Classifications

• • 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
  • A61K9/0031—Rectum, anus
• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • 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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
• • 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
  • A61K9/10—Dispersions; Emulsions
  • A61K9/12—Aerosols; Foams
  • A61K9/122—Foams; Dry foams

Definitions

• the present invention relates to a topical foam composition of rifaximin suitable for rectal administration, its process of manufacturing and its use for the treatment, prophylaxis, or maintenance of remission of colonic, anal or rectal dysfunction.
• Anal disorders including anal fissure, anal ulcer, and acute haemorrhoidal disease and benign conditions of the anal canal, are common amongst the subjects of all ages, races and sexes. However, these conditions can be problematic to treat and inconvenient if not painful to endure. A subject with an anal fissure or ulcer frequently experiences anal pain and bleeding, the pain being more pronounced during and after bowel movements.
• Haemorrhoids are specialized vascular areas lying subjacent the anal mucosa.
• Typical, non-surgical therapy includes bulk laxatives and sitz baths.
• Weg baths are helpful because they induce relaxation of the anal sphincter mechanism. (Shafik, "Role of warm-water bath in anorectal conditions: The thermosphincteric reflex, "J. Clin. Gastroenterol., 16:304-308, 1993).
• Topical anal therapy is also one of the approaches used in an effort to promote healing, relieve pain, and reduce swelling and inflammation. Many preparations have been tried including those containing local anesthetics, corticosteroids, astringents, antibiotics and other agents.
• oral administration is not always feasible or desirable.
• the potential for oral dosage form development is severely limited for active agents that are poorly absorbed in the upper gastrointestinal (GI) tract and unstable to proteolytic enzymes. Some agents cause local stomach or upper GI irritation or require doses in excess of 500 mg.
• Certain patient populations, notably children, the elderly, and those with swallowing problems, are often difficult to treat with oral tablets and capsules.
• treatment of some diseases is best achieved by direct administration near the affected area, particularly with diseases involving anorectal tissues.
• oral administration can be used for drugs targeted for some of these diseased tissues, exposure of the entire body compartment to the administered drug is inefficient and can lead to undesired adverse effects.
• Rectal drug administration is amenable, however, to both local and systemic drug delivery. It has been effectively utilized to treat local diseases of the anorectal area as well as to deliver drugs systemically as an alternative to oral administration. Some advantages of this targeted delivery which includes large surface area, ability to bypass first-pass metabolism, prolonged residence time makes this route more promising for delivery of locally acting drugs.
• Suppositories, solutions, suspensions, or retention enemas represent some of the rectal dosage forms.
• liquid preparations have very limited application, largely due to inconvenience of use and poor patient compliance.
• Semi-solid preparations like gels, foams or ointments for rectal administration can afford advantages over liquid formulations because retention of the dosage form in the rectal cavity reduces patient compliance problems.
• Neosporin® ointment which contains three antibiotics Neomycin, Polymyxin B Sulfate and Bacitracin Zinc
• antibiotics have not been found useful in treating the diseases.
• Rifaximin is a water insoluble, semisynthetic rifamycin-based non-systemic antibiotic belonging to the rifamycin class of antibiotics, and has the scientific name [(2S, 16Z, 18E,20.S,21 S,22R,23R,24R,25S,26S,27S,2SE)-5,6,21 ,23 ,25-pentahydroxy-27- methoxy-2,4, 11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-
• Rifaximin is soluble in alcohol, ethyl acetate, chloroform and toluene. It exerts its broad- spectrum antibacterial activity by inhibiting bacterial RNA synthesis in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, irritable bowel syndrome, small intestinal anal disease, Crohn's disease, and/or pancreatic insufficiency. Rifaximin is licensed by the U.S. Food and Drug Administration to treat traveler's diarrhea caused by E. coli.
• Rifaximin has low systemic absorption with Cnax of 3.4 ng/mL, T max of 0.8 hours and is moderately bound to plasma proteins (67.5%). It has half-life of 1.8 hours and is primarily excreted in feces (97% of administered dose) and 0.32% in the urine.
• Rifaximin is not absorbed by the oral route [Venturini A. P., Chemotherapy, 29, 1-3, (1983)] nor by topical application [Venturini A. P. et al., Drugs Exptl. Clin. Res., 13, 4, 233-6, (1987)].
• rifaximin Due to this particular pharmacokinetic behaviour, rifaximin has no toxicity at a dose of 2000 mg/kg/os, when administered orally in rats, and therefore, on the basis of the microbiological, pharmacodynamic and toxicological data, the drug has been used for the treatment of bacterial gastroenteritis, neurological symptoms and clinical symptoms of hepatic encephalopathy and for the pre-and post-surgical treatment of the gastrointestinal tract [Alvisi V. et al., J. Int. Med. Res., 15, 49-56, (1987), Testa R. et al., Drugs Exptl. Clin. Res., 11, 387-392, (1985), Gruttadauria G. et al., Eur. Rev. Med.
• Rifaximin is used for the treatment of pathologies caused by non-invasive strains of Escherichia coli, a micro-organism which is not able to penetrate into GI mucosa and therefore remains in contact with gastrointestinal fluids.
• Rifaximin is also approved for the treatment of pathologies whose etiology is in part or totally due to intestinal acute and chronic infections sustained by Gram-positive and 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.
• Rifaximin is available in tablets, granules for oral suspension and ointment, marketed in Europe and U.S.A. and in many other countries. Tablets, for example are currently marketed at the dosage of 200 mg for traveler's diarrhea under the brand name Xifaxan®.
• 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 patent also discloses a pharmaceutical antibacterial composition and a method of using it to treat antibacterial diseases of the gastrointestinal tract.
• European Patent No. EP0161534 to Cannata et al. discloses a process for the synthesis of pyrido-imidazo rifamycins. The process is described as an improvement over the '785 patent to Marchi in that the later process provides unsatisfactory yields from an industrial point of view.
• European Patent No. EP0858804 to Ferrieri et al. describes use of oral rifaximin compositions in the treatment of diarrhea from cryptosporidiosis.
• U.S. Pat. No. 5,352,679 to Ferrieri et al. describes use of rifaximin (INN) in formulations for treatment of gastric dyspepsia caused by Helicobacter pylori bacteria.
• the rifaximin formulations disclosed in the patent are in the form of tablet, capsule, sugar coated tablet, granules or syrup for oral administration.
• WO 2007/103448 discloses pharmaceutical preparations comprising an anti-rectal dysfunction agent and rifaximin.
• the preferred anti-rectal dysfunction is a nitric oxide modulating agent such as nitroglycerin.
• the examples disclosed in the patent application are related to the ointment containing rifaximin and nitroglycerine.
• EP-A-0468555 and EP-A-0395329 by Smith Kline & French and FR-A2647344 by Physiopharm discloses aqueous foam compositions in which the same substance or mixture of substances (namely one or more chlorofluorocarbons) is used as both a foaming agent and a propellant for expulsion of the composition out of a conventional aerosol can.
• the same substance or mixture of substances namely one or more chlorofluorocarbons
• topical formulations of rifaximin which are capable of providing the desired effect. It is known that topical treatment of infections or disturbances of the colon or rectum is more preferred than oral route, as the formulation is directly applied to the site of action and hence rapidly reaches and acts on the point at which the disturbance is located.
• topical delivery of active agents is achieved preferably by rectal administration using suppositories, enemas, ointments, creams and foam.
• suppository is the most common one.
• the suppository base is generally a fat but also water- soluble or water-miscible bases are utilized. To obtain a good bioavailability the active ingredient should come into contact with the rectal or colonic mucosa.
• Ointments and creams often do not create an environment for promoting respiration of the wound tissue and it is not favorable to the normal respiration of the skin. Moreover, there may be likelihood of experiencing pain and irritation during the application of ointments and creams, particularly to abraded, wounded or inflamed mucosa of the rectum or colon.
• Aqueous foamable preparations are the less common of the rectal preparation forms. They require a relatively complicated manufacture as well as complicated packaging compared with suppositories and enema. However, since better spreading effects are obtained with enema and foams than with suppositories more distal intestine regions can be reached thereby.
• Conventional foams for rectal or vaginal administration are filled in pressurized containers with a pharmaceutically active ingredient dissolved or suspended in a liquid vehicle, at least one propellant gas and a surfactant with foaming properties.
• a pharmaceutically active ingredient dissolved or suspended in a liquid vehicle
• at least one propellant gas and a surfactant with foaming properties.
• Examples based on mesalazine, peppermint, sucralfate or budesonide as the active ingredient dispersed in a liquid vehicle containing a foaming surfactant and administered for topical action in the colon using a pressurised atomiser with a propellant gas are described in EP-A-468 555. Because of the hydrophobic nature of rifaximin, it is virtually insoluble in water but is readily soluble in alcohols.
• solubilizers such as organic solvents, water-soluble alcohols.
• the formulations if prepared in this way may remain stable over a short period because large amounts of the active substance are decomposed within a short time.
• compositions of rifaximin suggested in the prior art are ointment and vaginal foam.
• the ointment is not in the form of ready to use, but can be prepared by a cumbersome process of crushing the rifaximin tablet in suitable oily vehicle and admixing this mixture with ointment base prior to the application.
• the vaginal foam when formulated may also not remain stable when provided in compressed gas packs.
• An object of the present invention is to provide a topical foam composition of rifaximin suitable for rectal administration. It is a particular object to provide effective formulations having either an aqueous and/or a non-aqueous vehicle.
• Another object of the present invention is to provide a topical foam composition of rifaximin having better spreading effect.
• Yet another object of the present invention is to provide a topical foam composition of rifaximin which remains stable over the storage period. Yet another object of the present invention is to provide a method of manufacturing the topical pharmaceutical composition of rifaximin suitable for rectal administration. Still another object of the present invention is to provide is to provide a method of treating, prophylaxis, or maintenance of remission of colonic or rectal dysfunction by administering the topical foam composition of rifaximin to patients in need thereof.
• a further another object of the present invention is to provide a topical foam composition of rifaximin for rectal administration which remains effective even after intestinal evacuation by the subject treated.
• a topical foam composition of rifaximin for rectal administration comprising one or more pharmaceutical excipients or carriers such as at least one surfactant and at least one propellant or mixtures thereof.
• a process of manufacturing the said topical foam composition of rifaximin According to a further aspect there is provided a process of manufacturing the said topical foam composition of rifaximin. According to a further aspect there is provided a topical foam composition of rifaximin for use in the preparation of a medicament suitable for administering to the rectum, colon and/or terminal ileum of a patient for the treatment, prophylaxis, or maintenance of remission of colonic or rectal dysfunction. According to yet another aspect there is provided a method of treating, preventing, or alleviating an anal disorder comprising administering the topical foam of rifaximin to a subject in need thereof.
• the present inventors have developed a topical foam composition of rifaximin which may achieve the aforesaid objectives and which also exhibit a topical anti-infective action.
• the present inventors have found that by utilizing appropriate combination of pharmaceutical excipients or carriers it is possible to achieve a topical pharmaceutical composition of rifaximin suitable for rectal administration and achieve the aforesaid objectives.
• the inventor shave found a way to formulate rifaximin as a topical foam composition by means of either an aqueous and/or non-aqueous vehicle.
• water soluble alkanols in topical foam composition comprising rifaximin, it remains stable over the storage period.
• the ratio of water soluble alkanol to water is preferably from about 0.05:10 to 10: 0.05, on a weight basis.
• Pharmaceutically acceptable water soluble alkanols which are suitable for use in the present invention may be selected from, but not limited to ethanol, polyalcohols such as a propylene glycol, glycerol, polyethyleneglycol, polypropylene glycol, propylene glycol glyceryl esters or mixtures thereof.
• Rifaximin is used throughout the description in broad sense to include not only rifaximin per se but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
• Rifaximin used may also be in Polymorphic form or amorphous form. Examples of polymorhic forms of rifaximin include, but not limited to polymorph [alpha], polymorph [beta], polymorph [gamma], polymorph [delta], and polymorph e of rifaximin , as described in U.S. Patent Application Ser. No. 10/728,090, U.S. Patent Application Ser. No. 1 1/135,651, European Patent Application No. 04005541 and European Patent Application No. 15227.
• the present invention provides a topical foam composition comprising rifaximin suitable for rectal administration in with one or more pharmaceutically acceptable excipients or carriers and which also remains stable over the storage period.
• the amount of rifaximin in the rectal foam composition according to the present invention preferably ranges from about 0.01% w/w to about 10% w/w, more preferably from about 0.5% w/w to about 8% w/w relative to the total weight of the composition.
• the present invention provides a topical foam composition
• a topical foam composition comprising rifaximin with one or more pharmaceutical excipient carrier in the form of a rectal foam filled in a compressed gas container, that upon valve actuation, emits a fine dispersion of liquid and/or solid materials in a gaseous medium.
• the said composition is easier to apply, less dense, and spread more easily than other topical dosage forms.
• the composition may be formulated in various ways to provide emollient or drying functions to the rectal mucosa, depending on the formulation constituents. Another benefit of the pharmaceutical composition of the present invention is ease of use by the patient and consumer acceptance.
• the topical foam composition may not contain mineral oils.
• the disadvantage of these components is that they might further irritate the already inflamed areas of the rectum or anus.
• the topical foam composition of the present invention comprises rifaximin, at least one surfactant and at least one propellant, water soluble alkanols, water and optionally other pharmaceutical excipients or carriers.
• suitable non-aqueous vehicle which may be employed in the topical foam composition of the invention, which include but not limited to vegetable oils, such as olive oil; injectable organic esters, such as ethyl oleate or mixtures thereof.
• the liquid vehicle may also be based on highly hydrophilic organic substances to allow the surfactant to perform its foaming action, which however preferably should not be inhibited by the other substances present in the formulation, such as the active principles and their stabilizers, whereas the specific adjuvants (such as foam consistency correctors) are preferably chosen from those with strong hydrophilic and lipophilic characteristics.
• the vehicle typically constitutes from 10% w/w to 95%w/w, preferably from 10% w/w to 90% w/w, more preferably from 20% to 70% w/w relative to the total weight of the composition.
• the vehicle employed in the topical foam composition of the present invention comprises water in an amount from approximately 20% w/w to approximately 90% w/w relative to the total weight of the composition and a water-soluble alkanol, preferably propylene glycol, in an amount from approximately 0% w/w to 50% w/w relative to the total weight of the composition.
• the vehicle contains 20-80% w/w water relative to the total weight of the composition.
• the vehicle contains 5-40% w/w water soluble alkanol relative to the total weight of the composition.
• the vehicle contains 20-80% w/w water relative to the total weight of the composition, and 5-40% w/w water soluble alkanol relative to the total weight of the composition.
• non-aqueous vehicle especially the water soluble alkanol, more especially the propylene glycol
• surface active agents which may be employed in the aqueous foam composition of the present invention include, but not limited to anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants.
• anionic surfactants include, but are not limited to, ammonium lauryl sulfate, sodium lauryl sulfate, ammonium laureth sulfate, sodium laureth sulfate, alkyl glyceryl ether sulfonate, triethylamine lauryl sulfate, triethylamine laureth sulfate, triethanolamine lauryl sulfate, triethanolamine laureth sulfate, monoethanolamine lauryl sulfate, monoethanolamine laureth sulfate, diethanolamine lauryl sulfate, diethanolamine laureth sulfate, lauric monoglyceride sodium sulfate, potassium lauryl sulfate, potassium laureth sulfate, sodium lauryl sarcosinate, sodium lauroyl sarcosinate, lauryl sarcosine, cocoyl sarcosine
• nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid esters, sorbitan esters, cetyl octanoate, cocamide DEA, cocamide MEA, cocamido propyl dimethyl amine oxide, coconut fatty acid diethanol amide, coconut fatty acid monoethanol amide, diglyceryl diisostearate, diglyceryl monoisostearate, diglyceryl monolaurate, diglyceryl monooleate, ethylene glycol distearate, ethylene glycol monostearate, ethoxylated castor oil, glyceryl monoisostearate, glyceryl monolaurate, glyceryl monomyristate, glyceryl monooleate, glyceryl monostearate, glyceryl tricaprylate/caprate, glyceryl triisostearate, glyceryl trioleate, glycol distearate, glycol monostearate, isooc
• amphoteric surfactants include, but are not limited to, sodium N-dodecyl- - alanine, sodium N-lauryl- -iminodipropionate, myristoamphoacetate, lauryl betaine, lauryl sulfobetaine, sodium 3-dodecyl-aminopropionate, sodium 3-dodecylaminopropane sulfonate, sodium lauroamphoacetate, cocodimethyl carboxymethyl betaine, cocoamidopropyl betaine, cocobetaine, lauryl amidopropyl betaine, oleyl betaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethyl alphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, lauryl bis-(2-hydroxyethyl)carboxymethyl betaine, stearyl bis-(2- hydroxypropyl)carboxymethyl betaine, oleyl dimethyl gamma-car
• cationic surfactants include, but are not limited to, behenyl trimethyl ammonium chloride, bis(acyloxyethyl)hydroxyethyl methyl ammonium methosulfate, cetrimonium bromide, cetrimonium chloride, cetyl trimethyl ammonium chloride, cocamido propylamine oxide, distearyl dimethyl ammonium chloride, ditallowedimonium chloride, guar hydroxypropyltrimonium chloride, lauralkonium chloride, lauryl dimethylamine oxide, lauryl dimethylbenzyl ammonium chloride, lauryl polyoxyethylene dimethylamine oxide, lauryl trimethyl ammonium chloride, lautrimonium chloride, methyl- 1 -oleyl amide ethyl -2-oleyl imidazolinium methyl sulfate, picolin benzyl ammonium chloride, polyquatemium, stearalkonium chloride, sterayl dimethylbenzyl
• the topical foam composition contains a lubricant.
• said lubricant is a silicone (e.g. polydimethylsiloxane). The silicone may further stabilize the foam-forming composition.
• the propellant used in the topical foam composition of the present invention is used to accomplish the foaming effect.
• the propellant may be chosen according to known principles for preparing a foamable composition of the aerosol type packed in a pressurized container and suitable for a rectal application.
• the propellant may be any suitable, pharmaceutically acceptable, gas such as a low molecular weight hydrocarbon e.g. isobutane, n-butane, propane, CFC, hydrocarbons; chlorofluorocarbons (CFCs); hydrochlorofluorocarbons (HCFCs); hydrofluoroalkanes (HFAs) such as HFA 134a and HFA 227; or air.
• the propellant comprises a mixture of n-butane, isobutane, propane.
• the propelling properties can vary depending on the type and quantity of propellant used and, consequently, the foam can reach more or less distant regions of the large intestine.
• the propellant may be present in an amount from 0.05 to 20% w/w, preferably 0.5 to 20% w/w, of the composition. Preferably, said amount is between 3 to 10%, more preferably between 7 to 9% w/w of the composition. Additionally, liquefied nitrogen may be present as pressurizing agent to obtain the required number of doses.
• topical foam composition according to the present invention may comprise at least one additional active ingredient suitable for rectal administration.
• Additional active agents may be selected from, but not limited to one or more of antiinflammatory agents, steroids (e.g. corticosteroids), additional antibiotics, anti-fungal agents, analgesics, or anti-neoplastic agents.
• antibiotics includes, but not limited to: dapsone, chloramphenicol, neomycin, cefaclor, cefadroxil, cephalexin, cephradine, erythromycin, clindamycin, lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin, dicl oxacillin, cyclacillin, picloxacillin, hetacillin, methicillin, nafcillin, penicillin, polymyxin, tetracycline, amphotericin-b, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin, perimycin, azaserine, griseofulvin, oligomycins, neomycin undecylenate, pyrroinitrin, siccanin, tuber
• Suitable antifungal agents includes but not limited to: allylamines such as butenafine, naftifine, imidazoles such as bifonazole, butoconazole, chlordantoin, chlormidazole, cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole, triazoles such as fluconazole, itraconazole, saperconazole, terconazole, and others such as acrisorcin, amorolf[iota]ne, biphenamine, bromosalicylchloranilide, buclosamide, calcium propionate, chlophenesin, ciclopirox, cl
• Antifungal agents may also include, for example, polyenes such as amphotericin-b, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartricin, natamycin, nystatin, pecilocin, perimycin, azaserine, griseofulvin, oligomycins, neomycin undecylenate, pyrroinitrin, siccanin, tubercidin, viridin, allylamines such as butenafine, naftifine, imidazoles such as bifonazole, butoconazole, chlordantoin, chlormidazole, cloconazole, clotrimazole, .
• polyenes such as amphotericin-b, candicidin, dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin, mepartric
• the other therapeutic agent can include steroid or a non-steroidal antiinflammatory agent.
• Useful non-steroidal anti-inflammatory agents include, but are not limited to, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid
• corticosteroid examples include but not limited to: hydrocortisone, i.e., 11-17- 21-trihydroxypregn-4-ene-3,20-dione or Cortisol, Cortisol acetate, hydrocortisone phosphate, hydrocortisone 21 -sodium succinate, hydrocortisone tebutate, corticosterone, corticosterone acetate, cortisone, cortisone acetate, cortisone 2 IB- cyclopentanepropionate, cortisone phosphate, triamcinolone hexacetonide, dexamethasone phosphate, desonide, betamethasone dipropionate, mometasone furate.
• hydrocortisone i.e., 11-17- 21-trihydroxypregn-4-ene-3,20-dione or Cortisol
• Cortisol acetate examples include but not limited to: hydrocortisone,
• corticosteroid and topical anesthetic may be employed together in the composition along with rifaximin.
• preferred treatments for use in combination therapy with the compositions of the present invention include, but not limited to: naproxen sodium (Anaprox(R) and Anaprox(R) DS, Roche), flurbiprofen (Ansaid(R); Pharmacia), diclofenac sodium + misoprostil (Arthrotec(R), Searle), valdecoxib (Bextra(R), Pharmacia), diclofenac potassium (Cataflam(R) and Voltaren(R), Novartis), celecoxib (Celebrex(R), Pfizer), sulindac (Clinoril(R), Merck), oxaprozin (Daypro(R), Pharmacia), salsalate (Disalcid(R), 3M), difhmisal (Dolobid(R), Merck), naproxen sodium (EC Naprosyn(R), Roche), piroxicam (
• Antineoplastic agents may also be included in the topical foam composition of the present invention along with the rifaximin include, but not limited to: vincristine, vinblastine, vindesine, busulfan, chlorambucil, spiroplatin, cisplatin, carboplatin, methotrexate, adriamycin, mitomycin, bleomycin, cytosi[pi]e arabinoside, arabinosyl adenine, mercaptopurine, mitotane, procarbazine, dactinomycin (antinomycin D), daunorubicin, doxorubicin hydrochloride, taxol, plicamycin, aminoglutethimide, estramustine, flutamide, leuprolide, megestrol acetate, tamoxifen, testolactone, trilostane, amsacrine (m-AMSA), asparaginase (L-asparaginase), etop
• Antiviral agents may also be included in the topical foam composition of the present invention along with the rifaximin include, but not limited to: acyclovir, amantadine, azidothymidine, ribavirin or vidarabine.
• the other therapeutic agent can be an analgesic.
• Useful analgesics include, but are not limited to, phenacetin, butacetin, acetaminophen, nefopam, acetoamidoquinone, and mixtures thereof.
• a topical anesthetic may be present in the composition of the invention.
• the topical anesthetic may include, but not limited to dibucaine, lidocaine, pramoxine, benzocaine, tetracaine.
• the topical anesthetic may be present in any amount which is effective in the practice of the treatment of anal disease.
• the present invention relates to a pharmaceutical combination product comprising rifaximin adapted for delivery to the colon and/or rectum and a compound selected from, but not limited, one or more of 5-acetyl salicylic acid (5-ASA), sulphasalazine, asalazine, prednisolone, or budesonide for simultaneous, separate, or sequential administration.
• the topical foam composition according to the present invention is usually packed in a suitable pressurized dispensing canister of the aerosol type well known in the art such as an aluminium canister. Each canister is sealed with a suitable foam dispensing valve.
• any valve or nozzle/valve assembly which provides a means for releasing the foam from the container and provides foam which is suitable for use in the present invention may be used.
• the foam that is formed from the composition of the present invention has superior properties.
• the advantages associated with the topical foam composition according to the present invention is that better results may be obtained in combating the disease and either a lower dosage of the active ingredient or less dosages per day may be necessary to obtain similar results when compared with prior art compositions. For instance, the increased spreading of the foam together with the longer exposure time to the active will result in optimal local effect at the target site.
• the foam of the present invention may not cause extra irritation of the inflamed target mucosa due to the absence of mineral oils as present in the prior art compositions.
• the topical foam composition of the present invention is presented in a suitable dispensing container, for example an aluminium aerosol container, fitted with a suitable metered or un- metered valve.
• a suitable dispensing container for example an aluminium aerosol container, fitted with a suitable metered or un- metered valve.
• Such containers are well known in the art.
• the container can be fitted or supplied together with an applicator device for insertion into the rectum to ensure more efficient administration of the foam.
• the dispensing container may be in the form of coated aluminium cans to prevent corrosion, such as epoxy-coated cans.
• the mixture of the mixing of the ingredients with propellant may be insured by shaking, optionally with the aid of a mixing bead.
• the can may be arranged for either "upside down” spraying with the valve at the bottom, or the can have a dip tube so that the foam can be sprayed while the can is upright with the valve at the top.
• the dispensing valve of the can allows rapid expansion of the propellant, which triggers and enhances the foaming action of the surfactant, which thus emerges to entrain the medicated liquid in the form of foam.
• the propellant expansion energy is absorbed mainly in forming the foam, thus allowing rectal application without risk.
• the foam may be generated at the moment of therapeutical application.
• the known formulation and dispensing technology used in the state of the art applicable to foam cans, for example in cosmetics is therefore suitable.
• the active agent is vehicled in the liquid state with at least one propellant and a surfactant with foaming action.
• the topical foam composition of the present invention is applied proximate or to the affected area of the external anus or distal anal canal of the subject. On administering such compositions, it is sufficient to obtain foams of medium consistency, with a minimum volume of 0.5g to lOg of foam introduced into the rectum.
• the present invention further provides a process of manufacturing the topical foam composition of rifaximin comprising:
• rifaximin is used in micronized form, preferably of the size less that about 200 microns. More preferably, the size may be less than about 150 microns or less.
• the active agent is solubilized or suspended in a suitable liquid vehicle containing a foaming surfactant. The liquid is placed in an atomizer can sealed by a dispensing valve and then pressurized by feeding a suitable quantity of propellant through the valve.
• the present composition can be prepared by mixing the ingredients in an appropriate manner and then filling into a suitable dispensing container, for example as described in the examples.
• topical foam composition comprising rifaximin further may comprise one or more pharmaceutical excipients, selected from, but are not limited to: emollient or humectants, pH adjusting agent, emulsifiers, foaming agents, fatty alcohol, preservative, chelating agents, antioxidants, suspending agents, thickening agents, permeation enhancers, occlusive agents, colorants and fragrances or combinations thereof.
• pharmaceutical excipients selected from, but are not limited to: emollient or humectants, pH adjusting agent, emulsifiers, foaming agents, fatty alcohol, preservative, chelating agents, antioxidants, suspending agents, thickening agents, permeation enhancers, occlusive agents, colorants and fragrances or combinations thereof.
• pH adjusting agents may be selected from, but not limited to, sodium hydroxide, citric acid, hydrochloric acid, acetic acid, phosphoric acid, succinic acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, magnesium aluminum silicates, malic acid, potassium citrate, sodium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, 1,2,3,4- butane tetracarboxylic acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, and combinations thereof, preferably triethanolamine is used.
• the topical foam composition according to the present invention topical comprises suitable pH adjusting agent to adjust the pH in the range from approximately 4 to 8.
• emulsifying waxes examples include non-ionic emulsifying waxes such as those described in the U.S. National Formulary (USNF) and 'Martindale'.
• An emulsifying wax may be incorporated in the topical composition of the present invention in order to stiffen the foam.
• the amount of emulsifying wax in the composition is preferably from 1% to 10% w/w based on the total weight of the composition.
• surfactants which may be employed in the topical foam composition of the present invention include, but not limited to fatty alcohol for example, cetyl stearyl, lauryl, myristyl, and palmityl alcohols, surfactants or mixtures thereof.
• a preferred surfactant is polyoxyethylene 10 stearyl ether, and, is preferably present in an amount from 0.1% to 1.0% w/w based on the total weight of the composition.
• a suitable surface active agent can be employed which performs the function of both foaming agent and surfactant.
• emollients and/or humectants which may be employed in the topical foam composition of the present invention include, but not limited to, polyhydric alcohols such as glycols, and polysaccharides, such as ethylene glycol, propylene glycol, butylene glycol, diethylene glycol, dipropylene glycol, glycerin, diglycerin, sorbitol, malvitol, trehalose, raffinose, xylitol, mannitol, polyethylene glycol, propylene glycol, polyglycerin, cholesterol, squaline, fatty acids, octyldodecanol, myristyl alcohol, urea, lanolin, lactic acid, esters such as isopropyl stearate, isopropyl myristate, isopropyl palmitate and isopropyl laurate and the like, preferably myristyl alcohol, octyld
• permeation enhancers may be incorporated in the topical foam composition of the present invention for delivery of the active ingredient to the mucosal surface.
• enhancers are detergents that include: sodium glycocholate, sodium taurocholate, polysorbate 80, sodium lauryl sulfate, lauric acid, and various alkyl glycosides.
• enhancers include: dextrins (cyclodextrin, dextran sulfate), fatty acids (phosphatidylcholine, lysophosphatidylcholine), heterocyclic compounds (azone), and small molecules (benzalkonium chloride, cetyltrimethylammonium bromide).
• suitable mucoadhesives may be used in the aqueous foam composition of the present invention to improve local retention of mucosally delivered of the active ingredient.
• Mucoadhesive compounds are primarily synthetic or natural polymers that can adhere to the wet mucosal surface. These include synthetic polymers such as, but not limited to monomelic alpha cyanoacrylate, polyacrylic acid, hydroxypropyl methylcellulose, and poly methacrylate derivatives. Glue-like polymers include epoxy resins and polyurethanes. Naturally occurring mucoadhesives include chitosan, hyaluronic acid and xanthan gum or mixtures thereof.
• Suitable emulsifiers include, but are not limited to, straight chain or branched fatty acids, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, propylene glycol stearate, glyceryl stearate, polyethylene glycol, fatty alcohols, polymeric ethylene oxide-propylene oxide block copolymers, and combinations thereof.
• One preferred emulsifier is cetyl alcohol.
• the emulsifier, for example the cetyl alcohol is preferably present in an amount from 0.1 to 5.0% w/w based on the total weight of the composition.
• Suitable suspending agents include, but are not limited to, alginic acid, bentonite, carbomer, carboxymethylcellulose and salts thereof, colloidal oatmeal, hydroxyethyl cellulose, hydroxypropylcellulose, microcrystalline cellulose, colloidal silicon dioxide, dextrin, gelatin, guar gum, xanthan gum, kaolin, magnesium aluminum silicate, maltitol, triglycerides, methylcellulose, polyoxyethylene fatty acid esters, polyvinylpyrrolidone, propylene glycol alginate, sodium alginate, sorbitan fatty acid esters, tragacanth, and combinations thereof.
• Suitable antioxidants include, but are not limited to, butylated hydroxytoluene, alpha tocopherol, ascorbic acid, fumaric acid, malic acid, butylated hydroxyanisole, propyl gallate, sodium ascorbate, sodium metabisulfite, ascorbyl palmitate, ascorbyl acetate, ascorbyl phosphate, Vitamin A, folic acid, fl arms or flavonoids, histidine, glycine, tyrosine, tryptophan, carotenoids, carotenes, alpha-Carotene, beta-Carotene, uric acid, pharmaceutically acceptable salts thereof, derivatives thereof, and combinations thereof.
• Suitable chelating agents include, but are not limited to, EDTA, disodium edetate, trans- 1,2- diaminocyclohexane-N,N,N',N'-tetraaceticacid monohydrate, N,N-bis(2- hydroxyethyl)glycine, l,3-diamino-2-hydroxypropane-N,N,N',N'-tetraacetic acid, 1,3- diaminopropane-N,N,N',N'-tetraacetic acid, ethylenediamine-N,N'-diacetic acid, ethylenediamine-N,N'-dipropionic acid, ethylenediamine-N,N'-bis(methylenephosphonic acid), N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid, ethylenediamine- ⁇ , ⁇ , ⁇ ', ⁇ '- tetrakis(methylenephosphonic acid), 0,0'
• Suitable emollients include, but are not limited to, myristyl lactate, isopropyl palmitate, light liquid paraffin, cetearyl alcohol, lanolin, lanolin derivatives, mineral oil, petrolatum, cetyl esters wax, cholesterol, glycerol, glycerol monostearate, isopropyl myristate, lecithin, and combinations thereof. Preservatives can be used to prevent the growth of fungi and other microorganisms.
• Suitable preservatives include, but are not limited to, benzoic acid, sorbic acid, butylparaben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.
• the preservative is preferably present in an amount from 0.01% to 0.20% w/w, preferably 0.1% to 0.20% w/w, based on the total weight of the composition. In a particular embodiment the composition contains 0.1 % to 0.18% w/w methyl paraben and 0.01 % to 0.02% w/w propyl paraben.
• antioxidants examples include, but not limited to sodium metabisulphite and advantageously this can be used in conjunction with a chelating agent such as a salt of EDTA, e.g. disodium edetate.
• a chelating agent such as a salt of EDTA, e.g. disodium edetate.
• the present invention further provides a method of treating, preventing, or alleviating anal disorders comprising administering to a subject in need thereof an effective amount of rifaximin.
• Anal disorders include one or more of anal fissure, anal ulcer, haemorrhoidal disease, levator spasm, inflammatory bowel disease with anal involvement, irritable bowel syndrome, diarrhea, microbe associated diarrhea, Clostridium difficile associated diarrhea, travelers' diarrhea, small intestinal anal disease, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, colitis, hepatic encephalopathy, or pouchitis.
• the composition of the invention is contacted with or applied to the affected anal area or proximate thereto such that an effective amount of active ingredient is administered.
• the amount of composition which is employed should be effective for the amelioration, control and/or healing of the anal disease and the prompt and dramatic control or relief of pain resulting from or associated with the disease.
• the anal disorder is or is caused by one or more of anal fissure, anal ulcer, and acute haemorrhoidal disease, irritable bowel syndrome, inflammatory bowel disease, (e.g., Crohn's and colitis), travelers' diarrhea, large intestinal anal disease, chronic pancreatitis, pancreatic insufficiency or post-surgical disease (e.g., pouchitis).
• anal fissure e.g., anal ulcer, and acute haemorrhoidal disease
• irritable bowel syndrome e.g., Crohn's and colitis
• travelers' diarrhea e.g., large intestinal anal disease
• chronic pancreatitis e.g., pancreatic insufficiency
• post-surgical disease e.g., pouchitis
• the effective amount is effective to treat a bacterial infection, e.g., anal diseases including, one or more of anal fissure; anar- ulcer, and acut haemorrhoidal disease, irritable bowel syndrome, travelers' diarrhea, small intestinal anal disease, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, colitis, hepatic encephalopathy, antibiotic associated colitis, and/or diverticular disease.
• a bacterial infection e.g., anal diseases including, one or more of anal fissure; anar- ulcer, and acut haemorrhoidal disease, irritable bowel syndrome, travelers' diarrhea, small intestinal anal disease, Crohn's disease, chronic pancreatitis, pancreatic insufficiency, colitis, hepatic encephalopathy, antibiotic associated colitis, and/or diverticular disease.
• anal diseases including, one or more of anal fissure; anar- ulcer, and acut haemorr
• step (3) Add propylene glycol to the solution of step (2) under homogenization.
• step (4) Add mixture of step (1) to the solution of step (3) under homogenization and allow to cool under stirring.

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• 2010
  • 2010-11-23 EP EP10784333.6A patent/EP2503989A2/de not_active Withdrawn
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