United States Patent (19) 11 Patent Number: 4,867,979 Sheth et al. 45 Date of Patent: Sep. 19, 1989 54 ANTIDIARRHEAL COMPOSITIONS AND 58 Field of Search ............... 424/195.1; 514/57, 867, USE THEREOF 514/165, 159, 222, 396, 466, 403, 420, 532, 429, (75) Inventors: Bhogilal B. Sheth, Norwalk; Sheri A. 567,568,579,553,415 Gilbert, Stratford; Jane F. Kinsel, 56) References Cited Derby, all of Conn. U.S. PATENT DOCUMENTS 73 Assignee: Richardson-Vicks Inc., Wilton, Conn. 4,588,589 5/1986 Sheth ................................ 424/195.1 21 Appl. No.: 913,755 Primary Examiner-John Rollins (22 Filed: Sep. 30, 1986 Attorney, Agent, or Firm-George W. Rauchfuss, Jr. 57 ABSTRACT Related U.S. Application Data Antidiarrheal compositions showing enhanced antidiar 62 Division of Ser. No. 646,832, Sep. 4, 1984, Pat. No. rheal activity comprise a non-steroidal anti-inflamma 4,666,716. tory drug compound and a polymeric hydroabsorptive 51 Int. Cl." ................... A61K 35/78; A61K 31/715; agent. A patient in need of remedial or preventive treat A61K 31/60; A61K 31/54 ment of diarrhea symptoms is administered an antidiarr 52 U.S. C. ................................... 424/195.1; 514/57; heally effective amount of said antidiarrheal composi 514/159; 514/165; 514/403; 514/466; 514/415; tions. 514/429; 514/532; 514/553; 514/567; 514/568; 514/579; 514/867; 514/226.5 22 Claims, 1 Drawing Sheet ISOBOLOGRAM FOR THE COMBINATION OF BUPROFEN (IBF) AND PSYLUM (PS) (HOUR POST-CHALLENGE) 300 2O O Oo IBF (mg/kg) U.S. Patent Sep. 19, 1989 4,867,979 SOBOLOGRAM FOR THE COMBINATION OF BUPROFEN (IBF) AND PSYLLUM (PS) (I HOUR POST-CHALLENGE) IBF (mg/kg) 4,867,979 1. 2 tite curb under the trademark Regal Mannan by Regal ANTDARRHEAL COMPOST ONS AND USE Vitamin Co., Costa Mesa, Calif. THEREOF The NSAID compounds whose antidiarrheal activity is potentiated by a polymeric hydroabsorptive agent of This is a division of application Ser. No. 646,832, filed this invention vary widely in their chemical structure Sept. 4, 1984, now U.S. Pat. No. 4,666,716. and in their biological profiles as analgesics, anti-inflam matory agents and antipyretic agents. Among the FIELD OF THE INVENTION classes of NSAID compounds found useful in the com This invention relates to antidiarrheal compositions positions of this invention there may be mentioned for of enhanced antidiarrheal activity and to the use thereof O example, salicylic acid derivatives, propionic acid de to treat a patient in need of preventative or remedial rivatives, indole and pyrole acetic acid derivatives, treatment of diarrhea symptoms. pyrazole derivatives, fenamate derivatives, oxicam de rivatives, phenylacetamide derivatives and the like. BACKGROUND OF THE INVENTION Among the members of this group of NSAID com Diarrhea can result from a variety of pathophysiolog 15 pounds there may be mentioned for example, aspirin, ical disorders including bacterial and parasitic infec salsalate, sodium salicylate, magnesium salicylate, acet tions, disease or debilitation of organs such as liver, aminophen, phenacetin, diflunisal, Zomepirac sodium, adrenal and others. It can also occur as a result of other ibuprofen, naproxen, fenoprofen calcium, piroxican, therapy or diet. In all cases, diarrhea is generally a flurbiprofen, mefenamic acid, sulindac, fenbufen, keto 20 profen, tolmetin sodium, indomethacin, meclofenamate symptom of organic gastrointestinal disorders and not sodium, phenylbutazone, and the like. itself a disorder. Chronic diarrhea is generally due to Especially preferred NSAID compounds in the anti intestinal hypermotility and rapid transport. It may also diarrheal compositions of this invention are aspirin, be due to, or accompanied by hypersecretion of acid indomethacin and ibuprofen. gastric juices or decreased reabsorption and may, in 25 While this invention envisions any antidiarrheally some instances, particularly those accompanied by hy effective potentiating combination combination of persecretion, be associated with emotional tension and NSAID compound and polymeric hydroabsorptive psychological conflicts. agents, the relative amounts of NSAID compound to Antidiarrheal compounds are, of course, wellknown polymeric hydroabsorptive agent in the compositions of in the medicinal arts and take various forms. In particu 30 this invention that provide the enhanced antidiarrheal lar there are a variety of products known which act activity is in the range of ratio of NSAID compound to systemically to provide antidiarrheal effects when ad polymeric hydroabsorptive agent of from about 1:30 to ministered in a manner which will enable the drug to be about 1:600, more preferably from about 1:75 to about taken into the system at effective therapeutic levels. 1:400 and most preferably from about 1:100 to about It is becoming increasingly evident from the litera 35 1:200, ture that non-steroidal anti-inflammatory drugs The compositions of the present invention can be (NSAID) are effective antidiarrheal agents, but gener prepared in forms suitable for administration to humans ally, only at high doses. It would be highly desirable, and animals by compounding an effective single dose however, if the antidiarrheal doses of the NSAID were amount of the composition of the active ingredients of much lower than-those typically reported for their anti this invention with known ingredients generally em inflammatory or analgesic activity and the antidiarrheal ployed in the preparation of therapeutic compositions activity of these NSAID could be potentiated so as to provided as tablets, capsules, lozenges, chewable loz provide more effective antidiarrheal activity. enges, pills, powder, granules, suspensions, or other SUMMARY OF THE INVENTION similar forms which can be taken orally. In general the 45 composition of the active ingredients of this invention Antidiarrheal compositions of enhanced antidiarrheal above are indicated for use as pharmacotherapeutic activity are provided by compositions of a NSAID and agents in a wide variety of mammalian conditions a polymeric hydroabsorptive agent. Administration of which require relief of diarrhea symptoms accompany an antidiarrheally effective amount of said compositions ing abnormal action of the gastrointestinal system. to patients would provide remedial or preventive treat 50 The dosage regimens in carrying out the pharmco ment of diarrhea symptoms. therapeutic methods utilizing the compositions of this invention are those which insure maximum therapeutic DETALS OF THE INVENTION response until improvement is obtained and thereafter The antidiarrheal activity of NSAID compounds has the minimum effective level which gives relief. Thus, in been found to be unexpectedly potentiated when admin 55 general, the dosages are those that are therapeutically istered concurrently with a polymeric hydroabsorptive effective in the treatment of diarrhea. In general, the agent. Preferred hydroabsorptive agents are nonionic single oral dose may contain up to the usual therapeutic polymeric hydroabsorptive agents and still more pre limit of the individual NSAID in combination with the ferred hydroabsorptive agents are psyllium and gluco appropriate amount of polymeric hydroabsorptive mannan. Especially preferred in psyllium. agent to achieve the appropriate ratios. For example, at Psyllium (plantagoe seed) useful in the compositions the 1:30 ratio, 400 mg ibuprofen might be combined of this invention is described in Pharmacopeia XX, page with 12 g polymer whereas 50 mg indomethacin might 634, U.S. Pharmacopeial Convention, Inc., 1980. be combined with 1.5g polymer. At the other extreme, Glucomannan useful in the compositions of this inven at an NSAID/polymer ratio of about 1:600, as little as 1 tion is described in the article titled “Japanese Diet 65 mg ibuprofen plug 600 mg polymer might be an effec Food” on page 22 of the September 1980 issue of Food tive dose. The preferred dose levels would be those that Engineering. Glucomannan is a hydrophilic hemicellu achieve optimal clinical antidiarrheal effectiveness at lose extract from the knojac root and is sold as an appe the lowest NSAID dose. The NSAID compound and 4,867,979 3 4. the polymeric hydroabsorptive agent may be adminis Sweetening agents, such as those set forth above, and tered concurrently or together as a single formulation. flavoring agents may be added to provide a palatable Fractional or multiple doses can of course be given oral preparation. These compositions may be preserved bearing in mind that in selecting the appropriate dosage by the addition of an anti-oxidant such as ascorbic acid. in any specific case, consideration must be given to the Dispersible powders and granules suitable for prepa patient's weight, general health, age, and other factors ration of an aqueous suspension by the addition of water which may influence response to the drug. The drug provide the active ingredients in admixture with dis response on oral administration usually follows within persing, wetting agent or suspending agents. These the first hour after administration and may be main excipients are suspending agents, for example, sodium tained for up to about 4 hours. The drug is generally O carboxymethyl cellulose, hydroxypropyl methylcellu given in single doses up to 8 times daily or as required lose, sodium alginate, polyvinylpyrrolidine, gum traga to maintain effective continuous relief of diarrhea symp canth and gun acacia; dispersing or wetting agents may toms be a naturally occurring phosphatide, for example, leci Compositions intended