WO2009047801A1 - Therapeutic combinations and compositions for the treatment of gastrointestinal disorders - Google Patents

Therapeutic combinations and compositions for the treatment of gastrointestinal disorders Download PDF

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Publication number
WO2009047801A1
WO2009047801A1 PCT/IN2008/000653 IN2008000653W WO2009047801A1 WO 2009047801 A1 WO2009047801 A1 WO 2009047801A1 IN 2008000653 W IN2008000653 W IN 2008000653W WO 2009047801 A1 WO2009047801 A1 WO 2009047801A1
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pharmaceutically acceptable
acceptable salt
metabolites
polymorph
enantiomer
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PCT/IN2008/000653
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French (fr)
Inventor
Harshal Jahagirdar
Umesh Badhe
Jisha Thomas
Rajesh Kulkarni
Shirishkumar Kulkarni
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Lupin Limited
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Priority to JP2010528530A priority Critical patent/JP2011500552A/en
Publication of WO2009047801A1 publication Critical patent/WO2009047801A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • This invention relates to pharmaceutical combinations of Mesalamine or a pharmaceutically acceptable salt or prodrugs thereof and Rifaximin or a pharmaceutically acceptable salt or prodrugs thereof to treat patients suffering from Inflammatory bowel disease (IBD) and/or irritable bowel syndrome (IBS).
  • This invention also relates to additive and/or synergistic combinations of Mesalamine and Rifaximin. Preferable those synergistic combinations are useful in treating subjects suffering from irritable bowel syndrome and Inflammatory bowel disease.
  • Mesalazine also known as Mesalamine or 5-aminosalicylic acid (5-ASA)
  • Mesalamine or 5-aminosalicylic acid (5-ASA) is an antiinflammatory drug used to treat inflammation of the digestive tract (Crohn's disease) and mild to moderate ulcerative colitis.
  • Mesalazine is a bowel-specific aminosalicylate drug that is metabolized in the gut and has its predominant actions there, thereby having fewer systemic side effects.
  • Mesalazine is used in the treatment of Crohn's disease and ulcerative colitis due to its antiinflammatory activity on the intestinal mucosa.
  • Asacol is a DR tablet (2x400mg TID, total dose 2.4 g).
  • Pentasa is a CR capsule (250 and 500mg, QID, total dose 4 g).
  • Lialda is a modified release (delayed and controlled, 2x1200mg, OD, total dose 2.4 g) tablet.
  • Canasa is a rectal suppository (500mg BID and 1000mg QD).
  • U.S. 4,632,921 further discloses a process for the production of readily soluble 5-ASA preparations by mixing 5-ASA with physiologically and toxicologically acceptable, basic auxiliaries and/or buffer mixtures, which in a 1% aqueous solution give pH-values in the range from 8 to 12, and the mixture obtained is processed in known manner to form tablets, film tablets, capsules or suppositories for use in the treatment of inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • U. S 4,880,794 discloses a method for the treatment of IBD comprising orally administering an effective amount of a composition consisting essentially of a pharmaceutically acceptable salt of free 5-ASA in admixture with a pharmaceutically acceptable carrier which will control the release of said effective amount of said salt of 5-ASA to the actual site of said disease.
  • U.S. 5,013,727 discloses a pharmaceutical composition containing as active ingredient 5- ASA or a pharmaceutically acceptable salt or ester thereof allowing the treatment of IBD by oral administration.
  • a particular slow-release tablet formulation and its preparation are disclosed.
  • 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 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 brand name "Xifaxan”.
  • IBD Inflammatory Bowel Disease
  • Crohn ' s disease is a chronic transmural inflammation of the bowel, which can affect the whole gastrointestinal tract, usually in a discontinuous pattern.
  • the initial location of CD is most commonly in the lower ileum. From here the inflammation typically spreads towards proximal parts of the small intestine. However, the colon is also often involved.
  • Ulcerative colitis is a chronic inflammatory bowel disease affecting only the colon and shows a continuous distribution in the gastrointestinal mucosa.
  • the focal point of the inflammation is in the distal part of the colon and the rectum. From this origin, the inflammation often spreads proximally. In the most severe cases, the whole colon is affected which is called as "pancolitis". About 30% of patients suffer from this severe form of UC.
  • Ulcerative colitis and Crohn disease occur in areas of the gastrointestinal tract with the highest concentrations of luminal bacteria.
  • the distal ileum contains 10 7 to 10 8 primarily anaerobic bacteria/gram of luminal contents, whereas the colon has 10 11 to 10 12 bacterial colonies/gram, with Bacteroides, Clostridium, and Bifidobacterium species predominating.
  • Chronic intestinal inflammation is the consequence of an overly aggressive cell-mediated immune response to commensal (normal endogenous) enteric bacteria in a genetically susceptible host. It is thought that bloating and flatulence, especially troublesome in patients with irritable bowel syndrome (IBS), may be caused by bacterial overgrowth in the small intestine. 10% to 84% of patients with IBS may have small intestinal bacterial overgrowth, as confirmed by lactulose breath tests.
  • IBS irritable bowel syndrome
  • TLR-1 to 9 Individual membrane-bound toll-like receptors (TLR-1 to 9) each recognize a different bacterial product. Similarly, NOD1 and NOD2 receptors bind intracellular peptidoglycan. Binding of bacterial adjuvants to these receptors activates nuclear factor- B (NF B), a central signaling pathway that initiates transcription of multiple proinflammatory molecules found in active IBD and experimental intestinal inflammation. Although intestinal epithelial cells do not constitutively express NOD2 and have low expression of TLR-4, these receptors are upregulated during active IBD by proinflammatory cytokines, particularly tumor necrosis factor (TNF), through an NF B-dependent mechanism. Although, normal commensal bacteria may provide the constant antigenic stimulus driving cell-mediated immune responses that cause chronic intestinal inflammation, the possibility remains that a classic pathogen could cause Crohn disease or ulcerative colitis.
  • TNF B tumor necrosis factor
  • Balfour et al 1 studied the use of antibiotics in the treatment of IBD. The studies concluded that broad-spectrum antibiotics are more effective than selective agents. Also the antigens and adjuvant from the commensal, nonpathogenic enteric bacteria that provides the constant immunological stimulus (there by inducing chronic cell mediated immune response) can be attenuated by decreasing the concentration of enteric bacterial species or by inhibiting bacterial invasion of tissue by using antibiotics.
  • IBS Irritable bowel syndrome
  • Mesalamine and Rifaximin are two different types of drugs offering some symptomatic relief to the IBD patients.
  • Mesalamine treats inflammation, whereas, Rifaximin reduces bioburden.
  • Current individual drug treatments needed larger doses per day, such as 2.4 to 4 g of Mesalamine or 1.2 g of Rifaximin.
  • Patient needs to take 2 to 16 tablets or capsules of Mesalamine or up to 6 tablets of Rifaximin per day.
  • One objective of the invention is to prepare pharmaceutical combination comprising of 5- ASA derivatives and its salts or prodrugs or polymorphs thereof and antiinfective drugs and its salts or prodrugs or polymorphs thereof.
  • Another objective of the present invention is treatment of IBS/IBD by the administration of Mesalamine and Rifaximin.
  • Another objective of the invention is to provide a Bioadhesive modified release pharmaceutical composition consisting of Mesalamine and its salts or prodrugs or polymorphs thereof and Rifaximin and its salts or prodrugs or polymorphs thereof, optionally coated with hydrophilic or hydrophobic polymers.
  • Another objective is to increase residence time of the pharmaceutical composition in the GIT by using bioadhesive polymers
  • Another objective of the invention is to prepare modified release pharmaceutical composition comprising of Mesalamine and its salts or prodrugs or polymorphs thereof and Rifaximin and its salts or prodrugs or polymorphs thereof for the treatment of IBS and/or IBD.
  • Another objective of the invention is to provide a modified release pharmaceutical composition containing both Mesalamine and Rifaximin in a single dosage form, for the treatment of inflammation and to decrease the bioburden.
  • Another objective of the invention is to prepare once daily or twice daily pharmaceutical composition containing both Mesalamine and Rifaximin
  • Another objective of the invention is to reduce the dose and dosing frequency of Mesalamine and Rifaximin for the effective treatment of irritable bowel syndrome and/or irritable bowel disease.
  • Another objective of the invention is to increase solubility of the pharmaceutical formulation comprising Mesalamine and Rifaximin by the addition of solubilizers.
  • Yet another objective of the present invention is to provide a pharmaceutical formulation comprising Mesalmine and Rifaximin, of which at leas! about 75% of drugs are released in colon, which was achieved by the enteric coating the dosage form with one or two polymers, which facilitate the dissolution of coating at a pH of between 5.5 and 6.5 and above.
  • This invention relates to pharmaceutical combinations of Mesalamine or a pharmaceutically acceptable salt thereof and Rifaximin releasing the drugs in lower GIT with enteric coating and one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipients, and the process of preparing it
  • Mesalamine can be used in the dose range of 0.8 to about 4.8 g per day and Rifaximin can be used in the dose range of 0.2 - 1.8 g per day which can be administered once a day or twice a day.
  • a day 1 means the dosage form(s) to be taken only one time in 24 hours by which the drug concentration is maintained for whole day in the body.
  • Twice a day' means th e dosage form(s) to be taken two times in 24 hours.
  • the active agents of the invention includes the corresponding pharmaceutically acceptable salts, prodrugs acceptable salt, enantiomer, polymorph or metabolites thereof which are know to the person skilled in art at the time of invention.
  • combination product includes: (1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;
  • a drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or
  • modified release formulation or dosage form or composition includes pharmaceutical preparations that achieve a desired release of the drug from the formulation.
  • a modified-release formulation can be designed to modify the manner in which the active ingredient is exposed to the desired target.
  • a modified-release formulation can be designed to focus the delivery of the active agent entirely in the distal large intestine, beginning at the cecum, and continuing through the ascending, transverse, and descending colon, and ending in the sigmoid colon.
  • a modified-release composition can be designed to focus the delivery of the drug in the proximal small intestine, beginning at the duodenum and ending at the ileum.
  • the modified- release formulations can be designed to begin releasing active agent in the jejunum and end their release in the transverse colon.
  • the possibilities and combinations are numerous, and are clearly not limited to these examples.
  • the modified release includes the sustained release, controlled release, delayed release etc.
  • modified-release encompasses "extended-release” and “delayed-release” formulations, as well as formulations having both extended-release and delayed-release characteristics.
  • An “extended-release” formulation can extend the period over which drug is released or targeted to the desired site.
  • a “delayed-release” formulation can be designed to delay the release of the pharmaceutically active compound for a specified period. Such formulations are referred to herein as “delayed-release” or “delayed-onset” formulations or dosage forms.
  • Modified-release formulations of the present invention include those that exhibit both a delayed- and extended-release, e.g., formulations that only begin releasing after a fixed period of time or after a physicochemical change has occurred, for example, then continue releasing over an extended period.
  • the modified release may also include pulasatile release, burst release and the like
  • pharmaceutically acceptable is meant a carrier comprised of a material that is not biologically or otherwise undesirable.
  • 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 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 surrounding media. The term bioadhesive and mucoadhesive can be used interchangeably.
  • bioadhesive and mucoadhesive of the present invention can also include the dosage, which retains along the length of GIT for the desired period of time. So, as to increase the mean residence time of the dosage forms.
  • 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 and /or colon, or in the area of the gastrointestinal tract where the drug is released from the pharmaceutical dosage form.
  • 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.
  • the increase in residence time of combination formulation in the colonic mucosa is achieved by bioadhesion wherein bioadhesion is achieved using polymers having affinity for colonic mucosa.
  • bioadhesion is achieved using polymers having affinity for colonic mucosa.
  • mucoadhesives for use in the embodiments disclosed herein include, but are not limited to, natural, semisynthetic and synthetic polymers.
  • the combination of the steroidal anti-inflammatory agent in combination with an anti infective agent is selected from the drugs like budesonide, Prednisone, prednisolone.
  • 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.
  • proteins e.g., hydrophilic proteins
  • the bioadhesive or mucoadhesive 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.
  • 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),
  • 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.
  • 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 or mucoadhesive 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.
  • the hydrophilic groups are selected to not to interfere and instead to enhance the bioadhesiveness of the polymers.
  • 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.
  • 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.
  • compositions 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.
  • 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 and the like and mixtures thereof.
  • 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
  • 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 or tribasic, 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 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 microspheres, matrix formulations, microencapsulation and powder/pellets/granules for suspension.
  • a semi-permeable membrane can surround the formulation containing the active substance of interest.
  • Semi-permeable membranes include those that are permeable to a greater or lesser extent to both water and solute.
  • This membrane can include water-insoluble and/or water-soluble polymers, and can exhibit pH-dependent and/or pH-independent solubility characteristics.
  • the characteristics of the polymeric membrane which may be determined by, e.g., the composition of the membrane, will determine the nature of release from the dosage form.
  • Matrix-type systems comprise an aminosalicylate active agent, mixed with either water- soluble, e.g., hydrophilic polymers, or water-insoluble, e.g., hydrophobic polymers.
  • water-soluble e.g., hydrophilic polymers
  • water-insoluble e.g., hydrophobic polymers.
  • the properties of the polymer used in a modified-release dosage form will affect the mechanism of release.
  • the release of the active agent from a dosage form containing a hydrophilic polymer can proceed via both surface diffusion and/or erosion.
  • Mechanisms of release from pharmaceutical systems are well known to those skilled in the art.
  • Matrix-type systems can also be monolithic or multiunit, and can be coated with water- soluble and/or water-insoluble polymeric membranes, examples that are described above.
  • Matrix formulations of the present invention can be prepared by using, for example, direct compression or wet granulation.
  • a functional coating as noted above, can then be applied in accordance with the invention.
  • a barrier or sealant coat can be applied over a matrix tablet core prior to application of a functional coating.
  • the barrier or sealant coat can serve the purpose of separating an active ingredient from a functional coating, which can interact with the active ingredient, or it can prevent moisture from contacting the active ingredient. Details of barriers and sealants are provided below.
  • the drug and/or pro-drug and optional pharmaceutically acceptable excipient(s) are dispersed within a polymeric matrix, which typically comprises one or more water-soluble polymers and/or one or more water-insoluble polymers.
  • the drug can be released from the dosage form by diffusion and/or erosion.
  • Suitable water-soluble polymers include, but are not limited to, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose.hydroxypropylcellulose.hdroxypropylmethylcellulose or polyethylene glycol, and/or mixtures thereof.
  • Suitable water-insoluble polymers also include, but are not limited to, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly (ethylene) high density, poly (ethylene oxide), poly (ethylene terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (
  • Matrix-based dosage form can comprise the drug or pro-drug, a filler, such as starch, lactose, or microcrystalline cellulose ; a binder, /controlled-release polymer, such as hydroxypropyl methylcellulose; a disintegrant,; a lubricant,; a surfactant, such as sodium lauryl sulfate or polysorbates; and a glidant, such as colloidal silicon dioxide or talc.
  • a filler such as starch, lactose, or microcrystalline cellulose
  • a binder, /controlled-release polymer such as hydroxypropyl methylcellulose
  • a disintegrant such as hydroxypropyl methylcellulose
  • a lubricant such as sodium lauryl sulfate or polysorbates
  • a glidant such as colloidal silicon dioxide or talc.
  • the amounts and types of polymers, and the ratio of water-soluble polymers to water- insoluble polymers in the inventive formulations are generally selected to achieve a desired release profile of the drug or pro-drug, as described below.
  • Amino methacrylate co-polymers such as Eudragit RS and Eudragit RL (Rohm Pharma) are suitable for use in the modified-release formulations of the present invention. These polymers are insoluble in pure water, dilute acids, buffer solutions, or digestive fluids over the entire physiological pH range. The polymers swell in water and digestive fluids independently of pH. In the swollen state they are then permeable to water and dissolved actives. The permeability of the polymers depends on the ratio of ethylacrylate (EA), methyl methacrylate (MMA), and trimethylammonioethyl methacrylate chloride (TAMCI) groups in the polymer.
  • EA ethylacrylate
  • MMA methyl methacrylate
  • TAMCI trimethylammonioethyl methacrylate chloride
  • Eudragit RL Those polymers having EA:MMA:TAMCI ratios of 1 :2:0.2 (Eudragit RL) are more permeable than those with ratios of 1 :2:0.1 (Eudragit RS).
  • Polymers of Eudragit RL are insoluble polymers of high permeability.
  • Polymers of Eudragit RS are insoluble films of low permeability.
  • the amino methacrylate co-polymers can be combined in any desired ratio.
  • a ratio of Eudragit RS:Eudragit RL (90:10) can be used.
  • the ratios can furthermore be adjusted to provide a delay in release of the drug or pro-drug.
  • the ratio of Eudragit RS:Eudragit RL can be about 100:0 to about 80:20, about 100:0 to about 90:10, or any ratio in between.
  • the less permeable polymer Eudragit RS would generally comprise the majority of the polymeric material.
  • the amino methacrylate co-polymers can be combined with the methacrylic acid co- polymers within the polymeric material in order to achieve the desired delay in release of the drug or pro-drug. Ratios of ammonio methacrylate co-polymer (e.g., Eudragit RS) to methacrylic acid co-polymer in the range of about 99:1 to about 20:80 can be used.
  • the two types of polymers can also be combined into the same polymeric material, or provided as separate coats that are applied to the core.
  • Eudragit polymers In addition to the Eudragit polymers described above, a number of other such copolymers can be used to control drug release. These include methacrylate ester co-polymers (e.g., Eudragit NE 30D). Further information on the Eudragit polymers can be found in "Chemistry and Application Properties of Polymethacrylate Coating Systems," in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (ed. James McGinity, Marcel Dekker Inc., New, York, pg 109-114).
  • Methyl acrylate copolymers and amino methacrylate copolymers of the type such as can be obtained under the tradename Eudragit. RTM. RS/RL/NE are particularly preferred. As functional groups, these polymers have ester groups (Eudragit. RTM. NE) or ammonium groups (Eudragit.RTM. RL/RS). Poly(ethyl acrylate, methyl methacrylate) and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) are preferred.
  • polymers are obtainable, for example, as poly(ethyl acrylate, methyl methacrylate) 2:1 in 40% strength aqueous dispersion as Eudragit.RTM.
  • NE 40 D and as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.1 in 12.5% strength isopropanolic solution as Eudragit.RTM. RS 12.5 and in the composition 1 :2:0.2 as Eudragit.RTM. RL 12.5.
  • the most preferred is Eudragit.RTM.
  • formulations of the present invention are intended to include formulations that are generic to treating all forms of IBD, and thus target their contents to both the distal small intestine and the large intestine.
  • Other formulations within the scope of the invention include those that are more specifically designed for treating a specific disease.
  • a formulation for treating ulcerative colitis can be designed to deliver its contents entirely to the colon.
  • the formulations of the present invention can exist as multi-unit or single-unit formulations.
  • multi-unit as used herein means a plurality of discrete or aggregated particles, beads, pellets, granules, tablets, or mixtures thereof, for example, without regard to their size, shape, or morphology.
  • Single-unit formulations include, for example, tablets, caplets, and pills.
  • a formulation and/or method of the invention can contain components that exhibit extended-release and modified-release properties, or both delayed- release and modified-release properties, or a combination of all three properties.
  • the modifications in the rates of release can be achieved in any number of ways.
  • Mechanisms can be dependent or independent of local pH in the intestine, and can also rely on local enzymatic activity to achieve the desired effect.
  • 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.
  • the additional coating prevents the dosage from contacting the mouth or esophagus.
  • 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.
  • Eudragit FS 3OD or other suitable polymer may be incorporated in coating composition to retard the release of the drug to ensure drug release in the colon.
  • the present invention is not limited to any of the particular (5-ASA) described herein.
  • the present invention extends to the use and formulation of any azo-bis compound that yields either 4-ASA and/or 5-ASA. Modified-release formulations of any such azo-bis compound are specifically contemplated.
  • drug refers to compounds useful in treating IBD or other diseases according to this invention, including but not limited to SASP, 5-ASA, and/or 4-ASA;
  • pro-drug refers to any compound that yields such drugs, including but not limited to olsalazine, balsalazine, and/or any other azo-containing compound that yields such drug.
  • the anti infective agents are not limited to Rifaximin, ciproflaxacin and metronidazole but also includes the antibiotics which acts on G.I micro flora.
  • These coating layers comprises one or more excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, fillers, polishing agents, coloring agents, antitacking agents and the like.
  • compositions 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
  • enteric coatings for delayed/modified release DR/MR
  • soluble pore formers e.g., PEG, PVA, sugars, salts, detergents, triethyl citrate, triacetin, etc.
  • 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.
  • 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.
  • 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.
  • suitable agents include purified grades of beeswax; fatty acids; long chain fatty alcohols, such as cetyl alcohol, myristyl alcohol, and stearyl alcohol; glycerides
  • a pharmaceutical composition comprises an active agents 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.
  • compositions of the present invention can optionally include one or more solubilizers, i.e., additives to increase the solubility of the pharmaceutical active ingredient or other composition components in the solid carrier.
  • solubilizers for, use in the compositions of the present invention include: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl
  • solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol), and water.
  • Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide,N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide.
  • Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, SLS, polyethylene glycols glycofurol and propylene glycol. Cyclodextrins polyoxomers, surfactants and like
  • 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.
  • the USP Il apparatus contained a paddle and rotated at a speed of 50 rpm for Mesalamine and 100 rpm for Rifaximin in 900ml dissolution media..
  • the tablet formulation was placed in the apparatus and dissolution was periodically measured.
  • the in vitro dissolution studies of are shown below;
  • a bioadhesive, controlled release once daily (600 mg) of 5-Amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof is explored.

Abstract

The present invention relates to pharmaceutical combinations of mesalamine or a pharmaceutically acceptable salt or prodrugs thereof and rifaximin or a pharmaceutically acceptable salt or prodrugs thereof to treat patients suffering from inflammatory bowel disease (IBD) and/or irritable bowel syndrome (IBS). The invention also relates to additive and/or synergistic combinations of mesalamine and rifaximin.

Description

THERAPEUTIC COMBINATIONS AND COMPOSITIONS FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS
FIELD OF THE INVENTION
This invention relates to pharmaceutical combinations of Mesalamine or a pharmaceutically acceptable salt or prodrugs thereof and Rifaximin or a pharmaceutically acceptable salt or prodrugs thereof to treat patients suffering from Inflammatory bowel disease (IBD) and/or irritable bowel syndrome (IBS). This invention also relates to additive and/or synergistic combinations of Mesalamine and Rifaximin. Preferable those synergistic combinations are useful in treating subjects suffering from irritable bowel syndrome and Inflammatory bowel disease.
BACKGROUND OF THE INVENTION
Mesalazine, also known as Mesalamine or 5-aminosalicylic acid (5-ASA), is an antiinflammatory drug used to treat inflammation of the digestive tract (Crohn's disease) and mild to moderate ulcerative colitis. Mesalazine is a bowel-specific aminosalicylate drug that is metabolized in the gut and has its predominant actions there, thereby having fewer systemic side effects. Mesalazine is used in the treatment of Crohn's disease and ulcerative colitis due to its antiinflammatory activity on the intestinal mucosa.
Several Mesalamine formulations are currently being marketed such as Asacol, Pentasa, Lialda, Canasa. Asacol is a DR tablet (2x400mg TID, total dose 2.4 g). Pentasa is a CR capsule (250 and 500mg, QID, total dose 4 g). Lialda is a modified release (delayed and controlled, 2x1200mg, OD, total dose 2.4 g) tablet. Canasa is a rectal suppository (500mg BID and 1000mg QD).
The mechanism of action of Mesalamine is not fully understood, but appears to be topical. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), is increased in patients with chronic inflammatory bowel disease, and it is possible that Mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon. Recent data also suggest that Mesalamine can inhibit the activation of NFKB, a nuclear transcription factor that regulates the transcription of many genes for pro-inflammatory proteins. U.S. 4,632,921 further discloses a process for the production of readily soluble 5-ASA preparations by mixing 5-ASA with physiologically and toxicologically acceptable, basic auxiliaries and/or buffer mixtures, which in a 1% aqueous solution give pH-values in the range from 8 to 12, and the mixture obtained is processed in known manner to form tablets, film tablets, capsules or suppositories for use in the treatment of inflammatory bowel disease (IBD).
U. S 4,880,794 discloses a method for the treatment of IBD comprising orally administering an effective amount of a composition consisting essentially of a pharmaceutically acceptable salt of free 5-ASA in admixture with a pharmaceutically acceptable carrier which will control the release of said effective amount of said salt of 5-ASA to the actual site of said disease.
U.S. 5,013,727 discloses a pharmaceutical composition containing as active ingredient 5- ASA or a pharmaceutically acceptable salt or ester thereof allowing the treatment of IBD by oral administration. A particular slow-release tablet formulation and its preparation are disclosed.
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 brand name "Xifaxan".
Inflammatory Bowel Disease (IBD) is a chronic and debilitating illness. It is characterized by chronic intestinal inflammation that often shows an intermittent course with acute attacks followed by periods of remission. Clinical symptoms during acute attacks include diarrhea, bleeding, abdominal pain, fever, joint pain, and weight loss. These symptoms can range from mild to severe, and may gradually and subtly develop from an initial minor discomfort, or may present themselves suddenly in full-blown form. IBD can manifest itself in a variety of forms, the most common of which are Crohn's disease and ulcerative colitis. Both of these diseases are similar in terms of clinical symptoms, even though their inflammation patterns are distributed differently in the Gl tract. Crohn's disease is a chronic transmural inflammation of the bowel, which can affect the whole gastrointestinal tract, usually in a discontinuous pattern. The initial location of CD is most commonly in the lower ileum. From here the inflammation typically spreads towards proximal parts of the small intestine. However, the colon is also often involved.
Ulcerative colitis is a chronic inflammatory bowel disease affecting only the colon and shows a continuous distribution in the gastrointestinal mucosa. In most patients the focal point of the inflammation is in the distal part of the colon and the rectum. From this origin, the inflammation often spreads proximally. In the most severe cases, the whole colon is affected which is called as "pancolitis". About 30% of patients suffer from this severe form of UC.
Ulcerative colitis and Crohn disease occur in areas of the gastrointestinal tract with the highest concentrations of luminal bacteria. The distal ileum contains 107 to 108 primarily anaerobic bacteria/gram of luminal contents, whereas the colon has 1011 to 1012 bacterial colonies/gram, with Bacteroides, Clostridium, and Bifidobacterium species predominating. Chronic intestinal inflammation is the consequence of an overly aggressive cell-mediated immune response to commensal (normal endogenous) enteric bacteria in a genetically susceptible host. It is thought that bloating and flatulence, especially troublesome in patients with irritable bowel syndrome (IBS), may be caused by bacterial overgrowth in the small intestine. 10% to 84% of patients with IBS may have small intestinal bacterial overgrowth, as confirmed by lactulose breath tests.
Individual membrane-bound toll-like receptors (TLR-1 to 9) each recognize a different bacterial product. Similarly, NOD1 and NOD2 receptors bind intracellular peptidoglycan. Binding of bacterial adjuvants to these receptors activates nuclear factor- B (NF B), a central signaling pathway that initiates transcription of multiple proinflammatory molecules found in active IBD and experimental intestinal inflammation. Although intestinal epithelial cells do not constitutively express NOD2 and have low expression of TLR-4, these receptors are upregulated during active IBD by proinflammatory cytokines, particularly tumor necrosis factor (TNF), through an NF B-dependent mechanism. Although, normal commensal bacteria may provide the constant antigenic stimulus driving cell-mediated immune responses that cause chronic intestinal inflammation, the possibility remains that a classic pathogen could cause Crohn disease or ulcerative colitis.
Balfour et al 1 studied the use of antibiotics in the treatment of IBD. The studies concluded that broad-spectrum antibiotics are more effective than selective agents. Also the antigens and adjuvant from the commensal, nonpathogenic enteric bacteria that provides the constant immunological stimulus (there by inducing chronic cell mediated immune response) can be attenuated by decreasing the concentration of enteric bacterial species or by inhibiting bacterial invasion of tissue by using antibiotics.
Shafran et al has conducted an open label studies as preliminary assessment of Rifaximin for the treatment of Crohn's disease Rifaximin 200mg was administered to the patients having the symptoms of the Crohn's disease for 4 months after which 78% of the patients showed improvement in the condition. So, it was proved that the rifaxine may be useful for the treatment of Crohn's disease.
Ginoeashetti et al conducted a study in which patents suffering from the colonic disorders were treated with 400mg twice daily of Rifaximin for 10 days and it was found that there is a decrease in the frequency of bleeding. So, the Rifaximin shows a promising results in the treatment in the IBS. Irritable bowel syndrome (IBS) is a disorder characterized most commonly by cramping, abdominal pain, bloating, constipation, and diarrhea. IBS causes a great deal of discomfort and distress, but it does not permanently harm the intestines and does not lead to a serious disease, such as cancer. Most people can control their symptoms with diet, stress management, and prescribed medications. For some people, however, IBS can be disabling. They may be unable to work, attend social events, or even travel short distances. Distrutti and etal studies indicate that the IBS is linked to inflammation of GIT their investigation on the role of the Mesalamine derivatives and assessed the pain by abdominal withdrawal response and spinal Cfos expression.
Mesalamine and Rifaximin are two different types of drugs offering some symptomatic relief to the IBD patients. Mesalamine treats inflammation, whereas, Rifaximin reduces bioburden. However, in both cases, the disease is not completely cured and needs long-term treatment and still the disease relapses. Current individual drug treatments needed larger doses per day, such as 2.4 to 4 g of Mesalamine or 1.2 g of Rifaximin. Patient needs to take 2 to 16 tablets or capsules of Mesalamine or up to 6 tablets of Rifaximin per day.
It is evident from the above discussion that currently there are only the individual drug dosage forms, which involve repeated administration of large amount of the drug for long period of time, which may not effectively cure the condition. As the disease condition is localized at the distal end of the GIT most of the conventional forms of the drugs release the therapeutic agent in the upper part which precipitates the adverse action and single drug dosage form available in the market may or may not release the drug at the site of the inflammation or infection which indeed cause the remission of the disease or worsen the condition and there is no patient compliance in the existing treatment. So, there is a need to develop a combination dosage form which release the drugs only in the lower part of the GIT for a longer period of time OBJECTIVE OF THE INVENTION:
One objective of the invention is to prepare pharmaceutical combination comprising of 5- ASA derivatives and its salts or prodrugs or polymorphs thereof and antiinfective drugs and its salts or prodrugs or polymorphs thereof.
Another objective of the present invention is treatment of IBS/IBD by the administration of Mesalamine and Rifaximin.
Another objective of the invention is to provide a Bioadhesive modified release pharmaceutical composition consisting of Mesalamine and its salts or prodrugs or polymorphs thereof and Rifaximin and its salts or prodrugs or polymorphs thereof, optionally coated with hydrophilic or hydrophobic polymers.
Another objective is to increase residence time of the pharmaceutical composition in the GIT by using bioadhesive polymers
Another objective of the invention is to prepare modified release pharmaceutical composition comprising of Mesalamine and its salts or prodrugs or polymorphs thereof and Rifaximin and its salts or prodrugs or polymorphs thereof for the treatment of IBS and/or IBD.
Another objective of the invention is to provide a modified release pharmaceutical composition containing both Mesalamine and Rifaximin in a single dosage form, for the treatment of inflammation and to decrease the bioburden.
Another objective of the invention is to prepare once daily or twice daily pharmaceutical composition containing both Mesalamine and Rifaximin
Another objective of the invention is to reduce the dose and dosing frequency of Mesalamine and Rifaximin for the effective treatment of irritable bowel syndrome and/or irritable bowel disease. Another objective of the invention is to increase solubility of the pharmaceutical formulation comprising Mesalamine and Rifaximin by the addition of solubilizers.
Yet another objective of the present invention is to provide a pharmaceutical formulation comprising Mesalmine and Rifaximin, of which at leas! about 75% of drugs are released in colon, which was achieved by the enteric coating the dosage form with one or two polymers, which facilitate the dissolution of coating at a pH of between 5.5 and 6.5 and above.
DETAIL DESCRIPTION OF THE INVENTION: This invention relates to pharmaceutical combinations of Mesalamine or a pharmaceutically acceptable salt thereof and Rifaximin releasing the drugs in lower GIT with enteric coating and one or more hydrophilic or hydrophobic release controlling agent(s) and pharmaceutical acceptable excipients, and the process of preparing it
Mesalamine can be used in the dose range of 0.8 to about 4.8 g per day and Rifaximin can be used in the dose range of 0.2 - 1.8 g per day which can be administered once a day or twice a day.
'Once a day1 means the dosage form(s) to be taken only one time in 24 hours by which the drug concentration is maintained for whole day in the body.
Twice a day' means th e dosage form(s) to be taken two times in 24 hours.
The active agents of the invention includes the corresponding pharmaceutically acceptable salts, prodrugs acceptable salt, enantiomer, polymorph or metabolites thereof which are know to the person skilled in art at the time of invention.
The term combination product includes: (1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; (2) Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products;
(3) A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose; or
(4) Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect.
The term "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.
The term "modified release" formulation or dosage form or composition includes pharmaceutical preparations that achieve a desired release of the drug from the formulation. A modified-release formulation can be designed to modify the manner in which the active ingredient is exposed to the desired target. For example, a modified-release formulation can be designed to focus the delivery of the active agent entirely in the distal large intestine, beginning at the cecum, and continuing through the ascending, transverse, and descending colon, and ending in the sigmoid colon. Alternatively, for example, a modified-release composition can be designed to focus the delivery of the drug in the proximal small intestine, beginning at the duodenum and ending at the ileum. In still other examples, the modified- release formulations can be designed to begin releasing active agent in the jejunum and end their release in the transverse colon. The possibilities and combinations are numerous, and are clearly not limited to these examples. The modified release includes the sustained release, controlled release, delayed release etc.
The term "modified-release" encompasses "extended-release" and "delayed-release" formulations, as well as formulations having both extended-release and delayed-release characteristics. An "extended-release" formulation can extend the period over which drug is released or targeted to the desired site. A "delayed-release" formulation can be designed to delay the release of the pharmaceutically active compound for a specified period. Such formulations are referred to herein as "delayed-release" or "delayed-onset" formulations or dosage forms. Modified-release formulations of the present invention include those that exhibit both a delayed- and extended-release, e.g., formulations that only begin releasing after a fixed period of time or after a physicochemical change has occurred, for example, then continue releasing over an extended period. The modified release may also include pulasatile release, burst release and the like
By "pharmaceutically acceptable" is meant a carrier comprised of a material that is not biologically or otherwise undesirable.
"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 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 surrounding media. The term bioadhesive and mucoadhesive can be used interchangeably.
The term bioadhesive and mucoadhesive of the present invention can also include the dosage, which retains along the length of GIT for the desired period of time. So, as to increase the mean residence time of the dosage forms. 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 and /or colon, or in the area of the gastrointestinal tract where the drug is released from 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 combination formulation in the colonic mucosa is achieved by bioadhesion wherein bioadhesion is achieved using polymers having affinity for colonic mucosa. Examples of mucoadhesives for use in the embodiments disclosed herein include, but are not limited to, natural, semisynthetic and synthetic polymers.
In one of the preffered embodiment of the present invention the combination of the steroidal anti-inflammatory agent in combination with an anti infective agent. The steroidal inflammatory agent is selected from the drugs like budesonide, Prednisone, prednisolone.
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.
The bioadhesive or mucoadhesive 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.
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 or mucoadhesive 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 or mucoadhesive 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 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.
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.
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 and the like 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 or tribasic, 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 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 microspheres, matrix formulations, microencapsulation and powder/pellets/granules for suspension.
With membrane-modified extended-release dosage forms, a semi-permeable membrane can surround the formulation containing the active substance of interest. Semi-permeable membranes include those that are permeable to a greater or lesser extent to both water and solute. This membrane can include water-insoluble and/or water-soluble polymers, and can exhibit pH-dependent and/or pH-independent solubility characteristics. Generally, the characteristics of the polymeric membrane, which may be determined by, e.g., the composition of the membrane, will determine the nature of release from the dosage form.
Matrix-type systems comprise an aminosalicylate active agent, mixed with either water- soluble, e.g., hydrophilic polymers, or water-insoluble, e.g., hydrophobic polymers. Generally, the properties of the polymer used in a modified-release dosage form will affect the mechanism of release. For example, the release of the active agent from a dosage form containing a hydrophilic polymer can proceed via both surface diffusion and/or erosion. Mechanisms of release from pharmaceutical systems are well known to those skilled in the art. Matrix-type systems can also be monolithic or multiunit, and can be coated with water- soluble and/or water-insoluble polymeric membranes, examples that are described above.
Matrix formulations of the present invention can be prepared by using, for example, direct compression or wet granulation. A functional coating, as noted above, can then be applied in accordance with the invention. Additionally, a barrier or sealant coat can be applied over a matrix tablet core prior to application of a functional coating. The barrier or sealant coat can serve the purpose of separating an active ingredient from a functional coating, which can interact with the active ingredient, or it can prevent moisture from contacting the active ingredient. Details of barriers and sealants are provided below.
In a matrix-based dosage form in accordance with the present invention, the drug and/or pro-drug and optional pharmaceutically acceptable excipient(s) are dispersed within a polymeric matrix, which typically comprises one or more water-soluble polymers and/or one or more water-insoluble polymers. The drug can be released from the dosage form by diffusion and/or erosion.
Suitable water-soluble polymers include, but are not limited to, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose.hydroxypropylcellulose.hdroxypropylmethylcellulose or polyethylene glycol, and/or mixtures thereof.
Suitable water-insoluble polymers also include, but are not limited to, ethylcellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly (ethylene), poly (ethylene) low density, poly (ethylene) high density, poly (ethylene oxide), poly (ethylene terephthalate), poly (vinyl isobutyl ether), poly (vinyl acetate), poly (vinyl chloride) or polyurethane, and/or mixtures thereof. Matrix-based dosage form can comprise the drug or pro-drug, a filler, such as starch, lactose, or microcrystalline cellulose ; a binder, /controlled-release polymer, such as hydroxypropyl methylcellulose; a disintegrant,; a lubricant,; a surfactant, such as sodium lauryl sulfate or polysorbates; and a glidant, such as colloidal silicon dioxide or talc.
The amounts and types of polymers, and the ratio of water-soluble polymers to water- insoluble polymers in the inventive formulations are generally selected to achieve a desired release profile of the drug or pro-drug, as described below.
Amino methacrylate co-polymers such as Eudragit RS and Eudragit RL (Rohm Pharma) are suitable for use in the modified-release formulations of the present invention. These polymers are insoluble in pure water, dilute acids, buffer solutions, or digestive fluids over the entire physiological pH range. The polymers swell in water and digestive fluids independently of pH. In the swollen state they are then permeable to water and dissolved actives. The permeability of the polymers depends on the ratio of ethylacrylate (EA), methyl methacrylate (MMA), and trimethylammonioethyl methacrylate chloride (TAMCI) groups in the polymer. Those polymers having EA:MMA:TAMCI ratios of 1 :2:0.2 (Eudragit RL) are more permeable than those with ratios of 1 :2:0.1 (Eudragit RS). Polymers of Eudragit RL are insoluble polymers of high permeability. Polymers of Eudragit RS are insoluble films of low permeability.
The amino methacrylate co-polymers can be combined in any desired ratio. For example, a ratio of Eudragit RS:Eudragit RL (90:10) can be used. The ratios can furthermore be adjusted to provide a delay in release of the drug or pro-drug. For example, the ratio of Eudragit RS:Eudragit RL can be about 100:0 to about 80:20, about 100:0 to about 90:10, or any ratio in between. In such formulations, the less permeable polymer Eudragit RS would generally comprise the majority of the polymeric material.
The amino methacrylate co-polymers can be combined with the methacrylic acid co- polymers within the polymeric material in order to achieve the desired delay in release of the drug or pro-drug. Ratios of ammonio methacrylate co-polymer (e.g., Eudragit RS) to methacrylic acid co-polymer in the range of about 99:1 to about 20:80 can be used. The two types of polymers can also be combined into the same polymeric material, or provided as separate coats that are applied to the core.
In addition to the Eudragit polymers described above, a number of other such copolymers can be used to control drug release. These include methacrylate ester co-polymers (e.g., Eudragit NE 30D). Further information on the Eudragit polymers can be found in "Chemistry and Application Properties of Polymethacrylate Coating Systems," in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (ed. James McGinity, Marcel Dekker Inc., New, York, pg 109-114).
Methyl acrylate copolymers and amino methacrylate copolymers of the type such as can be obtained under the tradename Eudragit. RTM. RS/RL/NE are particularly preferred. As functional groups, these polymers have ester groups (Eudragit. RTM. NE) or ammonium groups (Eudragit.RTM. RL/RS). Poly(ethyl acrylate, methyl methacrylate) and poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) are preferred. These polymers are obtainable, for example, as poly(ethyl acrylate, methyl methacrylate) 2:1 in 40% strength aqueous dispersion as Eudragit.RTM. NE 40 D and as poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.1 in 12.5% strength isopropanolic solution as Eudragit.RTM. RS 12.5 and in the composition 1 :2:0.2 as Eudragit.RTM. RL 12.5. The most preferred is Eudragit.RTM. NE 40 D
The formulations of the present invention are intended to include formulations that are generic to treating all forms of IBD, and thus target their contents to both the distal small intestine and the large intestine. Other formulations within the scope of the invention include those that are more specifically designed for treating a specific disease. For example, a formulation for treating ulcerative colitis can be designed to deliver its contents entirely to the colon.
The formulations of the present invention can exist as multi-unit or single-unit formulations. The term "multi-unit" as used herein means a plurality of discrete or aggregated particles, beads, pellets, granules, tablets, or mixtures thereof, for example, without regard to their size, shape, or morphology. Single-unit formulations include, for example, tablets, caplets, and pills.
The methods and formulations of the present invention are intended to encompass all possible combinations of components that exhibit modified-release and extended-release properties. For example, a formulation and/or method of the invention can contain components that exhibit extended-release and modified-release properties, or both delayed- release and modified-release properties, or a combination of all three properties.
The modifications in the rates of release, such as to create a delay or extension in release, can be achieved in any number of ways. Mechanisms can be dependent or independent of local pH in the intestine, and can also rely on local enzymatic activity to achieve the desired effect.
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 additional 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 3OD or other suitable polymer may be incorporated in coating composition to retard the release of the drug to ensure drug release in the colon.
The present invention is not limited to any of the particular (5-ASA) described herein. The present invention extends to the use and formulation of any azo-bis compound that yields either 4-ASA and/or 5-ASA. Modified-release formulations of any such azo-bis compound are specifically contemplated. Thus, as used herein in association with the present invention, the term "drug" refers to compounds useful in treating IBD or other diseases according to this invention, including but not limited to SASP, 5-ASA, and/or 4-ASA; the term "pro-drug" refers to any compound that yields such drugs, including but not limited to olsalazine, balsalazine, and/or any other azo-containing compound that yields such drug.
The anti infective agents are not limited to Rifaximin, ciproflaxacin and metronidazole but also includes the antibiotics which acts on G.I micro flora.
These coating layers comprises one or more excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, fillers, polishing agents, coloring agents, antitacking agents and the like.
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.
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.
In embodiments of the present invention, a pharmaceutical composition comprises an active agents 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.
The pharmaceutical compositions of the present invention can optionally include one or more solubilizers, i.e., additives to increase the solubility of the pharmaceutical active ingredient or other composition components in the solid carrier. Suitable solubilizers for, use in the compositions of the present invention include: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol, available commercially from BASF under the trade name Tetraglycol) or methoxy PEG (Union Carbide); amides, such as 2- pyrrolidone, 2-piperidone, .epsilon.-caprolactam, N-alkylpyrrolidone, N- hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters, such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, .epsilon.-caprolactone and isomers thereof, . delta. -valerolactone and isomers thereof, .beta.-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)), N-methyl pyrrolidones (Pharmasolve (ISP)), monooctanoin, diethylene glycol monoethyl ether (available from Gattefosse under the trade name Transcutol), and water.
Preferred solubilizers include triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide,N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, SLS, polyethylene glycols glycofurol and propylene glycol. Cyclodextrins polyoxomers, surfactants and like
Modified dosage ranges for mammals of other sizes and stages of development will be apparent to those of ordinary skill. In the practice of the present invention, the weight ratio of the Mesalamine and Rifaximin EXAMPLES Example 1 :
Figure imgf000021_0001
Figure imgf000022_0001
Manufacturing Procedure:
Mesalamine, Xanthan gum, Sodium alginate, MCC, HPMC were mixed, sieve and granulated. The final granules were lubricated Rifaximin, Hypromellose, Poloxamer, Mannitol were also granulated separately. Both the mixtures were compressed into bilayered tablets.
Dissolution data
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. The USP Il apparatus contained a paddle and rotated at a speed of 50 rpm for Mesalamine and 100 rpm for Rifaximin in 900ml dissolution media.. The tablet formulation was placed in the apparatus and dissolution was periodically measured. The in vitro dissolution studies of are shown below;
Figure imgf000022_0002
Example 2:
Figure imgf000023_0001
Manufacturing Procedure:
Mesalamine, Xanthan gum, Sodium alginate, MCC, HPMC were passed through suitable sieve and granulated. Dried granules mixed with sifted Rifaximin and finally lubricated and compressed into tablets and coated.
Example 3:
Figure imgf000023_0002
Figure imgf000024_0001
Example 4:
Figure imgf000024_0002
Example 5:
Figure imgf000025_0001
In a preferred embodiment of the present invention in order to improve the patient compliance and target the formulation in colon, a bioadhesive, controlled release once daily (600 mg) of 5-Amino salicylic acid or a pharmaceutically acceptable salt or enantiomer or polymorph or metabolites thereof is explored.
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.

Claims

1. The pharmaceutical combination consisting of 5-ASA derivatives and anti-infective,
2. The 5 ASA derivatives of claim 1 are selected from the group consisting of Mesalazine, Osalazine, Sulfasalazine and Balsalazine.
3. The antiinfective agent of claim 1 are selected from the group consisting of Rifaximin, Metronidazole, and Ciprofloxicin.
4. The pharmaceutical combination consisting of Mesalamine, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites thereof and Rifaximin, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites thereof.
5. The pharmaceutical composition of claim 4 having a Mesalamine dose in a range of 0.8 - 4.8 g per day.
6. The pharmaceutical composition of claim 4 having a Rifaximine dose in a range of 0.2 - 1.8 g per day.
7. The modified release pharmaceutical composition consisting of Mesalamine, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites and Rifaximin, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites for the treatment of IBD/IBS.
8. The modified release dosage form consisting of Mesalamine, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites thereof and Rifaximin, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites there of and optionally containing a solublizer.
9. A modified release pharmaceutical composition according to claim 8, wherein the solbilizers are selected from the group comprising of Polaxamer and SLS
10. The modified release pharmaceutical composition consisting of Mesalamine, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites of and Rifaximin, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites thereof, which release the drug over a period of about 10 to about 20 hours in the colon, wherein the composition is formulated to increase the residence time in the colon.
11. A modified release pharmaceutical composition according to any preceding claim, wherein the increase in residence time of dosage form in the gastrointestinal tract is achieved by bioadhesion.
12. A modified release pharmaceutical composition consisting of Mesalamine, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites of and Rifaximin, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites, optionally coated with enteric coating polymers to release the delivery at the lower end of GIT.
13. The modified release pharmaceutical composition according to claim 11 wherein enteric coating polymer consists of lipophilic polymers or hydrophilic polymers.
14. A modified release pharmaceutical composition according to claim 11 , wherein hydrophilic polymer is selected from the group comprising of ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose; xanthan gum, guar gum, locust bean gum; alginates; carbomer; poly vinylacetatae, polyvinylalcohol, povidone/polyethylene oxide, acrylic and methacrylic acid copolymers.
15. A modified release pharmaceutical composition according to claim 11, wherein hydrophobic release component is selected from the group comprising of beeswax; fatty acids; long chain fatty alcohols, glycerides .glyceryl esters of hydrogenated castor oil, mineral oil, hydrogenated vegetable oil, acetylated glycerides; ethyl cellulose, stearic acid, paraffin, carnauba wax.
16. The modified release dosage form according any preceding claim is a once a day or twice a day dosage form.
17. A method for the treatment of IBS/IBD by administering
(a) an amount of Mesalamine, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites thereof and
(b) an amount of Rifaximin, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites thereof.
18. The method of treatment according to claim 10 the treatment IBS/IBD includes the treatment Crohn's disease and Ulcerative colitis.
19. A method for the treatment of IBS/IBD by administering a composition comprising of two components a and b
(a) an amount of Mesalamine, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites thereof and
(b) an amount of Rifaximin, a pharmaceutically acceptable salt, enantiomer, polymorph or metabolites thereof and a pharmaceutically acceptable carrier.
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