MXPA99010215A - Pharmaceutical compositions of tizoxanide and nitazoxanide - Google Patents

Abstract

A pharmaceutical composition containing as active agent at least one compound selected among the group consisting of formula (I) and formula (II). The active agent is preferably in the form of particles having a particle size smaller than 200&mgr;m and a mean particle size of greater than 10&mgr;m. The pharmaceutical compositions are preferably stabilized with at least one pharmaceutically acceptable acid. The pharmaceutical compositions are particularly useful for treatment of opportunistic infections in persons with compromised or suppressed immune systems, and in treatment of infections of trematodes.

Description

PHARMACEUTICAL COMPOSITIONS OF TIZOXANIDE AND NITAZOXANIDE BACKGROUND OF THE INVENTION Technical Field of the Invention The present invention relates to a pharmaceutical composition containing as active agent at least one compound selected from the group characterized by the formula (I) and by the formula (II) Preferably, the active agent is in the form of particles with a particle size of less than 200 μm and an average particle size of greater than 10 μm. The present invention also relates to pharmaceutical compositions stabilized with at least one pharmaceutically acceptable acid. These pharmaceutical compositions are especially useful for the treatment of opportunistic infections in people with compromised or suppressed immune systems, as well as for the treatment of trematode infections. Description of Related Art There is a pressing need to develop methods for the treatment of a number of parasite and bacterial infections in humans that have compromised the immune system (AIDS, cancer patients, elderly people, aging, patients with organs transplanted or treated with immunosuppressive drugs). Trematode infections are another area of interest, especially in tropical climate zones. There is, therefore, a need for a pharmaceutical composition which can be tolerated even by humans with compromise of the immune system and which is stable in storage even in tropical environments. More specifically, Toxoplas a gondii is a protozoan that counts among the most important causes of latent infection of the central nervous system worldwide. There are many healthy people infected with the parasite, although usually the immune system keeps the infectious organism in check. T. gondii is the most frequent pathogen of the brain among AIDS patients. At present, the problem posed by toxoplasmosis has increased in importance, not only because of AIDS, but also because of the more widespread use of immunosuppressive drugs (for example, those administered to patients with organ transplants). Habitually, toxoplasmosis is treated with a combination of pyrimethamine and sulfadiazine. While the drugs are effective, they do not kill parasite cysts, so treatment should be continued with maintenance doses. Toxicity often requires interrupting the administration of the drug, especially in the case of patients with immunosuppression, and relapses occur. The statistics are unreliable and indicate mortality rates of approximately 70 percent in immunodeficient patients and a median survival of four months. The protozoan parasite Cryptosporidium parvum causes cryptosporidiosis. In people with normal immune functions, the diarrhea caused by C. parvum can be long and intense, but there is self-recovery. In contrast, in AIDS patients, cryptosporid diarrhea often means a threat to life. It is estimated that around 15-20 percent of AIDS sufferers suffer from this infection. Until now, there is no coherently effective or approved therapy against cryptosporidiosis. The most frequent pathogen among AIDS patients is Enterocytozoon bieneusi, a microsporidium that can be found in approximately one quarter of patients. At present it seems that this tiny parasite can be the cause of a large part of the cases of deficient absorption, diarrhea and debilitating disease that HIV patients have and that still have no explanation. There is not yet effective treatment. There are several other species of microsporidia that infect HIV positive patients, including Encephalitozoon hellem and cunicuü, and a new species called Septata intestinalis. A recent report indicates that the spread of infections by microsporidia is growing in importance. It is not possible to distinguish clinically the infection by the Isospora belli parasite from cryptosporidiosis. Most frequent parasite in tropical climates, it is reported that /. Belli is present in less than 1% of patients in the US, but its current incidence is probably higher. In general, the classifications indicate that Pneumocystis carinii is a protozoapo parasite, although some studies suggest that it could be a fungus, with which it shares certain genetic sequences. Usually, P carinu infects the lungs (Pneumocystis Capnii Pneumonia (PCP)). , the therapy is effective in approximately 40-60% of the patients, but there are problems among which the toxicity of the drugs can be mentioned, in particular in patients with immune compromise In the face of the many serious manifestations of human immunodeficiency virus infection ( HIV) in children, PCP stands out for its high incidence, exclusive age distribution and frequent mortality PCP is the most frequent serious opportunistic infection among children infected with HIV and its incidence in infants infected with HIV who do not receive prophylaxis is estimated in at least 12% during the first year of life Many infants die shortly after Development of this infection Mycobacterium Avium complex (MAC) is a group of infections caused by similar mycobacterial organisms, Mycobacterium avium and M intracellulare When MAC infection occurs in people with a preserved immune system, it usually presents as an infection of airways Often in AIDS patients, the infection is widespread (disseminated MAC or DMAC) and can compromise almost any organ of the system In a recent study, the presence of MAC bacteria was found in 43% of patients who survived 2 years after an AIDS diagnosis No standard therapy has been established for the disseminated MAC Usually, combinations of drugs are used that, if effective, should continue to be administered for life. There is an urgent need for more effective treatment. are especially susceptible to Mycobacterium tuberculum infection osis, and the development of the disease is rapid. Extrapulmonary tuberculosis is not common in patients not infected with HIV, but it does occur frequently in HIV-positive people. The CDC has established standards for the treatment of TB aimed at addressing the increase in multidrug-resistant TB (MDR-TB). The mortality of AIDS patients infected with MDR-TB is very high (approximately 80%) and the evolution of the disease is fulminating. Therefore, there is an urgent need to develop a method of treating these infections of increasing incidence and high mortality in humans and animals. It is also necessary to find a broad-spectrum drug to simplify the treatment of trematode infections. Currently, the specific trematode pathogen must first be identified and then the specific drug for that trematode must be prescribed. Many underdeveloped countries lack the equipment necessary to diagnose the specific trematode that is acting. The development of a broad-acting drug would eliminate the need for prior diagnosis. Schistosoma mansoni, the blood fluke, is the causative agent of schistosomiasis, a tropical disease that ranks second in importance after malaria among human parasites and the first among human infections caused by trematodes. Another important species that infects man is Schistosoma haematobium. In the world there are more than 200 million people suffering from schistosomiasis, including several hundred thousand in the United States.

The liver fluke, Fasciola hepatica, primarily attacks sheep, but humans can be accidental hosts. This parasite manages to survive in the presence of a vigorous immune response from the host. SE has suggested treatment with bithionol, which is not approved in the United States. There is, therefore, a need for a stable pharmaceutical composition in storage even in tropical environments that has broad action against trematodes. SUMMARY OF THE INVENTION It has been observed in clinical studies developed with animals and humans that the effectiveness of treatment with compounds of the formula (I) and (II) depends on the particle size of the substance of the active drug and the stability of the compounds. The disclosed pharmaceutical compositions are suitable for the treatment of infections by trematodes in humans and animals caused by schistosomes such as Schistosoma. mansoni, Schistosoma haematobium, Schistosoma mekongí, Schistosoma japonicum, Schistosoma intercalatum, Fasciola as Fasciola hepatica and Fasciola gigantica, Fasciolopsis biski, and Dicrocoelium dentnticum, Heterophyes heterophyes and Metagonimus yokogawa These pharmaceutical compositions are also effective for the treatment of infections opportunists of patients with compromised immune systems, such as Cryptospondium parvum, Isospora belli, Enterocytozoon bieneusi, Encepha tozoon intestinalis, Mycobacterium tuberculosis, Mycobactepum avium intracellulare, Pneumocystis carinn and Toxoplasma gondn The pharmaceutical composition can be presented in a form suitable for oral administration, in of solid doses, as a liquid suspension or as a cream. BRIEF DESCRIPTION OF THE FIGURES If a thorough understanding of the nature and objectives of the present invention is desired, reference should be made to the following detailed description, which is accompanied by figures, of which: Fig. 1 represents the percentage of inhibition and the cellular viability in the host of nitazoxanide against E. intestinalis. Fig. 2 represents the percentage of inhibition and cellular viability in the host of nitazoxanide against V. corneae. Fig. 3 represents the percentage of inhibition and cell viability in the albendazole host against E. intestinalis. Fig. 4 represents the percentage of inhibition and cell viability in the albendazole host against V. corneae. Figs. 5 and 6 present a curve of the optimal density values (OD) obtained for each culture cavity of T. gondii, depending on the concentration of the drug in the culture. Fig. 7 is a graph based on the effectiveness test of nitazoxanide against bacteria developed in a liquid broth. Fig. 8 indicates the percentage of active particles that have a size less than 0 μm. DETAILED DESCRIPTION OF THE INVENTION The method for the treatment of infections of the present invention comprises the administration of a pharmaceutical composition which includes, as an active agent, at least one compound selected from the group consisting of the desacetyl-nitazoxanide of the formula (I) - and by the nitazoxanide of the formula (II) Nitazoxanide (NTZ), the compound of formula (II), is the generic name for 2- (acetyloxy) -N- (5-nitro-2-thiazoli) bepzamide, which was originally synthesized by Rossignol and Cavier in 1975. 2mg of pitazoxanide can be dissolved in 1 ml of DMSO. Nitazoxanide is well absorbed orally. Until now, there has been no evidence that the compounds according to formula (I) and / or (II) were broadly effective against trematode infections, nor that they were sufficiently non-toxic to be tolerated by humans with immunodeficiency. certain uses of nitazoxanide are disclosed in U.S. Pat. No. 3,950,351, as well as in publications of the present inventor. The desacetyl-nitazoxanide, composed of the formula (I), sometimes called tizoxanide or d-NTZ and is a metabolite of nitazoxanide. In WO 95/28393, the present inventor disclosed a method for the manufacture of the composition containing a mixture of the compounds of the formula (I) and the formula (II). It has recently been observed that solid particles of the compound of formula (I), of the compound of formula (II) or of mixtures of both having a particle size comprised between 170 and 520 μm (mean particle size = 352 μm) have very limited efficacy when administered to humans and animals orally. The effectiveness of such particles is lower than that of existing pharmaceutical products and, therefore, unacceptable for existing standards or commercial purposes. It has also been observed in dogs that the oral administration of a single dose of 50 milligrams per kilogram of solid particles of the compound of the formula (I) and the compound of the formula (II) having a particle size less than 5 μm caused serious adverse reactions in these animals. It has been found that, in order to achieve effective and safe treatment of infections caused by parasites, bacteria, fungi and viruses in humans and animals, the pharmaceutical composition, whether in the form of solid doses or in oral suspension, must contain an effective dose of the active agent in the form of solid particles whose particle size is less than 200 μm and which contain the compound of the formula (I) and / or the compound of the formula (II), and which the average particle size of the solid particles active must be greater than 10 μm. A high content of active agent particles whose size exceeds 200 μm, with respect to the amount of particles having a size between 5 and 200 μm, significantly reduces the chemotherapeutic activity of the compounds. Preferably, the pharmaceutical compositions of the present invention contain no more than 5% by weight of active solid particles with a size greater than 200 μm. Even more preferably, the pharmaceutical compositions of the present invention contain substantially no solid particles with a size greater than 200 μm. A high content of particles of the active agent whose size is less than 5 μm, with respect to the amount of particles that have a size between 5 and 200 μm, can produce adverse effects in animals and in humans. On the other hand, It has been observed that particles whose size is less than 5 μm are rapidly absorbed from the gastrointestinal tract into the blood and are not as effective, therefore, against parasites, bacteria, fungi and viruses that are usually housed in the gastrointestinal tract of animals. and human beings. It was not possible for the person skilled in the art to foresee that the particle size of the compound of the formula (I) and the compound of the formula (II) could have such a significant effect on its antimicrobial activity in animals and humans. For example, in studies developed by the Inventor, other antiparasitic compounds such as albendazole, mebendazole, niclosamide, praziquantel and metronidazole have not shown such a marked difference in antiparasitic activity in animals and humans according to particle size. Furthermore, the person skilled in the art could not foresee that the particle size of the compound of the formula (I) and the compound of the formula (II) would have such an adverse effect on the tolerance in animals and humans to the administration of said agent Active The compound (s) of the formula (I) and (II) can be administered in the form of solid doses or in aqueous suspensions, and it is preferred that the pharmaceutical composition contains the effective dose of the active agent in the form of solid particles. of the formula (I) and / or (II) with a particle size of less than 200 μm, and average particle size greater than 10 μm, in a determination made with a Coulter® LS 100 counter. This equipment uses laser light at 750 nm to size the particles between 0.4 and 900 μm in diameter by light diffraction. The measurement of the samples is carried out in water with a small amount of Triton X-100 designed to increase the wettability and deflocculate the powder. The most advantageous average particle size of said active solid particles is between 10 and 100 μm, preferably between 20 and 50 μm. The following are examples of the preferred compositions: • a composition in which less than 10% by weight of the active solid particles has a particle size greater than 100 μm. • a composition in which at least 50% by weight of the active solid particles has a particle size of less than 50 μm. The most advantageous average particle size of said active solid particles is between 10 and 100 μm, preferably between 20 and 50 μm. According to a preferred embodiment of the composition, less than 10% of said active solid particles have a size of less than 5 μm. The agent or the active agents used in the solid dose or suspension form is for convenience a mixture of solid particles of compounds of the formula (I) and of the formula (II) with a particle size of less than 200 μm and that the content by weight of the compound of the formula (I) is between 0.5 and 20%, and preferably between 0.5 and 10%, with respect to the total weight of the compounds of the formula (I) and of the formula (II).

The present invention also relates to the pharmaceutical compositions described above which contain for convenience a least one pharmaceutically acceptable acid. Examples of such acids are citric acid, glutamic acid, succinic acid, ethanesulfonic acid, acetic acid, tartaric acid, ascorbic acid, methanesulfonic acid, fumaric acid, adipic acid, malic acid and mixtures thereof. Citric acid is extremely suitable. Their presence increases the stability of the agent or active agents. The ratio between the weight of the pharmaceutically acceptable acid / the weight of said active solid particles is comprised for greater convenience between 0.01 and 0.5, preferably between 0.03 and 0.2. Also for greater convenience, the amount of acid present is sufficient to adjust the pH of the suspension between 2 and 6, preferably between 3 and 5 and more preferably still, between 3.5 and 4.5. In WO / 95/28393, techniques for preparing the liquid and solid dosage forms of the pharmaceutical composition are disclosed, as well as preferred examples thereof, which are hereby incorporated by reference in their entirety. The compositions contain for convenience a wetting agent and possibly a starch derivative such as that disclosed in U.S. Pat. No. 5,578,621, the content of which is incorporated herein by reference in its entirety, which discloses possible wetting agents and starch derivatives. The wetting agent described in U.S. Pat. No. 5,578,621 fulfills the function of dispersing agent. Such pharmaceutical compositions, either in solid or liquid dosage form or in the form of creams or ointments, may optionally contain additional active agents such as antibiotics, antiviral agents or proton pump inhibitors. While not advantageous, it is possible for said pharmaceutical formulations to contain solid active particles of the compound of the formula (I) and / or the compound of the formula (II) with a size greater than 200 μm. The compositions may contain excipients known as such intended to obtain forms suitable for oral administration. In order to achieve an excellent level of efficacy against a broad spectrum of parasites, bacteria, fungi and viruses, the distribution factor is comprised for greater convenience between 0.8 and 2, preferably between 1.1 and 1 9 and more preferably should still be greater than 1.5 This distribution factor is calculated according to the following formula: Fgo% = (090% "010%) / ((090% + 010%) / 2) where: • F90% is the factor at 90%; • 09O% is the maximum particle size of the particle fraction corresponding to 90% of said active solid particles and • 01O% is the maximum particle size of the particle fraction corresponding to 10% of said active solid particles According to a specific embodiment of the present invention, the particles of a compound of the formula (I) and / or of the formula (II) are prepared according to the methods described hereinabove and then are ground so that less than 10 5 of said particles active is greater than 100 μm, less than 50% of said particles is greater than 50 μm and less than 10% of said active particles is less than 5 μm in size, the average particle size being between 20 and 50 μm. The active particles are then granulated by a mixture containing active solid particles and at least one granulating agent. Examples of granulating agents which may be mentioned are the following: polyvinylpyrrilidone, water, alcohol, hydroxyl cellulose sucrose and mixtures thereof. A pharmaceutically acceptable acid is added for convenience during the granulation process. The present invention relates to solid dosage forms containing a composition of the invention such as tablets, dispersible tablets, coated tablets, matrices, etc. The dosage form of the present invention contains, for example: active solid particles with a particle size of less than 200 μm, of which less than 10% have a size greater than 100 μm, less than 50% have greater than 50 μm and less than 10% has a size smaller than 5 μm, the average particle size being between 20 and 50 μm; • at least one granulating agent; • at least one wetting agent; • at least one starch derivative and • at least one pharmaceutically acceptable acid which is preferably added during the granulation process. Liquid dosage forms such as the aqueous suspensions of the present invention contain, for example: • as active agent, solid particles containing a compound of the formula (I) and / or a compound of the formula (II), which they have a particle size of less than 200 μm, it being further realized that less than 10% of said particles have a size greater than 100 μm, less than 50% of said particles have a size greater than 50 μm and less than 10% of said particles it has a size smaller than 5μm; • at least one granulating agent; • at least one wetting agent; • at least one pharmaceutically acceptable acid, the pH of the suspension being between 2 and 6, preferably between 3 and 5 and more preferably still, between 3.5 and 4.5; • at least one thickener, for example xanthan gum, gum aguar, crystalline cellulose, carruba gum, carboxymethylcellulose or a mixture thereof. The cream or ointment forms of the present invention suitable for oral administration contain, for example: • as active agent, solid particles containing a compound of the formula (I) and / or a compound of the formula (II), which they have a particle size of less than 200 μm, it being further realized that less than 10% of said particles have a size greater than 100 μm, less than 50% of said particles have a size greater than 50 μm and less than 10% of said particles it has a size smaller than 5μm; • at least one wetting agent; • at least one pharmaceutically acceptable acid, the pH of the suspension being between 2 and 6, preferably between 3 and 5 and more preferably still, between 3.5 and 4.5; • at least one thickener, for example xanthan gum, gum aguar, crystalline cellulose, carruba gum, carboxymethylcellulose or a mixture thereof. The cream or ointment forms suitable for topical or intravaginal applications contain, for example: • as active agent, solid particles containing a compound of the formula (I) and / or a compound of the formula (II), which have a particle size smaller than 200 μm, it being further realized that less than 10% of said particles have a size greater than 100 μm, less than 50% of said particles have a size greater than 50 μm and less than 10% of said particles have a size less than 5μ? m; • at least one wetting agent; • at least one pharmaceutically acceptable acid, the pH of the suspension being between 2 and 6, preferably between 3 and 5 and more preferably still, between 3.5 and 4.5; • cetyl alcohol and / or glyceride derivatives and / or propylene glycol; • at least one thickener, for example xanthan gum, gum aguar, crystalline cellulose, carruba gum, carboxymethylcellulose or a mixture thereof. DESCRIPTION OF THE PREPARATION OF THE PHARMACEUTICAL COMPOSITIONS The pure dry compound of the formula (I) and the pure dry compound of the formula (II) were subjected to trituration and the resulting crushed was passed through a mesh. After trituration, the particle size distribution of the compound of formula (I), of formula (II) or mixtures thereof was as indicated in Fig. 8. Fig. 8 shows the percentage of particles with a size smaller than 0 μm. From said figure it can be deduced that: • less than 10% by weight of the particles had a particle size of less than about 5 μm; • less than 10% by weight of the particles had a size greater than about 70 μm; • the average particle size was approximately 40 μm; • the distribution factor of the particles was approximately 1.73, this distribution factor being calculated according to the following formula: F90% = (090% "010%) ((090% + 010%) / 2) where: • F90% is the 90% factor; • 09O% is the maximum particle size of the particle fraction corresponding to 90% of said active solid particles and • 01O% is the maximum particle size of the particle fraction corresponding to 10% of said active solid particles. Specific examples of such compositions are presented in the following tables.

Table 1. Example of composition of dispersible tablets for oral administration containing as active agents a compound of the formula (I) and a compound of the formula (II).

Nitazoxanide (99%) + desacetyl-nitazoxanide (1%) 200 mg Microcrystalline cellulose Avicel pH 102 marketed by FMC-USA 1 16 mg Crospovidone 25 mg Magnesium stearate 3 mg Colloidal silicon dioxide 5 mg Citric acid 10 mg Flavor No. 877720 marketed by Robertet 10 mg Sodium saccharinate 2 mg Table 2. Example of composition of coated tablets for oral administration containing as active agents a compound of the formula (I) and a compound of the formula (II). Nitazoxanide 500 mg Corn starch 60 mg Pregelatinized corn starch 70 mg Hydroxypropyl methylcellulose 5 mg Sucrose 20 mg Sodium starch glycolate 30 mg Citric acid 25 mg Talc 8 mg Magnesium stearate 7 mg Coverages: Hot sugar solution or a film sprayed on tablets or granules containing 500 mg of the active agent. 1 Table 3. Example of composition of an aqueous solution for oral administration containing as active agents a compound of the formula (I) and a compound of the formula (II). The pH of the suspension was approximately 4.1. Nitazoxanide (98%) + desacetyl-nitazoxanide (2%) 2 g Distilled water 100 ml Sodium benzoate 0.2 g Sucrose 30.5 g Xanthan gum 0.2 g Microcrystalline cellulose and sodium carboxymethylcellulose Avicel RC-591 marketed by FMC-USA 0.8 g Citric acid 0.2 g Dehydrated sodium citrate 50 mg Strawberry flavor No. 877720 marketed by Robertet 125 mg Red tincture N ° 33 D and C 1 mg Table 4. Example of cream for oral administration containing as active agents a compound of the formula (I) and a compound of the formula (II). Nitazoxanide (98 5) + desacetyl nitazoxanide (2%) 500 mg Mineral oil 10 g Black sugar 1 g Microcrystalline cellulose and sodium carboxymethylcellulose Avicel RC-591 marketed by FMC-USA 0.8 g Citric acid 0.2 g Table 5. Example of cream or ointment for topical or intravaginal applications containing as active agents a compound of the formula (I) and a compound of the formula (II). Nitazoxanide (98 5) + desacetyl nitazoxanide (2%) 8 g Cremaphor A6 2g Cremaphor A25 1 .5 g Mineral oil 7g Luvitol EHO 7G Glycerol monoester 4 g Cetyl alcohol 3 g Simethicone 0.5 g Germaben II 1 g Propylene glycol 3.5 g Distilled water 62.5 g The pharmaceutical compositions of the present invention are compositions with a broad spectrum of action against parasites, bacteria, fungi and viruses, especially when the administration is oral. The pharmaceutical compositions disclosed above in the present invention proved very effective and safe in animals and humans. Specifically, in clinical studies performed with humans, it has been observed that the efficacy of the compositions described herein above was significantly greater for the treatment of infections by parasites than the same formulations of the active compound having a particle size comprised between 170 and 520 μm (mean particle size = 352 μm), even when larger particles were administered to patients in doses up to three times higher and for longer periods. Table 6 shows examples of cure rates.

Table 6. Comparison of the results obtained in human clinical studies using compounds of the formula (I) and of the formula (II) with a particle size comprised between 170 μm and 520 μm (mean = 352 μm) with the results obtained using the formula (I) and the formula (II) with a particle size comprised between 5 μm and 200 μm (mean = 34 μm). Compound of formula (I) (98%) + compound of formula (II) (2%) Particle size 170 to 520 μm Particle size 5 to 200 μm Dosage = 15 to 50 mg / kg / day for 3 Dosage = 15 to 50 mg / kg / day for 3 to 7 days days Cured quantity / Total = Capt. Cured / Total = Index Parasite percentage of cure per cent cure Blastocystis hominis 12/27 = 44% 10/10 = 100% Entamoeba histolytica 29/47 = 62% 106/133 = 80% Giardia lamblia 1 1/37 = 30% 50/73 = 68% Ascaris lumbpcoides 3/69 = 4 % 144/179 = 80% Trichuris trichiura 7/48 = 15% 58/79 = 73% For each of the parasites listed in Table 6, the corresponding percentage cure rates were significantly better in the case of patients treated with active particles whose size was between 5 and 200 μm than in the case of patients treated with particles. whose size was between 170 μm and 520 μm. The level of statistical significance in each case was p < 0.02 (using the standard? 2 test). This was the result, even though the doses of the active agent with larger particles were usually higher and were administered for a longer period than the doses of the active agent with particle size less than 200 μm. In neither of the two groups of patients there were serious adverse effects. In the tests carried out on animals, results similar to those indicated in the previous article were obtained. In addition, the adverse reactions observed in dogs after oral administration of a single dose of 50 milligrams per kilogram of the compound of formula (I) and the compound of formula (II) were not observed in extensive animal studies using the compound of formula (I) and the compound of formula (II) having a particle size comprised between 5 μm and 200 μm (mean> 10 μm), even when the same dose or a higher dose of said compounds was administered on a daily basis for 90 days or more. Moreover, said compositions were stable (still subjected to temperatures of 40 ° C and 65% relative humidity for six months or, in the case of liquid suspensions, when they remained in aqueous suspension under these conditions for three months). This result ensures that the active ingredients are not degraded and that the compositions maintain their effectiveness for a period of time after the preparation, which is suitable for medicinal and commercial applications. Next, the effectiveness of the pharmaceutical compositions will be demonstrated. EXAMPLE I CRYPTOSPORIDIUM PARVUM In a preliminary clinical trial, 30 patients affected with AIDS who suffered chronic cryptosporidial diarrhea with oral nitazoxanide at a dose of 500 to 2000 mg daily were treated. If diarrhea persisted, patients were given an additional dose of 2000 mg daily for another four weeks.

Twenty-eight patients completed two weeks or more of treatment and 16 of them were evaluated for their therapeutic response by the eighth week of treatment. Of this last group, 12 people experienced a reduction of 50 percent or more in the frequency of daily bowel movements, the presence of the parasite in the feces of 10 individuals was markedly reduced or completely disappeared and in four individuals the organism stopped being detected. Six patients satisfied positively the clinical and parasitological criteria Patients who received higher doses of the drug for longer periods were more likely to respond positively. An open registry study of nitazoxanide in cases of cryptosporidial diarrhea linked to AIDS recorded a decrease in stool in individuals taking doses of 500, 1000, 1500 and 2000 mg daily of the drug Participants had an average CD4 + count of 42 cells / mm3 (range 0-303 cells / mm3) and an average of 6.7 daily stools for an average of 15 months, the presence of Cryptosporidium parvum oocysts without other evident enteric pathogens was detected in the faeces. In almost all patients, therapy with azithromycin or paromomycin had failed. After 23 weeks of treatment, 9 patients from a group of 13 showed a complete clinical response (between one and three predominantly formed bowel movements daily) and 4 of the 13 showed a partial clinical response (a decrease of at least 50 per percent in daily stools or such a change in stool consistency so that 75 percent had shape) Towards the end of the study a total eradication of the parasite was observed in 8 patients on 1 1, while the remaining three showed a substantial reduction in the level of oocysts. A tendency towards better responses was observed with doses of 1000 mg daily or higher and a longer therapy. Two trial participants had urticating skin rashes. More than 90% of the individuals participated in the study for more than four weeks EXAMPLE II CRYPTOSPORIDIUM PARVUM Information on in vitro doses Nitazoxanide was dissolved in sterile dimethyl sulfoxide (DMSO) and applied to monolayer cultures of cells infected with intact C parvum oocysts in concentrations of 100 μg / ml, 10 μg / ml, 1 μg / ml and 0.1 μg / ml A second test was carried out with nitazoxanide at concentrations of 20, 2, 0 2 and 0.02 μg / ml. These concentrations were reached by serial dilution with a complete DMEM medium to obtain a final DMSO concentration of 0 5%. The control medium also contained 0 5% DMSO. A culture of MDBKF5D2 cells developed in 7 mm chambers was used in the experiment. As for Cryptosporidium parvum, GCH1 oocysts were used, 5 x 104 per cavity. The purpose of the experiment was to compare the effect of paromomycin (positive control) with that of nitazoxanide (experimental drug). The matepal used comprised anti-sporozoite rabbit serum of C parvum (0.1%) goat anti-rabbit antibody conjugated with fluorescein (1%). Toxicity assay 200 μl of the medium containing the nitazoxanide solution were placed in concentrations of 100, 10, 1 and 0 1 μg / ml and the corresponding controls in two 96-well plates containing confluent MDBKF5D2 cell monolayers and in two wells without monolayers. The drug was incubated on monolayers at 37 ° C and CO28%. At 24 hours (test 1) and at 48 hours (test 2) were added to each MTS cavity (Owen's solution) and PMS in concentrations of 333 μg / ml and 25 μM respectively. The plate was placed again in the dark incubator to develop for two hours. At two hours, 100 μl of each supernatant was transferred to a new microtitre plate and the values were measured with an ELISA kit at 490 nm. The results were recorded, which were analyzed. The percentage toxicity was calculated by subtracting the mean optical density (OD) of the drug supernatants from the mean optical density (OD) of the supernatants of the control medium (without drug), dividing the value obtained by the optical density of the control medium and multiplying then by 100, as indicated below: OD of the medium - OD of the drug x 100 OD of the medium Evaluation of intact C. parvum oocysts: They were incubated in nitazoxanide (100, 20, 10, 2, 1, 0.2, 0.1 and 0.02 μg / ml) 5 x 104 oocysts of C. parvum per cavity at 37 ° C (C02 8%) on monolayers of confluent MDBKF5D2 cells. The level of infection of each cavity was determined and analyzed by immunofluorescence at 24 and 48 hours. Percentage inhibition was calculated by subtracting the average parasite count / 10 fields from the cavities with the experimental drug from the average parasite count / 10 fields in the control medium (without drug), dividing the result by the mean count control and then multiplying by 100, as indicated below: Control medium count - experimental drug count x 100 Control medium count Results: Test 1: 24 hours Parasite count / 10 fields Not available due to toxicity Test 2: 48 hours * Parasite count / 10 fields Impact of nitazoxanide on intact C. parvum oocysts. In trial 1, nitazoxanide concentrations of 10, 1 and 0.1 resulted in inhibition levels of 94.4, 77.2 and 51.8% respectively, and toxicity levels of 65.1, 8.3 and 19.3 respectively. Although there was an almost complete inhibition of infection by parasites with a value of 10 μg / ml, a high toxicity is evident. With a value of 1 μg / ml of nitazoxanide, the comparison between parasite inhibition and cell toxicity with the respective values for paromomycin was favorable at a concentration of 2 mg / ml (77.2% inhibition and 8.3% toxicity). for nitazoxanide with a concentration of 1 μg / ml and 51% inhibition and 23 8% toxicity for paromomycin with a concentration of 2 mg / ml). In trial 2, the drug was modified to obtain a better distribution of the drug with minimal toxicity. Therefore, the cultures remained viable for 48 hours instead of the 24 hours of trial 1. Incubation for 48 hours clearly showed a greater relative cell toxicity than that which was evident for paromomycin in both trials. The 20 μg / ml concentration of nitazoxanide remained too toxic at 48 hours of incubation, despite the fact that the cell monolayer still seemed intact. It is possible that the high toxicity that should affect cell functions also affects the development of parasite infection With a concentration of 2 μg / ml of nitazoxanide, a considerable inhibition of parasite infection was observed with a relatively low cell toxicity. Older children also resulted in significant inhibition with low toxicity. At a drug concentration of 2 μg / ml, moderate cellular toxicity and an inhibitory activity of 94.90% indicate that 2 μg / ml nitazoxanide is superior to paromomycin 2 mg / ml for in vitro infection of C parvum (for example, a concentration 1000 times higher). EXAMPLE III CRYPTOSPORIDIUM PARVUM In vitro dose and storage information: The effect of nitazoxanide and deacetyl-nitazoxanide (NTZ and NTZidos) on intact C. parvum oocysts and monolayers of sporozoite-infected cells that had already passed through the stage was tested. of cyst at concentrations of 0, 1, 0.1 and 0.01 μg / ml. Each compound was dissolved in 100% dimethylsulfoxide (DMSO) and then diluted to the desired concentration with sterile DMEM. Each concentration of nitazoxapide and control media contained 0.025% DMSO as constant. A culture of MDBKF5D2 cells developed in 7 mm chambers was used in the experiment and GCH1 oocysts, 5 x 104 per cavity, were used for Cryptosporidium parvum. The purpose of the experiment was to compare the effect of paromomycin (positive control) with that of nitazoxanide (experimental drug). The material used included C. parvum anti-sporozoite rabbit serum (0.1%) goat anti-rabbit antibody conjugated with fluorescein (1%). Toxicity test: 200 μl of the medium containing the nitazoxanide solution in the aforementioned concentrations and the corresponding controls were placed in two 96-well plates containing monolayers of confluent MDBKF5D2 cells and in two cavities without monolayers. The drug was incubated on monolayers at 37 ° C and C02 8%. At 48 hours, MTS (Owen's solution) and PMS were added to each cavity in concentrations of 333 μg / ml and 25 μM, respectively. The plate was placed again in the dark incubator to develop for two hours. At two hours, 100 μl of each supernatant was transferred to a new microtitre plate and the values were measured with an ELISA kit at 490 nm. The results were recorded, which were analyzed. The percentage toxicity was calculated by subtracting the mean optical density (OD) of the drug supernatants from the mean optical density (OD) of the supernatants of the control medium (without drug), dividing the value obtained by the optical density of the control medium and multiplying then by 100, as indicated below: OD of the medium - QD of the drug x 100 OD of the medium The cito-toxicity scores were assigned as follows: 0.5% toxicity = 0, 6-25% toxicity = 1, 26- 50% toxicity = 2, 51-75 toxicity = 3 and 76-100% toxicity = 4 As a standard, the 0 and 1 cytotoxicity values should be considered acceptable. Values 2, 3 and 4 are considered too high for the cell monolayer. Evaluation of intact C parvum oocysts: 5 x 104 oocysts of C. parvum were incubated in nitazoxanide at the above-mentioned concentrations per cavity at 37 ° C (C02 8%) on monolayers of confluent MDBKF5D2 cells. The level of infection of each cavity was determined and analyzed on computer by means of immunofluorescence at 48 hours. The percentage of inhibition was calculated taking the average count of parasites / 10 fields in the cavities with the experimental drug and subtracting it from the average count of parasites / 10 fields in the control medium (without drug), dividing the result by counting the control medium and then multiplying by 100, as indicated below.

Control medium count - experimental drug count x 100 Control medium count Results: Evaluation of C. parvum oocysts (48 hours) Conc. - μg / ml; Parasite - Average parasite count / field (12 fields analyzed); % Inhib. - Percentage inhibition of infection by parasites; % Tox. - Percent toxicity of the drug for the cells It can be seen in the above data that the inhibitory activity of the NTZidos is the same as that of the NTZ of Example II. Both nitazoxanide and, desacetyl-nitazoxanide were equally effective in vitro against Cryptospohdium parvum when tests were conducted in parallel, obtaining 98 and 94% inhibition with 10 μg / ml and 1 μg / ml of each compound respectively. In the case of nitazoxanide, the lowest concentration that provided more than 90% inhibition was 1 μg / ml, while 50% inhibition could be obtained with lower concentrations of nitazoxanide, for example, 0.2, 0.1 and 0.02 μg / ml. In the same experimental conditions, the paromomycin used as a control was 2000 times less effective, with percentages of inhibition comprised between 51 and 83% for a concentration of 2000 μg / ml.

EXAMPLE IV E. INTESTINALIS AND V. CORNEA 2RK-13 cells (rabbit kidney cell line) were added to culture plates of 24 cavities, with a concentration of 2.6 x 105 cells per well (1.02 ml of medium; RPMI 1640 with 2 mM L-glutamine and fetal bovine serum inactivated by 5% heat). It was incubated at 37 ° C in a CO2 incubator overnight, at which time the cells were confluent (with a duplication, the number of cells could be estimated at 5 x 105 per cavity). Septata intestinalis organisms (developed by tissue culture) were added to the host cells in a ratio of 3: 1 with respect to the estimated host cells, that is, at a rate of 15 x 106 organisms per cavity. This proportion resulted in approximately 50% of the cells becoming infected. The drugs were dissolved in DMSO, water or methanol (depending on the solubility) to generate reserves with concentrations of 1.0 μg / ml that were stored at -70 ° C. The dilutions used in the experiments were performed in a culture medium of full fabric. All dilutions were tested in triplicate cavities. The medium was replaced every three or four days (with freshly diluted drugs).

On the sixth day (after adding parasites and drugs), the cells were analyzed to measure toxicity. We studied the control cells that had received drugs but were not infected with parasites to verify their confluence, morphology and also to observe the presence of dead or floating cells. Cells incubated with parasites were only observed to confirm that the parasites were infectious (ie to verify the presence of parasitophore vacuoles). The cells incubated with parasites and drugs were evaluated in order to verify the toxicity and the relative amount of parasitophore vacuoles (ie, high, medium or low quantity). On the tenth day, 100 μl of 10% SDS (final concentration 0.5%) was added to the culture cavities in order to break the membranes of the host cells and cause the release of microsporidia. The total amount of parasites present in each cavity was determined by counting an aliquot in a hematocytometer. The results were expressed as percentages of inhibition (relative to infected cells that did not receive a drug). The results are presented in Figs. 1 -4. EXAMPLE V TOXOPLASM GONDII The effects of nitazoxanide and desacetyl-nitazoxanide against the parasites were verified, more specifically, against the RH strain of Toxoplasma gondii, preserved by successive passages in mice. T. gondii was inoculated into cell cultures of MRC5 fibroblasts (Bio-Merieux, France) developed in 96-well microplates. 200 freshly collected tachyzoites were added to each culture cavity, except in the 8 control cavities (negative controls). After 4 hours of incubation, dilutions of the drug were added to the cultures. The nitazoxanide and the desacetyl-nitazoxanide (dNTZ) were tested at dient concentrations, from 8.10-4 and 40 mg / l. The drugs were initially diluted in DMSO at a concentration of 2 mg / ml and then serial dilutions were prepared in the culture medium. No precipitates were observed. Dilutions of the drug were added to the cultures (8 cavities for each dilution) and then the plates were incubated for 72 hours. The cultures were subsequently fixed with cold methanol. The evaluation of the development of T. gondii was carried out with ELISA using a rabbit anti-T. gondii antibody labeled with peroxidase. The optical density values were recorded for each cavity. The results are indicated in a graph that represents the OD values obtained for each culture cavity based on the concentration of the drug in the culture. The statistical analysis included a regression analysis with a 95% confidence interval and the determination of response curves to the drug from the OD values generated for each drug. A plaque was stained with Giemsa to study the cytopathic et on the cultures. Three separate experiments were performed. In each of them, two culture plates were used for each compound and in each plate 8 identical cavities were used for each drug concentration. Results: Similar results were obtained for the three groups of experiments. In Figures 5 a, b, c and 6 a, b, c the results of a representative experiment for each drug were plotted. Nitazoxanide (Fiqs 5 a, b, c): No inhibitory et was observed for concentrations between 10"4 mg / l and 0.3 mg / l. A significant et was observed for concentrations >; 0.6 mg / l and total inhibition of Toxoplasma development for concentrations > 2.5 mg / l. However, for the latter concentration, a marked toxicity was also noticed in the cell monolayer. At microscopic examination, the monolayer showed that NTZ at concentrations of 1.25 mg / l induced a cytopathic effect in parasitized cells, with an increase in the parasitophorous vacuole and a reduction in the number of intracellular parasites. The regression analysis indicated that the concentration that inhibited 50% could be estimated at 1.2 mg / l. Deacetyl nitazoxanide (Figs 6 a, b, c): Similar results were obtained from the trials with desacetyl nitazoxanide: there was no effect at concentrations between 10"4 mg / l and 0.3 mg / l, inhibition at concentrations> 0.6 mg / l and marked toxicity for concentrations> 2.5 mg / l The inhibitory concentration 50% could be estimated at 1.2 mg / l The results obtained were reproduced in three separate experiments, with evaluation of the inhibitory effect of the drug in repeated cultures for each concentration For both NTZ and deacetyl NTZ, a marked inhibition of the development of Toxoplasma could be detected at concentrations of approximately 1.2 mg / l, alterations of the parasitophore vacuole were observed although there were no alterations in the parasite itself. indicate that experimental drugs have a desirable activity against T. gondii and that an inhibitory effect can be expected in vivo if e achieves a concentration of approximately 1 mg / l in serum or tissues. EXAMPLE VI MYCOBACTERIA It was discovered that nitazoxanide has antimicrobial activity against TB organisms. The table below shows the results of a test of nitazoxanide and desacetyl nitazoxanide to determine its mean inhibitory concentration (MIC) in the case of Mycobacterium intracellular, carried out by means of the agar dilution technique. These results originate in several experiments, each of which took about 3 weeks to apply the dilution method when diluting Middlebrook. The indicated data indicate that, in the case of Mycobacteria, nitazoxanide has a MIC of 4 μg / ml when a standard strain of intracellular Mycobactehum from ATCC is used and an agar dilution assay is carried out. Mean inhibitory concentrations (MIC) of nitazoxanide and tizoxanide for Mycobacterium intracellulare MIC Nitazoxanide 2 μg / ml Tizoxanide 4 μg / ml * The MICs were determined by the standard agar dilution method using Middlebrook 7H1 1 agar for 3 weeks. For this experiment the standard strain M. intracellulare ATCC 13950 was used. FIG. 7 is a graph representing the effectiveness test of nitazoxanide against mycobacteria developed in liquid broth. An MTS colorimetric test was applied to determine the development over the course of 4 hours instead of the 3 weeks required by the agar count method. As can be observed in the data of Fig. 7, when the incorporation of nitazoxanide was added 72 hours after the start of the culture, an immediate effect on the development was produced when compared with the development of the control medium. A dose of 3 μg / ml of nitazoxanide stops the development during the following 24 hours, then a slow development takes place during the following two days. The dose of 50 μg / ml was completely bacteriostatic during the 144 hours of culture. EXAMPLE VII CYPTOSPORIDIUM PARVUM The effect of nitazoxanide against Cryptosporidium parvum in experimentally infected mice was studied. The nitazoxanide came from Romark Laboratories, L.C. of Tampa, State of Florida, USA The total human dose was modified (1 g / day for 7 days, ie 7 g) in order to apply it to mice as indicated by Paget and Barnes. In the case of mice (weighing approximately 20 grams), the human dose was multiplied by a factor of 0.0026 in order to obtain the total amount of drug needed for each host in the morning and evening for 7 consecutive days. Each mouse received a dose of 2.6 mg / day (7000 mg x 0.0026 / 7). The doses were administered by mouth through a syringe of plastic material equipped with an ad-hoc needle. Twenty (20) 2-day-old suckling mice were infected by oral administration of 100,000 Cryptospohdium parvum oocysts obtained from infected calves. Before administration to the mice, the oocysts were concentrated using a sugar solution, according to the technique described by Fayer and Ellis. Every day, swabs were impregnated with rectal material from each mouse using the Niehl-Nielsen staining technique described by Graczyk et al. The oocysts appeared in the feces 2 days after the oral infection of the animals. On the third day after infection, 10 mice received 1.3 mg of nitazoxanide in the morning and evening, for 7 consecutive days, while the remaining 10 mice were kept as untreated controls. Material obtained from rectal swabs obtained daily during the 7 days of treatment and during the 7 days after the end of it. The oocysts were suspended in oil and an account of 100 fields was made under a microscope. Results: The results shown in the following Table clearly indicate that nitazoxanide administered in daily doses of 2.6 mg / day for 7 consecutive days was effective against Cryptospo? Dium parvum, producing a reduction in the number of oocysts in the feces of the infected mice when the results were compared with the control animals. At the end of the third day of treatment, the number of oocysts present in the stool decreased in 6 of the 10 treated animals. At the end of the treatment on Day 7, the reduction in the number of oocysts was total and the treated animals were negative to the fecal analysis in comparison with the untreated controls. The effect was maintained for another 7 days after the end of treatment, as indicated by the negative tests carried out on the third and seventh days after the end of treatment: EXAMPLE VIII MYCOBACTERIUM The effect of nitazoxanide was compared with that of the isoniazid antibiotic. BCG (Bacillus Calmette-Guérin) was used in the protocol as mycobacterial strain. The sensitivity of this strain was the same as that of Mycobacterium tuberculosis, although this strain is less harmful and therefore does not require extreme precautions to contain the tuberculous agent. The mice were given daily doses of 4 mg / mouse in 0.2 ml of sunflower oil. The results of the mice treated with nitazoxanide were comparable with those obtained from the group that received isoniazid EXAMPLE IX F ASCI HEPATIC WAVE Trials were conducted to verify the in vitro efficacy of nytazoxanide and desacetyl-nitazoxanide against Fasciola hepatica. Three bovine calf livers attacked with fascioliasis were chosen from the Louisiana Veterinary Medicine Diagnostic Laboratory of Hardy's Meat Packers, Bunkie, Louisiana. Hepatic F. was extracted from the corresponding bile ducts. The parasites were washed in sterile saline for 1 hour and then transferred to sterile saline or RPMI (pH 7.4) for another three hours. The trematodes were then maintained in sterile RPMI rabbit serum (50:50 v / v) or sterile RPMI (pH 7.4) overnight at 37 ° C with CO25%. The in vitro culture (37 ° C, C025%) was carried out according to a modification to the method of Ibarra and Jenkins (Z. Parasitenkd., 70: 655-661, 1984). Applying a sterile technique, the parasites were washed twice for 2-3 minutes in a Hank's balanced salt solution (pH 7.2) and individually placed in six-well Linbro culture dish cavities each containing 10 ml aliquots of the designated solutions of the drug in the culture medium. The latter was a combination of RPMI 50:50 v / v rabbit serum with 2% rabbit blood plus 100 ppm penicillin and 100 ppm streptomycin. Only parasites with normal activity and morphology were used. Deposition solutions of NTZ and its metabolite D-NTZ from Romark were used, which were dissolved in DMSO (2000 μg / ml) and diluted in the culture medium using 100 ml volumetric flasks to obtain the specified concentrations of the drug (100, 50, 25, 10, 5, 3, 1 μg / ml). In each replicate, two control parasites were incorporated, one in a culture medium without medication without RBC and another in the culture medium without medication with RBC. The parasites were studied in terms of the effects of drug treatment, whether these were death, motility disturbances or morphological changes, * which were compared with the characteristics of the control parasites using a black light panel and a light lens. 3x increase. Results: Experiment 1: In the case of D-NTZ, with the doses of 50 and 100 μg, the parasites were dead or dying after one hour. In the first hour of treatment with 25 μg, four of the 7 parasites were dying, two were active and one of them was lethargic. After three hours all the parasites were dead except two lethargic trematodes. Only one of the lethargic trematodes survived for four hours. At the 10 μg dose, reduced activity was observed in parasites after 1, 3 and 4 hours and all of them were moribund or had died after 7 hours In the groups treated with doses of 5 μg and 3 μg, reduced activity was observed in some individuals for 24 hours, with a somewhat lesser effect in the case of the 3 μg dose, but all parasites treated with these doses died after 50 hours, with the exception of one lethargic parasite in each case. group In the group treated with a dose of 1 μg, a slower activity was observed in the course of 42-74 hours, but after 91 hours only 3 parasites remained active and one was dying With this last dose, after of 115 hours only a lethargic parasite survived In the control group with RBC mortality was observed at 66 hours (one parasite), at 91 hours (one parasite) and at 115 hours (four parasites) In the control group without RBC , all the parasites were alive s after 91 hours and only one of them had died after 115 hours Experiment 2 Slightly greater activity was observed in the case of NTZ than in that of D-NTZ, manifested by earlier effects on motility and mortality in the 8 replicates In the groups treated with doses of 100, 50 and 25 μg, all the parasites were killed or were dying after one hour, except one corresponding to the group that received 25 μg, which died after 3 hours At the beginning of hour 1 it was already proven reduction of the motility related to the drug in each of the other groups medicated with the dose of 10 μg at After 16 hours, a single parasite survived At 23 hours, there were only 2 lethargic parasites in the group that had received 3 μg, which died around the 41st hour In the group that received 1 μg, a parasite died in the 16th hour , three died at the 41st hour and five died at the 74th hour; at hour 91 there were still 3 active parasites and only one remained active at hour 1 15. In the control group with RBC, 7 of the 8 parasites were alive at hour 74, 3 were still alive at hour 91 and 2 survived even at hour 1 15. In the control group without RBC, 6 of the 8 parasites had activity at hour 74, 4 of them were active at the 91st hour and two continued active until the 1th hour. trematodes in the groups that received high doses (25, 50, 100 μg), was rapid and was associated with contractions and ventral 'curvature'. With lower medication levels, most parasites had slower activity over a period and showed greater relaxation and 'flattening' when they were dying or dead. Pollution was a limiting factor in the experimental results of some replicates after 91 h. In the case of the experiment with D-NTZ, at 1 15 hours an important development of bacteria or fungi was observed related to mortality. In the case of the experiment with NTZ, the excessive growth and mortality of the parasites in plates of whole replicas occurred at the 91th hour (two replications) and at the 1:15 hour (5 replications). Observations made at time 139 are not considered valid because of the general contamination of most plates. Conclusions: The experiments suggest an intense parasiticidal action of nitazoxanide in both groups of drugs tested. In the case of F. hepatica, nitazoxanide showed a somewhat higher parasiticidal activity than that of desacetyl-nitazoxanide, its main metabolite to which action was attributed to the liver. Rapid death of parasites occurs within the first hour with in vitro doses of D-NTZ > 50 μg, within the cuatros with doses of 25 μg and within 6-7 hours with doses of 10 μg. It is possible that the 10 μg dose constitutes a convenient value for single doses if the pharmacokinetic data indicate that tissue levels are maintained for periods > 6-8 hours after the single treatment. In treatments that lasted 74 hours (3 days), intense parasiticidal activity was observed in both compounds administered in doses of 3 and 5 μg. With the dose of 1 μg prolonged survival was observed close to that of the non-medicated parasites, although not equal to it. Consequently, the administration of this level of drug for parasites of the liver tissue for 3 or 4 days may be inadequate for the therapeutic effect. EXAMPLE X GASTIC FASCIOLA The effect of nitazoxanide on mature and immature individuals of Fasciola gigantica in experimentally infected rabbits was tested. They were collected in sheets of paper cellophane metacercarias encysted (EMC) of Fasciola gigantica after 28-35 days of infection of the corresponding miracidia in snails L. calludi. The technique described by Abdel-Ghany was used, in which the snails are exposed to artificial light daily for 30 minutes in clean dechlorinated running water. The resulting encysted metacercariae (EMC) were kept at 4 ° C in the refrigerator for 5 to 8 days under a surface of water until they were used to infect experimental animals. Forty (40) Boscat rabbits weighing between 1.5 and 2 kg each were included in the study, and they were divided into two treatment groups of 20 animals each. Group 1 animals were orally infected with 35-40 metacercariae. encysted wrapped in lettuce leaves that were placed at the base of the tongue With the hand, the mouths of the animals were kept closed until they swallowed the metacercariae. This Group 1 was used to test the efficacy of nitazoxanide against immature stages (4-5 days of age) of Fasciola gigantica. Animals of Group 1 were infected orally as indicated in the previous paragraph with 10-15 cystic metacercariae. These animals were used to test the efficacy of nitazoxanide against mature young trematodes (>; 10 weeks old). Four weeks after infection with immature stages of the parasite, ten animals from Group 1 received 35 mg doses of nitazoxanide in the morning and evening for 7 consecutive days. The remaining ten animals of Group 1 were left untreated, as controls. Ten weeks after infection with mature stages of the parasite, ten animals of Group 2 received 35 mg doses of nitazoxanide in the morning and evening for 7 consecutive days. The remaining ten animals of Group 2 were left untreated, as controls. The feeding of all the animals were dry rations until the end of the experiment. Seven days after administering the last dose of nitazoxanide, animals of all groups were sacrificed. The liver surface of the animals was examined for the presence of migratory necrotic furrows, especially in the case of the immature stage of the parasitic cycle.

The necrotic areas were studied by means of two surgical needles that were used to extract migratory juvenile parasites, according to the technique described by El-Bahy. Small slices of liver were cut, especially in the area near the migratory furrows and the fragments were macerated under a microscope in order to extract the existing parasites. The abdominal cavity and the surfaces of the viscera were washed with hot water. Subsequently, the washing water was collected, passed through a sieve and studied to isolate the young parasites. All the parasites present were counted, as well as the fragments of them, both in the treated animals and in the untreated animals of Groups 1 and 2. The living parasites had a clean color, were translucent, showed intact teguments and were easy to extract. of the liver tissue with warm water. The dead trematodes were gray in color and showed a cracked necrotic surface. The efficacy of nitazoxanide was calculated by the following formula:% efficacy = a - b x 100 where: a = number of parasites recovered from the faeces in the control animals b = number of parasites recovered from the feces in the treated animals.

Results The results of this study summarized in Table 7 indicate a significant decrease in the number of immature parasites recovered from the liver of rabbits belonging to the treated group, compared to those recovered from the control group. The average percentage of reduction was calculated at 46.77% (range: 40-60%).

Table 7. Efficacy of nitazoxanide against immature F. gigantica (4 weeks of age) in experimentally infected rabbits.

In the early mature stage of the infection, nitazoxanide showed a total effect (100% reduction) and the liver of the treated rabbits showed no parasites on examination, while the liver of the untreated specimens did, as indicated in Table 8 Table 8 Efficacy of nitazoxanide against mature F. gigantica in its juvenile stage (10 weeks of age) in experimentally infected rabbits.

Nitazoxanide administered at a dose of 70 mg / day for 7 consecutive days is moderately effective against the immature stage of Fasciola gigantica and is totally effective against the early mature stage of the parasite. EXAMPLE XI SCHISTOSOMA The effect of nitazoxanide against Schistosoma mansoni and Schistosoma haematobium was tested in experimentally infected rats. Forty (40) white mice weighing between 30 and 50 grams were used, divided into two treatment groups of 20 animals each. The first group was infected with 300-500 Schistosoma mansoni-free active nearby, suspended in 0.25 ml of distilled water, inoculated by intraperitoneal injection. The second group of animals was infected in the same way with Schistosoma haematobium near. Both groups were maintained for 70 days in the laboratory. Seventy days after infection, ten animals from each group were treated with nitazoxanide at oral doses of 1.3 mg administered in the morning and evening for 7 consecutive days. Seven days after the end of the treatment, all the mice were sacrificed and the parasites were extracted from the liver of each animal by perfusion with warm water (37 ° C). Schistosomes extracted from all animals, both treated and control animals, were counted. The efficacy of nitazoxanide was calculated according to the following formula:% efficacy = a - bx 100 where: a = amount of schistosomes recovered from the faeces in the control animals b = amount of schistosomes recovered from the feces in the animals treated. Results The results summarized in Tables 9 and 10 clearly indicate that nitazoxanide administered in daily doses of 2.6 mg / day for 7 consecutive days was more effective against Schistosoma haematobium, for which a reduction of 82.85% was registered with respect to to the control animals. In the case of Schistosoma mansoni, the reduction of parasites only reached 59.91% with respect to the control mice. These results confirm those recorded by Abaza et al. in human patients, for whom nitazoxanide was not effective against S. mansoni, as demonstrated by the positive egg count after treatment.

Table 9. Efficacy of nitazoxanide against mature parasites (13 weeks of age) of Schistosoma mansoni in mice.

Table 10. Efficacy of nitazoxanide against mature parasites (13 weeks of age) of Schistosoma haematobium in mice.

Claims (42)

1. CLAIMS 1 A pharmaceutical composition for administration characterized in that it comprises as active agent at least one compound selected from the group consisting of the compound of formula (I) and the compound of the formula (II) A composition according to claim 1, characterized in that said active compound has the form of active particles with a particle size of less than 200 μm and an average particle size greater than 10 μm. A composition according to claim 2, characterized in that the average particle size of said active particles is between 10 and 100 μm. A composition according to claim 2, characterized in that the average particle size of said active particles is between 20 and 50 μm. 5. A composition according to the invention. claim 2, characterized in that less than 10% by weight of said active particles has a particle size greater than 100 μm. 6. A composition according to claim 2, characterized in that at least 50% by weight of said active particles has a particle size of less than 50 μm. 7. A composition according to claim 2, characterized in that less than 10% of said active particles have a particle size of less than 5 μm. 8. A composition according to claim 2, characterized in that it comprises a mixture of active particles of compounds of the formula (I) and the formula (II), the ratio between the weight content of the compound of the formula (I) and the total content by weight of the compounds of formula (I) and of formula (II) a value comprised between 0.5 and 20%. 9. A composition according to claim 1, characterized in that said composition further contains at least one pharmaceutically acceptable acid. 10. A composition according to claim 9, characterized in that said pharmaceutically acceptable acid is selected from the group consisting of citric acid, glutamic acid, succinic acid, ethanesulfonic acid, acetic acid, tartaric acid, ascorbic acid, methanesulfonic acid, fumaric acid, Adipic acid, malic acid and mixtures thereof. eleven . A composition according to claim 9, characterized in that: said active agent has the form of solid particles with a particle size of less than 200 μm and an average particle size greater than 10 μm and the ratio "pharmaceutically acceptable acid weight / weight" of said solid particles "is between 0 01 and 0 05 12. A composition according to claim 1, characterized in that the weight ratio of the pharmaceutically acceptable acid / weight of said solid particles is between 0 03 and 0 2 13 The method for the treatment in non-immunodeficient mammals of infections caused by microorganisms selected from the group consisting of Cryptospopdium parvum, Isospora belli, Enterocytozoon bieneusi, Encephalistozoon intestmalis, Mycobacterium tuberculosis, Mycobactenum avium intracellulare, Pneumocystis cannn and Toxoplasma gondn, said method comprising the administration of a pharmaceutical composition Pharmacologic containing as active agent at least one of the compounds selected from the group consisting of a compound of formula (I) and a compound of the formula (II) A method according to claim 13, characterized in that said active agent has the form of particles with an average particle size comprised between 10 and 200 μm. A method according to claim 13, characterized in that said active agent has the form of particles with an average particle size comprised between 20 and 50 μm A method according to claim 13, characterized in that said pharmaceutical composition contains at least one pharmaceutically acceptable acid 17 A method according to claim 16, characterized in that said pharmaceutically acceptable acid is selected from a group consisting of citric acid, glutamic acid, succinic acid, ethanesulfonic acid, acetic acid, tartaric acid, ascorbic acid, methanesulfonic acid, fumaric acid, adipic acid, malic acid and mixtures thereof A method according to claim 13, characterized in that said active agent is a compound of the formula (I) A method according to claim 13, characterized in that said active agent is a compound of the formula (II) A method according to claim 13, characterized in that said mammal is human and because said agent active is administered daily in amounts comprised between 500-2000 mg. A method according to claim 20, characterized in that said active agent is administered daily in quantities comprised between 1000-1500 mg. 22 A method for treating parasitic infections of trematodes selected from the integrated group by Schistosoma Fasciola Fasciolopsis, Dicrocoelium, Heterophyes and Meta gonimus, said method comprising the administration of a pharmaceutical composition containing as active agent at least one compound selected from the group consisting of a compound of the formula (I) and a compound of the formula (II) 23 A method for the treatment of parasitapa infections by trematodes selected from the group consisting of Schistosoma mansom, Schistosoma haematobium, Schistosoma mekongí, Schistosoma japomcum, Schistosoma mtercalatum, Fasciola hepatica, Fasciola gigantica, Fasciolopsis biski, Dicrocoelium denthticum, Heterophyes heterophyes and Metagonimus yokogawa, said method comprising administering a pharmaceutical composition containing as active agent at least one compound selected from the group consisting of a compound of the formula (I) and a compound of the formula (II) 24. A method according to claim 23, characterized in that said active agent has the form of particles with an average particle size comprised between 10 and 200 μm. A method according to claim 24, characterized in that said active agent has the form of particles with an average particle size comprised between 20 and 50 μm 26. A method according to claim 23, characterized in that said pharmaceutical composition contains at least one pharmaceutically acceptable acid 27 A method according to claim 26, characterized in that said pharmaceutically acceptable acid is selected from a group consisting of citric acid, glutamic acid, succinic acid, ethanesulfonic acid, acetic acid, tartaric acid, ascorbic acid, methanesulfonic acid, fumaric acid, adipic acid, malic acid and mixtures thereof 28 A method according to the claim 26, characterized in that the rel The weight of the pharmaceutically acceptable acid / weight of said active particles is comprised between 0 01 and 0 5 A method according to claim 23, characterized in that said active agent is a compound of the formula (I) A method according to the claim 23, characterized in that said active agent is a compound of the formula (II) A pharmaceutical cream for topical administration characterized in that it comprises as active agent, solid particles of at least one compound selected from the group consisting of a compound of the formula (I) ) and a compound of the formula (II) (II) said particles further having a particle size of less than 200 μm and an average particle size of greater than 10 μm; at least one thickener; At least one wetting agent and at least one pharmaceutically acceptable acid, the pH of the cream being between 2 and 6. 32. A pharmaceutical cream according to claim 31, characterized in that it also comprises at least one additive selected from the group. composed of cetyl alcohol, glyceride derivatives, propylene glycol or mixtures thereof. 33. A pharmaceutical composition for oral administration containing the active agent in granulated form in the presence of a granulating agent, characterized in that: said active agent has the form of active solid particles of at least one compound selected from the group consisting of: composed of the formula (I): and a compound of the formula (II): (II) • said active particles have a particle size smaller than 200 μm and an average particle size greater than 10 μm A composition according to claim 33, characterized in that said granulating agent is selected from the group consisting of polyvinylpyrplidone, water , alcohol, hydroxyl cellulose sucrose and mixtures thereof A composition according to claim 33, characterized in that said active solid particles of the granulate contain at least one pharmaceutically acceptable acid. A composition according to claim 35, characterized in that said acid is pharmaceutically acceptable is selected from a group consisting of citric acid, glutamic acid, succinic acid, ethanesulfonic acid, acetic acid, tartaric acid, ascorbic acid, methanesulfonic acid, fumaric acid, adipic acid, malic acid and mixtures thereof A composition according to claim 35, characterized in that the weight ratio of the pharmaceutically acceptable acid / weight of said active agent is between 0 01 and 0 5. for oral administration containing the active agent, a wetting agent and a starch derivative, characterized in that said active agent has the form of active solid particles of a compound at least selected from the group consisting of the compound of the formula (I) the compound of the formula (II) • said active particles have a particle size smaller than 200 μm and an average particle size greater than 10 μm. 39. A pharmaceutical composition according to claim 38, characterized in that it also comprises a pharmaceutically acceptable acid. 40. A pharmaceutical composition according to claim 38, characterized in that the active particles are granulated in the presence of a granulating agent to form a granulated active agent containing between 2 and 99% by weight of said active compound and between 0.03 and 10% by weight of the active compound. granulating agent. 41. A pharmaceutical composition according to claim 40, characterized in that said granulating agent is selected from the group consisting of polyvinylpyrplidone, water, alcohol, hydroxyl cellulose sucrose and mixtures thereof. A liquid suspension of the active agent for oral administration, characterized in that it contains as • active agent, solid particles of a compound at least selected from the group consisting of the compound of the formula (I) and the compound of formula (II) said particles having a particle size of less than 200 μm and a mean particle size greater than 10 μm, and because • at least one pharmaceutically acceptable acid, with the pH of the suspension comprised between 2 and 6 A suspension according to claim 42, characterized in that its pH is comprised between 3 and 5 A suspension according to claim 42, characterized in that it also comprises a granulating agent PHARMACEUTICAL COMPOSITIONS OF TIZOXANIDE AND NZTAZOXANIDE Summary of the invention The present invention relates to a pharmaceutical composition which contains as active agent at least one compound selected from the group consisting of the formula (I) and the formula (II) The active agent preferably has the form of particles with a particle size of less than 200 μm and an average particle size of greater than 10 μm. Preferably, the pharmaceutical compositions are stabilized with at least one pharmaceutically acceptable acid. present invention are useful for the treatment of opportunistic infections in persons with compromised or suppressed immune system, as well as in the treatment of trematode infections