comprising ascorbic acid or a salt
thereof in a powdered form.
23. The kit of claim 16, further comprising a gelling agent in a
powdered form.
24. The kit of claim 16, further comprising a container in which to
combine the monobasic sodium phosphate, the dibasic sodium
phosphate, the aspartame, and the citric acid with water.
25. The kit of claim 24, further comprising instructions to combine
the monobasic sodium phosphate, the dibasic sodium phosphate, and
the flavorant with water.
26. The kit of claim 24, further comprising at least one anorectal
wipe, the anorectal wipe wetted with an aqueous solution including
a local anesthetic and a skin protectant.
27. A kit for colonic cleansing, comprising: a screw-top jar having
a lid, comprising: two screw-top plastic bottles, each containing
about 45 mL of an aqueous solution, the aqueous solution including
about 21.6 g of monobasic sodium phosphate and about 8.1 g of
dibasic sodium phosphate, two packets, each enclosing from 1 to 6
grams of a powder that comprises aspartame and a citrate, four
envelopes, each enclosing an anorectal wipe, the anorectal wipes
including a substrate wetted with an aqueous solution including an
anesthetic.
28. The kit of claim 27, where the two packets each enclose 2.0
g+/-10% by weight of the flavorant, where the flavorant comprises
aspartame, citrates, and artificial lemon flavoring.
29. A method for colonic cleaning, comprising: administering orally
to a subject an aqueous preparation including monobasic sodium
phosphate, dibasic sodium phosphate, aspartame, and a citrate.
30. The method of claim 29, where from 0.4 to 0.85 grams of
monobasic sodium phosphate and from 0.1 to 0.5 grams of dibasic
sodium phosphate are ingested per kilogram of body weight.
31. The method of claim 29, further comprising administering
additional liquids to the subject.
32. The method of claim 31, where the additional liquids comprise
oral re-hydration salts.
33. The method of claim 29, where the administering is performed
prior to a colonoscopy procedure.
34. The method of claim 29, where the administering is performed
prior to a radiological procedure.
35. The method of claim 29, where the administering is performed
prior to a surgical procedure.
36. The method of claim 29, where the aqueous preparation further
comprises ascorbic acid or a salt thereof.
37. The method of claim 29, where the aqueous preparation further
comprises from 0.25 g/L to 50 g/L of ascorbic acid or a salt
thereof.
38. The method of claim 29, where the aqueous preparation further
comprises a gelling agent.
Description
BACKGROUND
[0001] Colonoscopy screening coupled with polyp removal
(polypectomy) significantly reduces the incidence of colorectal
carcinoma. Unfortunately, of the 147,500 new cases of colorectal
carcinoma diagnosed in 2003, the American Cancer Society estimates
that only 37% of these cases were diagnosed early enough for
treatment to offer the best possible prognosis.
[0002] Colonoscopy screening should be repeated more frequently for
subjects who have previously undergone a polypectomy due to their
increased risk of recurrent polyp formation. However, in a
follow-up phase of the National Polyp Study, at least 20% of
subjects who had previously undergone polypectomies failed to
return for their follow-up screening. In a more recent study, where
8,865 subjects who had previously undergone a polypectomy underwent
a second colonoscopy screening, 2,704 (30.5%) were diagnosed with
recurrent polyps. A statistical analysis based on the data from
this report projected that 50% of subjects will have recurrent
polyps within 7.6 years. Despite this level of risk, many subjects
do not undergo additional screening.
[0003] Prior to colonoscopy, including virtual colonoscopy
procedures, the colon must be cleansed so the surgeon may see any
polyps that exist on the interior wall of the colon. Furthermore,
the colon also must be cleansed before radiological or surgical
procedures involving the colon. This cleansing generally entails
the drinking of one or more laxative solutions. Aqueous solutions
of sodium phosphate salts (monobasic and dibasic sodium phosphate),
such as FLEET.RTM. PHOSPHO-SODA.RTM., are very effective oral
laxatives and are extensively used prior to colonoscopy,
radiographic procedures, and surgery. For pre-colonoscopy use, a
split regimen is often preferred that includes one 45 mL dose given
the evening before colonoscopy and a second 45 mL dose given at
least three hours prior to the procedure on the following
morning.
[0004] One of the main reasons subjects cite for avoiding
colonoscopy re-screening is the unpleasant taste of these phosphate
based laxative solutions. Depending on the study, from 15 to 51% of
the subjects report discomfort in the form of nausea and vomiting.
The extremely salty taste of the laxative solution is believed to
be the cause of this discomfort. Frequently, subjects cannot
tolerate the ingestion of the complete initial dose of the
preparation, which often prevents them from consuming more than a
small portion of the second dose.
[0005] Thus, there is an ongoing need for better tasting laxative
solutions suitable for pre-colonoscopy colon cleansing. A better
tasting pre-colonoscopy laxative could increase subject compliance
with re-screening appointments. This increased compliance regarding
consumption of the laxative solution could reduce the need for
repeat procedures attributable to inadequate colon cleansing. The
materials and methods of the present invention provide phosphate
salt laxatives that are significantly more palatable than
conventional phosphate salt laxatives.
SUMMARY
[0006] Colonoscopy screening coupled with polyp removal
significantly reduces the incidence of colon cancer. Prior to
colonoscopy, the colon must be cleansed so the surgeon may see any
polyps that exist on the interior wall of the colon. Aqueous
solutions of sodium phosphate salts, such as FLEET.RTM.
PHOSPHO-SODA.RTM., are very effective oral laxatives and are
extensively used prior to colonoscopy. One of the main reasons
subjects cite for avoiding colonoscopy re-screening is the
unpleasant taste of these phosphate salt based laxative
solutions.
[0007] The present invention makes use of the discovery that adding
a flavorant that includes aspartame and a citrate, such as citric
acid and citrate salts, such as sodium and potassium citrate, to a
phosphate salt laxative significantly increases the palatability of
the laxative. The resultant flavorant/phosphate salt formulations
may increase the subject's willingness to consume the laxative,
thus decreasing the repeat rate for initial colonoscopy procedures
attributed to incomplete colon cleansing and increasing the
subject's willingness to undergo follow-up procedures.
[0008] In a first aspect, the invention is a composition for
colonic cleansing that may include a phosphate salt and a flavorant
that comprises aspartame and a citrate.
[0009] In a second aspect, the invention is a kit for colonic
cleansing that may include monobasic sodium phosphate, dibasic
sodium phosphate, aspartame, and a citrate.
[0010] In a third aspect, the invention is a method of colonic
cleansing that may include administering orally to a subject an
aqueous preparation including monobasic sodium phosphate, dibasic
sodium phosphate, aspartame, and a citrate.
[0011] The scope of the present invention is defined solely by the
appended claims, and is not affected to any degree by the
statements within this summary.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The invention can be better understood with reference to the
following drawings and description. The components in the figures
are not necessarily to scale, emphasis instead being placed upon
illustrating the principles of the invention. Moreover, in the
figures, like referenced numerals designate corresponding parts
throughout the different views.
[0013] FIG. 1 depicts a cut-away view of a colonic cleansing kit
having aspects of the present invention.
[0014] FIGS. 2A-2D depict individual components that may be found
in a colonic cleansing kit having aspects of the present
invention.
DETAILED DESCRIPTION
[0015] The present invention makes use of the discovery that adding
a flavorant that includes aspartame and a citrate to a phosphate
salt laxative significantly increases the palatability of the
laxative. The resultant flavorant/phosphate salt formulations may
improve subject compliance for both primary screening of
asymptomatic colorectal carcinoma, and for return surveillance in
those subjects who may benefit from more frequent colonoscopy. The
discovery that flavorants that include aspartame and a citrate are
substantially preferred in comparison to other flavoring regimes
was unexpected.
[0016] Phosphate salt laxatives, such as commercially available
FLEET.RTM. PHOSPHO-SODA.RTM. (C.B. Fleet, Lynchburg, Va.; National
Formulary Monograph USP 23/NF18, p. 1430), include monobasic sodium
phosphate (sodium dihydrogen phosphate, monohydrate)
(NaH.sub.2PO.sub.4.H.sub.2O) and dibasic sodium phosphate (disodium
hydrogen phosphate, heptahydrate) (Na.sub.2HPO.sub.4.7H.sub.2O) in
water. In one aspect, the phosphate salt laxative includes from
0.05 to 1.5 gram/mL of monobasic sodium phosphate and from 0.02 to
0.6 gram/mL of dibasic sodium phosphate. Phosphate salt laxatives
have a pH from about 4.4 to about 5.2 and may be produced in
multiple ways, such as by combining phosphoric acid with dibasic
sodium phosphate or with caustic soda. Laxatives of this type are
very stable, thus having a long shelf-life, and are considered to
work in a mild and very effective manner.
[0017] In another aspect, the phosphate salt laxative includes from
0.25 to 1 or from 0.4 to 1 gram/mL of monobasic sodium phosphate
and from 0.1 to 0.4 or from 0.13 to 0.25 gram/mL of dibasic sodium
phosphate. At present, an especially preferred phosphate salt
laxative includes about 0.48 g/mL of monobasic sodium phosphate and
about 0.18 g/mL of dibasic sodium phosphate. Phosphate salt
laxatives that include one phosphate salt, such as dibasic sodium
phosphate, also may be used.
[0018] In addition to a water solution, the phosphate salt laxative
may be incorporated into a gel. For example, an aqueous solution
containing the phosphate salts may be combined with a gelling agent
to form a gel. Suitable gelling agents may include gelatin, such as
Gelatin, Type A, 25 Bloom, 50 mesh, from Great Lakes Gelatin, PO
Box 917, Grayslake, Ill.; agar, such as Sigma brand Agar A-7002 Lot
71K0093; commercially available products that includes flavorings,
such a JELL-O.RTM. brand desert mix, and the like. In one aspect,
about 85 grams of JELL-O.RTM. may be boiled in about 130 mL of
water and combined with a near-boiling solution containing 45 mL of
FLEET.RTM. PHOSPHO-SODA.RTM. diluted with about 65 mL of water and
the flavorant. Additional details regarding the incorporation of a
phosphate salt laxative into a gel may be found in U.S. Pat. App.
20040071779 A1.
[0019] Prior to consumption, the flavorant may be added to the
phosphate salt laxative to increase its palatability. The flavorant
includes aspartame and a citrate. The citrate may include citric
acid, salts, such as sodium or potassium citrate, derivatives of
citrate, such as a citrate derivatized with ester functionality,
and the like. The flavorant also may include natural and/or
artificial flavorings, such as natural and/or artificial fruit
flavors, to further increase the palatability of the laxative.
[0020] The flavorant may be in the form of a commercially available
aspartame-based drink mixture. One such product is CRYSTAL
LIGHT.RTM. powder available from Kraft Foods, Northfield, Ill.
CRYSTAL LIGHT.RTM. powder includes aspartame, citric acid, and
fruit flavors that result in various drink flavors when the powder
is combined with water. For example, lemonade flavored CRYSTAL
LIGHT.RTM. powder includes citric acid, potassium citrate,
aspartame, maltodextrin, magnesium oxide, natural flavor,
acesulfame potassium, lemon juice solids, artificial color, yellow
5 lake, and BHA.
[0021] At present, CRYSTAL LIGHT.RTM. powder may be obtained that
will make various drink flavors, including pink lemonade, lemonade,
orange, tangerine-strawberry, raspberry-peach, and raspberry ice.
Other drink favors, such as raspberry lemonade, raspberry,
strawberry-kiwi, strawberry-orange-banana, pineapple-orange, and
grapefruit also may be used as flavorants. At present, Pink
Lemonade CRYSTAL LIGHT.RTM. powder is an especially preferred
flavorant for combination with the phosphate salt laxative. Less
preferred flavorants include natural sugars that may be digested,
especially when the natural sugars are present in significant
amounts. Digestion of such natural sugars may lead to hydrogen gas
formation in the colon that can ignite during polypectomy.
[0022] Preferable compositions may include from 15 to 75 mL, from
30 to 60 mL, or from 40 to 50 mL of phosphate salt laxative in
combination with from 1 to 10 grams, from 2 to 6 grams, or from 4
to 5 grams of CRYSTAL LIGHT.RTM. drink mix. The composition also
may include from 240 to 480 mL, from 300 to 420 mL, or from 270 to
450 mL of water. At present, an especially preferred composition
includes about 45 mL of a phosphate salt laxative that includes
about 0.48 g/mL of monobasic sodium phosphate and about 0.18 g/mL
of dibasic sodium phosphate, about 4.4 g of CRYSTAL LIGHT.RTM. Pink
Lemonade powder, and about 360 mL of water.
[0023] In another aspect, the flavorant may be in the form of a
reduced-filler aspartame-based mixture. In relation to a
commercially available aspartame-based drink mixture, such as
CRYSTAL LIGHT.RTM., a reduced-filler aspartame-based mixture has a
reduced amount of maltodextrin. Preferably, the reduced-filler
mixture also contains less natural flavoring and flowability
enhancers than commercially available drink mixtures. By reducing
the amount of maltodextrin, natural flavoring, and the like, the
amount of flavorant added to increase the palatability of the
phosphate salt laxative may be reduced.
[0024] A preferable reduced-filler flavorant includes aspartame,
citrates, artificial lemon flavoring, and plant extract. At
present, an especially preferred plant extract for use in a
reduced-filler flavorant is available from WILD Flavors, Inc.,
Erlanger, Ky. and is referred to as RESOLVER.RTM.. It is believed
that the plant extracts in RESOLVER.RTM.occupy the receptors on the
tongue that are responsible for bitter tastes, thus neutralizing
the otherwise bitter aspects of the flavorant and/or the phosphate
salt laxative.
[0025] In one aspect, from 1 to 3 grams, preferably about 2 grams
of the reduced-filler aspartame-based mixture is added to 40 to 50
mL of the phosphate salt laxative. At present, an especially
preferred composition includes about 45 mL of a phosphate salt
laxative that includes about 0.48 g/mL of monobasic sodium
phosphate and about 0.18 g/mL of dibasic sodium phosphate, 2.0
g+/-100% by weight of the reduced-filler aspartame-based mixture,
and about 360 mL of water.
[0026] In one aspect, the phosphate salts and the flavorant are
provided as dry powders that are mixed with water before
administration to a subject. In another aspect, the phosphate salts
are provided in water and mixed with the powdered flavorant. In
another aspect, the phosphate salts and the flavorant are each
provided in separate solutions, which are mixed before
administration. If a gelling agent is used, the phosphate salts and
the flavorant may be incorporated into the gel. In a preferred
aspect, a kit is provided that includes a water-based composition
including the phosphate salts that is mixed with the powdered
flavorant before administration. In this aspect, the powdered
flavorant also may include a powdered gelling agent. Additional
water also may be added to the formulation.
[0027] The composition also may include ascorbic acid or a salt
thereof. Due to the poor stability of ascorbic acid in solution,
the ascorbic acid may be separately packaged and added to the
phosphate salt laxative before use. In a preferred aspect, when the
flavorant is packaged as a dry powder, the ascorbic acid may be
packaged as a dry powder with the flavorant. When packaged as a dry
powder, such as with the flavorant, the ascorbic acid may be coated
to improve its stability. Suitable coatings include silicone, ethyl
cellulose, and the like. In one aspect, enough ascorbic acid is
added to provide a pre-administration solution concentration of
from 0.25 to 50 g/L or from 1 to 25 g/L. Additional details
regarding the use of ascorbic acid in laxative preparations may be
found in U.S. Pat. No. 5,274,001.
[0028] FIG. 1 depicts a cut-away view of a colonic cleansing kit
100 having aspects of the present invention. The kit 100 includes
an exterior package 110, one or more plastic containers 120, and
one or more envelope containers 130 and 140. The exterior package
110 may have paper and/or plastic components. The exterior package
110 may enclose multiple containers, such as containers 120, 130,
and 140, one or more supporting structures for the multiple
containers, usually having paper and/or plastic components,
instructions for use, and the like. The supporting structures may
be formed from stiff paper, STYROFOAM.TM., and the like.
[0029] FIGS. 2A-2D depict the individual components that may be
found in the colonic cleansing kit 100. As shown in FIG. 2A, the
exterior package 110, may take the form of a plastic jar 112 having
a removable screw-type lid 114. The diameter of the jar 112 may be
about 8 cm. The diameter of the lid 112 may allow attachment to the
jar 112.
[0030] FIGS. 2B-2D depict various types of containers that may be
included in the colonic cleansing kit 100. The containers may take
the form of bottles, tubs, sachets, envelopes, tubes, ampoules, and
the like, which may be formed in part or in whole from plastic,
glass, paper, foil, MYLAR.RTM., wax, and the like. The containers
may be equipped with fully or partially detachable lids that may
initially be part of the containers or may be affixed to the
containers by mechanical, adhesive, or other means.
[0031] FIG. 2B depicts two plastic bottles 120 having screw-top
lids 122, each containing about 45 mL of FLEET.RTM.
PHOSPHO-SODA.RTM. liquid 124. FIG. 2C depicts two packets 130 made
from foil-lined paper 132 that enclose the flavorant (not shown).
The packets 130 may be rectangular in shape, having a width of
about 4.1 to about 4.4 centimeters (cm) and a length of about 6.3
to about 7.6 cm. FIG. 2D depicts separate foil-lined paper
envelopes 140 enclosing anorectal wipes 142. The anorectal wipes
142 may be in the form of pads and the like, such as FLEET.RTM.
Pain-Relief Pre-Moistened anorectal pads. In one aspect, four
individually wrapped wipes are preferred. The anorectal wipes 142
may be rectangular in shape, having dimensions of about 4 cm by
about 7 cm.
[0032] The anorectal wipes 142 may be made from any suitable
substrate, such as cloth, paper, or combinations thereof, and may
be wetted with an aqueous solution that may include one or more
active ingredients, such as a local anesthetic (Pramoxine
Hydrochloride, for example) and a protectant (Glycerin, for
example). The aqueous solution also may include one or more
inactive ingredients, such as cetylpyridinium chloride, citric
acid, disodium EDTA, eucalyptol, menthol, octoxynol-9, sodium
benzoate, and sodium citrate.
[0033] The exterior package 110 of the kit 100 also may enclose an
instruction sheet (not shown) that includes directions regarding
when to consume the colonic cleansing composition in relation to
the time of a colonoscopy procedure, how to combine the FLEET.RTM.
PHOSPHO-SODA.RTM. liquid with the flavorant to form the colonic
cleansing composition, and how to apply the relief wipes to provide
the desired soothing effect.
[0034] By orally administering the compositions of the present
invention to a subject, the colon may be cleansed. Generally, the
compositions are administered so that from 0.4 to 0.85 grams of
monobasic sodium phosphate and from 0.1 to 0.5 grams of dibasic
sodium phosphate per kilogram of body weight are consumed. A first
aliquot of the composition may be administered to the subject about
14 hours prior to the colonoscopy. This initial dose may be
followed by a second aliquot of the composition administered about
3 hours prior to the colonoscopy. The subject should consume large
amounts of liquids, 3 to 4 Liters for example, in addition to the
composition to maintain adequate hydration. These additional
liquids may include aqueous solutions that include oral
re-hydration salts and/or electrolytes, such as GATORADE.RTM. and
other oral re-hydration beverages.
[0035] In the examples below, it was unexpectedly discovered that
subjects significantly preferred phosphate salt laxatives combined
with the flavorant that included aspartame and citric acid in
relation to other attempts to mask the taste of the laxative. The
data below demonstrated that an aspartame and citrate containing
flavorant proved superior at improving the palatability of a
phosphate salt laxative. Furthermore, the aspartame containing
flavorant significantly reduced the incidence of adverse events,
including anal irritation and abdominal cramps, in relation to
other flavoring regimes.
EXAMPLES
[0036] A study was undertaken to evaluate the preference,
tolerance, and palatability of FLEET.RTM. PHOSPHO-SODA.RTM.
laxative preparation flavored with flavoring regimes A through D in
multiple subjects. Each 45 mL portion of FLEET.RTM.
PHOSPHO-SODA.RTM. laxative included about 21.6 g of monobasic
sodium phosphate (monohydrate) and about 8.1 g of dibasic sodium
phosphate (heptahydrate). Flavoring regimes A through D are
summarized as follows:
[0037] (A) FLEET.RTM. PHOSPHO-SODA.RTM. (45 mL) and ginger-lemon
flavor in 720 mL of ginger ale (SCHWEPPES.RTM.). The resultant
solution was split into three 8 oz. portions that were consumed 10
minutes apart.
[0038] (B) FLEET.RTM. PHOSPHO-SODA.RTM. (45 mL) and cola flavor in
360 mL of cold water. The resultant solution was consumed at
once.
[0039] (C) FLEET.RTM. PHOSPHO-SODA.RTM. (45 mL) and ginger-lemon
flavor in 120 mL of cold water. The resultant solution was consumed
at once.
[0040] (D) FLEET.RTM. PHOSPHO-SODA.RTM. (45 mL) and CRYSTAL
LIGHT.RTM. Pink Lemonade flavorant (.about.4.42 g) in 360 mL of
cold water. The resultant solution was consumed at once.
[0041] Description of Study and Preparation Regimens.
[0042] The study employed a randomized, single-blind, balanced
incomplete block (BIB) design for sequence (order of
administration) and gender. Adult men and women who were scheduled
to undergo colonoscopy were randomly given one of the flavoring
regimes A through D at approximately 7:00 pm on the evening before
the colonoscopy. A second, but different, flavoring regime A
through D was given to the subject on the following morning,
approximately 10-12 hours after the first dose and approximately 3
hours before the colonoscopy. For example, a single subject could
receive flavoring regime A on the night before the procedure and
flavoring regime B on the morning of the procedure to generate an
"AB" preparation regimen.
[0043] Each of 72 subjects was randomly assigned to one of the
twelve possible flavoring regimens (AB, BA, CB, BC, AD, DA, CD, DC,
DB, BD, AC, and CA). This was accomplished by assigning each
subject the next available flavoring regime depending on the
subject's gender, based on the order in which they completed the
screening evaluations; and then assigning the subject to the
corresponding regimen from the randomization list. Two
randomization lists were used, one for males and one for females,
to assure balance of genders across the 12 treatment groups in the
study.
[0044] The physician performing the colonoscopy procedure did not
know which flavoring regimes had been given to each subject and the
subjects were instructed not to discuss their preparation regimen
with the physician. Each subject also was asked to consume
additional clear fluids to assure adequate hydration.
[0045] The subjects completed a questionnaire to evaluate their
acceptance, the tolerability, and the palatability of each
flavoring regime after each of the two doses. After the morning
flavoring regime was consumed, each subject also was asked
questions regarding their preferences for the two flavor regimens
they had experienced. These questions were directed preference
questions, and also an open-ended question for the subjects to
describe their experience.
[0046] Results and Evaluation.
[0047] Table 1 below illustrates the number of subjects that
underwent each flavoring regimen (Total) and their overall
preference rating (no preference between the morning and evening
regimen, some preference for the morning or the evening regimen, or
a large preference for the morning or the evening regimen),
depending on when they were given the flavoring regimen. Generally,
for pairs of flavoring regimens, preference ratings were similar
regardless of which flavor was given first. All subjects who
received the D regimen (FLEET.RTM. PHOSPHO-SODA.RTM. and CRYSTAL
LIGHT.RTM. Pink Lemonade as a flavorant) expressed a preference for
this regimen over all other regimens, regardless of their
respective flavors. TABLE-US-00001 TABLE 1 Morning Regimen Evening
Regimen Preparation Large Some No Some Large Total Preference
Regimen Preference Preference Preference Preference Preference
Subjects Indication AB 3 1 1 1 0 6 A.about.B BA 0 3 0 2 1 6 CB 0 1
1 1 3 6 B > C BC 3 1 1 1 0 6 AD 1 0 2 1 2 6 D > A DA 4 0 0 1
1 6 CD 0 1 0 4 2 7 D >> C DC 5 0 0 0 1 6 DB 4 0 2 0 0 6 D
> B BD 0 1 1 1 3 6 AC 3 0 1 2 0 6 A > C CA 1 1 1 1 2 6 Totals
24 9 10 15 15 73
[0048] Analysis of Items Relating to Adverse Events.
[0049] A linear model based on perceived intensity score was
utilized to analyze each adverse event. Each event was scored twice
by the subject, once in the evening and once in the morning, using
the assigned flavoring regimen. The model had gender, flavor
regimen, and time of administration as the factors. Models were
tested for interactions, but the p-values were above the specified
0.10 level of significance; thus, the interaction terms were
deleted and the models repeated with only the main effect
terms.
[0050] The least squares means are presented below in Table 2 for
each adverse event, in addition to the standard deviations and
p-values by gender, flavoring regime, and time of administration.
The table shows that adverse events were scored worse by females
than by males. Furthermore, abdominal cramps, abdominal bloating,
and indigestion were more intense during the evening administration
than during the morning administration, while weakness/faint
feeling, and thirst/dry mouth were worse during the morning.
TABLE-US-00002 TABLE 2 Time of Adverse Gender Administration Gender
Flavor Time Event Male Female PM AM Std Err p-value p-value p-value
Nausea 0.26 0.67 0.42 0.52 0.05 0.0056 0.8215 0.2602 Abdominal 0.52
0.55 0.73 0.34 0.05 0.6594 0.5119 <0.0001 Bloating Abdominal
0.30 0.52 0.57 0.25 0.05 0.0540 0.0545 <0.0001 Cramps Anal 0.45
0.96 0.66 0.75 0.07 0.0052 0.0195 0.3555 Irritation Weakness/ 0.13
0.24 0.06 0.30 0.04 0.1716 0.9195 0.0001 Faint feeling Chills 0.22
0.30 0.27 0.25 0.04 0.5257 0.2420 0.6876 Headache 0.15 0.37 0.20
0.32 0.05 0.0865 0.9520 0.1262 Thirst/Dry 0.24 0.33 0.18 0.38 0.05
0.3696 0.1591 0.0054 Mouth Indigestion 0.14 0.37 0.36 0.15 0.04
0.0173 0.5971 0.0014
[0051] The adverse event least square means for each of flavor
regimes A through D are presented below in Table 3. The intensity
of the adverse events were scored as 0=none, 1=mild, 2=moderate,
and 3=severe. Surprisingly, flavor regimen was significantly
related to anal irritation and abdominal cramping. Flavor regime D
(FLEET.RTM. PHOSPHO-SODA.RTM. and CRYSTAL LIGHT.RTM. Pink Lemonade
flavorant) showed from 34% to 53% less irritation than the other
flavor regimes. Flavor regime D also showed from 60% to 54% less
abdominal cramping than the other flavoring regimes. Furthermore,
the intensity of abdominal bloating, weakness/faint feeling, and
chills was also perceived to be lower by the subjects when using
flavoring regimen D. TABLE-US-00003 TABLE 3 Adverse Flavor Regimen
Event A B C D Std Error Nausea 0.47 0.41 0.47 0.53 0.15 Abdominal
0.60 0.55 0.57 0.43 0.09 Bloating Abdominal 0.49 0.44 0.50 0.20
0.09 Cramps Anal 0.80 0.94 0.67 0.44 0.11 Irritation Weakness/ 0.21
0.18 0.21 0.14 0.07 Faint feeling Chills 0.22 0.30 0.36 0.16 0.07
Headache 0.24 0.30 0.24 0.26 0.08 Thirst/ 0.18 0.19 0.42 0.34 0.08
Dry Mouth Indigestion 0.31 0.21 0.19 0.30 0.07
[0052] While various embodiments of the invention have been
described, it will be apparent to those of ordinary skill in the
art that other embodiments and implementations are possible within
the scope of the invention. Accordingly, the invention is not to be
restricted except in light of the attached claims and their
equivalents
* * * * *