WO2014076638A1 - Composición antiparasitaria de amplio espectro de nitazoxanida, probióticos y prebióticos - Google Patents
Composición antiparasitaria de amplio espectro de nitazoxanida, probióticos y prebióticos Download PDFInfo
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Definitions
- the present invention relates to a broad spectrum antiparasitic composition of Nitazoxanide with Probiotics (PBTs), in single doses, for the treatment of intestinal parasites in humans, caused by protozoa and / or helminths.
- this composition may contain
- Prebiotics which greatly improves clinical symptoms such as diarrhea.
- nitazoxanide is a 5-nitrotiazole with a broad spectrum antiparasitic activity for numerous species of protozoa and helminths.
- Probiotics are live microorganisms, which confer a benefit to the health of the host, when they are administered in sufficient quantities and that Prebiotics (PreBTs) are, in their majority, non-digestible carbohydrates that stimulate and favor the growth of PBTs.
- PreBTs Prebiotics
- Intestinal parasitic infestations are among the most significant causes of morbidity, mainly in developing countries. Helminth infestations are a public health problem worldwide. For example, helminthiasis chronically affects about one third of the world's population, with an estimated prevalence of one million cases of geohelminths, 900 million cases of trichuriasis, and 500 million cases of ancylostoma. Parasitic infestations mainly affect school-age children and are often easily transmitted in areas and populations where hygienic / sanitary measures are poor. The causes in the child population affected by i Intestinal parasites can be their immunological immaturity, malnutrition and poor development of hygienic habits. These parasitosis can lead to negative consequences, both physically and cognitively, in many parasitized children.
- the clinical characteristics of parasitic infestations have a wide range of signs and symptoms, ranging from gastrointestinal discomfort (nausea, vomiting, abdominal pain or abdominal spasms, obstruction and / or intestinal occlusion, diarrhea, dysentery, etc.), weight loss , dehydration anemia, anal itching, even liver abscess, pleuropulmonary, hives, etc.
- the symptoms in children are very varied. The most frequent are abdominal pain, diarrhea caused by poor absorption of food and intestinal irritation.
- NTZX is a 5-nitrotiazole with broad spectrum antiparasitic activity that has an active metabolite, tizoxanide.
- One of the mechanisms of action is due to the fact that NTZX, in parasites, is reduced to a toxic radical in a special organelle of carbohydrate metabolism, the hydrogenosome, which contains hydrogenated pyruvate-ferredoxin oxidoreductase and ferredoxin. Another effect is believed to be to interfere with the carbohydrate metabolism of helminths, blocking the citric acid cycle, leading to the accumulation of lactic acid and the death of the parasite.
- the Nitazoxanide compound was disclosed as a product in U.S.
- Patent 3,950,351 and its equivalents the holder of which is SPRL Phavic and the priority date is 8-8-73.
- US Patent 5 387 598 which belongs to Romark with priority date of 13-4-94 and which describes a formulation containing Nitazoxanide and Thizoxanide.
- Probiotics affect intestinal bacteria by increasing the number of beneficial anaerobic bacteria and decreasing the population of potentially pathogenic microorganisms.
- PBTs affect the intestinal ecosystem by stimulating the mucosal immune mechanisms and stimulating non-immune mechanisms through antagonism and competition with potential pathogens. It is thought that these phenomena mediate most of the beneficial effects, including reducing the incidence and severity of diarrhea, one of the most widely recognized uses of probiotics.
- probiotics generates different protective and defensive mechanisms at the intestinal level at three levels, namely:
- Bacteriocins and other peptides that interfere with the metabolism of bacteria, parasites, fungi and pathogenic viruses are Bacteriocins and other peptides that interfere with the metabolism of bacteria, parasites, fungi and pathogenic viruses.
- Strains such as Lactobacilus and Bifidobacterium are useful to reduce the severity and duration of infectious diarrhea.
- PBTs exert their antiparasitic effect by the mechanisms described and by modifying the parasite cycle in the intestine by decreasing the amount and viability of eggs and infesting forms and interfering with your metabolism [Travers MA et al, J Parasitol Res. Volume 2011, doi: 10.1155 / 2011/610769].
- Prebiotics are "Ingredients not digestible by man, selectively fermentable by bacteria that produce specific changes in the composition and / or activity of the gastrointestinal flora and confer benefits to the health of the host. [Gibson et al. 2010. Food Science and Technology Bulletin: Functional Foods 7 (1) 1-19.] In addition, prebiotics (PreBTs) stimulate the growth and activity of beneficial bacteria (PBTs) of the intestinal flora.
- PreBTs must meet the following characteristics: be resistant to the acidic environment of the stomach, enzymes and host hydrolysis factors; be fermentable, that is, be degraded and metabolized by the intestinal microbiota and produce selective stimulation of the growth and activity of intestinal bacteria, especially through the production of metabolites originated in the degradation of prebiotics.
- PreBTs must be stable to heat and desiccation, be safe and have organoleptic properties that make them fit for human consumption.
- Prebiotics produce the following benefits: 1) improve bowel function,
- PreBTs are mostly non-digestible carbohydrates; The best known are:
- Oligosaccharides They are widely used for the multiple benefits they produce, previously described for PreBTs. They are present in breast milk, they are added to infant formulas and foods.
- the present invention demonstrates the benefits of this formulation to improve the most important immune function of the organism, in the intestine, in which approximately 60% of all immune cells are found.
- Nitroimidazoles and Nitrofurans are widely used for the treatment of giardasis.
- PBTs and PreBTs By incorporating both PBTs and PreBTs, a significant improvement in gastrointestinal symptoms (such as diarrhea) was achieved, seeing reflected an almost "ad integrum" reconstitution of the histology of the intestinal mucosa affected by parasitic infestation.
- the present invention relates to a pharmaceutical composition, preferably oral, used as an antiparasitic and antidiarrheal comprising a therapeutically effective amount of the Nitazoxanide compound and a therapeutically effective amount of a Probiotic together with pharmaceutically acceptable excipients; and optionally, a therapeutically effective amount of a Prebiotic.
- the present invention relates to an oral pharmaceutical composition, used as an antiparasitic and antidiarrheal comprising a therapeutically effective amount of the Nitazoxanide compound and a therapeutically effective amount of a Probiotic together with pharmaceutically acceptable excipients.
- the present invention relates to an oral pharmaceutical composition, used as an antiparasitic and antidiarrheal comprising a therapeutically effective amount of the Nitazoxanide compound, a therapeutically effective amount of a Probiotic and a therapeutically effective amount of a Prebiotic together with pharmaceutically acceptable excipients. .
- the present invention relates to an oral pharmaceutical combination useful as an antiparasitic and antidiarrheal comprising a therapeutically effective amount of the Nitazoxanide compound and a therapeutically effective amount of at least one Probiotic; and optionally, a therapeutically effective amount of at least one Prebiotic.
- the present invention relates to a process for preparing an oral pharmaceutical combination useful as an antiparasitic and antidiarrheal comprising a therapeutically effective amount of the Nitazoxanide compound and a therapeutically effective amount of at least one Probiotic; and optionally, a therapeutically effective amount of at least one Prebiotic.
- Nitozoxanide is found in an amount of 50 to 1200 mg per dosage unit.
- the oral dosage unit of said composition may be one of the following pharmaceutical presentations: capsules, tablets, powders, sachets, microgranules, etc.
- the Probiotic is used in a range of 1 x 10 3 CFU at 1 x 10 14 CFU per dosage unit, preferably in a therapeutic range of 1 x 10 8 CFU.
- the Probiotic of the present invention comprises at least one bacterial strain selected from the group of the following species: Bifidobacteria sp, Lactobacillus sp, Bacilos sp, Lactococci, Streptococci sp, Enterococci and Yeasts.
- the probiotic is selected from the following strains: Bifidobacterium breve or brevis,
- Subtilis Bacilli Clausii, Streptococcus thermophilus, Streptococcus faecium, Streptococcus faecalis, Enterococci fecalis, Bacillus coagulans, Propionibacterium freudenreichii and Sacaromyces Boulardi.
- Said probiotic is in a range of 1 x 10 3 CFU at 1 x 10 14 CFU per dosage unit.
- the Prebiotic used is preferably in an amount of 50 to 15,000 mg per dosage unit and can be selected from the following groups: a) of the aliphatic alcohols: xylitol, sorbitol, lactitol;
- lactulose di and trisaccharides: lactulose, lactusucrosa, melibiosa, xilobiosa, stachiosa, rafinosa;
- oligosaccharides fructo-oligosaccharide, galacto-oligosaccharide, malto-oligosaccharide, xyl-oligosaccharide, isomalto-oligosaccharide, gentio-oligosaccharide.
- the fractionation of probiotics should be carried out in an area of controlled humidity, at no more than 20% relative ambient humidity and at a temperature of 25 ° C.
- the preparation and packaging of the product containing Probiotics must be done respecting the conditions mentioned.
- the fractionation of probiotics should be carried out in an area of controlled humidity, at no more than 20% relative ambient humidity and at a temperature of 25 ° C.
- the preparation and packaging of the product containing Probiotics must be done respecting the conditions mentioned.
- the fractionation of probiotics should be carried out in an area of controlled humidity, at no more than 20% relative ambient humidity and at a temperature of 25 ° C.
- the preparation and packaging of the product containing Probiotics must be done respecting the conditions mentioned.
- Nitazoxanide pregelatinized starch and microcrystalline cellulose.
- Lactobacillus acidophilus probiotics equivalent to 4 x 10 CFU
- the fractionation of probiotics should be carried out in an area of controlled humidity, at no more than 20% of relative ambient humidity and at 25 ° C of temperature.
- the preparation and packaging of the product containing Probiotics must be done respecting the conditions mentioned.
- thermobalance % taken at 105 ° C in thermobalance.
- the fractionation of probiotics should be carried out in an area of controlled humidity, at no more than 20% relative ambient humidity and at a temperature of 25 ° C.
- the preparation and packaging of the product containing Probiotics must be done respecting the conditions mentioned.
- the fractionation of probiotics should be carried out in an area of controlled humidity, at no more than 20% relative ambient humidity and at a temperature of 25 ° C.
- the preparation and packaging of the product containing Probiotics must be done respecting the conditions mentioned.
- Nitazoxanide 50% of the pregelatinized starch and microcrystalline cellulose.
- Each envelope contains mg%
- the fractionation of probiotics should be carried out in an area of controlled humidity, at no more than 20% relative ambient humidity and at a temperature of 25 ° C.
- the preparation and packaging of the product containing Probiotics must be done respecting the conditions mentioned.
- Xanthan gum Grind the mixture to fine powder. Add it to the mixer in point 1. Mix 5 minutes.
- Each envelope contains mg%
- the fractionation of probiotics should be carried out in an area of controlled humidity, at no more than 20% relative ambient humidity and at a temperature of 25 ° C.
- the preparation and packaging of the product containing Probiotics must be done respecting the conditions mentioned.
- Lactobacillus acidophilus probiotics equivalent to 4 x 10 CFU METHOD OF ELABORATION
- the fractionation of probiotics should be carried out in an area of controlled humidity, at no more than 20% relative ambient humidity and at 25 ° C temperature.
- the preparation and packaging of the product containing Probiotics must be done respecting the conditions mentioned. Grind the sugar to fine powder, reserve 20% of the grind, place the rest in a suitable mixer.
- thermobalance % taken at 105 ° C in thermobalance.
- Lactobacillus acidophilus Probiotic we use the Lactobacillus acidophilus Probiotic to exemplify the methods of elaboration, the following Probiotics can be used among others:
- the main objective of these in vivo studies was to evaluate the ability of the association NTZX + PreBTs + PBTs to reduce the incidence and duration of diarrhea and other gastrointestinal signs and symptoms in laboratory rats, previously infested with diarrhea causing parasites.
- the parasites used for this experiment were protozoa (Giardias intestinalis) and helminths (Hymenolepis nana).
- the concentration of protozoa and helminths inoculated to each animal was 1,000 trophozoites for the Giardias and 1,000 cysticercos for Hymenolepis nana.
- the secondary objectives were: a) To determine the incidence of adverse effects, investigating signs of pain, discomfort, etc.
- mice of the Sprague-Dawley strain were used which were selected, conditioned and divided into 4 groups (Control, NTZX Treatment, NTZX Treatment + PBTs and NTZX Treatment + PreBTs + PBTs).
- the histological technique used was to fix the intestine samples in formalin, ethyl alcohol, acetic acid, distilled water, preparation of the paraffin block and staining with Hematoxylin-eosin and microscopic observation of the processed material.
- the associations of NTZX and PBTs are constituted by the following components:
- NTZX NTZX
- PreBTs PBTs
- Both associations are in powder to reconstitute with 15 ml. of drinking water, which is administered to the animals orally, twice a day, together with the main meals of the day (lunch and dinner).
- the 60 rats were divided into four treatment groups of 15 individuals each, namely:
- Control group on day 1 they are given to ingest, together with their daily diet, different infestant strains of protozoa and helminths that cause diarrhea (Giardias intestinalis and Hymenolepis nana).
- Each treatment group was divided into 3 treatment series of 5 animals each to proceed with the experimentation (to facilitate their management, and carry out the observations of each group). Therefore, 3 treatment series were carried out with 5 animals per group (total of 20 animals per series.).
- the animals were conditioned, weighed, fed and maintained in a non-stress environment, separated in watertight compartments by treatment groups.
- Day 1 (Infestation Stage): The infesting forms of the parasite strains were inoculated orally in a suspension of 20 mL of drinking water to the first series of 20 animals. This inoculation was done 1 hour before lunch. The behavior was observed and the number and characteristics of the depositions were recorded. They were fed regularly "ad libitum".
- Day 11 (Start of Treatment): The 3 groups (NTZX, NTZX + PBTs and NTZX + PreBTs + PBTs) were started at the start of treatment, leaving the control group free of treatment, observing the natural evaluation of the disease. The behavior of the animals was observed and the number and characteristics of the depositions were recorded. They were fed regularly "ad libitum”.
- Day 12 to 13 (Treatment Stage): 3 days treatment of the 3 groups (NTZX, NTZX + PBTs and NTZX + PreBTs + PBTs), at a treatment frequency of 2 doses per day, leaving the control group free of treatment, observing the natural evaluation of the disease. The behavior of the animals and the number and characteristics of the depositions were recorded. They were fed regularly "ad libitum”.
- Table 1 details the incidence of diarrhea on average in the 3 series of 20 animals each.
- "Diarrhea” (according to WHO) is defined as deposition, three or more times a day (or more frequently) of loose (semi-liquid) or liquid stools.
- Table 2 details the characteristics of the stool during the study. It can be observed that the Control Group presented, throughout the entire study, feces of liquid consistency, however, after the active treatment, their consistency was normalized over time. It is also observed that, with the association of NTZX + PreBTs + PBT, already after 16 days of treatment, Stool is normal in 85% of cases, becoming almost completely normalized for the end of the study. The same is observed with the association of NTZX + PBTs, but with a slight lower percentage in the normal appearance of feces.
- Tables 3, 4 and 5 evaluated different clinical characteristics at the gastrointestinal level, to evaluate both the one caused by parasitosis (Control group), and the presence of some adverse effect to the active treatment. In all cases, in animals treated with Pre and PBT associations, clinical responses were better than in animals treated with NTZX alone.
- Treatment Group (including Control) of each of the 3 series, so that intestinal samples were taken from 24 animals, after being slaughtered. A microscopic count of parasites was carried out and the number of infested animals was detailed, as indicated in Table 6.
- Table 6 details the presence of parasitic elements in samples obtained from intestinal lavage.
- the 6 animals presented both Giardias (G) and Hymenolepis (H).
- G Giardias
- H Hymenolepis
- PBTs and PreBTs remains of Hymenolepis scolex were found, but without traces of the rest of the parasite.
- Table 7 details the changes suffered by the intestinal mucosa in the presence of parasitic infestation. Malabsortive type changes were observed in the control group and a significant improvement in the active group, where there was an ad integrum regeneration in the group with Pre and PBTs. This regeneration in the intestinal epithelium was correlated with a clinical improvement of the animals treated with the association of NTZX with Pre and PBTs.
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PCT/IB2013/060089 WO2014076638A1 (es) | 2012-11-13 | 2013-11-12 | Composición antiparasitaria de amplio espectro de nitazoxanida, probióticos y prebióticos |
Country Status (5)
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AR (1) | AR093252A1 (es) |
BR (1) | BR112015010651A2 (es) |
MX (1) | MX2012013178A (es) |
UY (1) | UY35037A (es) |
WO (1) | WO2014076638A1 (es) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108085265A (zh) * | 2016-11-22 | 2018-05-29 | 北京大北农科技集团股份有限公司 | 凝结芽孢杆菌新菌株及其微生态制剂和饲料 |
RU2779386C2 (ru) * | 2017-06-05 | 2022-09-06 | Проби Аб | Микробные композиции |
US11541082B2 (en) * | 2017-06-05 | 2023-01-03 | Probi Ab | Microbial compositions |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110279118B (zh) * | 2019-06-14 | 2022-09-13 | 浙江大学宁波理工学院 | 一种复合益生菌组合物、复合益生菌冻干粉胶囊及制备方法 |
CN114158735B (zh) * | 2021-12-06 | 2024-05-31 | 青岛东海药业有限公司 | 一种益生菌组合物及其应用 |
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2012
- 2012-11-13 MX MX2012013178A patent/MX2012013178A/es unknown
-
2013
- 2013-09-17 UY UY0001035037A patent/UY35037A/es unknown
- 2013-10-28 AR ARP130103932A patent/AR093252A1/es unknown
- 2013-11-12 BR BR112015010651A patent/BR112015010651A2/pt not_active Application Discontinuation
- 2013-11-12 WO PCT/IB2013/060089 patent/WO2014076638A1/es active Application Filing
Non-Patent Citations (4)
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BIENVENIDO G. YANGCO ET AL.: "Nitazoxanide and Probiotics for the treatment of recurrent Clostridium difficile infection in a peritoneal dialysis patient.", SOUTHERN MEDICAL JOURNAL, vol. 102, no. 7, July 2009 (2009-07-01), pages 746 - 747 * |
CARLOS G. TERAN ET AL.: "Nitazoxanide vs. Probiotics for the treatment of acute rotavirus diarrhea in children: a randomized, single-blind, controlled trial in Bolivian children.", INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, vol. 13, 2009, pages 518 - 523 * |
GEORGE RUSSE LL ET AL.: "Fecal bactoriotherapy for relapsing Clostridium difficile infection.", PEDIATRICS, vol. 126, no. 1, July 2010 (2010-07-01), pages 239 - 242 * |
SAIMA ASLAM ET AL.: "Treatment of Clostridium difficile-associated disease: old therapies and new strategies", vol. 5, September 2005 (2005-09-01), pages 549 - 557, Retrieved from the Internet <URL:http://ac.els-cdn.com/S1473309905702152/1-s2.0-S 1473309905702152 main.pdf? tid:::ecd6ce00-9958-11e3- b35a00000aacb35e&acdnat:::1392809476 4a41dca2c79d8eecbac73dad4bcfbbd9> [retrieved on 20140217] * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108085265A (zh) * | 2016-11-22 | 2018-05-29 | 北京大北农科技集团股份有限公司 | 凝结芽孢杆菌新菌株及其微生态制剂和饲料 |
CN108085265B (zh) * | 2016-11-22 | 2021-09-28 | 北京大北农科技集团股份有限公司 | 凝结芽孢杆菌新菌株及其微生态制剂和饲料 |
RU2779386C2 (ru) * | 2017-06-05 | 2022-09-06 | Проби Аб | Микробные композиции |
US11541082B2 (en) * | 2017-06-05 | 2023-01-03 | Probi Ab | Microbial compositions |
Also Published As
Publication number | Publication date |
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MX2012013178A (es) | 2014-05-22 |
AR093252A1 (es) | 2015-05-27 |
UY35037A (es) | 2014-05-30 |
BR112015010651A2 (pt) | 2017-07-11 |
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