WO1992016206A1 - Utilisation de l'acide 5-aminosalicylique dans le traitement de la phase diarrheique de la colopathie fonctionnelle - Google Patents

Utilisation de l'acide 5-aminosalicylique dans le traitement de la phase diarrheique de la colopathie fonctionnelle Download PDF

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Publication number
WO1992016206A1
WO1992016206A1 PCT/US1992/001848 US9201848W WO9216206A1 WO 1992016206 A1 WO1992016206 A1 WO 1992016206A1 US 9201848 W US9201848 W US 9201848W WO 9216206 A1 WO9216206 A1 WO 9216206A1
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active ingredient
asa
treatment according
pharmaceutical composition
ibs
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PCT/US1992/001848
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English (en)
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George Gilbert Cloyd
Allison Barretto Felarca
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Norwich Eaton Pharmaceuticals Inc.
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Publication of WO1992016206A1 publication Critical patent/WO1992016206A1/fr

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    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • 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
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • 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

Definitions

  • the present invention relates to the novel method of treating a human or other mammal afflicted with Irritable Bowel Syndrome - Diarrheal Phase or Type (hereinafter referred to as IBS-D) comprising the topical delivery to the intestinal tract of said human or other mammal of a safe and effective amount of a pharmaceutical composition consisting essentially of the active ingredient 5-aminosalicylic acid (hereinafter referred to as M 5-ASA M ), and pharmaceutically-acceptable excipients.
  • Said topical delivery is most preferably accomplished by the oral administration to said human or other mammal of a delayed-release composition consisting essentially of said 5-ASA active ingredient and a pharmaceutically-acceptable excipient.
  • IBS Irritable bowel syndrome
  • IBS is usually the diagnosis given when an individual suffers from certain characteristic symptoms affecting the gastrointestinal tract and after the existence of other disorders have been eliminated. Accordingly, IBS sufferers exhibit altered bowel habits (characterized either by alternating diarrhea and constipation, solely constipation, or solely diarrhea), as well as abdominal pain and/or cramping, and various other symptoms including flatulence and abdominal distension, bloating, and rumbling. There is no detectable radiological or histological evidence of organic pathology, i.e. the presence of an infectious agent or observable inflammation or other pathology in the intestinal tract.
  • IBS has been called functional bowel disorder, mucomembraneous colitis, nervous diarrhea, colonic neurosis, colonic dyspepsia, colonic dysfunction, spastic colon, mucous colitis, irritable colon syndrome, unhappy colon, dissynergia of the colon, and disordered gastrocolonic reflex. It is estimated that about 10% of the adult population suffers from IBS and that this disorder accounts for from about 40% to about 70% of office visits to gastroenterologists. It has also been suggested that IBS is one of the leading causes of absenteeism from work due to illness.
  • IBS-Diarrhea! phase or type (hereinafter referred to as IBS-D) and that 50% of IBS sufferers experience constipation only.
  • IBS-diarrheal type one-fifth experience only diarrhea
  • IBS-diarrheal phase the remaining four-fifths experience alternating diarrhea and constipation
  • IBS The cause of IBS has been extremely difficult to determine, and there has been little success in differentiating possible causes with regard to symptomatic characterizations. It has been reported that IBS stems from the ingestion of certain foodstuffs (often wheat gluten or lactose); other theories as to the cause of IBS have implicated disorders of gut motility, while many gastroenterologists, however, have attributed IBS to psychological factors. See generally, V. Alun Jones, et al., "Food Intolerance: A Major Factor in the Pathogenesis of Irritable Bowel Syndrome", The Lancet. Vol. 2, No. 8308, pp.
  • IBD ulcerative colitis and Crohn's disease
  • IBS-D ulcerative colitis and Crohn's disease
  • Ulcerative colitis is a chronic inflammatory disease of the colon of unknown etiology.
  • the disease causes inflammation of the mucosa of the colon, with extension to the submucosa in severe cases.
  • the colon, as well as the rectum is involved; it is less common for the ileum (the most distal portion of the small intestine) to be involved.
  • the ulcer formation and its extent may vary amongst individuals and amongst different regions of the intestinal tract of the same individual, and is often detectable via sigmoidoscopy or colonoscopy.
  • Crohn's disease also known as regional enteritis or colitis granulomatosa, is often characterized as being related to ulcerative colitis, since they are both inflammatory diseases of the intestine. Crohn's disease is most frequently located in the small intestine, especially in the ileum, but also may affect the jejunum (the middle part of the small intestine, just distal to the duodenum and proximal to the ileum) and any part of the colon, including the rectum. When the colon is involved, the differentiation of Crohn's disease from ulcerative colitis is considerably difficult.
  • IBD is distinguished from IBS by the presence of the inflammation of the mucosa and submucosa layers of the intestine, which is detectable usually by visual inspection (sigmoidoscopy or colonoscopy), but also by radiological or histological examination.
  • IBS is characterized by the lack of any detectable radiological or histological evidence of organic pathology, such as observable inflammation of layers deeper than the epithelium.
  • any detectable radiological or histological evidence of organic pathology such as observable inflammation of layers deeper than the epithelium.
  • Prostaglandins Gastrointestinal Effects and Peptic Ulcer Disease", Med. Clin. North. Am.. Vol. 65, No. 4, pp. 773-87, July 1981, hereinafter referred to as "Prostaglandins".
  • prostaglandins in specific and nonspecific inflammatory disorders has been suggested by several studies indicating that the condition of patients with a variety of intestinal disorders (including, in addition to IBS, radiation enteritis, ulcerative col tis, and food intolerance) improved when inhibitors of prostaglandin synthesis, such as aspirin or indomethacin, were administered. See Prostaglandins. pp. 781-2. Also reported therein, however, was the fact that information linking prostaglandins to said disorders is in a state of flux and the role of prostaglandins in IBS-D is uncertain.
  • Prostaglandins are a normal by-product of the inflammatory response and the finding of elevated prostagl ndin levels on inflammation does not necessarily indicate a pathogenetic role for prostaglandins.” See Prostaglandins at 782.
  • NSAIDs Non-Steroidal Anti-Inflammatory Drugs
  • potent prostaglandin synthetase inhibitors such as indomethacin and flurbiprofen
  • indomethacin and flurbiprofen have little effect on white cell accumulation and can, therefore, divert arachidonic acid metabolism along lipoxygenase pathways which have been shown to exist in human colonic mucosa.
  • prostaglandins inflammatory Bowel Disease, see e.g. Ligumsky et al., "Enhanced Thromboxane A2 and Prostacyclin Production by Cultured Rectal Mucosa in Ulcerative Colitis and Its Inhibition by Steroids and Sulfasalazine," Gastroenterology. Vol. 8, No. 3, pp.
  • prostaglandins are a normal by-product of an inflammatory response [such as that which would accompany both the topical
  • IBS-D adenosine-containing sarcoma
  • antispasmodic agents octilonium bromide, mebeverine, trimebutine, dicyclomine, and prifiniu bromide
  • anticholinergic agents atropine, belladonna, 1-hyoscyamine, propantheline bromide, and dicyclomine hydrochloride
  • anticholinergic/barbiturate combinations (tryciclamol and/or phenobarbital ; dicyclomine and/or phenobarbital)
  • antidepressants desipra ine, trimipramine, a itriptyline
  • bulking agents wheat bran, psyllium (ispaghul )
  • dopamine antagonists domperidone
  • carminatives peppermint oil
  • opioids loperamide
  • a human or other mammal suffering from IBS-D can be successfully treated with the topical delivery of 5-ASA or its salts and esters, to the intestinal tract of said human or mammal, preferably the large intestine.
  • the 5-ASA active ingredient has been shown to be effective alone, with no sodium cromoglycate-like agent, and to be generally well tolerated, with minimal to substantially no side effects. It is preferred to effect said topical delivery of the 5-ASA active ingredient by the oral administration of delayed-release tablets.
  • Said delayed-release tablets are most preferably formulated in such a way that the 5-ASA active ingredient is substantially topically delivered to the large intestine via a release of the active ingredient at a pH which is generally present only in the large intestine.
  • topical delivery of the 5-ASA active ingredient to the large intestine topical delivery of the active ingredient to the small intestine may be desirable alone, or in addition to, the topical delivery to the large intestine.
  • segment of the intestine to which the active ingredient will be topically delivered can be varied by employing various standard pharmaceutical dosage forms as delivery systems. When utilizing oral dosage forms, it is generally easier, and therefore more preferable, to vary coating methods, types, and/or thicknesses which are readily available to those skilled in the art.
  • the present invention embodies a novel method of treatment for a human or other mammal afflicted with IBS-D, which comprises the topical delivery to the intestinal tract of said human or other mammal of a safe and effective amount of a pharmaceutical composition consisting essentially of a 5-ASA active ingredient, and pharmaceutically-acceptable excipients.
  • Said topical delivery is preferably to the large intestine of said human or other mammal and is most preferably accomplished by the oral administration to said human or other mammal of a delayed-release composition consisting essentially of said 5-ASA active ingredient and pharmaceutically-acceptable excipients.
  • the present invention relates to a novel method of treatment for a human or other mammal afflicted with IBS-D which comprises the topical delivery to the intestinal tract of said human or other mammal, preferably to the large intestine, of a safe and effective amount of a pharmaceutical composition consisting essentially of a 5-ASA active ingredient and pharmaceutically- acceptable excipients.
  • Said topical delivery is most preferably achieved via the oral administration to said human or other mammal of a delayed-release composition consisting essentially of the 5-ASA active ingredient and pharmaceutically-acceptable excipients.
  • the present invention is directed to a method of treatment for IBS-D utilizing the topical delivery to the intestinal tract of a human or other mammal, preferably to the large intestine, of a safe and effective amount of a pharmaceutical composition consisting essentially of a 5-ASA active ingredient and pharmaceutically-acceptable excipients.
  • a pharmaceutical composition consisting essentially of a 5-ASA active ingredient and pharmaceutically-acceptable excipients.
  • 5-ASA active ingredient denotes 5-aminosalicylic acid, hereinafter referred to as “5-ASA” and, unless otherwise specified, encompasses the pure compound 5-aminosalicylic acid, as well as the pharmaceutically-acceptable salts or esters thereof, or any mixture thereof.
  • 5-Aminosali- cylic acid is often referred to as “mesalamine” and " esalazine” and is more properly referred to as 5-amino-2- hydroxybenzoic acid or 5-amino-2-hydroxybenzene-l-carboxylic acid.
  • any pharmaceutically-acceptable, non-toxic salt of 5-ASA may be used as the 5-ASA active ingredient in the composition of the present invention.
  • the salts of 5-ASA may be acid addition salts, in particular the hydrochloride, but any pharmaceutically-acceptable, non-toxic organic or inorganic acid salt may be used.
  • salts formed with the carboxylic acid group may be used, including, but not limited to, alkali metal salts (K, Na) and alkaline earth metal salts (Ca, Mg), the Ca- and Na- salts being preferred.
  • any pharmaceutically-acceptable, non-toxic ester of 5-ASA may be used as the 5-ASA active ingredient in the pharmaceutical composition described herein.
  • Particularly suitable esters are those meta- (or 5-) aminosalicylic esters and a number of related esters disclosed in Great Britain Patent Specification 1,581,444 of Halpern et al., assigned to Mundipharma A.G. of Switzerland, published December 17, 1980, hereby incorporated herein by reference.
  • a number of esters of ortho-, meta-, and para-salicylic acid are disclosed. Said esters are effective as ultraviolet ray screening compounds, thereby rendering themselves useful in preventing solar burning.
  • esters of 5-ASA which are suitable for use as the active ingredient in the invention disclosed herein are straight chain or branched chain Ci-Cis alkyl esters, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl ; straight chain or branched C2-C18 alkenyl esters, including, but not limited to, vinyl, alkyl, undecenyl, and linolenyl; C3-C8 cycloalkyl esters, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; aryl esters, including, but not limited to,
  • the proper selection of the 5-ASA active ingredient depends on the selected type of formulation, the disease pattern, especially the site and type of the disease, and the desired release of the active ingredient.
  • the physical and chemical characteristics of the active ingredient must be taken into account when selecting suitable pharma ⁇ ceutically-acceptable excipients for use in the pharmaceutical composition containing the 5-ASA active ingredient.
  • the pharma ⁇ ceutical composition and methods of the present invention may also contain other non-5-ASA active agents exhibiting different and/or additional biological activity. For instance, those compounds conventionally used in the treatment of diseases or disorders of the intestinal tract are of particular interest.
  • non-5-ASA active agents include non-steroidal anti-inflammatory drugs (i.e., NSAIDs), as described hereinbelow, preferably including, but not limited to, salicylates, indomethacin, flurbiprofen, diclofenac, naproxen, piroxicam, tebufelone and ibuprofen; steroids, including, but not limited to, hydrocortisone, prednisolone, prednisolone phosphate, prednisolone metasulpho-benzoate sodium, prednisolone sodium phosphate, beclomethasone diphosphonate, and beclomethasone valerate; compounds active in the relief of constipation and diarrhea; compounds active in the relief of spasm and in the improvement of motility, e.g.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • Non-5-ASA active agents do not include sodium cromoglycate.
  • Non-5-ASA active agents suitable for use herein are 5-aminosalicylic acid NSAID conjugates described by Moller et al., "Novel 5-Aminosalicylic Acid NSAID Conjugates: Synthesis, Pharmacological and Toxicological Properties," Europ. J. Med. Chem.. Vol. 24, No. 5, pp. 463-69, 1989, hereby incorporated by reference herein.
  • the described conjugates are produced by coupling the NSAID carboxyl-group with the 5-amino-group of 5-ASA.
  • 5-ASA derivatives of the NSAIDs diclofenac, ibuprofen, indomethacin, naproxen, and salicylic acid are particularly described, but conjugates of 5-ASA active ingredients and other NSAIDs are suitable for use as a non-ASA active agent in the method of treatment of the invention herein.
  • NSAIDs as used herein is an abbreviation for the phrase “Non-Steroidal Anti-Inflammatory Drugs” and includes, but is not limited to, alcofenac, antipyrine, aminopyrine, dipyrone, aminopyrone, phenylbutazone, clofezone, oxyphenbutazone, prexazone, apazone, benzydamine, bucolome, cinchophen, clonixin, ditrazol, epirizole, fenoprofen, floctafenine, flufenamic acid, glaphenine, indoprofen, ketoprofen, eclofenamic acid, mefenamic acid, niflumic acid, phenacetin, salidifamides, sulindac, suprofen, and tolmetin, preferably flurbiprofen, ibuprofen, indomethacin, naproxen, piroxicam, salicy
  • the effective oral dose depends on the extent of the disease and for adults it usually amounts to from about 1.0 g to about 6.0 g daily, preferably from about 2.0 g to about 5.0 g daily, most preferably from about 2.4 g to about 4.8 g daily. Generally, for oral administration, it is preferable to divide the total daily dosage into four equal parts, most preferably to be taken immediately before meals and at bedtime. For rectal administration, the daily dose is preferably from about l.Og to about 4.0g. When rectal administration is in the form of a suppository, the most preferred daily dose is about l.Og to about 2.0g, and it is generally preferable to divide the total daily dosage into two parts, one to be administered during the day and the other at bedtime. When the rectal administration is in the form of an enema, the most preferred daily dose is about 4.0g and it is generally preferable to administer the entire daily dosage in the form of a retention-type enema at bedtime.
  • a human or other mammal suffering from IBS-D can be successfully treated by the topical delivery of the 5-ASA active ingredient to the intestinal tract of said human or other mammal, preferably the large intestine.
  • the term "large intestine" as used herein includes that part of the intestine just distal to the small intestine, beginning with the cecum, including the ascending colon, the transverse colon, the descending colon, the sigmoid colon, and the rectum.
  • the preferred method of treatment for IBS-D as defined herein comprises the topical delivery of the 5-ASA active ingredient to the large intestine.
  • Said topical delivery is preferably achieved via a delayed-release oral dosage form prepared utilizing a pH-dependent coating which does not dissolve to release said active ingredient at pH below 7.0, but does dissolve at pH of 7.0 or above.
  • the said preferred method achieves the release of the active ingredient when the pH rises above 7.0, and this, for all practical purposes, results in release in the large intestine, generally beginning in the cecum. This method is preferred because it is believed that, for most IBS-D sufferers for most of the time, the problematic region of the intestinal tract is in the large intestine.
  • the preferred method herein involves the topical delivery of the 5-ASA active ingredient effected by release at a pH of 7.0 or above, generally, for most individuals most of the time, in the large intestine.
  • the term "small intestine” as used herein means the duodenum, the jejunum, and the ileum, i.e., that portion of the intestinal tract just distal to the duodenal sphincter of the fundus of the stomach and proximal to the large intestine.
  • the present invention is directed to a method of treatment for IBS-D utilizing the topical delivery to the intestinal tract of a human or other mammal, preferably to the large intestine, of a safe and effective amount of a pharmaceutical composition consisting essentially of a 5-ASA active ingredient and pharmaceutically-acceptable excipients.
  • a pharmaceutical composition consisting essentially of a 5-ASA active ingredient and pharmaceutically-acceptable excipients.
  • an oral dosage form i.e., either via delayed-release formulations or sustained- release formulations
  • any dosing method of the pharmaceutical composition which achieves topical delivery of the 5-ASA active ingredient to the intestinal tract is suitable for use as the method of treatment for IBS-D described herein.
  • oral dosage forms suitable for use herein may be delayed-release formulations or sustained-release formulations.
  • Topical delivery of the 5-ASA may also be achieved via rectal administration including, but not limited to, enemas and suppositories.
  • the active ingredient compositions can be formulated as tablets, capsules, suppositories or suspensions along with suitable pharmaceutical excipients which are well-known to those skilled in the art are described hereinbelow.
  • pharmaceutical composition means a combination consisting essentially of the 5-ASA active ingredient and pharmaceutically-acceptable excipients.
  • the pharmaceutical composition may additionally contain certain non-5-ASA active agents which will be described in detail hereinbelow.
  • safe and effective amount means an amount of a compound or composition high enough to significantly positively modify the symptoms and/or condition to be treated, but low enough to avoid serious " side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • the safe and effective amount of active ingredient for use in the method of the invention herein will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient being employed, the particular pharmaceutically-acceptable excipients utilized, and like factors within the knowledge and expertise of the attending physician.
  • pharmaceutically-acceptable excipients includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular 5-ASA active ingredient selected for use.
  • Pharma ⁇ ceutically-acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweeten ⁇ ing agents, flavoring agents, pharmaceutical grade dyes or pigments, and viscosity agents.
  • oral dosage form means any pharmaceutical composition intended to be administered to the gastrointestinal tract of an individual via the mouth of said individual, and for purposes of the present invention, the delivered form can be in the form of a tablet, suspension, or a capsule, coated or non-coated.
  • delayed-release refers to a topical delivery of an active ingredient which is effected by formulating the active ingredient in a pharmaceutical composition so that the release will be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no alteration in the delivery of the active ingredient.
  • the preferred method for effecting the delayed-release of the active ingredient involves coating (or otherwise encapsulating) said active ingredient with a substance which is not absorbed, or otherwise broken down, by the intestine to release said active ingredient until a specific desired point in the intestinal tract is reached.
  • the most preferred type of delayed-release formulation for use herein is achieved by coating the active ingredient with a substance which is pH-dependent, i.e., broken down at a pH which is generally present in the large intestine.
  • the selection of the coating material and/or the method of coating or otherwise combining the 5-ASA active ingredient with the selected coating material or other pharmaceutically-acceptable excipients may be varied or altered as is described herein or by any method known to one skilled in the art.
  • sustained-release means the type of release mechanism designed to effect the topical delivery of the active ingredient over an extended period of time, as contrasted to the delivery of a delayed-release type dose.
  • sustained-release type method for use herein involves the coating of granules of the 5-ASA active ingredient with a pH-independent coating and is described in U.S. Patent 4,496,552 to Halskov, incorporated by reference previously herein.
  • Said sustained-release dosage form effects the topical delivery of the 5-ASA active ingredient to both the small intestine and the large intestine.
  • the ultimate site of and/or the rate of topical delivery in the intestinal tract can be satisfactorily controlled by one skilled in the art, by manipulating any one or more of the following: (a) the active ingredient proper;
  • the solubility, acidity, and susceptibility to hydrolysis of the different 5-ASA active ingredient such as acid addition salts, salts formed with the carboxylic group, e.g., alkali metal salts, alkaline earth metal salts, etc., and esters, e.g., alkyl, alkenyl, aryl, aralkyl, may be used as guidelines for the proper choice.
  • suitable pH-conditions might be established within the coated particles by adding a suitable buffer to the active ingredient in accordance with the desired release pattern.
  • the excipients may also be varied, as long as they do not affect the activity of the particular 5-ASA active ingredient selected.
  • pharmaceutically-acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, solvents, cosolvents, surfactants, preservatives, sweetener agents, flavoring agents, buffer systems, pharmaceutical-grade dyes or pigments, and viscosity agents.
  • the preferred solvent is water.
  • Flavoring agents among those useful herein include those described in Remington's Pharmaceutical Sciences. 18th Edition, Mack Publishing Company, 1990, pp. 1288-1300, incorporated by reference herein.
  • Dyes or pigments among those useful herein include those described in Handbook of Pharmaceutical Excipients. pp. 81-90, 1986 by the American Pharmaceutical Association & the Pharmaceutical Society of Great Britain, incorporated by reference herein.
  • Preferred co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycol.
  • Preferred buffer systems include, but are not limited to, potassium acetate, boric, carbonic, phosphoric, succinic, malic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric and glutamic. Particularly preferred are phosphoric, tartaric, citric, and potassium acetate.
  • Preferred surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrose monoesters and lanolin esters and ethers.
  • Preferred preservatives include, but are not limited to, phenol, alkyl esters of parahydroxybenzoic acid, o-phenyl phenol benzoic acid and the salts thereof, boric acid and the salts thereof, sorbic acid and the salts thereof, chlorbutanol, benzyl alcohol, thimerosal, phenyl ercuric acetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, and propyl paraben. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methyl paraben and propyl paraben.
  • Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, and aspartame. Particularly preferred are sucrose and saccharin.
  • Preferred viscosity agents include, but are not limited to, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl- methylcellulose, carbomer, povidone, acacia, guar gum, xanthan gum and tragacanth. Particularly preferred are methylcellulose, carbomer, xanthan gum, guar gum, povidone and sodium car ⁇ boxymethyleel1ulose.
  • Preferred fillers include, but are not limited to, lactose and microcrystalline cellulose.
  • Preferred plasticizers include, but are not limited to, polyethylene glycol, propylene glycol, dibutyl phthalate, and castor oil.
  • Preferred polymers include, but are not limited to, ethylcellulose and Eudragit S ® 100 and Eudragit L ® 100, both manufactured by Rohm Pharma GmbH, Weiderstadt, West Germany.
  • Preferred lubricants include, but are not limited to, magnesium stearate, stearic acid, and talc. 1. Oral Administration of 5-ASA Pharmaceutical Compositions
  • the 5-ASA active ingredient can be reliably topically delivered, specifically to the entire intestinal tract, or any part thereof, preferably the large intestine, thereby substantially alleviating the symptoms of IBS-D.
  • an oral dosage form is preferred.
  • the most preferred oral dosage form is one which effects topical delivery to the large intestine and is prepared by coating a solid oral dosage form with a partly methyl esterified methacrylic acid polymer, utilizing the method described in U.K. Patent Application GB 2,123,695 of Rhodes et al., published February 8, 1984, assigned to J.B. Tillott, Ltd. hereby incorporated by reference herein.
  • any coating which is insoluble at a pH below 7.0 (i.e., that generally found in the stomach and the small intestine) but soluble at pH 7.0 or above (i.e., that present in the large intestine) can be used in the practice of the present invention. Accordingly, when it is desired to effect the topical delivery of the 5-ASA active ingredient to the large intestine, any coating which is wholly- or partially-insoluble at a pH below 7.0 and soluble at pH 7.0 or above is suitable.
  • the partly methyl esterified methacrylic acid polymer which is preferred for use as the coating must be applied to said solid oral dosage form in a sufficient thickness so that the entire coating does not dissolve in gastrointestinal fluids at a pH below 7.0, but does dissolve at a pH of 7.0 or above.
  • the dissolution or disintegration of the excipient coating generally does not occur until the entry of the coated dosage form into the. large intestine. In particular, there is substantially no release of the 5-ASA active ingredient upstream of the colon.
  • the most preferred system for use herein when topical delivery of the 5-ASA active ingredient to the large intestine is desired involves the coating of the solid oral dosage form itself and not the coating of individual particles or granules contained therein; hence, the preferred coated dosage form is relatively inexpensive and easy to manufacture. It must be remembered, however, that any method of coating said active ingredient composition which effects the topical delivery of the active ingredient to a desired portion of the intestinal tract is suitable for use in the method of treatment described herein; therefore, an alternative and suitable method is that described in U.S. Patent 4,496,553 to Halskov, previously incorporated by reference herein.
  • any anionic polymer exhibiting the requisite pH-dependent solubility profile can be used in the practice of the present invention to achieve topical delivery of the 5-ASA active ingredient to the large intestine.
  • the coating chosen must be compatible with the particular 5-ASA active ingredient selected.
  • the preferred polymers for use in the present invention are anionic carboxylic polymers. It is particularly preferred that the polymers are acrylic polymers, most preferably partly methyl-esterified methacrylic acid polymers, in which the ratio of anionic free carboxyl groups to ester groups is about 1 to 2.
  • a particularly suitable methacrylic acid copolymer is Eudragit S ® , manufactured by Rohm Pharma GmbH, Rothstadt, West Germany. In Eudragit S ® , the ratio of free carboxyl groups to ester groups is approximately 1:2. Further, said copolymer is known to be insoluble in gastrointestinal fluids having a pH below 5.5, generally 1.5-5.5, i.e., that generally present in gastric fluid, and poorly soluble at pH above 5.5 and below 7.0, i.e., that generally present in the fluid of the small intestine. Said copolymer is soluble at pH 7.0 and above, i.e., that generally present in the colon.
  • Eudragit L ® Another methacrylic acid copolymer which is suitable for use in coating oral dosage forms which can be employed in the method of treatment described herein, either alone or in combination with other coatings, is Eudragit L ® , manufactured by Rohm Pharma GmbH, Rothstadt, West Germany. Eudragit L ® differs from Eudragit S ® only insofar as the ratio of free carboxyl groups to ester groups is approximately 1:1. Eudragit L ® is also, like Eudragit S ® , insoluble at pH below 5.5, generally 1.5-5.5, such as that present in gastric juice, but, unlike Eudragit S ® , is readily soluble in gastrointestinal fluids having a pH of 5.5 and above, such as that present in small intestinal juice.
  • Eudragit L ® can be used alone as a coating which would provide topical delivery of the 5-ASA active ingredient beginning at the small intestine (more proximal than the terminal ileum) via a delayed-release mechanism.
  • Eudragit L ® being readily soluble in intestinal juice below pH 7.0, could be used in combination with Eudragit S ® , soluble in intestinal juice above pH 7.0, in order to effect a delayed-release composition which could be formulated to topically deliver the active ingredient at various segments of the intestinal tract; the more Eudragit L ® used, the more proximal release and delivery begins and the more Eudragit S ® used, the more distal release and delivery begins.
  • Example VIII For an Example showing the use of Eudragit L ® alone as a coating material, see Example VIII.
  • the coating can, and usually will, contain a plasticiser and possibly other coating excipients such as coloring agents, talc, and/or magnesium stearate, many of which are well known in the coating art.
  • a plasticiser usually will contain 10-25% by weight of a plasticiser, especially dibutyl phthalate.
  • Conventional coating techniques such as spray or pan coating are employed to apply the coating.
  • the coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.
  • a coating thickness of between 40 and 150 microns usually is required.
  • the coating thickness is between 60 and 130 microns, and most preferably between 70 and 100 microns.
  • a method suitable for use in coating a solid oral dosage form of a 5-ASA active ingredient which will effect the topical delivery of said active ingredient to the large intestine see Examples I-IV hereinbelow.
  • Another delayed-release type of oral dosage form suitable for achieving topical delivery of the 5-ASA active ingredient to the large intestine involves the use of a material, most preferably a resin, the dissolution of which is time-dependent, as opposed to the previously-mentioned methacrylic acid copolymer-type coatings which are pH-dependent.
  • the topical delivery of said active ingredient to the large intestine is accomplished by embedding individual particles of said active ingredient in a slowly-disintegrating or slowly-dissolving resin which has a particular dissolution profile such that the active ingredient remains substantially protected by the material while the particles travel through the stomach and the small intestine of an individual and that the active ingredient is substantially completely exposed at the time the particles reach the large intestine.
  • the preferred resin for use when employing this type of excipient material is a high-viscosity grade modified vinyl acetate resin such as Gelva C3-V30 ® , manufactured by The Monsanto Co., St. Louis, Missouri.
  • suitable resins are carboxylated polyvinyl acetates, polyvinyl/maleic anhydride copolymers, ethylcellulose, cellulose polymers, methylacrylic acid/methyl methylacrylate copolymers, waxes, and mixtures thereof, including mixtures with shellac.
  • the method of treatment preferably embodies the use of a coated delayed-release tablet containing 5-ASA
  • other methods used to insure the topical delivery of the active ingredient to the intestinal tract can certainly be used in the treatment of IBS-D.
  • U.S. Patent 4,496,553 to Halskov previously incorporated by reference herein, describes a method which involves formulating 5-ASA in a sustained-release tablet and specifies ethylcellulose as the preferred coating material.
  • it is granules of the 5-ASA active ingredient which are coated in the method described by Halskov.
  • Said oral dosage form is characterized by a core comprising the 5-ASA active ingredient, freferably in the form of a weak base or a weak acid, upon which core there is provided a first, inner layer of a diffusion membrane comprised of ethylcellulose and/or copolymers of polyethyl acrylate, methyl methacrylate, trimethylammonium ethyl methacrylate chloride, or mixtures thereof. Further, on said inner layer there is provided a second layer of an excipient material, preferably of anionic polymers, fatty acids, or mixtures thereof, having a pk a of about 4.5 to about 7.0, preferably about 6.0 to about 6.5.
  • Rectal administration may be in the form of suppositories or enemas, or can be effected by the delivery of the 5-ASA ingredient to the large intestine via the application of a suspension, solution, emulsion, creme or the like through a tube inserted into the rectum.
  • One method of achieving the topical delivery of the 5-ASA active ingredient via rectal administration is an enema form comprised of a bisulfite suspension containing a 5-ASA active ingredient.
  • a preferred enema suspension is that described in U.S. Patent 4,657,900 to Powell et al., issued April 14, 1987, and assigned to Rowell Laboratories, Baudette, Minnesota, hereby incorporated by reference herein.
  • the aqueous suspension of the 5-ASA active ingredient is preferably rendered storage stable against color formation by storing the suspension in a single-dose polyethylene bottle, which is specifically adapted for the rectal administration of the suspension.
  • the said suspension is stored in a substantially oxygen-free atmosphere and contains up to about 0.25% by weight of bisulfite.
  • the suspension is protected from exposure to atmospheric oxygen during storage by sealing the plastic bottle, in a substantially oxygen-free atmosphere, in a plastic pouch having a low oxygen transmission rate.
  • a chelating agent such as ethylenediaminetetraacetic acid (hereinafter referred to as "EDTA").
  • the bisulfite and the EDTA can be supplied in any convenient form, e.g., as a soluble salt thereof, such as an alkali metal salt, and can be dissolved in the water used to form the 5-ASA active ingredient solutions prior to, preferably concurrently with, or less.desirably after, dissolving the 5-ASA active ingredient therein.
  • the 5-ASA active ingredient suspension suitable for us& as an enema in the method of treatment described herein should preferably also contain a conventional bacteriostatic agent, for example sodium benzoate, to ensure against bacterial contamination.
  • Other desired pharmaceutically-acceptable excipients and non-5-ASA active agents as described herein may also be utilized.
  • preferable enema suspensions see Examples XIV-XVI.
  • a suppository containing the 5-ASA active ingredient is suitable as a method to effect the topical delivery of 5-ASA active ingredient to the large intestine, thereby serving as a method of treatment for IBS-D.
  • One type of suppository suitable for use in the present invention is described in U.S. Patent 3,932,613 to Chapura, issued January 13, 1976, assigned to Norwich Eaton Pharmaceuticals, Inc., hereby incorporated by reference herein.
  • a suitable suppository formulation for use herein as a treatment for IBS-D see Example XIV.
  • Example I The following non-limiting Examples are provided to further illustrate the methods and compositions of the present invention.
  • Example I The following non-limiting Examples are provided to further illustrate the methods and compositions of the present invention.
  • a coating composition is prepared in the form of a lacquer containing the following excipients, per tablet:
  • a coating of 5.6w/w% dried lacquer substance (i.e., about 70 microns thick) is applied by spraying the above composition onto 400mg 5-ASA caplet-shaped tablets, each weighing 507.6mg and each containing:
  • a patient suffering from IBS-D is given eight 5-ASA tablets utilizing the same dosing regimen as described in Example I.
  • 5-ASA tablets are prepared as described in Example I, except that the active ingredients of the caplet-shaped tablet are, instead of 400mg of 5-ASA, 300mg of 5-ASA and lOOmg of indomethacin.
  • Example III A patient suffering from IBS-D is given eight 5-ASA tablets utilizing the same dosing regimen as described in Example I.
  • the 5-ASA tablets are prepared as described in Example I, except that the active ingredients of the caplet-shaped tablet are, instead of 400mg 5-ASA, 200mg naproxen and 200mg 5-ASA.
  • Example IV the active ingredients of the caplet-shaped tablet are, instead of 400mg 5-ASA, 200mg naproxen and 200mg 5-ASA.
  • a patient suffering from IBS-D is given eight 5-ASA tablets utilizing the same dosing regimen as described in Example I.
  • 5-ASA tablets are prepared as described in Example I, except the active ingredients of the caplet-shaped tablet are, instead of 400mg 5-ASA, 300mg tebufelone and lOO g 5-ASA.
  • a patient suffering from IBS-D is given eight 5-ASA tablets,
  • 5-ASA tablets are prepared so that they achieve topical delivery of 5-ASA to both the small intestine and the large intestine.
  • the tablets are prepared as described below:
  • 5-ASA granules 250g of 5-ASA are granulated to a particle size of from 0.7-lmm with 25g of polyvinylpyrrolidone dissolved in isopropanol (1:9W/W). Upon evaporation of the isopropanol, the resulting dry granulate is sprayed with 45g of ethylcellulose dissolved in acetone (3:97W/W) resulting in granulate particles individually coated with ethylcellulose upon evaporation of the acetone.
  • 270g of microcrystalline cellulose and 60g of potato starch are granulated with about 33g of the above polyvinylpyrrolidone solution to the same particle size.
  • the resulting 320g of the 5-ASA coated granules prepared in Part A. hereinabove is mixed with a lubricant mixture consisting of 3g zinc stearate and 27g talc and with the filler granulate prepared in Part B. hereinabove to form 650g of total granulate. Said total granulate is pressed to form tablets with a diameter of 13.5mm and a weight of 650 mg/tablet, each containing 250mg of 5-ASA.
  • a patient suffering from IBS-D is given eight tablets at intervals described in Example V.
  • the tablets are prepared according to the method set forth in Example V herein except that acetone is used instead of isopropanol in the polyvinyl- pyrrolidone solution in Parts A. and B.
  • Example V A patient suffering from IBS-D is given eight tablets at intervals described in Example V.
  • the tablets are prepared according to the method set forth in Example V, except that the ethylcellulose in Part A. is replaced with hydroxypropylmethyl- cellulose.
  • Exa ple VIII Exa ple VIII
  • a patient suffering from IBS-D is given four 5-ASA tablets prepared as described below, one immediately preceding each meal and at bedtime.
  • the tablets are prepared so that they achieve the topical delivery of 5-ASA to the small intestine is described below.
  • a coating composition is prepared from a lacquer containing the following excipients, per tablet:
  • a coating weight of 5.0w/w% dried lacquer substance (about 75 microns thick) is applied by conventional pan coating to 600mg 5-ASA tablets, so that oval-shaped tablets, each weighing 800mg, result.
  • the composition of each tablet is as follows:
  • Example IX A patient suffering from IBS-D is given 5-ASA tablets at intervals described in Example VIII.
  • the tablets are prepared as described in Example VIII, except that the active ingredients of the caplet-shaped tablet are, instead of 600mg 5-ASA, 400mg 5-ASA and 200mg indomethacin.
  • Example X A patient suffering from IBS-D is given 5-ASA tablets at intervals described in Example VIII. The tablets are prepared as described in Example VIII, except that the active ingredients of the caplet-shaped tablet are, instead of 600mg 5-ASA, 300mg naproxen and 300mg 5-ASA.
  • Example XI the active ingredients of the caplet-shaped tablet are, instead of 600mg 5-ASA, 300mg naproxen and 300mg 5-ASA.
  • a patient suffering from IBS-D is given 5-ASA tablets at intervals described in Example VIII.
  • the tablets are prepared as described in Example VIII, except that the active ingredients of the caplet-shaped tablet are, instead of 600mg 5-ASA, 400mg tebufelone and 200mg 5-ASA.
  • Example XII A patient suffering from IBS-D is given 12 of the 250mg 5-ASA tablets, 3 immediately before each meal and at bedtime.
  • 5-ASA tablets prepared as described below are suitable for effecting the topical delivery of 5-ASA to the intestinal tract.
  • Granulated 5-ASA active ingredient having a granular size of 0.6mm to 1.5mm and comprising 60% of active ingredient are provided with a diffusion membrane as follows:
  • 5-ASA active ingredient granules are sprayed with a solution of 50% by weight of ethylcellulose and 50% by weight of polyethyl acrylate- ethyl methacrylate:trimethylammonium ethyl methacrylate:trimethylammonium ethyl methacrylate chloride copolymer with the weight % 65:32.5:2.5 (Eudragit RL ® , manufactured by Rohm Pharma GmbH, Weiderstadt, West Germany) dissolved in methylene chloride/isopropanol in a fluidized bed. The concentration of polymer in the solvent mixture is 4% by weight.
  • the 5-ASA granules (equivalent to 250mg 5-ASA active ingredient) covered with a diffusion membrane are covered with an outer layer of hydroxypropylcellulose phthalate dissolved in methylene chloride/ethanol mixture, utilizing the same technique described above for the diffusion membrane.
  • the inner diffusion membrane is applied in an amount of 12g/m2 and the outer layer of anionic polymer is applied in an amount of 16g/m2.
  • Examples XIII A patient suffering from IBS-D is administered a suppository prepared as described below, twice daily, for a period of 3-6 weeks.
  • the suppository containing 5-ASA is prepared containing the following ingredients:
  • the suppository is prepared utilizing the following method:
  • the theobroma oil and the white wax are melted in a suitable vessel with gentle heat (approximately 40 ⁇ -60 ⁇ C) to form a melted excipient base.
  • the 5-ASA is combined with said base until uniformly dispersed.
  • the melted base containing the 5-ASA is poured into a chilled mold that is lightly lubricated with mineral oil.
  • the mold is then subjected to cold temperatures (ideally, below freezing) until the melted base solidifies.
  • the formed suppository is then removed from the mold and is then wrapped in aluminum foil.
  • the patient should retain each suppository in the rectum for 1-3 hours, or longer, if possible. At the conclusion of that therapy, the patient has no abdominal pain and is experiencing normal and regular bowel movements.
  • Examole XIV A patient suffering from IBS-D is administered the enema prepared as described above, once daily for 3-6 weeks, at bedtime.
  • the enema is prepared as a 5-ASA suspension having the following composition:
  • the 5-ASA suspension is prepared as described below: A. Purification of 5-ASA lOOg of 95% 5-ASA (technical grade) is dissolved in 2,000ml of 2N HCl (AR grade) while heating to 60'C-80*C to facilitate rate of solution. The hot solution is filtered through a suitable acid stable filtering medium (analytical filter paper) to remove any undissolved material. 20g of decolorizing activated charcoal (e.g. Darco G-60) is added to the tan colored hot filtrate and mixed for approximately 5 minutes while the temperature of the solution is maintained at about 60'C. The solution is once again filtered through the filtering medium as described above and the filtrate is cooled to 15 * C-20 * C.
  • a suitable acid stable filtering medium analytical filter paper
  • the pH of the filtrate is raised to about 3.5-4.0 with approximately 560ml of high purity 28.6% (7.14N) NaOH.
  • the 5-ASA begins to precipitate.
  • the precipitated 5-ASA is collected by vacuum filtration.
  • the mother liquor is retained and washed with U.S.P. water until the rinse is free of sodium and chloride.
  • the mother liquor is then washed twice each time with 200ml of anhydrous ethanol (SDA-JA).
  • SDA-JA anhydrous ethanol
  • the suspension prepared in part B. above is poured into a commercially available 60ml capacity single-dose collapsible white opaque low-density polyethylene bottles with snapping necks. Nitrogen gas is flushed into the bottles to displace head space air and each is capped with a special snap-on lubricated rectal applicator covered with a press fitted removable protec ⁇ tive plastic cap.
  • An oxygen barrier is provided in the bottles filled as described above by inserting each of the bottles into a polyester/aluminum foil/polyethylene laminate heat sealable 6-1/2" x 8" plastic pouch (Kapak Corporation, St. Louis Park, MN) and flushing each pouch with nitrogen and immediately heat sealing each pouch.
  • a patient suffering from IBS-D is administered the enema prepared as described above once daily for 3-6 weeks and at the conclusion of such therapy, is free of abdominal pain and is experiencing normal and regular bowel movements.
  • Example XV A patient suffering from IBS-D is administered the enema prepared as described above once daily for 3-6 weeks and at the conclusion of such therapy, is free of abdominal pain and is experiencing normal and regular bowel movements.
  • An enema suspension suitable for use in the treatment of IBS-D is prepared as described in Example XIV, except that Step A., the purification of the 5-ASA, is conducted as described below: 1810g of USP water is charged into a 4 liter beaker and 196g sulfuric acid (RR) is slowly added to the water while stirring. lOOg (pure beads) of technical grade (about 90-95% purity) 5-ASA is slowly added and dissolved. The temperature of the resulting solution is maintained at 60 * C-80 * C. 20g activated charcoal is added to the solution and the solution is stirred for 5-30 minutes. The temperature is maintained at 60'C-80 * C while the charcoal suspension is filtered through analytical filter paper. The filtrate is cooled to O'C-5'C.
  • 0.5g sodium bisulfite USP is added to the suspension.
  • 160g sodium hydroxide USP is dissolved in 400g water USP and the solution is cooled to 0.5'C.
  • the cooled solution is next slowly added to the 5-ASA solution while stirring to about pH 3.5, using a pH meter. Additional IN sodium hydroxide may be utilized to properly adjust the pH if needed.
  • the resultant 5-ASA slurry is cooled to 0 * C-5 * C and the 5-ASA crystals are separated from the slurry using a Buchner funnel and vacuum pump.
  • the filtrate is discarded and the crystal bed is rinsed with USP water at 2'C-5 * C until the rinse is free of sulfate and sodium ions.
  • a vacuum is used to remove water from the crystal bed.
  • the crystal bed is rinsed with 300g alcohol S0A-3A.
  • a vacuum is used to remove alcohol from the crystals. After the crystals are trayed out, they are dried at 75 * C-90'C for 6-8 hours.
  • Example XVI An enema suspension suitable for use in the treatment of IBS-D is prepared as described in Example XIV above, except that the stable aqueous 5-ASA suspension is made utilizing the same procedure and the same excipients as set forth in Part B. therein, except that the amounts of the excipients used are as set forth below:
  • a 63-year-old Caucasian male presents with moderate to severe abdominal pain and frequent and severe diarrhea.
  • the patient is diagnosed as having IBS-D by the exclusion of organic pathology.
  • the patient is treated with a total daily drug dose of 4.8g 5-ASA via the ingestion of 12 tablets, 3 immediately preceding each meal and at bedtime, prepared as described in Example I.
  • Examole XVIII A 57-year-old Caucasian female presents with frequent diarrhea and generally moderate abdominal pain which intensifies shortly before she experiences the diarrhea.
  • the patient is diagnosed as having IBS-D by the exclusion of organic pathology.
  • the patient is treated with a total daily dose of 3.2g of 5-ASA via the ingestion of 8 tablets, 2 immediately preceding each meal and at bedtime, prepared as described in Example I.
  • Example XIX A 34-year-old Caucasian male presents with alternating moderate diarrhea and mild constipation and constant mild abdominal pain.
  • the patient is diagnosed as having IBS-D by the exclusion of organic pathology.
  • the patient is treated with a total daily dose of 2.4 grams of 5-ASA via the ingestion of 6 tablets, 2 immediately preceding each meal, prepared as described in Example I. After 4 weeks of the above-described therapy, the patient has substantially no abdominal pain and has normal and regular bowel movements.
  • Example XX A 50-year-old Caucasian female presents with frequent diarrhea accompanied by moderate to severe abdominal cramping.
  • the patient is diagnosed as having IBS-D by the exclusion of organic pathology.
  • the patient is treated with 2.4 grams of 5-ASA via the ingestion of 6 tablets, 2 immediately before each meal, prepared as described in Example I. After 4 weeks of the above-described therapy, the patient has substantially no abdominal cramping and is experiencing normal and regular bowel movements.
  • Example XXI A 68-year-old Caucasian male presents with painless but frequent diarrhea.
  • the patient is diagnosed as having IBS-D by the exclusion of organic pathology.
  • the patient is treated with a total daily dose of 1.6g of 5-ASA via the ingestion of 4 tablets, one immediately preceding each meal and at bedtime, prepared as described in Example I. After 2 weeks of the above-specified therapy, the patient is experiencing normal and regular bowel movements.

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Abstract

L'invention se rapporte à un procédé permettant de traiter une personne ou tout autre mammifère souffrant de colopathie fonctionnelle en phase diarrhéique et qui consiste à procéder à l'administration topique par l'intestin, de préférence le gros intestin, d'une quantité sûre et efficace d'une composition pharmaceutique constituée essentiellement par l'ingrédient actif 5-ASA et par des excipients pharmaceutiquement acceptables. Cette administration topique est de préférence obtenue par l'ingestion par la personne ou le mammifère d'une composition à libération retardée constituée essentiellement par l'ingrédient actif 5-ASA et par un excipient pharmaceutiquement acceptable.
PCT/US1992/001848 1991-03-15 1992-03-05 Utilisation de l'acide 5-aminosalicylique dans le traitement de la phase diarrheique de la colopathie fonctionnelle WO1992016206A1 (fr)

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WO2006102446A2 (fr) * 2005-03-21 2006-09-28 Sandoz Ag Composition multiparticulaire a liberation modifiee
WO2009047802A2 (fr) * 2007-10-10 2009-04-16 Lupin Limited Nouvelle formulation bioadhésive à libération modifiée d'acide 5-aminosalicylique ou de ses sels et de ses métabolites destinée au traitement du colon
US20120094963A1 (en) * 2008-12-23 2012-04-19 of Queen Elizabeth near Dublin Targeting prodrugs and compositions for the treatment of gastrointestinal diseases
US8337886B2 (en) 1997-07-30 2012-12-25 Dr. Falk Pharma Gmbh Pellet formulation for the treatment of the intestinal tract
US8865688B2 (en) 2008-10-03 2014-10-21 Dr. Falk Pharma Gmbh Compositions and methods for treatment of bowel diseases with granulated mesalamine
EP2614045B1 (fr) 2010-09-10 2015-11-18 Pharmazell GmbH Procédé de production d'acide 5-aminosalicylique cristallin
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US8337886B2 (en) 1997-07-30 2012-12-25 Dr. Falk Pharma Gmbh Pellet formulation for the treatment of the intestinal tract
US8956647B2 (en) 1997-07-30 2015-02-17 Dr. Falk Pharma Gmbh Pellet formulation for the treatment of the intestinal tract
US8940328B2 (en) 1997-07-30 2015-01-27 Dr. Falk Pharma Gmbh Pellet formulation for the treatment of the intestinal tract
US8911778B2 (en) 1997-07-30 2014-12-16 Dr. Falk Pharma Gmbh Pellet formulation for the treatment of the intestinal tract
US8496965B2 (en) 1997-07-30 2013-07-30 Dr. Falk Pharma Gmbh Pellet formulation for the treatment of the intenstinal tract
WO2000006132A3 (fr) * 1998-07-28 2000-04-27 Chiesi Farma Spa Formulations pharmaceutiques servant a traiter la maladie intestinale inflammatoire
WO2000006132A2 (fr) * 1998-07-28 2000-02-10 Chiesi Farmaceutici S.P.A. Formulations pharmaceutiques servant a traiter la maladie intestinale inflammatoire
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AU1577092A (en) 1992-10-21
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