FIELD OF THE INVENTION
This invention relates to pharmaceutical composition of rifaximin with once daily dosage
and the process of preparing it.
BACKGROUND OF THE INVENTION
The antibiotic rifaximin was originally disclosed in Italy as IT Patent 1154655. The
related U.S. Pat. No. 4,341,785 to Marchi et al. discloses imidazo-rifamicyn derivatives
having antibacterial utility, and the related process for preparing it. The US 785 patent
also discloses a pharmaceutical antibacterial composition and a method of using it to
treat antibacterial diseases of the gastrointestinal tract.
Rifaximin is essentially a non-absorbable, non-systemic, semi-synthetic antibiotic,
related to rifamycin. The antimicrobial spectrum (in vitro) includes most gram-positive
and gram-negative bacteria; and both aerobes and anaerobes. Rifaximin is approved in
certain countries for the treatment of pathologies whose etiology is in part or totally due
to intestinal acute and chronic infections sustained by Gram-positive and Gram-negative
bacteria, with diarrhea syndromes, altered intestinal microbial flora, summer diarrhea-
like episodes, traveler's diarrhea and enterocolitis; pre- and post- surgery prophylaxis of
the infective complications in gastro intestinal surgery; and hyperammonaemia therapy
as coadjutant. The drug has been found to have no significant side effects.
Rifaximin is currently marketed as tablets at the dosage of 200 mg for traveller's diarrhea
under the brandname "Xiafan".
Oral drug administration is by far the most preferable route for taking medications.
However, the therapeutic window of many drugs is limited by their short circulating half-
life and site of action in a defined segment of the gastrointestinal tract. Such limitations
lead in many cases to frequent dosing of these medications to achieve the required
therapeutic effect. This results in "pill burden" and consequently, decreased patient
compliance. Once the dosage form passes the required site of action, the drug will not
be effective. Further on oral administration, normal or pathological stomach voiding and
intestinal peristaltic movements may reduce the time for which a drug-releasing dosage
form remains in the gastrointestinal tract or at the required site of action. Specifically,
during pathological conditions such as diarrhea, peristaltic movement of the Gl Tract is
2

increased. Therefore, Gl transit time of dosage forms is lesser than normal. Hence
conventional dosage forms have shorter residence time at the required site of action. A
rational approach to solve this problem and to improve pharmacodynamic profiles is to
retain the drug reservoir above its site of action, and to release the drug in a controlled
manner, for a prolonged period of time. Thus, there is always a need to develop a novel
pharmaceutical formulation of rifaximin having increased residence time in the gastro
intestinal tract for the treatment of infections locally in the gastrointestinal tract.
Another group of drugs that could benefit from retained and controlled release in the
gastrointestinal tract are those meant for the treatment of pathologies located in the
stomach, the duodenum or the small intestine or colon.
Significant effort has been spent on identifying ways to slow down the Gl transit of the
therapeutic. The advantages of controlled release products are well known in the
pharmaceutical field and include the ability to maintain the medicament at the required
site of action over a comparatively longer period of time while increasing patient
compliance by reducing the number of administrations necessary to achieve the same.
Another solution to this problem can be found in formulation or dosage form materials
with bioadhesive characteristics, bioadhesiveness being defined as the ability of a
material (synthetic or biologic) to adhere to biologic tissues for a prolonged period of
time. The purpose of the bioadhesive dosage form is to keep a pharmaceutical dosage
form in the required site of action for an extended period of time, ensuring release of
effective amounts of the active ingredient throughout the bioadhesion period.
Considering the properties of the gastrointestinal tract, the following characteristics are
sought after in a gastrointestinal retention system: for effective retention in the
gastrointestinal tract to suit the clinical demand; convenient intake to facilitate patient
compliance; sufficient drug loading capacity; control over the drug release profile; full
degradation and evacuation of the system once the drug release is over; no effect on
gastric motility including emptying pattern, and no other local adverse effects.
With respect to the above reasons, to maximize the therapeutic efficacy of non-systemic
antibiotic in the treatment, novel pharmaceutical formulations are provided herein and
include, for example, modified release tablets, which adheres to the gastrointestinal
mucosa reducing the chances for expulsion of the dosage form from the gastrointestinal
3

tract thus having increased residence time and prolonging contact thereby improving the
efficacy of locally acting agents. The dosing frequency of non-systemic antibiotics is
reduced and hence the patient compliance is increased.
OBJECTS OF THE INVENTION
The object of the present invention is to provide a pharmaceutical composition
comprising a therapeutically effective amount of rifaximin or a pharmaceutically
acceptable salt or enantiomer or polymorph thereof, pharmaceutically acceptable
excipient(s), optionally one or more controlled release agent(s) and solubilizing agents
thereof, wherein the composition is formulated to increase the residence time of rifaximin
in the gastrointestinal tract.
Another object of the present invention is to provide a pharmaceutical composition of
rifaximin comprising: at least two entities wherein one entity is an immediate release or
fast release and the other is controlled release.
Another object of the present invention is to provide a pharmaceutical composition of
rifaximin comprising: at least two entities wherein one entity is an immediate release or
fast release and the other is a bioadhesive.
Another object of the present invention is to provide a pharmaceutical composition of
rifaximin comprising: at least two entities wherein one entity is controlled release and the
other is a bioadhesive.
Another object of the invention is to provide a pharmaceutical composition in the form of
a multilayer tablet comprising, a) at least one layer which comprises, a therapeutically
effective amount of rifaximin or a pharmaceutically acceptable salt or enantiomer or
polymorph thereof, pharmaceutically acceptable excipient(s); wherein the said layer
provides a immediate or fast release of rifaximin; and b) at least another layer which
provides increased residence time of the dosage form in the gastrointestina tract.
Another object of the invention is to produce a pharmaceutical composition in the form of
a multilayer tablet comprising, a) at least one layer which comprises, a therapeutically
effective amount of rifaximin or a pharmaceutically acceptable salt or enantiomer or
polymorph thereof, pharmaceutically acceptable excipient(s); wherein the said layer
4

provides a controlled release rifaximin; and b) at least another layer which provides
increased residence time of the dosage form in the gastrointestinal tract.
Another object of the invention is to provide a pharmaceutical composition comprising
rifaximin administered once daily is used to increase patient compliance for treatment of
traveler's diarrhea, hepatic encephalopathy, infectious diarrhea, diverticular disease, an
antibacterial prophylactic prior to colon surgery, irritable bowel syndrome, Crohn's
disease, Clostridum difficile-associated diarrhea, small intestinal bacterial overgrowth,
traveler's diarrhea prophylaxis, dysentery, pouchitis, peptic ulcer disease, surgical
prophylaxis and gastric dyspepsia.
Another object of the invention is to provide a pharmaceutical composition comprising
rifaximin administered once daily is used to increase patient compliance for treatment of
traveler's diarrhea.
Another object of the present invention is to provide a pharmaceutical formulation
comprising rifaximin having an in vitro dissolution profile, when measured in a type II
Paddle dissolution apparatus, in 6.8 phosphate buffer with 1.5% SLS at about 100 rpm,
as follows (a) less than about 15% of the rifaximin is released after about 2 hour, (b) less
than about 50% of the rifaximin is released after about 8 hours, (c) between about 70%
and about 85% of the rifaximin is released after about 16 hours, (d) between about 90 %
and about 98% of rifaximin is released after about 20 hours (e) at least about 90% of
rifaximin is released after about 22 hours.
Yet another object of the present invention is to provide a pharmaceutical formulation
comprising rifaximin having an in vitro dissolution profile, when measured in a type II
Paddle dissolution apparatus, in 6.8 phosphate buffer with 1.5% SLS at about 100 rpm,
at least about 75% of rifaximin is released after about 22 hours.
Yet another object of the invention is to provide a pharmaceutical composition
comprising a therapeutically effective amount of rifaximin or a pharmaceutically
acceptable salt or enantiomer or polymorph thereof, pharmaceutically acceptable
excipient(s), optionally one or more controlled release agent(s) and solubilizing agents
thereof, wherein the composition is formulated to increase the residence time of rifaximin
in the gastrointestinal tract having an adhesive strength, measured as a force of
5

detachment, of atleast 100mN when measured using advanced force gauge equipment
(manufactured by Mecmesin, West Sussex, England).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed towards a pharmaceutical composition comprising a
therapeutically effective amount of rifaximin or a pharmaceutically acceptable salt or
enantiomer or polymorph thereof, pharmaceutically acceptable excipient(s), optionally
one or more controlled release agent(s) and solubilizing agents thereof, wherein the
composition is formulated to increase the residence time of rifaximin in the
gastrointestinal tract.
"Therapeutically effective amount" means that the amount of active agent, which halts or
reduces the progress of the condition being treated or which otherwise completely or
partly cures or acts palliatively on the condition. A person skilled in the art can easily
determine such an amount by routine experimentation and with an undue burden.
"Controlled release," means drug delivery system releasing the drug at a predetermined
rate, locally or systemically, for a specified period of time. Controlled release can be
used interchangeably with prolonged release, programmed release, timed release,
extended release, sustained release and other such dosage forms.
"Optional" or "optionally" means that the subsequently described circumstance may or
may not occur, so that the description includes instances where the circumstance occurs
and instances where it does not.
By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not
biologically or otherwise undesirable.
"Entities" or "Entity" can be interchangeably used with granules, pellets, beads,
minitablets and the like.
"Bioadhesion" is defined as the ability of a material to adhere to a biological tissue for an
extended period of time. Bioadhesion is one solution to the problem of inadequate
residence time resulting from stomach emptying and intestinal peristalsis, and from
displacement by ciliary movement. For sufficient bioadhesion to occur, an intimate
contact must exist between the bioadhesive and the receptor tissue, the bioadhesive
6

must penetrate into the crevice of the tissue surface and/or mucus, and mechanical,
electrostatic, or chemical bonds must form. Bioadhesive properties of polymers are
affected by both the nature of the polymer and by the nature of the surround ng media.
Bioadhesive and mucoadhesive can be used interchangeably.
For purposes of this invention, residence time is the time required for a pharmaceutical
dosage form to transit through the stomach to the rectum i.e. the pharmaceutical dosage
forms of the invention may have an increased retention time in the stomach and/or small
and/or large intestine, or in the area of the gastrointestinal tract that absorbs the drug
contained in the pharmaceutical dosage form. For example, pharmaceutical dosage
forms of the invention can be retained in the small intestine (or one or two portions
thereof, selected from the duodenum, the jejunum and the ileum). These pharmaceutical
dosage forms as a whole, may include a bioadhesive polymeric coating that is applied to
at least one surface of the dosage form.
In a preferred embodiment of the present invention the increase in residence time of
rifaximin formulation in the gastrointestinal tract is achieved by bioadhesion wherein
bioadhesion is achieved using polymers having affinity for gastrointestinal mucosa.
Examples of mucoadhesives for use in the embodiments disclosed herein include, but
are not limited to, natural, semisynthetic and synthetic polymers.
Natural polymers include but are not limited to proteins (e.g., hydrophilic proteins), such
as pectin, zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen,
chitosan, oligosaccharides and polysaccharides such as cellulose, dextrans, tamarind
seed polysaccharide, gellan, carrageenan, xanthan gum, gum Arabic; hyaluronic acid,
polyhyaluronic acid, alginic acid, sodium alginate.
When the bioadhesive polymer is a synthetic polymer, the synthetic polymer is typically
selected from but are not limited to polyamides, polycarbonates, polyalkylenes,
polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl
alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone,
polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic and
methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid), poly(lactide-co-
glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid), poly(maleic acid), and
blends and copolymers or mixtures thereof.
7

Other polymers suitable for use in the invention include, but are not limited to, methyl
cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate
butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate,
cellulose sulfate sodium salt, poly(methyl methacrylate), poly(ethyl methacrylate),
poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate),
poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),
poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl
acrylate) polyethylene, polypropylene, poly(ethylene glycol), poly(ethylene oxide), poly
(ethylene terephthalate), polyvinyl acetate), polyvinyl chloride, polystyrene, polyvinyl
pyrrolidone, and polyvinylphenol. Polylactides, polyglycolides and copolymers thereof,
poly(ethylene terephthalate), poly(butyric acid), poly(valeric acid), poly(lactide-co-
caprolactone), poly[lactide-co- glycolide], polyanhydrides (e.g., poly(adipic anhydride)),
polyorthoesters, blends and copolymers thereof.
Another group of polymers suitable for use as bioadhesive polymers but not necessarily
limited to polymers having a hydrophobic backbone with at least one hydrophobic group
pendant from the backbone. Suitable hydrophobic groups are groups that are generally
non-polar. Examples of such hydrophobic groups include alkyl, alkenyl and alkynyl
groups. Preferably, the hydrophobic groups are selected to not interfere and instead to
enhance the bioadhesiveness of the polymers.
A further group of polymers suitable for use as bioadhesive polymers but not necessarily
limited to polymers having a hydrophobic backbone with at least one hydrophilic group
pendant from the backbone. Suitable hydrophilic groups include groups that are capable
of hydrogen bonding or electrostatically bonding to another functional group. Example of
such hydrophilic groups include negatively charged groups such as carboxylic acids,
sulfonic acids and phosponic acids, positively charged groups such as (protonated)
amines and neutral, polar groups such as amides and imines.
Preferably, the hydrophilic groups are selected to not to interfere and instead to enhance
the bioadhesiveness of the polymers. In embodiments of the present invention, a
8

pharmaceutical composition comprises an active agent and atleast one swellable
polymer.
Swellable polymers include, but are not limited to, a crosslinked poly(acrylic acid), a
poly(alkylene oxide), a polyvinyl alcohol), a polyvinyl pyrrolidone); a polyurethane
hydrogel, a maleic anhydride polymer, such as a maleic anhydride copolymer, a
cellulose polymer, a polysaccharide, starch, and starch based polymers.
Polymers can be modified by increasing the number of carboxylic groups accessible
during biodegradation, or on the polymer surface. The polymers can also be modified by
binding amino groups to the polymer. The polymers can be modified using any of a
number of different coupling chemistries available in the art to covalently attach ligand
molecules with bioadhesive properties to the surface-exposed molecules of the
polymeric microspheres.
Lectins can be covalently attached to polymers to render them target specific to the
mucin and mucosal cell layer. The attachment of any positively charged ligand, such as
polyethyleneimine or polylysine, to a polymer may improve bioadhesion due to the
electrostatic attraction of the cationic groups coating the beads to the net negative
charge of the mucus. The mucopolysaccharides and mucoproteins of the mucin layer,
especially the sialic acid residues, are responsible for the negative charge coating. Any
ligand with a high binding affinity for mucin could also be covalently linked to most
polymers with the appropriate chemistry, such as with carbodiimidazole (GDI), and be
expected to influence the binding to the gut. For example, polyclonal antibodies raised
against components of mucin or else intact mucin, when covalently coupled to a
polymer, would provide for increased bioadhesion. Similarly, antibodies directed against
specific cell surface receptors exposed on the lumenal surface of the intestinal tract
would increase the residence time when coupled to polymers using the appropriate
chemistry. The ligand affinity need not be based only on electrostatic charge, but other
useful physical parameters such as solubility in mucin or specific affinity to carbohydrate
groups.
The covalent attachment of any of the natural components of mucin in either pure or
partially purified form to the polymers generally increases the solubility of the polymer in
9

the mucin layer. The list of useful ligands include but are not limited to the following:
sialic acid, neuraminic acid, n-acetyl-neuraminic acid, n- glycolylneuraminic acid, 4-
acetyl-n-acetylneuraminic acid, diacetyl-n- acetylneuraminic acid, glucuronic acid,
iduronic acid, galactose, glucose, mannose, fucose, any of the partially purified fractions
prepared by chemical treatment of naturally occurring mucin, e.g., mucoproteins,
mucopolysaccharides and mucopolysaccharide-protein complexes, and antibodies
immunoreactive against proteins or sugar structure on the mucosal surface.
The attachment of polyamino acids containing extra pendant carboxylic acid side
groups, such as polyaspartic acid and polyglutamic acid, may also increase
bioadhesiveness. The polyamino chains would increase bioadhesion by means of chain
entanglement in mucin strands as well as by increased carboxylic charge.
Solubilizing agents are the agents that help the drug to solubilize either in formulation or
in the site of absorption or action. Solubilizing agents include but are not limited to
surfactants, cyclodextrin and its derivatives, lipophilic substances or any combination
thereof.
Unlimiting examples of surfactants include water-soluble or water dispersible nonionic,
semi-polar nonionic, anionic, cationic, amphoteric, or zwitterionic surface-active agents;
or any combination thereof.
Other solubilizing agents include but not necessarily limited to vitamin E substance and
its derivatives; monohydric alcohol esters such as trialkyl citrates, lactones and lower
alcohol fatty acid esters; nitrogen-containing solvents; phospholipids; glycerol acetates
such as acetin, diacetin and triacetin; glycerol fatty acid esters such as mono-, di- and
triglycerides and acetylated mono- and diglycerides; propylene glycol esters; ethylene
glycol esters; and combinations thereof.
Pharmaceutically acceptable excipients include but are not limited to binders, diluents,
lubricants, glidants and surface-active agents.
The amount of additive employed will depend upon how much active agent is to be
used. One excipient can perform more than one function.
10

Binders include, but are not limited to, starches such as potato starch, wheat starch,
corn starch; microcrystalline cellulose such as products known under the registered
trade marks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose,
sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid
glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl
amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations
there of and other materials known to one of ordinary skill in the art and mixtures thereof.
Fillers or diluents, which include, but are not limited to confectioner's sugar,
compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose,
starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate,
calcium phosphate dibasic ortribasic, calcium sulphate, and the like can be used.
Lubricants may be selected from, but are not limited to, those conventionally known in
the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate,
mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered
cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium
silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of
ordinary skill in the art.
The present formulations may optionally contain a surface-active agent. The preferred
agent is poloaxmer. However, other agents may also be employed such as dioctyl
sodium sulfosuccinate (DSS), triethanolamine, sodium lauryl sulphate (SLS),
polyoxyethylene sorbitan and poloxalkol derivatives, quaternary ammonium salts or
other pharmaceutically acceptable surface-active agents known to one ordinary skilled in
the art.
The pharmaceutical formulation according to the present invention include but is not
limited to tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive
tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified
release tablets, pulsatile release tablets, timed release tablets), pellets, beads, granules,
sustained release formulations, capsules, microcapsules, tablets in capsules and
11

microspheres, matrix formulations, microencapsulation and powder/pellets/granules for
suspension.
The pharmaceutical dosage form of the invention can optionally have one or more
coatings such as film coating, sugar coating, enteric coating, bioadhesive coating and
other coatings known in the art. These coatings help pharmaceutical formulations to
release the drug at the required site of action. In one example, the addit onal coating
prevents the dosage from contacting the mouth or esophagus. In another example, the
additional coating remains intact until reaching the small intestine (e.g., an enteric
coating). Premature exposure of a bioadhesive layer or dissolution of a pharmaceutical
dosage form in the mouth can be prevented with a layer or coating of hydrophilic
polymers such as HPMC or gelatin. Optionally, Eudragit FS 30D or other suitable
polymer may be incorporated in coating composition to retard the release of the drug to
ensure drug release in the colon.
These coating layers comprises one or more excipients selected from the group
comprising coating agents, opacifiers, taste-masking agents, fillers, polishing agents,
colouring agents, antitacking agents and the like.
Coating agents which are useful in the coating process, include, but are not limited to,
polysaccharides such as maltodextrin, alkyl celluloses such as methyl or ethyl cellulose,
hydroxyalkylcelluloses (e.g. hydroxypropylcellulose or hydroxypropylmethylcelluloses);
polyvinylpyrrolidone, acacia, corn, sucrose, gelatin,shellac, cellulose acetate pthalate,
lipids, synthetic resins,acrylic polymers,opadry, polyvinyl alcohol (PVA), copolymers of
vinylpyrrolidone and vinyl acetate (e.g. marketed under the brand name of Plasdone)
and polymers based on methacrylic acid such as those marketed under the brand name
of Eudragit. These may be applied from aqueous or non-aqueous systems or
combinations of aqueous and non-aqueous systems as appropriate. Additives can be
included along with the film formers to obtain satisfactory films. These additives can
include plasticizers such as dibutyl phthalate, triethyl citrate, polyethylene glycol(PEG)
and the like, antitacking agents such as talc, stearic acid, magnesium stearate and
colloidal silicon dioxide and the like, surfactants such as polysorbates and sodium lauryl
sulphate.fillers such as talc, precipitated calcium carbonate, Polishing agents such as
Beeswax, carnauba wax, synthetic chlorinated wax and opacifying agents such as
12

titanium dioxide and the like. All these excipients can be used at levels well known to the
persons skilled in the art.
Pharmaceutical dosage forms of the invention can be coated by a wide variety of
methods. Suitable methods include compression coating, coating in a fluidized bed or a
pan and hot melt (extrusion) coating. Such methods are well known to those skilled in
the art.
Non-permeable coatings of insoluble polymers, e.g., cellulose acetate, ethylcellulose,
can be used as enteric coatings for delayed/modified release (DR/MR) by inclusion of
soluble pore formers in the coating, e.g., PEG, PVA, sugars, salts, detergents, triethyl
citrate, triacetin, etc.
Also, coatings of polymers that are susceptible to enzymatic cleavage by colonic
bacteria are another means of ensuring release to distal ileum and ascending colon.
Materials such as calcium pectinate can be applied as coatings to dosage form and
multiparticulates and disintegrate in the lower gastrointestinal tract, due to bacterial
action. Calcium pectinate capsules for encapsulation of bioadhesive multiparticulates are
also available.
In a preferred embodiment of the present invention the pharmaceutical formulation is
multiplayer tablets comprising a first, a second and/or a third layer, where each layer
includes one or more excipient(s).
Multi-layer or gradient tablets can be assembled in several different ways.
In one embodiment, the tablet comprises at least one solid core and two outer layers,
each comprising one or more pharmaceutical polymers and/or pharmaceutical
excipients. The core comprises active ingredient and rate-controlling polymer. The two
outer layers are bioadhesive.
In another embodiment, the tablet comprises at least one core and two outer layers,
each comprising drug and one or more pharmaceutical polymers and/or pharmaceutical
13

excipients. Such tablets can also be used to commence release of different drugs at
different times, by inclusion of different drugs in separate layers.
In another embodiment, the multi-layer tablet consists of a core and two outer layers,
each comprising a drug and one or more pharmaceutical polymers or pharmaceutical
excipients, wherein at least one polymer or excipient is hydrophobic.
In another preferred embodiment the present invention relates to formulation which
consists of multilayer tablet wherein atleast one layer consist of a controlled release
polymer and the active ingredient and at least one layer which consist of bioadhesive
polymer, where each layer includes one or more excipients.
In another embodiment the present invention relates to formulation which consists of
multilayer tablet wherein atleast one layer consist of a controlled release polymer and at
least one layer which consist of bioadhesive polymer, where each layer includes one or
more excipients and drug.
The controlled release polymers can be hydrophilic, hydrophobic or combination thereof.
The hydrophilic rate-controlling polymer includes but are not limited to
hydroxyethylcellulose, hydroxypropyl cellulose, Hydroxypropyl Methylcellulose, sodium
carboxymethyl cellulose, sodium alginate, carbomer (Carbopol(TM)), xanthan gum, guar
gum, locust bean gum, poly vinyl acetate, polyvinyl alcohol. Preferably the rate-
controlling polymer is hydroxypropylmethylcellulose (Low viscosity grade).
The hydrophobic rate controlling agent in matrix includes but are not limited to
hydrogenated vegetable oil, but other suitable agents include purified grades of
beeswax; fatty acids; long chain fatty alcohols, such as cetyl alcohol, myristyl alcohol,
and stearyl alcohol; glycerides such as glyceryl esters of fatty acids like glyceryl
monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like;
oils such as mineral oil and the like, or acetylated glycerides; ethyl cellulose,stearic acid ,
paraffin, carnauba wax, talc; and the stearate salts such as calcium, magnesium, zinc
and other materials known to one of ordinary skill in the art.
14

In embodiments of the present invention, a pharmaceutical composition comprises an
active agent and atleast one swellable polymer. Swellable polymers include, but are not
limited to, a crosslinked poly(acrylic acid), a poly(alkylene oxide), a polyvinyl alcohol), a
polyvinyl pyrrolidone); a polyurethane hydrogel, a maleic anhydride polymer, such as a
maleic anhydride copolymer, a cellulose polymer, a polysaccharide, starch, and starch
based polymers.
In another embodiment of the present invention the pharmaceutical composition of
rifaximin comprises: at least two entities wherein one entity is an immediate release or
fast release and the other is controlled release.
In another embodiment of the present invention the pharmaceutical composition of
rifaximin comprises: at least two entities wherein one entity is an immediate release or
fast release and the other is a bioadhesive.
In another embodiment of the present invention the pharmaceutical composition of
rifaximin comprises: at least two entities wherein one entity is controlled release and the
other is a bioadhesive.
The pharmaceutical composition of the invention can be formed by various methods
known in the art such as by dry granulation, wet granulation, melt granulation, direct
compression, double compression, extrusion spheronization, layering and the like.
In a preferred embodiment, the process of making the pharmaceutical formulation of the
invention comprises as described below:
i) blending the active agent and pharmaceutically acceptable additives,
ii) subjecting the blend to slugging/compaction to form a coprimate
iii) converting the coprimate to granules and
iv) compressing the granules to form the solid oral dosage form.
v) the compressed granules are optionally coated.
Compaction of the blend into coprimate may be carried out using a slugging technique or
roller compaction. The milling of the granules may be carried out according to
conventional milling methods.
15

The process of wet granulation includes aqueous or non-aqueous granulation. The wet
granulation process comprises the admixing of the active ingredient wth diluent(s)
and/or rate controlling polymer, and granulation of the blend with the binder mass to
form the wet mass followed by drying and sizing. The binder may optionally be admixed
with the dry blend and granulation performed with aqueous or non-aqueous solvent. The
solvent for the non-aqueous granulation is selected from ethanol, isopropyl alcohol and
dichloromethane.
Rifaximin is approved for the treatment of travelers' diarrhea in adults and in children 12-
years of age and older. Rifaximin has also been evaluated for the treatment of hepatic
encephalopathy, infectious diarrhea, and diverticular disease and as an antibacterial
prophylactic prior to colon surgery, gastric dyspepsia caused by bacteria known as
Helicobacter pylori.
In an aspect of the present invention includes a method of increasing patient compliance
for treatment of traveler's diarrhea, hepatic encephalopathy, infectious diarrhea,
diverticular disease, an antibacterial prophylactic prior to colon surgery, irritable bowel
syndrome, Crohn's disease, Clostridum difficile-associated diarrhea, small intestinal
bacterial overgrowth, traveler's diarrhea prophylaxis, dysentery, pouchitis, peptic ulcer
disease, surgical prophylaxis and gastric dyspepsia by administering once daily dosage
form comprising rifaximin.
The pharmaceutical composition of the present invention contain, for example, form
about 0.1% to 90% of rifaximin. Presently for the approved indication of travelers'
diarrhea, rifaximin is administered 200 milligrams orally 3 times a day as immediate
release dosage form for 3 days in adults and in children 12-years of age and older. The
therapeutic dose varies according to the body weight and the acuteness of the
pathology; a daily dose between 20mg and 2400 mg, preferably 200mg to 2000mg,
administered in a single dose or divided into 2 or 3 doses.
In a preferred embodiment of the present invention in order to improve the patient
compliance and target the formulation in intestine, a bioadhesive, controlled release
once daily (600 mg) of rifaximin is explored.
16

The foregoing examples are illustrative embodiments of the invention and are merely
exemplary. A person skilled in the art may make variations and modifications without
deviating from the spirit and scope of the invention. All such modifications and variations
are intended to be included within the scope of the invention.
EXAMPLES
Ingredients %w/w
Rifaximin 30
Hydroxypropylmethyl 10
cellulose) HPMC
Polaxomer 10
Dliuents (e.g.,Mannitol or 40
DCP or MCC)
Colloidal silicon dioxide 5
Magnesium stearate 5
Example 1
A) First Laver
Procedure:
i) Sift Rifaximin, diluent, HPMC and Polaxomer through suitable seive.
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
B) Second Layer

Ingredients %w/w
HPMC 50
Polyethylene Oxide (PEO) 35
Colloidal silicon dioxide 10
Magnesium stearate 5
i) Sift HPMC and PEO through suitable seive
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Blends of A and B are then compressed into bilayer tablets or tablet in tablet or
individually compressed into mini-tablets and filled into capsules.
17

Example 2
A) First Layer

Ingredients %w/w
Rifaximin 40
Dliuents (e.g.,Mannitol or 15
DCP or MCC)
HPMC 15
PEO 20
Colloidal silicon dioxide 7
Magnesium stearate 3
Water QS

Procedure:
i) Sift Rifaximin, diluent and PEO through specific sieve and mix in a blender.
ii) Add HPMC to water under stirring.
iii) Granulate (i) with (ii) and dry the wet mass in a fluid bed dryer.
iv) Granules of (iii) passed through suitable sieve.
v) Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
vi) Lubricate (iv) with (v).
B) Second laver

Ingredients %w/w
HPMC 50
PEO 35
Colloidal silicon dioxide 10
Magnesium stearate 5
i) Sift HPMC and PEO through suitable seive
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Compress both A and B to form bilayer tablet or individually compressed into mini-
tablets and filled into capsules.
Example 3
A) First Laver

Ingredients %w/w
Rifaximin 50
Dliuents (e.g.,Mannitol orDCP or MCC) 15
HPMC 10
PEO 20
18

Colloidal silicon dioxide 3
Magnesium stearate 2
IPA QS
Methylene chloride QS
i) Sift Rifaximin, diluent and PEO through suitable sieve and mix in a blender.
ii) Add HPMC to I PA: Methylene chloride under stirring.
iii) Granulate (i) with (ii) and dry the wet mass in a fluid bed dryer.
iv) Granules of (iii) passed through suitable sieve.
v) Sift colloidal silicon dioxide and magnesium stearate through specific seive
vi) Lubricate (iv) with (v).
B) Second layer

Ingredients %w/w
HPMC 50
PEO 35
Colloidal silicon dioxide 10
Magnesium stearate 5
i) Sift HPMC and PEO through compress both the layers into bilayer tablets
Seive
ii)dry blend (i) in an blender.
iii)sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Compress both A and B to form bilayer tablet or individually compressed into mini-
tablets and filled into capsules.
Example 4

Ingredients %w/w
Rifaximin 50
Dliuents (e.g.,Mannitol 10
or DCP or MCC
HPMC 10
Sodium Lauryl sulphate 5
Xanthan gum 15
Colloidal silicon dioxide 5
Maanesium stearate 5
Procedure:
i) Sift Rifaximin, Diluent,HPMC, SLS and Xanthan gum through suitable seive.
19

ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
v)The blend is then compressed into tablets.
Example 5

Ingredients %w/w
Rifaximin 50
Dliuents (e.g.,Mannitolor DCP or MCC 15
HPMC 15
PEO 15
Colloidal silicon dioxide 3
Magnesium stearate 2
Water QS
Procedure:
i)Sift Rifaximin, Diluent, HPMC and PEO through suitable seive.
ii)Dry blend (i) in an blender.
iii)Granulate (ii) with water and dry the wet mass in fluid bed dryer.
iv)Granules obtained in (iii) are sifted through suitable seive.
v)Sift Colloidal silicon dioxide and magnesium stearate through suitable seive.
vi) Lubricate (iv) with (v).
vii) Blend of step (vi) is then compressed into tablets.
Example 6

Ingredients %w/w
Rifaximin 60
Dliuents (e.g.,Mannitol or DCP or MCC) 10
HPMC 12
PEO 13
Colloidal silicon dioxide 3
Magnesium stearate 2
I PA QS
Methylene chloride QS
Procedure:
i)Sift Rifaximin, Diluent, HPMC and PEO through suitable seive
ii)Dry blend (i) in an blender.
20

iii)Granulate (ii) with IPA:methylene (70:30) chloride and dry the wet mass in fluid bed
dryer.
iv)Granules obtained in (iii) are sifted through suitable seive.
v)Sift Colloidal silicon dioxide and magnesium stearate through specific seive.
vi) Lubricate (iv) with (v).
vii) Blend of step (vi) is then compressed into tablets.
Example 7

Ingredients %w/w
Rifaximin 50
Dliuents (e.g.,Mannitolor DCP or MCC 15
HPMC 10
PEO 15
Colloidal silicon dioxide 5
Magnesium stearate 5
Procedure:
i)Sift Rifaximin, Diluent, HPMC and PEO through suitable seive.
ii)Dry blend (i) in an blender.
iii) Sift Colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Add half quantity of (iii) to (ii) and mix in a blender.
v)Compact blend of (iv) using a roller compactor at a pressure.
vi) Sift (v) through suitable seive to obtain granules.
vii) Mix remaining quantity of (iii) and (vi) in a blender.
viii) Blend of (vii) is compressed into tablets.
Example 8
B) First and Third Layer

Ingredients %W/W
HPMC 40
Xanthan Gum 20
Carbopol 25
Collodial Silicon Dioxide 10
Magnesium Stearate 5
Procedure:
i) Sift HPMC, Xanthan gum and Carbopol through suitable seive.
ii)Dry blend (i) in an blender.
21

iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
A) Middle layer

Ingredients %W/W
Rifaximin 40
Diluents (E.g. Mannitol or DCP or MCC) 30
HPMC 15
Polaxomer 5
Colloidal silicon dioxide 5
Magnesium Stearate 5
i) Sift Rifaximin, diluent, HPMC, SLS and xanthan gum through suiatble seive
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Blends of A and B are compressed into trilayer tablets
Example 9
B) First and Third Layer

Ingredients %W/W
HPMC 40
Xanthan gum 20
Carbopol 25
Colloidal silicon dioxide 10
Magnesium stearate 5
Procedure:
i) Sift HPMC, Xanthan gum and Carbopol through suitable seive
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
A) Middle layer

Ingredients %W/W
Rifaximin 50
Diluents (e.g. .Mannitol or DCP or MCC) 15
HPMC 10
22

PEO 15
Colloidal silicon dioxide 7
Magnesium stearate 3
Water QS
i) Sift Rifaximin, diluent, and PEO through suitable seive
ii)dry blend (i) in an blender.
iii)Mix HPMC in water under stirring
iii)Granulate (ii) with (iii) and dry the wet mass in fluid bed dryer.
iv)Granules obtained in (iii) are sifted through suitable seive.
v)Sift Colloidal silicon dioxide and magnesium stearate through suitable seive.
vi) Lubricate (iv) with (v).
vii) Blend of A and B is then compressed into trilayered tablet.
Example 10
B) First and Third Layer

Ingredients %W/W
HPMC 40
Xanthan gum 20
Carbopol 25
Colloidal silicon dioxide 10
Magnesium stearate 5
Procedure:
i) Sift HPMC, Xanthan gum and Carbopol through suiatble seive.
ii)dry blend (i) in an blender.
iii)sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
A) Middle layer

Ingredients %W/W
Rifaximin 40
Diluents (e.g.,Mannitol or DCP or 20
MCC)
HPMC 20
PEO 15
Colloidal silicon dioxide 3
Magnesium stearate 2
I PA QS
Methylene chloride QS
i) Sift Rifaximin, diluent, and PEO through suitable seive.
ii)Dry blend (i) in an blender.
23

iii)Mix HPMC in IPA:Methylene chloride under stirring.
iv)Granulate (ii) with (iii) and dry the wet mass in fluid bed dryer.
v)Granules obtained in (iii) are sifted through suitable seive.
vi)Sift Colloidal silicon dioxide and magnesium stearate through suitable seive.
vii) Lubricate (iv) with (v).
Blend A and B are then compressed into trilayer tablet.
Ingredients %W/W
Rifaximin 30
Xanthan gum 30
Water QS
Calcium Chloride 10
Water QS
Sodium Alginate 25
Magnesium Stearate 5
Example 11
Procedure:
i) Sodium alginate is suspended in water and rifaximin was suspended in this colloidal
solution.
ii) Calcium Chloride is dissolved in water and kept aside.
iii) Add step (i) into step (ii) dropwise to make beads under stirring, further filter the
solution to separate the beads and dry the beads.
iv) Mix the dried beads with xanthan gum and sodium alginate.
v) Lubricate the beads of step (iv) with magnesium stearate and fill into capsules or
sachets or filled in water with sweetening and flavouring agents as a powder for
suspension .
Example 12

Ingredients %W/W
Rifaximin 40
Diluents (e.g., Mannitol or DCP or MCC) 30
Sodium CMC 15
I PA QS
PEO 10
Magnesium Stearate 5
Procedure:
i) Sift Rifaximin, Diluent,sodium CMC and PEO through suitable seive .
ii)Granulate blend of step (i) with IPA.
iii)Dry the granules of step (ii) and sift through suitable seive.
24

iv)Lubricate the granules of step (iii) with magnesium stearate.
v)The bioadhesive granules of step (iv) can be further compressed into tablets using
suitable diluents and lubricants or filled into capsules or sachets or filled into bottle with
sweetening and flavouring agents as a powder for suspension.
Example 13

Ingredients %W/W
Rifaximin 50
Microcrystalline cellulose (MCC) 20
PEO 18
HPMC 10
I PA QS
Magnesium Stearate 2
Procedure:
Spheronization
i)Sift MCC,Rifaximin, PEO and HPMC through suitable seive.
ii)Step (i) is mixed with IPA.
iii)Wet mass of step (ii) is passed through Extruder and further spheronized to get the
round pellets
Hot melt extrusion
i) Sift MCC,Rifaximin, PEO and HPMC through suitable seive.
ii)Step (i) is mixed thoroughly and heated at 70°C.
iii)The soft mass thus obtained is extruded through an extruder and spheronized to get
pellets.
The pellets can be filled into capsules, sachets or filled in bottles in water with
sweetening and flavouring agents as a powder for suspension or compressed into
tablets.
Example 14

Ingredients %W/W
Rifaximin 20
Diluents (e.g. Mannitol or DCP or MCC) 30
Xanthan gum 15
Polaxomer 10
Sodium Alginate 15
Colloidal silicon dioxide 5
Magnesium Stearate 5
25

Procedure:
i)Rifaximin, Diluents, Xanthan gum, Polaxomer and sodium alginateare sifted through
suitable seive.
ii) Step (i) is dry blended in a blender.
iii)Lubricants are sifted through specific seive and mixed with step (ii).
iv)Blend of step (iii) is then compressed into mini tablets.
v)These mini tablets can be filled into capsules.
Example 15
Ingredients %w/w
Rifaximin 90
Hydroxypropylmethyl 5
cellulose HPMC
Colloidal silicon dioxide 3
Magnesium stearate 2
A) First Layer
Procedure:
i) Sift Rifaximin and HPMC through suitable seive.
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
B) Second Layer

Ingredients %w/w
HPMC 49
Polyethylene Oxide (PEO) 49
Colloidal silicon dioxide 1
Magnesium stearate 1
i) Sift HPMC and PEO through suitable seive
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Blends of A and B are then compressed into bilayer tablets or tablet in tablet
Example 16
A) First Layer

Ingredients %w/w
Rifaximin 50
Diluents (e.g.Mannitol or DCP or 15
MCC)
Hydroxypropylmethyl cellulose 15
26

HPMC
PEO 15
Colloidal silicon dioxide 3
Magnesium stearate 2
Water QS
Procedure:
i) Sift Rifaximin, diluent and PEO through specific sieve and mix in a blender.
ii) Add HPMC to water under stirring.
iii) Granulate (i) with (ii) and dry the wet mass in a fluid bed dryer.
iv) Granules of (iii) passed through suitable sieve.
v) Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
vi) Lubricate (iv) with (v).
B) Second layer
Ingredients %w/w
HPMC 81.5
PEO 16
Colloidal silicon dioxide 1.5
Magnesium stearate 1
i) Sift HPMC and PEO through suitable seive
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Compress both A and B to form bilayer tablet.
Example 17
A) First Layer

Ingredients %w/w
Rifaximin 50
Diluents (e.g.Mannitol or DCP or MCC) 15
Hydroxypropylmethyl cellulose HPMC 10
PEO 20
Colloidal silicon dioxide 3
Magnesium stearate 2
I PA QS
Methylene Chloride QS
Procedure:
i) Sift Rifaximin, diluent and PEO through suitable sieve and mix in a blender.
27

ii) Add HPMC to IPA:Methylene chloride under stirring.
iii) Granulate (i) with (ii) and dry the wet mass in a fluid bed dryer.
iv) Granules of (iii) passed through suitable sieve.
v) Sift colloidal silicon dioxide and magnesium stearate through specific seive
vi) Lubricate (iv) with (v).
B) Second layer
Ingredients %w/w
HPMC 49
PEO 49
Colloidal silicon dioxide 1
Magnesium stearate 1
i) Sift HPMC and PEO through suitable seive
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
Compress both A and B to form bilayer tablet.
Example 18

Ingredients %w/w
Rifaximin 40
Dliuents (e.g.,Mannitol or DCP or MCC 17
HPMC 20
Sodium Lauryl sulphate 5
Xanthan gum 15
Colloidal silicon dioxide 2
Magnesium stearate 1
Procedure:
i) Sift Rifaximin, Diluent,HPMC, SLS and Xanthan gum through suitable seive.
ii)Dry blend (i) in an blender.
iii)Sift colloidal silicon dioxide and magnesium stearate through suitable seive.
iv)Lubricate (ii) with (iii) in a blender.
v)The blend is then compressed into tablets.
HPMC = Hydroxy propyl methyl cellulose
PEO = Polyethyeleneoxide
DCP = Dicalcium phosphate
MCC = Microcrystalline cellulose
MA 1 = Methacrylic acid copolymer L 100
MA2 = Methacrylic acid copolymer S 100
IPA = Isopropyl Alcohol
28

DISSOLUTION
The formulations of the invention have a prolonged in vitro release rate. The in vitro test
used to measure release rate of the active agent from a formulation of the invention was
as follows. A solution of 900 ml of a 6.8 pH phosphate buffer, 1.5% SLS was placed in a
apparatus capable of agitation. The apparatus contained a paddle and rotated at a
speed of 100 rpm. The tablet formulation was placed in the apparatus and dissolution
was periodically measured. The in vitro dissolution studies of Example 3 is as shown
below:

Time (hrs.) Cumulative % drug release
0 0.00
1 6.82
2 12.86
4 22.46
8 42.70
10 52.64
12 62.00
14 72.40
16 80.06
18 87.24
20 93.64
22 98.90
DETERMINATION OF BIOADHESION
Bioadhesion was determined by tensiometric method. For the determination, an
advanced force gauge equipment (mfg. by Mecmesin, West Sussex, England) was
used. Freshly excised Sheep intestinal tissue was taken and stored in a Tyrode solution
at 4°C until used for the experiment. The tissue was cut into pieces (3x4 cm) and
mounted on the glass slide and tightened with a thread. 0.5ml Phosphate buffered saline
(PBS) was placed on the tissue. The bioadhesive tablet of example 1 was placed on this
tissue and another 0.5 ml PBS was placed on the tablet. A glass slide with a 10 g weight
was placed on the tablet and it was allowed to hydrate for 10min., 30 min , 60 min., and
840 min. At the specific time interval, the hydrated tablet along with slide was mounted
on the stage of the bioadhesion apparatus. Probe was then lowered at fixed speed of 0.2
mm/sec, and upper slide was attached to the hook of the probe by means of a thread.
The peak detachment force was considered as the bioadhesive force as evident from
the graph as provided in Figure 1. The force required to separate the tablet from
biological substrate was recorded in mN.
29

We Claim:
1. A pharmaceutical composition comprising a therapeutically effective amount of
rifaximin or a pharmaceutically acceptable salt or enantiomer or polymorph
thereof, pharmaceutically acceptable excipient(s), optionally one or more
controlled release agent(s) and solubilizing agents thereof, wherein the
composition is formulated to increase the residence time of rifaximin in the
gastrointestinal tract.
2. A pharmaceutical composition as in claim 1, wherein the increase in residence
time of rifaximin formulation in the gastrointestinal tract is achieved by
bioadhesion.
3. A pharmaceutical composition as in claim 2, wherein bioadhesion is achieved
with polymers having affinity for gastrointestinal mucosa selected from a group
comprising polycarbophils, carbomers, lectins, pectine, zein, modified zein,
casein, gelatin, gluten, serum albumin, collagen, chitosan, oligosaccharides and
polysaccharides such as cellulose their derivatives such as methyl cellulose,
ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
hydroxybutylmethyl cellulose, cellulose acetate, cellulose propionate, cellulose
acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose
triacetate, cellulose sulfate sodium salt, dextrans, tamarind seed polysaccharide,
gellan, carrageenan; hyaluronic acid, polyhyaluronic acid, alginic acid, sodium
alginate; gums like xanthan gum, guar gum, gum Arabic locust bean gum; poly
vinylacetatae, polyvinylalcohol, povidone/polyethylene oxide, acrylic and
methacrylic acid their copolymers, polyamides, polycarbonates, polyalkylenes,
polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl
alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone,
polyglycolides, polysiloxanes, polyurethanes, polystyrene, polymers of acrylic
and methacrylic esters, polylactides, poly(butyric acid), poly(valeric acid),
poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, poly(fumaric acid),
poly(maleic acid), polymers having a hydrophobic backbone with at least one
hydrophilic group pendant from the backbone, polymers having a hydrophobic
backbone with at least one hydrophobic group pendant from the backbone, and
blends and copolymers or mixtures thereof.
30

4. A pharmaceutical composition as in claim 2, wherein bioadhesion is provided for
a period ranging from about 0.5 hours to about 24 hours.
5. A pharmaceutical composition according to claim 1, wherein controlled release
agent is selected from the group comprising hydrophilic polymer or hydrophobic
polymer or combinations thereof.
6. A pharmaceutical composition according to claim 5, wherein hydrophilic polymer
is selected from the group comprising carbohydrates like celluloses their
derivatives such as ethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxypropylethylcellulose; gums like xanthan
gum, guar gum, locust bean gum; alginates; carbomer; poly vinylacetatae,
polyvinylalcohol, povidone/polyethylene oxide, acrylic and methacrylic acid
copolymers and mixtures thereof.
7. A pharmaceutical composition according to claim 5, wherein hydrophobic release
component is selected from the group comprising beeswax; fatty acids; long
chain fatty alcohols, such as cetyl alcohol, myristyl alcohol, stearyl alcohol;
glycerides such as glyceryl esters of fatty acids like glyceryl rnonostearate,
glyceryl distearate, glyceryl esters of hydrogenated castor oil, mineral oil,
hydrogenated vegetable oil, acetylated glycerides; ethyl cellulose, stearic acid,
paraffin, carnauba wax, talc; stearate salts such as calcium, magnesium, zinc
and mixtures thereof.
8. A pharmaceutical composition as in claim 1, wherein solubilizing agent(s) include
but are not limited to surfactant(s) such as water-soluble or water dispersible
nonionic, semi-polar nonionic, anionic, cationic, amphoteric, or zwitterionic
surface-active agents; cyclodextrin and its derivatives; lipophilic substances;
vitamin E and its derivatives; monohydric alcohol esters such as trialkyl citrates,
lactones and lower alcohol fatty acid esters; nitrogen-containing solvents;
phospholipids; glycerol acetates such as acetin, diacetin and triacetin; glycerol
fatty acid esters such as mono-, di- and triglycerides and acetylated mono- and
diglycerides; propylene glycol esters; ethylene glycol esters or any combination
thereof.
31

9. A pharmaceutical composition according to claim 1, wherein pharmaceutically
acceptable excipients are selected from the group comprising binders, diluents,
lubricants, surfactants and glidants.
10. A pharmaceutical composition according to claim 9, wherein the binder is one or
more selected from the group comprising carbohydrates like celluloses their
derivatives; starches; gums; polyvinylpyrrolidone, povidone, syrup, polyethylene
oxide, polyacryl amide, poly-N-vinyl amide, sodium carboxymethyl cellulose,
polyethylene glycol, gelatin, polyethylene oxide, poly propylene glycol,
tragacanth, alginic acid and combinations thereof.
11. A pharmaceutical composition according to claim 9, wherein diluent is one or
more selected from the group comprising carbohydrates, derivatives of
carbohydrates, polyols, sugar alcohols, carbonate, sulphate or phosphate salts of
inorganic metals or mixtures thereof.
12. A pharmaceutical composition according to claim 9, wherein lubricant is one or
more selected from the group comprising magnesium, aluminium, zinc or calcium
stearate, sodium stearyl fumarate, polyethylene glycol, mineral oil, stearic acid,
hydrogenated vegetable oil, glyceryl behenate, glyceryl palmitostearate, glyceryl
stearate, cornstarch, talc, calcium silicate, magnesium silicate, colloidal silicon
dioxide, silicon hydrogel, and mixtures thereof.
13. A pharmaceutical composition according to claim 9, wherein surfactant can be
selected from ionic or non-ionic or zwitterionic surfactants.
14. A pharmaceutical composition according to claim 9, wherein the glidant is one or
more selected from the group comprising silicon dioxide, colloidal silica,
powdered cellulose, talc, tribasic calcium phosphate and mixtures thereof.
15. A pharmaceutical composition according to claim 1, is a once-daily dosage form.
16. A pharmaceutical composition according to claim 1, is a once-daily dosage form
comprising 200 to 2400mg of rifaximin.
32

17. A pharmaceutical composition according to claim 1, is a once-daily dosage form
comprising 600mg of rifaximin.
18. A pharmaceutical composition as in claim 1 is administered to increase patient
compliance for treatment of traveler's diarrhea, hepatic encephalopathy,
infectious diarrhea, diverticular disease, an antibacterial prophylactic prior to
colon surgery, irritable bowel syndrome, Crohn's disease, Clostridum difficile-
associated diarrhea, small intestinal bacterial overgrowth, traveler's diarrhea
prophylaxis, dysentery, pouchitis, peptic ulcer disease, surgical prophylaxis and
gastric dyspepsia.
19. A pharmaceutical composition as in claim 1 is used to treat traveler's diarrhea,
hepatic encephalopathy, infectious diarrhea, diverticular disease, an antibacterial
prophylactic prior to colon surgery, irritable bowel syndrome, Crohn's disease,
Clostridum difficile-associated diarrhea, small intestinal bacterial overgrowth,
traveler's diarrhea prophylaxis, dysentery, pouchitis, peptic ulcer disease,
surgical prophylaxis and gastric dyspepsia.
20. A pharmaceutical composition as in claim 1 is used for the treatment of traveler's
diarrhea.
21. A pharmaceutical composition according to claim 1, is further coated wherein the
coating includes film coating, sugar coating, enteric coating, bioadhesive or
mucoadhesive coating.
22. A pharmaceutical composition according to claim 21, wherein the coating layer
comprises coating agents, plasticizers, antitacking agents, surfactants, coloring
agents, opacifiers or mixtures thereof.
23. A pharmaceutical composition of rifaximin comprising: at least two entities
wherein one entity is an immediate release or fast release and the other is
controlled release.
33

24. A pharmaceutical composition of rifaximin comprising: at least two entities
wherein one entity is an immediate release or fast release and the other is a
bioadhesive.
25. A pharmaceutical composition of rifaximin comprising: at least two entities
wherein one entity is controlled release and the other is a bioadhesive.
26. A pharmaceutical composition according to claim 1, is tablets, pellets, beads,
granules, sustained release formulations, capsules, microcapsules, tablets in
capsules, microspheres or powders/pellets/beads/granules for suspension.
27. A pharmaceutical composition according to claim 26 wherein tablets include
single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets,
caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, modified
release tablets, pulsatile release tablets and timed release tablets.
28. A pharmaceutical composition in the form of a multilayer tablet comprising, a) at
least one layer which comprises, a therapeutically effective amount of active
principle(s) or a pharmaceutically acceptable salt or enantiomer or polymorph
thereof, pharmaceutically acceptable excipient(s); wherein the said layer
provides a immediate or fast release of active principle(s); and b) at least one
layer which provides increased residence time of the dosage form in the
gastrointestinal tract.
29. A pharmaceutical composition in the form of a multilayer tablet comprising, a) at
least one layer which comprises, a therapeutically effective amount of rifaximin or
a pharmaceutically acceptable salt or enantiomer or polymorph thereof,
pharmaceutically acceptable excipient(s); wherein the said layer provides a
controlled release rifaximin; and b) at least one layer which provides increased
residence time of the dosage form in the gastrointestinal tract.
30. A pharmaceutical composition comprising rifaximin administered once daily is
used to increase patient compliance for treatment of traveler's diarrhea, hepatic
encephalopathy, infectious diarrhea, diverticular disease, an antibacterial
prophylactic prior to colon surgery, irritable bowel syndrome, Crohn's disease,
Clostridum difficile-associated diarrhea, small intestinal bacterial overgrowth,
34

traveler's diarrhea prophylaxis, dysentery, pouchitis, peptic ulcer disease,
surgical prophylaxis and gastric dyspepsia.
35
31. A pharmaceutical composition comprising rifaximin administered once daily is
used to increase patient compliance for treatment of traveler's diarrhea.
32. A pharmaceutical formulation comprising rifaximin having an in vitro dissolution
profile, when measured in a type II Paddle dissolution apparatus, in 6.8
phosphate buffer with 1.5% SLS at about 100 rpm, as follows (a) less than about
15% of the rifaximin is released after about 2 hour, (b) less than about 50% of the
rifaximin is released after about 8 hours, (c) between about 70% and about 85%
of the rifaximin is released after about 16 hours, (d) between about 90 % and
about 98% of rifaximin is released after about 20 hours (e) at least about 90% of
rifaximin is released after about 22 hours.
33. A pharmaceutical formulation comprising rifaximin having an in vitro dissolution
profile, when measured in a type II Paddle dissolution apparatus, in 6.8
phosphate buffer with 1.5% SLS at about 100 rpm, at least about 75% of
rifaximin is released after about 22 hours.
34. A pharmaceutical composition comprising a therapeutically effective amount of
rifaximin or a pharmaceutically acceptable salt or enantiomer or polymorph
thereof, pharmaceutically acceptable excipient(s), optionally one or more
controlled release agent(s) and solubilizing agents thereof, wherein the
composition is formulated to increase the residence time of rifaximin in the
gastrointestinal tract having an adhesive strength, measured as a force of
detachment, of atleast 100mN when measured using advanced force gauge
equipment (manufactured by Mecmesin, West Sussex, England).

A pharmaceutical composition comprising a therapeutically effective amount of rifaximin
or a pharmaceutically acceptable salt or enantiomer or polymorph thereof,
pharmaceutically acceptable excipient(s), optionally one or more controlled release
agent(s) and solubilizing agents thereof, wherein the composition is formulated to
increase the residence time of rifaximin in the gastrointestinal tract. The pharmaceutical
composition in the form of a multilayer tablet comprising, at least one layer which
comprises, a therapeutically effective amount of rifaximin or a pharmaceutically
acceptable salt or enantiomer or polymorph thereof, pharmaceutically acceptable
excipient(s); wherein the said layer provides a controlled release rifaximin; and at least
one layer which provides increased residence time of the dosage form in the
gastrointestinal tract. The composition is administered once daily and has defined
dissolution profile.