"PHARMACEUTICAL COMPOSITIONS, METHOD, AND USE OF FORMULATION FOR THE TREATMENT AND PREVENTION OF INFECTIONS ASSOCIATED WITH HELICOBACTER PYLORI IN MAMMALS AND HUMANS". Field of Invention: The present invention relates to pharmaceutical compositions, which associate antibiotics with proton pump inhibitors and their applications in the treatment and prevention of infections caused by Helicobacter pylori . More precisely, the present invention relates to oral pharmaceutical compositions containing three active drugs against H. pylori infections, where at least an antibiotic belongs to nitrofuran class and is associated to at least a second antibiotic that can be of macrolide or tetracycline class and are associated to an proton pump inhibitor. The H. pylori infection constitutes a relevant environmental acquired factor responsible for the pathogenesis of a wide spectrum of gastric and duodenal disorders. The infection is still acquired in childhood and the disease prevalence can reach 80% in adult individuals. The World Health Organization considers this bacterium a carcinogenic agent of Group I for gastric cancer occurrence, including gastric carcinoma and lymphoma, and its eradication in positively diagnosed individuals is the best control against severe forms of the disease. Although the H. pylori is sensitive to a series of antibiotics in vitro, in many treatments a transient suppression is observed but a complete eradication does not occur within a month after the treatment has finished. The development of appropriate eradication methods for chronic
H. pylori infections in vivo is not simple and currently it is only obtained by associating drugs having different action mechanisms. The administration of a single antibiotic has showed not to be efficient to eradicate the infection and the association of two antibiotics not always showed to be effective. The infection control and treatment are accomplished by combining antibiotics with drugs that reduces the acidity of the stomach, such as proton pump inhibitors. This process is known as triple therapy. The main antibiotics used include bismuth salts
(colloidal bismuth subsalicylate and subcitrate), ranitidine bismuth citrate, nitroimidazoles such as tinidazole and metronidazole, tetracyclins, amoxicillin, macrolide antibiotics as clarithromycin, and azithromycin, and nitrofurans (nitrofurantoin and furazolidone) . Among the inhibitors of proton pump, the omeprazole (20 to 40- mg), pantoprazole (40-mg), and lanzoprazole (30-mg) are the most used. The European Patent EP 0282131 describes examples of active antibiotics against H. pylori . Besides the antibiotics above described this patent includes sulfonamides, nimorazole, aminoglycosides (gentamycin, neomycin, canamycin, amicacin or streptomycin) ; macrolides as erythromycin, clindamycin or rifampicin; penicillins as penicillin G, penicillin V, ampicillin or mezlocillin; polypeptides as bacitracin or polymixin; tetracyclines, also including chlortetracycline, oxytetracycline, minocycline or doxycycline; or other antibiotics as carbapenems, cephalosporins, ciprofloxacin, norfloxacin, ofloxacin, pefloxacin; and, chloramphenicol .
The more used treatment consists in the association of a proton pump inhibitor with two or more antibiotics. As these drugs are available in different dosage forms, the treatment requests the administration of several pharmaceutical units a day. A very used scheme relates to the association of the proton pump inhibitor with clarithromycin tablets (500 mg) and amoxicillin (1000 mg) b.i.d. or t.i.d. for the period from seven to fourteen days. Several therapeutic schemes alternating antibiotics and proton pump inhibitors that should reach >90% infection inhibition levels are being evaluated. In case of a retreatment need, as a disease recurrence, the use of nitroimidazoles and macrolides, which have already been used in the initial treatment, it is not recommended and other antibiotics must be used.
A recent problem that has been particularly affecting the H. pylori infection treatment relates to the rapid development of strains resistant to clarithromycin treatment in the entire world where the drug is being used. The proportion of clarithromycin-resistant H. pylori is increasing to a ratio of 2 to 5% a year. A similar background relates to the emergence of metronidazole- resistant strains. In the case of Brazil, the emergence of treatment-resistant H. pylori strains has been observed with greater prevalence to metronidazole and amoxicillin antibiotics. In our studies the incidence of patients with resistant strains was 42% to metronidazole and 29% to amoxicillin. Levels lower than 10% were observed for clarithromycin (7%), tetracycline (7%) and furazolidone
(4%) . These studies show the urgency of new methods and medicines for controlling the H. pylori infection (Mendonga S, Ecclissato C, Sartori MS, Godoy AP, Guerzoni RA, Degger M, Pedrazzoli J Jr. Prevalence of Helicobacter pylori resistance to metronidazole, clarithromycin, amoxicillin, tetracycline, and furazolidone in Brazil. Helicobacter 2000; 5(2):79-83). Moreover, in all these schemes the number of pharmaceutical units is high, being administered at least 3 to 6 units/day of dosage forms resulting in a series of discomforts to patient and increasing the treatment costs, as well as decreasing the treatment adhesion that is considered one of the main causes of the therapeutic failure.
The object of the present invention concerns to a new medicine and a new treatment and prevention method for recurrence of gastric infection caused by H. pylori . For the present invention purposes, the combined administration or drug association signifies that the association of an proton pump inhibitor with one or more interest antibiotics to combat the H. pylori infection can be made in the same formulation or in different formulations administered within a maximum of 24 hours (the treatment duration is from 7 to 14 days) . For use in separated dosage forms, the associations are preferentially available in a single device, e.g. single blister and can be made available in tablets or capsules containing alone or associated drugs, making easy the identification and the use for the patient.
The pharmaceutical composition of the present invention includes, added to the furazolidone, a second
antibiotic that can be a macrolide antibiotic, preferentially clarithromycin or a tetracycline and a proton pump inhibitor. The proton pump inhibitor inclusion aids in the elimination of H. pylori and it can be useful for the treatment once patients frequently are dyspeptic at the beginning of the treatment.
A typical formulation that characterizes the present invention contains furazolidone, clarithromycin and omeprazole or furazolidone, tetracycline and omeprazole. Lanzoprazole or pantoprazol can be an alternative proton pump inhibitor.
In order to reduce the administration of pharmaceutical units during treatment, the use of associations of one or two antibiotics with proton pump inhibitors in a same formulation has been proposed. The patent US 5,945,124 describes an oral dosage form, tablets or pellets, comprising the association of pantoprazole, a proton pump inhibitor, with an antibiotic in controlled- release forms presenting multilayers that slowly release the incorporated drugs. In this patent the advance of the technique lies in the fact of obtaining a controlled- release dosage form, which protects the proton pump inhibitor from gastric degradation, however, the available clinical data indicate that it still requests association with other antibiotics.
The patent US 6,132,768 describes an oral dosage form containing a proton pump inhibitor in combination, in the same formulation, with an antibiotic, where part of the proton pump inhibitor is slowly released. This inhibitor
can be presented in a pellet form and is associated to the antibiotic in capsules for oral use or both drugs can be contained in tablets. They can also be in different pharmaceutical units, but one of them, the one containing the inhibitor, of controlled release.
The patent US 6,136,344 describes an oral dosage form consisting of tablets, which associate at least an antibiotic with proton pump inhibitors in enteric-coated pellet form. The antibiotics applied are amoxicillin, clarithromycin, metronidazole or a combination between them.
The patent US 6,319,904 describes a dosage form with adherence to the gastrointestinal tract associating an antibiotic and a proton pump inhibitor. The antibiotics mentioned in it include benzylpenicillin, piperacillin, mecillinam, cefixime, cefaclor and erythromycin.
However, such combinations have relatively brief activity duration and request high antibiotic doses that are repeatedly administered 3 or 4 times a day, resulting in severe adverse effects where several cases of treatment resistance have been reported. Based on these results, the present invention describes pharmaceutical compositions comprising at least two antibiotics associated to a proton pump inhibitor. The association of antibiotics is necessary in order to reach at least 90% of bacterium elimination that allows reducing the treatment duration and thus avoiding the emergence of resistant strains.
In the search of a good model of triple therapy, our group is working in the study of different treatment
regimens associating at least two antibiotics and a proton pump inhibitor. A recent study showed that the association of the use of ranitidine for 2 weeks with a model of triple therapy consisting of the association of furazolidone (200 mg after breakfast and dinner), bismuth subcitrate (240 mg after meals) and tetracycline (500 mg, 10 minutes before each meal) for seven days, increased the effectiveness in reducing gastric ulcer but it didn't increase the H. pylori eradication compared to triple therapy model administered separately. Two hundred and eleven patients with a diagnosis of duodenal ulcer and H. pylori positive were enrolled in the study. Both schemes, with and without ranitidine, were efficient in the ulcer reduction compared with triple therapy separately, but the eradication of the infection was effective only in the group where the therapy triple without ranitidine was applied; showing levels >90% of eradication in the group without ranitidine and 84% with ranitidine (Magalha.es AF, Macedo C, Hauck JR, Carvalhaes A, De Nucci G, Magna LA, Pedrazzoli J Jr. Acid suppression with ranitidine plus oral triple therapy improves ulcer healing but not Helicobacter pylori eradication. Hepatogastroenterology 1998; 45 (24) :2161-4) .
In another independent study Liu et al. demonstrated that the association of furazolidone (100 mg/day) in administration seven-day regimens with clarithromycin (250 mg/day) with a bismuth derivative (240 mg/day) or a proton pump inhibitor (omeprazole, 20 mg/day) can contribute to increase the effectiveness of H. pylori eradication. This dosage shown to be effective in the eradication of
metronidazole-resistant strains with levels >90% of suppression (Liu WZ, Xiao SD, Shi Y, Wu SM, Zhang DZ, Xu WW, Tytgat GN. Furazolidone-containing short-term triple therapies are effective in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther 1999; 13(3) :317- 22) .
Similar results have been observed in Brazilian patients experiencing duodenal ulcer that were subjected to treatment with a combination of omeprazole (20 to 40 mg/day), clarithromycin (500 mg/day) and furazolidone (200 mg/day) for one week. Three months following the treatment 90% eradication with mild side effects were observed and no treatment suspension was necessary. Relevant data relates to the omeprazole dose, once there was not difference between the two studied dosages (Dani R, Queiroz DM, Dias MG, Franco JM, Magalhaes LC, Mendes GS, Moreira LS, De Castro LP, Toppa NH, Rocha GA, Cabral MM, Salles PG. Omeprazole, clarithromycin and furazolidone for the eradication of Helicobacter pylori in patients with duodenal ulcer. Aliment Pharmacol Ther 1999; 13(12) :1647- 52) .
A recent work has supported that the association of furazolidone (200 mg) , omeprazole (20 mg) and tetracycline (500 mg) b.i.d. is a safety, low-cost, and effective method for the eradication of the infection (Mansour-Ghanaei F, Fallah MS, Shafaghi A. Eradication of Helicobacter pylori in duodenal ulcer disease tetracycline & furazolidone vs. metronidazole & amoxicillin in omeprazole based triple therapy. Med Sci Monit 2002; 8 (3) :PI27-30) . Similar results
in patients receiving the same antibiotics administered three times a day were observed. These patients were non- responsive to a previous treatment with macrolide and nitroimidazole antibiotics (Silva FM, Eisig JN, Chehter EZ, Silva JJ, Laudanna AA. Omeprazole, furazolidone, and tetracycline: an eradication treatment for resistant H. pylori in Brazilian patients with peptic ulcer disease. Rev Hosp Clin Fac Med Sao Paulo 2002; 57 (5) : 205-8) . The available clinical data shows that other proton pump inhibitors can be used with similar effectiveness (Coelho LG, Martins GM, Passos MC, Bueno ML, Sanches BS, Lopes LG, Miranda CH, Castro LP. Once-daily, low-cost, highly effective Helicobacter pylori treatment to family members of gastric cancer patients. Aliment Pharmacol Ther 2003;17(1) :131-6) .
The advantage of such association can be linked to the fact that the proton pump inhibitor acts changing the pharmacokinetics of antibiotics contributing to increase the effectiveness of these drugs. On the one hand the omeprazole reduces the furazolidone absorption that can contribute to reduce the side effects, since this decreased absorption does not result in decreased activity for this antibiotic (Calafatti SA, Ortiz RA, Deguer M, Martinez M, Pedrazzoli J Jr. Effect of acid secretion blockade by omeprazole on the relative bioavailability of orally administered furazolidone in healthy volunteers. Br J Clin Pharmacol 2001; 52 (2) : 205-9) . On the other hand, acting synergically, the omeprazole increases the clarithromycin concentration in gastric juice of patients infected with JJ.
pylori . Our studies suggest that an active transfer of clarithromycin from plasma to gastric juice occurs under the influence of omeprazole. (Pedrazzoli J Jr, Calafatti SA, Ortiz RA, Dias FE, Deguer M, Mendes FD, Bento AP, Pereira AA, Piovesana H, Ferraz JG, Lerner F, de Nucci G. Transfer of clarithromycin to gastric juice is enhanced by omeprazole in Helicobacter pylori-infected individuals. Scand J Gastroenterol 2001; 36 (12) : 1248-53) .
Although literature data demonstrates that this antibiotic combination presents a series of therapeutic advantages for the eradication of the infection, the state- of-the-art shows that until now a pharmaceutical composition containing combined antibiotics and proton pump inhibitors associating furazolidone with tetracycline or clarithromycin does not exist in the same formulation. SUMMARY OF THE INVENTION
The novelty of the present invention relates to the association of two antibiotics, being furazolidone the first and clarithromycin or tetracycline the second, with a proton pump inhibitor in a single oral formulation in order to explore the advantages of this association against Helicobacter infection in mammals and humans. DETAILED DESCRIPTION OF THE INVENTION
In a first example, the present invention makes available, in an acceptable pharmaceutical vehicle, an oral pharmaceutical composition aiming treatment of gastric disorders caused by JJ. pylori , including furazolidone as a first antibiotic and a second antibiotic of the
tetracycline or macrolide group and a proton pump inhibitor.
In a second example, the present invention makes available, in an acceptable pharmaceutical vehicle, a therapeutic method for the treatment and prevention of JJ. pylori infection in treatment-resistant and -sensitive patients using the conventional drugs and therapeutic methods, involving the administration of safety and effective therapeutic doses of a dosage form that contains, in the same formulation, furazolidone as a first antibiotic and a second antibiotic of the tetracycline or macrolide group and a proton pump inhibitor.
The pharmaceutical compositions of the present invention, used in the methods proposed by the present invention, should be prepared using state-of-the-art knowledge techniques, which involve the unitary operations of homogenization, mixture, humectation, granulation, drying, compression, micronization, coating, dispersion, among other available techniques, should involve in the composition the excipients necessary for developing oral dosage forms that are known by the state-of-the-art. For the oral administration the pharmaceutical composition should be presented in tablets, pellets, capsules, pastilles, suspensions, and powders in sachets or lyophilized powder form for suspension. Techniques of slow or sustained-release should be applied in a granule form or coated particles, multilayer-tablets, or microgranules.
The concentrations of antibiotics and proton pump inhibitor in pharmaceutical compositions and therapeutic
methods proposed in the present invention are in accordance with the available data that assures the safety and effectiveness in the eradication of JJ. pylori infection. The typical dose of furazolidone is 50 to 1000 mg/day, being typically used 100 to 200 mg per formulation and can be administered b.i.d or t.i.d. For tetracycline the typical dose is between 50 mg/day and 4000 mg/day, the most typical dose used is 2000 mg/day. For clarithromycin the typical dose is between 50 mg/day and 4000 mg/day, the most typical dose used is 1000 mg/day. For proton pump inhibitors the typical dose ranges between 20 and 500 mg, more typically around 20 to 80 mg/day.
The pharmaceutical compositions above mentioned can be administered once a day or more, but preferably one to three times a day until the infection eradication that can range from seven to fourteen days and can be extended to 28 days at the doctor's discretion.
The present invention can be better illustrated by the following examples: Example 1
Formulation containing furazolidone, clarithromycin and a proton pump inhibitor
All formulations provided in the present invention were prepared from wet granulation that results in a granulate that can be used in a second stage of compression or capsule filling. Due to the powder volume for each formulation, each unit was designed for obtaining tablets of -750 to 1000 mg (total individual weight), or capsules 0 and 00. The selected formulations contain in its
composition: furazolidone (100 to 200 mg) , clarithromycin (500 mg) or tetracycline (500 to 600 mg) , and omeprazole (20 to 40 mg) . The humectation was obtained using water or aqueous solutions containing gelatin, sucrose or hydroalcoholic solutions, or organic solutions containing polymer. In the present example were employed the following polymers as coating: derivatives of Eudragit (S100, L100, RTML and NE30D) and derivatives of poly-esters as poly-ε- caprolactone or derivatives of poly-lactic and glycolic acid that were used in the organic solution form, or aqueous dispersion of nanoparticles previously prepared. Lactose, cellulose and derivatives were used as diluent and starch, PVP or gelatin were used as agglutinant agents. Triethyl citrate and butyl diphthalate were used as plasticizer. Magnesium Stearate were used to optimize the granulate fluidity. To obtain the granulates and tablets, spray dryer and coating techniques by atomization were used. Table I. Mass Composition and percentage of antibiotic granulated/tablet formulation and omeprazole.
Components Mass (g) % (w/w)
Clarithromycin 500 50 A
Furazolidone 100 10 B
Omeprazole 40 4 C
Microcrystalline Cellulose 50 5 D
Gelatin 50 5 E
Lactose M 200 260 26 F
TOTAL 1000 100
The methodology used in the preparation of clarithromycin-containing granulate was the wet granulation. The description of the technique employed to prepare this formulation is the following: - To weigh and sieve all components by using a 14-mesh sieve; soon afterwards, the powders A, B, C, D, E, and F are mixed. The mixture was humidified by adding slowly and gradually 50 to 70 mL of deionized water and then homogenized until a homogeneous wet mass is formed. This wet mixture was passed through a 14-mesh sieve and immediately after dried in a stove at 37°C over twelve hours, until obtaining a granulate with moisture residue <2%. Optionally, a gelatin solution can be used for the humectation. The granulate was calibrated in a 14-mesh sieve. This granulate was coated by atomization or spray dryer with solutions of Eudragit S100, LlOO, RTML, or NE30D or polymeric nanoparticles at concentrations from 5 to 15%. The coated granulate has been used for filling the capsules or, after addition of magnesium stearate, the tablets were obtained from appropriate compression machine.
Table II. Mass Composition and percentage of antibiotic granulate and omeprazole
Components Mass (g) % (w/w)
Clarithromycin 500 50 A
Furazolidone 100 10 B
Omeprazole 40 4 C
Gelatin 70 7 D
Croscarmellose sodium 20 2 E
Lactose M 200 270 27 F
TOTAL 1000 100
Wet granulation was the methodology used in the granulate preparation. The description of the technique employed to prepare this formulation is the following:
To weigh and sieve all components by using a 14-mesh sieve; soon afterwards, the powders A, B, C, D, E, and F are mixed. The mixture was humidified by adding slowly and gradually 50 to 70 mL of deionized water and then homogenized until a homogeneous wet mass is formed. This wet mixture was passed through a 14-mesh sieve and immediately after dried in a stove at 37 °C over twelve hours, until obtaining a granulate with moisture residue <2%. The granulate was calibrated in a 14-mesh sieve. This granulate was coated by atomization or spray dryer with solutions of Eudragit S100, LlOO, RTML, or NE30D or polymeric nanoparticles at concentrations from 5 to 15%. Magnesium stearate was added to granulate that was used for filling the capsules or the tablets were obtained from appropriate compression machine. Optionally, the tablets
can be obtained before the polymeric coating and be coated by atomization with these solutions.
Example 2
Formulation containing furazolidone, tetracycline and a proton pump inhibitor
Table III. Mass Composition of antibiotic granulate and omeprazole,
Components Mass (g) % (w/w)
Tetracycline 600 54.5 A
Furazolidone 100 9.1 B
Omeprazole 40 3.6 C
Microcrystalline Cellulose 50 4.6 D
Gelatin 50 4.6 E
Lactose M 200 260 23.6 F
TOTAL 1100 100
Wet granulation was the methodology used in the granulate preparation. The description of the technique employed to prepare this formulation is the following:
To weigh and sieve by using a 14-mesh sieve; soon afterwards, the powders B, C, D, E, and F are mixed. The mixture was humidified by adding slowly and gradually 50 to 70 mL of water and homogenized until a homogeneous wet mass is formed. This wet mixture was passed through a 14-mesh sieve and then dried in a stove at 37°C over twelve hours, until obtaining a granulate with moisture residue <2%. The granulate was calibrated in a 14-mesh sieve. This granulate was coated by atomization or spray dryer with solutions of Eudragit S100, LlOO, RTML, or NE30D or polymeric nanoparticles at concentrations from 5 to 15%. Magnesium
stearate was added to the granulate and was used for filling the capsules following the addition of component A or, after addition of magnesium stearate, the tablets were obtained from appropriate compression machine. Optionally, the tablets can be obtained before the polymeric coating and be coated by atomization with these solutions. Example 3 :
Preparation of tablets containing clarithromicin, furazolidone and pantoprazole The method of preparation was the coating of granulates with Eudragit containing each drug isolated and, after drying and characterization, the final granulate containing the three drugs was prepared. The composition of the formulation is described in the Table IV. Tabela IV. Mass Composition of antibiotics granulate and omeprazole.
Components Mass (g) % (w/w)
Clarithromycin 100 50 A Pantoprazole 3,33 1, 66 B Furazolidone 16,6 8,3 C Croscarmelose 2 1 D
Lactose 62,92 31,46 E
Methyl cellulose 1 0,5 F
Eudragit S100 12,15 6,08 G
Magnesium Sterarate 2 1 H
TOTAL 200 100
Wet granulation was the methodology used in the granulate preparation. The description of the technique employed to prepare this formulation is the following:
To weigh all components using a semi-analytical balance. After that, to sieve the powders previously weighed using a 14-mesh sieve. In a first stage, each drug
(A, B, and C) was individually granulated in the presence of Eudragit S100*. For that, an Eudragit solution in acetone or isopropyl alcohol, containing a plasticizer (dibutyl phthalate or triethyl citrate at 10% w/w polymer concentration) was prepared. In the second stage, the obtained granulates were homogenized with components D and E; then, this mixture was humidified using an aqueous methylcellulose solution (F) at 2% in phosphate buffer pH 6.5. In this stage, by using a 24-mesh sieve, 750 u granulometry, a homogeneous granulate was obtained. After that, the granulate was dried in a stove at 37 °C for 12 H, enough time to obtain a residue with moisture lower than 2%. The granulate was calibrated in a 24-mesh sieve and then the component H was added. After homogenization, in a compressing machine using 15-mm punches calibrated to provide tablets from 1 to 1.5 grams, preferentially 1.2 grams, the granulate was compressed. Following the compression, the tablets were coated with Eudragit S100 or Eudragit LlOO solution in isopropyl alcohol, containing a binding agent at 10% w/w polymer concentration.
*Optionally, Eudragit LlOO was used; in this case a methylcellulose solution in buffer pH 6.0 was used in the granulation phase.
Example 4 : Preparation Of tablets containing tetracycline, furazolidone, and pantoprazole
It is known that wet granulation of solid dosage forms containing tetracycline may lead to degradation of the drug that becomes incompatible with the clinical use. In the present example a formulation by direct compression and dry route was prepared and no aqueous solvent was used. The preparation technique has consisted in the development of Eudragit-covered granulate containing furazolidone and pantoprazole separately. In a second stage, after the drying and characterization, the granulate containing the three drugs was prepared. The composition of Formulation 2 is described in Table V. Table V: Mass composition and percentage of the clarithromycin tablet granulate.
Components Mass (g) % (w/w)
Tetracycline 55 50 A Pantoprazole 1,91 1,74 B Furazolidone 6,40 5,81 C Croscarmelose 1 0,91 D
Lactose 21,1 10,54 E
Hydroxy-propyl-beta- -Cyclodextrine 21,1 19,18 F
Eudragit S100 10 9,1 G
Magnesium Stearate 3 2,72 H
TOTAL 110 100
Dry granulation was the methodology used in the preparation of the granulate of Formulation 1. The technique used for preparing this formulation is described below: - To weigh all components using a semi-analytical balance and sieve the powders previously weighed by using a 14-mesh sieve. With the aid of a pistil, moisten the component F (cyclodextrin) with ethanol in a mortar and add the tetracycline. To homogenize the mixture for approximately 30 minutes and evaporate the solvent under vacuum for approximately 12 hours. After drying, with the aid of a pistil, grind the mixture and sieve by using a 24- mesh sieve. After that, the other drugs B and C were individually granulated in the presence of Eudragit S100. For that, an Eudragit solution in acetone or isopropyl alcohol containing a plasticizer (dibutyl phthalate or triethyl citrate at 10% w/w polymer concentration) was prepared and sieved through a 24-mesh sieve. In a third stage, the obtained granulates were mixed with components D and E, and then this mixture was homogenized. The obtained granulate was calibrated in 24-mesh sieve and the component H was added. After homogenization, in a compressing machine using 15-mm punches calibrated to provide tablets from 1 to 1.5 grams, preferentially 1.2 grams, the granulate was compressed. Following the compression, the tablets were coated with Eudragit S100 or Eudragit LlOO solution in isopropyl alcohol or acetone, containing a binding agent at 10% w/w polymer concentration.
Example 5 : Drug-Release Kinetics
In order to assess the effectiveness of the coating, the tablets obtained from the examples above were subjected to a study of release kinetics. After the tablet incubation with approximately 900 to lOOOmL hydrochloric acid 0.1 M, in the first two hours samples were collected and subjected to analysis by HPLC. Two hours later, the pH was adjusted between 6.8 and 7.5 with phosphate buffer and samples were collected over 4 to 6 subsequent hours. In the first two hours, no amount of drug was detected in the collected samples and the tablets remained intact in acid medium. After the medium alkalinization, a degradation of the coating layer happens and the total drugs are released within the studied period. Example 6 Treatment of patients with JJ. pylori infection
Ten patients non-responsive to a treatment with metronidazole or clarithromycin for JJ. pylori received treatment associating omeprazole (20-mg) , furazolidone (200-mg) , and clarithromycin (500-mg) . After a period from seven to 14 days all patients were cured, showing infection eradication rates >90%.
The oral solid dosage forms, object of the present invention, can still contain other pharmaceutical degree excipients, such as binders, disintegrating agents, diluents, coating agents, lubricants and sustained-release agents. The most desirable binders for the present invention include gelatin, starch, sodium alginate,
carboxymethylcellulose, hydroxymethylpropylcellulose, ethylpropylmethylcellulose, polyethylene glycol, and lactose. The disintegrating agents can include starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, and alginates. The diluents that best allow obtaining the present invention include lactose, sorbitol, mannitol, dextrose, cellulose and derivatives, calcium carbonate. Among the coating agents we can include acrylic acid polymers and co-polymers, and methacrylates and their esters, waxes and derivatives of polymers and co-polymers prepared from lactic and glycolic acid polyesters and from caprolactone. The most desirable lubricants include magnesium stearate, calcium stearate, stearic acid, sodium oleate, talc. Among the binding agents, the most desirable are triethyl citrate, butyl phthalate and polyethylene glycol.
The changes and variations that would be obvious to a person with common knowledge in the art should be considered within the scope of the present invention, and their nature is to be established from the description above .