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WO2017011430A1 - Compositions et procédés de nettoyage du côlon - Google Patents

Compositions et procédés de nettoyage du côlon Download PDF

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Publication number
WO2017011430A1
WO2017011430A1 PCT/US2016/041841 US2016041841W WO2017011430A1 WO 2017011430 A1 WO2017011430 A1 WO 2017011430A1 US 2016041841 W US2016041841 W US 2016041841W WO 2017011430 A1 WO2017011430 A1 WO 2017011430A1
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Prior art keywords
effective amount
patient
range
sodium phosphate
psyllium
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PCT/US2016/041841
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George M. Halow
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/77—Polymers containing oxygen of oxiranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/68—Plantaginaceae (Plantain Family)

Definitions

  • the invention pertains to the field of medicine. More particularly, the invention pertains to compositions and methods for rapid bowel cleansing which are particularly useful for preparing the bowel prior to surgery or diagnostic procedures such as colonoscopies.
  • Gastrointestinal agents for regulating bowel movement are conveniently placed into two categories: laxatives and bowel cleansers.
  • Laxatives are formulated for long term use, with the intention of eliminating constipation and obtaining a regular bowel function.
  • Many laxatives work by stimulating bowel motility (peristalsis) in various ways, as by distending the gut with bulking or osmotic agents, or by directly stimulating the bowel nerves or muscles with stimulant laxatives.
  • Other laxatives function as stool softeners or lubricants.
  • the various types of laxatives are often combined in attempts to maximize efficacy or to reduce side effects of the agents.
  • Bowel cleansers also called purgatives, cathartics, and lavages, are formulated for rapid emptying of the bowel and are intended for short-term use only. They are commonly used as "bowel preps" for emptying the bowel prior to surgery, childbirth, or diagnostic procedures and usually include an osmotic or stimulant laxative administered by either the oral route or the anal route. While purgatives formulated for patient use as enemas are often prescribed before examinations, they are awkward to handle and are frequently not properly administered, so orally-administered preparations are generally preferred.
  • compositions for rapid bowel cleansing in common use have disadvantages which discourage patient compliance.
  • the most commonly prescribed oral bowel preps today for bowel examination include sodium phosphate compositions in varying proportions of mono-and dibasic species and polyethylene glycol (PEG) in combination with electrolytes.
  • Sodium phosphate is a saline osmotic laxative, sold, for example, under the trademark Fleet Phospho-Soda® (C.B. Fleet Co., Lynchburg, VA), which contains both monobasic and dibasic uncoated sodium phosphate powders. It is also sold under the trademark Visicol® as monobasic and dibasic sodium phosphates in tablet form.
  • This laxative when formulated and used as a bowel cleanser, is associated with nausea, vomiting, and symptoms of electrolyte imbalance; the product also has an unpleasant taste. As a result, patient compliance is difficult to obtain, particularly when the cleanser is supplemented with, for example, another saline agent such as a magnesium salt, or a bowel stimulant such as bisacodyl.
  • PEG is known for its successful use as a long-term osmotic laxative in combination with dietary fiber (as described in U.S. Pat. No. 5,710,183, issued January 20, 1998 to Halow, and incorporated herein by reference)
  • PEG purgatives such as those sold under the trademark Colyte® (Braintree Laboratories, Braintree, MA)
  • Colyte® Braintree Laboratories, Braintree, MA
  • these purgatives normally include electrolytes to counterbalance electrolyte loss during treatment, symptoms of electrolyte imbalance are, notwithstanding, often experienced by the patient.
  • Methods and kits aid in preparing a patient for a colon procedure.
  • an effective amount of sodium phosphate, an effective amount of polyethylene glycol, an effective amount of bisacodyl, and an effective amount of psyllium are administered to the patient during a 24-hour period just prior to the colon procedure to provide a bowel cleansing of the patient for the colon procedure.
  • a kit includes an effective amount of sodium phosphate, an effective amount of polyethylene glycol, an effective amount of bisacodyl, and an effective amount of psyllium.
  • the methods and kits may optionally include lubiprostone, linaclotide, and/or naloxegol for administration to the patient to provide a more thorough bowel cleansing.
  • a method of preparing a patient for a colon procedure includes administering, to the patient during a 24-hour period just prior to the colon procedure, an effective amount of sodium phosphate, an effective amount of polyethylene glycol, an effective amount of bisacodyl, an effective amount of psyllium and an effective amount of lubiprostone to provide a bowel cleansing of the patient for the colon procedure.
  • a method of preparing a patient for a colon procedure includes administering, to the patient during a 24-hour period just prior to the colon procedure, an effective amount of sodium phosphate, an effective amount of polyethylene glycol, an effective amount of bisacodyl, an effective amount of psyllium and an effective amount of linaclotide to provide a bowel cleansing of the patient for the colon procedure.
  • a method of preparing a patient for a colon procedure includes administering to the patient during a 24-hour period just prior to the colon procedure, an effective amount of naloxegol and, after administering the effective amount of naloxegol, administering an effective amount of sodium phosphate, an effective amount of polyethylene glycol, an effective amount of bisacodyl, and an effective amount of psyllium to provide a bowel cleansing of the patient for the colon procedure.
  • a method of preparing a patient for a colon procedure includes administering to the patient during a 24-hour period just prior to the colon procedure, an effective amount of sodium phosphate, an effective amount of polyethylene glycol, an effective amount of bisacodyl, and an effective amount of psyllium to provide a bowel cleansing of the patient for the colon procedure; and administering to the patient a low-residue meal after administering at least one dose of the effective amount of sodium phosphate, the effective amount of polyethylene glycol, the effective amount of bisacodyl, and the effective amount of psyllium, but prior to the colon procedure.
  • a method of preparing a patient for a colon procedure includes administering to the patient during a 24-hour period just prior to the colon procedure, an effective amount of sodium phosphate, an effective amount of polyethylene glycol, an effective amount of bisacodyl, and an effective amount of psyllium, and flushing a lining of the bowel with carbonated water.
  • a method of preparing a child or adolescent patient between 8 and 18 years of age for a colon procedure includes administering to the patient during a 24-hour period just prior to the colon procedure about 2 to 7.5 grams of sodium phosphate, about 1.2 to 1.8 grams of polyethylene glycol per kilogram of weight of the patient, about 5 to 15 mg of bisacodyl, and about 1.5 to 4 grams of psyllium to provide a bowel cleansing of the patient for the colon procedure.
  • a kit for cleansing a bowel of a renal patient for a colon procedure includes an effective amount of magnesium citrate (1:1), an effective amount of polyethylene glycol, an effective amount of bisacodyl, and an effective amount of psyllium, where administration of the effective amount of sodium phosphate, the effective amount of polyethylene glycol, the effective amount of bisacodyl, and the effective amount of psyllium to the patient during a 24-hour period provides a bowel cleansing of the renal patient.
  • a method of preparing a renal patient for a colon procedure includes administering to the patient during a 24-hour period just prior to the colon procedure, an effective amount of magnesium citrate (1:1), an effective amount of polyethylene glycol, an effective amount of bisacodyl, and an effective amount of psyllium to provide a bowel cleansing of the patient for the colon procedure.
  • a kit for cleansing a bowel of a patient for a colon procedure includes an effective amount of sodium phosphate, an effective amount of polyethylene glycol, an effective amount of bisacodyl, an effective amount of psyllium, and at least one additional component selected from the group consisting of an effective amount of lubiprostone, an effective amount of linaclotide, and an effective amount of naloxegol.
  • Administration of the effective amount of sodium phosphate, the effective amount of polyethylene glycol, the effective amount of bisacodyl, the effective amount of psyllium and the at least one additional component provides a bowel cleansing of the patient.
  • Administration of an effective amount of sodium phosphate, an effective amount of polyethylene glycol, an effective amount of bisacodyl, and an effective amount of psyllium to a patient during a 24-hour period prior to a colon procedure preferably provides a bowel cleansing of the patient for the colon procedure.
  • lubiprostone or linaclotide are also administered to the patient prior to the colon procedure.
  • the compositions described herein stimulate the small bowel and the small bowel helps flush the colon without irritating the bowel. This results in a better, less irritating bowel cleansing than prior art compositions.
  • any food-grade or pharmaceutical-grade PEG may be used in a bowel cleansing composition.
  • polymers having molecular weights above about 900, which are solid at room temperature and soluble in or miscible with water, are preferred.
  • Polymers having average molecular weights between about 3000 and 8000 are exemplary; PEG 4000, which is nearly odorless and tasteless and widely available in "pharmaceutical grade'VUnited States Pharmacopeia (USP) grade, or PEG 3350, are very suitable.
  • Other suitable PEG powders are commercially available, as from the Spectrum Chemical Mfg. Company, Gardena, CA.
  • Non-powdered PEG is preferably comminuted to a particle size that is readily soluble in water before use.
  • the bowel cleansing composition preferably includes a sodium phosphate powder in the form of a pharmaceutical USP grade free flowing powder of anhydrous dibasic sodium phosphate (Na 2 HP0 4 , disodium phosphate), optionally in combination with monobasic sodium phosphate monohydrate (NaH 2 P0 4 -H 2 0, monosodium phosphate), or anhydrous, such as conventionally used in saline laxatives, for example, the powders described in the Fleet Phospho-Soda® laxative composition discussed above.
  • the phosphate powder provides a bowel cleansing composition with a saline osmotic effect, which complements the effect of the PEG component and is used in amounts which provide the desired osmolarity for this purpose.
  • the phosphate and PEG powders are preferably dissolved by mixing into an aqueous carrier, which may be any appropriate predetermined desired aqueous carrier, such as water or juice.
  • a dry preparation bowel cleansing composition contains about 60 to 80% by weight PEG and 20 to 40% by weight of phosphate component.
  • phosphate component refers to either disodium phosphate alone, or disodium phosphate in combination with monosodium phosphate.
  • the amount of PEG in a bowel cleansing composition is about 70 to 80% by weight, and 20 to 30% by weight sodium phosphate, based on the total amount of PEG and phosphate; the combined PEG and phosphate should make up no less than about 80% by weight of a bowel cleansing composition containing additives for optimum results.
  • Compositions containing about 75 to 80% by weight PEG and 20 to 25% by weight phosphate are particularly contemplated.
  • at least a majority (greater than about 50% by weight) of the phosphate present is disodium phosphate; if monosodium phosphate is included in the composition, it should usually make up less than one -half, and preferably less than one-quarter, of the phosphate content of the composition.
  • a dry prep composition containing from about 45 to 70 grams powdered PEG and 10 to 30 grams phosphate powder, preferably about 55 to 65 grams PEG and 15 to 25 grams phosphate powder, is dissolved or suspended in an aqueous liquid of choice, such as water, tea, or juice.
  • a single dose dry prep composition containing from about 58 to 63 gram PEG and from about 15 to 20 grams phosphate powder, for example, 60 grams powdered PEG and 18 grams sodium phosphate powder, preferably disodium phosphate powder, is dissolved in about 1 to 1.5 quarts of water or other aqueous liquid, for oral ingestion.
  • compositions may be dissolved in a smaller portion of water, such as eight fluid ounces, and the remainder of the liquid taken in conjunction with this solution.
  • the amount of water or other aqueous medium, in which the dry prep composition is dissolved or which is taken with the dry prep composition, is not critical; however, for optimum bowel cleansing, at least about a pint should be used, and preferably at least a quart, depending upon the patient' s total liquid intake during the treatment.
  • lower molecular weight PEG polymers such as PEG 400, which are liquid at room temperature, may be used as a base, and the phosphate powder dissolved or dispersed therein; the solution may then be diluted to taste with the desired aqueous liquid.
  • the single dosage drinks so prepared are taken from twice per day to four times per day on the day preceding the colonoscopy or other procedure, depending upon the degree of clean-out required and the presence of complicating bowel conditions such as constipation.
  • the patient is restricted to a clear liquid diet while on the regimen, i.e., a diet of liquids containing no significant solid material.
  • Suitable clear liquids include, but are not limited to, apple juice, tea, plain gelatin, 7-Up® soft drink, Sprite® soft drink, chicken broth, and beef broth. If the patient receives a sufficient amount of liquids containing sodium and potassium ions to satisfy hunger, no supplemental electrolytes need be used with the PEG/phosphate compositions.
  • the compositions may be taken in conjunction with a bowel stimulant such as bisacodyl, generally available over-the- counter in products sold, for example, under the trademarks Dulcolax® or BiscoLax®.
  • bisacodyl should not be taken in powder form to avoid neutralization with stomach acids.
  • Enteric-coated 10 milligram tablets once or twice a day may be suitable. Two 5-mg tablets may be taken as an alternative to one 10-mg tablet.
  • the bowel cleansing compositions may include, or be taken in conjunction with, conventional additives such as flavoring or coloring agents.
  • an herbal bowel stimulant such as Cascara sagrada may also be included in or taken in conjunction with the bowel cleansing compositions.
  • psyllium or other fiber commonly used as a stool-bulking agent may be optionally added to or taken with the bowel cleansing compositions, both for its laxative properties and its potential ability to counteract any adverse effects of the other components.
  • Patients were prepared for colonoscopy with a bowel cleansing composition of 60 grams PEG powder and 18 grams disodium phosphate powder per dose.
  • Each patient was given two single-dose packets of bowel cleansing composition for self- administration on the day preceding the colonoscopy, with instructions to dissolve each dose in water and drink the first dose at 10 a.m. and the second at 4 p.m.
  • a clear liquid diet was prescribed for that day.
  • a flavor packet containing powdered Crystal Light® iced tea was provided for use as desired with the bowel cleansing composition to encourage drinking.
  • a 61 year-old female had weight loss and decrease in appetite. She underwent a clear liquid diet the day before with bowel cleansing composition taken at 10 a.m. and at 4 p.m. Good prep and adequate view of the colon was verified by multiple photographs, including a view of the transverse colon, during colonoscopy.
  • the bowel cleansing composition was taken at 10 a.m. and 4 p.m. on the day before the exam, with a clear liquid diet.
  • the bowel prep was good, with adequate view of colon, including the transverse colon. The patient had no complaints.
  • a bowel cleansing composition includes PEG, monobasic and/or dibasic sodium phosphate, bisacodyl, psyllium, optionally lubiprostone, and optionally linaclotide.
  • the bowel cleansing composition is tailored toward adult usage.
  • adult bowel cleansing is accomplished by administration of 10 to 30 g of sodium phosphate, 45 to 70 g of PEG, 5 to 30 mg of bisacodyl, 2.5 to 30 g of psyllium, optionally 12 to 60 ⁇ g of lubiprostone, and optionally 145 to 290 ⁇ g of linaclotide, preferably administered in two separate doses the day before the procedure, as described above.
  • the lubiprostone dosage is more preferably in the range of 24 to 48 ⁇ g and the linaclotide dosage is more preferably about 145 ⁇ g or about 290 ⁇ g.
  • the sodium phosphate and PEG are preferably dissolved in up to two quarts of water or a flavored water beverage.
  • the biscodyl, psyllium, lubiprostone, and/or linaclotide may be administered simultaneously with the sodium phosphate and PEG or at a different time during the administration period.
  • the biscodyl, psyllium, lubiprostone, and linaclotide may be dissolved or dispersed in the same aqueous carrier as the sodium phosphate and PEG or may be taken in other aqueous carriers or taken in another form, such as, for example, a pill or a capsule.
  • the bowel cleansing composition includes 16 to
  • each dose administered to the patient contains less than 20 grams of sodium phosphate and the patient is preferably administered two doses during the administration period.
  • At least 30 different adult patients with written consent have been administered a bowel cleansing composition as described above, including sodium phosphate, polyethylene glycol, bisacodyl, and psyllium. Two have been given an evening meal including buttered toast. Four have been given an evening meal pancakes with syrup. At least 70 different adult patients in total have been administered a bowel cleansing composition as described above, including sodium phosphate, polyethylene glycol, bisacodyl, and psyllium. All of the patients have done well.
  • the bowel cleansing composition has additionally included at least one of lubiprostone, linaclotide, and naloxegol. All of the patients receiving a bowel cleansing composition containing at least one of these additional components have done well.
  • the administration of sodium phosphate, PEG, bisacodyl, and psyllium has been observed to produce better bowel cleanout than administration of sodium phosphate and PEG without bisacodyl and psyllium. More specifically, the psyllium has been observed to bind bile salts to better clean out bile from the bowel, such as by a flush with water by the scope during a colonoscopy.
  • the bowel cleansing composition and method are adapted for a patient with certain predetermined conditions.
  • the bowel cleansing composition is preferably as disclosed above, with the exception that the sodium phosphate is replaced with magnesium citrate (1:1).
  • compositions and methods may also optionally include one or more of the following components discussed herein: lubiprostone, linaclotide, and naloxegol.
  • Opioids a class of drugs for pain treatment and management, are known for reducing the motility of the gastrointestinal tract, leading to opioid-induced constipation. Opioids are commonly given to treat both acute and chronic pain, including, but not limited to, pain associated with terminal conditions and degenerative conditions, such as, for example, rheumatoid arthritis.
  • Bowel cleansings for patients with opioid-induced constipation tend to be particularly difficult.
  • a patient with opioid-induced constipation is preferably given 10 to 40 mg of naloxegol, currently marketed under the trademark Movantik® (AstraZeneca AB Corp., Sodertalje, Sweden), in one dose, preferably in the morning the day before the procedure, and more preferably first thing in the morning the day before the procedure.
  • the dosage of naloxegol is about 25 mg.
  • the patient is preferably maintained on a clear liquid diet at least from the morning of the day before the colon procedure up to the evening before the colon procedure as part of the bowel cleansing procedure.
  • the patient may eat a predetermined evening meal (preferably a low-residue meal) the evening before the colon procedure.
  • a predetermined evening meal preferably a low-residue meal
  • a low -residue meal is a meal with foods that are acceptable for a low-residue diet, which is a diet designed to reduce the frequency and volume of stools while prolonging intestinal transit time.
  • the evening meal may include, but is not limited to, buttered toast or pancakes with syrup.
  • a patient who has a procedure scheduled in the afternoon may take a portion of the bowel cleansing composition the day before the procedure, and the remaining portion of the bowel cleansing composition the morning of the procedure (at least four hours before the procedure).
  • the patients take half (typically a quart) of the bowel cleansing composition the day before the procedure and the other half (typically a quart) the morning of the procedure.
  • the patients may also eat an evening meal (preferably a low-residue meal consistent with a low-residue diet) the evening before the procedure.
  • the evening meal may include, but is not limited to, pancakes with syrup or buttered toast.
  • the bowel cleansing composition is for an adolescent or a child.
  • the PEG dosage is preferably 1.2 to 1.8 grams, and more preferably about 1.5 grams, per kilogram of weight of the adolescent up to a maximum of 100 grams or of weight of the child up to a maximum of 30 grams.
  • an adolescent bowel cleansing composition for an adolescent 12 to 18 years of age preferably includes 4.5 to 7.5 g, and more preferably about 6 g, of sodium phosphate; 2 to 4 g, and more preferably about 3 g, of psyllium; and 5 to 15 mg, and more preferably about 10 mg, of bisacodyl.
  • a child bowel cleansing composition for a child 8 to 12 years of age preferably includes 2 to 4 g, and more preferably about 3 g, of sodium phosphate; 1.5 to 2.5 g, and more preferably about 2 g, of psyllium; and 5 to 15 mg, and more preferably about 10 mg, of bisacodyl.
  • Any of the bowel cleansing compositions described herein may be administered to the patient with no supplemental electrolytes. Any of the bowel cleansing compositions described herein may be administered as described additionally to the patient for a second day prior to the colon procedure to assure a thorough bowel cleansing.
  • the bowel of the patient may be black as a result of the bleeder, making imaging of the bowel during a GI (GI) bleeder patient
  • preparation of a GI bleeder patient for a colonoscopy includes, in addition to the previously-described administration of a bowel cleansing composition, the use of carbonated water in place of non-carbonated water in flushing the bowel lining prior to imaging.
  • the carbonated water cleans the bowel lining better than non-carbonated water by removing more of the black coloration from the GI bleeder to allow for better imaging of the bowel during a colonoscopy.
  • the carbonated water is preferably seltzer water. Alternatively, club soda may be use as the carbonated water.

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Abstract

L'invention concerne des procédés et des kits qui contribuent à préparer un patient à une intervention sur le côlon. Dans certains modes de réalisation, une dose efficace de phosphate de sodium, une dose efficace de polyéthylèneglycol, une dose efficace de bisacodyl, et une dose efficace de psyllium sont administrées au patient pendant une période de 24 heures juste avant l'intervention sur le côlon pour réaliser un nettoyage du côlon du patient en vue de l'intervention sur le côlon. Dans certains modes de réalisation, un kit comprend une dose efficace de phosphate de sodium, une dose efficace de polyéthylèneglycol, une dose efficace de bisacodyl et une dose efficace de psyllium. Les procédés et les kits peuvent éventuellement comprendre de la lubiprostone, du linaclotide et/ou du naloxegol destinés à être administrés au patient pour permettre un nettoyage plus complet du côlon.
PCT/US2016/041841 2015-07-13 2016-07-12 Compositions et procédés de nettoyage du côlon Ceased WO2017011430A1 (fr)

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US62/191,681 2015-07-13

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5173296A (en) * 1990-11-16 1992-12-22 The Procter & Gamble Company Compositions containing psyllium
US20050244368A1 (en) * 2004-04-29 2005-11-03 Pashankar Dinesh S Pre-endoscopic use of polyethylene glycol compositions
US20100159026A1 (en) * 2003-11-19 2010-06-24 Salix Pharmaceuticals, Ltd. Colonic purgative composition with soluble binding agent
US20140178492A1 (en) * 2002-07-15 2014-06-26 George M. Halow Bowel cleansing composition
US20140242124A1 (en) * 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonists of Guanylate Cyclase and Their Uses
CA2927719A1 (fr) * 2013-10-17 2015-04-23 Yoon Sik Kang Composition de lavage intestinal

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5173296A (en) * 1990-11-16 1992-12-22 The Procter & Gamble Company Compositions containing psyllium
US20140178492A1 (en) * 2002-07-15 2014-06-26 George M. Halow Bowel cleansing composition
US20100159026A1 (en) * 2003-11-19 2010-06-24 Salix Pharmaceuticals, Ltd. Colonic purgative composition with soluble binding agent
US20050244368A1 (en) * 2004-04-29 2005-11-03 Pashankar Dinesh S Pre-endoscopic use of polyethylene glycol compositions
US20140242124A1 (en) * 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonists of Guanylate Cyclase and Their Uses
CA2927719A1 (fr) * 2013-10-17 2015-04-23 Yoon Sik Kang Composition de lavage intestinal

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GRIGG ET AL.: "Lubiprostone Used With Polyethylene Glycol in Diabetic Patients Enhances Colonoscopy Preparation Quality", WORLD JOURNAL OF GASTROINTESTINAL ENDOSCOPY, vol. 1, no. Issue 7, 16 July 2010 (2010-07-16), pages 263 - 267, XP055344540, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998835/pdf/WJGE-2-263.pdf> [retrieved on 20160826] *

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