(12) United States Patent (10) Patent No.: US 8,383,151 B2 Jahagirdar Et Al

USOO8383151B2

(12) United States Patent (10) Patent No.: US 8,383,151 B2 Jahagirdar et al. (45) Date of Patent: Feb. 26, 2013

(54) PHARMACEUTICAL COMPOSITIONS OF FOREIGN PATENT DOCUMENTS RFAXIMIN IT 1154655 1, 1987 WO WO 2006/094.737 * 9/2006 (75) Inventors: Harshal Anil Jahagirdar, Pune (IN); Rajesh Kulkarni, Pune (IN); * cited by examiner Shirishkumar Kulkarni, Pune (IN) Primary Examiner — Robert A Wax (73) Assignee: Lupin Limited, Mumbai, Maharashtra Assistant Examiner — Hasan Ahmed (IN) (74) Attorney, Agent, or Firm — Merchant & Gould P.C. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (57) ABSTRACT U.S.C. 154(b) by 410 days. A pharmaceutical composition comprising therapeutically effective amount of rifaximin orpharmaceutically acceptable (21) Appl. No.: 12/144,453 salt or enantiomer or polymorph thereof, pharmaceutically acceptable excipient(s) and release controlling agent(s). (22) Filed: Jun. 23, 2008 Pharmaceutical composition of rifaximin comprising: at least (65) Prior Publication Data two entities wherein one entity is an immediate release or fast release and the other is controlled release. The pharmaceuti US 2009/002894.0 A1 Jan. 29, 2009 cal composition in the form of multilayer tablet comprising, at least one layer comprising, therapeutically effective (30) Foreign Application Priority Data amount of rifaximin or pharmaceutically acceptable salt or enantiomer or polymorph thereof, pharmaceutically accept Jul. 6, 2007 (IN) ...... 968/KOL/2007 able excipient(s); said layer providing controlled release rifaximin; and at least one layer which provides increased (51) Int. Cl. residence time of the dosage form in the gastrointestinal tract. A6 IK9/20 (2006.01) The pharmaceutical formulation comprising rifaximin hav (52) U.S. Cl...... 424/464; 424/468; 514/279:514/394; ing an in vitro dissolution profile, wherein about 70% of 514/964 rifaximin is released in about 24 hours. The composition (58) Field of Classification Search ...... None comprising therapeutically effective amount of rifaximin or See application file for complete search history. pharmaceutically acceptable salt(s) or enantiomer(s) or poly morph(s) thereof, one or more release controlling agent(s) (56) References Cited and pharmaceutically acceptable excipient(s) causing patho U.S. PATENT DOCUMENTS genic eradication. 4,341,785 A 7, 1982 Marchi et al. 2010.00 16333 A1 1/2010 Flanner et al...... 514,254.11 39 Claims, 1 Drawing Sheet U.S. Patent Feb. 26, 2013 US 8,383,151 B2

Bioadhesion Measurement

2500

20 OO

1500 200 400 600 800 1000 1200 Hydration time (min) US 8,383,151 B2 1. 2 PHARMACEUTICAL COMPOSITIONS OF able salt(s) or enantiomer(s) or polymorph(s) thereof, one or RFAXIMIN more release controlling agent(s) and pharmaceutically acceptable excipient(s), wherein the composition is formu FIELD OF THE INVENTION lated to increase the residence time of rifaximin in the gas trointestinal tract. This invention relates to pharmaceutical compositions of Another object of the invention is to provide a pharmaceu rifaximin for controlling the release and/or increasing the tical composition comprising rifaximin used to increase residence time in the gastrointestinal tract and the process of patient compliance for treatment of traveler's diarrhea, preparing them. hepatic encephalopathy, infectious diarrhea, diverticular dis 10 ease, an antibacterial prophylactic prior to colon Surgery, BACKGROUND OF THE INVENTION irritable bowel syndrome, Crohn's disease, Clostridum diffi cile-associated diarrhea, Small intestinal bacterial over The antibiotic rifaximin was originally disclosed in Italy as growth, traveler's diarrhea prophylaxis, dysentery, pouchitis, IT Patent 1154655. The related U.S. Pat. No. 4,341,785 to peptic ulcer disease, Surgical prophylaxis and gastric dyspep Marchi et al. discloses imidazo-rifamycin derivatives having 15 antibacterial utility, and the related process for preparing it. sia. Another object of the invention is to provide a pharma The US 785 patent also discloses a pharmaceutical antibac ceutical composition comprising rifaximin used to increase terial composition and a method of using it to treat antibac patient compliance for treatment of traveler's diarrhea. terial diseases of the gastrointestinal tract (GIT). Yet another object of the invention is to provide a method of Rifaximin is essentially a non-absorbable, non-systemic, treating klebsiella induced traveler's diarrhea comprising semi-synthetic antibiotic, related to rifamycin. The antimi administering a once daily pharmaceutical composition com crobial spectrum (in vitro) includes most gram-positive and prising therapeutically effective amount of rifaximinor phar gram-negative bacteria; and both aerobes and anaerobes. maceutically acceptable salt(s) or enantiomer(s) or polymor Rifaximinisapproved in certain countries for the treatment of ph(s) thereof, one or more release controlling agent(s) and pathologies whose etiology is in part or totally due to intes 25 pharmaceutically acceptable excipient(s). tinal acute and chronic infections Sustained by Gram-positive Another object of the present invention is to provide a and Gram-negative bacteria, with diarrhea Syndromes, pharmaceutical composition of rifaximin comprising: at least altered intestinal microbial flora, summer diarrhea-like epi two entities wherein one entity is an immediate release or fast sodes, traveler's diarrhea and enterocolitis; pre- and post release and the other is controlled release. Surgery prophylaxis of the infective complications in gastro 30 Another object of the present invention is to provide a intestinal Surgery; and hyperammonaemia therapy as coadju pharmaceutical composition of rifaximin comprising: at least tant. The drug has been found to have no significant side two entities wherein one entity is controlled release and the effects. other is a bioadhesive. Rifaximin is currently marketed as tablets at the dosage of Another object of the invention is to produce a pharmaceu 200 mg for traveler's diarrhea under the brand name 35 tical composition in the form of a multilayer tablet compris “Xifaxan(R)'. ing, a) at least one layer which comprises, a therapeutically Oral drug administration is by far the most preferable route effective amount of rifaximin or a pharmaceutically accept for taking medications. However, on oral administration, nor able salt(s) or enantiomer(s) or polymorph(s) thereof, phar mal or pathological stomach Voiding and intestinal peristaltic maceutically acceptable excipient(s); wherein the said layer movements limit the time for which a drug-releasing dosage 40 provides a controlled release rifaximin; and b) at least another form remains in the gastrointestinal tractor at the required site layer which provides increased residence time of the dosage of action. As the drug is locally acting it should remain at the form in the gastrointestinal tract. site of action/in the GIT for the sufficient period of time. Yet another object of the present invention is to provide a Specifically, during pathological conditions such as diarrhea, pharmaceutical formulation comprising rifaximin having an peristaltic movement of the GI Tract is increased. Therefore, 45 in vitro dissolution profile, when measured in a type II Paddle GI transit time of dosage forms is lesser than normal. Hence dissolution apparatus, in 6.8 phosphate buffer with 1.5% conventional dosage forms have shorter residence time at the sodium lauryl sulphate (SLS) at about 100 rpm, wherein required site of action and need to be dosed frequently in about 70% of rifaximin is released in about 24 hours. order to be therapeutically effective. A rational approach to Another object of the invention is to provide a once daily Solve this problem and to improve pharmacodynamic profiles 50 pharmaceutical composition comprising rifaximin having an is to retain the drug reservoir at the site of action, and to in vitro dissolution profile, when measured in a type II Paddle release the drug in a controlled manner, for a prolonged dissolution apparatus, in 6.8 phosphate buffer with 1.5% SLS period of time. We have now developed a controlled release at about 100 rpm, wherein about 20% to about 50% of the and/or mucoadhesive dosage form of rifaximin, which Sur drug is released in about 8 hrs, about 30% to about 70% of prisingly extends the GI residence time of rifaximin. 55 drug is released in about 12 hrs and about more than 70% of drug is released in about 24 hrs. OBJECTS OF THE INVENTION Yet another object of the invention is to provide a pharma ceutical composition comprising a therapeutically effective The object of the present invention is to provide a pharma amount of rifaximinor a pharmaceutically acceptable salt(s) ceutical composition comprising a therapeutically effective 60 or enantiomer(s) or polymorph(s) thereof, one or more amount of rifaximin or a pharmaceutically acceptable salt(s) release controlling agent(s) and pharmaceutically acceptable or enantiomer(s) or polymorph(s) thereof, one or more excipient(s), wherein the composition is formulated to release controlling agent(s) and pharmaceutically acceptable increase the residence time of rifaximin in the gastrointestinal excipient(s). tract having an adhesive strength, measured as a force of Another object of the present invention is to provide a 65 detachment, of at least 100 mN when measured using pharmaceutical composition comprising a therapeutically advanced force gauge equipment (manufactured by Mec effective amount of rifaximin or a pharmaceutically accept mesin, West Sussex, England). US 8,383,151 B2 3 4 Another object of the invention is to provide a once daily “Entities' or “Entity” can be interchangeably used with pharmaceutical composition comprising therapeutically granules, pellets, beads, minitablets and the like. effective amount of rifaximin orpharmaceutically acceptable “Bioadhesion' is defined as the ability of a material to salt(s) or enantiomer(s) or polymorph(s) thereof, one or more adhere to a biological tissue for an extended period of time. release controlling agent(s) and pharmaceutically acceptable 5 Bioadhesion is one solution to the problem of inadequate excipient(s) which results in eradication of at least 70% of residence time resulting from stomach emptying and intesti pathogens. nal peristalsis, and from displacement by ciliary movement. Another object of the invention is to provide a once daily Bioadhesive properties of polymers are affected by both the pharmaceutical composition comprising therapeutically nature of the polymer and by the nature of the Surrounding effective amount of rifaximin orpharmaceutically acceptable 10 media. salt(s) or enantiomer(s) or polymorph(s) thereof, one or more Bioadhesive and mucoadhesive can be used interchange release controlling agent(s) and pharmaceutically acceptable ably. excipient(s) resulting in time for last unformed stools for E. “Increased residence time’ for purpose of this invention, coli positive population in the range of about 8 to about 90hrs. residence time is the time required for a pharmaceutical dos Another object of the invention is to provide a once daily 15 age form to transit through the stomach to the rectum i.e. the pharmaceutical composition comprising therapeutically pharmaceutical dosage forms of the invention may have an effective amount of rifaximin orpharmaceutically acceptable increased retention time in the stomach and/or Small and/or salt(s) or enantiomer(s) or polymorph(s) thereof, one or more large intestine, or in the area of the gastrointestinal tract that release controlling agent(s) and pharmaceutically acceptable is site of action or absorption of the drug contained in the excipient(s) resulting in time for last unformed stools for E. pharmaceutical dosage form. For example, pharmaceutical coli positive population in the range of about 20 to about 90 dosage forms of the invention can be retained in the Small hrs. intestine (or one or two portions thereof, selected from the duodenum, the jejunum and the ileum). These pharmaceuti BRIEF DESCRIPTION OF THE FIGURE cal dosage forms as a whole, may include a controlled release 25 or bioadhesive coating that is applied to at least one Surface of FIG. 1 is a graph showing the Bioadhesion Measurement the dosage form. with peak detachment force as a function of hydration time. In a preferred embodiment of the present invention the As determined by tensionmetric method, the force required to increase in residence time of rifaximin formulation in the separate the tablet from biological substrate was recorded in gastrointestinal tract is achieved by bioadhesion wherein bio mN. Support for this is found on page 33 in the Determination 30 adhesion is achieved using polymers having affinity for gas of Bioadhesion section of the specification. trointestinal mucosa. Examples of mucoadhesives for use in the embodiments disclosed herein include, but are not limited DETAILED DESCRIPTION OF THE INVENTION to, natural, semisynthetic and synthetic polymers. Natural polymers include but are not limited to proteins The present invention is directed towards a pharmaceutical 35 (e.g., hydrophilic proteins). Such as pectin, Zein, modified composition comprising atherapeutically effective amount of Zein, casein, gelatin, gluten, serum albumin, or collagen, chi rifaximin or a pharmaceutically acceptable salt(s) or enanti tosan, oligosaccharides and polysaccharides such as cellu omer(s) or polymorph(s) thereof, one or more release lose, dextrans, tamarind seed polysaccharide, gellan, carrag controlling agent(s) and pharmaceutically acceptable excipi eenan, Xanthan gum, gum Arabic: hyaluronic acid, ent(s). 40 polyhyaluronic acid, alginic acid, sodium alginate. The present invention is further directed towards a phar When the bioadhesive polymer is a synthetic polymer, the maceutical composition comprising a therapeutically effec synthetic polymer is typically selected from but are not lim tive amount of rifaximin or a pharmaceutically acceptable ited to polyamides, polycarbonates, polyalkylenes, polyalky salt(s) or enantiomer(s) or polymorph(s) thereof, one or more lene glycols, polyalkylene oxides, polyalkylene terephtha release controlling agent(s) and pharmaceutically acceptable 45 lates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, excipient(s) wherein the composition is formulated to polyvinylhalides, polyvinylpyrrolidone, polyglycolides, pol increase the residence time of rifaximin in the gastrointestinal ysiloxanes, polyurethanes, polystyrene, polymers of acrylic tract. and methacrylic esters, polylactides, poly(butyric acid), poly “Therapeutically effective amount’ means that the amount (Valeric acid), poly(lactide-co-glycolide), polyanhydrides, of active agent, which halts or reduces the progress of the 50 polyorthoesters, poly(fumaric acid), poly(maleic acid), and condition being treated or which otherwise completely or blends and copolymers or mixtures thereof. partly cures or acts palliatively on the condition. A person Other polymers suitable for use in the invention include, skilled in the art can easily determine Such an amount by but are not limited to, methyl cellulose, ethyl cellulose, routine experimentation and with an undue burden. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, “Controlled release.” means drug delivery system releas 55 hydroxybutylmethyl cellulose, cellulose acetate, cellulose ing the drug at a predetermined rate, locally or systemically, propionate, cellulose acetate butyrate, cellulose acetate for a specified period of time. Controlled release can be used phthalate, carboxymethyl cellulose, cellulose triacetate, cel interchangeably with prolonged release, programmed lulose Sulfate sodium salt, poly(methyl methacrylate), poly release, timed release, extended release, Sustained release and (ethyl methacrylate), poly (butyl methacrylate), poly(isobu other such dosage forms. 60 tyl methacrylate), poly(hexyl methacrylate), poly(isodecyl "Optional' or “optionally’ means that the subsequently methacrylate), poly(lauryl methacrylate), poly(phenyl meth described circumstance may or may not occur, so that the acrylate), poly(methyl acrylate), poly(isopropyl acrylate), description includes instances where the circumstance occurs poly(isobutyl acrylate), poly(octadecyl acrylate) polyethyl and instances where it does not. ene, polypropylene, poly(ethylene glycol), poly(ethylene By “pharmaceutically acceptable' is meant a carrier com 65 oxide), poly (ethylene terephthalate), polyvinyl acetate), prised of a material that is not biologically or otherwise unde polyvinyl chloride, polystyrene, polyvinyl pyrrolidone, and sirable. polyvinylphenol. Polylactides, polyglycolides and copoly US 8,383,151 B2 5 6 mers thereof, poly(ethylene terephthalate), poly(butyric mucin layer. The list of useful ligands include but are not acid), poly(Valeric acid), poly(lactide-co-caprolactone), poly limited to the following: sialic acid, neuraminic acid, lactide-co-glycolide, polyanhydrides (e.g., poly(adipic n-acetyl-neuraminic acid, n-glycolylneuraminic acid, anhydride)), polyorthoesters, blends and copolymers thereof. 4-acetyl-n-acetylneuraminic acid, diacetyl-n-acetyl Another group of polymers Suitable for use as bioadhesive 5 neuraminic acid, glucuronic acid, iduronic acid, galactose, polymers but not necessarily limited to polymers having a glucose, mannose, fructose, any of the partially purified frac hydrophobic backbone with at least one hydrophobic group tions prepared by chemical treatment of naturally occurring pendant from the backbone. Suitable hydrophobic groups are mucin, e.g., mucoproteins, mucopolysaccharides and muco groups that are generally non-polar. Examples of such hydro polysaccharide-protein complexes, and antibodies immu phobic groups include alkyl, alkenyl and alkynyl groups. 10 noreactive against proteins or Sugar structure on the mucosal Preferably, the hydrophobic groups are selected to not inter Surface. fere and instead to enhance the bioadhesiveness of the poly The attachment of polyamino acids containing extra pen CS. dant carboxylic acid side groups, such as polyaspartic acid A further group of polymers suitable for use as bioadhesive and polyglutamic acid, may also increase bioadhesiveness. polymers but not necessarily limited to polymers having a 15 The polyamino chains would increase bioadhesion by means hydrophobic backbone with at least one hydrophilic group of chain entanglement in mucin Strands as well as by pendant from the backbone. Suitable hydrophilic groups increased carboxylic charge. include groups that are capable of hydrogen bonding or elec In another embodiment the formulation of the present trostatically bonding to another functional group. Example of invention further comprises solubilizing agents defined as the Such hydrophilic groups include negatively charged groups agents that help the drug to solubilize either informulation or Such as carboxylic acids, Sulfonic acids and phosphonic in the site of absorption or action. Solubilizing agents include acids, positively charged groups such as (protonated) amines but are not limited to Surfactants, cyclodextrin and its deriva and neutral, polar groups such as amides and imines. tives, lipophilic Substances or any combination thereof. Preferably, the hydrophilic groups are selected not to inter Unlimiting examples of Surfactants include water-soluble fere and instead to enhance the bioadhesiveness of the poly 25 or water dispersible nonionic, semi-polar nonionic, anionic, mers. In embodiments of the present invention, a pharmaceu cationic, amphoteric, or Zwitterionic Surface-active agents; or tical composition comprises an active agent and at least one any combination thereof. swellable polymer. Other solubilizing agents include but not necessarily lim Swellable polymers include, but are not limited to, a ited to vitamin E substance and its derivatives; monohydric crosslinked poly(acrylic acid), a poly(alkylene oxide), a poly 30 alcohol esters such as trialkyl citrates, lactones and lower vinyl alcohol), a polyvinyl pyrrolidone); a polyurethane alcohol fatty acid esters; nitrogen-containing solvents; phos hydrogel, a maleic anhydride polymer, such as a maleic anhy pholipids; glycerol acetates such as acetin, diacetin and tri dride copolymer, a cellulose polymer, a polysaccharide, acetin; glycerol fatty acid esters such as mono-, di- and trig starch, and starch based polymers. lycerides and acetylated mono- and diglycerides; propylene Polymers can be modified by increasing the number of 35 glycol esters; ethylene glycol esters; and combinations carboxylic groups accessible during biodegradation, or on the thereof. polymer surface. The polymers can also be modified by bind Pharmaceutically acceptable excipients include but are not ing amino groups to the polymer. The polymers can be modi limited to binders, diluents, lubricants, glidants and Surface fied using any of a number of different coupling chemistries active agents. available in the art to covalently attach ligand molecules with 40 The amount of additive employed will depend upon how bioadhesive properties to the surface-exposed molecules of much active agent is to be used. One excipient can perform the polymeric microspheres. more than one function. Lectins can be covalently attached to polymers to render Binders include, but are not limited to, starches such as them target specific to the mucin and mucosal cell layer. The potato starch, wheat starch, corn starch; microcrystalline cel attachment of any positively charged ligand, such as polyeth 45 lulose such as products known under the registered trade yleneimine or polylysine, to a polymer may improve bioad marks Avicel, Filtrak, Hewetenor Pharmacel; celluloses such hesion due to the electrostatic attraction of the cationic groups as hydroxypropyl cellulose, hydroxyethyl cellulose, hydrox coating the beads to the net negative charge of the mucus. The ypropylmethyl cellulose (HPMC), ethyl cellulose, sodium mucopolysaccharides and mucoproteins of the mucin layer, carboxy methyl cellulose; natural gums like acacia, alginic especially the sialic acid residues, are responsible for the 50 acid, guar gum, liquid glucose, dextrin, poVidone, Syrup. negative charge coating. Any ligand with a high binding affin polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl ity for mucin could also be covalently linked to most poly amide, polyethylene glycol, gelatin, poly propylene glycol, mers with the appropriate chemistry, Such as with carbodi tragacanth, combinations there of and other materials known imidazole (CDI), and be expected to influence the binding to to one of ordinary skill in the art and mixtures thereof. the gut. For example, polyclonal antibodies raised against 55 Fillers or diluents, which include, but are not limited to components of mucin or else intact mucin, when covalently confectioner's Sugar, compressible Sugar, dextrates, dextrin, coupled to a polymer, would provide for increased bioadhe dextrose, fructose, lactitol, mannitol. Sucrose, starch, lactose, Sion. Similarly, antibodies directed against specific cell Sur Xylitol, Sorbitol, talc, microcrystalline cellulose, calcium car face receptors exposed on the lumenal Surface of the intestinal bonate, calcium phosphate dibasic or tribasic, calcium Sul tract would increase the residence time when coupled to 60 phate, and the like can be used. polymers using the appropriate chemistry. The ligandaffinity Lubricants may be selected from, but are not limited to, need not be based only on electrostatic charge, but other those conventionally known in the art such as Mg, Al or Ca or useful physical parameters such as Solubility in mucin or Zn Stearate, polyethylene glycol, glyceryl behenate, mineral specific affinity to carbohydrate groups. oil, Sodium Stearyl fumarate, Stearic acid, hydrogenated veg The covalent attachment of any of the natural components 65 etable oil and talc. of mucin in either pure or partially purified form to the poly Glidants include, but are not limited to, silicon dioxide; mers generally increases the solubility of the polymer in the magnesium trisilicate, powdered cellulose, starch, talc and US 8,383,151 B2 7 8 tribasic calcium phosphate, calcium silicate, magnesium sili include compression coating, coating in a fluidized bed or a cate, colloidal silicon dioxide, silicon hydrogel and other pan and hot melt (extrusion) coating. Such methods are well materials known to one of ordinary skill in the art. known to those skilled in the art. The present formulations may optionally contain a surface Non-permeable coatings of insoluble polymers, e.g., cel active agent. The preferred agent is copolymers composed of 5 lulose acetate, ethylcellulose, can be used as enteric coatings a central hydrophobic chain of polyoxypropylene (poly (pro for delayed/modified release (DR/MR) by inclusion of pylene oxide)) and polyoxyethylene (poly(ethylene oxide)) soluble pore formers in the coating, e.g., PEG, PVA, Sugars, that is well known as poloxamer. However, other agents may salts, detergents, triethylcitrate, triacetin, etc. also be employed Such as dioctyl Sodium sulfo Succinate Also, coatings of polymers that are susceptible to enzy (DSS), triethanolamine, sodium lauryl Sulphate (SLS), poly 10 matic cleavage by colonic bacteria are another means of oxyethylene Sorbitan and poloxalkol derivatives, quaternary ensuring release to distal ileum and ascending colon. Mate ammonium salts or other pharmaceutically acceptable Sur rials such as calcium pectinate can be applied as coatings to face-active agents known to one ordinary skilled in the art. dosage form and multiparticulates and disintegrate in the The pharmaceutical formulation according to the present lower gastrointestinal tract, due to bacterial action. Calcium invention include but is not limited to tablets (single layered 15 pectinate capsules for encapsulation of bioadhesive multipar tablets, multilayered tablets, mini tablets, bioadhesive tablets, ticulates are also available. caplets, matrix tablets, tablet within a tablet, mucoadhesive In an embodiment the coating further comprises the drug. tablets, modified release tablets, pulsatile release tablets, In a preferred embodiment of the present invention the timed release tablets), pellets, beads, granules, Sustained pharmaceutical formulation is multilayer tablets comprising release formulations, capsules, microcapsules, tablets in cap a first, a second and/or a third layer, where each layer includes Sules and microspheres, matrix formulations, microencapsu one or more excipient(s). lation and powder/pellets/granules for Suspension. Multi-layer or gradient tablets can be assembled in several The pharmaceutical dosage form of the invention can different ways. optionally have one or more coatings Such as film coating, In one embodiment, the tablet comprises at least one solid Sugar coating, enteric coating, bioadhesive coating and other 25 core and two outer layers, each comprising one or more coatings known in the art. These coatings help pharmaceuti pharmaceutical polymers and/or pharmaceutical excipients. cal formulations to release the drug at the required site of The core comprises active ingredient and rate-controlling action. In one example, the additional coating prevents the polymer. The two outer layers are bioadhesive. dosage from contacting the mouth or esophagus. In another In another embodiment, the tablet comprises at least one example, the additional coating remains intact until reaching 30 core and two outer layers, each comprising drug and one or the Small intestine (e.g., an enteric coating). Premature expo more pharmaceutical polymers and/or pharmaceutical sure of a bioadhesive layer or dissolution of a pharmaceutical excipients. Such tablets can also be used to commence release dosage form in the mouth can be prevented with a layer or of different drugs at different times, by inclusion of different coating of hydrophilic polymers such as HPMC or gelatin. drugs in separate layers. Optionally, Eudragit FS 30D or other suitable polymer may 35 In another embodiment, the multi-layer tablet comprises of be incorporated in coating composition to retard the release of a core and two outer layers, each comprising a drug and one the drug to ensure drug release in the colon. or more pharmaceutical polymers or pharmaceutical excipi These coating layers comprises one or more excipients ents, wherein at least one polymer or excipient is hydropho selected from the group comprising coating agents, opacifi bic. ers, taste-masking agents, fillers, polishing agents, colouring 40 In another preferred embodiment the present invention agents, antitacking agents and the like. relates to formulation which comprises multilayer tablet Coating agents which are useful in the coating process, wherein at least one layer consist of a release controlling include, but are not limited to, polysaccharides such as mal polymer and the active ingredient and at least one layer which todextrin, alkyl celluloses such as methyl or ethyl cellulose, consist of bioadhesive polymer, where each layer includes hydroxyalkylcelluloses (e.g. hydroxypropylcellulose or 45 one or more excipients. hydroxypropylmethylcelluloses); polyvinylpyrrolidone, aca In another embodiment the present invention relates to cia, corn, Sucrose, gelatin, shellac, cellulose acetate pthalate, formulation which comprises multilayer tablet wherein at lipids, synthetic resins, acrylic polymers, opadry, polyvinyl least one layer consist of a release controlling polymer and at alcohol (PVA), copolymers of vinylpyrrolidone and vinyl least one layer which consist of bioadhesive polymer, where acetate (e.g. marketed under the brand name of Plasdone) and 50 each layer includes one or more excipients and drug. polymers based on methacrylic acid Such as those marketed The release controlling polymers can be hydrophilic, under the brand name of Eudragit. These may be applied from hydrophobic or combination thereof. aqueous or non-aqueous systems or combinations of aqueous The hydrophilic rate-controlling polymer includes but are and non-aqueous systems as appropriate. Additives can be not limited to hydroxyethylcellulose, hydroxypropyl cellu included along with the film formers to obtain satisfactory 55 lose, Hydroxypropyl Methylcellulose, sodium carboxym films. These additives can include plasticizers such as dibutyl ethyl cellulose, sodium alginate, carbomer (CarbopolTM), phthalate, triethylcitrate, polyethylene glycol (PEG) and the Xanthan gum, guar gum, locust bean gum, poly Vinyl acetate, like, antitacking agents such as talc, Stearic acid, magnesium polyvinyl alcohol. Preferably the rate-controlling polymer is Stearate and colloidal silicon dioxide and the like, Surfactants hydroxypropylmethylcellulose (Low Viscosity grade). Such as polysorbates and sodium lauryl Sulphate, fillers such 60 The hydrophobic rate controlling agent in matrix includes as talc, precipitated calcium carbonate, Polishing agents such but are not limited to hydrogenated vegetable oil, but other as Beeswax, carnauba wax, synthetic chlorinated wax and Suitable agents include purified grades of beeswax, fatty opacifying agents such as titanium dioxide and the like. All acids; long chain fatty alcohols, such as cetyl alcohol, myri these excipients can be used at levels well known to the styl alcohol, and Stearyl alcohol, glycerides such as glyceryl persons skilled in the art. 65 esters of fatty acids like glyceryl monostearate, glyceryl dis Pharmaceutical dosage forms of the invention can be tearate, glyceryl esters of hydrogenated castor oil and the like; coated by a wide variety of methods. Suitable methods oils such as mineral oil and the like, or acetylated glycerides; US 8,383,151 B2 10 ethyl cellulose, Stearic acid, paraffin, carnauba wax, talc, and peptic ulcer disease, Surgical prophylaxis and gastric dyspep the Stearate salts such as calcium, magnesium, Zinc and other sia by administering once daily dosage form comprising materials known to one of ordinary skill in the art. rifaximin. In embodiments of the present invention, a pharmaceutical The pharmaceutical composition of the present invention composition comprises an active agent and at least one contain, for example, from about 0.1% to 90% of rifaximin. swellable polymer. Swellable polymers include, but are not Presently for the approved indication of travelers diarrhea, limited to, a crosslinked poly(acrylic acid), a poly(alkylene rifaximin is administered 200 milligrams orally 3 times a day oxide), a polyvinyl alcohol), a polyvinyl pyrrolidone); a poly as immediate release dosage form for 3 days in adults and in urethane hydrogel, a maleic anhydride polymer, Such as a children 12-years of age and older. The therapeutic dose maleic anhydride copolymer, a cellulose polymer, a polysac 10 charide, starch, and starch based polymers. varies according to the body weight and the acuteness of the In another embodiment of the present invention the phar pathology; a daily dose between 20 mg and 2400 mg, prefer maceutical composition of rifaximin comprises: at least two ably 200 mg to 2000 mg, administered in a single dose or entities wherein one entity is an immediate release or fast divided into 2 or 3 doses. release and the other is controlled release. 15 In an embodiment of the present invention in order to In another embodiment of the present invention the phar improve the patient compliance and target the formulation in maceutical composition of rifaximin comprises: at least two intestine, a bioadhesive, controlled release once daily (600 entities wherein one entity is an immediate release or fast mg) of rifaximin is explored. release and the other is a bioadhesive. The foregoing examples are illustrative embodiments of In another embodiment of the present invention the phar the invention and are merely exemplary. A person skilled in maceutical composition of rifaximin comprises: at least two the art may make variations and modifications without devi entities wherein one entity is controlled release and the other ating from the spirit and Scope of the invention. All Such is a bioadhesive. modifications and variations are intended to be included The pharmaceutical composition of the invention can be within the scope of the invention. formed by various methods known in the art such as by dry 25 granulation, wet granulation, melt granulation, direct com EXAMPLES pression, double compression, extrusion spheronization, lay ering and the like. Example 1 In a preferred embodiment, the process of making the pharmaceutical formulation of the invention comprises as 30 A First Layer described below: vi) blending the active agent and pharmaceutically accept able additives, vii) Subjecting the blend to slugging/compaction to form a Ingredients % Wiw coprimate 35 viii) Converting the coprimate to granules and Rifaximin 30 iX) Compressing the granules to form the Solid oral dosage Hydroxypropylmethyl 10 form. cellulose) HPMC Poloxamer 10 X) The compressed granules are optionally coated. Diluents (e.g., Mannitol or 40 Compaction of the blend into coprimate may be carried out 40 DCP or MCC) using a slugging technique or roller compaction. The milling Colloidal silicon dioxide 5 of the granules may be carried out according to conventional Magnesium stearate 5 milling methods. The process of wet granulation includes aqueous or non Procedure: aqueous granulation. The wet granulation process comprises 45 i) Sift Rifaximin, diluent, HPMC and Poloxamer through the admixing of the active ingredient with diluent(s) and/or suitable sieve. rate controlling polymer, and granulation of the blend with ii) Dry blend (i) in a blender. the binder mass to form the wet mass followed by drying and iii) Sift colloidal silicon dioxide and magnesium Stearate sizing. The binder may optionally be admixed with the dry through suitable sieve. blend and granulation performed with aqueous or non-aque 50 iv) Lubricate (ii) with (iii) in a blender. ous solvent. The solvent for the non-aqueous granulation is selected from ethanol, isopropyl alcohol and dichlo B) Second Layer romethane. Rifaximin is approved for the treatment of travelers’ diar rhea in adults and in children 12-years of age and older. 55 Rifaximin has also been evaluated for the treatment of hepatic encephalopathy, infectious diarrhea, and diverticular disease Ingredients % Wiw and as an antibacterial prophylactic prior to colon Surgery, HPMC 50 gastric dyspepsia caused by bacteria known as Helicobacter Polyethylene Oxide (PEO) 35 pylori. 60 Colloidal silicon dioxide 10 In an aspect of the present invention includes a method of Magnesium stearate 5 increasing patient compliance for treatment of traveler's diar rhea, hepatic encephalopathy, infectious diarrhea, diverticu i) Sift HPMC and PEO through suitable sieve lar disease, an antibacterial prophylactic prior to colon Sur ii) Dry blend (i) in a blender. gery, irritable bowel syndrome, Crohn's disease, Clostridum 65 iii) Sift colloidal silicon dioxide and magnesium Stearate difficile-associated diarrhea, Small intestinal bacterial over through suitable sieve. growth, traveler's diarrhea prophylaxis, dysentery, pouchitis, iv) Lubricate (ii) with (iii) in a blender. US 8,383,151 B2 11 Blends of A and B are then compressed into bilayer tablets ortablet in tabletorindividually compressed into mini-tablets and filled into capsules. Composition % Wiw The uncoated tablet then film coated 2-3% weight gain with following composition. 5 Eudragit L 100 40 Eudragit S 100 40 TEC 8 Ingredients % Wiw Talc 12 Hypromellose 67 10 IPA QS Lactose monohydrate 17 Water QS Polyethylene glycol 3 Talc 4 Titanium dioxide 3 Iron Oxide Red 3 Yellow Iron Oxide 3 15 Example 3 Water Q.S. A) First Layer Example 2 A) First Layer Ingredients % Wiw Rifaximin 50 25 Diluents (e.g., Mannitol or 15 DCP or MCC) Ingredients % Wiw HPMC 10 Rifaximin 40 PEO 2O Diluents (e.g., Mannitol or 15 Colloidal silicon dioxide 3 DCP or MCC) Magnesium stearate 2 HPMC 15 30 IPA QS PEO 2O Methylene chloride QS Colloidal silicon dioxide 7 Magnesium Stearate 3 Water QS Procedure:

35 i) Sift Rifaximin, diluent and PEO through suitable sieve and Procedure: mix in a blender. i) Sift Rifaximin, diluent and PEO through specific sieve and ii) Add HPMC to IPA: Methylene chloride under stirring. mix in a blender. iii) Granulate (i) with (ii) and dry the wet mass in a fluid bed ii) Add HPMC to water under stirring. dryer. iii) Granulate (i) with (ii) and dry the wet mass in a fluid bed 40 dryer. iv) Granules of (iii) passed through suitable sieve. iv) Granules of (iii) passed through suitable sieve. V) Sift colloidal silicon dioxide and magnesium Stearate V) Sift colloidal silicon dioxide and magnesium Stearate through specific sieve through suitable sieve. vi) Lubricate (iv) with (v). vi) Lubricate (iv) with (v). 45 B) Second Layer B) Second Layer

Ingredients % Wiw Ingredients % Wiw

HPMC 50 HPMC 50 PEO 35 PEO 35 Colloidal silicon dioxide 10 55 Colloidal silicon dioxide 10 Magnesium Stearate 5 Magnesium Stearate 5 i) Sift HPMC and PEO through suitable sieve i) Sift HPMC and PEO through compress both the layers into ii) Dry blend (i) in a blender. 60 bilayer tablets. Seive iii) Sift colloidal silicon dioxide and magnesium Stearate ii) dry blend (i) in a blender. through suitable sieve. iii) sift colloidal silicon dioxide and magnesium Stearate iv) Lubricate (ii) with (iii) in a blender. through suitable sieve. Compress both A and B to form bilayer tablet or individu ally compressed into mini-tablets and filled into capsules. 65 iv) Lubricate (ii) with (iii) in a blender. The uncoated tablet then Enteric coated with 5-10% weight Compress both A and B to form bilayer tablet or individu gain with following composition. ally compressed into mini-tablets and filled into capsules. US 8,383,151 B2 14 Example 4 Procedure: i) Sift Rifaximin, Diluent, HPMC and PEO through suitable sieve ii) Dry blend (i) in a blender. iii) Granulate (ii) with IPA:methylene (70:30) chloride and Ingredients % Wiw dry the wet mass in fluid bed dryer. Rifaximin 50 iv) Granules obtained in (iii) are sifted through suitable sieve. Diluents (e.g., Mannitol 10 v) Sift Colloidal silicon dioxide and magnesium stearate or DCP or MCC through specific sieve. HPMC 10 vi) Lubricate (iv) with (v). Sodium Lauryl Sulphate 5 10 vii) Blend of step (vi) is then compressed into tablets. Xanthan gum 15 Colloidal silicon dioxide 5 Example 7 Magnesium Stearate 5

Procedure: 15 i) Sift Rifaximin, Diluent, HPMC, SLS and Xanthan gum Ingredients % Wiw through suitable sieve. Rifaximin 50 ii) Dry blend (i) in a blender. Diluents (e.g., Mannitol 15 iii) Sift colloidal silicon dioxide and magnesium Stearate or DCP or MCC through suitable sieve. HPMC 10 PEO 15 iv) Lubricate (ii) with (iii) in a blender. Colloidal silicon dioxide 5 v) The blend is then compressed into tablets. Magnesium Stearate 5

Example 5 25 Procedure: i) Sift Rifaximin, Diluent, HPMC and PEO through suitable sieve. ii) Dry blend (i) in a blender. iii) Sift Colloidal silicon dioxide and magnesium stearate Ingredients % Wiw 30 through suitable sieve. Rifaximin 50 iv) Add half quantity of (iii) to (ii) and mix in a blender. Diluents (e.g., Mannitol 15 V) Compact blend of (iv) using a roller compactor at a pres or DCP or MCC SUC. HPMC 15 vi) Sift (v) through suitable seive to obtain granules. PEO 15 Colloidal silicon dioxide 3 35 vii) Mix remaining quantity of (iii) and (vi) in a blender. Magnesium Stearate 2 viii) Blend of (vii) is compressed into tablets. Water QS Example 8

Procedure: A) First and Third Layer i) Sift Rifaximin, Diluent, HPMC and PEO through suitable 40 sieve. ii) Dry blend (i) in a blender. iii) Granulate (ii) with water and dry the wet mass in fluidbed Ingredients 9% WW dryer. 45 HPMC 40 iv) Granules obtained in (iii) are sifted through suitable sieve. Xanthan Gum 2O Carbopol 25 v) Sift Colloidal silicon dioxide and magnesium stearate Collodial Silicon Dioxide 10 through suitable sieve. Magnesium Stearate 5 vi) Lubricate (iv) with (v). 50 vii) Blend of step (vi) is then compressed into tablets. Procedure: i) Sift HPMC, Xanthan gum and Carbopol through suitable Example 6 sieve. ii) Dry blend (i) in a blender. 55 iii) Sift colloidal silicon dioxide and magnesium Stearate through suitable sieve. Ingredients % Wiw iv) Lubricate (ii) with (iii) in a blender. B) Middle Layer Rifaximin 60 Diluents (e.g., Mannitol or DCP or 10 MCC) 60 HPMC 12 PEO 13 Colloidal silicon dioxide 3 Ingredients 9% WW Magnesium Stearate 2 IPA QS Rifaximin 40 Methylene chloride QS 65 Diluents (E.g. Mannitol or DCP or MCC) 30 HPMC 15 US 8,383,151 B2 16 -continued vi) Lubricate (iv) with (v). vii) Blend of A and B is then compressed into trilayered Ingredients 9% WW tablet. Poloxamer 5 Colloidal silicon dioxide 5 Example 10 Magnesium Stearate 5 A) First and Third Layer i) Sift Rifaximin, diluent, HPMC, SLS and Xanthan gum through suitable sieve 10 ii) Dry blend (i) in a blender. iii) Sift colloidal silicon dioxide and magnesium Stearate Ingredients 9% WW through suitable sieve. HPMC 40 15 Xanthan gum 2O iv) Lubricate (ii) with (iii) in a blender. Carbopol 25 Colloidal silicon dioxide 10 Blends of A and B are compressed into trilayer tablets Magnesium Stearate 5 Example 9 Procedure: i) Sift HPMC, Xanthan gum and Carbopol through suitable A) First and Third Layer sieve. ii) dry blend (i) in a blender. iii) sift colloidal silicon dioxide and magnesium Stearate 25 through suitable sieve. Ingredients 9% WW iv) Lubricate (ii) with (iii) in a blender. HPMC 40 Xanthan gum 2O B) Middle Layer Carbopol 25 30 Colloidal silicon dioxide 10 Magnesium stearate 5

Procedure: Ingredients 9% WW 35 Rifaximin 40 i) Sift HPMC, Xanthan gum and Carbopol through suitable Diluents (e.g., Mannitol or DCP or 2O sieve MCC) HPMC 2O ii) Dry blend (i) in a blender. PEO 15 iii) Sift colloidal silicon dioxide and magnesium Stearate Colloidal silicon dioxide 3 40 Magnesium stearate 2 through suitable sieve. IPA QS iv) Lubricate (ii) with (iii) in a blender. Methylene chloride QS

B) Middle Layer i) Sift Rifaximin, diluent, and PEO through suitable sieve. 45 ii) Dry blend (i) in a blender. iii) Mix HPMC in IPA:Methylene chloride under stirring. iv) Granulate (ii) with (iii) and dry the wet mass in fluid bed Ingredients 9% WW dryer. 50 Rifaximin 50 V) Granules obtained in (iii) are sifted through suitable sieve. Diluents (e.g., Mannitol or DCP or MCC) 15 vi) Sift Colloidal silicon dioxide and magnesium stearate HPMC 10 PEO 15 through suitable sieve. Colloidal silicon dioxide 7 vii) Lubricate (iv) with (v). Magnesium stearate 3 55 Water qS Blend A and B are then compressed into trilayer tablet. Example 11 i) Sift Rifaximin, diluent, and PEO through suitable sieve ii) dry blend (i) in a blender. 60 iii) Mix HPMC in water under stirring iii) Granulate (ii) with (iii) and dry the wet mass in fluid bed Ingredients 9% WW dryer. Rifaximin 30 Xanthan gum 30 iv) Granules obtained in (iii) are sifted through suitable sieve. 65 Water QS v) Sift Colloidal silicon dioxide and magnesium stearate Calcium Chloride 10 through suitable sieve. US 8,383,151 B2 18 -continued Hot Melt Extrusion i) Sift MCC, Rifaximin, PEO and HPMC through suitable Ingredients 9% WW S1W. Water QS ii) Step (i) is mixed thoroughly and heated at 70° C. Sodium Alginate 25 iii) The soft mass thus obtained is extruded through an Magnesium Stearate 5 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 Procedure: powder for Suspension or compressed into tablets. i) Sodium alginate is suspended in water and rifaximin was Suspended in this colloidal Solution. 10 Example 14 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. 15 Ingredients 9% WW iv) Mix the dried beads with Xanthan gum and sodium algi nate. Rifaximin 2O Diluents (e.g. Mannitol or DCP or MCC) 30 V) Lubricate the beads of step (iv) with magnesium Stearate Xanthan gum 15 and fill into capsules or sachets or filled in water with Sweet Poloxamer 10 ening and flavouring agents as a powder for Suspension. Sodium Alginate 15 Colloidal silicon dioxide 5 Example 12 Magnesium Stearate 5 Procedure: i) Rifaximin, Diluents, Xanthan gum, Poloxamer and sodium 25 alginate are sifted through suitable sieve. Ingredients 9% WW ii) Step (i) is dry blended in a blender. iii) Lubricants are sifted through specific sieve and mixed Rifaximin 40 with step (ii). Diluents (e.g., Mannitol or DCP or MCC) 30 Sodium CMC 15 30 iv) Blend of step (iii) is then compressed into mini tablets. IPA QS v) These mini tablets can be filled into capsules. PEO 10 Magnesium Stearate 5 Example 15 A) First Layer Procedure: 35 i) Sift Rifaximin, Diluent, sodium CMC and PEO through suitable sieve. ii) Granulate blend of step (i) with IPA. iii) Dry the granules of step (ii) and sift through suitable sieve. Ingredients % Wiw 40 iv) Lubricate the granules of step (iii) with magnesium Stear Rifaximin 90 ate. Hydroxypropylmethyl 5 cellulose HPMC v) The bioadhesive granules of step (iv) can be further com Colloidal silicon dioxide 3 pressed into tablets using Suitable diluents and lubricants or Magnesium Stearate 2 filled into capsules or sachets or filled into bottle with Sweet ening and flavouring agents as a powder for Suspension. 45 Procedure: i) Sift Rifaximin and HPMC through suitable sieve. Example 13 ii) Dry blend (i) in a blender. iii) Sift colloidal silicon dioxide and magnesium Stearate 50 through suitable sieve. iv) Lubricate (ii) with (iii) in a blender. Ingredients 9% WW B) Second Layer Rifaximin 50 Microcrystalline cellulose (MCC) 2O 55 PEO 18 HPMC 10 IPA QS Magnesium Stearate 2 Ingredients % Wiw HPMC 49 60 Polyethylene Oxide (PEO) 49 Procedure: Colloidal silicon dioxide 1 Spheronization Magnesium stearate 1 i) Sift MCC, Rifaximin, PEO and HPMC through suitable sieve. i) Sift HPMC and PEO through suitable sieve ii) Step (i) is mixed with IPA. 65 ii) Dry blend (i) in a blender. iii) Wet mass of step (ii) is passed through Extruder and iii) Sift colloidal silicon dioxide and magnesium Stearate further spheronized to get the round pellets through suitable sieve. US 8,383,151 B2 19 20 iv) Lubricate (ii) with (iii) in a blender. Procedure: Blends of A and B are then compressed into bilayer tablets i) Sift Rifaximin, diluent and PEO through suitable sieve and or tablet in tablet mix in a blender. ii) Add HPMC to IPA:Methylene chloride under stirring. Example 16 iii) Granulate (i) with (ii) and dry the wet mass in a fluid bed dryer. A) First Layer iv) Granules of (iii) passed through suitable sieve. V) Sift colloidal silicon dioxide and magnesium Stearate through specific sieve 10 vi) Lubricate (iv) with (v).

Ingredients % Wiw B) Second Layer Rifaximin 50 Diluents (e.g. Mannitol or DCP or 15 MCC) 15 Hydroxypropylmethyl cellulose 15 HPMC Ingredients % Wiw PEO 15 Colloidal silicon dioxide 3 HPMC 49 Magnesium Stearate 2 PEO 49 Water QS Colloidal silicon dioxide 1 Magnesium Stearate 1

Procedure: i) Sift Rifaximin, diluent and PEO through specific sieve and i) Sift HPMC and PEO through suitable sieve mix in a blender. ii) Dry blend (i) in a blender. 25 iii) Sift colloidal silicon dioxide and magnesium Stearate ii) Add HPMC to water under stirring. through suitable sieve. iii) Granulate (i) with (ii) and dry the wet mass in a fluid bed iv) Lubricate (ii) with (iii) in a blender. dryer. Compress both A and B to form bilayer tablet. iv) Granules of (iii) passed through suitable sieve. V) Sift colloidal silicon dioxide and magnesium Stearate Example 18 through suitable sieve. 30 vi) Lubricate (iv) with (v). B) Second Layer Ingredients % Wiw 35 Rifaximin 40 Diluents (e.g., Mannitol or DCP or MCC 17 HPMC 2O Ingredients % Wiw Sodium Lauryl Sulphate 5 Xanthan gum 15 HPMC 81.5 40 Colloidal silicon dioxide 2 PEO 16 Magnesium stearate 1 Colloidal silicon dioxide 1.5 Magnesium Stearate 1 Procedure: i) Sift HPMC and PEO through suitable sieve i) Sift Rifaximin, Diluent, HPMC, SLS and Xanthan gum ii) Dry blend (i) in a blender. 45 through suitable sieve. iii) Sift colloidal silicon dioxide and magnesium Stearate ii) Dry blend (i) in a blender. through suitable sieve. iii) Sift colloidal silicon dioxide and magnesium Stearate iv) Lubricate (ii) with (iii) in a blender. through suitable sieve. Compress both A and B to form bilayer tablet. iv) Lubricate (ii) with (iii) in a blender. 50 v) The blend is then compressed into tablets. HPMC=Hydroxy propyl methyl cellulose Example 17 PEO-Polyethyeleneoxide DCP-Dicalcium phosphate A) First Layer MCC=Microcrystalline cellulose 55 MA 1=Methacrylic acid copolymer L 100 MA2=Methacrylic acid copolymer S 100 IPA=Isopropyl Alcohol Ingredients % ww Dissolution Rifaximin 50 The formulations of the invention have a prolonged in vitro 60 release rate. The in vitro test used to measure release rate of Diluents (e.g. Mannitol or DCP or MCC) 15 Hydroxypropylmethyl cellulose HPMC 10 the active agent from a formulation of the invention was as PEO 2O follows. A solution of 900 ml of a 6.8 pH phosphate buffer, Colloidal silicon dioxide 3 1.5% SLS was placed in an apparatus capable of agitation. Magnesium stearate 2 IPA QS The apparatus used in present invention is type II Paddle Methylene Chloride QS 65 dissolution apparatus, 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 US 8,383,151 B2 21 22 Example 1 is such that about 20% to 50% of drug is released TABLE 2 in about 8 hrs, about 30% to about 70% of drug is released in about 12 hrs and about more than 70% of drug is released in Mean TLUS For E. Coli Positive Population about 24 hrs. Rifaxmin ER 600 mg OD Xifaxan (R) 200 mg TID Determination of Bioadhesion Mean (hrs) Mean (hrs) Bioadhesion was determined by tensiometric method. For Site 1 60.52 (n = 14) 60.52 (n = 6) the determination, an advanced force gauge equipment (mfg. Site 2 44.16 (n = 6) 37.54 (n = 8) by Mecmesin, West Sussex, England) was used. Freshly excised Sheep intestinal tissue was taken and stored in a 10 Time for last unformed stools for E. coli positive popula Tyrode solution at 4°C. until used for the experiment. The tion ranges from about 20 to about 90 hrs, preferably from tissue was cut into pieces (3x4 cm) and mounted on the glass about 25 to about 85 hrs. slide and tightened with a thread. 0.5 ml Phosphate buffered saline (PBS) was placed on the tissue. The bioadhesive tablet TABLE 3 of the present invention was placed on this tissue and another 15 Microbiological Eradication Post Treatment 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 Rifaximin ER 600 mg OD Xifaxan (R) 200 mg TID for 10 min., 30 min. 60 min., and 840 min. At the specific Site 1 100% (n = 14) 100% (n = 6) time interval, the hydrated tablet along with slide was Site 2 83.33% (n = 6) 100% (n = 8) mounted on the stage of the bioadhesion apparatus. Probe was then lowered at fixed speed of 0.2 mm/sec. and upper slide *At the end of treatment one patient was still E. Coipositive. was attached to the hook of the probe by means of a thread. Based on the above results, it can be stated that rifaximin The peak detachment force was considered as the bioadhesive ER will increases patient compliance as it is similar in effi force as evident from the graph as provided in FIG. 1. The is cacy to Xifaxan R) but has to be administered once daily in force required to separate the tablet from biological substrate comparison to Xifaxan R) which is administered thrice daily. was recorded in mN. Further, it has been surprisingly found that rifaximin ER Treatment of Traveler's Diarrhea 600 mg given once daily was also effective in treating Kleb siella caused traveler's diarrhea. A randomized, open labeled, multi-centered, comparative 30 The invention claimed is: pilot clinical trial was carried out using the medicinal prepa 1. A controlled release pharmaceutical composition com ration containing extended release tablet containing 600 mg prising: of rifaximin, administered once daily as test and commer a.a single active agent consisting ofatherapeutically effec cially marketed dosage form containing 200 mg of rifaximin tive amount of rifaximinor pharmaceutically acceptable given thrice daily (Xifaxan R) as reference. The study was is salt(s) or enantiomer(s) or polymorph(s) thereof; designed to demonstrate the similar clinical efficacy com b. one or more release controlling agent(s); and pared to Xifaxan R. c. pharmaceutically acceptable excipient(s): E. Coli is the baseline pathogen with sufficient numbers to wherein the pharmaceutical composition has an in vitro dis determine the similar clinical efficacy compared to solution profile, when measured in a type II Paddle dissolu Xifaxan R. 40 tion apparatus, in 6.8 phosphate buffer with 1.5% SLS at about 100 rpm, in which about 20% to about 50% of the drug The primary efficacy endpoint was time to last unformed is released in about 8 hrs, about 30% to about 70% of drug is stool (TLUS) and secondary end point was eradication of released in about 12 hrs and about more than 70% of drug is pathogen. Therapy was taken for 3 days. The intent to treat released in about 24 hrs. (ITT) population was defined as all subjects randomized to 45 2. The controlled release pharmaceutical composition treatment. according to claim 1, wherein the composition is formulated A total of 66 patients were randomized to receive study to increase the residence time of rifaximin in the gastrointes treatment. Out of this 33 were randomized to receive rifaxi tinal tract. min ER and 31 to receive Xifaxan R. In rifaximin group 20 out 3. The controlled release pharmaceutical composition of 33 patients were E. coli positive. In Xifaxan R) group 14 out 50 according to claim 2, wherein the increase in residence time of 31 were E. coli positive. The results of TLUS are presented of rifaximin formulation in the gastrointestinal tract is in Table 1, Table 2 and Table 3 for the ITT, E. coli positive achieved by bioadhesion using one or more bioadhesive poly patients and E. Coli eradication respectively. TLUS was mea mer(s). Sured in hours. 4. The controlled release pharmaceutical composition 55 according to claim 3, wherein the polymer comprises poly TABLE 1. carbophils, carbomers, lectins, pectin, Zein, modified Zein, casein, gelatin, gluten, serum albumin, collagen, chitosan, Mean TLUS For ITT Population cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl Rifaxmin ER 600 mg OD Xifaxan (R) 200 mg TID cellulose, hydroxypropylmethyl cellulose, hydroxybutylm Mean (hrs) Mean (hrs) 60 ethyl cellulose, cellulose acetate, cellulose propionate, cellu lose acetate butyrate, cellulose acetate phthalate, carboxym Site 1 58.81 (n = 19) 60.56 (n = 19) ethyl cellulose, cellulose triacetate, cellulose sulfate sodium Site 2 34.90 (n = 14) 34.35 (n = 12) salt, dextrans, tamarind seed polysaccharide, gellan, carrag eenan, hyaluronic acid, polyhyaluronic acid, alginic acid, Time for last unformed stools for intent to treat population 65 Sodium alginate; gum, polyvinylacetate, polyvinylalcohol, ranges from about 8 to about 90hrs, preferably from about 10 poVidone/polyethylene oxide, acrylic and methacrylic acid to about 85 hrs. their copolymers, polyamides, polycarbonates, polyalky US 8,383,151 B2 23 24 lenes, polyalkylene glycols, polyalkylene oxides, polyalky 13. The controlled release pharmaceutical composition lene terephthalates, polyvinyl alcohols, polyvinyl ethers, according to claim 9, wherein the Surfactant comprises ionic polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, or non-ionic or Zwitterionic Surfactants. polyglycolides, polysiloxanes, polyurethanes, polystyrene, 14. The controlled release pharmaceutical composition polymers of acrylic and methacrylic esters, polylactides, poly according to claim 9, wherein the glidant comprises silicon (butyric acid), poly(Valeric acid), poly(lactide-co-glycolide), dioxide, colloidal silica, powdered cellulose, talc, tribasic polyanhydrides, polyorthoesters, poly(fumaric acid), poly calcium phosphate, or mixtures thereof. (maleic acid), polymers having a hydrophobic backbone with 15. The controlled release pharmaceutical composition at least one hydrophilic group pendant from the backbone, according to claim 1, which is a once-daily dosage form. 10 16. The controlled release pharmaceutical composition polymers having a hydrophobic backbone with at least one according to claim 1, which is a once-daily dosage form hydrophobic group pendant from the backbone, blends comprising 20 to 2400 mg of rifaximin. thereof, copolymers thereof; or mixtures thereof. 17. The controlled release pharmaceutical composition 5. The controlled release pharmaceutical composition according to claim 1, which is a once-daily dosage form according to claim 1, wherein the release controlling agent 15 comprising 550 mg of rifaximin. comprises hydrophilic polymer, hydrophobic agent, or mix 18. The controlled release pharmaceutical composition tures thereof. according to claim 1, which is a once-daily dosage form 6. The controlled release pharmaceutical composition comprising 600 mg of rifaximin. according to claim 5, wherein the hydrophilic polymer com 19. A method comprising, administering a controlled prises cellulose, ethylcellulose, hydroxypropylcellulose, release pharmaceutical composition according to claim 1 to hydroxypropylmethylcellulose, hydroxypropylethylcellu increase patient compliance for treatment of traveler's diar lose; Xanthan gum, guar gum, locust bean gum; alginates: rhea, hepatic encephalopathy, infectious diarrhea, diverticu carbomer, polyvinylacetate, polyvinylalcohol, povidone? lar disease, an antibacterial prophylactic prior to colon Sur polyethylene oxide, acrylic and methacrylic acid copolymers, gery, irritable bowel syndrome, Crohn's disease, Clostridum or mixtures thereof. 25 difficile-associated diarrhea, Small intestinal bacterial over 7. The controlled release pharmaceutical composition growth, traveler's diarrhea prophylaxis, dysentery, pouchitis, according to claim 5, wherein the hydrophobic release com peptic ulcer disease, Surgical prophylaxis, or gastric dyspep ponent comprises beeswax; fatty acids; long chain fatty alco S1a. hols, such as cetyl alcohol, myristyl alcohol, Stearyl alcohol; 20. A method comprising, administering a controlled glycerides such as glyceryl esters of fatty acids like glyceryl 30 release pharmaceutical composition according to claim 1 to treat traveler's diarrhea, hepatic encephalopathy, infectious monostearate, glyceryl distearate, glyceryl esters of hydroge diarrhea, diverticular disease, an antibacterial prophylactic nated castor oil, mineral oil, hydrogenated vegetable oil, prior to colon surgery, irritable bowel syndrome, Crohn's acetylated glycerides; ethyl cellulose, Stearic acid, paraffin, disease, Clostridum difficile-associated diarrhea, Small intes carnauba wax, talc, Stearate salts such as calcium, magne 35 tinal bacterial overgrowth, traveler's diarrhea prophylaxis, sium, Zinc or mixtures thereof. dysentery, pouchitis, peptic ulcer disease, Surgical prophy 8. The controlled release pharmaceutical composition laxis, or gastric dyspepsia. according to claim 1, further comprising a solubilizing agent 21. The method of claim 20, comprising administering the comprising Surfactant; cyclodextrin and its derivatives; lipo controlled release pharmaceutical composition according to philic Substances; Vitamin E and its derivatives; monohydric 40 claim 1 for the treatment of traveler's diarrhea. alcohol esters; nitrogen-containing solvents; phospholipids; 22. The method of claim 21, comprising administering the glycerol acetates; glycerol fatty acid esters; propylene glycol controlled release pharmaceutical composition according to esters; ethylene glycol esters; or a mixture thereof. claim 1 for the treatment of traveler's diarrhea caused by E. 9. The controlled release pharmaceutical composition coli. according to claim 1, wherein the pharmaceutically accept 45 23. A method of treating klebsiella induced traveler's diar able excipient comprises binders, diluents, lubricants, Surfac rhea comprising administering a once daily controlled release tants, glidants, or mixtures thereof. pharmaceutical composition comprising: 10. The controlled release pharmaceutical composition a.a single active agent consisting of therapeutically effec according to claim 9, wherein the binder comprises cellulose, tive amount of rifaximinor pharmaceutically acceptable cellulose derivative; starches; gums; polyvinylpyrrolidone, 50 salt(s) or enantiomer(s) or polymorph(s) thereof; poVidone, syrup, polyethylene oxide, polyacrylamide, poly b. one or more release controlling agent(s); and N-vinyl amide, sodium carboxymethyl cellulose, polyethyl c. pharmaceutically acceptable excipient(s): ene glycol, gelatin, polyethylene oxide, poly propylene gly wherein the pharmaceutical composition has an in vitro dis col, tragacanth, alginic acid, or mixtures thereof. solution profile, when measured in a type II Paddle dissolu 11. The controlled release pharmaceutical composition 55 tion apparatus, in 6.8 phosphate buffer with 1.5% SLS at according to claim 9, wherein the diluent comprises carbo about 100 rpm, in which about 20% to about 50% of the drug hydrates, derivatives of carbohydrates, polyols, Sugar alco is released in about 8 hrs, about 30% to about 70% of drug is hols, carbonate, Sulphate orphosphate salts of inorganic met released in about 12 hrs and about more than 70% of drug is als, or mixtures thereof. released in about 24 hrs. 12. The controlled release pharmaceutical composition 60 24. The controlled release pharmaceutical composition according to claim 9, wherein the lubricant comprises mag according to claim 1, comprising a coating, wherein the coat nesium, aluminium, Zinc or calcium Stearate, sodium Stearyl ing comprises film coating, Sugar coating, enteric coating, fumarate, polyethylene glycol, mineral oil, Stearic acid, bioadhesive, or mucoadhesive coating. hydrogenated vegetable oil, glyceryl behenate, glyceryl 25. The controlled release pharmaceutical composition palmitostearate, glyceryl Stearate, cornstarch, talc, calcium 65 according to claim 24, wherein the coating comprises coating silicate, magnesium silicate, colloidal silicon dioxide, silicon agents, plasticizers, antitacking agents, Surfactants, coloring hydrogel, or mixtures thereof. agents, opacifiers, or mixtures thereof. US 8,383,151 B2 25 26 26. A controlled release pharmaceutical composition of b. one or more release controlling agent(s); and rifaximin according to claim 1 comprising: at least two enti c. pharmaceutically acceptable excipient(s): ties wherein one entity is an immediate release or fast release which results in eradication of at least 70% of pathogens: and the other is controlled release. wherein the pharmaceutical composition has an in vitro dis 27. The controlled release pharmaceutical composition of 5 solution profile, when measured in a type II Paddle dissolu rifaximinaccording to claim 1, comprising: at least two enti tion apparatus, in 6.8 phosphate buffer with 1.5% SLS at ties wherein one entity is controlled release and the other is about 100 rpm, in which about 20% to about 50% of the drug bioadhesive. is released in about 8 hrs, about 30% to about 70% of drug is 28. The controlled release pharmaceutical composition released in about 12 hrs and about more than 70% of drug is according to claim 1, which is in the form of tablets, pellets, 10 released in about 24 hrs. beads, granules, Sustained release formulations, capsules, 33. The once daily controlled release pharmaceutical com microcapsules, tablets in capsules, microspheres or powders/ position according to claim 32, wherein the pathogen is E. pellets/beads/granules for Suspension. coli. 29. The controlled release pharmaceutical composition 34. The once daily controlled release pharmaceutical com according to claim 28 wherein the tablets comprise single 15 position according to claim 32, wherein the pathogenis Kleb layered tablets, multilayered tablets, mini tablets, bioadhe siella. sive tablets, caplets, matrix tablets, tablet within a tablet, 35. A once daily controlled release pharmaceutical com mucoadhesive tablets, modified release tablets, pulsatile position comprising: release tablets, and timed release tablets. a.a single active agent consisting of therapeutically effec 30. A controlled release pharmaceutical composition in the tive amount of rifaximinor pharmaceutically acceptable form of a multilayer tablet according to claim 1 comprising, salt(s) or enantiomer(s) or polymorph(s) thereof; a) at least one layer which comprises, a therapeutically effec b. one or more release controlling agent(s); and tive amount of rifaximin or a pharmaceutically acceptable c. pharmaceutically acceptable excipient(s): salt(s) or enantiomer(s) or polymorph(s) thereof, pharmaceu wherein the pharmaceutical composition results in time for tically acceptable excipient(s); wherein the said layer pro 25 last unformed stools for intent to treat population in the vides a controlled release rifaximin; and b) at least one layer range of about 8 to about 90 hrs: which provides increased residence time of the dosage form wherein the pharmaceutical composition has an in vitro dis in the gastrointestinal tract. solution profile, when measured in a type II Paddle dissolu 31. A controlled release pharmaceutical composition com tion apparatus, in 6.8 phosphate buffer with 1.5% SLS at prising: 30 about 100 rpm, in which about 20% to about 50% of the drug a.a single active agent consisting ofatherapeutically effec is released in about 8 hrs, about 30% to about 70% of drug is tive amount of rifaximin or a pharmaceutically accept released in about 12 hrs and about more than 70% of drug is able salt(s) or enantiomer(s) or polymorph(s) thereof. released in about 24 hrs. b. one or more release controlling agent(s); and 36. The once daily controlled release pharmaceutical com c. pharmaceutically acceptable excipient(s): 35 position according to claim 35, wherein the pharmaceutical wherein the composition is formulated to increase the resi composition results in time for last unformed Stools for intent dence time of rifaximin in the gastrointestinal tract having an to treat population in the range of about 10 to about 85 hrs. adhesive strength, measured as a force of detachment, of at 37. The once daily controlled release pharmaceutical com least 100 mN when measured using advanced force gauge position according to claim 35, wherein the pharmaceutical equipment; 40 composition results in time for last unformed stools for E. coli wherein the pharmaceutical composition has an in vitro dis positive population in the range of about 20 to about 90 hrs. solution profile, when measured in a type II Paddle dissolu 38. The once daily controlled release pharmaceutical com tion apparatus, in 6.8 phosphate buffer with 1.5% SLS at position according to claim 37, wherein the pharmaceutical about 100 rpm, in which about 20% to about 50% of the drug composition results in time for last unformed stools for E. coli is released in about 8 hrs, about 30% to about 70% of drug is 45 positive population in the range of about 25 to about 85 hrs. released in about 12 hrs and about more than 70% of drug is 39. The controlled release pharmaceutical composition of released in about 24 hrs. claim 1, wherein the active agent comprises an antibiotic and 32. A once daily controlled release pharmaceutical com the antibiotic is a therapeutically effective amount of rifaxi position comprising: min or pharmaceutically acceptable salt(s) or enantiomer(s) a. a single active agent consisting of therapeutically effec 50 or polymorph(s) thereof. tive amount of rifaximinor pharmaceutically acceptable salt(s) or enantiomer(s) or polymorph(s) thereof; k k k k k