TOPICAL FOAM COMPOSITION
FIELD OF INVENTION:
5 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:
10 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.
15 Haemorrhoids are specialized vascular areas lying subjacent to 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, "Journal of Clinical Gastroenterology., 16:304-308,
20 1993).
Topical anal therapy is also used as one of the approaches 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
25 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
30 swallowing problems, are often difficult to treat with oral tablets and capsules. Additionally,
5
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2
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
10 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
15 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 have been convincingly shown to reduce the
healing time or to reliably ameliorate associated pain.
Treatments, such as with Neosporin® ointment (which contains three antibiotics Neomycin,
20 Polymyxin B Sulfate and Bacitracin Zinc), are very sensitizing. Hence, there is still a need in
the art to provide compositions useful to reduce the healing time, which alleviate pain and
promote healing of the affected rectal and anal tissues.
Rifaximin is a water insoluble semi-synthetic rifamycin-based non-systemic antibiotic
belonging to the rifamycin class of antibiotics, and has the scientific name
25 [(2S, 162, 18E,20S,21S,22R,23R,24R,25S,26S,27 S,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]. Rifaximin has the following chemical formula.
wo 2011/061516
0 Ho •..
H,C)Lo
1-\C,...o ...
PCT/GB2010/002161
3
Rifaximin has been described to be endowed with an antibacterial activity similar to the
activityofrifampin [Venturini A. P. and Marchi E., Chemiotherapia, 5 (4), 257-256, (1986)].
5 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. eta!., Chemiotherapia, 3, (6), 373-377, (1984)] due to the zwitterionic nature of the
compound, which cannot be absorbed by the gastrointestinal tract [Marchi E. eta!., Journal
ofMedicinal Chemistry., 28, 960-963, (1985)].
10
Rifaximin is soluble in alcohol, ethyl acetate, chloroform and toluene. It exerts its broadspectrum
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.
15 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
20 excreted in feces (97% of administered dose) and 0.32% in the urine.
25
Rifaximin is not absorbed by the oral route [Venturini A. P., Chemotherapy, 29, 1-3, (1983)]
nor by topical application [Venturini A. P. et a/., Drugs Under Experimental and Clinical
Research., 13, 4, 233-6, (1987)].
Due to this particular pharmacokinetic behavior, rifaximin has no toxicity at a dose of 2000
mglkglos, when administered orally in rats, and therefore, on the basis ofthe microbiological,
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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., Journal of International Medical Research., 15, 49-56, (1987), Testa R. et
5 al., Drugs under Experimental and Clinical Research., 11, 387-392, (1985), Gruttadauria G.
et al., European Review for Medical and Pharmacological Sciences., 9, 100-105, (1987)].
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
10 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 Gramnegative
bacteria, with diarrhea syndromes, altered intestinal microbial flora, summer
15 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
20 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®.
US5352679 discloses use of rifaximin in formulations for treatment of gastric dyspepsia
caused by Helicobacter pylori bacteria. The rifaximin formulations disclosed in the patent are
25 in the form of a tablet (such as a sugar coated tablet), capsule, granules or syrup for oral
administration.
30
US5314904 and US6140355 disclose compositions containing rifaximin for treatment of
vaginal infections.
W02007/l 03448 discloses pharmaceutical preparations comprising an anti-rectal
dysfunction agent and rifaximin. The preferred anti-rectal dysfunction,. is .. a, nitnc. oxide
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modulating agent such as nitroglycerin. The examples disclosed in the patent application are
related to the ointment containing rifaximin and nitroglycerine.
W02004/03 7225 discloses cosmetic or pharmaceutical foam carrier suitable for inclusion of
5 both water soluble and oil soluble pharmaceutical and cosmetic agents.
EP0468555 and EP0395329 disclose 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
1 0 aerosol can.
However, there is little disclosure in prior art about the topical formulations of rifaximin
which are capable of providing the desired therapeutic effect.
15 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
20 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-soluble but may
also be water-soluble or water-miscible base. To obtain a good bioavailability the active
ingredient should come into contact with the rectal or colonic mucosa.
25 Ointments and creams often do not create an environment for promoting respiration of the
wounded tissue and which 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.
30
Aqueous foarnable preparations are the less common of the rectal preparation forms. They
require relatively complicated manufacture as well as ... complicated packaging as compared ,
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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.
5 Although the delivery of active ingredient using foam can provide various advantages as
compared to the other topical delivery fonns 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 collapse of the foam or alternatively the foam is
10 not formed at all, especially when administration is to occur via an applicator nozzle with
small diameter. Most foam dosage fonns 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 ofDrug Delivery, 2003, vol. 1(1), pp. 71-75). However, only a few are commercially
15 available.
20
Conventional foams for rectal or vaginal administration are filled in pressurised containers
with a pharmaceutically active ingredient dissolved or suspended in a liquid vehicle, at least
one propellant gas and a surfactant with foaming properties.
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
25 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 still remained challenging. The suitable
compositions of rifaxirnin suggested in the prior art are ointment and vaginal foam. The
30 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 admixingthis mixture with ointment
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base prior to the application. Moreover, the vaginal foam when formulated may also not
remain stable when provided in compressed gas packs.
Thus there still exists a need to develop a topical foam composition of rifaximin suitable for
5 rectal administration with increased diffusion, useful in reduction of healing time, alleviate
pain and promote healing of the affected rectal and anal tissues and also remains stable
during the storage period.
10
OBJECT OF THE INVENTION:
An object of the present invention is to provide a topical foam composition of rifaximin
suitable for rectal administration.
Another object of the present invention is to provide a topical foam composition of rifaximin
15 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.
20 One more object of the present invention is to provide a process for preparing 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 for treating,
prophylaxis, or maintenance of remission of colonic or rectal dysfunction by administering
25 the topical foam composition of rifaximin to patients in need thereof.
30
A further 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.
5
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SUMMARY OF THE INVENTION:
According to the first aspect of the present invention there is provided a topical foam
composition of rifaximin for rectal administration.
According to the second aspect of the present invention there is provided a topical foam
composition of rifaximin for rectal administration wherein rifaximin is in the nanosize form.
According to a third aspect of the present invention there is provided a topical foam
10 composition of rifaximin for rectal administration comprising one or more pharmaceutical
excipients or carriers.
15
20
25
30
According to a fourth aspect of the present invention there is provided a process of preparing
the said topical foam composition of rifaximin.
According to a fifth aspect of the present invention 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 sixth 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.
DETAILED DESCRIPTION OF THE INVENTION:
The inventors have developed a topical foam composition of rifaximin which may achieve
the aforesaid objectives and which also exhibits a topical anti-infective action.
Surprisingly, the inventors have found that by utilizing nanosized rifaximin it is possible to
increase the dispersion of Rifaximin which is suitable for rectal administration.
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Nanonization of hydrophobic or poorly water-soluble drugs generally involves the production
of drug nanocrystals through either chemical precipitation (bottom-up technology) or
disintegration (top-down technology). Different methods may be utilized to reduce the
5 particle size of the hydrophobic or poorly water soluble drugs. [Huabing Chen et al.,
discusses the various methods to develop nanoformulations in "Nanonization strategies for
poorly water-soluble drugs," Drug Discovery Today, Volume 00, Number 00, March 201 0].
Nanosizing leads to increase in the exposure of surface area of rifaximin particles leading to
1 0 an increase in the rate of dissolution.
The present invention thus provides a pharmaceutical composition, comprising rifaximin
wherein rifaximin is in the nanosize range.
The term "Rifaximin" is used in broad sense to include not only "Rifaximin" per se but also
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
15 pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers,
pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs,
pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.
The nanoparticles of the present invention can be obtained by any of the process such as but
20 not limited to milling, precipitation, homogenization and the like ..
The pharmaceutical composition of the present invention comprises rifaximin having an
effective particle size range of less than 1 OOOnm, preferably less than 500nm. The effective
particle size is preferably at least 10 nm. In an embodiment the effective particle size is in the
25 range from 200 to 300 run. In an embodiment, at least 50% ofthe rifaximin particles have an
effective particle size in the range from 1 0 to less than 1 000 nm. In an embodiment, at least
50% of the particles have an effective particle size in the range 200 to 300 nm.
According to one embodiment of the present invention, the process of milling comprises
30 dispersing rifaximin particles in a liquid dispersion medium in which rifaximin is poorly
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soluble, followed by applying mechanical means in the presence of grinding media to reduce
the particle size of rifaximin to the desired effective average particle size.
According to another embodiment of the present invention, the process of precipitation
5 comprises dissolving rifaximin in a suitable solvent, adding the dissolved rifaximin to a
solution comprising at least one surface stabilizer; and causing precipitation by using an
appropriate non-solvent.
According to another embodiment of the present invention, the process of homogenization
10 comprises dispersing rifaximin particles in a liquid dispersion medium, followed by
subjecting the dispersion to homogenization to reduce the particle size of the rifaximin to the
desired effective average particle size.
According to another embodiment of the present invention, the process of high pressure
15 homogenization comprises rifaximin presuspension (containing rifaximin in the micrometer
range) by subjecting the rifaximin to air jet milling in the presence of an aqueous surfactant
solution. The presuspension is then subjected to high-pressure homogenization in which it
passes through a very small homogenizer gap of about 25 Jlm which leads to a high streaming
velocity. High-pressure homogenization is based on the principle of cavitations (i.e., the
20 formation, growth, and implosive collapse of vapor bubbles in a liquid.
According to another embodiment of the present invention, the process of spray-freeze
drying involves the atomization of an aqueous rifaximin solution into a spray chamber filled
with a cryogenic liquid (liquid nitrogen) or halocarbon refrigerant such as chlorofluorocarbon
25 or fluorocarbon. The water is removed by sublimation after the liquid droplets solidify.
30
According to another embodiment of the present invention, the process of supercritical fluid
technology involves controlled crystallization of rifaximin from dispersion in supercritical
fluids, carbon dioxide.
According to another embodiment of the present invention, the process of double
emulsion/solvent evaporation technique involves preparation of oil/water (o/w) emulsions
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with subsequent removal of the oil phase through evaporation. The emulsions are prepared by
emulsifying the organic phase containing rifaximin, polymer and organic solvent in an
aqueous solution containing emulsifier. The organic solvent diffuses out of the polymer
phase and into the aqueous phase, and is then evaporated, forming rifaximin-loaded
5 polymeric nanoparticles.
According to a further embodiment of the present invention, the process of PRINT (Particle
replication in non-wetting templates) involves utilization of a low surface energy
fluoropolymeric mold that enables high-resolution imprint lithography, to fabricate a variety
10 of organic particles. PRINT can precisely manipulate particle size of rifaximin ranging from
20 nm to more than 1 00 J..lm.
According to a further embodiment of the present invention, the process of thermal
condensation involves use of capillary aerosol generator (CAG) to produce high
15 concentration condensation submicron to micron sized aerosols from rifaximin solutions.
20
According to a further embodiment of the present invention, the process of ultrasonication
involves application of ultrasound during particle synthesis or precipitation, which leads to
smaller particles of rifaximin and increased size uniformity.
According to a further embodiment of the present invention, the process of spray drying
involves supplying the feed solution at room temperature and pumping it through the nozzle
where it is atomized by the nozzle gas. The atomized solution is then dried by preheated
drying gas in a special chamber to remove water moisture from the system, thus forming dry
25 particles of rifaximin.
According to a preferred embodiment of the present invention, reducing the particle size to a
nanosize range involves nanomilling of rifaximin preferably with at least one surface
stabilizer, at least one viscosity building agent and at least one polymer to form the
nanomilled slurry.
30 The term "Rifaximin" is used in broad sense to include not only "Rifaximin" per se but also
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
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pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers,
pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs,
pharmaceutically acceptable prodrugs, pharmaceutically acceptable complexes etc.
5 The amount of rifaximin in the rectal foam composition according to the present invention
ranges from about 0.01% w/w to 10% w/w, preferably about 0.5% w/w to about 8% w/w of
the total weight of the composition.
The composition preferably contains a vehicle, which is preferably a water soluble alkanol.
10 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,
polyethylene glycol, polypropylene glycol, propylene glycol glyceryl esters or mixtures
thereof.
15 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 may range between about 0.05:10 to 10: 0.05 on a weight
basis.
20 Thus, in an embodiment, the present invention provides a topical foam composition
comprising rifaximin wherein rifaximin is in the nanosize range with one or more
pharmaceutical excipient/carrier in a suitable dosage form for rectal delivery
In another embodiment of the present invention the nanomilled Rifaximin is provided as a
25 rectal foam filled in a compressed gas container, which 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
30 drying functions to the rectal mucosa, depending on the formulation constituents.
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Another benefit of the pharmaceutical composition of the present invention is ease of use by
the patient and consumer acceptance.
In a preferred embodiment, the topical foam composition of the present invention comprises
5 rifaximin wherein rifaximin is in the nanosize range, at least one surfactant and at least one
propellant, water soluble alkanols, water and optionally any other pharmaceutical excipients
or carriers.
Although mixture of water soluble alkanols is preferred vehicle for the topical non-aqueous
foam composition according to the present invention, suitable non-aqueous vehicle which
10 may be employed in the topical foam composition of the invention, which include but are not
limited to stearyl alcohol, glyceryl monoricinoleate, glyceryl mono stearate, propane-1 ,2-diol,
butane-1 ,3-diol, mink oil, cetyl alcohol, ispropyl isostearate, stearic acid, isobutyl palmitate,
isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol,
isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, isopropyl
15 myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polythylene glycol,
triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, sunflower seed oil, evening
primrose oil, castor oil, lanolin alcohols, petrolatum, mineral oil, butyl myristate, isostearic
acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl
myristate, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol
20 monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether,
dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran, glycerin, sorbitol, sodium 2-
pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, soaps and fatty alcohols.
25
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 must not be inhibited by
the other substances present in the formulation, such as the active principles, stabilizers,
whereas the specific adjuvants (such as foam consistency correctors) must be chosen from
30 those with strong hydrophilic and lipophilic characteristics.
5
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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 20% w/w to 50%
10 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
15 composition.
20
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.
Surface active agents which may be employed in the aqueous foam composition of the
present invention include, but are not limited to anionic surfactants, non-ionic surfactants,
cationic surfactants, and amphoteric surfactants.
Anionic surfactants include, but are not limited to, ammonium lauryl sulfate, sodium lauryl
25 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,
30 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,
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monoethano1amine 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
5 sulfosuccinate, diammonium lauryl sulfosuccinate, tetrasodium N-(1,2-dicarboxyethyl)-Noctadecylsulfosuccinate,
diamyl ester of sodium sulfosuccinic acid, dihexyl ester of sodium
sulfosuccinic acid, dioctyl esters of. sodium sulfosuccinic acid, docusate sodium, and
combinations thereof.
Nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid esters,
10 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
15 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, lauryllmyristyl amide DEA, lauryl/myristyl dimethyl
amine oxide, methyl gluceth, methyl glucose sesquistearate, oleamide DEA, PEG-distearate,
20 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
25 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.
30 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
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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-
5 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.
1 0 Cationic surfactants include, but are not limited to, bebenyl 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
15 dimethylbenzyl ammonium chloride, lauryl polyoxyethylene dimethylamine oxide, lauryl
trimethyl ammonium chloride, lautrimonium chloride, methyl-1-oleyl amide ethyl-2-oleyl
imidazolinium methyl sulfate, picolin benzyl ammonium chloride, polyquatemium,
stearalkonium chloride, sterayl dimethylbenzyl ammonium chloride, stearyl trimethyl
ammomum chloride, trimetbylglycine, and combinations thereof.
20 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.
It will be appreciated by the person skilled in the art that amongst the two or more surfactants
25 selected; at least one surfactant selected may provide the emulsifying action whereas the
other may provide a foam-stabilizing action. The surfactant(s) is desirably chosen are 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.
30
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17
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.
5 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,
10 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
15 and, consequently, the foam can reach more or less distant regions ofthe 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
20 a 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.
25 Additional active agents may be may be selected from, but are not limited to one or more
anti-inflammatory agents, steroids (e.g. corticosteroids), additional antibiotics, anti-fungal
agents, analgesics, or anti-neoplastic agents.
Suitable antibiotics include, but are not limited to, dapsone, chloramphenicol, neomycin,
30 cefaclor, cefadroxil, cephalexin, cephradine, erythromycin, clindamycin, lincomycin,
amoxicillin, ampicillin, bacampicillin, carbenicillin, dicl oxacillin, cyclacillin, picloxacillin,
hetacillin, methicillin, nafcillin, penicillin, polymyxin, tetracycline, amphotericin-b.
5
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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.
Suitable anitfungal agents include but are 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,
10 sulconazole, tioconazole, triazoles such as fluconazole, itraconazole, saperconazole,
terconazole, and others such as acrisorcin, amorolfTiota]ne, biphenamine,
bromosalicylchloranilide, buclosamide, calcium propionate, chlophenesin, ciclopirox,
cloxyquin, coparaf:fTiota ]nate, diamthazole, dihydrochloride, exalamide, flucytosine,
halethazole, hexetidine, Ioflucarban, nifuratel, potassium iodide, propionates, propionic acid,
15 pyrithione, salicylanilide, sulbentine, tenonitrozole, triacetin, ujothion, undecylenic acid.
Antifungal agents may also include, polyenes such as amphotericin-b. candicidin,
dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartricin,
natamycin, nystatin, pecilocin, perimycin, azaserine, griseofulvin, oligomycins, neomycin
20 undecylenate, pyrroinitrin, siccanin, tubercidin, viridin, 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,
25 terconazole, acrisorcin, amorolfTiota]ne, biphenamine, bromosalicylchloranilide,
buclosamide, calcium propionate, chlophenesin, ciclopirox, cloxyquin, coparaffiiota]nate,
diamthazole, dihydrochloride, exalamide, flucytosine, halethazole, hexetidine, Ioflucarban,
nifuratel, potassium iodide, propionates, propionic acid, pyrithione, salicylanilide, sulbentine,
tenonitrozole, triacetin, ujothion or undecylenic acid.
30
Other therapeutic agents can include a steroidal or non-steroidal antiinflammatory agent.
Non-steroidal anti-inflammatory agents, include, but are not .Jimited to, aspirin, ibuprofen,
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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,
5 mefenamic acid, meclofenamic acid, flufenamic acid, niflum[iota]c acid, tolfenamic acid,
diflurisal, flufenisal, piroxicam, sudoxicam, 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,
10 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.
15
Suitable corticosteroids include but are 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
20 phosphate, triamcinolone hexacetonide, dexamethasone phosphate, desonide, betamethasone
dipropionate, mometasone furate.
25
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
30 (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
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(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),
5 SmithK.line), 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 rifaximin which include, but not limited to, vincristine, vinblastine,
10 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),
15 asparaginase (L-asparaginase), etoposide, and interferon a-2a and 2b.
20
Antiviral agents may also be included in the topical foam composition of the present
invention along with the rifaximin which include, but are not limited to, acyclovir,
amantadine, azidothymidine, ribavirin and vidarabine.
In a case, where pain in a component of the target disorder, the other therapeutic agent can be
an analgesic. Useful analgesics include, but are not limited to, phenacetin, butacetin,
acetaminophen, nefopam, acetoamidoquinone, and mixtures thereof.
25 Optionally, a topical anesthetic may also be present in the composition of the invention. For
instance, the topical anesthetic may include, but are not limited to dibucaine, lidocaine,
pramoxine, benzocaine, tetracaine. In general, the topical anesthetic may be present in any
amount which is effective.
30 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),
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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
5 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
10 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
15 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.
20
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 unmetered
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
25 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 mixing of the ingredients with
propellant may be insured by shaking, optionally with the aid of a mixing bead. The can may
30 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.
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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.
5 The propellant expansion energy is absorbed mainly in forming the foam, thus allowing
rectal application without risk.
10
According to the present invention, the foam may be generated at the moment of therapeutic
application.
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,
15 with a minimum volume of0.5g to lOg of foam introduced into the rectum.
The present invention further provides a process of manufacturing the topical foam
composition of rifaximin comprising rifaximin in a nanosize range.
20 According to another embodiment of the present invention the topical foam composition of
rifaximin comprising rifaximin in a nanosize range can be made by
(1) Heating the mixture of emulsifying wax, emulsifier, with surfactant and preservativewater
separately.
(2) Adding water soluble alkanol to the preservative-water solution and then mixing with oily
25 phase of step (1)
30
(3) Adding nano milled rifaximin to the above mixture under stirring and adjusting the
required pH using a suitable pH adjusting agent.
( 4) Making up the volume of the mixture by adding purified water and finally filling the
blend in metal cans and charging the can with propellant.
According to a preferred embodiment of the present invention, Rifaximin can be reduced to a
nanosize range by (a) Homogenizing the dispersion of drug,. surfactant along with
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pharmaceutically acceptable carriers (b) Nanomilling the homogenized dispersion obtained in
step (a)
It will be appreciated by the person skilled in the art that the topical foam composition
5 comprising rifaximin may further comprise one or more pharmaceutical excipients, selected
from, but which are not limited to, emollients or humectants, pH adjusting agents,
emulsifiers, foaming agents, fatty alcohols, preservatives, chelating agents, antioxidants,
suspending agents, thickening agents, permeation enhancers, occlusive agents, colorants and
fragrances or combinations thereof.
10
Suitable pH adjusting agents, may be selected from, but are 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 citrate, sodium
15 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.
In a preferred embodiment, the topical foam composition according to the present invention
20 comprises a suitable pH adjusting agent to adjust the pH in the range from approximately 4 to
8.
Emulsifying waxes, which 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
25 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.
Surfactants, which may be employed in the topical foam composition of the present
invention, include, but are not limited to fatty alcohols such as, cetyl stearyl, lauryl, myristyl,
30 and palmityl alcohols, surfactants or mixtures thereof
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In another embodiment according to the present invention, a suitable surface active agent can
be employed which performs the function ofboth foaming agent and surfactant.
Suitable emollients and/or humectants, which may be employed in the topical foam
5 composition of the present invention, include, but are 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
10 as isopropyl stearate, isopropyl myristate, isopropyl palmitate and isopropyl laurate and the
like, preferably myristyl alcohol, octyldodecanol, propylene glycol .
Permeation enhancers may also be incorporated in the topical foam composition of the
present invention for delivery of the active ingredient to the mucosal surface. Enhancers
15 which may be employed in the topical foam composition of the present invention include, but
are not limited to, sodium glycocholate, sodium taurocholate, polysorbate 80, sodium lauryl
sulfate, lauric acid, various alkyl glycosides, dextrins ( cyclodextrin, dextran sulfate), fatty
acids (phosphatidylcholine, lysophosphatidylcholine), heterocyclic compounds (azone), and
small molecules (benzalkonium chloride, cetyltrimethylammonium bromide.
20
In another preferred embodiment, suitable mucoadhesives may also be employed in the
aqueous foam composition of the present invention to improve local retention of mucosally
delivered active ingredient.
25 Mucoadhesive compounds are primarily synthetic or natural polymers that can adhere to the
wet mucosal surface. These include synthetic polymers such as, but which are 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
30 mixtures thereof.
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25
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 oxidepropylene
oxide block copolymers, and combinations thereof. One preferred emulsifier is
5 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 ofthe composition.
Suitable suspending agents include, but are not limited to, alginic acid, bentonite, carbomer,
10 carboxymethyl cellulose and salts thereof, colloidal oatmeal, hydroxyethylcellulose,
hydroxypropylcellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin,
guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol, triglycerides,
methylcellulose, polyoxyethylene fatty acid esters, polyvinylpyrrolidone, propylene glycol
alginate, sodium alginate, sorbitan fatty acid esters, tragacanth, and combinations thereof.
15
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,
20 tryptophan, carotenoids, carotenes, alpha-Carotene, beta-Carotene, unc acid,
pharmaceutically acceptable salts thereof, derivatives thereof, and combinations thereof.
Suitable chelating agents include, but are not limited to, EDT A, disodium edetate, trans-1 ,2-
diaminocyclohexane-N ,N,N',N'-tetraaceticacid monohydrate, N ,N-bis(2-
25 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, ethylenediamineN,
N,N',N'-tetrakis(methylenephosphonic acid), O,O'-bis(2-aminoethyl)ethyleneglycol-
30 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,
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nitrilotripropionic acid, nitrilotris(methylenephosphonic acid), 7,19,30-trioxa-
1,4,10,13,16,22,27,33-octaazabicyclo[l11,11,1]pentatriacon- tane hexahydrobromide,
triethylenetetramine-N,N,N',N",N"',N"'-hexaacetic acid, and combinations thereof.
5 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.
1 0 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, propylparaben, sodium benzoate, sodium propionate, benzalkonium
chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol,
phenol, phenylethyl alcohol, thimerosal, and combinations thereof. The preservative is
15 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 antioxidants include, but are not limited to sodium metabisulphite and
20 advantageously this can be used in conjunction with a chelating agent such as a salt of
EDT A, 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
25 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.
30
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In a preferred embodiment, the treatment involves contacting or application of the
pharmaceutical composition of the present invention to the affected anal area or proximate
thereto, such that an effective amount of active ingredient is administered.
5 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
10 anal fissure, anal ulcer, acute hemorrhoidal 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., pouchtis).
In a further embodiment, the effective amount is effective to treat a bacterial infection, e.g.,
15 anal diseases including, one or more of anal fissure, anal ulcer, and acute hemorrhoidal
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.
20 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.
Example 1
Sr. Qty/ Unit
No.
Ingredients
(% w/w)
1 Rifaximin 5
2 Docusate sodium 0.1
3 SLS 0.3
4 Propylene glycol 20.00
5 Emulsifying wax 1.50
6 Cetyl alcohol 0.18
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7 Polyoxyethylene 10 stearyl ether 0.25
8 Methyl hydroxybenzoate or Methyl paraben 0.10
9 Propyl hydroxybenzoate or propyl paraben 0.01
10 Triethanolamine
q. s. to pH
6.0
11 Purified water
q. s. to 100
g
12 Propellant (Propane/ n· Butane/ !so butane) 4.00 g
Total 104.00 g
Process:
(1) Mixture of emulsifying wax, cetyl alcohol and polyoxyethylene stearyl ether were heated.
(2) Methyl paraben or methyl hydroxybenzoate and propyl paraben or propyl
5 hydroxybenzoate were heated with water.
(3) Propylene glycol was added to the solution of step (2) under homogenization.
(4) Mixture of step (1) was added to the solution of step (3) under homogenization and
cooled under stirring.
(5) Rifaximin nanomilled slurry was added to the above mixture and homogenized to cool at
1 0 room temperature.
15
(6) A solution of triethanolamine was added to the above mixture for adjusting the pH about
6.
(7) Volume was made up by adding purified water
(8) The blend was filled in metal cans and the can was charged 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
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29
I 6. I Propane/ n- butane/ iso-butane ,2.00- 10.00
Process:
1. Heat part quantity ofTriglycerides of capric/ caprylic acid, BHT, Propylparaben and
cetostearyl alcohol to about 60 - 70°C.
5 2. Homogenize the above mixture for 10 minutes and allow to cool.
3. Separately, heat part quantity ofTriglycerides of capric/caprylic acid and rifaximin and
homogenize for 1 0 minutes.
4. Add the above mixture step (3) in the mixture obtained in step (2) maintained at 45°C
under stirring.
10 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.
It will be readily apparent to one skilled in the art that varying substitutions and
15 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
20 invention.
25
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
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30
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.

CLAIMS:
1. A pharmaceutical composition for topical rectal administration in the form of a foam,
the composition comprising rifaximin in the form of nanoparticles.
5
2. A composition according to claim 1, further comprising an aqueous or non-aqueous
vehicle.
3. A composition according to claim 2, comprising wherein the non-aqueous vehicle is
10 one or more pharmaceutically acceptably alkanols; one or more pharmaceutically acceptable
vegetable oils; or one or more pharmaceutically acceptable organic esters.
4. A composition according to claim 3, wherein the water soluble alkanol is ethanol;
propylene glycol; glycerol; polyethyleneglycol; polypropylene glycol; propylene glycol; a
15 glyceryl ester; or a mixture thereof.
20
5. A composition according to claim 2, 3 or 4, wherein the vehicle comprises a water
soluble akanol and water, and wherein the w/w ratio of the water soluble alkanol to water
from 0.05:10 to 10:0.05.
6. A composition according to any one of claims 2 to 5, wherein the vehicle constitutes
from 10% w/w to 90% w/w ofthe total weight of the composition.
7. A composition according to any one of claim 2 to 6, wherein the vehicle comprises
25 water in an amount from 20% w/w to 90% w/w of the total weight of the composition, and a
water-soluble alkanol in an amount from 0% w/w to 50% w/w of the total weight of the
composition.
8. A composition according to any preceding claim, further comprising at least one
30 surfactant.
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9. A composition according to claim 8, wherein the surfactant is present in an amount of
from 0.1 to 1.0 w/w of the total weight of the composition.
10. A composition according to any preceding claim, further comprising at least one
5 propellant.
11. A composition according to claim 10, wherein the propellant is present in an amount
from 2 to 20% w/w of the total weight of the composition.
10 12. A composition according to any preceding claim, further comprising at least one
solubilizer.
13. A composition according to any preceding claim, further comprising at least one
emulsifier.
15
14. A composition according to claim 13, wherein the emulsifier is present in an amount
from 1% to 15% w/w of the total weight of the composition.
15. A composition according to any preceding claim, further comprising at least one
20 antioxidant.
16. A composition according to any preceding claim, further comprising at least one
preservative.
25 17. A composition according to claim 16, wherein the preservative is present m an
amount from 0.1% to 0.2% wlw of the total weight of the composition.
18. A composition according to any one of the preceding claims, further comprising a
silicone.
30
19. A composition according to any one of the preceding claims, comprising from 0.01%
to 10% w/w rifaximin of the total weight of the composition.
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20. A composition according to any preceding claim, which does not contain any mineral
oil.
5 21. A composition according to any one of the preceding claims, wherein the composition
further comprises 5-acetyl salicylic acid (5-ASA), sulphasalazine, asalazine, prednisolone, or
budesonide.
22. A composition according to any preceding claim, wherein the rifaximin particles
10 having an effective particle size ranging form 1 0 to 1000 run.
23. A pharmaceutical composition for topical rectal administration in the form of a foam,
the composition comprising the following components in w/w:
Ingredients
Quantity
%w/w
Rifaximin having an
effective particle size in the 5
range 1 0 to 1000 nm
Docusate sodium 0.1
SLS 0.3
Propylene glycol 20.00
Emulsifying wax 1.50
Cetyl alcohol 0.18
Polyoxyethylene 10 stearyl
0.25
ether
Methyl hydroxybenzoate or
0.10
Methyl paraben
Propyl hydroxybenzoate or
0.01
propyl paraben
Triethanolamine q. s. to pH 6.0
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Purified water
Propellant (Propane/ nButane/
Isobutane)
PCT/GB2010/002161
34
q. s. to 100 g
4.00 g
24. A phannaceutical composition as defined in any one of claims 1 to 23 for
administration to the rectum, colon and/or terminal ileum of a patient for the treatment,
5 prophylaxis, or maintenance of remission of a disorder of the rectum, colon, terminal ileum
or anus.
25. The use of a pharmaceutical composition as defined in any one of claims 1 to 23 in
the manufacture of a medicament for administration to the rectum, colon and/or terminal
10 ileum of a patient for the treatment, prophylaxis, or maintenance of a disorder of the rectum,
colon, terminal ileum or anus.
26. A method of treating, preventing, or alleviating a disorder of the rectum, colon,
terminal ileum or anus, comprising administering an effective amount of a pharmaceutical
15 composition according to any one of claims 1 to 23 to a subject in need thereof.
27. A process for manufacturing a pharmaceutical composition containing rifaximin,
comprising:
(1) heating a mixture of emulsifier and surfactant to form an oily phase;
20 (2) separately heating a mixture of a preservative and water;
25
(3) adding a water soluble alkanol to the preservative-water mixture and then mixing with
oily phase of step ( 1 ); and
(4) Adding rifaximin in the form of nanosized particles to the above mixture under stirring
and adjusting the required pH to a desired value using a pH adjusting agent.
28. A process according to claim 27, further comprising heating an emulsifying wax with
the emulsifier and surfactant in step (1).
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29. A process according to claim 30, further comprising optionally adding purified water
to the product of step ( 4 ), then filling the product into a dispenser and charging the dispenser
with a propellant.
5 30. A process according to claim 27,r 28 or 29, wherein the nanosized particles are
prepared by reducing the rifaximin to a nanosize range by (a) homogenizing a dispersion of
rifaximin with a surfactant in a pharmaceutically acceptable carrier; (b) nanomilling the
homogenized dispersion obtained in step (a).
10 31. A process according to claim 27, 28, 29 or 30, wherein the particle size of the
rifaximin is less than about 1 000 nm.
15
32. The use of a silicone as a lubricant and a stabilizer in a rectal form composition
containing rifaximin.
33. A dispenser for a pharmaceutical composition as defined in any one of claims 1 to 23,
comprising a canister containing under pressure the pharmaceutical composition; a metering
valve for measuring a metered dose of the composition from the canister for administration to
a patient in need thereof; and an actuator for actuating discharge of the metered dose of the
20 formulation to patient in the form of a foam.
25
30
34. A dispenser according to claim 33, wherein the metered dose comprises 0.5g to 1 Og
of the pharmaceutical composition.