Diarrhea can be a debilitating disease in both children and adults. In developing countries diseases that result in diarrhea are the largest single cause of death among infants and children. Fluid and weight loss from diarrhea can result in severe dehydration, electrolyte imbalance, and acid-base disturbance.
The development of oral rehydration therapy has reduced morbidity and mortality from acute diarrheal diseases, particularly in less developed countries. Oral rehydration solutions (ORS) typically consist of a mixture of electrolytes and a carbohydrate component such as glucose or sucrose. The World Health Organization (WHO) recommends that oral rehydration solutions contain 20 g of glucose, 3.5 g sodium chloride, 2.5 g sodium hydrogen carbonate, 2.9 g trisodium citrate dehydrate and 1.5 g potassium chloride. These are to be mixed with one liter of water. This and similar glucose-based oral rehydration solutions have provided a simple means for treating or preventing dehydration due to acute diarrhea in infants and children. However, while glucose-based solutions stimulate the intestinal absorption of fluid and electrolytes from isotonic luminal contents, they do not aid in the reabsorption of fluid secreted by the intestine and thus do not lessen the severity of diarrhea. This lack of efficacy in controlling diarrhea constitutes a barrier to global acceptance of oral rehydration therapy and indicates that there is a need for a superior product.
Many studies have indicated that oral rehydration solutions prepared from rice may not only ameliorate dehydration, but may also decrease diarrheal fluid loss and reduce stool output. Rice is cheap, safe, and easily obtained and eaten by a large fraction of the world population. However, rice, as used in several studies discussed below, has some disadvantages including the need for cooking, the possibility of incorrect preparation, its relative insolubility in liquid resulting in rapid precipitation after mixing, and the need for it to be spoon fed to infants. The rice-based oral rehydration solution of the instant invention, produced through a process that utilizes enzymatic digestion of the cellulose and protein fractions of rice flour, retains the advantages of a rice-based solution and overcomes these disadvantages.
Patra et al., (Archives of Disease in Childhood, 57:910-912, 1982) demonstrated in a controlled trial of oral rehydration therapy for infants and young children with acute diarrhea the superiority of a rice-based oral solution to the WHO recommended glucose electrolyte solution as shown by a lower rate of stool output, a shorter duration of diarrhea, and a smaller intake of rehydration fluid. In the solution of Patra et al. glucose was replaced by "pop rice" powder. Pop rice, which is commonly consumed in the Indian subcontinent, is prepared by popping unhusked rice on heated sand. In this study the pop rice was made into powder form and dissolved in the rehydration fluid before use. The rehydration solution was fed by cup and spoon or directly from a cup. Thus, although the efficacy of a rice-based solution was demonstrated, the methods of preparation and delivery had the disadvantage of requiring on-site activity by the person feeding the patient.
In a randomized trial of children and adults suffering from cholera or cholera-like diarrhea, Molla et al., (Bulletin of the World Health Organization, 63(4):751-756, 1985) found that rice-based oral rehydration solutions decreased the stool volume more effectively than glucose or sucrose oral rehydration solutions. In this study, rice powder was boiled in water to produce a colloidal suspension. After cooling, electrolytes were added to the gruel mixture. The mixture had to be prepared shortly before administration and was fed to patients by their attendants.
Bhan et al., (Journal of Pediatric Gastroenterology and Nutrition, 6:392-399, 1987) found a trend toward improvement in efficacy, as measured by recovery from diarrhea with 72 hours, with pop rice ORS as compared with the standard glucose electrolyte solution or with a mung bean solution in children suffering from acute diarrhea caused predominantly by rotavirus or Escherichia coli. In this study rice was obtained from the local market and made into powder form before use. It was then mixed in boiled water, and given to the mother to be fed by cup and spoon.
In a controlled clinical trial with infants with acute diarrhea El-Mougi et al., (Journal of Pediatric Gastroenterology and Nutrition 7:572-576, 1988) demonstrated the efficacy of rice powder-based oral rehydration solutions. Rice powder and salts were placed in packets and dissolved in hot water and stirred at the time of utilization. It was then cooked until a gel was formed, cooled, and consumed warm in a semi-liquid form. It was determined that the rice powder-based ORS did not ferment before 24 hours even without refrigeration. Outcome measurements, including watery stool output, showed that rice ORS is at least as good, and possibly better than glucose ORS therapeutically and nutritionally. The authors concluded by advocating additional food technology research to make a rice enriched ORS ready for use by mothers who do not read directions well. The present inventors have produced such a product.
Results of a clinical trial reported by Pizarro et al., (New England Journal of Medicine 324:517-521, 1991) indicated that stable, ready-to-use commercially prepared rice-based oral electrolyte solutions containing rice-syrup solids were more efficient than glucose-based solutions in promoting fluid and electrolyte absorption during rehydration in infants with acute diarrhea. This study demonstrates the utility of a rice-based, ready-to use commercially prepared ORS. However, the rice-based ORS of this study contained only rice glucose polymers, not whole rice, unlike the present invention, and the solution was not produced by the method of the present inventors.
Gore et al., (British Medical Journal 304:287-291, 1992) undertook a meta-analysis of clinical trials that compared the benefit of rice oral rehydration salts solutions with the glucose-based WHO oral rehydration salts solution for treating and preventing dehydration in patients with severe dehydrating diarrhea. Using stool output during the first 24 hours as the main outcome measure they found that rice solution significantly reduces stool output in adults and children with cholera and to a lesser extent reduces the rate of stool loss in infants and children with acute non-cholera diarrhea. This meta-analysis serves to confirm the results of previous individual trials of rice-based solutions, thereby underscoring the desirability of producing a product that delivers a rice-based ORS in a commercially available, safe, and easily ingested form as was done by the present inventors.
Islam et al., (Archives of Disease in Childhood 71:19-23, 1994) conducted a prospective, randomized controlled trial to evaluate the efficacy and digestibility of rice-based oral rehydration therapy in infants less than 6 months old compared with WHO ORS. The results of this trial support the hypothesis that rice oral rehydration therapy can be safely and effectively used in the management of acute diarrhea in infants younger than 6 months. These findings are consistent with the results of previous studies, discussed above, conducted with older children and adults.
Tao et al.(U.S. Pat. No. 5,096,894) disclose a ready-to-use ORS comprising a mixture of rice dextrin and electrolytes and a process for clarifying rice dextrins. Rice dextrins are rice syrup sugars containing glucose polymers of varying lengths. By contrast the present inventors use rice flour obtained from ground rice in the preparation of a ready-to-use ORS or an ORS in powdered form. Tao et al. teach that rice flour is not suitable as a carbohydrate component for a clear, shelf-stable, ready-to-use ORS because of its insolubility, product appearance, and problems associated with sterilization. These problems have all been successfully solved in the instant invention, which has the additional attribute of being nipple feedable.
Lebenthal (U.S. Pat. No. 5,120,539, WO 92/12721) discloses a method for treating diarrhea in infants by administering a solution containing a complex carbohydrate that has been hydrolyzed by .alpha.-amylase. Rice powder is one of the carbohydrates that can be used in preparing the diarrhea treatment product disclosed by Lebenthal. Lebenthal does not address problems of osmolality and the propensity of the powder to precipitate out of solution. By contrast, the instant invention results in a stable product of low osmolality capable of being ingested through the nipple of a bottle.
Shacknai et al. (Wo 91/15199) disclose a composition for treating diarrhea that is suitable for children and adults and comprises a nutritional substance, a synthetic fiber, and electrolytes. Rice flour is one of the nutritional substances that can be used in this composition. Method and conditions of production are not taught, nor is product stability or viscosity addressed.
An object of the present invention is to provide a ready-to-use ORS containing rice flour in a stable form with low osmolality and low viscosity suitable for delivery to infants through the nipple of a bottle, or a powdered form of the product that can be reconstituted before use and that has the same desirable properties. A further object of the present invention is to provide an improved rice flour based ORS that results in lower net fluid intake and reduced stool output during the rehydration period of treatment of children with dehydration caused by acute diarrhea.