Antidiarrheal compositions and use thereof

This invention relates to antidiarrheal drugs of increased antidiarrheal activity and their use in the treatment of a patient in need of preventive or curative treatment of the symptoms of diarrhea.

Diarrhea can result from a variety of pathophysiological dysfunctions, including bacterial and parasitic infections, disease or weakening of organs such as the liver, adrenal glands, and others. It can also occur as a result of another therapy or diet. In all cases, diarrhea is generally a symptom of organic gastrointestinal dysfunction and not itself a dysfunction. Chronic diarrhea is generally due to intestinal hypermotility and rapid transportation. It may also be due to, or be accompanied by, hypersecretion of acidic gastric juices or reduced absorption, and in some cases, particularly those accompanied by hypersecretion, may be associated with emotional tension and psychological conflict.

Antidiarrheal compounds are, of course, well known in the medical fields and take various forms. In particular, a variety of products are known to act systemically, providing anti-diarrheal effects when administered in a manner that will enable the drug to be incorporated into the system in effective therapeutic amounts.

It has become increasingly apparent from the literature that non-steroidal anti-inflammatory drugs (NSAIDs) are effective anti-diarrheal agents, but generally only in high doses. However, it would be very desirable if the antidiarrheal doses of the NSAIDs were much lower than those typically reported for their anti-inflammatory or analgesic activity, and the antidiarrheal activity of these NSAIDs could be potentiated to provide more effective antidiarrheal activity.

Antidiarrheals of increased antidiarrheal activity are provided by compositions of an NSAID and a polymeric water absorbent. Administration of an antidiarrheally effective amount of these compositions to patients would provide curative or preventive treatment for the symptoms of diarrhea.

The antidiarrheal activity of the NSAID compounds has been found to be unexpectedly potentiated when administered concurrently with a polymeric water absorbent. Preferred water absorbents are nonionic polymeric water absorbents and more preferred water absorbents are psyllium seeds and glucomannan. Psyllium seed is particularly preferred.

Psyllium seeds (plantago seeds) useful in the compositions of this invention are described in Pharmacopeia XX, page 634, US Pharmacopeial Convention, Inc., 1980. Glucomannan useful in the compositions of this invention is described in the article entitled "Japanese Diet Food" on page 22 of the September 1980 issue of Food Engineering. Glucomannan is a hydrophilic hemicellulose extract from the konjac root and is sold under the Regal Mannan trademark as an appetite suppressant by Regal Vitamin Co., Costa Mesa, California.

The NSAID compounds, the antidiarrheal activity of which is potentiated by a polymeric water-absorbing agent of this invention, differ widely in their chemical structure and biological profiles as analgesics, anti-inflammatory agents and antipyretics. Of the classes of NSAID compounds found to be useful in the compositions of this invention, there can be mentioned, for example, salicylic acid derivatives, propionic acid derivatives, indole and pyrroleacetic acid derivatives, pyrazole derivatives, fenamate derivatives, oxicam derivatives and phenylacetamide derivatives. Of the members of this group of NSAID compounds, for example, Aspirin®, salsalate, sodium salicylate, magnesium salicylate, acetaminophen, phenacetin, diflunisal, zomepirac sodium, ibuprofen, naproxen, fenoprofen calcium, piroxicam, flurbiprofen, kefenopenic acid, mefacenamic acid , Tolmetin sodium, indomethacin, meclofenamate sodium and phenylbutazone.

Particularly preferred NSAID compounds in the antidiarrheal drugs of this invention are Aspirin®, indomethacin and ibuprofen.

While this invention presents any anti-diarrheal potentiating combination of the NSAID compound and the polymeric water-absorbent, the relative amounts of the NSAID compound to the polymeric water-absorbent in the compositions of this invention that provide the increased antidiarrheal activity are in a ratio range of the NSAID -Connection to the polymeric water-absorbing agent from 1:30 to 1: 600, more preferably from 1:75 to 1: 400 and most preferably from 1: 100 to 1: 200.

The compositions of the present invention can be prepared in forms suitable for administration to humans and animals by mixing an effective single dose amount of the composition of the active ingredients of this invention with known ingredients which are generally used in the preparation of therapeutic compositions, such as tablets, capsules, lozenges , Chewing pills, pills, powders, granules, suspensions or other similar forms are provided, that can be taken orally. In general, the foregoing composition of the active ingredients of this invention is indicated for use as pharmacotherapeutic agents in a wide variety of mammalian conditions which require relief of the symptoms of diarrhea accompanying abnormal movement of the gastrointestinal system.

The dosage regimens for performing the pharmacotherapeutic procedures using the compositions of this invention are those that ensure a maximum therapeutic response until improvement occurs and then the minimally effective amount that provides relief. Thus, the dosages are generally those that are therapeutically effective in treating diarrhea. Generally, the single oral dose can contain up to the usual therapeutic limit of the single NSAID in combination with the appropriate amount of polymeric water absorbent to adjust the ratio. For example, at a 1:30 ratio, 400 mg of ibuprofen could be combined with 12 g of polymer, while 50 mg of indomethacin could be combined with 1.5 g of polymer. At the other extreme, with an NSAID / polymer ratio of about 1: 600, as little as 1 mg ibuprofen plus 600 mg polymer could be an effective dose. The preferred dose levels would be those that achieve optimal clinical antidiarrheal activity at the lowest dose of NSAID. The NSAID compound and the polymeric water absorbent can be administered simultaneously or together as a single formulation. Divided or multiple doses can, of course, be given, not forgetting that in choosing the appropriate dosage in any particular case, the patient's weight, general health, age and other factors must be taken into account that affect the response to the Can affect drug. The drug response to oral administration usually follows within the first hour after administration and can be maintained for up to 4 hours. The drug is generally given in single doses up to 8 times a day or according to maintenance of the effective continuous relief of diarrhea symptoms.

Compositions intended for oral use can be prepared by methods generally known in the art. Such compositions may contain one or more agents selected from sweeteners, flavors, colors or preservatives to provide a pharmaceutically elegant and tasty preparation. Orally, they can be administered in tablets, troches, oily suspensions, dispersible powders or granules or hard or soft capsules, which contain the active ingredients in a mixture with non-toxic pharmaceutically acceptable drug carriers. The pharmaceutical carriers can be, for example, inert diluents, such as calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, lactose, cellulose, microcrystalline cellulose, starch, modified starch, dextrose, sucrose, mannitol, sorbitol; Binders, for example polyvinylpyrrolidone, cellulose ethers, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and ethyl cellulose, natural gums, such as gum arabic, tragacanth, pectin, guar and karaya, gelatin, alginates, starch, modified starch, polyethylene cellulose, microcellulose Sugars such as sucrose, sorbitol and glucose, corn syrups, polyvinyl alcohols, polyacrylamides or polyvinyloxoazolidone; for solution-promoting agents, such as crosslinked polyvinylpyrrolidone, sodium starch glycolate, crosslinked carboxymethyl cellulose, ion exchange resins, starch, modified starches, microcrystalline cellulose, cellulose, cellulose derivatives, alginates, alginic acid or clay; Lubricants, lubricants and non-stick agents such as silicone fluids, hydrogenated vegetable oils, light mineral oil, microfine silica, metal stearates, stearic acid, polyethylene glycol, talc, corn starch, sodium benzoate, sodium acetate, polyoxyethylene monostearate, magnesium carbonate or magnesium oxide. The tablets may be uncoated, or may be coated by known methods to make them more effective, to delay dissolution or absorption or to make them more palatable, or for other reasons for which orally administered drugs have previously been provided in a coated form ,

Formulations for oral use can also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, binder, on solvent-promoting agents, lubricants, lubricants or non-stick agents, as described above for tablets, or as soft gelatin capsules in which the Active ingredient is mixed with an oil medium, for example peanut oil, liquid paraffin or olive oil.

Oily suspensions can be formulated by suspending the composition of the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those set forth above, and flavoring agents can be added to provide a tasty oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules, which are suitable for the production of an aqueous suspension by adding water, provide the active substances in admixture with dispersants, wetting agents or suspending agents. These excipients are suspending agents, for example sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidine, gum tragacanth and gum arabic; Dispersants or wetting agents can be a naturally occurring phosphatide, for example lecithin; or condensation products from an alkylene oxide with fatty acids, for example polyoxyethylene stearate; or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol; or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexite, for example polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitan hydrides, for example polyoxyethylene sorbitan monooleate. They can also include one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavors and one or more sweeteners such as sucrose.

In general, these compositions may be tableted or otherwise formulated for oral use in such a way that between 100 and 100 parts by weight of the composition contains between 5 and 95 parts by weight of the active compounds.

The increased antidiarrheal efficacy for the compositions of this invention was demonstrated by a castor oil-induced diarrheal experiment in rats, which is a modified experiment by Niemegeers et al., Pharmaceutical Research. 22, 516-518 (1972). The modified experiment was as follows. An NSAID compound such as Aspirin® (ASA), Indomethacin (I) or Ibuprofen (IBF), and a polymeric water absorbent such as Psyllium Seed (PS) or Glucomannan (GM) were used alone and in ratios of NSAID to polymeric agent 1:75, 1: 200; 1: 400 and 1: 600 evaluated. The test materials were suspended in 0.25% methyl cellulose and administered to groups of 10 to 45 rats that had fasted via oral intubation. One hour after treatment, each rat was given 1.0 ml of castor oil via intubation and each rat was placed in a single cage lined with absorbent paper. The papers were examined and replaced every hour up to 6 hours after the castor oil stimulus. The antidiarrheal efficacy was quantified as an "all or nothing reaction"; if an animal showed evidence of diarrhea, the animal was considered unprotected at all subsequent times.

The mean effective antidiarrheal doses (ED 50 values) for the individual components and for the combinations were determined on the basis of the dose-response data generated with the above-mentioned test protocol, hourly up to six hours after the treatment. Drug interactions were evaluated using the model developed by Finney, Probit Analysis, Cambridge Univ. Press, 3rd edition (1971) and Bliss, Ann. Appl. Biol. 26, p. 585-615 (1939). If the slopes of dose-response data for the individual drugs and their combination were parallel, the data were analyzed according to the simple similar effect model. In those cases where there was significant non-parallelism, the data were analyzed according to the model of independent joint effects.

Results

The ED50 of the individual drugs and the actual and predicted ED50 of the combinations are tabulated below; unless otherwise noted, data were analyzed according to the simple similar effect model: ED50 values ​​(mg / kg) combination ratio actual (NSAID + polymer) predicted NSAID + polymer relative increase IBF / PS (1 hour) single Drugs 1. Because of significant non-parallelism, the data does not fit the simple similar effect model and was analyzed as an independent joint effect.

Based on the relative effectiveness of the actual value to the predicted values, a significant increase in effectiveness was found with ibuprofen / psyllium seed ratios of 1:75, 1: 200 and 1: 400. The effectiveness of the combinations after 1 hour was 64-69% greater than expected based on the individual components. After 2 hours, the effectiveness of the 1: 400 ratio was 86% greater than expected. The interaction for ibuprofen and psyllium seeds 1 hour after stimulus is shown in the drawing by data in Loewe isobolograms (S. Loewe: Pharm. Rev. 9: 237-242, 1957). In the drawing, the diagonal line connecting the ED50 of the two separately given drugs represents simple additivity of the drug effects. The dashed lines on either side of the diagonal line indicate the 95% confidence limits for this additivity line. The ED50 values ​​of the combinations that fall below the curve (between the lower dashed line and the origin) indicate the potentiation (unexpected increase) of the effects, while those above the upper dashed line show an antagonism between the two drugs would suggest. The four diagonal lines radiating from the origin represent the dose ratios of ibuprofen to psyllium seeds used in rats given the combined drug doses. The horizontal and vertical stripes through each ED50 point are the 95% confidence limits. The visual estimates from the isobologram of the drawing indicate that in the method of the invention, compositions with a ratio of an NSAID compound such as ibuprofen to a polymeric water absorbent such as psyllium seeds from 1:30 to greater than 1: 400 unexpectedly one result in increased effectiveness.

The relative efficacy data in the table set out above shows that the combination of indomethacin with water-absorbent polymeric psyllium seeds was up to four times more effective than predicted based on an addition of the efficacies of indomethacin and psyllium seeds after 1, 2 and 4 hours. The efficacy of the combination of ibuprofen and glucomannan was 37% greater than expected based on the efficacy of the individual components and the efficacy of the combination of Aspirin® and psyllium seeds was 28 to 56% greater than expected based on the efficacy of the individual components.