PHARMACEUTICAL COMPOSITIONS FOR USE IN GASTROINTESTINAL WASHES

Abstract: An orally administered pharmaceutical composition for use in gastrointestinal washes or as a cathartic laxative contains (1) at least two sweeteners, wherein at least one of the sweeteners is non-metabolizable and a second sweetener may be metabolizable, and/or (2) a flavoring agent adsorbed on a water-soluble non-metabolizable substrate.

Description: PHARMACEUTICAL COMPOSITIONS FOR USE IN GASTROINTESTINAL WASHES BACKGROUND OF THE INVENTION 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 gastro¬ intestinal cleansing in preparation for endoscopic exami¬ nation 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. When a powerful gastrointestinal wash is required, these preparations are generally administered orally in a quantity of about four liters. Prior to 1980, gastrointestinal lavages for clean¬ ing 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 poly¬ ethylene glycol (PEG) combined with sodium chloride, potassium chloride, sodium bicarbonate, sodium sulfate and water. 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. These advantages represent substantial improvements which derive from two essential characteristics of the PEG/electrolyte compositions, namely their isoosmoticity with the physiological liquids, and the balance of the ionic species in solution, so as to compensate the trans¬ port mechanisms which regulate gastrointestinal absorption. These characteristics result in substantial isoto- nicity between the PEG/electrolyte compositions and the intra- and extracellular fluids at the tissues of the digestive tube walls resulting in virtually no net absorp¬ tion or excretion of ions or water. This allows the administration of large volumes without significant changes in fluid and electrolyte balance. A serious drawback of known lavage compositions is their bland or even, in the case of PEG/electrolyte compo¬ sitions, 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 cor¬ rectors must not be added when preparing the solutions. Furthermore, in any of the preparations of the known art, it is not opportune to add substantial quanti¬ ties 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 electro- cautery. Neither is it opportune to introduce 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. Neither is it always oppor¬ tune to introduce 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. With synthetic sweeteners, there is a further problem in addition to the aforesaid general problems, namely the problem of toxicity at high doses, so that the acceptable daily dose (ADD) must be taken into account. Remembering that the preparations of the known art are taken orally in a quantity of four liters of solution per unit of administration, practically all known synthetic sweeteners would have to be administered in effective doses which are incompatible with the ADD fixed by regulations. It is desirable that 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. However, 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 dis¬ closes a dry medicinal preparation for preparing a drink¬ able solution with a laxative effect, wherein the prepara- tion 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. The composition disclosed in the above-referenced 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 UBST1TUTE SHEET RULE 26 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 refer¬ ence, 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. According to the present invention it has now been found possible to provide preparations for oral use as gastric lavages and cathartic laxatives which, while being unaltered in terms of their capacity for gastrointestinal washing, are of substantially changed taste in the sense of being in fact pleasant for the patient without causing dangerous levels of gas production or having other unde- sired effects. SUMMARY OF THE INVENTION According to one aspect, this invention, which produces the aforesaid surprising effects and other advan- tages 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, anhy¬ drous sodium sulphate, sodium bicarbonate, sodium chloride and potassium chloride, or other unflavored or unpleasantly flavored formulations. In one embodiment, the composition of this inven- tion comprises a liquid, preferably but not necessarily an electrolyte solution, containing at least two sweeteners, wherein at least one of the sweeteners is non-metaboliz¬ able. Another aspect of this invention is 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 two sweeteners, at least one of the sweeteners being 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. In other embodiments of this invention, a method is provided for obtaining a laxative effect on an animal (including humans) by administering to the animal a laxa¬ tive effective amount of a composition of this invention. Suitability of various combinations of the inven¬ tion for a particular use may be determined by a new method comprising measuring hydrogen gas and methane gas quanti¬ ties 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. This in vitro method provides several advantages over in vivo methods of gas measurement. For example, the in vitro method measures total gas production without the sampling errors inherent in sampling gases in a few select¬ ed areas of the colon. Furthermore, the gas concentrations reported in the n 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. In preferred embodiments, the 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 glycyrrhizi- nate and commercially available under the trademark Magnasweet®. In preferred embodiments, 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. The 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. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Preferred 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. While other liquids are known for gastric lavages and cathartic laxatives and may be used in the present invention, it is preferred to use electrolyte solutions which typically contain polyethylene glycol (PEG) , anhy¬ drous sodium sulfate, alkali metal bicarbonate, sodium chloride, and potassium chloride. Generally, 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, prefera¬ bly from about 0.7 to about 0.8, and most preferably from about 0.7 to about 0.75, grams of potassium chloride. Preferably, 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. According to the present invention, the use of two sweeteners, at least one of which is non-metabolizable, 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. Preferably, it is an artificial sweetener, e.g., saccharin or cyclamate. Most preferably, it is 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 sweet¬ eners needed. It is preferred that the second sweetener also have a flavor-enhancing effect. Particularly preferred sweeteners for use as the second sweetener are those based on monoammonium glycyrrhizinate. Examples of such sweeteners are mono¬ ammonium salts of a triterpenoid saponin, comprising a glycone of glycyrrhetinic acid and a sugar moiety of the glucuronic acid units. Such salts are commercially avail¬ able 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. The Magnasweet® 100 series enhance the overall sweetness of the product and effectively mask bitter, harsh and astringent aftertastes. Of the various products in the Magnasweet® 100 series, the most preferred for purposes of this invention is Magnasweet®185. It contains 1-10% of ethyl altol, 5-20% of corn syrup, and 70-90% of monoammonium gly¬ cyrrhizinate pentahydrate which can be of natural or of synthetic origin. Additionallly, 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 sweet- ener and optional flavoring, to mask any unpleasant taste effect of the non-metabolizable sweetener and, if neces¬ sary, 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. If 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. In another particularly preferred embodiment of this invention, 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 composi¬ tion of this invention in an amount effective to enhance the flavor of the composition. Typically, 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. In a particularly preferred embodiment, the flavor¬ ing 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, are commonly used to adsorb flavor oils in order to produce dry flavor systems. However, fermenta¬ tion 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. In this invention, 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. - lo ¬ in general, 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. Examples of water-soluble non-metabolizable sub¬ strates 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, KC1, Na 2 S0 4 and NaHC0 3 ; and water soluble polymers such as poly¬ ethylene glycol (PEG) , hydroxy propyl methyl cellulose (HPMC) , hydroxy propyl cellulose (HPC) , carboxy methyl cellulose (CMC) , hydroxy ethyl cellulose (HEC) and poly¬ propylene glycol (PPG) . These water-soluble non-metaboliz- able substrates may, in a preferred embodiment, be compo¬ nents 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. In another embodiment, 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. Specific embodiments include compositions of the following formulations per 0.5 liter of aqueous solution: polyethyleneglycol (3000-4000) 29.5 g ± 20% anhydrous sodium sulfate 2.843 g ± 10% sodium bicarbonate 0.843 g ± 10% sodium chloride 0.733 g ± 10% potassium chloride 0.371 g ± 10% saccharin 0.010-0.320 g sodium cyclamate 0.01-0.100 g a second sweetener 0.040-0.160 g II. polyethyleneglycol (3000-4000) 29.5 g ± 20% anhydrous sodium sulfate 2.843 g ± 10% sodium bicarbonate 0.843 g ± 10% sodium chloride 0.733 g ± 10% potassium chloride 0.371 g ± 10% saccharin 0.010-0.025 g sodium cyclamate 0.040-0.100 g a second sweetener 0.040-0.080 g flavoring <1.000 g III. polyethyleneglycol (3000-4000) 29.5 g ± 20% anhydrous sodium sulfate 2.843 g ± 10% sodium bicarbonate 0.843 g ± 10% sodium chloride 0.733 g ± 10% potassium chloride 0.371 g ± 10% saccharin 0.010-0.320 g a second sweetener 0.040-0.160 g flavoring <1.000 g Compositions of this invention can be prepared by mixing the dry ingredients in a standard blender, and then combining the resulting mixture with water. 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. Examples of the ingestible compositions are the pharmaceutical compositions of this invention. Preferably, 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 composi¬ tion combination are measured, preferably by gas chromatog¬ raphy. The amount of hydrogen gas and methane gas gener- ated 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. This measurement technique can be used to determine the suitability of gastric lavage and cathartic laxative compositions of the type described above for various diagnostic and presurgical procedures. For example, H 2 production at levels of 40,00C parts per million (ppm) or methane production at levels of 50,000 ppm causes danger of explosion in diagnostic and surgical procedures such as those using electrocautery, laser techniques, and the like. Accordingly, the preferred compositions of the present invention are those which result in statistically signifi- cant 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 com¬ bined with at least one other sweetener and/or comprising a flavoring agent on a water-soluble non-metabolizable substrate. The 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 pyelogra- phy, and emergency procedures, e.g., gastrointestinal flush, such as for poison removal. The characteristics and advantages of the invention will be more apparent from the following non-limiting examples. EXAMPLES EXAMPLES 1-7 An in vitro test system is employed to determine the quantities of hydrogen and methane gases produced as a consequence of the metabolism of various flavored Colyte® formulations by human intestinal bacteria. Colyte® con¬ tains PEG 3350, 60g; NaCl, 1.46g; KC1 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 quanti- tatively determined after 0, 1, 2, 4 and 24 hours incuba¬ tion 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 re- quired for experimental use. Freshly passed fecal speci¬ mens 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. On the day of a given experiment, 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 facili- tate 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 syring¬ es and stopcocks. In addition, 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. The flavor formulations and controls tested in Examples 1-7 are listed in Table I. TABLE I Example 1: Raw ate l Gr Prosweet® sweetener comprising dextrose and flavor ingredients is available from Virginia Dare Extract Co. , Inc., Brooklyn, NY. Example 6: Raw Material Grams Colyte 139.150 Natural and Artificial Lemon Juice 1.000 Pure Instant Tea, Micromilled 4.200 Nutrasweet (aspartame) 0.510 A microgrowth medium. The entire contents of each powdered formulation are 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 trans¬ ferred to a two-liter volumetric flask and the volume brought to two liters with 0.02M phosphate buffer. An aliquot of each solubilized test formulation is then transferred to a 300 ml Erlenmeyer flask for deoxygenating. Argon gas is bubbled rapidly through the solution with vigorous stirring for one hour. Sixty ml of the deoxygenated solution are then drawn into a sealed syringe, and the syringe and contents are brought to 37°C in a water bath. Three grams of freshly passed human feces are weighed out in a 250 ml blender vessel which is then sealed tightly with a screw cap. 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. In all experiments 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 rp s. Gas samples (0.5 ml) are removed at 0, l, 2, 4 and 24 hours for analysis. Gas samples are obtained by passing a 3", 21 G needle attached to a l 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 neces¬ sary in argon prior to injection into the gas chromato- graph. 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 molecu- lar 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. The average amounts in ppm for all eight subjects of hydrogen gas produced by anaerobic metabolism of all test materials and for all time intervals sampled are shown in TABLE II, for the four methane non-producers in TABLE III, and for the four methane producers in TABLE IV. All three tables depict the mean, standard deviation and minimum and maximum values detected for each sample. The low to negative numbers shown for the zero time analyses reflect the endogenous metabolism of the fecal-buffer blank controls which were subtracted from all other values obtained. For all formulations overall (n=8) , the volume of H 2 rises and then declines. 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. None of the formulations with two sweeteners of the invention (Examples 1, 2, 5 and 7) produce hydrogen levels approaching the 120,700 ppm (mean peak level 45,653 ppm) obtained with 1% glucose as the positive control (Example 4) after 4 hours of incubation, or the 40,000 ppm level considered to be potentially explosive. 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. Hydrogen levels obtained by incubation of the test material with fecal specimens obtained from known methane producers are shown in Table IV. Only low (less than 1,000 ppm) to barely detectable hydrogen levels are obtained throughout the 24 hour incubation period for all flavor formulations tested in this group. This is believed to be a result of H 2 consumption in methane production. The levels of methane gas production by all sam¬ ples, in ppm, for Examples 1-7 are presented in Table V. TABLE II Examples 1-7: Hydrogen Production Mean ± Std. Dev. (Min, Max) Example No. Hour 0 Hour 1 Hour 2 1 269 ± 407 1554 ± 1764 1299 ± 1478 ( 0 , 1174) ( -40 , 4070) ( 0 , 3320) 2 44 ± 245 4041 ± 3945 3694 ± 3863 O { -275 , 596) ( 125 , 9040) ( 75 9766) 3 -69 ± 340 -50 ± 1261 196 ± 1310 ( -845 , 359) (-2010, 2650) (-1275, 3250) 361 ± 466 15246 ± 12803 29228 ± 23960 ( 3 , 1194) ( 170 , 35670) ( 380 , 60250) 94 ± 399 2878 ± 2925 2450 ± 2556 ( -640 , 759) ( 55 , 6765) ( 35 , 6765) 6 152 ± 624 8359 ± 8647 9943 ± 9750 ( -813 , 1434 ( 150 , 22070) ( 270 , 22200) ( 7 11 ± 287 4980 ± 5247 5325 ± 5665 ( -565 , 494) { 80 , 12270) ( 250 , 14765) ( B E III Hour 4 Hour 24 1786 ± 958 252 ± 509 ( 680 , 2925) ( -359 , 864) 5130 ± 1392 237 ± 494 4270 , 7210) ( -394 , 703) 581 ± 1970 118 ± 444 (-720, 3500) (-383, 698) 83183 ± 27170 54817 ± 15375 (56650 , 120700) (38940 , 75807) 3566 ± 676 457 t 605 ( 2950 , 4485) ( -382 , 1048) 13488 ± 3956 606 ± 1019 ( 8770 , 18270) ( -388 , 1942) 5378 ± 1661 1861 ± 1208 ( 4110 , 7810) ( 667 , 3348) TABL CO CXI 3 CO a m: t CD TABLE V Exam p les 1-7: Methane Production Mean ± Std. Dev. (Min, Max) Example Mn. Hour 0 Hour 1 Hour 2 Hour 4 1 Hour 24 37 52 583 ± -5 643 129) 752 ± 830 ( 0 , 1455) 1061 ± 1160 ( -2 , 1930) 3314 ± 2572 0 , 2675) ( -76 , 8648 ) 31 ± 88 1073 ± 1153 ( -11 , 249) 1482 ± 1592 ( 2364) 1998 ± 2156 ( -11 , 3270) 5497 ± 6079 ( 0 , 4642) ( -75 , 13175 ) 0 ± 12 1 ± 259 ( -17 , 23) 35 ± 397 (-585 , 255) 146 ± 588 (-828 , 453) 921 ± (-991 , 2572 929) ( -3570 , 40 ± 53 4163 ) 1966 ± 2184 0 , 145) 4251 ± 4698 ( 4521) 7159 ± 7829 ( -11 , 10430) 28713 ± 31678 ( 0 , 16859) ( -70 , 67766) 20 ± 35 1051 ± 1150 ( -7 , 89) 1412 ± 1539 2685) 1930 ± 2128 ( -11 , 3512) 5653 ± 6438 ( 0 , 5053) ( -75 , 14530) 28 ± 48 1528 ± 1656 ( -5 , 134) 2778 ± 3033 ( 5120) 4101 ± 4421 ( -3 , 7230) 11681 ± 12100 ( 0 , 10320) ( -72 , 29106) 14 ± 18 1145 ± 1241 ( -5 , 45) 2057 ± 2237 ( 0 , 2515) 3662 ± 4572 ( -11 , 4830) 21690 t 25872 ( 0 , 9517) ( -55 , 60192) σ> In general, the time course of methane production is found to be the reverse image of that for hydrogen production; very low levels are detectable during the early sampling intervals, and these levels increase with time up to 24 hours. In this overall assessment of methane production. 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) . The levels of methane obtained via anaerobic metabolism of the test materials by fecal specimens obtained from known methane non-producers are shown in Table VI. For all formulations tested and for all time intervals sampled, methane levels remain essentially at base line values throughout the 24 hour incubation period. 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. TABLE VI Examples 1-7: Hydrogen Production (Methane Non-Producers) Mean ± Std. Dev. (Min, Max) TABLE VII Examples 1-7: Methane Production (Methane Producers) Mean 1 Std. Dev. (Min, Max) The results of these examples consistently demon¬ strate that the addition of various flavored Colyte solutions to the fecal homogenates result in much less production of H 2 and CH 4 than is the case with the addition of 1% glucose, but a somewhat greater production than is observed with unflavored Colyte solution. 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 homo- genates. 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 Examples 8-13 are carried out to determine whether a lower concentration of Magnasweet® 185 sweetener ("MAG 185") or a higher concentration of Nutrasweet® sweetener (i.e., Aspartame ("APM")) is sufficient to mask the flavor of a Colyte solution. 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". The contents of each part are 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. Into each of beakers A and D are placed 100 mg of 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) . None of the six formulations in Examples 8-13 mask the salty taste of the Colyte solution. EXAMPLES 14-26 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. TABLE VIII o/ * artificial ** natural *** o/w did not go into solution The formulations shown in Table VIII above are prepared by dividing a Colyte solution (prepared by blending until clear 263.31 g/dose of Colyte BMB and 800.86 g/dose of water) into 13 1-liter doses, and adding to each dose the required amounts of Magnasweet® 135 sweetener and flavoring agent, as shown in Table VIII. The contents of each dose are 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. Each sample is tasted. The composition containing chocolate (Example 18) is almost acceptable. The compositions containing berry and cherry are almost as good as strawberry flavored compositions. Strawberry compositions containing MAG 185 taste better than any of the compositions prepared in Examples 14-26. EXAMPLES 27-36 Nine compositions are prepared, having the formu¬ lations shown in Table IX. TABLE IX Amounts (σram) Saccharin 0.1 0.1 0.1 * APM = aspartame The compositions prepared in Examples 28-37 are tasted and the results are shown in Table X. TABLE X Example No. Taste 27 Salty, slightly bad taste 28 Slightly pineapple, watery tasting neutralized tasting; 29 good pineapple taste, sweet 30 odd taste, coconut 31 slightly bad taste, not salty, coco¬ nut, thick tasting 32 sweet, coconut, slightly salty at end 33 licorice, not sweet enough, slightly salty 34 strawberry, not sweet enough, slightly salty 35 slightly salty, licorice, not bad, strawberry 36 pineapple taste, sweet

Claims: WHAT IS CLAIMED IS: 1. An orally administered pharmaceutical compo¬ sition for use in gastrointestinal washes or as a cathartic laxative, comprising a liquid containing at least two sweeteners, at least one said sweetener being non-metabolizable. 2. A composition according to claim 1, further comprising an electrolyte solution. 3. A composition according to claim 1 , wherein an in vitro combination of said electrolyte solution with feces samples from methane non-producing subjects at a solution: feces parts ratio of 20:1 produces a statisti¬ cally significant average of hydrogen gas which meets FDA safety standards. 4. A composition according to claim 3, wherein said combination of the electrolyte solution and the feces sample at a solution:feces parts ratio of 20:1 produces less than 4000 ppm of hydrogen gas. 5. A composition according to claim 4, wherein said combination of the electrolyte solution and the feces sample at a solution:feces parts ratio of 20:1 produces less than 3000 ppm of hydrogen gas. 6. A composition according to claim l, wherein at least one said sweetener is metabolizable. 7. A composition according to claim 1, wherein at least one said non-metabolizable sweetener is saccharin or cyclamate. 8. A composition according to claim 7, wherein the saccharin is sodium saccharin dihydrate. 9. A composition according to claim 8, wherein the amount of sodium saccharin dihydrate ranges from about 0.01 to about 0.30 grams per liter of the composition. 10. A composition according to claim l, wherein sweeteners are present in a total amount ranging from about 0.015 to about 2.3 grams per liter of the composi¬ tion. 11. A composition according to claim 1, wherein the amount of said at least one non-metabolizable sweetener ranges from about 0.01 to about 0.3 grams b weight per liter of the composition. 12. A composition according to claim 6, wherei the at least one metabolizable sweetener is based o monoammonium glycyrrhizinate. 13. A composition according to claim 13, furthe comprising at least one flavoring. 14. A composition according to claim 13, wherei the flavoring is at least one member selected from th group consisting of pineapple, mandarin orange, orange grape, strawberry, caramel, pina colada, cherry, iced tea, chocolate, cola, lemon, plum, apple, apricot, raspberry, grapefruit, bilberry, banana, lemon-lime, citrus-berry an kiwi. 15. A composition according to claim 2, wherei said electrolyte solution contains polyethylene glycol, sodium sulfate, sodium bicarbonate, sodium chloride an potassium chloride. 16. A method of obtaining a laxative effect on an animal comprising administering to said animal a laxative effective amount of the composition of claim 2. 17. A dry preblend for preparation of an orally administered pharmaceutical composition for use in gastro¬ intestinal washes or as a cathartic laxative by mixing with water, the dry preblend comprising a dry precursor containing at least two sweeteners, at least one said sweetener being non-metabolizable. 18. A dry preblend according to claim 17, wherein the dry precursor comprises an electrolyte blend. 19. A dry preblend for preparation of an orally administered pharmaceutical composition for use in gastro¬ intestinal washes or as a cathartic laxative by mixing with water, the dry preblend comprising a dry precursor containing at least one flavoring agent adsorbed on a water-soluble non-metabolizable substrate. 20. A dry preblend according to claim 17, further comprising a dry electrolyte blend. 21. A dry preblend according to claim 17, wherein said substrate is at least one member selected from the group consisting of artificial sweeteners, flavor enhancers, salts and water-soluble polymers. 22. A dry preblend according to claim 19, wherein said substrate is at least one salt selected from the group consisting of NaCl, KC1, Na 2 S0 4 and NaHC0 3 . 23. A dry preblend according to claim 21, wherein said substrate is at least one water soluble polymer selected from the group consisting of PEG, HPMC, HPC, CMC, HEC and PPG. 24. A dry preblend according to claim 20, wherein at least a portion of said substrate is comprised of at least one component of said electrolyte blend. 25. A dry preblend according to claim 20, wherein said electrolyte blend comprises PEG, sodium sulfate, sodium bicarbonate, sodium chloride and potassium chloride. 26. A dry preblend according to claim 19, further comprising at least one non-metabolizable sweetener. 27. A dry preblend according to claim 19, further comprising at least two sweeteners. 28. A dry preblend according to claim 27, wherein said sweeteners comprise saccharin or cyclamate and at least one second sweetener. 29. A dry preblend according to claim 28, wherein said metabolizable at least one second sweetener is based on monoammonium glycyrrhizinate. 30. A dry preblend according to claim 28, wherein the saccharin is sodium saccharin dihydrate. 31. A dry preblend according to claim 19, wherein an in vitro combination of a gastric lavage or cathartic laxative prepared with said dry preblend, water and feces samples from methane non-producing subjects at a solution: feces parts ratio of 20:1 produces a statistically signif¬ icant average amount of hydrogen gas which meets FDA safety standards. 32. A dry preblend according to claim 31, wherei said average is less than 4000 p of hydrogen gas. 33. A dry preblend according to claim 32, wherein said average is less than 3000 pm of hydrogen gas. 34. A dry preblend according to claim 19, wherein said flavoring is a flavor oil. 35. A dry preblend according to claim 19, wherein said flavoring is a fruit flavoring. 36. A dry preblend according to claim 19, wherein said flavoring is at least one member selected from the group consisting of pineapple, mandarin orange, orange, grape, strawberry, caramel, pina colada, cherry, iced tea, cola, chocolate, lemon, plum, apple, apricot, raspberry, grapefruit, bilberry, banana, lemon-lime, citrus-berry, and kiwi. 37. An orally administered pharmaceutical compo¬ sition for use in gastrointestinal washes or as a cathartic laxative, having been produced by mixing water with a dry preblend comprising at least one flavoring adsorbed on at least one non-metabolizable water soluble substrate wherein said substrate is a material other than PEG, Si0 2 , KC1, NaCl, NaHC0 3 or Na 2 S0 4 . 38. A composition according to claim 37, wherein the water soluble substrate is selected from the group consisting of HPMC, HPC, CMC, HEC and PPG. 39. A method, of making an orally administered pharmaceutical composition for use in gastrointestinal washes or as a cathartic laxative, comprising adsorbing a flavoring on a water-soluble non-metabolizable substrate, and mixing the resultant substrate with a liquid base for said composition. 40. A method according to claim 39, further comprising mixing an electrolyte blend with said liquid. 41. A method according to claim 39, wherein said substrate is at least one member selected from the group consisting of artificial sweeteners, flavor enhancers, salts and water-soluble polymers. 42. A method according to claim 40, wherein at least a portion of said substrate is comprised of at least one component of said electrolyte blend. 43. A method according to claim 42, further comprising mixing at least two sweeteners with said liquid, at least one said sweetener being non- metabolizable. 44. A method of obtaining a laxative effect on an animal comprising administering to said animal a laxative effective amount of the composition of claim 37. 45. An orally administered pharmaceutical compo¬ sition for use in gastrointestinal washes, particularly for diagnostic use, or as a cathartic laxative, comprising per 0.5 liter of an aqueous solution: polyethyleneglycol (3000-4000) 29.5 g ± 20% anhydrous sodium sulfate 2.843 g ± 10% sodium bicarbonate 0.843 g ± 10% sodium chloride 0.733 g ± 10% potassium chloride 0.371 g ± 10% saccharin 0.010-0.320 g a second sweetener 0.040-0.160 g flavoring <1.000 g 46. The composition as claimed in claim 45, further comprising sodium cyclamate. 47. The composition as claimed in claim 45, comprising per 0.5 liter of an aqueous solution: polyethyleneglycol (3000-4000) 29.5 g ± 20% anhydrous sodium sulfate 2.843 g ± 10% sodium bicarbonate 0.843 g ± 10% sodium chloride 0.733 g ± 10% potassium chloride 0.371 g ± 10% saccharin 0.010-0.320 g sodium cyclamate 0.01-0.100 g a second sweetener 0.040-0.160 g 48. The composition as claimed in claim 45, adapted for use as a gastrointestinal wash to be adminis¬ tered in a maximum dose of four liters of solution, said composition comprising per 0.5 liter of an aqueous solution: polyethyleneglycol (3000-4000) 29.5 g ± 20% anhydrous sodium sulfate 2.843 g ± 10% sodium bicarbonate 0.843 g ± 10% sodium chloride 0.733 g ± 10% potassium chloride 0.371 g ± 10% saccharin 0.010-0.025 g sodium cyclamate 0.040-0.100 g a second sweetener 0.040-0.080 g flavoring <1.000 g 49. The composition as claimed in claim 45, adapted for use as cathartic laxative to be administered in a maximum dose of one liter of solution, said composi- tion comprising per 0.5 liter of an aqueous solution: polyethyleneglycol (3000-4000) 29.5 g ± 20% anhydrous sodium sulfate 2.843 g ± 10% sodium bicarbonate 0.843 g ± 10% sodium chloride 0.733 g ± 10% potassium chloride 0.371 g ± 10% saccharin 0.010-0.320 g a second sweetener 0.040-0.160 g flavoring <1.000 g 50. A method of obtaining a laxative effect on a warm blooded animal comprising administering to said warm blooded animal a laxative effective amount of the composi¬ tion of claim 45.

Inventors: BILALI ESSAT, CURRO FREDERICK A, FEARY TOM, KAUFMAN MICHELE B, PARASHOS DEMETRA, VAIDYA BHUPENDRA R, WILLIAMS GREGORY CHARLES, BILALI, ESSAT, CURRO, FREDERICK, A., FEARY, TOM, KAUFMAN, MICHELE, B., PARASHOS, DEMETRA, VAIDYA, BHUPENDRA, R., WILLIAMS, GREGORY, CHARLES
Applicants: BLOCK DRUG CO, BLOCK DRUG COMPANY, INC.
Application year: 1993
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K33, A61K47, A61P1