Pharmaceutical Composition
FIELD OF INVENTION:
The present invention relates to a pharmaceutical composition comprising an antibacterial
drug, a process for preparing such pharmaceutical composition, and its use for the treatment
and/or prevention of colonic diseases.
BACKGROUND AND PRIOR ART:
One of the major obstacles to the development of highly potent pharmaceutical formulations
is the poor water solubility of many drugs. Approximately 40% of potential drugs identified
by pharmaceutical companies are poorly soluble in water, which greatly hinders their clinical
use. Low water solubility limits the bioavailability and absorption of these agents.
Rifaximin is a semisynthetic antibiotic belonging to the rifamycin class of antimicrobial
drugs exhibiting in vitro activity against Gram-positive, Gram-negative and anaerobic
bacteria. Rifaximin acts by inhibiting bacterial ribonucleic acid (RNA) synthesis. Rifaximin
is chemically named as[(2 ,16Z 85,20 .21S,22 ,23R,24R,255,26S,27S,28^-5,6,21,23,25-
pentahydroxy-27-methoxy-2,4,l l,16,20,22,24,26-octamethyl-2,7 (epoxypentadeca-
[1,1 l,13]trienimino)benzofuro [4,5-e]pyrido[l,2-a]-benzimida-zole l ,1 (2H)-dione,25-
acetate]. Rifaximin has the following chemical formula.
Rifaximin has been indicated for the treatment of traveler's diarrhea caused by non-invasive
strains of Escherichia coli, a micro-organism which is not able to penetrate into
gastrointestinal (GI) mucosa and therefore remains in contact with gastrointestinal fluids.
Rifaximin is highly effective in preventing and treating traveler's diarrhea, with fewer side
effects and a low risk of developing antibiotic resistance.
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
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 a poorly water-soluble and minimally absorbed (<0.4%) drug with in vitro
activity against enteric Gram-negative bacteria including enteric pathogens. [Gerard L et al,
Rifaximin, a non-absorbable rifamycin antibiotic for use in nonsystemic gastrointestinal
infections. Expert Review of Anti-infective therapy, 3(2), 201-21 , (2005)].
It has also been reported that rifaximin is characterized by negligible systemic absorption,
due to its chemical and physical characteristics [Descombe J J et al, Pharmacokinetic study
of rifaximin after oral administration in healthy volunteers. International Journal of Clinical
Pharmacology Research, 4 (2), 51-56, (1994)].
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, Journal
of Medicinal Chemistry., 28, 960-963, (1985)].
Hence in addition to poor water solubility, rifaximin has no systemic absorption which poses
a challenge to formulate suitable formulations of rifaximin.
Rifaximin is currently available as 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®.
WO2007/047253 discloses methods of increasing the aqueous solubility of an antifungal
azole using hydroxybutenyl cyclodextrins.
WO2010/067072 discloses complexes of rifaximin and process for preparing such
complexes.
EP0858804 discloses use of oral rifaximin compositions in the treatment of diarrhea from
cryptosporidiosis. The rifaximin formulations disclosed in the patent are in the form of tablet,
capsule, sugar coated tablet, granules or syrup for oral administration.
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
in the form of tablet, capsule, sugar coated tablet, granules or syrup for oral administration.
Several strategies and formulations have been employed to overcome these limitations of
solubility and poor systemic absorption. Although existing strategies such as complexing
drugs with cyclodextrins, conjugation to dendrimers, salt formation of ionizable drugs and
the use of co-solvents have been shown to improve drug solubility, solubilization methods
that can improve the absorption of the drug are still highly desirable.
Hence, there still exists a need to develop and formulate a suitable composition of rifaximin
that overcome the problems mentioned in the prior art.
OBJECT OF THE INVENTION:
The object of the present invention is to provide a pharmaceutical composition of nanosized
rifaximin having improved surface area and solubility.
Another object of the present invention is to provide a process for preparing the
pharmaceutical composition comprising nanosized rifaximin.
Yet another object of the present invention is to provide a method for treatment and/or
prevention of colonic diseases which comprises administering a pharmaceutical composition
comprising nanosized rifaximin.
SUMMARY OF THE INVENTION:
According to one aspect of the present invention there is provided a pharmaceutical
composition comprising rifaximin or a pharmaceutically acceptable salt, solvate, derivative,
hydrate, enantiomer, polymorph, prodrug, complex, or mixture thereof.
According to another aspect of the present invention there is provided a pharmaceutical
composition comprising rifaximin or a pharmaceutically acceptable salt, solvate, derivative,
hydrate, enantiomer, polymorph, prodrug, complex or mixture thereof wherein the rifaximin
is in the nanosize range.
According to yet another aspect of the present invention there is provided a process for
preparing a pharmaceutical composition comprising rifaximin or a pharmaceutically
acceptable salt, solvate, derivative, hydrate, enantiomer, polymorph, prodrug, complex or
mixture thereof wherein the rifaximin is in the nanosize range.
According to a further aspect of the present invention there is provided a method of treatment
and/or prevention of colonic diseases using a pharmaceutical composition comprising
rifaximin or a pharmaceutically acceptable salt, solvate, derivative, hydrate, enantiomer,
polymorph, prodrug, complex or mixture thereof wherein the rifaximin is in the nanosize
range.
DETAILED DESCRIPTION OF THE INVENTION:
Rifaximin is a poorly water-soluble drug exhibiting minimal absorption. Rifaximin is also
characterized by negligible systemic absorption, due to its chemical and physical
characteristics and hence it has been difficult to formulate rifaximin in any suitable dosage
form
The inventors of the present invention have found that the solubility properties of rifaximin
were improved by nanosizing rifaximin thus leading to better localized therapeutic effect for
example in the colon.
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
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 2010].
Nanosizing leads to increase in the exposure of surface area of rifaximin particles leading to
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 its
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, 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
not limited to milling, precipitation and homogenization.
The pharmaceutical composition of the present invention comprises rifaximin having an
effective particle size range of less than 2000nm, preferably below lOOOnm.
According to one embodiment of the present invention, the process of milling comprises
dispersing rifaximin particles in a liquid dispersion medium in which rifaximin is poorly
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
involves the formation of crystalline or semi-crystalline rifaximin nanoparticles by nucleation
and the growth of drug crystals. In a typical procedure, drug molecules are first dissolved in
an appropriate organic solvent such as acetone, tetrahydrofuran or N-methyl-2-pyrrolidone at
a super saturation concentration to allow for the nucleation of drug seeds. Drug nanocrystals
are then formed by adding the organic mixture to an aritisolvent like water in the presence of
stabilizers such surfactants. The choice of solvents and stabilizers and the mixing process are
key factors to control the size and stability of the drug nanocrystals.
According to one another embodiment of the present invention, the process of
homogenization involves passing a suspension of crystalline rifaximin and stabilizers through
the narrow gap of a homogenizer at high pressure (500-2000 bar). The pressure creates
powerful disruptive forces such as cavitation, collision and shearing, which disintegrate
coarse particles to nanoparticles.
According to yet another embodiment of the present invention, the process of high pressure
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 25 which leads to a high streaming
velocity. High-pressure homogenization is based on the principle of cavitations (i.e., the
formation, growth, and implosive collapse of vapor bubbles in a liquid).
According to one more 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
or fluorocarbon. The water is removed by sublimation after the liquid droplets solidify.
According to a still 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
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
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
of organic particles. PRINT can precisely manipulate particle size of rifaximin ranging from
20 nm to more than 100 nm.
According to one further embodiment of the present invention, the process of thermal
condensation involves use of capillary aerosol generator (CAG) to produce high
concentration condensation submicron to micron sized aerosols from rifaximin solutions.
According to still 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 another 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
particles of rifaximin.
According to a preferred embodiment of the present invention, the namomilled rifixamin may
be obtained by nanomilling of rifaximin with at least one surface stabilizer, at least one
viscosity building agent and at least one polymer.
The present invention thus provides a pharmaceutical composition comprising granules of
rifaximin, wherein rifaximin is in the nanosize range and the granules comprise at least one
surface stabilizer, at least one viscosity building agent and at least one polymer along with
rifaximin and optionally other pharmaceutically acceptable carriers.
Surface stabilizer, according to the present inventions, means surfactants that are capable of
stabilizing the increased surfaced charge of the nanomilled drug. Suitable amphoteric, nonionic,
cationic or anionic surfactants may be included in the pharmaceutical composition of
the present invention.
According to the present invention, surfactant may comprise one or more, but not limited to
Polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl amine oxide,
Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB)
Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, Ndimethyldodecylamine-
N-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10
lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil,
Nonylphenol ethoxylate, Cyclodextrins, Lecithin, Methylbenzethonium chloride.
Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates,
Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural
oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated &
sulphated, Ethoxylated aliphatic alcohol, polyoxyethylene surfactants, carboxylic esters
Polyethylene glycol esters, Anhydrosorbitol ester & it's ethoxylated derivatives, Glycol
esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene
fatty acid amides, Quaternary ammonium salts, Amines with amide linkages,
Polyoxyethylene alkyl & alicyclic amines, ,,,tetrakis substituted ethylenediamines 2-
alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-aminopropionic acid/ sodium salt, N-tallow
3 -iminodipropionate disodium salt, N-carboxymethyl n dimethyl n-9 octadecenyl
ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine sodium salt or mixtures
thereof etc.
Viscosity builders means, excipients that are capable of stabilizing the nanoparticles by
increasing the viscosity of the formulation and thus preventing physical interaction of
nanoparticles under the operating conditions employed.
According to the present invention, viscosity builders, may comprise one or more, but not
limited to derivatives of sugars, such as lactose, saccharose, hydrolyzed starch (maltodextrin)
etc or mixtures thereof.
Polymers or polymers blends, according to the present invention, may comprise one or more
hydrophilic polymers, but not limited to cellulose derivates like hydroxypropylcellulose,
hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose polymers
hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene and
carboxymethyl hydroxyethylcellulose; acrylics like acrylic acid, acrylamide, and maleic
anhydride polymers, acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum,
agar, pectin, carrageenan, gelatin, casein, zein and alginates, carboxypolymethylene,
bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives and
copolymers or mixtures thereof.
In one embodiment the percentage weight of active ingredient in the slurry ranges from 5%
to 60%w/w.
The nanoparticulate rifaximin compositions of the invention can be administered to a subject
via any conventional means including, but not limited to, orally, rectally, ocularly,

parenterally (e.g., intravenous, intramuscular, or subcutaneous), intracisternally,
intravaginally, intraperitoneally, locally (e.g., powders, ointments or drops), or buccal route.
In an embodiment, the rifaximin composition according to the invention is not a rectal
formulation.
In an embodiment, the rifaximin composition according to the invention is not a rectal foam
formulation.
Moreover, the nanoparticulate rifaximin compositions of the invention can be formulated into
any suitable dosage form, including but not limited to liquid dispersions, gels, aerosols,
ointments, creams, controlled release formulations, lyophilized formulations, tablets,
capsules, delayed release formulations, extended release formulations, pulsatile release
formulations, and mixed immediate release and controlled release formulations.
The nanomilled rifaximin compositions can be formulated for parenteral injection (e.g.,
intravenous, intramuscular, or subcutaneous), oral administration in solid, liquid, or aerosol
form, foams (vaginal, rectal), vaginal, rectal, ocular, local (powders, ointments or drops),
buccal, intraci sternal, intraperitoneal, or topical administration, and the like.
Nanoparticulate rifaximin compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions
or emulsions, and sterile powders for reconstitution into sterile injectable solutions or
dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include
but are not limited to, water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol,
and the like) and suitable mixtures thereof, vegetable oils and injectable organic esters.
The nanoparticulate rifaximin compositions may also contain excipients such as preserving,
wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can
be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol,
phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as
sugars, sodium chloride, and the like.
Solid dosage forms for oral administration include, but are not limited to, capsules, tablets,
pills, powders, and granules. In such solid dosage forms, the active agent is admixed with at
least one of the following: (a) one or more inert excipients (or carriers) (b) fillers or extenders
(c) binders (d) humectants (e) disintegrating agents (f) solution retarders (g) absorption
accelerators (h) wetting agents (i) adsorbents and (j) lubricants. For capsules, tablets, and
pills, the dosage forms may also comprise buffering agents.
The nanomilled granules obtained, according to the present invention, may either be
encapsulated in capsules or be compressed to form tablets or may be provided as sachets or
be provided as powders for reconstitution.
The solid dosage form, according to the present invention, may also optionally be coated.
More preferably, the formulation may be seal coated and further enteric coated.
According to an embodiment of the present invention, there is a seal coat between the core
containing rifaximin, and the enteric coat. The seal coat comprises one or more
pharmaceutically acceptable film-forming polymers and pharmaceutically acceptable
excipients(s). The seal coat provides a smooth base for the application of the enteric coat,
prolongs the resistance of the core to the acidic conditions, improves stability by minimizing
the interaction between drug in the core and the enteric polymer in the enteric layer from
coming into direct contact with each other; and also improves stability of drug from light
exposure. The smoothing function of the separating coat is purely mechanical, the objective
of which is to improve the coverage of the enteric coat and to avoid thin spots in it, caused by
bumps and irregularities on the core.
According to the present invention, the seal coat comprises film forming polymeric materials,
such as but not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose,
polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, hypromellose, acacia, gelatin
to increase adherence and coherence of the seal coat.
According to another embodiment of the present invention, the enteric coat is present over
the seal coat. The enteric coat comprises of materials such as, but not limited to, neutralized
methacrylic acid copolymers such as, EUDRAGIT L 30 D-55, EUDRAGIT LI00-55,
EUDRAGIT S 100, EASTACRYL 30D, KOLLICOAT MAE 30 DP, KOLLICOAT MAE
100 P; cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and
combinations thereof.
According to the present invention, the enteric coat of the present invention may include a
plasticizer, surfactant, pigments, anti- adherents, opacifying agents, colorants and the like,
which are routinely employed in the preparation of coating solution or suspension.
The plasticizers used in the present invention may comprise polyethylene glycol, tributyl
sebacate, acetylated monoglycerides, glycerin, triacetin, phthalate esters, castor oil, sorbitol,
polysorbates such as sorbitan monolaurate (Span 20), sorbitan monopalmitate, sorbitan
monostearate, sorbitan monoisostearate; citrate ester type plasticizers like triethyl citrate,
citrate phthalate; propylene glycol, glycerin, polyethylene glycol (low & high molecular
weight), dibutyl sebacate, tributyl sebacate; dibutyltartrate, dibutyl phthalate, glycerol
palmitosterate and mixtures thereof.
The anti-adherent used in the present invention may comprise talc, magnesium stearate,
fumed silica, micronized silica and silicon dioxide and mixtures thereof.
Alternatively, the nanomilled slurry may also be used to formulate liquid dosage forms.
Liquid nanoparticulate rifaximin dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In
addition to rifaximin, the liquid dosage forms may comprise inert diluents commonly used in
the art, such as water or other solvents, solubilizing agents, and emulsifiers.
Besides such inert diluents, the composition can also include adjuvants, such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
1
In addition to rifaximin, the liquid dosage forms may comprise inert diluents, such as water
or other solvents, solubilizing agents, suspending agents, emulsifying agents, sweetening
agents, flavoring agents, perfuming agents, pH adjusting agents and preservatives.
Suitable excipients may be used for formulating the various dosage forms according to the
present invention.
Emulsifying agents may comprise one or more, but not limited to, ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyl eneglycol, 1,3-
butyleneglycol, dimethylformamide, oils, such as cottonseed oil, groundnut oil, corn germ
oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol,
polyethyleneglycols, fatty acid esters of sorbitan, or mixtures thereof.
Suspending agents may comprise one or more, but not limited to, methylcellulose,
hydroxypropylmethylcellulose, microcrystalline cellulose, hydroxybutylmethylcellulose
hydroxyethylmethylcellulose, ethylhydroxyethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, carboxymethylcellulose sodium, xanthan gum, silicon dioxide and
mixtures thereof.
According to the present invention, pharmaceutically acceptable carriers, diluents or fillers
for use in the pharmaceutical composition of the present invention may comprise one or
more, but not limited to lactose (for example, spray-dried lactose, a-lactose, -lactose)
lactose available under the trade mark Tablettose, various grades of lactose available under
the trade mark Pharmatose or other commercially available forms of lactose, lactitol,
saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmellose
sodium, microcrystalline cellulose (for example, microcrystalline cellulose available under
the trade mark Avicel), hydroxypropylcellulose, L-hydroxypropylcellulose (low substituted),
hydroxypropyl methylcellulose (HPMC), methylcellulose polymers (such as, for example,
Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose,
sodium carboxymethylcellulose, carboxymethylene, carboxymethyl hydroxyethylcellulose
and other cellulose derivatives, starches or modified starches (including potato starch, corn
starch, maize starch and rice starch) and mixtures thereof.
According to the present invention, glidants and lubricants may also be incorporated in the
pharmaceutical composition of the present invention, which may comprise one or more, but
not limited to stearic acid and pharmaceutically acceptable salts or esters thereof (for
example, magnesium stearate, calcium stearate, sodium stearyl fumarate or other metallic
stearate), talc, waxes (for example, microcrystalline waxes) and glycerides, light mineral oil,
PEG, silica acid or a derivative or salt thereof (for example, silicates, silicon dioxide,
colloidal silicon dioxide and polymers thereof, crospovidone, magnesium aluminosilicate
and/ or magnesium alumino metasilicate), sucrose ester of fatty acids, hydrogenated
vegetable oils (for example, hydrogenated castor oil), or mixtures thereof.
According to the present invention, suitable binders may also be present in the in the
pharmaceutical composition of the present invention, which may comprise one or more, but
not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene glycol(s),
acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as ethyl cellulose,
methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium
carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum, tragacanth, sodium alginate,
or mixtures thereof or any other suitable binder.
According to the present invention, suitable disintegrants may also be present in the in the
pharmaceutical composition of the present invention, which may comprise one or more, but
not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymethylcellulose
(CMC), sodium CMC, calcium CMC, croscarmellose sodium; starches exemplified under
examples of fillers and also carboxymethyl starch, hydroxylpropyl starch, modified starch;
crystalline cellulose, sodium starch glycolate; alginic acid or a salt thereof, such as sodium
alginate or their equivalents and mixtures thereof.
Further, the pharmaceutical composition according to the present invention may further
comprise at least one additional active ingredient.
cJ
Additional active agents may be selected from, but not limited to one or more of ant i
inflammatory agents, steroids (e.g. corticosteroids), additional antibiotics, anti-fungal agents,
anti-viral agents, analgesics, or anti-neoplastic agents.
Suitable antibiotics include, but are not limited to, dapsone, chloramphenicol, neomycin,
cefaclor, cefadroxil, cephalexin, cephradine, erythromycin, clindamycin, lincomycin,
amoxicillin, ampicillin, bacampicillin, carbenicillin, dicl oxacillin, cyclacillin, picloxacillin,
hetacillin, methiciltin, nafcillin, penicillin, polymyxin, tetracycline, amphotericin-b,
candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin,
mepartncin, 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, flutrimazoie, isoconazole,
ketoconazole, lanoconazole, miconazole, om'oconazole, oxiconazole nitrate, sertaconazole,
sulconazole, tioconazole, triazoles such as fluconazole, itraconazole, saperconazole,
terconazole, and others such as acrisorcin, amorolfine, biphenamine,
bromosalicylchloranilide, buclosamide, calcium propionate, chlophenesin, ciclopirox,
cloxyquin, coparaffinate, diamthazole, dihydrochloride, exalamide, flucytosine, halethazole,
hexetidine, Ioflucarban, nifuratel, potassium iodide, propionates, propionic acid, 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
undecylenate, pyrroinitrin, siccanin, tubercidin, viridin, allylamines such as butenafine,
naftifine, imidazoles such as bifonazole, butoconazole, chlordantoin, chlormidazole,
cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazoie, isoconazole,
ketoconazole, lanoconazole, miconazole, omoconazole, oxiconazole nitrate, sertaconazole,
sulconazole, tioconazole, triazoles such as fluconazole, itraconazole, saperconazole,
terconazole, acrisorcin, amorolfine, biphenamine, bromosalicylchloranilide, buclosamide,
calcium propionate, chlophenesin, ciclopirox, cloxyquin, coparaffmate, diamthazole,
dihydrochloride, exalamide, flucytosine, halethazole, hexetidine, Ioflucarban, nifuratel,
potassium iodide, propionates, propionic acid, pyrithione, salicylanilide, sulbentine,
tenonitrozole, triacetin, ujothion or undecylenic acid.
Other therapeutic agents can include a steroidal or non-steroidal antiinflammatory agent.
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, niflumic 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.
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 2 1 -sodium succinate, hydrocortisone tebutate, corticosterone, corticosterone
acetate, cortisone, cortisone acetate, cortisone 2IB- cyclopentanepropionate, cortisone
phosphate, triamcinolone hexacetonide, dexamethasone phosphate, desonide, betamethasone
dipropionate, mometasone furate.
Antineoplastic agents may also be included in the pharmaceutical composition of the present
invention along with rifaximin which include, but are not limited to, vincristine, vinblastine,
ί 7
vindesine, busulfan, chlorambucil, spiroplatin, cisplatin, carboplatin, methotrexate,
adriamycin, mitomycin, bleomycin, cytosine arabinoside, arabinosyl adenine,
mercaptopurine, mitotane, procarbazine, dactinomycin (antinomycin D), daunorubicin,
doxorubicin hydrochloride, taxol, plicamycin, aminoglutethimide, estramustine, flutamide,
leuprolide, megestrol acetate, tamoxifen, testolactone, tnlostane, amsacrine (m-AMSA),
asparaginase (L-asparaginase), etoposide, and interferon a-2a and 2b.
Antiviral agents may also be included in the pharmaceutical composition of the present
invention along with the rifaximin which include, but are not limited to, acyclovir,
amantadine, azidothymidine, ribavirin and vidarabine.
In a further embodiment, the pharmaceutical composition according to the present invention
may be used to treat a bacterial infection, e.g., 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.
The present invention further provides a method of treatment and/or prevention of colonic
diseases, which method comprising administering to a subject in need thereof an effective
amount of rifaximin, wherein the rifaximin is in the nanosize range.
There is further provided a process for preparing the pharmaceutical compositions which
process comprises
(a) Homogenizing the dispersion of rifaximin, docusate sodium, sucrose, HPMC (b)
Nanomilling the homogenized dispersion obtained in step (a)
(c) Adsorbing the nanomilled slurry obtained in step (b) on a mixture of lactose
monohydrate, microcrystalline cellulose and crospovidone to form granules.
According to one embodiment the pharmaceutical composition of the present invention, may
be prepared by a process which comprises (a) preparing a dispersion of rifaximin with
Docusate sodium, HPMC, sodium lauryl sulphate and sucrose in purified water under stirring
conditions (b) homogenizing the dispersion of step (a) and then nanomilling the homogenized
dispersion (c) adsorbing the nanomilled drug by spraying the nanomilled slurry on lactose
monohydrate, microcrystalline cellulose and crospovidone mixture in fluidized bed
granulator (d) drying and blending the granules obtained (e) lubricating the granules and
finally compressing into tablets (f) the tablets obtained were seal coated and then enteric
coated.
The nanomilled rifaximin composition prepared according to the present invention exhibited
a dissolution profile which is showing an improvement over the prior art composition as
evident from Fig 1. This might further lead to a considerably enhanced bioavailability of the
active ingredient compared to that obtained with the compositions of the prior art.
The following examples are for the purpose of illustration of the invention only and is not
intended in any way to limit the scope of the present invention.
Example 1
Sr. No. Ingredients Qty mg/tablet
Binder Solution
1. Rifaximin 200.00
2. Docusate Sodium 2.00
3. Hydroxypropylmethylcellulose 3cps 40.00
4. Sodium lauryl sulphate IP 5.50
5. Sucrose IP 69.00
6. Purified water IP q.s
Dry Mix
7. Lactose Monohydrate(200 mesh) 200.00
8. Microcrystalline Cellulose IP (Avicel PH 101) 200.00
9. Crospovidone IP 25.00
Lubrication
10. Crospovidone IP 30.00
11. Magnesium Stearate 03.50
Total 775.00
Seal Coating
12. Hydroxypropylmethylcellulose 3cps IP 15.00
13. Isopropyl Alcohol P q.s
14. Dichloromethane BP q.s
Total 790.00
Enteric Coating
15. Eudragit L (30% dispersion) 26.00
16. Talc 13.00
17. Tri-Ethyl Citrate 13.00
18. Water q.s.
Total 842.00
Process:
1. Dispersion of rifaximin with Docusate sodium, HPMC, sodium lauryl sulphate and sucrose
was prepared in purified water under stirring conditions
2 . Above dispersion was homogenized and then Nanomilled
3 . Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator.
4 . Granules obtained were sized and lubricated.
5 . Lubricated granules were finally compressed into tablets
6. The tablets obtained were seal coated and then enteric coated.
Example 2
Sr. No. Ingredients Qty mg/tablet
Binder Solution
1. Rifaximin 200.00
2 . Docusate Sodium IP 2.00
3. Hydroxypropylmethylcellulose 3cps TP 40.00
4. Sodium lauryl sulphate IP 5.50
5. Sucrose IP 69.00
6. Purified water IP q.s
Dry Mix
7. Lactose Monohydrate(200 mesh) IP 200.00
8. Microcrystalline Cellulose IP (Avicel PH 101) 200.00
9. Crospovidone IP 25.00
Lubrication
10. Crospovidone IP 30.00
11. Magnesium Stearate IP 03.50
Total 775.00
Seal Coating
12. Hydroxypropylmethylcellulose 3cps IP 15.00
13. Isopropyl Alcohol IP q.s
14. Dichloromethane BP q.s
Total 790.00
Enteric Coating
15. Hydroxypropyl Methylcellulose Pthalate 26.00
16. Triacetin 13.00
17. Isopropyl Alcohol IP q.s.
18. Dichloromethane BP q.s.
Total 818.60
Process:
1. Dispersion of rifaximin with Docusate sodium, HPMC, sodium lauryl sulphate and sucrose
was prepared in purified water under stirring conditions
2. Above dispersion was homogenized and then Nanomilled
3 . Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator.
4. Granules obtained were sized and lubricated.
5. Lubricated granules were finally compressed into tablets
6. The tablets obtained were seal coated and then enteric coated.
Example 3
Sr. No. Ingredients Qty mg/tablet
Binder Solution
1. Rifaximin 200.00
2. Docusate Sodium IP 2.00
3. Hydroxypropylmethylcellulose 3cps IP 40.00
4. Sodium lauryl sulphate IP 5.50
5. Sucrose IP 69.00
6. Purified water P q.s
Dry Mix
7. Lactose Monohydrate(200 mesh) IP 200.00
8. Microcrystalline Cellulose EP (Avicel PH 101) 200.00
9. Crospovidone EP 25.00
Lubrication
10. Crospovidone EP 30.00
1. Magnesium Stearate EP 03.50
Total 775.00
Seal Coating
12. Hydroxypropylmethylcellulose 3cps EP 15.00
13. Isopropyl Alcohol P q.s
14. Dichloromethane BP q.s
Total 790.00
Enteric Coating
15. Cellulose Acetate Pthalate 26.00
16. Triacetin 2.60
17. Isopropyl Alcohol EP q.s.
18. Dichloromethane BP q.s.
Total 818.60
Process:
1. Dispersion of nfaximin with Docusate sodium, HPMC, sodium lauryl sulphate and sucrose
was prepared in purified water under stirring conditions
2. Above dispersion was homogenized and then Nanomilled
3. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator.
4. Granules obtained were sized and lubricated.
5. Lubricated granules were finally compressed into tablets
6. The tablets obtained were seal coated and then enteric coated.
Example 4
Sr. No. Ingredients Qty mg/tablet
Binder Solution
1. Rifaximin 200.00
2. Docusate Sodium IP 2.00
3. Hydroxypropylmethylcellulose 3cps IP 40.00
4. Sodium lauryl sulphate IP 5.50
5. Sucrose IP 69.00
6. Purified water IP q.s
Dry Mix
7. Lactose Monohydrate(200 mesh) IP 200,00
8. Microcrystalline Cellulose IP (Avicel PH 101) 200.00
9 . Crospovidone IP 25.00
Lubrication
10. Crospovidone IP 30.00
11. Magnesium Stearate IP 03.50
Total 775.00
Seal Coating
12. Hydroxypropylmethylcellulose 3cps IP 15.00
13. Isopropyl Alcohol IP q.s
14. Dichloromethane BP q.s
Total 790.00
Enteric Coating
15. Eudragit SlOO 26.00
16. Talc 13.00
17. Tri-Ethyl Citrate 13.00
18. Water q.s.
Total 842.00
Process:
1. Dispersion of nfaximin with Docusate sodium, HPMC, sodium lauryl sulphate and sucrose
was prepared in purified water under stirring conditions
2. Above dispersion was homogenized and then Nanomilled
3. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator.
4. Granules obtained were sized and lubricated.
5. Lubricated granules were finally compressed into tablets
6. The tablets obtained were seal coated and then enteric coated.
Example 5
Sr. No. Ingredients Qty mg/tablet
Binder Solution
1. Rifaximin 200.00
2. Docusate Sodium IP 2.00
3. Hydroxypropylmethylcellulose 3cps IP 40.00
4. Sodium lauryl sulphate IP 5.50
5. Sucrose IP 69.00
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate(200 mesh) IP 200.00
8. Microcrystalline Cellulose IP (Avicel PH 101) 200.00
9. Crospovidone IP 25.00
Lubrication
10. Crospovidone IP 30.00
11. Magnesium Stearate IP 03.50
Total 775.00
Seal Coating
12. Hydroxypropylmethylcellulose 3cps IP 15.00
13. Isopropyl Alcohol IP q.s
14. Dichloromethane BP q.s
Total 790.00
Enteric Coating
15. Eudragit L (30% dispersion) 13.00
16. Eudragit SlOO 13.00
17. Talc 13.00
18. Tri-Ethyl Citrate 13.00
19. Water q.s.
Total 842.00
Process:
1. Dispersion of rifaximin with Docusate sodium, HPMC, sodium lauryl sulphate and sucrose
was prepared in purified water under stirring conditions
2. Above dispersion was homogenized and then NanomiUed
3. NanomiUed drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator.
4. Granules obtained were sized and lubricated.
5. Lubricated granules were finally compressed into tablets
6. The tablets obtained were seal coated and then enteric coated.
Example 6:
Sr. No. Ingredients Qty mg/tablet
Binder Solution
1. Rifaximin 200.00
2. Docusate Sodium IP 2.00
3. Hydroxypropylmethylcellulose 3cps IP 40.00
4. Sodium lauryl sulphate IP 5.50
5. Sucrose IP 69.00
6. Purified water IP q.s
Dry Mix
7. Lactose Monohydrate 124.50
9. Crospovidone IP 73.00
Blending
10. Microcrystalline cellulose (Avicel pH 102) 50.00
11. Sodium Starch Glycolate (Type A) 20.00
12. Talc 3.00
13. Croscarmellose sodium 100.00
Lubrication
14. Magnesium Stearate 3.00
Total 690.00
Enteric Coating
15. Eudragit L 100-55 27.5
16. Talc 10.46
17. Tri-Ethyl Citrate 5.13
18. Red Iron Oxide 0.91
18. Water q.s.
19. Isopropyl Alcohol q.s.
Total 734.00
Process:
. Dispersion of rifaximin with Docusate sodium, HPMC, sodium lauryl sulphate and sucrose
was prepared in purified water under stirring conditions
2. Above dispersion was homogenized and then Nanomilled
3. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate, and
crospovidone mixture in a fluidized bed granulator.
4. Granules obtained were blended, sized and lubricated.
5. Lubricated granules were finally compressed into tablets
6. The tablets obtained were then enteric coated.
Example 7
Dissolution of a composition according to the invention and a composition according to the
prior art.
According to present invention dissolution study was carried out in an aqueous medium
containing a surfactant 0.5% SLS. The paddle method (US Pharmacopoeia) was used under
the following conditions: volume of medium 900 ml; medium temperature: 37° C ; blade
rotation speed 50 rpm; samples taken: every 0 minutes.
Table 1:
The composition according to present invention consisted of Rifaximin 200mg tablets
prepared according to Example 6. The prior art composition contained Rifaximin [200mg]
colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose,
microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, talc, and
titanium dioxide.
The results obtained are shown graphically in FIG. 1, on which the percentage of dissolution
is shown. As shown in table 1 and Fig 1, approximately 54% of the active from nano
composition dissolved in 10 minutes and almost 100% of active dissolved within 30 minutes
while prior art formulation dissolved only 66% in 30 minutes. These results clearly show that
the compositions of the present invention have a dissolution profile which is distinctly better
than the prior art composition.
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.
Claims
1. A composition comprising rifaximin in the form of particles, wherein substantially all
the particles have a particle size less than or equal to 2 micrometres.
2. A composition according to claim 1, wherein substantially all the particles have a
particle size less than or equal to 1 micrometre.
3. A composition according to claim 1 or 2, further comprising at least one surface
stabilizer, at least one viscosity building agent and/or at least one polymer, wherein
substantially all the particles have a particle size less than or equal to 2 micrometre.
4. A composition according to claim 3, wherein substantially all the particles have a
particle size less than or equal to 1 micrometre,
5. A composition according to claim 3 or 4, wherein the surface stabilizer is a surfactant.
6. A composition according to claim 5, wherein the surfactant is an amphoteric, nonionic,
cationic or anionic surfactant.
7. A composition according to claim 5 or 6, wherein the surfactant is a polysorbates;
sodium dodecyl sulfate (sodium lauryl sulfate); lauryl dimethyl amine oxide; docusate
sodium; cetyl trimethyl ammonium bromide (CTAB); a polyethoxylated alcohol; a
polyoxyethylene sorbitan; Octoxynol; N,N-dimethyldodecylamine-N-oxide;
hexadecyltnmethylammonium bromide, polyoxyl 10 lauryl ether, brij, a bile salt, such as
sodium deoxycholate or sodium cholate; a polyoxyl castor oil; nonylphenol ethoxylate; a
Cyclodextrin; lecithin; methylbenzethonium chloride; a carboxylate; a sulphonate; a
petroleum sulphonate; an alkylbenzenesulphonates; a naphthalenesulphonate; and olefin
sulphonate; a sulphate surfactant; an alkyl sulphate; a sulphated natural oil or fat; a sulphated
ester; a sulphated alkanolamide; an alkylphenol, optionally ethoxylated and sulphated; an
ethoxylated aliphatic alcohol; polyoxyethylene; a carboxylic ester; a polyethylene glycol
esters; an anhydrosorbitol ester or an ethoxylated derivative therof; a glycol ester of a fatty
acid; a carboxylic amide; a monoalkanolamine condensate; a polyoxyethylene fatty acid
amide; a quaternary ammonium salt; an amine with amide linkages; a polyoxyethylene alkyl
amine; a polyoxyethylene alicyclic amine; a ,,,tetrakis substituted ethylenediamine; a
2-alkyl-l-hydroxyethyl-2-imidazoline; N-coco-3-aminopropionic acid or a sodium salt
5 thereof; N-tallow-3-iminodipropionate disodium salt; N-carboxymethyl-n-dimethyl-n-9
octadecenyl ammonium hydroxide; n-cocoamidethyl-n-hydroxyethylglycine sodium salt; or
mixtures thereof.
8. A composition according to claim 5, 6 or 7, wherein the surfactant is docusate sodium
10 and/or sodium lauryl sulphate.
9. A composition according any one of claims 3 to 8, wherein the viscosity building
agent is lactose; sucrose; saccharose; a hydrolyzed starch, such as maltodextrin; or a mixture
thereof.
15
10. A composition according to claim 9, wherein the viscosity building agent is sucrose.
11. A composition according any one of claims 3 to 10, wherein the polymer is
hydroxypropylcellulose; hydroxymethylcellulose; hydroxypropylmethylcellulose; a
20 methylcellulose polymer; hydroxyethylcellulose; sodium carboxymethylcellulose;
carboxymethylene hydroxyethylcellulose and/or carboxymethyl hydroxyethylcellulose; an
acrylic polymer, such as acrylic acid, acrylamide, and maleic anhydride polymers and
copolymers; or a blend thereof; or a mixture thereof.
25 12. A composition according to claim 12, wherein the polymer is
hydroxypropylmethylcellulose.
1 . A composition according to any one of the preceding claims, wherein substantially all
the particles have a particle size above 1 nanometre.
14. A composition according to any one of the preceding claims, further comprising a
pharmaceutically acceptable carrier, wherein said particles have been adsorbed onto the
surface of the carrier.
5 15. A pharmaceutical composition comprising a composition according to any one of
claims 1 to 14.
16. A pharmaceutical composition comprising a composition according to any one of
claims 1 to 15, in combination with a pharmaceutically acceptable carrier.
10
17. A pharmaceutical composition according to claim 16, wherein the carrier comprises:
one or more diluents or fillers; one or more binders; one or more lubricants; one or more
glidants; one or more disintegrants; one or more preservatives; one or more humectants; one
or more solution retarders; one or more absorption accelerators; one or more wetting agents;
15 one or more adsorbents; one or more buffering agents; or a mixture thereof.
18. A pharmaceutical composition according to claim 16 or 17, which is for oral, ocular,
parenteral, intracisternal, intravaginal, intraperitoneal, or buccal administration.
20 19. A pharmaceutical composition according to claim 16 or 17, which is for oral
administration.
20. A pharmaceutical composition according to any one of claims 1 to 19, which is a
solid oral dosage form.
25
2 . A pharmaceutical composition according to claim or 20, which is in the form of a
capsule, tablet, powder, or granules.
22. A pharmaceutical composition according to claim 20 or 21, further comprising an
30 enteric coating.
23. A composition according to any one of claims 1 to 14 for use in treating a bacterial
infection.
24. The use of a composition according to any one of claims 1 to 14 in the manufacture of
a medicament for treating a bacterial infection.
25. A method of treating a bacterial infection comprising administering a therapeutically
effective amount of a composition according to any one of claims 1 to 14 to a patient in need
thereof.
26. A process for preparing a pharmaceutical composition, which process comprises the
steps of: homogenizing rifaximin, at least one surface stabiliser, at least one viscosity
building agent, and at least one polymer to produce a homogenized dispersion of the
rifaximin in the surface active agent, the viscosity building agent and the polymer; milling
said homogenized dispersion to produce a slurry of particles having a particle size less than
or equal to 2 micrometres; and adsorbing the milled slurry on carrier to form granules.