MXPA99003517A - Enteric formulations of proanthocyanidin polymer antidiarrheal compositions - Google Patents

Abstract

Pharmaceutical compositions containing a proanthocyanidin polymer composition which are useful for the treatment and prevention of secretory diarrhea are provided. The invention specifically relates to pharmaceutical formulations of a proanthocyanidin polymer composition which has been isolated from a Croton spp. or a Calophyllum spp. In particular, the invention relates to a formulation of a proanthocyanidin polymer composition which protects the composition from the effects of stomach acid after oral administration, particularly to those formulations which are enteric coated. Methods for use of the formulations as well as methods for use of the proanthocyanidin polymer composition in combination with an effective amount of a compound effective either to inhibit secretion of stomach acid or to neutralize stomach acid are disclosed.

Description

ENTRERIC FORMULATIONS OF ANTI-DIARRHEA COMPOSITIONS OF PROANTOCIANIDINE POLYMERS 1. FIELD OF THE INVENTION The present invention relates to pharmaceutical formulations of proanthocyanidin polymer compositions that are effective for the treatment of diarrhea. Particularly, the invention relates to pharmaceutical formulations of a proanthocyanidin polymer composition, which has been isolated from a Croton spp or Calophyllum spp, said formulations are effective for the treatment of secretory diarrhea, particularly for the reduction of fluid loss and the resulting dehydration associated with secretory diarrhea. A preferred embodiment of the present invention relates to pharmaceutical formulations - of proanthocyanidin polymer compositions which protect the compositions against the acidic environment of the stomach after oral administration, and particularly to enteric-coated formulations. 2. BACKGROUND OF THE INVENTION Quotations or identification of any reference in Section 2 or any other section of this application should not be construed as recognition that said reference is available as a prior art for the present invention. 2. 1 SECRETARY DIARRHEA Secretory diarrhea, also known as watery diarrhea, is the main source of disease and mortality in developing countries, particularly infants and young children, and also affects a significant proportion of visitors from developed countries who travel to developing countries and can also affect anyone visiting a foreign country (what is known as "traveler's diarrhea"). The secretory diarrhea is characterized by the loss of fluid and the loss of electrolytes through the intestinal tract, which causes severe dehydration and endangers life. Secretory diarrhea is caused by several bacterial, viral, and protozoan pathogens and is also caused by other non-infectious etiologies such as, for example, ulcerative colitis, inflammatory bowel syndrome, and cancer and neoplasms of the gastrointestinal tract. In fact, it is believed that all types of diarrheal diseases may have a secretory component. The two main bacterial sources of secretory diarrhea are Vibrio cholerae and Escherichia coli. The enterotoxigenic types of E. coli represent a major source of secretory diarrhea in developing countries and are the leading cause of traveler's diarrhea. Other strains of E. coli that cause diarrhea include enterohemorrhagic, enteroinvasive and enteropathogenic strains. Other bacterial agents that cause secretory diarrhea include other Vibrio spp., Campylobacter spp., Salmonella spp., Aeromonas spp. , Plesiomonas spp., Shigella spp., Klebsiella spp. , Citrobacter spp.-, Yersinia spp., Clostridium spp., Bacteriodes spp. , Staphylococcus spp., And Bacillus spp, as well as other enteric bacteria. Secretory diarrhea can also be caused by protozoan pathogens such as, for example, Clyptosporidium spp, for example Cryptosporidium parvum. See generally Hollan, 1990, Clinmicrobiol. Rev. 3: 345; Harris, 1988, Ann. Clin. Lab. Sci. 18: 102; Gracey, 1986, Clin. In Gastroent. 15:21; Ooms and Degryse, 1986, Beterinary Res. Comm. 10: 355; Black, 1982, Med. Clin. Ñor Am., 66: 611. V. cholerae, the enterotoxigenic strains of E. coli and several other enteric bacteria cause secretory diarrhea by similar mechanisms. These pathogens produce a toxin that binds to a specific receptor in the apical membrane of the intestinal epithelium. The binding of the receptor triggers signal transduction mediated by adenylate cyclase or guanylate cyclase that causes an increase in cAMP or cGMP. This regulatory cascade, apparently acting through the phosphorylation of specific apical membrane proteins, stimulates chloride efflux in the intestines from intestinal epithelial crypt cells and inhibits the normal resorption of sodium and chloride ions by hairless cells. intestinal epithelial. The increase in the concentration of chloride and sodium ions osmotically attracts water in the intestinal lumen, which results in dehydration and loss of electrolytes. Agents that reduce the chloride ion secretion will therefore prevent the movement of fluid in the intestines and the net elimination of the resulting fluid. Accordingly, such agents are essentially useful for the treatment and prevention of dangerous dehydration and loss of electrolytes associated with secretory diarrhea. The pharmaceutical compositions of the present invention are especially useful for the treatment of traveler's diarrhea and non-specific diarrhea. Traveler's diarrhea, which is a type of secretory diarrhea, is defined as diarrhea that affects citizens of industrialized countries when they travel to "third world" countries. An example of traveler's diarrhea is the diarrhea suffered by North American citizens who travel to Mexico for the first time and have diarrhea within three to five days after their arrival (Catelli & amp; amp;; Carose, 1995, Chemotherapy 4 (supp.l): 20-32). It is estimated that bacteria are responsible for 85% of cases of traveler's diarrhea, with the main etiological agents being Escherichia coli enterotoxigenica (ETEC), Shigella spp, and Campylobacter jejuni. Protozoa and viruses also cause traveler's diarrhea but less frequently than bacteria (DuPont, 1995, Chemotherapy 4supp.1): 33-39). In Mexico, in the summer months (from May to November), the predominant etiologic agent associated with traveler's diarrhea is ETEC, while in the winter months the main organism is Capylobacter jejuni (DuPont, 1995, "Traveler's diarrhea", M. Blaser et al., Eds., Pages 299-31, Raven Press, New York). Approximately 40% of people in the United States who travel to Mexico for the first time suffer from traveler's diarrhea. In contrast to traveler's diarrhea, nonspecific diarrhea (NSD), which also appears to have a secretory component, is an acute, endemic, diarrheal disease afflicting indigenous populations. The rate of attacks of non-specific diarrhea in Mexican residents is 7% (H. L. DuPont personal communication). Unlike traveler's diarrhea, however, nonspecific diarrhea usually does not respond to antibiotic therapy and its etiology is unknown. Since 1975, DuPont and colleagues at the University of Texas Health Sciences Center in Houston have conducted a series of clinical trials in Mexico to study the efficacy of several antidiarrheal drugs. Based on the results of the placebo groups of these studies, they were able to characterize the natural history of traveler's diarrhea and non-specific diarrhea in Mexican and Mexican national passers-by, respectively. The data show clear differences in both intensity and duration of diarrheal disease between patients with traveler's diarrhea in the summer and patients with non-specific diarrhea. In 5-day evaluations, the duration of the illness (average time to the last stools not formed since the time of the beginning of the participation in the study) was 69 hours in the case of North American travelers compared to 38 hours in the case of Mexican nationals (p = 0.0001). If the total number of evacuations that happened from the time of the beginning of participation in the study is analyzed (0-120 hours), travelers from the United States of America have 10.6 evacuations versus 5.6 evacuations in the case of Mexican residents ( p = 0.0001) (HL DuPont, personal communication). Even though we do not have much data on travelers' diarrhea that occurs in the winter months in Mexico in general, diarrheal disease in newcomers from the United States of America is similar to diarrhea suffered by American residents after a stay. of several months in Mexico. It tends to be less severe than traveler's diarrhea in the summer, and more severe than non-specific diarrhea (H.L. DuPont, personal communication). The secretory diarrheas are also associated with viral infections such as diarrheas that accompany infection with the Human Immunodeficiency Virus (HIV) as well as Acquired Immune Deficiency Syndrome (AIDS), and rotavirus infection in particular, almost all patients with AIDS suffer from diarrhea at some point during the course of the disease and 30% of patients with AIDS suffer from chronic diarrhea. The diarrhea that accompanies AIDS has been called chronic diarrhea associated with HIV. This diarrheal component of HIV disease is believed to be caused, at least in some patients, by a secondary infection of protozoan pathogens, particularly Cryptosporidium spp. In addition, rotavirus infection is a major cause of diarrhea, especially in infants and young children in developing countries. Secretory diarrhea is also a major problem in non-human animals, particularly in animals of agricultural holdings such as cattle, pigs, sheep, birds, especially chickens, as well as equine animals and other domestic animals such as, for example, canine and feline animals. Diarrheic disease is especially common in animals on young and recently weaned farms. Diarrheal disease in farm animals, especially animals raised for food such as cattle, sheep and pigs, is frequently caused by bacterial pathogens such as enterotoxigenic, enterohemorrhagic and other E coli, Salmonella spp., Clostridium perfringens, Bacteriodes fragilis , Campyobacter - spp., And Yersina enterocolitica. In addition, protozoan pathogens, particularly Cryptosporidium parvum, and viral agents, particularly rotaviruses and coronaviruses, are significant causes of diarrhea in farm animals. Other viral agents that have been implicated in the diarrhea of farm animals include togaviruses, parvoviruses, caliciviruses, adenoviruses, bredaviruses, and astroviruses. See generally Holland, 1990, clin. Microbiology Rev. 3 .: 345; see also Gutzwiller and Blum, 1996, AJVR 57:56; Strombeck, 1995, Veterinary Quarterly 17 (Suppl 1): S12; Vermunt, 1994, Austral. Veterinary j. 71:33; Driesen et al., 1993, Austral. Veterinary J. 70: 259; Mouricout, 1991, Eur. J. Epide iol. 7: 588; Ooms and Degryse, 1986, Veterinary Res. Comm. 10: 355 2.2 PLANT EXTRACTS CONTAINING TANNINS OR PROANTOCIANIDINS AND USE AGAINST DIARRHEA Tannins are found in a wide variety of plants and are classified as hydrolysable or condensed. Proanthocyanidins are a group of condensed tannins and are further described below. Many plants used in traditional medicine as a treatment or prophylaxis for diarrhea contain tannins and proanthocyanidins in particular, (see, for example, Yoshida et al., 1993, Phytochemistry 32: 1033, Yoshida et al., 1992, Chem. Pharm. Bull. , 40: 1997; Tamaka et al., 1992, Chem. Pharm. Bull. 40: 2092). Raw extracts of medicinal plants, for example, Pycanthus angolenis and Baphia crisp, have anti-diarrheal qualities in animal tests (Onwukaeme and Anuforo, 1993, Discovery and Innovation, 5: 317, Onwukaeme and Lot, 1991, Phytotherapy Res., 5: 254 ). Crude extracts containing tannins, particularly extracts of carob bean pods and sweet chestnut wood, have been proposed as treatments or prophylactic treatment of diarrhea (European Patent Number 5,043,160; European Patent Number 481, 396). Raw plant extracts containing proanthocyanidins were also proposed as treatments or prophylactic treatment of diarrhea. For example, crude fruit cascade extracts containing anthocyanidins as well as other compounds have been suggested for use against diarrhea (North American Patent Number 4,857,327). The bark of the Q. Pétrea tree, which is traditionally used against diarrhea, contains oligomeric pro-ancyanidins (Konig and Scholz, 1994, J. Nat. Prod.57: 1411, Pallenbach, 1993, Planta Med., 59: 264). A fraction of bark extract from Sclerocarya birrea, which also contains procyanidins, reduced intestinal contractions associated with experimentally induced diarrhea (Galvez et al., 1993, Phyt. Res., 7:25; Galvez et al., 1991, Phyt. Res., 5: 276). However, none of these studies demonstrates that proanthocyanidins are specifically responsible for the antidiarrheal activity of the extracts. Other studies suggest that certain preparations containing proanthocyanidins may interfere with the action of cholera toxin in the intestines. The crude extract of tea containing catechins (proanthocyanidin monomers), prevents the morphological changes induced by cholera toxin in cultured CHO cells and the accumulation of intestinal fluid induced by cholera toxin in mice when said extract was administered five minutes after the cholera toxin (Toda et al., 1991, J. App. Bact., 70: 109). However, the crude tea extract could not prevent the accumulation of fluid in the mouse intestine when administered 30 minutes after the cholera toxin, and the catechins were not shown to be the active agent of the extract. In addition, a fraction of Guazuma ulmifolia extract containing proanthocyanidins reduced the flow of ions induced by cholera toxin in intestinal tissue isolated from rabbit, apparently through a physical interaction of polymeric proanthocyanidins with cholera toxin as determined by of an SDS-PAGE analysis (Horn et al., 1996, Phytochemistry 42: 109; Horn et al., 1995, Planta Med., 61: 208). The addition of the fraction after the addition of the cholera toxin, however, had no effect on the secretion of fluoride ion. Thus, completely contrary to the present invention is the fraction could not effectively reduce or prevent the loss of fluid after exposure to the agent causing the secretory diarrhea and therefore can not be useful as a therapeutic agent to control secretory diarrhea. Proanthocyanidins have different physiological effects, according to its structure and source. Other proanthocyanidins are in fact contraindicated for the treatment or prevention of diarrhea. Oligomeric proanthocyanidins isolated from black beans showed increased chloride secretion and reduced sodium resorption in isolated intestinal tissue (Silverstein, 1989, "Procyanidin from Black Bean (Phaseolus Vulgaris): Effects on Transport of Sodium, Cloride, Glucose, and Alanine in the Rat Ileum, (Black Bean Procyanidin) (Phaseolus Vulgaris): (Effects on the Transport of Sodium, Chloride, Glucose and Alanine in Rat Ileum), Washington State University (Thesis)). The increased ionic concentration in the intestine would therefore promote the accumulation of fluid in the intestinal Lumen and would gratify the loss of fluid and electrolyte and the dehydration associated with secretory diarrhea. In fact, the reference specifically teaches that proanthocyanidins should not be used for the treatment of diarrhea and suggests that pro-cyanidinins may cause secretory diarrhea. 2.3 PROANTOCIANIDINES Proanthocyanidins and proanthocyanidin polymers are phenolic substances found in a wide variety of plants, particularly plants that grow in a wooded environment (for example, Croton spp and Calophyllu spp.). The general chemical structure of a polymer proanthocyanidin consists of linear chains of units of 5, 7, 3 ', 4' tetrahydroxy or 5, 7, 3 ', 5'pentahydroxy flavonoid 3-ol joined together through common bonds C ( 4) - (6) and / or C (4) -C (8) as shown below.

Biosynthetic studies have indicated that proanthocyanidin polymers consist of monomer units of the type illustrated below. See Fletcher et al., 1977, .c.S. Perkin, 1: 1628. 2 »R * H 2b R = OH The monomeric unit (generally called "leucoanthocyanidin") of the polymer chain can be based on either two stereochemistries of the C ring, in a 2 and / or 4 position called cis (epicatechin) or trans (catechin). Accordingly, the polymer chains are based on different structural units: they create a wide variation of polymeric proanthocyanidins and a large number of possible isomers (Hemingway et al., 1982, J.C.S. Perkin, 1: 1217) 13 CNMR has been useful in identifying the structures of polymeric proanthocyanidins and a recent study has elucidated the chemistry of bimeric, trimeric and tetrameric proanthocyanidins. Larger polymers of the 3-ol flavonoid units predominate in most plants and are found with average molecular weights greater than 2,000 daltons, and contain 6 or more units (Newman et al., 1987, Mag. Res. Chem. 25 : 118). 2.4. ETHNOBOTANICAL USES OF EXTRACTS AND COMPOUNDS OF CROTON AND CALOPHYLLUM SPECIES Several different types of Croton tree, including Croton sakutari, Croton gossypifolius, Croton palanostima, Croton lechleri, Croton erythrochilus and Croton draconoides, found in South America, produce a sap of red viscous latex type called Dragon's Blood. The Dragon Blood is frequently used by mestizos and indigenous people of the Amazonian region of Peru to treat cold and diarrhea. It is taken internally for tonsillitis, throat infections, tuberculosis, peptic ulcers, intestinal disorders, rheumatism and to increase fertility and is used by both adults and children. It is also used very frequently to stop bleeding, to cure injuries caused by the herpes virus and to heal wounds. The sap is placed directly on open wounds as an anti-infective substance and to accelerate the healing process. It is also used as a vaginal wash in cases of excessive bleeding. It has been found that Dragon Blood draconoides and Croton lechleri contain an alkaloid identified as taspina, which has an anti-inflammatory activity (Persinos et al., 1979, J. Pharm.Sci., 68: 124). Taspina also inhibits RNA-directed DNA polymerase activity in bird myeloblastosis virus, Rauscher leukemia virus, and monkey sarcoma virus (Sthi, 1977, Canadian J. Pharm. Sci. , 12: 7). Several phenolic and diterpene compounds isolated from the Dragon's Blood were tested to determine their antitumor, antibacterial and wound healing properties (Chen et al., Panta Med., 60: 541). The proanthocyanidins in the sap showed little antitumor or antibacterial activity and a slight wound healing activity. U.S. Patent No. 5,211,944, described for the first time the isolation of proanthocyanidin polymer composition from Croton spp and the use of the composition as an antiviral agent (see also Ubillas et al., 1994, Phytomedicine, 1:77). The polymer composition of proanthocyanidin has an antiviral activity against several viruses including herpes viruses, for influenza, parainfluenza, respiratory syncytial.

Calophyllum inophylum is a tree that is found from India to the eastern part of Africa and Polynesia. The oil of the seeds of this tree is used in folk medicine as anti-parasitic in the treatment of mange, tub, and dermatosis as well as for other uses such as, for example, analgesic. In Indochina, the resin powder is used for the treatment of ulcers and the healing of wounds. In Indonesia, the cortex is applied externally to treat swollen glands and, internally, diuretic. The saps are used as an emollient for chest pain as well as for tumors and swelling. Leaf extracts are used as a rinse for inflamed eyes. Cambodians use leaf extracts in inhalations for the treatment of vertigo and migraine. Natives of Samoa use sap as poison for dates. The American patent number 5, 211,944 also present the isolation of a proanthocyanidin polymer composition from Calophyllum inophylum and the use of this composition as an antiviral agent. It has been determined that the proanthocyanidin polymer compositions of the present invention are unstable in the presence of acids and subject to deactivation by the acid environment of the stomach. Prior to the present application, no presentation has been made of the pharmaceutical composition of a proanthocyanidin polymer composition isolated either from Croton spp or from Calophyllum spp which protects the composition of proanthocyanidin polymers against the acidity of the gastric fluid of such Thus, the proanthocyanidin polymer composition can be administered orally for the treatment of secretory diarrhea. There remains a need for an effective pharmaceutical composition, whose administration reduces the flow of ions in the intestine caused by secretory diarrhea. This agent would be useful to avoid the loss of fluid and electrolyte and dehydration caused by secretory diarrhea. The object of the present invention is to provide an effective pharmaceutical formulation of an antidiarrheal agent that meets this need, and specifically to provide a pharmaceutical formulation that protects the antidiarrheal agent from the acidity of the stomach as well as methods for the treatment of diarrhea using the formulation pharmaceutical 3. COMPENDIUM OF THE INVENTION The present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of an antidiarrheal agent comprising a proanthocyanidin polymer composition. The polymer composition of proanthocyanidin is prepared from a Croton spp, preferably Croton lechleri. The polymer composition of proanthocyanidin can also be prepared from Calophyllum spp. , particularly Calophyllu inophylum. The pharmaceutical compositions of the present invention are formulated to protect the polymer composition of proanthocyanidin against degradation by acidic conditions of the stomach. In a preferred embodiment, the proanthocyanidin composition is enteric coated. In another preferred embodiment, the proanthocyanidin polymer composition is provided in combination with a substance to reduce the secretion of stomach acid or layers to reduce the acidity of the stomach fluid. The present invention also encompasses methods for treatment and diarrhea, particularly secretory diarrhea, in warm-blooded animals, including humans, comprising administration to a non-human animal, or a human being suffering from diarrhea, of a composition Pharmaceutical comprising a therapeutically active amount of a proanthocyanidin polymer composition isolated from a Croton spp, or Calophyllum spp. or a pharmaceutically acceptable derivative thereof formulated to protect the proanthocyanidin polymer composition against the action of stomach acids, and a pharmaceutically acceptable carrier. In addition, the present invention encompasses methods for the treatment of secretory diarrhea in animals, including humans, comprising administration to a non-human animal or to a human suffering from diarrhea, of (a) a pharmaceutical composition comprising a therapeutically effective amount of a proanthocyanidin polymer composition isolated from a Croton spp. or a Calophyllu spp, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier; and (b) a pharmaceutical composition comprising either an effective amount to inhibit the secretion of stomach acids from a compound that is effective to inhibit the secretion of stomach acids or that comprises an amount effective to neutralize stomach acids from a compound that it is effective to neutralize stomach acids and, a pharmaceutically acceptable carrier. The present invention also provides methods for preventing diarrhea in warm-blooded animals, including humans comprising administration to a non-human animal or to a human being at risk of developing diarrhea, of a pharmaceutical composition comprising an amount prophylactically effective of a proanthocyanidin polymer composition isolated from a Croton spp or Calophyllum spp. or a pharmaceutically acceptable derivative thereof, formulated to protect the polymer composition of proanthocyanidin against the action of stomach acids, and a pharmaceutically acceptable carrier. 4. BRIEF DESCRIPTION OF THE FIGURES Figure 1. A layer of HPLC chromatograms showing the chromatographic profiles of the proanthocyanidin polymer compositions from C. Lechleri after various treatments such as absorption of UV radiation in milliabsorption units (mAU) over the chromatography time in minutes. The chromatogram plotted in the form of the dotted line represents the profile of the proanthocyanidin polymer composition after incubation in water ("in water"), the solid line represents the profile of the proanthocyanidin polymer composition after incubation in HCl for 0.03 hours ("HCl after 0.03 hours"), and the dashed line represents the polymer composition of proanthocyanidin from the profile of C. lechleri after incubation in HCl for 2.0 hours ("HCl after 2.0 hours") . Figure 2. An HPLC chromatogram of a sample of the proanthocyanidin polymer composition from C lechleri after incubation in simulated gastric fluid at a temperature of 37 ° C for 0.03 hours. The chromatogram is represented in the graph as UV radiation absorption (mAU) in minutes. Figure 3. An HPLC chromatogram of a sample of the proanthocyanidin polymer composition from C. Lechleri after incubation in simulated gastric fluid at a temperature of 37 ° C for 2 hours. The chromatogram is graphically represented as the absorption of UV radiation (mAU) over time in minutes. Figure 4. An HPLC chromatogram of a sample of the proanthocyanidin polymer composition from C. lechleri after incubation in simulated gastric fluid at a temperature of 37 ° C for 2 hours, and followed by incubation for an additional 4 hours after 1: 1 dilution in simulated intestinal fluid. The chromatogram is presented by a graph as UV absorption (mAU) over time in minutes. Figure 5. An HPLC chromatogram of a sample of the proanthocyanidin polymers composition from C. Lechleri after incubation in simulated gastric fluid at a temperature of 37 ° C for two hours, followed by incubation for an additional 6 hours after of 1: 1 dilution in simulated intestinal fluid. The chromatogram is presented in graph as UV radiation absorption (mAU) over time in minutes. Figure 6. A graph of the percentage of peak area ("peak area percentage"), as calculated by the peak area definition of the HPLC profile of the proanthocyanidin polymer composition of C. Lechleri in the test medium by area peak of the HPLC profile of the proanthocyanidin polymer composition in water and multiplying this by 100, as a function of the incubation time in hours. The line with empty squares represents the percentage peak area of the polymer composition of proanthocyanidin after incubation in SGF (simulated gastric fluid). The dotted line with diamonds represents the percentage peak area of the proanthocyanidin polymer composition after 2 hours of incubation in SGF and then 1: 1 dilution in SIF (simulated intestinal fluid) for further incubation. Figure 7. This bar graph depicts the effect of the enteric coated formulation of the proanthocyanidin polymer composition from C. Lechleri on the accumulation of intestinal fluid in mice exposed to cholera toxin. The results appear as average for each group of A-C mice, of the ratio of fluid accumulation in mg fluid / mg intestine. Mice in group A were treated only with water; mice in group B were treated with 131 mg of proanthocyanidin polymer composition with enteric coating in guar gum / kg; mice in group C received «EUDRAGIT®» and sugar with guar gum. Mice in all groups were evaluated 7 hours after exposure to cholera toxin. See section 7, infra, for more details. Figure 8. This bar graph depicts the effect of the enteric-coated formulation of the proanthocyanidin polymer composition from C. Lechleri on accumulation. of intestinal fluid in mice exposed to cholera toxin. The results appear as average for groups of mice A and B, of the ratio of fluid accumulation in mg fluid / g intestine. The mice of group A were treated "EUDRAGIR®" and sugar in water, and the mice of group B were treated with 131 mg of enteric-coated proanthocyanidin polymer composition / kg. 5. DETAILED DESCRIPTION OF THE INVENTION 5.1 PREPARATION OF THE COMPOSITION OF PROANTOCIANIDINE POLYMERS The proanthocyanidin polymer composition, effective for the treatment of diarrhea, comprises monomeric units of proanthocyanidins. Leucoanthocyanidins are generally monomeric flavonoids which include catechins, epicatechins, gallocatechins, galloepicatexins, flavonols, flavonols, and flavan-3,4-diols, leucocyanidins and anthocyanidins. The polymer composition of proanthocyanidins useful for the treatment of secretory diarrhea comprises polymers of 2 to 30 flavonoid units, preferably 2 to 15 flavonoid units, more preferably 2 to 11 flavonoid units, and more preferably an average of 7. flavonoid units with an average molecular weight of 2100 daltons. The polymer composition of proanthocyanidin used in the present invention is preferably isolated from a Croton spp or Calophyllum spp by the method presented in U.S. Patent No. 5,211,944, which is incorporated herein by reference. In a preferred embodiment, the proanthocyanidin polymer composition is isolated from Croton lechleri. In another embodiment, the proanthocyanidin polymer composition is isolated from Calophyllum inophylum. 5.2 PHARMACEUTICAL FORMULATIONS The polymer composition of proanthocyanidin is unstable in the acidic environment of the stomach and has been found to be stable at a pH of 5.0 to about pH 8.0 (see section 6 below). Thus, the invention offers pharmaceutical formulations of proanthocyanidin polymer compositions that protect the compositions against the acidity of gastric secretions. In a preferred embodiment, the pharmaceutical formulations of the present invention contain the proanthocyanidin polymer composition with an enteric coating together with another pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical compositions containing the proanthocyanidin polymer composition alternatively include one or more substances which either neutralize the stomach acids or are active to prevent the secretion of stomach acids. These formulations can be prepared by methods known in the art, see, for example, the methods described in Pharmaceutical Sciences, 18th Edition, ed. Alfonso R. Gennaro, Mack Publishing Co., Easton, PA, 1990. The polymer composition of proanthocyanidin may be offered in any therapeutically acceptable dosage form. The pharmaceutical composition can be formulated for oral administration such as, but not limited to, pharmaceutical powders, crystals, granules, small particles (including particles of the micrometer size, such as microspheres and microcapsules), particular ( which include particles of the size of the order of millimeters), beads, microbeads, pellets, pills, microtablets, compressed tablets or crushed tablets, molded tablets or crushed tablets as well as capsules, either hard or soft and containing the composition as a powder, particle, bead, solution or suspension. The pharmaceutical composition can also be formulated for oral administration in the form of a solution or suspension in an aqueous liquid, as a liquid incorporated in a gel capsule or as any other formulation suitable for administration, or. for rectal administration, as for example suppository, enema or another convenient form. The polymeric proanthocyanidin composition can also be provided in the form of a controlled release system (see, e.g., Langer, 1990, Science 249: 1527-1533). The pharmaceutical formulation can also include any type of pharmaceutically acceptable excipients, additives or vehicles. For example, but not to limit, diluents or fillers, such as dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, sorbitol, sucrose, inositol, powdered sugar, bentonite, Microcrystalline cellulose or hydroxypropylmethylcellulose can be added to the proanthocyanidin polymer composition to increase the volume of the composition. Also, binders such as, but not limited to, starch, gelatin, sucrose, glucose, dextrose, molasses, acacia gum lactose, sodium alginate, Irish moss extract, panwar gum, can be added to the formulation. ghatti gum, isapol shell mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, Veegum and larch arabogalactan, polyethylene glycol, ethylcellulose, and waxes, in order to increase their cohesive qualities. In addition, lubricants such as talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, carbocera, lauryl sulfate, etc. can be added to the formulation. sodium, and magnesium lauryl sulfate, but not limited to them. Likewise, sliding substances can be added, such as, but not limited to, colloidal silicon dioxide or talcum powder in order to improve the flow characteristics of a powder formulation. Finally, disintegrants may be added, such as, but not limited to, starches, clays, celluloses, algins, gums, cross-linked polymers (eg, croscarmellose, crospovidone, and sodium starch glycolate), Veegum, methylcellulose, agar, bentonite. , cellulose and wood products, natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, or lauryl sodium sulfate with starch, in order to facilitate the disintegration of the formulation in the intestine . In a preferred embodiment of the present invention, the proanthocyanidin polymer composition is formulated with a substance that protects the proanthocyanidin polymer composition against stomach acids. In a more preferred embodiment, the proanthocyanidin composition has an enteric coating. Enteric coatings are coatings that remain intact in the stomach, but dissolve and release the contents of the dosage form once they reach the small intestine. A large number of coatings are prepared with ingredients having acid groups in such a way that the very low pH present in the stomach, ie a pH of 1.5 to 2.5, the acid groups are not ionized and the coating remains in an insoluble form not dissociated At higher pH levels, such as for example levels found in the vicinity of the intestine, the enteric coating is converted to an ionized form, which can be dissolved to release the proanthocyanidin composition. Other enteric coatings remain intact until their degradation by enzymes in the small intestine, and others break after a defined exposure to moisture, in such a way that the coatings remain intact until after passage in the small intestines. Polymers useful for the preparation of enteric coatings include, but are not limited to, shellac, starch and phthalates of amylose acetate, styrene-maleic acid copolymers, cellulose acetate succinates, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate (grades HP-50 and HP-55), ethylcellulose, fats, butyl stearate, and methacrylic acid-methacrylic acid ester copolymers with ionizable acid groups ("EUDRAGIT®") as for example «EUDRAGIT® L 30D», «EUDRAGIT® RL 30D», 2EUDRAGIR® RS 30D »and« EUDRAGIT® L 100-55 ». In a preferred embodiment, the pharmaceutical composition contains a proanthocyanidin polymer composition and the enteric coating polymer "EUDRAGIT®" L 30D ", an anionic copolymer of methacrylic acid and methyl acrylate with an average molecular weight of 250,000 daltons. The disintegration of the enteric coatings occurs either by hydrolysis or intestinal enzymes or by emulsification and dispersion by bile salts, depending on the type of coating used. For example, esterases hydrolyse esterbutyl stearate in butanol and stearic acid, and as butanol dissolves, stearic acid is released from the drug. In addition, bile salts emulsify and disperse ethylcellulose, hydroxypropylmethylcellulose, fats and fatty derivatives. Other types of coatings are removed according to the time of contact with moisture, such as coatings prepared from powdered carnauba wax, stearic acid, and vegetable fibers of agar and elm bark breakage after the plant fibers have absorbed the humidity and they have swollen. The time required for the disintegration depends on the thickness of the coating and the ratio between the vegetable fibers and the wax. The application of the enteric coating on the proanthocyanidin polymer composition can be achieved by any method known in the art for the application of enteric coatings. For example, but not to limit the present invention, the enteric polymers can be applied by using solutions based on organic solvents containing from 5 to 10% w / w of polymer for spray applications and up to 30% w / w of polymer for coating in container. Solvents commonly employed include, but are not limited to, acetone, mixtures of acetone / ethyl acetate, mixtures of methylene chloride / methanol, and tertiary mixtures containing these solvents. Some polymers such as methacrylic acid-methacrylic acid ester copolymers ("EUDRAGIT®") can be applied by using water as a solvent. The volatility of the solvent system must be adapted to avoid glue due to stickiness and to avoid the high porosity of the coating due to premature spray drying or due to polymer precipitation as the solvent evaporates. In addition, plasticizers can be added to the enteric coating to prevent cracking in the coating film. Suitable plasticizers include the low molecular weight phthalate esters, such as for example diethyl phthalate, acetylated monoglycerides, triethyl citrate / polyethylene glycol tributyl citrate and triacetin. In general, plasticizers are added at a concentration of 10% by weight of the weight of the enteric coating polymer. Other additives, such as emulsifiers, for example detergents and simethicone, and powders, such as talc, can be added to the coating in order to improve the strength and smoothness of the coating. In addition, pigments can be added to the coatings to add color to the pharmaceutical formulation. In a preferred embodiment, the pharmaceutical composition of the proanthocyanidin polymer composition is provided as beads with enteric coatings in hard shell gelatin capsules. The beads of proanthocyanidin polymers are prepared by mixing a proanthocyanidin polymer composition with hydroxymethylpropylmethylcellulose and layering the mixture with pellet overlays (sugar spheres). The beads are then coated with an Opadry Clear seal coating (mixed with water). A preferred enteric coating for the proanthocyanidin polymer composition is "EUDRAGIT® L 30D" applied as an aqueous dispersion containing 30% w / w of dry polymer substance, which is supplied with sodium lauryl sulphate at 0.7% NF (FLF) and polysorbate 80 NF at 2.3% (Tween 20) as emulsifiers, to which plasticizers, polyethylene glycol and citric acid esters are added, to improve the elasticity of the coating, and talc is added to reduce the tendency of the enteric coating polymer to agglutinate during the application process and to increase the smoothness of the film coating. The final composition of the enteric coated beads is 17.3% w / w of pellet seeds, 64.5 w / w of proanthocyanidin polymer composition, 1.5% w / w of hydroxypropylmethylcellulose, 0.5% w / w of Opadry Clear, 14.5 % weight / weight of «EUDRAGIT ® L 30D», 1.45% weight / weight of triethyl citrate and 0.25% weight / weight of glyceride monostearate. This pharmaceutical formulation can be prepared by any method known in the art or by the method described in section 8.1, infra. In another preferred embodiment, the pharmaceutical composition of the proanthocyanidin polymer composition is formulated as enteric coated granules or powder. (microspheres with a diameter of 300-500 microns) provided either in hard shell gelatin capsules or suspended in an oral solution for pediatric administration. The enteric coated proanthocyanidin polymer granules or powder can also be mixed with food, particularly for pediatric administration. This preparation can be prepared using well-known techniques such as for example the method described in section 8.2 below. In general, the granules and powder of the proanthocyanidin I polymer composition can be prepared using any method known in the art such as, but not limited to, crystallization, spray drying or any method of grinding, preferably using a mixer / former. of high-speed granules. Examples of high speed granule mixers / formers include the "LITTLEFORD LODIGE®" mixer, the "LITTLEFORD LODIGE ®" granule mixer / former, and the GRAL ® granule mixer / former. During the mixing of the powder with high shear, the solutions of granulation agents, which are known as binders, are sprayed onto the powder to cause the powder particles to agglomerate, thereby forming larger particles or granules. Granulation agents • useful for the preparation of proanthocyanidin polymer composition granules, include, but are not limited to, cellulose derivatives (including carboxymethylcelluloses, methylcellulose, and ethylcellulose), gelatin, glucose, polyvinylpyrrolidone (PVP), starch paste, sorbitol, sucrose, dextrose, molasses, lactose, acacia gum, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage isapol husks, Veegum and larch arabogalastan, polyethylene glycol, and waxes. Granulation agents can be added in concentrations that are 1 30% of the mass of the particles or granules.

The powder or granules of the proanthocyanidin polymer composition are preferably coated using the fluid bedding equipment. The powder granules are then covered with an Opadry clear seal coating (mixed with water). A preferred enteric coating for the proanthocyanidin polymer composition is "EUDRAGIT ® L 30D" which is applied as an aqueous dispersion containing 30% w / w of dry polymeric substance which is supplied with 0.7% sodium lauryl sulfate NF (SLS) ) and 2.3% polysorbate 80 NF (Tween 20) as emulsifiers, to which plasticizers, polyethylene glycol and citric acid esters are added, to improve the elasticity of the coating, and talc is added to reduce the tendency of enteric coating polymers to agglutinate during the application process and to increase the smoothness of the film coating. The final composition of the enteric-coated powder was 81.8% w / w of proanthocyanidin polymer composition, 1.5% w / w of hydroxypropylmethylcellulose, 0.5% w / w of Opadry clear, 14.5% w / w "EUDRAGIT ® L 30D", 1.45% weight / weight of triethyl citrate, and 0.25% weight / weight of glyceride monostearate. The final composition of the enteric coated granules is 81.8% w / w of proanthocyanidin polymer composition, 10% polivilpyrrolidone, 1.5% w / w hydroxypropylmethylcellulose, 0.5% w / w Opadry clear, 14.5% w / w «EUDRAGIT ® L 30D», 1.45% weight / weight of triethyl citrate, and 0.25% weight / weight of glyceride monostearate. The powder particles and granules of enteric coated proanthocyanidin polymer composition can be further suspended in a solution for oral administration, particularly for pediatric administration. The suspension can be prepared from aqueous solutions to which thickeners and protective colloids are added to increase the viscosity of the solution in order to avoid rapid sedimentation of the coated powder particles or granules. Any material that increases the resistance of the hydration layer formed around the particles suspended by molecular interactions and that is pharmaceutically compatible with the composition of proanthocyanidin polymers can be used as an expressor, such as, but not limited to, gelatin, natural gums (e.g., tragacanth, xanthan, guar, acacia, panwar, ghatti, etc.) and cellulose derivatives, e.g., sodium carboxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, etc. ,). Optionally, a surfactant such as Tween may be added to improve the action of the expressing agent. A preferred suspension solution is a 2% w / w solution of hydroxypropylmethylcellulose in water containing 0.2% Tween. In another embodiment, the proanthocyanidin polymer composition is formulated as enteric coated tablets. In this embodiment, the proanthocyanidin polymer composition is formed into granules with any pharmaceutically acceptable diluent (such as those mentioned above) by the methods described above for the preparation of the granules of the proanthocyanidin polymer composition. The granules are then compressed into tablets using any method well known in the art for example, but not limited to the wet granulation method, the dry granulation method or the direct compression method. A preferred diluent is microcrystalline cellulose ("AVICEL ® PH 200/300"). In addition, disintegrants, such as those described above and lubricants such as those described above, can also be added to the tablet formulation. A preferred tablet formulation contains 250 mg of * proanthocyanidin polymer composition, 7.5 mg of disintegrant ("AC-DI-SOL®" (cross-linked sodium carboxymethylcellulose) 1.75 mg of the magnesium stearate lubricant and the weight of "AVICEL® PH 200 / 300 »required for the mixture to reach 350 mg The tablets are coated with an enteric coating mixture prepared from 250 grams of« EUDRAGIT ® L30D-55 », 7.5 grams of triethyl citrate, 37.5 grams of talc and 205 grams of water This formulation can be prepared by any method well known in the art or by the method described in section 8.3 below The proanthocyanidin polymer composition formed into small particles (which include particles of a size u on the order of micrometers, such as microspheres and microcapsules), particles (which include particles with a size of the order of millimeters), pharmaceutical crystals, pellets, pills and microns Roperlas can be coated by using a fluid bed process. This process employs a fluid bedding equipment such as the equipment supplied by «GLATT ®», «AEROMATIC ®», «WORSTER ®», or others, by means of which the nuclei of the proanthocyanidin polymer composition are stirred in a cylindrical containers closed by means of an air stream, which is introduced from below, and the enteric coating is formed by dew, drying in the cores during the fluidization time. To coat the tablets in capsules, an Accela-Cota process ("MANESTRY®") can be used. In this process, the tablets or capsules are placed in a rotating cylindrical casing container with holes and dew units are installed inside the container and the container. Dry air is introduced through rotating tablets or capsules. Any other type of coating container, such as the "GLATT®" immersion process, the "DRIAM®" triple-skin device, the "STEINBERG®" unit, the "PELLEGRINI®" unit, or the "WALTHER" unit ® »can also employees. In another preferred embodiment, the proanthocyanidin polymer composition is provided as a suppository for rectal administration. The suppositories can be formulated with any pharmaceutically acceptable base substance for the preparation of suppositories and which is compatible with the proanthocyanidin polymer composition. Since rectal administration does not expose the composition of proanthocyanidin polymers to the stomach acid environment, pharmaceutical formulations for rectal administration do not require formulation to protect the composition against acidic conditions. Suppository bases that can be used to prepare suppositories with the proanthocyanidin polymer composition include, but are not limited to, cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycol mixtures or polyethylene glycol fatty acids or glycol combinations. surfactant or non-ionic surfactant materials (such as polyoxyethylene sorbitan fatty acid esters (Tweens), polyoxyethylene stearates, and mixtures of fatty acid esters and sorbitan (Span and Arlacel)). However, due to the hydrophilic nature of the proanthocyanidin polymer composition, a hydrophilic base for the suppository is suggested. A preferred suppository formulation for the proanthocyanidin polymer composition is prepared from 91 grams of glycerin, 9 grams of sodium stearate, 5 grams of purified water, and may also be from 5 to 50% weight / weight of the composition of proanthocyanidin polymers. Alternatively, the suppository may contain 10 grams of proanthocyanidin polymer composition, 20 grams of gelatin, and 70 grams of glycerin. Suppositories prepared from the proanthocyanidin polymer composition can be formed by any method known in the art including, but not limited to, compression molding, melting, or preferably molded in the melted state. The method for the preparation of suppositories from the proanthocyanidin polymer composition is described in section 8.4, infra. In another embodiment, the proanthocyanidin polymer composition is formulated with a compound or with several compounds that neutralize stomach acids. Alternatively, the pharmaceutical composition containing the proanthocyanidin polymer composition is administered either concurrently with the administration of a pharmaceutical composition that neutralizes the stomach acids or subsequent to the administration of a pharmaceutical composition that neutralizes the stomach acids. Compounds, such as for example antacids that are useful for neutralizing stomach acids include, but are not limited to, aluminum carbonate, aluminum hydroxide, bismuth subnitrate, bismuth subsalicylate, calcium carbonate, sodium dihydroxyaluminum carbonate, magaldrate, carbonate magnesium, magnesium hydroxide, magnesium oxide, and mixtures thereof. In another embodiment, the proanthocyanidin polymer composition is formulated with a compound or with several compounds that inhibit the secretion of stomach acids. Alternatively, the pharmaceutical composition containing the proanthocyanidin polymer composition is administered either concurrently or subsequent to the administration of an active pharmaceutical composition to inhibit the secretion of stomach acids. Useful compounds for inhibiting the secretion of stomach acids include, but are not limited to, ranitidine, nizatidine, famotidine, cimetidine, and misoprostol. 5.3 APPLICATIONS OR METHODS OF USE The polymer composition of proanthocyanidin reduces chloride flow through intestinal epithelial cells and reduces fluid movement in the intestinal lumen resulting in fluid loss and dehydration associated with secretory diarrhea. Thus, the pharmaceutical formulations and methods of the present invention are useful in prophylactic and therapeutic applications against secretory diarrhea, particularly to prevent dehydration and loss of electrolyte that accompanies secretory diarrhea. The pharmaceutical formulations and the polymer composition of proanthocyanidin can be used therapeutically or prophylactically against any type of secretory diarrhea in humans or animals. In a preferred embodiment, the pharmaceutical formulation is used to treat secretory diarrhea caused by enteric bacteria. These enteric bacteria include, but are not limited to, Vibrio cholerae, E. coli, including enteropathogenic, enterotoxigenic, enteroadherent, enterohemorrhagic, or enteroinvasive types of E. coli, other Vibrio spp., Campylobacter spp., Salmonella spp, Aeromonas spp. , Plesiomonas spp, Shigella spp, Klebsiella spp, Citrobacter spp, Yersina spp, Clostridium spp, Bacteriodes spp, Staphylococcus spp, and Bacillus spp. This modality also includes the treatment of traveler's diarrhea. In another embodiment, the pharmaceutical formulation is used to treat secretory diarrhea caused by protozoa including, but not limited to, Giardia and Cryptosporidium SPP- / particularly Cryptosporidium parvum. In another embodiment, the pharmaceutical formulation is used to treat secretory diarrhea caused by non-infectious etiology, such as, but not limited to, nonspecific diarrhea, intestinal inflammation syndrome, ulcerative colitis, and cancers and neoplasms of the gastrointestinal tract. In another embodiment, the pharmaceutical formulations of the present invention is used for the treatment of chronic diarrhea associated with HIV in patients with AIDS. In another embodiment, the pharmaceutical formulation is used for the treatment of diarrhea in infants or children including, but not limited to, diarrhea caused by rotavirus. The pharmaceutical formulations of the present invention can also be used to treat diarrhea in non-human animals, especially in animals of agricultural holdings such as, but not limited to, bovines, pigs, sheep, birds (such as chickens) and equines and others. domesticated animals such as dogs and cats. Particularly, the pharmaceutical formulations of the present invention can be used to treat diarrheal disease in non-human animals, particularly meat animals such as cattle, sheep and pigs, caused by bacterial pathogens, such as enterotoxigenic, enterohemorrhagic and other E. coli pathogens. , Salmonella spp, Clostridium perfringens, Bacteriodes fragilis, Campylobacter spp, and Yersinia enterocolitica, protozoan pathogens, particularly Cryptosporidium parvum, and viral agents, particularly rotaviruses and coronaviruses, but also togaviruses, parvoviruses, adenoviruses, bredaviruses, and astroviruses. Additionally, the pharmaceutical formulations of the present invention can also be administered prophylactically to humans and non-human animals to prevent the development of secretory diarrhea. As an example, but not to limit the present invention, a pharmaceutical formulation of proanthocyanidin polymer composition can be administered to tourists traveling to a country where there is a risk of traveler's diarrhea, at a time or moments when they are effective in preventing the disease . The pharmaceutical compositions of the present invention can be administered to patients with AIDS to prevent the occurrence of Chronic Diarrhea Associated with HIV. Likewise, the pharmaceutical compositions of the present invention can be administered to children in a community threatened by an epidemic of cholera or an epidemic caused by rotavirus to prevent the spread of the disease. In the same way, the pharmaceutical compositions of the present invention can be administered to animals of agricultural holdings, particularly young or newly weaned animals to avoid the development of diarrheal disease. When employed in accordance with the formulations and methods of the present invention as a treatment for secretory diarrhea, the effective dosage ranges of the pharmaceutical formulations of the proanthocyanidin polymer composition for oral administration are within a range of 0.1 to 100 mg. / kg per day, preferably from about 0.1 to about 40 mg / kg per day, optionally from 0.1 to 25 mg / kg per day, and also optionally from 0.1 to 10 mg / kg per day. It will be noted that the appropriate dose will depend on the type and severity of the secretory diarrhea. It has been found that human subjects can tolerate at least up to 2 grams of the proanthocyanidin polymer composition per day (25-30 mg / kg / day) for up to 2 days. It is believed that doses may exceed 40 mg / kg per day, optionally up to 100 mg / kg per day, if these dosages are necessary to treat secretory diarrhea. When employed in accordance with the formulations and methods of the present invention as a prophylactic treatment for secretory diarrhea, the effective dosage ranges of the pharmaceutical formulations of the proanthocyanidin polymerase composition for oral administration are within the range of 0.1 to 100. mg / kg per day, preferably from 0.1 to approximately 40 mg / kg per day, optionally from 0.1 to 25 mg / kg per day, and also optionally from 0.1 to 10 mg / kg per day. It will be noted that the appropriate dose will depend on the type and severity of the secretory diarrhea to be avoided. It has been found that human subjects can tolerate up to at least 2 grams of proanthocyanidin polymer composition per day (25-30 mg / kg / day) for up to 2 days. It is considered that doses may exceed 40 mg / kg per day, optionally up to 100 mg / kg per day, if such dosages are necessary to prevent secretory diarrhea. The proanthocyanidin polymer composition can be administered for the treatment or prevention of secretory diarrhea of any therapeutically acceptable pharmaceutical form. The pharmaceutical composition can be administered orally, in the following non-limiting forms of the invention: pharmaceutical crystals, granules, small particles including particles of a size of the order of micrometers, such as for example mocroesféras and microcapsules, particles (including particles millimeters in size), beads, microbeads, pellets, pills, microtablets, compressed tablets or crushed tablets, molded tablets, or tablet crushes, and in capsules, which are either hard or soft and contain the composition in the form of a powder, particles, beads, solution or suspension, the pharmaceutical composition can also be administered orally as a solution or suspension in an aqueous liquid, as a liquid incorporated in a gel capsule or as any other formulation suitable for administration, or rectally, as a suppository, enema or another convenient form. In a preferred embodiment, an enteric coated pharmaceutical composition containing the proanthocyanidin polymer composition for the treatment or prevention of secretory diarrhea is administered. Preferred enteric-coated formulations include, enteric-coated beads in a hard-shelled gelatin capsule, enteric-coated microspheres in the hard shell gelatin capsule, enteric-coated microspheres in a suspension or mixed with foods, which are preparations especially suitable for pediatric administration and enteric coated tablets. In another embodiment, the pharmaceutical composition containing the proanthocyanidin polymer composition and a compound that neutralizes stomach acids or inhibits the secretion of stomach acids is administered for the treatment of secretory diarrhea. In another embodiment, a pharmaceutical composition containing the proanthocyanidin polymer composition is administered concurrently or subsequent to the administration of a pharmaceutical composition which either neutralizes the stomach acids or inhibits the secretion of stomach acids for the treatment of secretory diarrhea. The proanthocyanidin polymer composition can also be formulated as a suppository for rectal administration. The pharmaceutical formulations of the present invention can also be administered either alone or in combination with other agents for the treatment or improvement of symptoms of secretory diarrhea such as rehydration agents., antibiotics, anti-mobility agents, and fluid absorbers, such as attapulgite. The pharmaceutical formulations of the present invention can also be incorporated into animal feeds for use in the treatment of secretory diarrhea in animals, such as for example cattle, pigs, sheep, birds, horses, dogs and cats. The following series of examples is presented for the purpose of illustrating and not limiting the scope of the present invention. 6. EXAMPLE: EFFECT OF SIMULATED GASTRIC FLUID, FLUID SIMULATED INTESTINAL AND HYDROCHLORIC ACID ON THE COMPOSITION OF PROANTOCIANIDINE POLYMERS FROM DE C. Lechleri After the oral administration of the proanthocyanidin polymer composition from C. Lechleri, neither the polymers nor the polymer derivatives were detected in plasma samples from humans or animals. However, polymers were detected and these polymers quantified in animal plasma after intravenous administration. This entails the hypothesis that the composition of proanthocyanidin polymers, when administered orally, is altered in the gastrointestinal tract and a species that is derived from the proanthocyanidin polymer composition but is not detectable by the HPLC method used, is then absorbed in a systemic circulation. A second possibility is that the proanthocyanidin polymer composition is absorbed intact in the gastrointestinal tract but is rapidly transformed after absorption. There is another possibility that the polymers of. Proanthocyanidin of large molecular weights are not absorbed neither in the stomach nor in the intestine. Therefore, this research was conducted to understand the effects of HCl, simulated gastric juice, and simulated intestinal fluid on the stability of the proanthocyanidin polymer composition from C. lechleri. These conditions were chosen to mimic the chemical conditions of the digestive tract. Incubation with HCl produced a reduction of about 25% in the concentration of the proanthocyanidin polymer composition within a few minutes. A similar reduction of 32% was observed within a few minutes after the incubation of simulated gastric confluent proanthocyanidin polymer (SGF) composition, and a 48% reduction was observed after 2 hours of incubation. The additional loss observed after incubation in sham gastric fluid compared to the observed loss after incubation of HCl, could be due to the binding of the proanthocyanidin polymer composition with the pepsin in the simulated gastric fluid. When, after incubation in simulated gastric fluid, the mixture of proanthocyanidin polymer composition and simulated gastric fluid was incubated with a simulated intestinal fluid, no further significant reduction in concentration was observed. 6.1 MATERIALS AND METHODS After oral administration, the drug is in contact with the gastric fluid for approximately 2 to 3 hours before moving to the duodenum where the fluid gastric fluid and the drug mix rapidly with the intestinal fluid accordingly, so that better mimic in vivo conditions, the polymer composition of proanthocyanidin was first incubated in simulated gastric fluid for 2 hours and then diluted with simulated intestinal fluid in the ratio of 1: 1 and incubated for an additional 6 hours at a temperature of 37 ° C . In addition, the polymer composition of proanthocyanidin was incubated in simulated gastric fluid (SGF), hydrochloric acid (HCl) or water at a temperature of 37 ° C. Aliquots were taken from each of the treatment samples at different time intervals and the amount of proanthocyanidin polymer composition was quantified by HPLC. Preparation of test mixtures and samples: 1. Simulated gastric fluid (SGF) was prepared in accordance with USP XX, page 1105 by dissolving 2.0 g of sodium chloride and 3.2 g of pepsin (from the porcine stomach mucosa, sigma ) in 7.0 ml of hydrochloric acid and with a sufficient amount of water (Fisher's HPLC grade) to reach 1000 ml. This test solution had a pH of about 1.2. . A simulated intestinal fluid (SIF) was prepared in accordance with USP XX, page 1105 by dissolving 6.8 g of potassium phosphate monobasic in 250 ml of water and by adding 190 ml of 0.2 N sodium hydroxide and 400 ml of Water. Then 10.0 g of pancreatin (from porcine pancreas, Sigma) were added, mixed and the resulting solution was adjusted to a pH of 7.5 +/- 0.1 with NaOH. 0.2 N. The solution was diluted with water to 1000 ml. 3. Hydrochloric acid (pH = 1.7) was prepared by adding 800 μl of 12 N hydrochloric acid to 100 ml of water. 4. A solution of proanthocyanidin polymer was prepared by dissolving 1.0 g of the proanthocyanidin polymer composition from C. Lechleri in 10 ml of distilled water. Procedures: The stock solution of proanthocyanidin polymer composition was diluted 1:20 (up to a total volume of 10 ml) in SGF or in purified water. The test solutions were incubated in an oven at a temperature of 37 ° C and 1 ml aliquots were taken while stirring at time intervals of 0.03, 0.5 and 2.0 hours. After the aliquots were centrifuged for 10 minutes at 14,000 rpm, 700 μl of the supernatant was removed and neutralized with 1 N NaOH containing 50 mM of dibasic sodium phosphate to pH 7.0 +/- 0.1. At the end of the 2 hour incubation period, SIF was added to the proanthocyanidin polymer composition in SGF in a ratio of 1: 1 and the pH was adjusted to 7.0 +/- 0.1. Aliquots were taken which were processed according to what was described above at 2, 2.5, 4 and 6 hours after the initial mixing with SGF. The neutralized supernatant was diluted 1: 9 in tetrahydrofuran (HPLC grade, Fisher). The samples were assayed by HPLC in a Hewlett Packard 1050 High Performance Liquid Chromatograph using a 5m PLgel 500 A column (Polymer Laboratories) (300 x 7.5 mm) and a 5 m guard column (50 x 7.5 mm), with a mobile phase of 95% tetrahydrofuran and 5% water, an injection volume of 50 ml, a flow rate of 1 ml / min and an experiment time of 11 minutes. The proanthocyanidin polymers were detected by the UV absorption test at a wavelength of 280 nm. 6.2 RESULTS AND COMMENTS The HPLC method used for the quantification of proanthocyanidin polymers did not include derivation or ion exchange and measures the unbound "free" proanthocyanidin polymers and not the proanthocyanidin polymers bound to the protein. In addition, HPLC chromatography is based on size exclusion chromatography and therefore detects changes in the molecular size (polymerization or degradation) of the proanthocyanidin polymers but not the chemical alterations that do not affect the size or the molar extinction coefficient at 280 nm. Effect of HCl on the composition of proanthocyanidin polymers: To test the effect of HCl (a major component of gastric fluid) on the composition of proanthocyanidin polymers from C. lechleri in vitro, the polymer composition of proanthocyanidin was incubated for 2 hours. hours in HCl at a pH of 1.2. Samples were taken after 0.03, 0.5 and 2.0 hours of incubation and analyzed using HPLC. The peak area for the HPLC profile of the proanthocyanidin polymer composition after incubation in HCl was compared to the peak area for the profile of the proanthocyanidin polymer composition after incubation in water (Table 1). TABLE 1. CHLORHYDRIC ACID EFECTS (PH = 1.7) ON THE COMPOSITION OF PROANTOCIANIDINE POLYMERS Time, h Sample -1 Sample -2 Average% peak area-% peak area (n = 2) 0.03 94 67 81 0.5 73 71 72 2.0 77 70 74 * the percentage of peak area was calculated by dividing the peak area of the profile of the proanthocyanidin polymer composition in the test medium over the peak area of the profile of the proanthocyanidin polymer composition in water (control ) and multiplying by 100. The results indicate that after 0.03 hours in HCl the peak area of the proanthocyanidin polymer profile, ie, the concentration of the proanthocyanidin polymer composition was reduced by 19%. After 0.5 hours and 2.0 hours of incubation with HCl, the peak area of the proanthocyanidin polymer profile was reduced by 28% and 26%, respectively. These results indicate that most of the decrease in the proanthocyanidin polymer composition due to HCl exposure occurred within the first 2-3 minutes of incubation. Figure 1 shows chromatograms of samples of the proanthocyanidin polymer composition after incubation in water and in HCl for 0.03 hours, and in HCl for 2.0 hours. In addition to the evident reduction area of the proanthocyanidin polymer profile peak after incubation for 2 hours in HCl, a remarkable change was observed in shoulder retention time. A possible interpretation of the observed change in shoulder retention time from 5.8 to 6.2 min after incubation of the HCl composition is in HCl decompose the proanthocyanidin polymers into slightly lower molecular weight subunits with longer retention time than the retention time of the original compound. Effects of SGF on the composition of proanthocyanidin polymers. When the proanthocyanidin polymer composition of C. lechleri was added to SGF, the mixture formed an opaque red precipitate. To determine whether the precipitate was due to pepsin or sodium chloride, the polymer composition of proanthocyanidin was added at a final concentration of 5 mg / ml to either SGF without sodium chloride or to SGF without pepsin. After centrifugation mixes at 14,000 revolutions per minute for 10 minutes, only the mixture containing pepsin was opaque red with precipitation, indicating that the precipitation is due to the interaction of the proanthocyanidin polymer composition with pepsin. After an incubation period of 2 minutes (0.03 hours) of the proanthocyanidin polymer composition solution in SGF, an HPLC analysis showed a reduction of about 32% in the peak area of the proanthocyanidin polymer profile. Samples taken 0.5 and 2.0 after incubation at 37 ° C showed no further significant change in the peak area of the proanthocyanidin polymer profile. The chromatograms of the proanthocyanidin polymer samples incubated for 2 minutes and 2 hours in SGF are shown in Figures 2 and 3, respectively, and the peak area data from this experiment are illustrated in Table 2. TABLE 2: EFFECTS OF SGF ON THE COMPOSITION OF POLYMERS OF PROANTOCIANIDIN IN VITRO. Time, h Sample -1 Sample -2 Average% peak area% peak area (n = 2) 0.03 59 76 68 0.5 70 67 69 2.0 54 49 52 6.0 45 55 50 The percentage of peak area was calculated by dividing the peak area of the profile of the proanthocyanidin polymer composition in the test medium between the peak area of the profile of the proanthocyanidin polymer composition in water (control) and multiplying by 100. Most of the reduction in the concentration of proanthocyanidin polymers was observed within 2 minutes of exposure to SGF. In addition, the decrease in the proanthocyanidin polymer composition detected by the HPLC assay may be due to a combination of the effects of acid degradation in SGF and binding to pepsin in the SGF. The rapid decrease of the peak area under the curve after the addition of the proanthocyanidin polymer composition to the SGF solution is demonstrated in Figures 4 and 5 which show sample chromatograms of the proanthocyanidin polymer composition after 2 minutes and 2 hours. hours of incubation in SGF, respectively. Effect of SIF on the composition of proanthocyanidin polymers To better understand the fate of the proanthocyanidin polymer composition from C. lechleri in the small intestines, the effect of intestinal fluid on the composition of proanthocyanidin polymers was investigated in vitro. To better indicate the conditions in vivo, the polymer composition of proanthocyanidin was first incubated in simulated gastric fluid for 2 hours and then diluted with simulated intestinal fluid in a ratio of 1: 1 and incubated for an additional 6 hours at a temperature of 37 °. C. Samples removed at various time intervals after the addition of SIF to the proanthocyanidin polymer composition solution of SGF were analyzed by HPLC. Representative chromatograms appear in Figures 4 and 5. The results appear in Table 3 and Figure 6 and indicate that SIF did not significantly reduce the amount of proanthocyanidin polymer composition. TABLE 3. SIF INTERACTION WITH SGF-COMPOSITION MIXER OF PROANTOCIANIDINE POLYMERS AFTER 2 HOURS OF INCUBATION IN SGF FOLLOWED FOR 4 HOURS OF INCUBATION AFTER 1: 1 DILUTION IN SIF. Weather, h Sample • 1 Sample • 2 Average% peak area% peak area (n = 2) 2. 0 44 52 48 2. 5 50 42 46 4. 0 59 45 52 6. 0 45 55 50 The percentage of peak area was calculated by dividing the peak area of the profile of the proanthocyanidin polymer composition in the test medium in the peak area of the profile of the proanthocyanidin polymer composition in water (control) and multiplying by 100. 6.3 CONCLUSION The incubation conditions tested in this study mimic the conditions found by the composition of proanthocyanidin polymers from C. lechleri after peroral administration. A certain loss of the proanthocyanidin polymer composition (25-32%) was observed within minutes of incubation of the composition with dilute HCl and SGF. The greater loss observed after incubation in SGF compared to the loss after incubation in HCl could be due to the binding of the proanthocyanidin polymer composition to the pepsin in SGF. When the solution of proanthocyanidin polymers in simulated gastric fluids was incubated with simulated intestinal fluid, no further significant reduction in the proanthocyanidin polymer composition was observed. Because the method used to analyze the composition of proanthocyanidin polymers was based on size exclusion chromatography, caution should be exercised regarding the interpretation of the results presented here because the method can not differentiate between a polymer composition of native proanthocyanidin and a proanthocyanidin polymer composition that has been chemically altered in a way that does not significantly change its size. 7. EXAMPLE: EVALUATION OF THE EFFECT OF A COMPOSITION OF PROANTOCIANIDINE POLYMERS WITH ENTREME COATING ON THE ACCUMULATION OF FLUID IN COLON TOXIN TREATED MICE The purpose of this study was to determine the effect of a prepared enteric coated proanthocyanidin polymer composition. from Croton lechleri on the accumulation of fluid in the intestinal tract of mice treated with cholera toxin (CT). The pathophysiological mechanism by which cholera toxin produces an accumulation of fluid in mice is identical to the mechanism by which cholera toxin and other bacterial toxins produce fluid accumulation in humans. The reduction of fluid in this model by a test compound indicates that the compound is useful as an antidiarrheal agent. The initial time (tO), the mice received cholera toxins (15μg per average body weight of approximately 20g9 by oral forced feeding and were anorectally sealed with a cyano-acrylamide ester, three hours later (t3h), was administered by oral forced feeding a single dose of enteric coated proanthocyanidin polymer composition (131 mg / kg) suspended in 0.75% guar gum (vehicle) was also administered to 2 control groups water and a control solution consisting of an equivalent concentration of "EUDRAGIT ®" and sugar in vehicle After 7 hours (t7 h) of exposure to the cholera toxin, the mice were sacrificed and the entire murine intestinal tract was isolated from the pylorus to the rectum, including The entire intestine of the murine intestinal tract was isolated because, although the accumulation of fluid occurs in the small intestine, a certain amount of flu gone leaks in the large intestine. Fluid accumulation (AF) was measured as the ratio between the mass of fluid accumulated in the intestinal tract and the rectum, including the caecum, versus the mass in the intestinal tract minus the mass of the fluid. Under the conditions of the experiment, the enteric coated orally administered proanthocyanidin polymer composition significantly reduces the accumulation of fluid in the intestinal tract of sealed adult mice treated with the cholera toxin. Oral administration of a enteric-coated proanthocyanidin polymer composition 8131 mg / kg) reduced the rate of fluid accumulation by an average of 45% and 38% compared to the ratio of average fluid accumulation in controls treated with water and controls that received «EUDRAGIT®» / sugar / vehicle, respectively. 7.1 PREPARATION OF CHOLERA TOXIN AND THE COMPOSITIONS OF PROANTOCIANIDINE POLYMERS. The following materials were obtained from commercial suppliers: cholera toxin (List Biological Lab. Lot number CVX-48-3D); cyano-acrylamide ester (Borden Inc., Columbus, OH); feeding needles for animals (Popper and Sons, Hyde Park, NY); sodium bicarbonate (ACROS lot number 83559/1); guar gum (Sigma lot number 94H0195); «EUDRAGIT®» L30D (PMRS, lot number R10538); maya sugar spheres 40-60 (PMRS, lot number R10542). To prepare the stock solution of cholera toxin, one milliliter of HPLC grade water (Mili Q) was added to a bottle containing 1 mg of cholera toxin and 2 different bottles were combined and stored at 4 ° C. The solution of cholera toxins for administration to animals was recently prepared by diluting 240 μl of cholera toxin stock solution with 560 μl of 7% w / v NaHCO 3. The final concentration of NaHCO 3 was 4.9%. Each mouse received 15 μg of cholera toxin in volume of 50 μl by forced oral feeding at the initial time (tO). The formulation for the composition of enteric-coated proanthocyanidin polymers from C. lechleri contained 17.3% (w / w) of pellet seed (sugar sphere, maua 46/60) (Paulaur, lot number 60084060), 64.6% proanthocyanidin polymer composition, 1.5% hydroxypropylmethylcellulose (HPMC, Dow Chemical Co, lot number MM9410162E), 0.5% Opadry Clear (Colorcon, lot number S835563), 14.5% "EUDRAGIT® L 30D" (Rohm Tech, lot number 1250514132 ), 1.45% triethyl citrate (Morflex, lot number N5C291), glyceryl monostearate (Rohm tech, lot number 502-229), and purified water (USP). The solution for coating the proanthocyanidin polymer composition on the sugar spheres was prepared by the addition of HPMC and the proanthocyanidin polymer composition to purified water (USP) and by mixing until dissolved. The pelleted seeds were loaded into the product bowl of the fluid bed processor (Niro-Precision Coater). The proanthocyanidin / HPMC polymer composition solution was then sprayed on fluidized pellet seeds, while maintaining the target bed temperature at 30-35 ° C. The layer application process continued until the entire solution was applied. Once the application of proanthocyanidin polymer composition layers was finished, an Opadry Clear seal coating (prepared by mixing Opadry Clear with USP purified water) was applied, keeping the bed temperature within a range of 30 to 35. ° C. Once the seal coating was applied, the pellets were discharged and sieved through lOOOμ and 425μ sieves and the coated spheres greater than 425 micras and less than 1000 micras were loaded back into the fluid bed processor. Meanwhile, the enteric coating solution was prepared by the addition of triethyl citrate and glyceride monostearate to water that had been heated to 65 ° C under continuous stirring. This solution was added to "EUDRAGIT ® L 30D-55" with mixing. The resulting enteric coating solution was then sprayed onto the coated spheres in the fluid bed processor, at a bed temperature comprised within a range of 30 to 35 ° C until all the enteric coating solution had been applied over the beads . To facilitate oral forced feeding and to avoid instantaneous settlement of the beads, a thickener agent, guar gum, was used. 100 ml of 0.7% guar gum was prepared and adjusted to pH 2 with 2 ml of 0.5 M HCl. The beads of proanthocyanidin polymer composition as enteric coating were suspended in a 0.7% guar gum solution. A control solution consisting of equivalent final concentrations of "EUDRAGIT®" and sugar was also prepared in a 0.7% guar gum solution. 7.2 METHODS AND RESULTS The experiments were conducted in accordance with Richardson and Kuhn, 1986, Infect. And Immun. 54: 522-528. Male mice 50 to 52 days old with body masses located within a range of 15.7 to 18.7 g were used. The test animals were wild type C57B1 / 6 mice and were obtained from Charles River Lab. All animals were kept in metabolism cages with water ad libidum throughout the experiment. The mice were kept without food for 24 hours before the start of the experiment and during the course of the experiment. Initially (tO h), mice received 15 μg of cholera toxin by forced oral feeding and were sealed anorectally with a cyano-acrylamide ester (Superglue). Three hours later (t3 h), the mice received by oral forced feeding either the suspension of the enteric-coated proanthocyanidin polymer composition in a guar gum solution or in a control solution. After a 7-hour exposure (t7 h) to the cholera toxin, the mice were sacrificed and the entire intestinal tract of murine was isolated from the pylorus to the rectum, including the caecum. Care was taken not to break the tissue and cause no loss of fluid and the tissue of the mesentery and connective connective was then removed. The mass of tissue and fluid within was determined using an analytical balance. The tissue was then opened longitudinally, the fluid was removed, and the tissue was dried. The accumulation of fluid was measured as the ratio between the mass of fluid accumulated in the intestine (thin and large, including the caecum) versus the mass of the intestine minus the mass of the fluid. Statistical comparisons of the fluid accumulation ratio for several treatments were carried out by analysis of variance using Microsoft Excel (version 5.79), a p value of p <was used.0.05 to determine the significance. A multiple-range test of Duncan was performed to determine whether statistically significant reductions in the accumulated fluid ratios induced by cholera toxin were observed in the mice receiving the enteric coated proanthocyanidin polymer composition compared to the animals they received only water or "EUDRAGIT ®" plus sugar in a 0.75% guar gum solution. In the experiment described below, a total of 24 mice (8 mice per treatment) were treated as follows: Group A: The mice received cholera toxin followed by a single dose of water at t 3 and were sacrificed to t7. after the administration of the cholera toxin. Group B: mice received cholera toxin at tO. At t3 the mice received a single dose of enteric coated proanthocyanidin polymer composition (131 mg / kg body weight). The vehicle consisted of a 0.75% acidified guar gum solution. All animals were sacrificed at t7. Group C: mice received cholera toxin at tO. At t3, mice received a single dose of an equivalent concentration of "EUDRAGIT ®" and sugar (1.33 mg of "EUDRAGIT ®" plus 1046 mg of sugar / kg body weight). The vehicle consisted of a 0.65% acidified guar gum solution. All animals were sacrificed to t7 based on preliminary studies indicating the need for a longer incubation time to ensure complete transfer of the coated beads in the intestine, all animals were sacrificed in T7 from the toxin administration of anger. To achieve more reliable results, the number of animals was increased to 8 mice per group. Table 4 and Figure 7 show the effect of the enteric-coated proanthocyanidin polymer composition on the fluid secretion induced by cholera toxin in the dried adult mouse model. As can be seen, a single dose of 131 mg of proanthocyanidin / kg polymer composition significantly reduced (p <0.05) the accumulation of fluid induced by cholera toxins after a 7-hour incubation with cholera toxin. Compared to the results after control treatments (groups A and C), enteric-coated proanthocyanidin polymer composition beads (group B) significantly reduced the rate of fluid accumulation by an average of 45% and 38% respectively. In this experiment none of the mice died as a result of treatment by forced oral feeding. TABLE 4. THE EFFECT OF COMPOSITION PEARLS OF PROANTOCIANIDINE POLYMERS WITH ENTREME COATING ON ACCUMULATION OF INTESTINAL FLUID IN COLON TOXIN TREATED MICE Group No. of mice Treatment Fluid accumulation (mg of fluid / mg of intestine) A 8 H20 1.28 ± 0.09 a B 8 131 mg of 0.71 ± 0.17 b composition t of proanthocyanidin polymers in a guar gum / kg solution C 8 «EUDRAGIT ®» Y 1.15 ± 0.16 a and sugar / guar gum solution * Values with different letters differ significantly (p <0.05) in the Duncan multiple range test. Under the experimental conditions, the enteric-coated proanthocyanidin polymer composition significantly reduced the accumulation of fluid in the intestine of sealed adult mice treated with cholera toxin. Based on these results oral administration of the enteric coated proanthocyanidin polymer composition (131 mg / kg) reduced the rate of fluid accumulation by an average of 30% compared to the average fluid accumulation rate in «EUDRAGIT ® »more controls with sulfur. The results of an additional experiment using 18-20 mice per group are shown in Figure 8 and Table 5, and these results confirm the results of the initial experiment. Mice in group B, which received 131 mg of the proanthocyanidin polymer composition / kg three hours (t3) after exposure to cholera toxin, showed a significant reduction in fluid accumulation compared to the mice that received «EUDRAGIT®» and sugar in water at t3. TABLE 5: THE EFFECT OF COMPOSITION PEARLS OF PROANTOCIANIDINE POLYMERS WITH ENTREMENTAL COATING ON ACCUMULATION OF INTESTINAL FLUID IN CHOLERA TOXIN TREATED MICE Group No. of to hr 3 hr Fluid accumulation of mice (mg of fluid / mg of intestine) At 20 CT / NaHC03 «EUDRAGIT» 1.34 + 0.09a * and sugar / H20 B 18 CT / NaHC03 131 mg / kg 0.75 ± 0.10b * composition of proanthocyanidin polymers * Different conventional values differ significantly (p <0.001) in T test 8. EXAMPLE: PREPARATION OF PHARMACEUTICAL FORMULATIONS The following describes illustrative methods for the preparation and packaging of different preferred pharmaceutical formulations of the proanthocyanidin polymer composition from C. Lechleri in accordance with the present invention. 8.1 PEARLS WITH ENTREME ENCAPSULATED CLADDING. Below are detailed descriptions of the batch formulas and methods used to prepare the formulation of encapsulated enteric-coated proanthocyanidin polymer composition beads. Each hard shell gelatin capsule contained 250 mg of enteric coating beads of proanthocyanidin polymer composition. The capsules were packaged HDPE bottles containing 16 capsules of 250 mg (16) each formulation for enteric coated proanthocyanidin polymer composition beads containing 17.3% (w / w) of pelleted seeds (sugar spheres in size) 40/60, Paulaur, number 60084060), 64.5% proanthocyanidin polymer composition of C. Lechleri, 1.5% hydroxypropylmethylcellulose (Methocel E5 Premium, Cow Chemical Co., lot number MM9410162E), 0.5% Opadry Clear (Colorcon, lot number S83563), 14.5% of "EUDRAGIT® L30D" (Rohm Tech., Lot number 1250514132), 1.45% triethyl citrate (Morflex, lot number N5X291), glyceryl monostearate (Imwintor-900, Rohm Tech, lot number 502-229), and purified water (USP). The applied coating solution containing the proanthocyanidin polymer composition was prepared by the addition of hydroxypropylmethylcellulose and the composition of proanthocyanidin polymers to purified water (USP) and by mixing to dissolution. The pelleted seeds were loaded into the product bowl of the fluid bed processor (Nior-Precision Coater). The polymer solution was then applied to the pellet seeds by spraying the solution in the fluidized pellet seeds at a bed temperature comprised within a range of 30 to 35 ° C. Once the polymer layer formation of proanthocyanidin was completed, a seal coating was applied using Opadry Clear (Preparing it by mixing Opadry Clear with purified water USP) with a bed temperature comprised within a range of 30 to 35 ° C after the application of the seal coating the pellets were unloaded and sieved through 1000 μ sieves and 425μ and layer spheres greater than 425μ and less than lOOOμ were reloaded into the fluid bed processor. Meanwhile, the enteric coating solution was prepared by mixing triethyl and glyceride monostearate with water that had been heated to a temperature of 65 ° C and then mixing this solution with "EUDRAGIT ® 130d-55". The resulting enteric coating solution was then sprayed onto the layered spheres in the fluid bed processor at a bed temperature of 30 to 35 ° C, until the application of the entire enteric coating solution on the beads. Based on the results of the HPLC assay indicating that the proanthocyanidin polymer composition is present in a concentration of 52.9%, the enteric coated beads were filled manually into a size 0 hard shell gelatin capsule to provide a dosage of 250 mg and were then packaged in a suitable HDPE bottle with a heat induction lined cap. TABLE 6: LOT FORMULA Product: proanthocyanidin polymer beads with enteric coating Lot size: 5.78.0 gm Raw Material Quantity used per batch Spheres of sweetened Pellets, 100.0 gm NF (40/60) Polymer composition of 372.8 gm Proanthocyanidin Hydroxypropylmethylcellulose E5, 8.7 gm USP (K29 / 32) Opadry Clear (YS-1-19025A) 2.9 gm «EUDRAGIT ® L30D-55» 279.4 gm (30% solid) Triethyl citrate NF 8.4 gm Glycerol monostearate 1.4 gm Water, USP (removed during 1284.8 gm Processing) 8.2 GRANULES WITH ENTREME COATING AND POWDER PARTICLES The following describes a method for formulating the polymer composition of proanthocyanidin as granules or powder with enteric coating (microspheres with a diameter of 300-500μ) either in gelatin capsules in hard shell or suspended in an oral solution. The proanthocyanidin polymer composition powder particles are prepared by mixing with high cutting power of the proanthocyanidin and hydroxypropylmethylcellulose polymer composition in a high speed mixer / granulator. The proanthocyanidin polymer composition granules are prepared by spraying polyvinylpyrrolidone onto the powder in the high speed mixer / granulator in such a manner that the powder particles agglomerate to form larger granules. Using a fluid bedding equipment, the granules or powder are then covered with an Opadry Clear seal coating (mixed with water) and then coated with the enteric coating "EUDRAGIT ® L30D" applied in the form of an aqueous dispersion containing 30% weight / weight of a dry methacrylate polymer substance, which is supplied with 0.7% sodium lauryl sulfate NF (SLS) and 2.3% polysorbate 80 NF (Tween 20) as emulsifiers, to which plasticizers are added, citrate of triethyl and glyceryl monostearate to improve the elasticity of the coating. The final composition of the enteric coated powder is 81.8% w / w of proanthocyanidin polymer composition, 1.5% w / w of hydroxypropylmethylcellulose, 0.5% w / w of Opadry Clear, 14.5% w / w of "EUDRAGIT ® L30D" , 1.45% weight / weight of triethyl citrate and 0.25% weight / weight of glyceryl monostearate. The final composition of the enteric coated granules is 81.8% w / w of the proanthocyanidin polymer composition, 10% polyvinylpyrrolidone, 1.5% w / w hydroxypropylmethylcellulose, 0.5% w / w Opady Clear, 14.5% w / w of «EUDRAGIT ® L30D», 1.45% weight / weight of triethyl citrate, 0.25% w / w of glyceryl monostearate. The granules or particles of the enteric coated proanthocyanidin polymer composition can be filled into a hard capsule gelatin capsule in an amount that provides adequate dosage. The granules or powder particles of enteric coated proanthocyanidin polymer composition can also be suspended in a solution with oral administration, particularly for pediatric administration. The suspension solution is prepared by wetting two grams of hydroxypropylmethylcellulose in 97.8 ml of distilled water and 0.2 grams of Tween 80; mixing this preparation until homogeneity by sonication, heating the solution to 402C and stirring it for 3 hours; and then adding the particles or powder granules of proanthocyanidin polymer composition with enteric coating to the homogeneous solution. 8. 3 COMPRESSED TABLETS WITH ENTREME COATING A method for formulating the composition of proanthocyanidin polymers as enteric coating tablets is described below. For each 350 mg tablet, 250 mg of a proanthocyanidin polymer composition are granulated with 7 mg of cross-linked sodium carboxymethylcellulose ("AC-DI-SOL®") and a sufficient mass of microcrystalline cellulose ("AVICEL® PH 200/300" ) to bring the total mass to 350 mg. These ingredients are mixed for 20 to 30 minutes in a V-mixer. After 20 to 30 minutes of mixing, 1.75 mg of magnesium stearate is added and the mixture is mixed for an additional 4 to 5 minutes. The resulting granules are compressed in a rotary tablet press using standard 5 / 16th inch concave punches. The tablets are coated with an enteric coating mixture prepared from 250 grams of "EUDRAGIT® L30 D-55", 7.5 triethyl citrate to 37.5 grams of talc and 205 grams of water. The tablets are then placed in a perforated container coater (for example, the ACCELA-COTA® System) and rotated at 15 revolutions per minute at a temperature of 40sc. The enteric coating formulation is sprayed using the following conditions: inlet air temperature of 442C-483C, outlet air temperature of 29 = C-322C, product temperature of 26SC-302C, 1-mm spray nozzle, a container speed of 30 to 32 revolutions per minute, a flow of air of 30-32 CFM, and a spray pressure of 20 PSI. The tablets are finally subjected to curing for 30 minutes as the container rotates at 15 revolutions per minute with an inlet air temperature of 60 sec and then, after heat closure, the tablets are rotated at 15 revolutions per minute until the cooling of the tablets at room temperature. 8.4. SUPPOSITORIES The formulation of the proanthocyanidin polymer composition as a suppository for rectal administration is described below. A suppository formulation for the proanthocyanidin polymer composition can be prepared by heating 91 grams of glycerin to 120 ° C by dissolving 9 grams of sodium stearate in the heated glycerin, then adding 5 grams of purified water. 5 to 50% of the proanthocyanidin polymer composition is added to the base and the mixture is then poured into a suitable mold. Alternatively, the suppository can be prepared by heating 20 grams of gelatin and 70 grams of glycerin at a temperature of 70 seconds and stirring for 2 hours, then adding 10 grams of proanthocyanidin polymer composition dissolved in purified water by sonication for 5 minutes, and stirring at 402C until a homogeneous mixture is achieved. The preparation can then be emptied into a mold suitable for the preparation of suppositories. 9. EXAMPLE: EFFECT OF COMPOSITION FORMULATIONS OF PROANTOCIANIDINE POLYMERS IN PATIENTS WHICH SUFFER FROM TRAVELER'S DIARRHEA OR NON-SPECIFIC DIARRHEA The following is a summary of the provisional results obtained from the initial 20 patients of a clinical trial in an open safety label. and effectiveness of the proanthocyanidin polymer composition from C. Lechleri for the symptomatic treatment of acute nonspecific diarrhea and traveler's diarrhea. 9.1 STUDY OF SAFETY AND EFFICACY IN HUMAN BEINGS A total of 20 patients with traveler's diarrhea were assigned to the study .. The population of patients consisted of young patients (average age = 24 years) of male and female sex who were students United States in Mexico. The students were recruited by the investigator when they entered the country and were asked to report to the clinic after presenting diarrhea and before the start of any other medical treatment. The patients were evaluated in terms of the following parameters: a) Frequency of habitual evacuations (number of bowel movements per day or per week). b) Date and time of the onset of diarrhea. c) Number of evacuations in the last 24 hours, d) categorized according to the consistency of the e) following way: -formed: retains its original shape in water -Blanda: adapts to the shape of the container -Water: can be emptied (Evacuations of mixed form (for example soft / gouache) were classified in the category ultimately formed (for example gouache). f) Symptoms during the last 24 hours, including: - flares - anal irritation - Tenesmus - Urgency (inability to delay evacuations for 15 minutes) - Fecal incontinence (decreased control of bowel movements) - Inconvenience (interference with normal activities ) -Nausea -Vomito -Increased intestinal gas. After finishing the sieving evaluations, samples were obtained for baseline laboratory tests and the first dose of study medication was administered. The patients received an initial loading dose of 1250 mg of the enteric coated proanthocyanidin polymer composition with 3 or more doses of 250 mg every 6 hours during the first 24 hours of treatment, and then 500 mg four times a day giving a total of 2 grams per day on the second day of dosing. The polymer composition of proanthocyanidin was administered only for 2 days. During the baseline clinical visit, participants in the study were trained to accurately complete the daily and study forms, and the following evaluation parameters were considered; 1. Safety The patients were asked about any experimental adverse events during the study. These events were categorized in terms of severity, duration, relationship with the study drug and any action taken. The blood and urine obtained at the beginning and at the end of the study were used to evaluate the changes. 2. Efficacy Efficacy was evaluated from the clinical and daily visits of patients. The essential efficacy parameters measured were the frequency of the evacuations, the consistency of the evacuations and the time since the last evacuation not formed. 9.2 RESULTS During the study, no significant adverse effects were observed in any of the patients that could be attributed to the composition of proanthocyanidin polymers.

The primary efficacy parameters for this trial included the frequency reported by the patients of the evacuations and the time of the last evacuation not formed.

These data appear in table 7. TABLE 7: REPORTED FREQUENCY OF EVACUATIONS (20 PATIENTS TREATMENTS) Time • Evacuations per day (Medium) 24 hours before the entrance 5.6 Day 1 4.0 Day 2 2.9 Day 3 2.1 Habitual 1.6 On average, the frequency of abnormal bowel movements showed a tendency towards normality during the three days of the study. The average number of evacuations per day returned to an almost normal frequency for day 3. Four patients returned to the normal frequency of evacuations on the third day of the study. In addition, the time until the last non-formed evacuation was 30.3 hours on average. Baseline reports and follow-up of gastrointestinal symptoms were obtained. Patients were asked to rate the severity (mild, moderate or severe) of 9 symptoms, including nausea, vomiting, cramps, gas, urgency, tenesmus, anal irritation, incontinence and inconvenience. A total of 9 patients completely resolved their symptoms at the end of the third day of the study. Table 8 shows the number of patients who resolved all the symptoms at the indicated time. TABLE 8: RESOLUTION OF ALL SYMPTOMS ACCORDING TO THE TIME (20 PATIENTS TREATED) Time Number of patients, total resolution 24 hours 1 48 hours 2 60 hours 4 72 hours 2 A total score of the symptoms was obtained by assigning a score of 0 for the absence of symptoms, 1 in the case of mild symptoms, 2 in the case of moderate symptoms and 3 in the case of severe symptoms. The total scores for all patients in each given period of time were averaged and appear in the table 9. TABLE 9: RATING OF SYMPTOMS PER FUNCTION OF TIME (20 PATIENTS TREATED) Time Average score Entry 8.9 12 hours 6.1 24 hours 4.5 36 hours 3.8 48 hours 3.0 60 hours 1.8 72 hours 1.1 Based on our review of the data we reached the following conclusions: 1. While the drug was generally well tolerated, 3 patients had severe nausea, self-limited, possibly related to the study drug. However, none of the patients was withdrawn from the study due to an adverse event. . No significant change was observed in serum chemistry or hematology during the treatment period. Six patients had mild changes in their urinalysis. We do not believe that these changes in urine tests represent significant adverse effects. It was unclear if these changes were the result of the study drug or the evolution of its underlying disease. . The frequency of evacuations had a tendency to return to the normal frequency in the 3-day study period. 4. The time until the last average non-formed evacuation was 30.3 hours compared to the 69 hours reported in historical controls. In summary, we conclude that an enteric formulation of the proanthocyanidin polymer composition of C. lechleri is useful for improving the frequency of bowel movements and gastrointestinal symptoms in patients suffering from traveler's diarrhea. Overall, the drug seems safe, with nausea being the most frequent side effect. The invention described and claimed herein is not limited in scope to the specific embodiments presented herein since these embodiments are for the purpose of illustrating various aspects of the invention any equivalent embodiment is within the scope of this invention. In fact, several modifications of the invention in addition to those presented and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications also fall within the scope of the appended claims. All publications mentioned here are incorporated by reference in their entirety.

Claims (5)

1. CLAIMS 1. A pharmaceutical composition comprising a therapeutically effective amount of a proanthocyanidin polymer composition isolated from a Croton spp. or of a Calophyllum ssp. or a pharmaceutically acceptable derivative thereof formulated to protect the proanthocyanidin polymer composition against the action of stomach acid; and a pharmaceutically acceptable vehicle.
2. 2. The pharmaceutical composition of claim 1, wherein the Croton ssp. is Crotón Lechleri.
3. 3. The pharmaceutical composition of claim 1, wherein the composition comprises an enteric coating. 4. The pharmaceutical composition of claim 3, wherein the composition is formulated as a capsule, said capsule having no enteric coating. . The pharmaceutical composition of claim 3, wherein the enteric coating consists of a copolymer of methacrylic acid-methacrylic acid ester with acid-ionizable groups. . The pharmaceutical composition of claim 5, wherein the enteric coating further comprises one or more plasticizer compounds. . The pharmaceutical composition of claim 6, wherein the plasticizer compounds are polyethylene glycol ester and citric acid ester. 8. The pharmaceutical composition of claim 7, wherein the composition is formulated in the form of a compressed tablet. 9. The pharmaceutical composition of claim 7, wherein the composition is formulated as a capsule containing beads, said beads comprising a sugar sphere, a layer of the proanthocyanidin polymer composition and an enteric coating layer. 10. The pharmaceutical composition of claim 7, wherein the composition is formulated as a microsphere from 300 microns to 500 microns, said microspheres comprising granules of the proanthocyanidin polymer composition and an enteric coating layer. 11. The pharmaceutical composition of claim 10, wherein the microspheres are filled in a capsule. 12. The pharmaceutical composition of claim 10, wherein the microspheres are further formulated into a suspension. The pharmaceutical composition of claim 1, wherein the proanthocyanidin polymer composition is formulated with a substance that inhibits the secretion of stomach acid.
4. 4. The pharmaceutical composition of claim 1, wherein the proanthocyanidin polymer composition is formulated with a substance that neutralizes stomach acid. 15. A pharmaceutical composition comprising a therapeutically effective amount of a proanthocyanidin polymer composition isolated from a Croton ssp. or of a Calophyllum ssp. or a pharmaceutically acceptable derivative thereof, which is formulated as a suppository in a pharmaceutically acceptable carrier. 16. A method for the treatment of secretory diarrhea in animals, including humans, comprising: administering, to a non-human animal or to a human being suffering from diarrhea, a pharmaceutical composition comprising a therapeutically effective amount of a proanthocyanidin polymer composition isolated from a Croton ssp. or a Calophyllum ssp. or of a pharmaceutically acceptable derivative thereof, formulated to protect the polymer composition of proanthocyanidin against the action of stomach acid, and a pharmaceutically acceptable carrier. 17. The method of claim 16, wherein the Croton ssp. is Crotón lechleri. 18. The method of claim 16, wherein the composition comprises an enteric coating. 19. The method of claim 18, wherein the composition is formulated as a capsule, said capsule has an enteric coating or does not. The method of claim 18, wherein the enteric coating consists of a copolymer of methacrylic acid-methacrylic acid ester with acid-ionizable groups. 21. The method of claim 20, wherein the enteric coating further comprises one or more plasticizer compounds. 22. The method of claim 21, wherein the plasticizer compounds are polyethylene glycol ester and citric acid ester. 23. The method of claim 22, wherein the composition is formulated as a compressed tablet. The method of claim 22, wherein the composition is formulated as a capsule containing beads, said beads comprising a sugar sphere, a layer of the proanthocyanidin polymer composition and an enteric coating layer. 25. The method of claim 22, wherein the composition is formulated as a capsule containing microspheres of 300 microns to 500 microns, said microspheres comprising granules of the proanthocyanidin polymer composition and an enteric coating layer. 26. The method of claim 16, wherein the proanthocyanidin polymer composition is formulated with a substance that inhibits the secretion of stomach acid. . The method of claim 16, wherein the proanthocyanidin polymer composition is formulated with a substance that neutralizes stomach acid. . The method of claim 16 wherein the diarrhea is caused by a bacterium. . The method of claim 28, wherein the bacterium is selected from the group of Escherichia coli, Vibrio ssp., Campylobacter spp., Salmonella spp., Aeromonas spp., Plesiomonas spp. Shigella spp., Klebsiella spp., Citrobacter spp., Yersinia spp., Clostridium spp., Bacteriodes spp., Staphylococcus spp., And Bacillus spp. . The method of claim 29, wherein the bacterium is either enterotoxigenic Escherichia coli or Campylobacter jejuni. . The method of claim 16, wherein the secretory diarrhea is caused by a non-infectious etiology. . The method of claim 31, wherein the non-infectious etiology is selected from the group consisting of non-specific diarrhea, ulcerative colitis, inflammatory bowel syndrome, and cancers and neoplasms of the gastrointestinal tract. The method of claim 16, wherein the human being suffering from diarrhea is an infant or a child. 34. The method of claim 16, wherein a human being is treated for chronic diarrhea associated with HIV. 35. The method of claim 34, wherein chronic diarrhea associated with HIV is caused by Cryptosporidium spp. 36. The method of claim 16, wherein a non-human animal is treated for secretory diarrhea. 37. The method of claim 36, wherein the non-human animal is selected from the group _ which consists of cattle, pigs, sheep, birds, equines, canines, and felines. 38. The method of claim 37, wherein the secretory diarrhea is caused by an agent selected from the group consisting of Escherichia coli, Salmonella spp., Clostridium perfringens, Bacteriodes fragilis, Campylobacter spp. , Yersinia enterocolitica, Cryptosporidium spp. , rotavirus and coronavirus. 39. The method of claim 36, wherein the pharmaceutical composition is administered in animal feed. 40. The method of claim 16, wherein the pharmaceutical composition is administered orally. 41. The method of claim 40 wherein the pharmaceutical composition is administered orally in food. 42. The method of claim 40, wherein the human or non-human animal receives between 0.1 and 40 mg / kg per day of the proanthocyanidin polymer composition. . A method for the treatment of secretory diarrhea in animals, including humans, comprising: administering to a non-human animal or a human suffering from diarrhea, a pharmaceutical composition comprising a therapeutically effective amount of a polymer composition of proanthocyanidin isolated from a Croton spp., or Calophyllum spp. or a pharmaceutically acceptable derivative thereof, which is formulated as a suppository for rectal administration in a pharmaceutically acceptable carrier. . A method for the treatment of secretory diarrhea in animals, including humans, comprising: administration to a non-human animal or to a human suffering from diarrhea, of (a) - a pharmaceutical composition comprising an amount therapeutically Effectiveness of a proanthocyanidin polymer composition isolated from a Croton spp. or a Calophyllum spp. or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier; and (b) a pharmaceutical composition comprising an amount effective to inhibit the secretion of stomach acid from a compound effective to inhibit the secretion of stomach acid, and a pharmaceutically acceptable carrier. 45. The method of claim 44, wherein the pharmaceutical composition containing the proanthocyanidin polymer composition is administered at a time after administration of the pharmaceutical composition containing the compound effective to inhibit the secretion of stomach acid but during the period of inhibition. of the secretion of stomach acid. 46. The method of claim 44, wherein the pharmaceutical composition containing the proanthocyanidin polymer composition is administered concurrently with the pharmaceutical composition containing the compound effective to inhibit the secretion of stomach acid. 47. The method of claim 44, where diarrhea is caused by bacteria. 48. The method of claim 47, wherein the bacterium is selected from the group of Escherichia coli, Vibrio spp., Campylobacter spp., Salmonella spp., Aeromonas spp., Plesiomonas spp., Shigella spp., Klebsiella spp., Citrobacter spp. ., Yersinia spp., Clostridium spp., Bacteriodes spp., Staphylococcus spp., And Bacillus spp. 9. The method of claim 48, wherein the bacterium is either enterotoxigenic Escherichia eolia or Campylobacter j juni. The method of claim 44, wherein the secretory diarrhea is caused by a non-infectious etiology. 51. The method of claim 50, wherein the non-infectious etiology is selected from the group consisting of nonspecific diarrhea, ulcerative colitis, inflammatory bowel syndrome, and cancers and neoplasms of the gastrointestinal tract. 52. The method of claim 44, wherein the human being suffering from diarrhea is an infant or a child. 53. The method of claim 44, wherein the human being is treated for chronic diarrhea associated with HIV. 54. The method of claim 53, wherein chronic diarrhea associated with HIV is caused by Cryptosporidium spp. 55. The method of claim 44, wherein the non-human animal is treated for secretory diarrhea. 56. The method of claim 55, wherein the pharmaceutical composition is administered in animal feeds. 57. The method of claim 44, wherein the pharmaceutical composition is administered orally. 58. The method of claim 57 wherein the pharmaceutical composition is orally administered in foods. 59. The method of claim 57, wherein the human or non-human animal receives between 0.1 and 40 mg / kg per day of the proanthocyanidin polymer composition. 60. A method for the treatment of secretory diarrhea in animals, including humans, comprising: administration to a non-human animal or to a human being suffering from diarrhea, of (a) a pharmaceutical composition comprising an amount Therapeutically effective of a proanthocyanidin polymer composition isolated from a Croton spp. or a Calophyllum spp. or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier; and (b) a pharmaceutical composition comprising an amount effective to neutralize the stomach acid of a compound effective to neutralize stomach acid, and a pharmaceutically acceptable carrier. . The method of claim 60, wherein the pharmaceutical composition containing the proanthocyanidin polymer composition is administered at a time after administration of the pharmaceutical composition containing the effective compound to neutralize the stomach acid but during the period in which stomach acid is neutralized. . The method of claim 60, wherein the pharmaceutical composition containing the proanthocyanidin polymer composition is administered concurrently with the pharmaceutical composition containing the compound effective to neutralize the stomach acid. . The method of claim 60, wherein the diarrhea is caused by a bacterium. . The method of claim 63, wherein the bacterium is selected from the group consisting of Escherichia coli, Vibrio spp., Campylobacter spp., Salmonella spp., Aeromonas spp., Plesiomonas spp., Shigella spp., Klebsiella spp., Citrobacter spp. ., Yersinia spp., Clostridium spp., Bacteriodes spp., Staphylococcus spp., And Bacillus spp. . The method of claim 64, wherein the bacterium is either enterotoxigenic Escherichia eolia or Campylobacter jejuni. . The method of claim 60, wherein the secretory diarrhea is caused by a non-infectious etiology. . The method of claim 66, wherein the non-infectious etiology is selected from the group consisting of non-specific diarrhea, ulcerative colitis, inflammatory bowel syndrome, and cancers and neoplasms of the gastrointestinal tract. . The method of claim 60, wherein the human being suffering from diarrhea is an infant or a child. - The method of claim 60, wherein the human being is treated for chronic diarrhea associated with HIV. The method of claim 69, wherein chronic diarrhea associated with HIV is caused by Cryptosporidium spp. 71. The method of claim 60, wherein a non-human animal is treated for secretory diarrhea. 72. The method of claim 71, wherein the pharmaceutical composition is administered in animal feeds. 73. The method of claim 60, wherein the pharmaceutical composition is administered orally. 74. The method of claim 73, wherein the pharmaceutical composition is administered orally in food. 75. The method of claim 73, wherein the human or non-human animal receives between 0.1 and 40 mg / kg per day of the proanthocyanidin polymer composition. 76. A method for preventing secretory diarrhea in animals, including humans, comprising: administering to a non-human animal or a human being at risk of developing diarrhea, a pharmaceutical composition comprising a prophylactically effective amount of a Proanthocyanidin polymer composition isolated from a Croton spp. or a Calophyllum spp. or a pharmaceutically acceptable derivative thereof formulated to protect the proanthocyanidin polymer composition against the action of stomach acid, and a pharmaceutically acceptable carrier. 77. The method of claim 76, wherein the Croton spp is Croton lechleri. 78. The method of claim 76, wherein the composition comprises an enteric coating. 79. The method of claim 78, wherein the composition is formulated with a capsule, said capsule having an enteric coating or not. 80. The method of claim 78, wherein the enteric coating consists of a copolymer of methacrylic acid-methacrylic acid ester with acid-ionizable groups. 81. The method of claim 80, wherein the enteric coating further comprises one or more plasticizer compounds. 82. The method of claim 81, wherein the plasticizer compounds are polyethylene glycol ester and citric acid ester. 83. The method of claim 82, wherein the composition is formulated as a compressed tablet. 84. The method of claim 82, wherein the composition is formulated as a capsule containing beads, said beads comprising a sugar sphere, a layer of the proanthocyanidin polymer composition and an enteric coating layer. The method of claim 82, wherein the composition is formulated as a capsule containing microspheres from 300 microns to 500 microns, said microspheres comprising granules of the proanthocyanidin polymer composition and an enteric coating layer. 86. The method of claim 76 wherein the diarrhea to be avoided is caused by a bacterium. 87. The method of claim 86, wherein the bacterium is selected from the group consisting of Escherichia coli, Vibrio spp., Campylobacter spp., Salmonella spp., Aeromonas spp., Plesiomonas spp., Shigella spp., Klebsiella spp., Citrobacter spp., Yersinia spp., Clostridium spp., Bacteriodes spp., Staphylococcus spp., And Bacillus spp. 88. The method of claim 87, wherein the bacterium is either enterotoxigenic Escherichia eolia or Campylobacter jejuni. 89. The method of claim 76, wherein the secretory diarrhea is caused by a non-infectious etiology. 90. The method of claim 89, wherein the non-infectious etiology is selected from the group consisting of nonspecific diarrhea, ulcerative colitis, inflammatory bowel syndrome, and cancers and neoplasms of the gastrointestinal tract. 91. The method of claim 76, wherein the human being at risk of developing diarrhea is an infant or a child. 92. The method of claim 76, wherein the diarrhea to be avoided is chronic diarrhea associated with HIV. 93. The method of claim 92, wherein the chronic diarrhea associated with HIV is caused by Cryptosporidium spp. 94. The method of claim 76, wherein secretory diarrhea should be avoided in a non-human animal. 95. The method of claim 94, wherein the non-human animal is selected from the group consisting of bovines, pigs, sheep, birds, equines, canines, and felines. 96. The method of claim 95, wherein the secretory diarrhea is caused by an agent selected from the group consisting of Escherichia coli, Salmonella spp., Clostridium perfringens, Bacteriodes fragilis, Campylobacter spp., Yersinia enterocolitica, Cryptosporidium spp., Rotavirus. and coronavirus. 97. The method of claim 94, wherein the pharmaceutical composition is administered in the feed of the animals. 98. The method of claim 76, wherein the pharmaceutical composition is administered orally. 99. The method of claim 98, wherein the pharmaceutical composition is administered orally in foods. 100. The method of claim 99, wherein the human or non-human animal receives between 0.1 and 40 mg / kg per day of the proanthocyanidin polymer composition.