Note: Descriptions are shown in the official language in which they were submitted.
WO 2011/061519 PCT/GB2010/002164
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Topical Foam Composition
Technical Field
The present invention relates to a topical foam composition of rifaximin
suitable for rectal
administration, its process of manufacturing and its use for the treatment,
prophylaxis, or
maintenance of remission of colonic, anal or rectal dysfunction.
Background and prior art:
Anal disorders including anal fissure, anal ulcer, and acute haemorrhoidal
disease and benign
conditions of the anal canal, are common amongst the subjects of all ages,
races and sexes.
However, these conditions can be problematic to treat and inconvenient if not
painful to
endure. A subject with an anal fissure or ulcer frequently experiences anal
pain and bleeding,
the pain being more pronounced during and after bowel movements.
Haemorrhoids are specialized vascular areas lying subjacent the anal mucosa.
Various therapies have been devised to treat these anal disorders. Typical,
non-surgical
therapy includes bulk laxatives and sitz baths. Sitz baths are helpful because
they induce
relaxation of the anal sphincter mechanism. (Shafik, "Role of warm-water bath
in anorectal
conditions: The thermosphincteric reflex, "J. Clin. Gastroenterol., 16:304-
308, 1993).
Topical anal therapy is also one of the approaches used in an effort to
promote healing, relieve
pain, and reduce swelling and inflammation. Many preparations have been tried
including
those containing local anesthetics, corticosteroids, astringents, antibiotics
and other agents.
Although administration via the peroral route is the most commonly targeted
goal of new drug
and dosage form research and development, oral administration is not always
feasible or
desirable. The potential for oral dosage form development is severely limited
for active agents
that are poorly absorbed in the upper gastrointestinal (GI) tract and unstable
to proteolytic
enzymes. Some agents cause local stomach or upper GI irritation or require
doses in excess of
500 mg. Certain patient populations, notably children, the elderly, and those
with swallowing
WO 2011/061519 PCT/GB2010/002164
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problems, are often difficult to treat with oral tablets and capsules.
Additionally, treatment of
some diseases is best achieved by direct administration near the affected
area, particularly
with diseases involving anorectal tissues. Although oral administration can be
used for drugs
targeted for some of these diseased tissues, exposure of the entire body
compartment to the
administered drug is inefficient and can lead to undesired adverse effects.
Rectal drug administration is amenable, however, to both local and systemic
drug delivery. It
has been effectively utilized to treat local diseases of the anorectal area as
well as to deliver
drugs systemically as an alternative to oral administration. Some advantages
of this targeted
delivery which includes large surface area, ability to bypass first-pass
metabolism, prolonged
residence time makes this route more promising for delivery of locally acting
drugs.
Suppositories, solutions, suspensions, or retention enemas represent some of
the rectal dosage
forms. Of these, liquid preparations have very limited application, largely
due to
inconvenience of use and poor patient compliance. Semi-solid preparations like
gels, foams or
ointments for rectal administration can afford advantages over liquid
formulations because
retention of the dosage form in the rectal cavity reduces patient compliance
problems.
However, none of the formulations available has been convincingly shown to
reduce the
healing time or to reliably ameliorate associated pain and some of the
treatments, such as
Neosporin ointment (which contains three antibiotics Neomycin, Polymyxin B
Sulfate and
Bacitracin Zinc), are very sensitizing. In conclusion, antibiotics have not
been found useful in
treating the diseases. There was a need in the art to provide compositions
useful to reduce
healing time, alleviate pain and promote healing of the affected rectal and
anal tissues.
Rifaximin is a water insoluble, semisynthetic rifamycin-based non-systemic
antibiotic
belonging to the rifamycin class of antibiotics, and has the scientific name
[(2S,16Z,18E,20S,21 S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-
27-
methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-
[1,11,13]trienimino)benzofuro [4,5-e]pyrido[1,2-a]-benzimida-zole-1,15(2H)-
dione,25-
acetate].
WO 2011/061519 PCT/GB2010/002164
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Rifaximin has been described to be endowed with an antibacterial activity
similar to the
activity of rifampin [Venturini A. P. and Marchi E., Chemiotherapia, 5 (4),
257-256, (1986)].
However, its mechanism of action differs from rifampin in that it is not
absorbed through the
systemic route after oral administration [Venturini A. P., Chemotherapy, 29, 1-
3, (1983) and
Cellai L. et al., Chemiotherapia, 3, (6), 373-377, (1984)] due to the
zwitterionic nature of the
compound, which cannot be absorbed by the gastrointestinal tract [Marchi E. et
al., J. Med.
Chem., 28, 960-963, (1985)].
Rifaximin is soluble in alcohol, ethyl acetate, chloroform and toluene. It
exerts its broad-
spectrum antibacterial activity by inhibiting bacterial RNA synthesis in the
gastrointestinal
tract against localized gastrointestinal bacteria that cause infectious
diarrhea, irritable bowel
syndrome, small intestinal anal disease, Crohn's disease, and/or pancreatic
insufficiency.
Rifaximin is licensed by the U.S. Food and Drug Administration to treat
traveler's diarrhea
caused by E. coli.
Rifaximin has low systemic absorption with Cmax of 3.4 ng/mL, Tmax of 0.8
hours and is
moderately bound to plasma proteins (67.5%). It has half-life of 1.8 hours and
is primarily
excreted in feces (97% of administered dose) and 0.32% in the urine.
Rifaximin is not absorbed by the oral route [Venturini A. P., Chemotherapy,
29, 1-3, (1983)]
nor by topical application [Venturini A. P. et al., Drugs Exptl. Clin. Res.,
13, 4, 233-6,
(1987)].
Due to this particular pharmacokinetic behaviour, rifaximin has no toxicity at
a dose of 2000
mg/kg/os, when administered orally in rats, and therefore, on the basis of the
microbiological,
pharmacodynamic and toxicological data, the drug has been used for the
treatment of bacterial
gastroenteritis, neurological symptoms and clinical symptoms of hepatic
encephalopathy and
for the pre-and post-surgical treatment of the gastrointestinal tract [Alvisi
V. et al., J. Int.
Med. Res., 15, 49-56, (1987), Testa R. et al., Drugs Exptl. Clin. Res., 11,
387-392, (1985),
Gruttadauria G. et al., Eur. Rev. Med. Pharm. Sci., 9, 100-105, (1987)].
WO 2011/061519 PCT/GB2010/002164
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Rifaximin is used for the treatment of pathologies caused by non-invasive
strains of
Escherichia coli, a micro-organism which is not able to penetrate into GI
mucosa and
therefore remains in contact with gastrointestinal fluids.
Rifaximin is also approved for the treatment of pathologies whose etiology is
in part or totally
due to intestinal acute and chronic infections sustained by Gram-positive and
Gram-negative
bacteria, with diarrhea syndromes, altered intestinal microbial flora, summer
diarrhea-like
episodes, traveler's diarrhea and enterocolitis; pre- and post- surgery
prophylaxis of the
infective complications in gastro intestinal surgery; and hyperammonaemia
therapy as
coadjutant.
Rifaximin is available in tablets, granules for oral suspension and ointment,
marketed in
Europe and U.S.A. and in many other countries. Tablets, for example are
currently marketed
at the dosage of 200 mg for traveler's diarrhea under the brand name Xifaxan .
Italian Patent 1,154, 655 and in U.S. Pat. No. 4,341,785 both discloses the
compound 4-
desoxy-4'-methyl-pyrido [1'2':1.2] imidazo [5.4-c] rifamycin SV which is
rifaximin.
U.S. Pat. No. 7,045,620 S.p.A. to to Alfa Wassermann and W02006/094662 both
discloses
polymorphic forms of rifaximin.
U.S. Pat. No. 4,341,785 to Marchi et al. discloses imidazo-rifamicyn
derivatives having
antibacterial utility, and the related process for preparing it. The patent
also discloses a
pharmaceutical antibacterial composition and a method of using it to treat
antibacterial
diseases of the gastrointestinal tract.
European Patent No. EP0161534 to Cannata et al. discloses a process for the
synthesis of
pyrido-imidazo rifamycins. The process is described as an improvement over the
'785 patent
to Marchi in that the later process provides unsatisfactory yields from an
industrial point of
view.
WO 2011/061519 PCT/GB2010/002164
European Patent No. EP0858804 to Ferrieri et al. describes use of oral
rifaximin compositions
in the treatment of diarrhea from cryptosporidiosis.
U.S. Pat. No. 5,352,679 to Ferrieri et al. describes use of rifaximin (INN) in
formulations for
5 treatment of gastric dyspepsia caused by Helicobacter pylori bacteria. The
rifaximin
formulations disclosed in the patent are in the form of tablet, capsule, sugar
coated tablet,
granules or syrup for oral administration.
U.S. Pat. Nos. 5,314,904 and 6,140,355 both to Egidio et at. disclose
compositions containing
rifaximin for treatment of vaginal infections.
WO 2007/103448 discloses pharmaceutical preparations comprising an anti-rectal
dysfunction agent and rifaximin. The preferred anti-rectal dysfunction is a
nitric oxide
modulating agent such as nitroglycerin. The examples disclosed in the patent
application are
related to the ointment containing rifaximin and nitroglycerine.
EP-A-0468555 and EP-A-0395329, by Smith Kline & French and FR-A2647344 by
Physiopharm discloses aqueous foam compositions in which the same substance or
mixture of
substances (namely one or more chlorofluorocarbons) is used as both a foaming
agent and a
propellant for expulsion of the composition out of a conventional aerosol can.
However, there is little disclosure in the prior art about the topical
formulations of rifaximin
which are capable of providing the desired effect.
It is known that topical treatment of infections or disturbances of the colon
or rectum is more
preferred than oral route, as the formulation is directly applied to the site
of action and hence
rapidly reaches and acts on the point at which the disturbance is located.
According to the state of the art, topical delivery of active agents is
achieved preferably by
rectal administration using suppositories, enemas, ointments, creams and foam.
Of these the
suppository is the most common one. The suppository base is generally a fat
but also water-
WO 2011/061519 PCT/GB2010/002164
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soluble or water-miscible bases are utilized. To obtain a good bioavailability
the active
ingredient should come into contact with the rectal or colonic mucosa.
Ointments and creams often do not create an environment for promoting
respiration of the
wound tissue and it is not favorable to the normal respiration of the skin.
Moreover, there may
be likelihood of experiencing pain and irritation during the application of
ointments and
creams, particularly to abraded, wounded or inflamed mucosa of the rectum or
colon.
Aqueous foamable preparations are the less common of the rectal preparation
forms. They
require a relatively complicated manufacture as well as complicated packaging
compared with
suppositories and enema. However, since better spreading effects are obtained
with enema
and foams than with suppositories more distal intestine regions can be reached
thereby.
Although the delivery of active ingredient using foam can provide various
advantages as
compared to the other topical delivery forms such as better spreading in the
surrounding
tissues, rectal foams are complicated formulations which may not form under
arbitrary
circumstances because it requires a special balance between the foam-forming
components.
Slight shifts in the composition may result in a collapse of the foam or
alternatively the foam
is not formed at all, especially when administration is to occur via an
applicator nozzle with
small diameter. Most foam dosage forms for rectal delivery have incorporated
corticosteroids
to date, although some products have also been used to deliver antiseptics,
antifungal agents,
anti-inflammatory agents, local anesthetic agents, skin emollients, and
protectants (American
Journal of Drug Delivery, 2003, vol. 1(1), pp. 71-75). However, only a few are
commercially
available as yet.
Conventional foams for rectal or vaginal administration are filled in
pressurized containers
with a pharmaceutically active ingredient dissolved or suspended in a liquid
vehicle, at least
one propellant gas and a surfactant with foaming properties. Examples based on
mesalazine,
peppermint, sucralfate or budesonide as the active ingredient dispersed in a
liquid vehicle
containing a foaming surfactant and administered for topical action in the
colon using a
pressurised atomiser with a propellant gas are described in EP-A-468 555.
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Because of the hydrophobic nature of rifaximin, it is virtually insoluble in
water but is readily
soluble in alcohols. An adequate amount of active substance can be dissolved
by the use of
solubilizers such as organic solvents, water-soluble alcohols. However the
formulations if
prepared in this way; may remain stable over a short period because large
amounts of the
active substance are decomposed within a short time.
Because of this problem, topical rifaximin formulations which can be used
directly by the
patient in the administration form ready for use have remained challenging.
The suitable
compositions of rifaximin suggested in the prior art are ointment and vaginal
foam. The
ointment is not in the form of ready to use, but can be prepared by a
cumbersome process of
crushing the rifaximin tablet in suitable oily vehicle and admixing this
mixture with ointment
base prior to the application. Moreover, the vaginal foam when formulated may
also not
remain stable when provided in compressed gas packs.
Thus, there exists a need to develop a topical foam composition of rifaximin
suitable for rectal
administration, useful to reduce healing time, alleviate pain and promote
healing of the
affected rectal and anal tissues which also remains stable over the storage
period.
However, there are problems in producing an effective stable rifaximin
composition, suitable
for rectal administration, in either an aqueous and/or non-aqueous vehicle.
Object
An object of the present invention is to provide a topical foam composition of
rifaximin
suitable for rectal administration. It is a particular object to provide
effective formulations
having either an aqueous and/or a non-aqueous vehicle.
Another object of the present invention is to provide a topical foam
composition of rifaximin
having better spreading effect.
Yet another object of the present invention is to provide a topical foam
composition of
rifaximin which remains stable over the storage period.
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Yet another object of the present invention is to provide a method of
manufacturing the
topical pharmaceutical composition of rifaximin suitable for rectal
administration.
Still another object of the present invention is to provide is to provide a
method of treating,
prophylaxis, or maintenance of remission of colonic or rectal dysfunction by
administering
the topical foam composition of rifaximin to patients in need thereof.
A further another object of the present invention is to provide a topical foam
composition of
rifaximin for rectal administration which remains effective even after
intestinal evacuation by
the subject treated.
Summary
According to the first aspect of the present invention there is provided a
topical foam
composition of rifaximin for rectal administration.
According to a further aspect there is provided a topical foam composition of
rifaximin for
rectal administration comprising one or more pharmaceutical excipients or
carriers such as at
least one surfactant and at least one propellant or mixtures thereof.
According to a further aspect there is provided a process of manufacturing the
said topical
foam composition of rifaximin.
According to a further aspect there is provided a topical foam composition of
rifaximin for
use in the preparation of a medicament suitable for administering to the
rectum, colon and/or
terminal ileum of a patient for the treatment, prophylaxis, or maintenance of
remission of
colonic or rectal dysfunction.
According to yet another aspect there is provided a method of treating,
preventing, or
alleviating an anal disorder comprising administering the topical foam of
rifaximin to a
subject in need thereof.
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Detailed description
As discussed above, there is a need to develop a topical foam composition of
rifaximin
suitable for rectal administration.
The present inventors have developed a topical foam composition of rifaximin
which may
achieve the aforesaid objectives and which also exhibit a topical anti-
infective action.
Surprisingly, the present inventors have found that by utilizing appropriate
combination of
pharmaceutical excipients or carriers it is possible to achieve a topical
pharmaceutical
composition of rifaximin suitable for rectal administration and achieve the
aforesaid
objectives. Specifically, the inventor shave found a way to formulate
rifaximin as a topical
foam composition by means of either an aqueous and/or non-aqueous vehicle.
In particular, by use of a specific ratio of water soluble alkanols to water
in topical foam
composition comprising rifaximin, it remains stable over the storage period.
The ratio of
water soluble alkanol to water is preferably from about 0.05:10 to 10: 0.05,
on a weight basis.
Pharmaceutically acceptable water soluble alkanols which are suitable for use
in the present
invention may be selected from, but not limited to ethanol, polyalcohols such
as a propylene
glycol, glycerol, polyethyleneglycol, polypropylene glycol, propylene glycol
glyceryl esters
or mixtures thereof.
As used herein, the term `rifaximin' is used throughout the description in
broad sense to
include not only rifaximin per se but also its pharmaceutically acceptable
salts,
pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers,
pharmaceutically acceptable derivatives, pharmaceutically acceptable
polymorphs or
pharmaceutically acceptable prodrugs thereof Rifaximin used may also be in
Polymorphic
form or amorphous form. Examples of polymorhic forms of rifaximin include, but
not limited
to polymorph [alpha], polymorph [beta], polymorph [gamma], polymorph [delta],
and
polymorph e of rifaximin, as described in U.S. Patent Application Ser. No.
10/728,090, U.S.
WO 2011/061519 PCT/GB2010/002164
Patent Application Ser. No. 11/135,651, European Patent Application No.
04005541 and
European Patent Application No. 15227.
The present invention provides a topical foam composition comprising rifaximin
suitable for
5 rectal administration in with one or more pharmaceutically acceptable
excipients or carriers
and which also remains stable over the storage period.
The amount of rifaximin in the rectal foam composition according to the
present invention
preferably ranges from about 0.01% w/w to about 10% w/w, more preferably from
about
10 0.5% w/w to about 8% w/w relative to the total weight of the composition.
In an embodiment, the present invention provides a topical foam composition
comprising
rifaximin with one or more pharmaceutical excipient/carrier in the form of a
rectal foam filled
in a compressed gas container, that upon valve actuation, emits a fine
dispersion of liquid
and/or solid materials in a gaseous medium. The said composition is easier to
apply, less
dense, and spread more easily than other topical dosage forms. Alternatively,
the composition
may be formulated in various ways to provide emollient or drying functions to
the rectal
mucosa, depending on the formulation constituents. Another benefit of the
pharmaceutical
composition of the present invention is ease of use by the patient and
consumer acceptance.
In a further embodiment, the topical foam composition may not contain mineral
oils. The
disadvantage of these components is that they might further irritate the
already inflamed areas
of the rectum or anus.
In a preferred embodiment, the topical foam composition of the present
invention comprises
rifaximin, at least one surfactant and at least one propellant, water soluble
alkanols, water and
optionally other pharmaceutical excipients or carriers.
Although a mixture of water soluble alkanols is the preferred vehicle for the
topical foam
composition according to the present invention, suitable non-aqueous vehicle
which may be
employed in the topical foam composition of the invention, which include but
not limited to
WO 2011/061519 PCT/GB2010/002164
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vegetable oils, such as olive oil; injectable organic esters, such as ethyl
oleate or mixtures
thereof
It is also desirable to use a suitable vehicle which is compatible with the
rectal and colonic
mucosa.
Alternatively, the liquid vehicle may also be based on highly hydrophilic
organic substances
to allow the surfactant to perform its foaming action, which however
preferably should not be
inhibited by the other substances present in the formulation, such as the
active principles and
their stabilizers, whereas the specific adjuvants (such as foam consistency
correctors) are
preferably chosen from those with strong hydrophilic and lipophilic
characteristics.
The vehicle typically constitutes from 10% w/w to 95%w/w, preferably from 10%
w/w to
90% w/w, more preferably from 20% to 70% w/w relative to the total weight of
the
composition.
In a preferred embodiment, the vehicle employed in the topical foam
composition of the
present invention comprises water in an amount from approximately 20% w/w to
approximately 90% w/w relative to the total weight of the composition and a
water-soluble
alkanol, preferably propylene glycol, in an amount from approximately 0% w/w
to 50% w/w
relative to the total weight of the composition. Preferably, the vehicle
contains 20-80% w/w
water relative to the total weight of the composition. Preferably the vehicle
contains 5-40%
w/w water soluble alkanol relative to the total weight of the composition.
Most preferably, the
vehicle contains 20-80% w/w water relative to the total weight of the
composition, and 5-40%
w/w water soluble alkanol relative to the total weight of the composition.
The preferred amount of non-aqueous vehicle, especially the water soluble
alkanol, more
especially the propylene glycol, is from 10% to 40% w/w based on the total
weight of the
composition.
Examples of surface active agents which may be employed in the aqueous foam
composition
of the present invention include, but not limited to anionic surfactants, non-
ionic surfactants,
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cationic surfactants, and amphoteric surfactants. Examples of anionic
surfactants include, but
are not limited to, ammonium lauryl sulfate, sodium lauryl sulfate, ammonium
laureth sulfate,
sodium laureth sulfate, alkyl glyceryl ether sulfonate, triethylamine lauryl
sulfate,
triethylamine laureth sulfate, triethanolamine lauryl sulfate, triethanolamine
laureth sulfate,
monoethanolamine lauryl sulfate, monoethanolamine laureth sulfate,
diethanolamine lauryl
sulfate, diethanolamine laureth sulfate, lauric monoglyceride sodium sulfate,
potassium lauryl
sulfate, potassium laureth sulfate, sodium lauryl sarcosinate, sodium lauroyl
sarcosinate,
lauryl sarcosine, cocoyl sarcosine, ammonium cocoyl sulfate, ammonium lauroyl
sulfate,
sodium cocoyl sulfate, sodium lauroyl sulfate, potassium cocoyl sulfate,
potassium lauryl
sulfate, triethanolamine lauryl sulfate, triethanolamine lauryl sulfate,
monoethanolamine
cocoyl sulfate, monoethanolamine lauryl sulfate, sodium tridecyl benzene
sulfonate, sodium
dodecyl benzene sulfonate, sodium and ammonium salts of coconut alkyl
triethylene glycol
ether sulfate; tallow alkyl triethylene glycol ether sulfate, tallow alkyl
hexaoxyethylene
sulfate, disodium N-octadecylsulfosuccinate, disodium lauryl sulfosuccinate,
diammonium
lauryl sulfosuccinate, tetrasodium N-(1,2-dicarboxyethyl)-N-
octadecylsulfosuccinate, diamyl
ester of sodium sulfosuccinic acid, dihexyl ester of sodium sulfosuccinic
acid, dioctyl esters
of sodium sulfosuccinic acid, docusate sodium, and combinations thereof. The
preferred
amount of surfactant, is present in an amount from 0.1% to 10.0% w/w based on
the total
weight of the composition; more preferably, in an amount from 0.1% to 8.0% w/w
based on
the total weight of the composition.
Examples of nonionic surfactants include, but are not limited to,
polyoxyethylene fatty acid
esters, sorbitan esters, cetyl octanoate, cocamide DEA, cocamide MEA, cocamido
propyl
dimethyl amine oxide, coconut fatty acid diethanol amide, coconut fatty acid
monoethanol
amide, diglyceryl diisostearate, diglyceryl monoisostearate, diglyceryl
monolaurate,
diglyceryl monooleate, ethylene glycol distearate, ethylene glycol
monostearate, ethoxylated
castor oil, glyceryl monoisostearate, glyceryl monolaurate, glyceryl
monomyristate, glyceryl
monooleate, glyceryl monostearate, glyceryl tricaprylate/caprate, glyceryl
triisostearate,
glyceryl trioleate, glycol distearate, glycol monostearate, isooctyl stearate,
lauramide DEA,
lauric acid diethanol amide, lauric acid monoethanol amide, lauric/myristic
acid diethanol
amide, lauryl dimethyl amine oxide, lauryl/myristyl amide DEA, lauryl/myristyl
dimethyl
amine oxide, methyl gluceth, methyl glucose sesquistearate, oleamide DEA, PEG-
distearate,
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polyoxyethylene butyl ether, polyoxyethylene cetyl ether, polyoxyethylene
lauryl amine,
polyoxyethylene lauryl ester, polyoxyethylene lauryl ether, polyoxyethylene
nonylphenyl
ether, polyoxyethylene octyl ether, polyoxyethylene octylphenyl ether,
polyoxyethylene oleyl
amine, polyoxyethylene oleyl cetyl ether, polyoxyethylene oleyl ester,
polyoxyethylene oleyl
ether, polyoxyethylene stearyl amine, polyoxyethylene stearyl ester,
polyoxyethylene stearyl
ether, polyoxyethylene tallow amine, polyoxyethylene tridecyl ether, propylene
glycol
monostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan
monopalmitate, sorbitan
monostearate, sorbitan sesquioleate, sorbitan trioleate, stearamide DEA,
stearic acid diethanol
amide, stearic acid monoethanol amide, laureth-4, and combinations thereof.
Examples of amphoteric surfactants include, but are not limited to, sodium N-
dodecyl- -
alanine, sodium N-lauryl- -iminodipropionate, myristoamphoacetate, lauryl
betaine, lauryl
sulfobetaine, sodium 3-dodecyl-aminopropionate, sodium 3-dodecylaminopropane
sulfonate,
sodium lauroamphoacetate, cocodimethyl carboxymethyl betaine, cocoamidopropyl
betaine,
cocobetaine, lauryl amidopropyl betaine, oleyl betaine, lauryl dimethyl
carboxymethyl
betaine, lauryl dimethyl alphacarboxyethyl betaine, cetyl dimethyl
carboxymethyl betaine,
lauryl bis-(2-hydroxyethyl)carboxymethyl betaine, stearyl bis-(2-
hydroxypropyl)carboxymethyl betaine, oleyl dimethyl gamma-carboxypropyl
betaine, lauryl
bis-(2-hydroxypropyl)alpha-carboxyethyl betaine, oleamidopropyl betaine, coco
dimethyl
sulfopropyl betaine, stearyl dimethyl sulfopropyl betaine, lauryl dimethyl
sulfoethyl betaine,
lauryl bis-(2-hydroxyethyl)sulfopropyl betaine, and combinations thereof.
Examples of cationic surfactants include, but are not limited to, behenyl
trimethyl ammonium
chloride, bis(acyloxyethyl)hydroxyethyl methyl ammonium methosulfate,
cetrimonium
bromide, cetrimonium chloride, cetyl trimethyl ammonium chloride, cocamido
propylamine
oxide, distearyl dimethyl ammonium chloride, ditallowedimonium chloride, guar
hydroxypropyltrimonium chloride, lauralkonium chloride, lauryl dimethylamine
oxide, lauryl
dimethylbenzyl ammonium chloride, lauryl polyoxyethylene dimethylamine oxide,
lauryl
trimethyl ammonium chloride, lautrimonium chloride, methyl-l-oleyl amide ethyl-
2-oleyl
imidazolinium methyl sulfate, picolin benzyl ammonium chloride, polyquatemium,
stearalkonium chloride, sterayl dimethylbenzyl ammonium chloride, stearyl
trimethyl
ammonium chloride, trimethylglycine,. and. combinations thereof..
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14
It will be appreciated by the person skilled in the art that amongst the two
or more surfactants
selected, at least one surfactant selected may provide the emulsifying action
whereas the other
may provide a foam-stabilizing action. It will also be appreciated that at
least one surfactant
employed may possess emulsifying action and another surfactant employed may
possess foam
stabilizing action. The surfactant(s) is desirably chosen such that it remains
compatible with
the rectal and colonic mucosa and will be present in an amount which achieves
the desired
pharmaceutical effect but which does not give rise to problems of irritation.
In a further embodiment of the present invention, the topical foam composition
contains a
lubricant. Preferably, said lubricant is a silicone (e.g.
polydimethylsiloxane). The silicone may
further stabilize the foam-forming composition.
The propellant used in the topical foam composition of the present invention
is used to
accomplish the foaming effect. The propellant may be chosen according to known
principles
for preparing a foamable composition of the aerosol type packed in a
pressurized container
and suitable for a rectal application. The propellant may be any suitable,
pharmaceutically
acceptable, gas such as a low molecular weight hydrocarbon e.g. isobutane, n-
butane,
propane, CFC, hydrocarbons; chlorofluorocarbons (CFCs);
hydrochlorofluorocarbons
(HCFCs); hydrofluoroalkanes (HFAs) such as HFA 134a and HFA 227; or air.
Preferably, the
propellant comprises a mixture of n-butane, isobutane, propane.
The propelling properties can vary depending on the type and quantity of
propellant used and,
consequently, the foam can reach more or less distant regions of the large
intestine.
The propellant may be present in an amount from 0.05 to 20% w/w, preferably
0.5 to 20%
w/w, of the composition. Preferably, said amount is between 3 to 10%, more
preferably
between 7 to 9% w/w of the composition. Additionally, liquefied nitrogen may
be present as
pressurizing agent to obtain the required number of doses.
Further, the topical foam composition according to the present invention may
comprise at
least one additional active ingredient suitable for rectal administration..
WO 2011/061519 PCT/GB2010/002164
Additional active agents may be may be selected from, but not limited to one
or more of anti-
inflammatory agents, steroids (e.g. corticosteroids), additional antibiotics,
anti-fungal agents,
analgesics, or anti-neoplastic agents.
5
Examples of suitable antibiotics includes, but not limited to: dapsone,
chioramphenicol,
neomycin, cefaclor, cefadroxil, cephalexin, cephradine, erythromycin,
clindamycin,
lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin, dicl
oxacillin, cyclacillin,
picloxacillin, hetacillin, methicillin, nafcillin, penicillin, polymyxin,
tetracycline,
10 amphotericin-b, candicidin, dermostatin, filipin, fungichromin, hachimycin,
hamycin,
lucensomycin, mepartricin, natamycin, nystatin, pecilocin, perimycin,
azaserine, griseofulvin,
oligomycins, neomycin undecylenate, pyrroinitrin, siccanin, tubercidin,
viridin, picloxacillin,
hetacillin, methicillin, nafcillin, penicillin, polymyxin, or tetracycline.
15 Examples of suitable anitfungal agents includes but not limited to:
allylamines such as
butenafine, naftifine, imidazoles such as bifonazole, butoconazole,
chlordantoin,
chlormidazole, cloconazole, clotrimazole, econazole, enilconazole,
fenticonazole,
flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole,
omoconazole,
oxiconazole nitrate, sertaconazole, sulconazole, tioconazole, triazoles such
as fluconazole,
itraconazole, saperconazole, terconazole, and others such as acrisorcin,
amorolftiota]ne,
biphenamine, bromosalicylchloranilide, buclosamide, calcium propionate,
chlophenesin,
ciclopirox, cloxyquin, coparaff[iota]nate, diamthazole, dihydrochloride,
exalamide,
flucytosine, halethazole, hexetidine, loflucarban, nifuratel, potassium
iodide, propionates,
propionic acid, pyrithione, salicylanilide, sulbentine, tenonitrozole,
triacetin, ujothion,
undecylenic acid.
Antifungal agents may also include, for example, polyenes such as amphotericin-
b,
candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin,
lucensomycin,
mepartricin, natamycin, nystatin, pecilocin, perimycin, azaserine,
griseofulvin, oligomycins,
neomycin undecylenate, pyrroinitrin, siccanin, tubercidin, viridin,
allylamines such as
butenafine, naftifine, imidazoles such as bifonazole, butoconazole,
chlordantoin,
chlormidazole, cloconazole, clotrimazole,. econazole,, enilconazole,.
fenticonazole,
WO 2011/061519 PCT/GB2010/002164
16
flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole,
omoconazole,
oxiconazole nitrate, sertaconazole, sulconazole, tioconazole, triazoles such
as fluconazole,
itraconazole, saperconazole, terconazole, acrisorcin, amorolfjiota]ne,
biphenamine,
bromosalicylchloranilide, buclosamide, calcium propionate, chlophenesin,
ciclopirox,
cloxyquin, coparaff[iota]nate, diamthazole, dihydrochloride, exalamide,
flucytosine,
halethazole, hexetidine, loflucarban, nifuratel, potassium iodide,
propionates, propionic acid,
pyrithione, salicylanilide, sulbentine, tenonitrozole, triacetin, ujothion, or
undecylenic acid.
The other therapeutic agent can include steroid or a non-steroidal
antiinflammatory agent.
Useful non-steroidal anti-inflammatory agents, include, but are not limited
to, aspirin,
ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen,
flubufen,
ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,
muroprofen,
trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic
acid, indomethacin,
sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,
clidanac, oxpinac,
mefenamic acid, meclofenamic acid, flufenamic acid, niflum[iota]c acid,
tolfenamic acid,
diflurisal, flufenisal, piroxicam, sudoxicarn, isoxicam; salicylic acid
derivatives, including
aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate,
diflunisal,
salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophennol
derivatives including
acetaminophen and phenacetin; indole and indene acetic acids, including
indomethacin,
sulindac, and etodolac; heteroaryl acetic acids, including tolmetin,
diclofenac, and ketorolac;
anthranilic acids (fenamates), including mefenamic acid, and meclofenamic
acid; enolic acids,
including oxicams (piroxicam, tenoxicam), and pyrazolidinediones
(phenylbutazone,
oxyphenthartazone); and alkanones, including nabumetone and pharmaceutically
acceptable
salts thereof and mixtures thereof.
Examples of suitable corticosteroid includes but not limited to:
hydrocortisone, i.e., 11-17-
21-trihydroxypregn-4-ene-3,20-dione or Cortisol, Cortisol acetate,
hydrocortisone phosphate,
hydrocortisone 21 -sodium succinate, hydrocortisone tebutate, corticosterone,
corticosterone
acetate, cortisone, cortisone acetate, cortisone 21B- cyclopentanepropionate,
cortisone
phosphate, triamcinolone hexacetonide, dexamethasone phosphate, desonide,
betamethasone
dipropionate, mometasone furate.
WO 2011/061519 PCT/GB2010/002164
17
The corticosteroid and topical anesthetic may be employed together in the
composition along
with rifaximin.
For inflammation, preferred treatments for use in combination therapy with the
compositions
of the present invention include, but not limited to: naproxen sodium
(Anaprox(R) and
Anaprox(R) DS, Roche), flurbiprofen (Ansaid(R); Pharmacia), diclofenac sodium
+
misoprostil (Arthrotec(R), Searle), valdecoxib (Bextra(R), Pharmacia),
diclofenac potassium
(Cataflam(R) and Voltaren(R), Novartis), celecoxib (Celebrex(R), Pfizer),
sulindac
(Clinoril(R), Merck), oxaprozin (Daypro(R), Pharmacia), salsalate
(Disalcid(R), 3M),
difhmisal (Dolobid(R), Merck), naproxen sodium (EC Naprosyn(R), Roche),
piroxicam
(Feldene(R), Pfizer), indomethacin (Indocin(R) and Indocin SR(R), Merck),
etodolac
(Lodine(R) and Lodine XL(R), Wyeth), meloxicam (Mobic(R), Boehringer
Ingelheim),
ibuprofen (Motrin(R), Pharmacia), naproxen (Naprelan(R), Elan), naproxen
(Naprosyn(R),
Roche), ketoprofen (Orudis(R) and Oruvail(R), Wyeth), nabumetone (Relafen(R),
SmithKline), tolmetin sodium (Tolectin(R), McNeil), choline magnesium
trisalicylate
(Trilisate(R), Purdue Fredrick), and rofecoxib (Vioxx(R), Merck).
Antineoplastic agents may also be included in the topical foam composition of
the present
invention along with the rifaximin include, but not limited to: vincristine,
vinblastine,
vindesine, busulfan, chlorambucil, spiroplatin, cisplatin, carboplatin,
methotrexate,
adriamycin, mitomycin, bleomycin, cytosi[pi]e arabinoside, arabinosyl adenine,
mercaptopurine, mitotane, procarbazine, dactinomycin (antinomycin D),
daunorubicin,
doxorubicin hydrochloride, taxol, plicamycin, aminoglutethimide, estramustine,
flutamide,
leuprolide, megestrol acetate, tamoxifen, testolactone, trilostane, amsacrine
(m-AMSA),
asparaginase (L-asparaginase), etoposide, and interferon a-2a and 2b.
Antiviral agents may also be included in the topical foam composition of the
present
invention along with the rifaximin include, but not limited to: acyclovir,
amantadine,
azidothymidine, ribavirin or vidarabine. In any case where pain in a component
of the target
disorder, the other therapeutic agent can be an analgesic. Useful analgesics
include, but are
WO 2011/061519 PCT/GB2010/002164
18
not limited to, phenacetin, butacetin, acetaminophen, nefopam,
acetoamidoquinone, and
mixtures thereof.
Optionally, a topical anesthetic may be present in the composition of the
invention. For
instance, the topical anesthetic may include, but not limited to dibucaine,
lidocaine,
pramoxine, benzocaine, tetracaine. In general, the topical anesthetic may be
present in any
amount which is effective in the practice of the treatment of anal disease.
In a preferred embodiment, the present invention relates to a pharmaceutical
combination
product comprising rifaximin adapted for delivery to the colon and/or rectum
and a compound
selected from, but not limited, one or more of 5-acetyl salicylic acid (5-
ASA), sulphasalazine,
asalazine, prednisolone, or budesonide for simultaneous, separate, or
sequential
administration.
The topical foam composition according to the present invention is usually
packed in a
suitable pressurized dispensing canister of the aerosol type well known in the
art such as an
aluminium canister. Each canister is sealed with a suitable foam dispensing
valve. Any valve
or nozzle/valve assembly which provides a means for releasing the foam from
the container
and provides foam which is suitable for use in the present invention may be
used. The foam
that is formed from the composition of the present invention has superior
properties. The
advantages associated with the topical foam composition according to the
present invention is
that better results may be obtained in combating the disease and either a
lower dosage of the
active ingredient or less dosages per day may be necessary to obtain similar
results when
compared with prior art compositions. For instance, the increased spreading of
the foam
together with the longer exposure time to the active will result in optimal
local effect at the
target site. Also, the foam of the present invention may not cause extra
irritation of the
inflamed target mucosa due to the absence of mineral oils as present in the
prior art
compositions. Due to these superior properties of the foam, the current
invention may
represent a valuable alternative to previously known medicines used for the
treatment of rectal
diseases.
WO 2011/061519 PCT/GB2010/002164
19
The topical foam composition of the present invention is presented in a
suitable dispensing
container, for example an aluminium aerosol container, fitted with a suitable
metered or un-
metered valve. Such containers are well known in the art. Where desired, the
container can be
fitted or supplied together with an applicator device for insertion into the
rectum to ensure
more efficient administration of the foam.
The dispensing container may be in the form of coated aluminium cans to
prevent corrosion,
such as epoxy-coated cans. At the time of application, the mixture of the
mixing of the
ingredients with propellant may be insured by shaking, optionally with the aid
of a mixing
bead. The can may be arranged for either "upside down" spraying with the valve
at the
bottom, or the can have a dip tube so that the foam can be sprayed while the
can is upright
with the valve at the top.
During the use, the dispensing valve of the can allows rapid expansion of the
propellant,
which triggers and enhances the foaming action of the surfactant, which thus
emerges to
entrain the medicated liquid in the form of foam.
The propellant expansion energy is absorbed mainly in forming the foam, thus
allowing rectal
application without risk.
According to the present invention, the foam may be generated at the moment of
therapeutical
application. Hence the known formulation and dispensing technology used in the
state of the
art applicable to foam cans, for example in cosmetics is therefore suitable.
Preferably, the
active agent is vehicled in the liquid state with at least one propellant and
a surfactant with
foaming action.
The topical foam composition of the present invention is applied proximate or
to the affected
area of the external anus or distal anal canal of the subject.
On administering such compositions, it is sufficient to obtain foams of medium
consistency,
with a minimum volume of 0.5g to l Og of foam introduced into the rectum.
WO 2011/061519 PCT/GB2010/002164
The present invention further provides a process of manufacturing the topical
foam
composition of rifaximin comprising:
(1) Heating the mixture of emulsifying wax, emulsifier with surfactant and
preservative-water
separately.
5 (2) Adding water soluble alkanol to the preservative-water solution and then
mixing with oily
phase of step (1)
(3) Adding rifaximin to the above mixture under stirring and adjust the
required pH using
suitable pH adjusting agent.
(4) Make up the volume of the mixture by addition of purified water and
finally fill the blend
10 in metal cans and charge the can with propellant.
In a preferred embodiment, rifaximin is used in micronized form, preferably of
the size less
that about 200 microns. More preferably, the size may be less than about 150
microns or less.
15 The active agent is solubilized or suspended in a suitable liquid vehicle
containing a foaming
surfactant. The liquid is placed in an atomizer can sealed by a dispensing
valve and then
pressurized by feeding a suitable quantity of propellant through the valve.
The present composition can be prepared by mixing the ingredients in an
appropriate manner
20 and then filling into a suitable dispensing container, for example as
described in the examples.
It will be appreciated by the person skilled in the art that the topical foam
composition
comprising rifaximin further may comprise one or more pharmaceutical
excipients, selected
from, but are not limited to: emollient or humectants, pH adjusting agent,
emulsifiers,
foaming agents, fatty alcohol, preservative, chelating agents, antioxidants,
suspending agents,
thickening agents, permeation enhancers, occlusive agents, colorants and
fragrances or
combinations thereof.
Examples of suitable pH adjusting agents may be selected from, but not limited
to, sodium
hydroxide, citric acid, hydrochloric acid, acetic acid, phosphoric acid,
succinic acid, sodium
hydroxide, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium
carbonate, magnesium carbonate, magnesium aluminum silicates, malic acid,
potassium
WO 2011/061519 PCT/GB2010/002164
21
citrate, sodium citrate, sodium phosphate, lactic acid, gluconic acid,
tartaric acid, 1,2,3,4-
butane tetracarboxylic acid, fumaric acid, diethanolamine, monoethanolamine,
sodium
carbonate, sodium bicarbonate, triethanolamine, and combinations thereof,
preferably
triethanolamine is used.
In a preferred embodiment, the topical foam composition according to the
present invention
topical comprises suitable pH adjusting agent to adjust the pH in the range
from
approximately 4 to 8.
Examples of the emulsifying waxes that can be used in the topical foam
composition of the
present invention are non-ionic emulsifying waxes such as those described in
the U.S.
National Formulary (USNF) and `Martindale'. An emulsifying wax may be
incorporated in
the topical composition of the present invention in order to stiffen the foam.
The amount of
emulsifying wax in the composition is preferably from 1% to 10% w/w based on
the total
weight of the composition.
Examples of surfactants which may be employed in the topical foam composition
of the
present invention include, but not limited to fatty alcohol for example, cetyl
stearyl, lauryl,
myristyl, and palmityl alcohols, surfactants or mixtures thereof. A preferred
surfactant is
polyoxyethylene 10 stearyl ether. and, is preferably present in an amount from
0.1% to 1.0%
w/w based on the total weight of the composition.
In another embodiment according to the present invention, a suitable surface
active agent can
be employed which performs the function of both foaming agent and surfactant.
Examples of suitable emollients and/or humectants which may be employed in the
topical
foam composition of the present invention include, but not limited to,
polyhydric alcohols
such as glycols, and polysaccharides, such as ethylene glycol, propylene
glycol, butylene
glycol, diethylene glycol, dipropylene glycol, glycerin, diglycerin, sorbitol,
malvitol,
trehalose, raffinose, xylitol, mannitol, polyethylene glycol, propylene
glycol, polyglycerin,
cholesterol, squaline, fatty acids, octyldodecanol, myristyl alcohol, urea,
lanolin, lactic acid,
esters such as isopropyl stearate, isopropyl myristate, isopropyl palmitate
and isopropyl
laurate and the like, preferably myristyl alcohol, octyldodecanol, propylene
glycol.
WO 2011/061519 PCT/GB2010/002164
22
In a preferred embodiment for mucosal delivery, permeation enhancers may be
incorporated
in the topical foam composition of the present invention for delivery of the
active ingredient
to the mucosal surface. Most types of enhancers are detergents that include:
sodium
glycocholate, sodium taurocholate, polysorbate 80, sodium lauryl sulfate,
lauric acid, and
various alkyl glycosides. Other examples of enhancers include: dextrins
(cyclodextrin,
dextran sulfate), fatty acids (phosphatidylcholine, lysophosphatidylcholine),
heterocyclic
compounds (azone), and small molecules (benzalkonium chloride,
cetyltrimethylammonium
bromide). Each is contemplated for use in the present invention as are other
unlisted
ingredients typically used for such purpose, as would be appreciated by one of
skill in the art.
In another preferred embodiment, suitable mucoadhesives may be used in the
aqueous foam
composition of the present invention to improve local retention of mucosally
delivered of the
active ingredient.
Mucoadhesive compounds are primarily synthetic or natural polymers that can
adhere to the
wet mucosal surface. These include synthetic polymers such as, but not limited
to monomeric
alpha cyanoacrylate, polyacrylic acid, hydroxypropyl methylcellulose, and poly
methacrylate
derivatives. Glue-like polymers include epoxy resins and polyurethanes.
Naturally occurring
mucoadhesives include chitosan, hyaluronic acid and xanthan gum or mixtures
thereof.
Suitable emulsifiers include, but are not limited to, straight chain or
branched fatty acids,
polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters,
propylene glycol stearate,
glyceryl stearate, polyethylene glycol, fatty alcohols, polymeric ethylene
oxide-propylene
oxide block copolymers, and combinations thereof. One preferred emulsifier is
cetyl alcohol.
The emulsifier, for example the cetyl alcohol is preferably present in an
amount from 0.1 to
5.0% w/w based on the total weight of the composition.
Suitable suspending agents include, but are not limited to, alginic acid,
bentonite, carbomer,
carboxymethylcellulose and salts thereof, colloidal oatmeal,
hydroxyethylcellulose,
hydroxypropylcellulose, microcrystalline cellulose, colloidal silicon dioxide,
dextrin, gelatin,
guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol,
triglycerides,
WO 2011/061519 PCT/GB2010/002164
23
methylcellulose, polyoxyethylene fatty acid esters, polyvinylpyrrolidone,
propylene glycol
alginate, sodium alginate, sorbitan fatty acid esters, tragacanth, and
combinations thereof
Suitable antioxidants include, but are not limited to, butylated
hydroxytoluene, alpha
tocopherol, ascorbic acid, fumaric acid, malic acid, butylated hydroxyanisole,
propyl gallate,
sodium ascorbate, sodium metabisulfite, ascorbyl palmitate, ascorbyl acetate,
ascorbyl
phosphate, Vitamin A, folic acid, flavons or flavonoids, histidine, glycine,
tyrosine,
tryptophan, carotenoids, carotenes, alpha-Carotene, beta-Carotene, uric acid,
pharmaceutically
acceptable salts thereof, derivatives thereof, and combinations thereof
Suitable chelating agents include, but are not limited to, EDTA, disodium
edetate, trans-1,2-
diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate, N,N-bis(2-
hydroxyethyl)glycine, 1,3-diamino-2-hydroxypropane-N,N,N',N'-tetraacetic acid,
1,3-
diaminopropane-N,N,N',N'-tetraacetic acid, ethylenediamine-N,N'-diacetic acid,
ethylenediamine-N,N'-dipropionic acid, ethylenediamine-N,N'-
bis(methylenephosphonic
acid), N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid,
ethylenediamine-N,N,N',N'-
tetrakis(methylenephosphonic acid), O,O'-bis(2-aminoethyl)ethyleneglycol-
N,N,N',N'-
tetraacetic acid, N,N-bis(2-hydroxybenzyl)ethylenediamine-N,N-diacetic acid,
1,6-
hexamethylenediamine-N,N,N',N'-tetraacetic acid, N-(2-
hydroxyethyl)iminodiacetic acid,
iminodiacetic acid, 1,2-diaminopropane-N,N,N',N'-tetraacetic acid,
nitrilotriacetic acid,
nitrilotripropionic acid, nitrilotris(methylenephosphonic acid), 7,19,30-
trioxa-
1,4,10,13,16,22,27,33-octaazabicyclo[111,11,1]pentatriacon- tane
hexahydrobromide,
triethylenetetramine-N,N,N',N",N"',N"'-hexaacetic acid, and combinations
thereof
Suitable emollients include, but are not limited to, myristyl lactate,
isopropyl palmitate, light
liquid paraffin, cetearyl alcohol, lanolin, lanolin derivatives, mineral oil,
petrolatum, cetyl
esters wax, cholesterol, glycerol, glycerol monostearate, isopropyl myristate,
lecithin, and
combinations thereof.
Preservatives can be used to prevent the growth of fungi and other
microorganisms. Suitable
preservatives include, but are not limited to, benzoic acid, sorbic acid,
butylparaben, ethyl
paraben, methyl paraben, propyl paraben, sodium benzoate; sodium propionate,
benzalkonium
WO 2011/061519 PCT/GB2010/002164
24
chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,
chlorobutanol,
phenol, phenylethyl alcohol, thimerosal, and combinations thereof. The
preservative is
preferably present in an amount from 0.01% to 0.20% w/w, preferably 0.1% to
0.20% w/w,
based on the total weight of the composition. In a particular embodiment the
composition
contains 0.1% to 0.18% w/w methyl paraben and 0.01% to 0.02% w/w propyl
paraben.
Examples of suitable antioxidant include, but not limited to sodium
metabisulphite and
advantageously this can be used in conjunction with a chelating agent such as
a salt of EDTA,
e.g. disodium edetate.
The present invention further provides a method of treating, preventing, or
alleviating anal
disorders comprising administering to a subject in need thereof an effective
amount of
rifaximin. Anal disorders include one or more of anal fissure, anal ulcer,
haemorrhoidal
disease, levator spasm, inflammatory bowel disease with anal involvement,
irritable bowel
syndrome, diarrhea, microbe associated diarrhea, Clostridium difficile
associated diarrhea,
travelers' diarrhea, small intestinal anal disease, Crohn's disease, chronic
pancreatitis,
pancreatic insufficiency, colitis, hepatic encephalopathy, or pouchitis. In
treatment according
to the invention, the composition of the invention is contacted with or
applied to the affected
anal area or proximate thereto such that an effective amount of active
ingredient is
administered.
In a preferred embodiment, the amount of composition which is employed should
be effective
for the amelioration, control and/or healing of the anal disease and the
prompt and dramatic
control or relief of pain resulting from or associated with the disease.
According to yet another embodiment, the anal disorder is or is caused by one
or more of anal
fissure, anal ulcer, and acute haemorrhoidal disease, irritable bowel
syndrome, inflammatory
bowel disease, (e.g., Crohn's and colitis), travelers' diarrhea, large
intestinal anal disease,
chronic pancreatitis, pancreatic insufficiency or post-surgical disease (e.g.,
pouchitis).
In a further embodiment, the effective amount is effective to treat a
bacterial infection, e.g.,
anal diseases including, one or more of anal fissured anal- ulcer; and, acute
haemorrhoidal
WO 2011/061519 PCT/GB2010/002164
disease, irritable bowel syndrome, travelers' diarrhea, small intestinal anal
disease, Crohn's
disease, chronic pancreatitis, pancreatic insufficiency, colitis, hepatic
encephalopathy,
antibiotic associated colitis, and/or diverticular disease.
5 The following examples are for the purpose of illustration of the invention
only and are not
intended in any way to limit the scope of the present invention.
Examples
10 Example 1
Sr. Qty/ Unit (%
Ingredients
No. w/w)
1 Rifaximin 5
2 Propylene glycol 20.00
3 Emulsifying wax 1.50
4 Cetyl alcohol 0.18
5 Polyoxyethylene 10 stearyl ether 0.25
6 Methyl hydroxybenzoate or Methyl paraben 0.10
7 Propyl hydroxybenzoate or propyl paraben 0.01
8 Triethanolamine q. s. to pH 6.0
9 Purified water q. s. to 100 g
10 Propellant (Propane/ n-Butane/ Isobutane) 4.00 g
Total 104.00 g
Process:
(1) Heat the emulsifying wax, cetyl alcohol and polyoxyethylene 10 stearyl
ether.
15 (2) Heat methyl paraben or methyl hydroxybenzoate and propyl paraben or
propyl
hydroxybenzoate with water.
(3) Add propylene glycol to the solution of step (2) under homogenization.
WO 2011/061519 PCT/GB2010/002164
26
(4) Add mixture of step (1) to the solution of step (3) under homogenization
and allow to cool
under stirring.
(5) Add rifaximin (micronized, less than 200 microns) to the above mixture and
homogenize
to cool at room temperature.
(6) A solution of triethanolamine is added to the above mixture to adjust the
pH about 6.
(7) Make up the volume of the mixture by addition of purified water
(8) Finally fill the blend in metal cans and charge the can with propellant.
Example 2 (Non aqueous foam)
Sr. Ingredients Qty/ unit (%
No w/w
1. Rifaximin 5.00
2. Cetostearyl Alcohol 2.00-8-00
3. Triglycerides of capric/caprylic acid 80.00 - 95.00
4. Propyl paraben 0.01-0.02
5. Butylated hydroxytoluene (BHT) 0.01-0.1
6. Propane/ n- butane/ iso-butane 2.00 -10.00
Process:
1. Heat part quantity of Triglycerides of capric/ caprylic acid, BHT, Propyl
paraben and
cetostearyl alcohol to about 60 - 70 C.
2. Homogenize the above mixture for 10 minutes and allow to cool.
3..Separately, heat part quantity of Triglycerides of capric/caprylic acid and
rifaximin and
homogenize for 10 minutes.
4. Add the above mixture step (3) in the mixture obtained in step (2)
maintained at 45 C
under stirring.
5. Cool to room temperature under stirring and fill the prepared blend in
aluminium canisters
and seal with dispensing valves
6. Charge specified amount of propellant through these valves.
WO 2011/061519 PCT/GB2010/002164
27
It will be readily apparent to one skilled in the art that varying
substitutions and modifications
may be made to the invention disclosed herein without departing from the
spirit of the
invention. Thus, it should be understood that although the present invention
has been
specifically disclosed by the preferred embodiments and optional features,
modification and
variation of the concepts herein disclosed may be resorted to by those skilled
in the art, and
such modifications and variations are considered to be falling within the
scope of the
invention.
It is to be understood that the phraseology and terminology used herein is for
the purpose of
description and should not be regarded as limiting. The use of "including,"
"comprising," or
"having" and variations thereof herein is meant to encompass the items listed
thereafter and
equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims,
the singular forms
"a," "an" and "the" include plural references unless the context clearly
dictates otherwise.
Thus, for example, reference to "a propellant" includes a single propellant as
well as two or
more different propellants; reference to a "cosolvent" refers to a single
cosolvent or to
combinations of two or more cosolvents, and the like.
