WO1994012191A1 - Compositions pharmaceutiques utilisees dans les lavages gastro-intestinaux - Google Patents

Compositions pharmaceutiques utilisees dans les lavages gastro-intestinaux Download PDF

Info

Publication number
WO1994012191A1
WO1994012191A1 PCT/US1993/011479 US9311479W WO9412191A1 WO 1994012191 A1 WO1994012191 A1 WO 1994012191A1 US 9311479 W US9311479 W US 9311479W WO 9412191 A1 WO9412191 A1 WO 9412191A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
sweetener
metabolizable
dry
flavoring
Prior art date
Application number
PCT/US1993/011479
Other languages
English (en)
Inventor
Gregory Charles Williams
Bhupendra R. Vaidya
Demetra Parashos
Essat Bilali
Tom Feary
Michele B. Kaufman
Frederick A. Curro
Original Assignee
Block Drug Company, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Block Drug Company, Inc. filed Critical Block Drug Company, Inc.
Priority to EP94902415A priority Critical patent/EP0670725A1/fr
Priority to AU56797/94A priority patent/AU5679794A/en
Priority to JP6513395A priority patent/JPH08505609A/ja
Priority to CA002149674A priority patent/CA2149674A1/fr
Publication of WO1994012191A1 publication Critical patent/WO1994012191A1/fr

Links

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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives

Definitions

  • This invention relates to orally administered pharmaceutical compositions. More particularly, this invention relates to orally administered pharmaceutical compositions for use in gastrointestinal washes or as cathartic laxatives.
  • Lavage solutions can be used to provide gastrointestinal cleansing in preparation for endoscopic examination and in preparation for diagnostic and surgical procedures such as colonoscopy, double-contrast barium enema x-rays, intravenous pyelography, and emergency procedures, e.g., emergency gastrointestinal flush, such as for poison removal, among other uses.
  • diagnostic and surgical procedures such as colonoscopy, double-contrast barium enema x-rays, intravenous pyelography, and emergency procedures, e.g., emergency gastrointestinal flush, such as for poison removal, among other uses.
  • emergency procedures e.g., emergency gastrointestinal flush, such as for poison removal, among other uses.
  • these preparations are generally administered orally in a quantity of about four liters.
  • gastrointestinal lavages for cleaning the bowel often involved ingestion of aqueous solutions such as isotonic saline or electrolyte solutions. More recently, lavage solutions known as Golytely ® (Braintree Laboratories, Inc., Braintree, MA) and Colyte ® (Reed & Carnick, Piscataway, N.J.) have become more popular. Other gastric lavages and cathartic laxatives are also known.
  • the Colyte ® and Golytely ® products contain polyethylene glycol (PEG) combined with sodium chloride, potassium chloride, sodium bicarbonate, sodium sulfate and water.
  • PEG polyethylene glycol
  • Advantages of using the Colyte and Golytely PEG/electrolyte compositions are a drastic reduction in the wash time (from 2-3 days to 4-5 hours) and the minimization of water and electrolyte losses.
  • PEG/electrolyte compositions namely their isoosmoticity with the physiological liquids, and the balance of the ionic species in solution, so as to compensate the transport mechanisms which regulate gastrointestinal absorption.
  • a serious drawback of known lavage compositions is their bland or even, in the case of PEG/electrolyte compositions, decidedly unpleasant bitter, saline taste, and "slimey" mouth-feel, which in more sensitive patients can lead to vomiting, thereby preventing ingestion.
  • the requirement of solution isotonicity which is necessary to obtain the aforesaid advantages, does not generally allow, or at least makes very problematic, the introduction of water-soluble adjuvants into known formulations as they would alter this isotonicity. In this respect, some commercial preparations expressly state that taste correctors must not be added when preparing the solutions.
  • any of the preparations of the known art it is not opportune to add substantial quantities of substances which can be fermented by the intestinal flora, because gas could form which could be extremely dangerous in cases of, e.g., colonoscopy with electrocautery.
  • water- soluble substances in quantities such as to alter the osmotic conditions or pH of electrolyte solutions. The effect might be to lose the advantageous effectiveness and tolerance of the preparation.
  • electrolytes which would significantly alter the concentration of one or more ionic species present in electrolyte preparations. The result could be similar to that produced by altering the osmolarity.
  • a further impediment to adding water-soluble substances for taste correction is that even the most common natural sweeteners such as saccharose, fructose, glucose and sorbitol may cause fermentation of the preparation and a change in its osmolarity.
  • flavoring agents be added to gastric lavages and cathartic laxatives in order to enhance the flavor of these compositions. It is preferable that in dry flavor systems these flavoring agents be adsorbed on substrates because the use of substrates aids in material handling and avoids agglomeration in the dry preblend prior to its combination with water.
  • Metabolizable substrates such as acacia, dextrin and starch, are commonly used to adsorb flavor oils.
  • metabolizable substrates have the drawback of being fermented by intestinal bacteria which causes formation of hydrogen gas and methane gas. Such gas formation is undesirable because of the potential risk of explosion during electrocautery in the colon. The risk of explosion is increased if other metabolizable substances are also present.
  • German Published Patent Application 3807712 discloses a dry medicinal preparation for preparing a drinkable solution with a laxative effect, wherein the preparation contains electrolytes, polyethylene glycol, alkali hydrogen carbonate, citric acid, and optionally further contains Dimeticon, sodium sulfate, kiwi flavor, food dye, sodium saccharin, or cyclamate and a highly dispersed silicon dioxide on which the flavor is adsorbed.
  • German document includes only one sweetener, i.e., saccharin or cyclamate, and uses silicon dioxide as a substrate for the flavor. Saccharin, however, leaves an unpleasant after taste, and its use, as well as use of cyclamate, may pose health hazards in high dosages. Furthermore, dose restrictions based on ADD limit the amount of saccharin or cyclamate which can be used and thereby limits their sweetening/masking effectiveness. Furthermore, the use of insoluble silicon dioxide as a substrate in the composition taught in the German reference, is undesirable. The presence of insoluble silicon dioxide or other insoluble solid substrate may cause uncertainty as to complete solubilization during solution preparation. Further, an insoluble solid substrate may be deposited on the walls of the gastrointestinal tract, potentially inhibiting diagnostic or surgical procedures.
  • this invention which produces the aforesaid surprising effects and other advantages which will be apparent hereinafter, comprises an orally administered pharmaceutical composition for use in gastrointestinal washes, particularly for diagnostic or surgical preparation use, or as a cathartic laxative. It may be based on liquid lavage/laxative formulations, for example of the type containing polyethyleneglycol, anhydrous sodium sulphate, sodium bicarbonate, sodium chloride and potassium chloride, or other unflavored or unpleasantly flavored formulations.
  • the composition of this invention comprises a liquid, preferably but not necessarily an electrolyte solution, containing at least two sweeteners, wherein at least one of the sweeteners is non-metabolizable.
  • This invention is also directed to a dry preblend for preparation of an orally administered pharmaceutical composition for use in gastrointestinal washes or as a cathartic laxative by mixing with water, wherein the dry preblend contains at least one flavoring adsorbed on a water-soluble non-metabolizable substrate.
  • the present invention is further directed to the compositions made by mixing water with the dry preblends described above.
  • a method for obtaining a laxative effect on an animal (including humans) by administering to the animal a laxative effective amount of a composition of this invention.
  • Suitability of various combinations of the invention for a particular use may be determined by a new method comprising measuring hydrogen gas and methane gas quantities generated by intestinal bacteria-promoted metabolism of an ingestible composition, wherein a feces sample is combined in vitro with the ingestible composition, and the amount of gas generated by the combination is measured in vitro.
  • the in vitro method measures total gas production without the sampling errors inherent in sampling gases in a few selected areas of the colon. Furthermore, the gas concentrations reported in the in vitro method are undiluted, whereas in vivo data are diluted by air insufflation necessitated by colonoscopy. Also, the gas concentrations reported in the in vitro method indicate total gas generated, undiluted by their in vivo distribution throughout the colon.
  • compositions and preblends of this invention contain two sweeteners and a flavoring agent, wherein one of the sweeteners is non- metabolizable, preferably saccharin and/or cyclamate, and the other sweetener is metabolizable, preferably a metabolizable sweetener based on monoammonium glycyrrhizinate and commercially available under the trademark Magnasweet ® .
  • the flavoring agents used in the present invention are adsorbed onto a water-soluble non-metabolizable substrate before being combined with a liquid to form the gastric lavage or cathartic laxative.
  • compositions provided by this invention have a pleasant taste and can easily be taken by patients, do not exert a bad influence upon the electrolyte balance in the living body, have a rapid and excellent cleansing effect, and minimize production of hydrogen and methane gas.
  • compositions of this invention contain a gastric lavage or cathartic laxative liquid which contains at least two sweeteners, at least one of which is non- metabolizable.
  • electrolyte solutions typically contain polyethylene glycol (PEG), anhydrous sodium sulfate, alkali metal bicarbonate, sodium chloride, and potassium chloride.
  • such electrolyte solutions contain per liter of aqueous solution from about 40 to about 120, preferably from about 50 to about 70 and, most preferably, from about 57 to about 63, grams of PEG; from about 4 to about 7, preferably from about 5.4 to about 6.0, and most preferably, from about 5.6 to about 5.8, grams of anhydrous sodium sulfate; from about 1.0 to about 2.0, preferably, from about 1.5 to about 1.8, and most preferably from about 1.5 to about 1.7, grams of alkali metal bicarbonate; from about l to about 4, preferably from about 1.4 to about 1.6, and most preferably from about 1.4 to about 1.5, grams of sodium chloride; and from about 0.2 to about 0.9, preferably from about 0.7 to about 0.8, and most preferably from about 0.7 to about 0.75, grams of potassium chloride.
  • the PEG used in this invention has a molecular weight of at least 3000, preferably between 3000 and 6000, and most preferably between 3000 and 4000.
  • the preferred alkali metal bicarbonate is sodium bicarbonate.
  • the use of two sweeteners can provide a pleasant taste, and even overcome the unpleasant taste associated with PEG/electrolyte compositions, without causing fermentation problems.
  • the non-metabolizable sweetener(s) used in this invention is substantially not fermentable by intestinal bacteria.
  • it is an artificial sweetener, e.g., saccharin or cyclamate.
  • saccharin or cyclamate e.g., saccharin or cyclamate.
  • sodium saccharin dihydrate e.g., sodium saccharin dihydrate.
  • the second sweetener may be a sweetener which is non-metabolizable or metabolizable, i.e., fermentable by intestinal bacteria, if, at amounts which are too small to cause fermentation problems, it effectively contributes to masking any unpleasant flavor of the lavage/laxative liquid and to mask adverse taste effects of the non-metabolizable sweetener such as the unpleasant aftertaste associated with saccharin. Combinations of the sweetener mixture with a flavoring agent will further reduce the amount of sweeteners needed. It is preferred that the second sweetener also have a flavor-enhancing effect.
  • sweeteners for use as the second sweetener are those based on monoammonium glycyrrhizinate.
  • sweeteners are monoammonium salts of a triterpenoid saponin, comprising a glycone of glycyrrhetinic acid and a sugar moiety of the glucuronic acid units.
  • Such salts are commercially available from MacAndrews & Forbes Co. (MaFco) under the Magnasweet ® 100 series. The series is based on MaFco brand monoammonium glycyrrhizinate (MAG), a white crystalline powder derived from the root of the licorice plant, glycrrhiza glabra.
  • MAG monoammonium glycyrrhizinate
  • the Magnasweet ® 100 series enhance the overall sweetness of the product and effectively mask bitter, harsh and astringent aftertastes.
  • Magnasweet ® 185 contains 1-10% of ethyl maltol, 5-20% of corn syrup, and 70-90% of monoammonium glycyrrhizinate pentahydrate which can be of natural or of synthetic origin.
  • a second sweetener may be a Prosweet ® product available from Virginia Dare Extract Co.
  • the non-metabolizable sweetener or sweeteners used in this invention are present in an amount effective to improve the taste and/or mask any unpleasant taste of the lavage or laxative composition when combined with the second sweetener(s). Generally, this amount ranges from about 0.01 to about 0.3, preferably from about 0.025 to about 0.25, and most preferably from about 0.04 to about 0.16, grams per liter of aqueous solution.
  • the amount of the second sweetener is that amount effective, when combined with the non-metabolizable sweetener and optional flavoring, to mask any unpleasant taste effect of the non-metabolizable sweetener and, if necessary, contribute to the improvement of the taste and/or masking of unpleasant taste of the lavage or laxative composition while, if metabolizable, being present in a small enough amount to avoid causing fermentation and gas production problems.
  • the metabolizable sweetener is a Magnasweet ® or Prosweet ® sweetener, it will typically be present in an amount ranging from about 0.005 to about 2.0, preferably from about 0.01 to about 0.72, and most preferably from about 0.015 to about 0.245, grams per liter of aqueous solution.
  • a flavoring agent is used in the lavage or laxative composition.
  • Flavoring agents useful in this invention include fruit flavorings, such as pineapple, mandarin orange, strawberry, pina colada, cherry, lemon, plum, apple, orange, grape, apricot, raspberry, grapefruit, bilberry, banana, lemon-lime, citrus berry, and kiwi.
  • Other suitable flavoring agents include caramel, iced tea, cola and chocolate.
  • the flavoring agent if any, is used in a composition of this invention in an amount effective to enhance the flavor of the composition.
  • the flavoring agent is used in an amount ranging from about 0.005 to about 2.5, preferably from about 0.027 to about 1.38, and most preferably from about 0.005 to about 0.25, grams per liter of aqueous solution.
  • the flavoring agent is adsorbed on a water soluble non-metabolizable substrate in preparation of the dry precursor to the lavage or laxative liquid composition to prevent agglomeration of the precursor due to addition of the flavoring agent and to enhance the mixing and dissolution of such dry precursor into the liquid base of the liquid lavage or laxative.
  • Metabolizable carbohydrates such as acacia, dextrin and starch
  • acacia, dextrin and starch are commonly used to adsorb flavor oils in order to produce dry flavor systems.
  • fermentation of these metabolizable carbohydrates by intestinal bacteria produces hydrogen and methane gas, which is undesirable because of the risk of explosions during electrocautery, particularly when combined in lavage or laxative compositions which contain some, albeit small, amounts of other metabolizable substances such as the second sweetener of the embodiments described above.
  • water-soluble non-metabolizable substrates have been found to be effective and safe for adsorbing flavor oils without causing or combining with other components to cause fermentation problems.
  • the water-soluble non-metabolizable substrate may be used in the present invention in an amount ranging from about 2 to about 28, preferably from about 7 to about 23, and most preferably from about 10 to about 20, parts by weight per 100 parts of the flavoring oil.
  • water-soluble non-metabolizable substrates suitable for use in this invention include, but are not limited to, artificial sweeteners such as saccharin or cyclamates; flavor enhancers; salts such as NaCl, KCl, Na 2 SO 4 and NaHCO 3 ; and water soluble polymers such as polyethylene glycol (PEG), hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose (HPC), carboxy methyl cellulose (CMC), hydroxy ethyl cellulose (HEC) and polypropylene glycol (PPG).
  • artificial sweeteners such as saccharin or cyclamates
  • flavor enhancers such as NaCl, KCl, Na 2 SO 4 and NaHCO 3
  • water soluble polymers such as polyethylene glycol (PEG), hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose (HPC), carboxy methyl cellulose (CMC), hydroxy ethyl cellulose (HEC) and polypropylene glycol
  • water-soluble non-metaboliz- able substrates may, in a preferred embodiment, be components of the final lavage or laxative which would be present in any event, such as the PEG of a PEG-based lavage or laxative, and/or the salts of an electrolyte-based or PEG/electrolyte-based lavage or laxative.
  • the water-soluble non-metabolizable substrates may be additional components, so long as these additional components do not unacceptably detract from the needed properties of the gastric lavage or laxative.
  • Dry flavor systems may be produced by using these water-soluble non-metabolizable substrates with the desired flavor oils or agents and by applying conventional drying techniques such as freeze drying and spray drying.
  • the newly formulated, water-soluble non-metabolizable dry flavor system can be safely and effectively used in oral gastric lavage and cathartic laxative solutions.
  • This invention is further directed to dry preblends containing at least one dry precursor for a gastric lavage or cathartic laxative, preferably PEG and/or an electrolyte blend, and at least one flavoring adsorbed on a water- soluble non-metabolizable substrate such as those mentioned above.
  • compositions of the following formulations per 0.5 liter of aqueous solution I.
  • compositions of this invention can be prepared by mixing the dry ingredients in a standard blender, and then combining the resulting mixture with water.
  • composition of this invention For colon cleansing, individuals are generally lavaged with the composition of this invention at a rate of about 12 to 36 milliliters per minute and most preferably 24 milliliters per minute.
  • a very useful novel method for measuring hydrogen gas and methane gas quantities generated by intestinal bacteria-promoted metabolism of an ingestible composition comprises combining feces samples from a statistically significant population, preferably of animals (such as humans) with methane-producing and non-methane producing bacterial flora, with samples of the ingestible composition in vitro, and measuring the gas quantities generated in vitro.
  • compositions of this invention are the pharmaceutical compositions of this invention.
  • the feces sample and the ingestible composition are each deoxygenated before they are combined. It is also preferred that the deoxygenated feces sample and the deoxygenated ingestible composition are blended under anaerobic conditions to form a fecal homogenate.
  • the deoxygenated ingestible composition is typically contained in a phosphate buffer, preferably having a pH of 6.95 to 7.25 and most preferably of about 7.
  • the amount of hydrogen gas and methane gas produced in the fecal homogenate or fecal sample/ingestible composition combination are measured, preferably by gas chromatography.
  • the amount of hydrogen gas and methane gas generated over time can be measured, for example, by incubating the fecal homogenate or fecal sample/ingestible composition at 37°C, with constant mixing, under anaerobic conditions, and then determining the hydrogen gas and methane gas levels by gas chromatography.
  • compositions of the present invention are those which result in statistically significant average H 2 production, using feces samples from methane non-producing subjects at a solution:feces parts ratio of 20:1, at a level of no more than 4,000 ppm, preferably no more than 3,000 ppm. These levels, though subject to change, meet current FDA safety standards. Such levels can readily be attained with compositions of the invention comprising at least one non-metabolizable sweetener combined with at least one other sweetener and/or comprising a flavoring agent on a water-soluble non-metabolizable substrate.
  • compositions of this invention can be used to provide gastrointestinal cleansing in preparation for endoscopic examination and in preparation for diagnostic and surgical procedures, such as, for example, colonoscopy, double-contrast barium enema x-rays, intravenous pyelography, and emergency procedures, e.g., gastrointestinal flush, such as for poison removal.
  • diagnostic and surgical procedures such as, for example, colonoscopy, double-contrast barium enema x-rays, intravenous pyelography, and emergency procedures, e.g., gastrointestinal flush, such as for poison removal.
  • Colyte ® contains PEG 3350, 60g; NaCl, 1.46g; KCl 0.745g; sodium bicarbonate, 1.68g; anhydrous sodium sulfate, 5.68g. Seven formulations, including positive and negative controls, are prepared in phosphate buffer. Each of these is tested for gas production with homogenates of eight human stool specimens: four obtained from known methane producers and four from methane non-producers. Gas production is quantitatively determined after 0, 1, 2, 4 and 24 hours incubation of the formulations in fecal homogenates at 37°C under anaerobic conditions.
  • Seven flavor formulations are reconstituted in 0.02M phosphate buffer, pH 7.0, and deoxygenated as required for experimental use.
  • Freshly passed fecal specimens are obtained from healthy human volunteers (four methane producers, four methane non-producers) free of antibiotic use for at least two months prior to the study.
  • fecal homogenates are prepared under anaerobic conditions using deoxygenated 0.02M phosphate buffer or deoxygenated flavor formulations prepared in 0.02M phosphate buffer. Aliquots of these materials are transferred to sealed syringes containing 25 ml argon gas and incubated at 37°C with constant mixing for 24 hours. Gas samples are removed at 0, 1, 2 , 4 and 24 hours for analysis of H 2 and CH 4 by gas chromatography.
  • Incubations are carried out in syringes to facilitate maintenance of anaerobic conditions while allowing multiple sampling.
  • the 1:20 fecal dilution (3 grams homogenized feces in 60 ml test material) represents the maximum fecal concentration which will not clog the syringes and stopcocks.
  • rigorous pH control is necessary to make valid comparisons of hydrogen production (hydrogen production decreases rapidly with acidification); more concentrated fecal homogenates do not adequately maintain the required pH range.
  • Prosweet ® sweetener comprising dextrose and flavor ingredients is available from Virginia Dare Extract Co., Inc., Brooklyn, NY.
  • each powdered formulation is transferred to a large beaker containing 1500 ml 0.02M phosphate buffer, pH 7.0, placed on a magnetic stirrer. Mixing is continued until all components of the formulation are in solution. The resultant solution is then transferred to a two-liter volumetric flask and the volume brought to two liters with 0.02M phosphate buffer.
  • the blender interior and fecal sample are then deoxygenated by constant flushing with argon gas for 20 minutes.
  • Sixty ml of the prewarmed and deoxygenated test material are then added to the blender by needle and homogenized or blended briefly to completely mix the fecal sample with solubilized test material.
  • the ratio of feces to test material is 1:20.
  • a 60 ml syringe containing argon is attached to a blender tubing outlet.
  • the argon is flushed into the blender and then 5 ml of the homogenate are removed. Twenty-five ml of argon are then added to the 5 ml of homogenate.
  • a rubber septum (sleeve stopper) is then placed onto the end of a stopcock attached to the syringe. The loaded, sealed sample syringes are then transferred to a shaking 37° incubator set for 130 rpms.
  • Gas samples (0.5 ml) are removed at 0, 1, 2, 4 and 24 hours for analysis. Gas samples are obtained by passing a 3", 21 G needle attached to a 1 ml gas tight flask syringe through the sleeve stopper and through the stopcock (in the open position) directly into the gas space of the sample syringe. These samples are then diluted as necessary in argon prior to injection into the gas chromatograph.
  • Hydrogen analyses are performed on a Beckman GC 72- 5 gas chromatograph equipped with a gas sampling valve and a six foot x 1/4" stainless steel column packed with molecular sieve grade 6A.
  • the oven temperature is 100°C and the carrier gas is argon (30 ml/min).
  • a reducing gas detector (Trave Analytical, Menlo Park, CA) is employed to quantitate H 2 .
  • Methane analyses are performed on a Hewlett Packard 58880A Series Gas Chromatograph equipped with a nine foot x 1/4" stainless steel column packed with molecular sieve.
  • the oven temperature is 100°C and the common gas argon (30 ml/min).
  • a hydrogen flame detector is used to quantitate CH 4 . Gas production at each sample time is calculated from the concentration of H 2 or CH 4 in the syringe and the volume of gas in the syringes, to the nearest ml.
  • Example 1 produces the lowest amount of hydrogen gas of all flavored formulations tested, while Example 6 with only one sweetener produces the highest levels of hydrogen gas among the materials tested.
  • Example III The hydrogen levels produced by incubation of the test materials from fecal specimens obtained from known methane non-producers are shown in Table III. Maximum levels are reached by two hours of incubation and then gradually decline to baseline values by the end of the 24 hour incubation period. In this group, the lowest hydrogen level of a flavored formulation is again obtained with Example 1, with Example 6 producing the highest levels. None of the flavored formulations produce H 2 levels approaching the 120,700 ppm (mean peak level 83,183 ppm) produced by 1% glucose as the positive control (Example 4) at 4 hours.
  • Example 1 produces the lowest amount of methane gas while Example 6 produces the highest level of methane gas (at 24 hours) of the flavor formulations. None of the flavor formulations produce methane at the levels exhibited by the 1% glucose positive control (Example 4).
  • Example VII The levels of methane gas observed on incubation of the test formulations with fecal specimens obtained from the four known methane producers are illustrated in Table VII. None of the flavor formulations produce methane gas levels approaching those of the 1% glucose control (Example 4). Metabolism of Example 1 produces the least methane while Example 6 produces the highest level of methane observed in the flavor formulations.
  • the 1% glucose positive control utilized in this study generates peak levels of 120,700 ppm of hydrogen and 67,788 ppm of methane overall for the eight fecal homogenates.
  • the iced tea formulation with a single sweetener produces the highest peak levels of hydrogen and methane of the flavor formulations at 22,200 ppm of hydrogen and 29,106 ppm of methane overall for the eight fecal homogenates.
  • Examples 8-13 are carried out to determine whether a lower concentration of Magnasweet ® 185 sweetener ("MAG
  • APM Aspartame
  • a Colyte solution is prepared by blending a Colyte composition (1579.86g) with water (4805.16 g) to form a solution. Then, 1579.9 g of the Colyte solution and 4805.2 g of deionized water are mixed until clear and then divided into two equal parts. One part is labeled "S” for strawberry, and the other is labeled "C” for caramel. Strawberry flavoring (0.3831 g) is added to the beaker marked "S”. Caramel flavoring (0.3831 g) is added to the beaker marked "C”.
  • each part is blended well and then subdivided into 3 smaller beakers for a total of 6 beakers, which are labeled A-F, corresponding to Examples 8-13, respectively.
  • Beakers A-C contain strawberry flavoring while beakers D-F contain caramel flavoring.
  • MAG 185 Into each of beakers B and E are placed 200 mg of MAG 185. Into each of beakers C and F are placed 215 mg of APM. The contents of each beaker are mixed well and diluted to volume (2 ml liquid with 6 ml water).
  • Examples 14-26 illustrate the suitability of flavors other than strawberry and caramel to mask the flavor of a Colyte composition.
  • the flavors are listed in Table VIII.
  • each dose is mixed well and then diluted to volume 1 ml liquid with 3 ml water.
  • the pH value of each sample is measured and is presented in Table VIII.
  • composition containing chocolate (Example 18) is almost acceptable.
  • compositions containing berry and cherry are almost as good as strawberry flavored compositions.
  • compositions having the formulations shown in Table IX.
  • compositions prepared in Examples 28-37 are tasted and the results are shown in Table X.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Une composition pharmaceutique administrée par voie orale utilisée dans les lavages gastro-intestinaux ou comme laxatif cathartique contient (1) au moins deux édulcorants, au moins un des édulcorants est non métabolisable et un second édulcorant peut être métabolisable, et/ou (2) un agent aromatique absorbé sur un substrat non métabolisable soluble dans l'eau.
PCT/US1993/011479 1992-11-24 1993-11-24 Compositions pharmaceutiques utilisees dans les lavages gastro-intestinaux WO1994012191A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP94902415A EP0670725A1 (fr) 1992-11-24 1993-11-24 Compositions pharmaceutiques utilisees dans les lavages gastro-intestinaux
AU56797/94A AU5679794A (en) 1992-11-24 1993-11-24 Pharmaceutical compositions for use in gastrointestinal washes
JP6513395A JPH08505609A (ja) 1992-11-24 1993-11-24 胃腸洗浄用薬剤組成物
CA002149674A CA2149674A1 (fr) 1992-11-24 1993-11-24 Compositions pharmaceutiques pour lavages gastro-intestinaux

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US98072292A 1992-11-24 1992-11-24
US07/980,722 1992-11-24

Publications (1)

Publication Number Publication Date
WO1994012191A1 true WO1994012191A1 (fr) 1994-06-09

Family

ID=25527796

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/011479 WO1994012191A1 (fr) 1992-11-24 1993-11-24 Compositions pharmaceutiques utilisees dans les lavages gastro-intestinaux

Country Status (6)

Country Link
EP (1) EP0670725A1 (fr)
JP (1) JPH08505609A (fr)
AU (1) AU5679794A (fr)
CA (1) CA2149674A1 (fr)
MX (1) MX9307359A (fr)
WO (1) WO1994012191A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007044681A2 (fr) * 2005-10-07 2007-04-19 C.B. Fleet Company, Incorporated Reduction de la salinite a l'aide d'edulcorants
WO2010081781A1 (fr) * 2009-01-13 2010-07-22 Universite Libre De Bruxelles Composition nutritionnelle énergétique comprenant un laxatif, des électrolytes et des taux de glucides
GB2471037A (en) * 2005-10-07 2010-12-15 Cb Fleet Co Inc Bowel cleansing composition comprising sweeteners
US7867521B2 (en) 2004-09-03 2011-01-11 C.B. Fleet Company, Incorporated Aspartame and citrate flavored phosphate salt laxative
US7985429B2 (en) 2006-03-03 2011-07-26 C. B. Fleet Company, Inc. Flavored colonic cleansing system
US7998510B2 (en) 2006-08-17 2011-08-16 C. B. Fleet Company, Inc. Low dose colonic cleansing system
US9468686B2 (en) 2009-07-30 2016-10-18 Norgine Bv Solutions comprising polyethylene glycol and electrolytes

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005187448A (ja) * 2004-04-02 2005-07-14 Ajinomoto Co Inc 腸管洗浄用組成物
WO2014144407A1 (fr) 2013-03-15 2014-09-18 Braintree Laboratories, Inc. Comprimés de composition pharmaceutique orale à double utilisation de sels de sulfate et leurs procédés d'utilisation
KR101423005B1 (ko) 2013-10-17 2014-07-28 강윤식 장 세정용 조성물

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4673582A (en) * 1985-03-19 1987-06-16 Universite Claude Bernard/Lyon 1 Novel sweetening agents, process for sweetening various products and compositions containing such sweetening agents
US5077048A (en) * 1988-07-13 1991-12-31 Morishita Pharmaceutical Co., Ltd. Bowel lavage composition
US5124144A (en) * 1989-04-17 1992-06-23 Giuliani S.P.A. Orally administered pharmaceutical composition for use in gastrointestinal washes, in particular for diagnostic use, or as a cathartic laxative

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4673582A (en) * 1985-03-19 1987-06-16 Universite Claude Bernard/Lyon 1 Novel sweetening agents, process for sweetening various products and compositions containing such sweetening agents
US5077048A (en) * 1988-07-13 1991-12-31 Morishita Pharmaceutical Co., Ltd. Bowel lavage composition
US5124144A (en) * 1989-04-17 1992-06-23 Giuliani S.P.A. Orally administered pharmaceutical composition for use in gastrointestinal washes, in particular for diagnostic use, or as a cathartic laxative

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7867521B2 (en) 2004-09-03 2011-01-11 C.B. Fleet Company, Incorporated Aspartame and citrate flavored phosphate salt laxative
WO2007044681A3 (fr) * 2005-10-07 2007-06-07 Cb Fleet Co Inc Reduction de la salinite a l'aide d'edulcorants
GB2446074A (en) * 2005-10-07 2008-07-30 Cb Fleet Co Inc Reduction of saltiness with sweeteners
WO2007044681A2 (fr) * 2005-10-07 2007-04-19 C.B. Fleet Company, Incorporated Reduction de la salinite a l'aide d'edulcorants
GB2471037A (en) * 2005-10-07 2010-12-15 Cb Fleet Co Inc Bowel cleansing composition comprising sweeteners
GB2446074B (en) * 2005-10-07 2011-03-23 Cb Fleet Co Inc Reduction of saltiness with sweeteners
US7985429B2 (en) 2006-03-03 2011-07-26 C. B. Fleet Company, Inc. Flavored colonic cleansing system
US8425944B2 (en) 2006-03-03 2013-04-23 C. B. Fleet Company, Inc. Flavored colonic cleansing system
US8263136B2 (en) 2006-08-17 2012-09-11 C.B. Fleet Company Inc. Low dose colonic cleansing system
US7998510B2 (en) 2006-08-17 2011-08-16 C. B. Fleet Company, Inc. Low dose colonic cleansing system
WO2010081781A1 (fr) * 2009-01-13 2010-07-22 Universite Libre De Bruxelles Composition nutritionnelle énergétique comprenant un laxatif, des électrolytes et des taux de glucides
CN102271687A (zh) * 2009-01-13 2011-12-07 布鲁塞尔大学 包含轻泻剂、电解质和碳水化合物的能量营养型组合物
US9468686B2 (en) 2009-07-30 2016-10-18 Norgine Bv Solutions comprising polyethylene glycol and electrolytes

Also Published As

Publication number Publication date
AU5679794A (en) 1994-06-22
MX9307359A (es) 1994-06-30
EP0670725A1 (fr) 1995-09-13
CA2149674A1 (fr) 1994-06-09
JPH08505609A (ja) 1996-06-18

Similar Documents

Publication Publication Date Title
US11241404B2 (en) Method, composition and package for bowel cleansing
EP2233147B1 (fr) Solution salée pour le nettoyage du colon
RU2426526C2 (ru) Снижение солености с помощью подсластителей
US20110293747A1 (en) Colon cleansing solution
US5124144A (en) Orally administered pharmaceutical composition for use in gastrointestinal washes, in particular for diagnostic use, or as a cathartic laxative
US8425944B2 (en) Flavored colonic cleansing system
EP0858326B1 (fr) Preparations purgatives non aqueuses pour le colon
WO1994012191A1 (fr) Compositions pharmaceutiques utilisees dans les lavages gastro-intestinaux
EA027526B1 (ru) Раствор и композиция, набор и способ очищения толстой кишки
JPH0813737B2 (ja) シロツプ剤
JP2721929B2 (ja) 腸管洗浄用組成物
EP1180367A1 (fr) Desodorisants contre les odeurs de sulfures de fermentation intestinale

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2149674

Country of ref document: CA

Ref document number: 1994902415

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1994902415

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1994902415

Country of ref document: EP