Note: Descriptions are shown in the official language in which they were submitted.
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EFFERVESCENT LAXATIVES
Field of the Invention:
The present invention is directed to a novel over-the-counter (OTC) laxative
as an
improved, replacement therapy to current stimulant laxatives.
Background of the Invention:
to Within the next 2 to 3 years, the Food and Drug Administration (FDA)
appears likely
to discontinue OTC approval of several current stimulant laxatives. Over the
last
decade, positive carcinogenicity and/or genotoxicity results have resulted in
FDA
banning danthron (mid-1980's) and in 1997, the FDA delisted phenolphthalein as
an
OTC laxative due to safety issues.
Specifically, in June 1998, the FDA has continued to pressure the OTC
stimulant
laxative category, reclassifying remaining approved stimulants: senna,
cascara, aloe,
bisacodyl, from Category I (safe and effective) to Category III (more data
needed), and
requiring manufacturers to provide updated carcinogenicity and genotoxicity
2o evaluations for these laxative actives. Failure to meet this mandate,
and/or prove
safety will result in further delisting of laxative actives from the tentative
final
monographs (TFM), (Fed. Reg. 63: 33592-33595, June 19, 1998). Indeed, in a
recent
review of scientific literature, van Gorkom et al., concluded that anthranoid
laxatives,
which include the active moieties in senna extracts, and the chemical
laxatives
phenolphthalein bisacodyl, can have a potential role in both promotion and
initiation
of tumorgenesis, and may be associated with increased risk for colorectal
cancer (van
Gorkom, B.A.P.; de Vries, E.G.E.; Karrenbeld, A.; Kleibeuker, J.H. Anthranoid
laxatives and their potential carcinogenic effects. Alimentary Pharmacology &
Therapeutics, Vol. 13: pp. 443-452, 1999. Hence the potential for further
delistings
3o are strong.
Hence, there is a strong potential for dramatic change to this segment of the
OTC
laxative market over the next several years. If the events which followed the
FDA
action to ban phenolphthalein recur, any FDA action will be followed by
similar
delisting in other countries.
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While bulk fiber products, such as Metamucil~ and Citrucel~, are presently
available,
a large number of individuals have found that these products have unacceptable
product aesthetics (e.g., taste, viscosity, volume etc). Therefore new
alternative
therapies to these bulk fiber laxatives based on ease of use and aesthetic
properties are
desired.
One group of the newer alternative therapies for bowel cleansing prior to
colonoscopic
exam or GI surgery are the prescription isosmotic bowel evacuant solutions,
such as
Golytely~ and Nulytely~ (Braintree Labs, Braintree, MA, USA). Similar
prescription
products are marketed in the US by Colyte~ by Schwarz Pharma, and in Europe an
osmotic laxative by Movicol~ (Norgine, Lmtd., Middlesex, UK). Recently, a new
laxative containing only polyethylene glycol 3350 NF, has also been introduced
in the
US (Miralax~, Braintree Labs, Braintree, MA, USA), where it is available only
by
prescription.
All of these products contain polyethylene glycol (PEG) as the active
ingredient. In
most products, the PEG is mixed with various salts to provide a laxative
action with
osmotic balance. This is required when the products are used in the high
volumes (2-4
L) required for colonic purgation and cleansing. In high volume these PEG-
containing
agents provide excellent colonic cleansing prior to GI surgical or
colonoscopic
procedures. They neither stimulate water and electrolyte secretion into the GI
tract,
nor do the products result in significant water and electrolyte absorption;
essentially,
the volume of ingested liquid simply passes through the GI tract. For this
indicated
usage as a bowel evacuant, patients are instructed to drink 2 to 4 liters over
several
hours.
US Patent 5,710,183, Halow, G., discloses a PEG composition with a fiber
bulking
agent for clinical treatment of constipation and/or diarrhea.
3o US 5,124,144, Castagnola et al., discloses what is a PEG/electrolyte
product for use as
a cathartic laxative.
WO 87/00754, Fordtran, J., discloses a low-sodium laxative and lavage solution
containing PEG with various electrolytes added such as sodium, potassium,
chloride
and bicarbonate.
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DE 3807712, Deyhle et al., discloses a laxative formulation also containing
electrolytes, PEG, alkali hydrogen carbonate and citric acid.
RU 2111741, Chumak et al. discloses use of a reduced lavage volume, 2 liters,
of PEG
with an electrolyte solution. The electrolyte mixture contains sodium
bicarbonate and
citric acid which may be in an amount sufficient to provide effervescence.
WO 98/43654, Jacob et al., is directed towards a non-aqueous colonic purgative
containing magnesium salts and potentially polyethylene glycol.
io
JP 4198126 OTSUKA PHARM CO LTD discloses a liquid preparation of PEG and
electrolytes along with oc-aminoacid. for colon irrigation. The oc-amino acids
are used
as antioxidants to stabilize PEG and prevent formation of formaldehyde. This
was an
attributed problem of PEG-based laxatives early in their product life. Use of
the
15 highly purified PEG's today overcome these issues. The levels of product
0.01 °lo
range (0.1 g/L,) are also too low to provide any appreciable effervescence.
Summary of the Invention
The present invention is directed to a pharmaceutical formulation comprising
2o polyethylene glycol (PEG) 3350, and a pharmaceutically acceptable
effervescent
coupling system.
Another aspect of the present invention is a method of administering to a
mammal, an
effective amount of the above noted pharmaceutical formulation for the
treatment of
25 constipation, or for the treatment of fecal impaction, in a mammal in need
thereof.
Detailed Description of the Invention
The present invention is directed towards an effervescent formulation of an
osmotic
bowel evacuant solution, such as a polyethylene glycol based product. These
3o formulations provide for an acceptable level of laxative efficacy, with
superior safety
advantages over current stimulants, which are under FDA review for safety
concerns.
Further, these formulations should be safe and appropriate for use in
pediatric
constipation.
35 The effervescent/PEG osmotic formulation offers an alternative that
provides for a
new, and safe, product as a replacement to the current technologies. The PEG
based
osmotic formulations have proven to be both safe and highly physician
recommended.
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However, an effervescent/PEG based formulation, for use as an OTC laxative
would
require consumption of a much smaller volume, such as one or two 4-8 oz doses
over
a 24 hour period. Several published studies have shown utility of the PEG-
based
technology for use as a laxative with low-volume dosage. E. Corazziari, D.
Badiali,
F.L. Habib, G. Reboa, G. Pitto, G. Mazzacca, F. Sabbatini, R. Galeazzi, Te,
Cilluffo, I.
Vantini, E. Bardelli, F. Baldi. Small volume isosmotic polyethylene glycol
electrolyte
balanced solution (PMF-100) in treatment of chronic nonorganic constipation.
Digestive Diseases & Sciences, Vol. 41: 1636-1642, 1996.
J.A. DiPalma, P.H. deRidder, R.C. Orlando, B. E. Kolts, M.v.B. Cleveland. A
randomized placebo-controlled, multicenter study of the safety and efficacy of
Braintree 851 laxative. Gastroenterology, Vol. 112: A722, 1997.
P. Culbert, H. Gillett, A. Ferguson. Highly effective oral therapy
(polyethylene
glycol/electrolyte solution) for faecal impaction and severe constipation.
Clinical
Drug Investigation, Vol. 16: 355-360, 1998.
A. Attar, M. Lemann, A. Ferguson, M. Halphen, M.-C. Boutron, B. Flourie, E.
Alix,
2o M. Salmeron, F. Guillemot, S. Chaussade, A.-M. Menard, J. Moreau, G.
Naudin, M.
Barthet. Comparison of a low dose polyethylene glycol electrolyte solution
with
lactulose for treatment of chronic constipation. Gut, Vol. 44: 226-230, 1999.
Therefore, one aspect of the present invention is the use of an osmotic acting
composition containing polyethylene-glycol based systems, ( preferably, PEG
3350
NF, or PEG 4000 NF, in combination with an effervescent coupling system, which
is
diluted with a suitable volume of a liquid, such as water, or juice.
The effervescent couple comprises a basic ingredient and an acidic ingredient,
the
3o basic ingredient liberating carbon dioxide when it and the acidic
ingredient are
contacted with added water.
The amount of the effervescent couple is selected at a level sufficient to
cause a "fizzy
reaction" without itself causing discomfort in the patients mouth.
The effervescent couple typically comprises citric acid or sodium hydrogen
citrate and
sodium bicarbonate, but other physiologically acceptable acid/alkaline or
alkaline
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earth metal carbonate mixtures may be used, for example tartaric, adipic,
fumaric or
malic acids, and sodium, potassium or calcium (bi)carbonates or sodium glycine
carbonate.
In general it has been found that preferred taste characteristics are
exhibited when the
relative proportions of the components of the effervescent couple on a
chemical
molecular equivalent basis are in the range of 3:1 to 3:4, more preferably
about 1.4 to
1.9: l, expressed as the ratio of molecular equivalents of the basic component
to the
acidic component, where the basic and acid components are sodium bicarbonate
(NaHC03) and citric acid, respectively. However, it is possible to utilize
much less
bicarbonate and acid than a number of well known effervescent systems. The
examples herein will demonstrate usefulness of high and low levels of
effervescent
coupling reagents. In terms of a preferred combination of sodium bicarbonate
and
citric acid, these values represent on a weight basis, a range from 3:1 to 0.6-
0.8:1,
I S preferably approximately 1:1 expressed as the ratio of basic to acidic
component.
However, in some formulations, the choice of flavouring agents may result in
optimization of taste characteristics when there is an excess of acidic
component, for
example, on a chemical molecular equivalent basis of from about 11:3 to 4:3
expressed as the ratio of acidic to basic component. For the combination of
citric acid
and sodium bicarbonate this may represent 5:1 to 1:1 on a weight basis.
The weight of the acidic component in the formulation may be in the range 7%
to
31%, preferably 9% to 18%, by weight.
The weight of the basic component in the formulation may be in the range 7% to
32%,
preferably 9% to 18%, by weight.
Preferred combinations comprise sodium bicarbonate with citric acid (or sodium
3o hydrogen citrate) or malic acid in a weight ratio of 2: 1 to 1:1.
Other preferred combinations may substitute potassium bicarbonate for part or
all of
the sodium bicarbonate as the basic component of the effervescent couple. To
maintain molecular equivalence, substitution of potassium bicarbonate for
sodium
bicarbonate is at a ratio of approximately 1.2:1. Potassium bicarbonate can be
used
with any of the above acid components.
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The preferred level of the coupling agents, preferably bicarbonate and citrate
for an
effervescence mixture, is about 2.3 gram NaHC03 (sodium bicarbonate) and 2.2
gram citric acid. This dose provides very significant ANC (acid neutralizing
capacity) approximately 20 mEq. However, the levels can be reduced by a factor
of
4-5 and still provide some degree of effervescence (e.g., 0.5 g NaHC03 and 0.4
g
citric acid).
It is recognized that additional excipients may be added to the formulation,
such as
flavouring agents, colouring agents, sweetning agents, antioxidants, and other
well
1 o known agents for stability and packaging considerations.
A preferred PEG for use herein is PEG 3350, a nonabsorbable and inert polymer
of
about 3,000 molecular weight. Generally, the range of PEG 3350 for a 125 to
240
ml reconstitution in liquid will be from a about 5 grams to about 30 gms,
preferably
15 from about 10 to about 20 gms, more preferably 13 to 17 grams. Treatment
may be
once or more daily, up to 4 times daily, but preferably once daily.
In contrast to bulk-fibers, the resulting effervescent/PEG-based formulations
when
made into a liquid dosage, are non-viscous and are optimally be provided to
consumers
2o as either bulk powder, or preferably as single dose powder sachets, for
dissolution in a
suitable liquid, such as water or juice. The product would dissolve rapidly
(within
seconds) and completely, and does not thicken on standing.
Based on volume consumed (e.g., one or two 4-8 oz doses), performance
attributes
25 would be consistent with those presently desired by stimulant laxative
users (rapid
action, clean-out), but without the negative side-effects of cramping and gas,
and
without systemic exposure potentially harmful agents.
The required dosage for use as a laxative may be one which is equivalent to
the
30 "minimally effective dose", i.e., one that requires 2 to 3 days treatment
before
significant effect, having a similar onset and action to the bulk fiber based
laxatives.
Or the dosage could be increased to be equivalent in action to the current
stimulant
based products, having an earlier onset of action (a few hours to overnight).
35 The present invention is useful as primary treatment for both occasional
and chronic
constipation, and for the treatment of fecal impaction (at a higher dose).
Another
aspect of the present invention is the treatment of upper GI symptoms
associated with
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such constipation, such as heartburn or bloating. Suitably, the composition
herein may
also be used for other constipation related disorders, such as irritable bowel
syndrome,
diverticular disease, and hemorrhoids.
METHODS OF PREPARATION
The following examples illustrates the invention but is not intended to limit
the scope
thereof. All parts and percentages are by weight unless otherwise indicated.
EXAMPLE 1
to A preferred example provides as sachet for reconstitution in 240 ml water
for use as
laxative.
PEG S. s
17.0 g polyethylene glycol (PEG) 3350 NF
Effervescent Coupling Rea.eg nts:
1.50 g NaHC03
1.00 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as
a
2o sachet to be added to a 8 ounce glass of water.
EXAMPLE 2
Another preferred examples provides as sachet for reconstitution in 240 ml
water for
use as laxative.
PEG System:
17.0 g polyethylene glycol (PEG) 3350 NF
Effervescent Coupling Rea e~ nts:
2.32 g NaHC03
2.18 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as
a
sachet to be added to a 8 ounce glass of water.
EXAMPLE 3
Another preferred examples provides as sachet for reconstitution in 125 - 180
ml
water for use as laxative.
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PEG System:
13.12 g PEG 3350
0.78 g flavoring ingredients
Effervescent Cowling Rea eg~ nts:
2.32 g NaHC03
2.18 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as
a
sachet to be added to a 4-6 ounce glass of water.
l0
EXAMPLE 4
Another preferred examples provides as sachet for reconstitution in 125 - 180
ml
water for use as laxative.
PEG System:
13.12 g PEG 3350
0.78 g flavoring ingredients
Effervescent Coupling eg nts:
1.50 g NaHC03
1.00 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as
a
sachet to be added to a 4-6 ounce glass of water.
D V A A iTDT D C
Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
PEG S, s
8.5 g PEG 3350
0.06 g flavoring mixture (for flavored product)
3o Effervescent Coupling Rea en~ts:
2.32 g NaHC03
2.18 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as
a
sachet to be added to a 4-6 ounce glass of water.
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EXAMPLE 6
Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
PEG S, s
8.5 g PEG 3350
0.06 g flavoring mixture (for flavored product)
Effervescent Coupling_Reagents:
1.50 g NaHC03
1.00 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as
a
sachet to be added to a 4-6 ounce glass of water.
EXAMPLE 7
Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
PEG System:
13.125 g PEG 3350
Effervescent Coupling Rea eg1 nts:
2.32 g NaHC03
2.18 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as
a
sachet to be added to a 4-6 ounce glass of water.
EXAMPLE 8
Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
PEG System:
13.125 g PEG 3350
Effervescent Coupling Rea eg ntsts:
1.50 g NaHC03
1.00 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as
a
sachet to be added to a 4-6 ounce glass of water.
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EXAMPLE 7
Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
PEG System:
13.125 g PEG 3350
Effervescent Coupling Rea~yents:
2.32 g NaHC03
2.18 g Citric Acid
to
The PEG solution is combined with effervescent coupling system and packaged as
a
sachet to be added to a 4-6 ounce glass of water.
All publications, including but not limited to patents and patent
applications, cited in
this specification are herein incorporated by reference as if each individual
publication
were specifically and individually indicated to be incorporated by reference
herein as
though fully set forth.
The above description fully discloses the invention including preferred
embodiments
thereof. Modifications and improvements of the embodiments specifically
disclosed
herein are within the scope of the following claims. Without further
elaboration, it is
believed that one skilled in the art can, using the preceding description,
utilize the
present invention to its fullest extent. Therefore the Examples herein are to
be
construed as merely illustrative and not a limitation of the scope of the
present
invention in any way. The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows.
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