USE OF FERACRYL FOR THE TREATMENT OF PEPTIC/DUODENAL ULCER AND/OR CHOLERA

Abstract: A novel pharmaceutical preparation for the treatment of peptic/duodenal ulcers caused by Helicobacter Pylori (H. Pylori) and/or cholera caused by Vibrio.cholerae comprising feracrylum having a concentration of between 1% w/v to 10% w/v of the composition. The preparation can be formulated as a syrup, capsule and tablet form or it can be administered along with other adjuvants and drugs such as proton pump inhibitors like Omeprazole or H2 antagonists like ranitidine, famotidine, etc. The invention also provides a novel method to treat peptic and duodenal ulcers and cholera using the above preparation.

Description: USE OF FERACRYL FOR THE TREA ENT OF PEPTIC/DUODENAL ULCER AND/OR CHOLERA Field of the invention This invention relates to a novel preparation for the treatment of peptic/duodenal ulcers and/or cholera. More particularly the invention relates to a preparation of feracrylum for the treatment of peptic and duodenal ulcers caused by the bacteria Helicobacter Pylori (H. Pylori) and/or the treatment of cholera caused by the strains of Vibrio.cholerae. The preparation can be formulated as a syrup, capsule and tablet form or it can be administered alone with proton pump inhibitors like Omeprazole or H2 antagonists like ranitidine, famotidine, etc. The invention also provides a novel method to treat peptic and duodenal ulcers and cholera. Background of invention Peptic and duodenal ulcers are most common disease. Until the 1980s, the cause of peptic ulcer disease was thought to be due to excess secretion of acid and pepsin by the gastric mucosa or the diminished ability of the gastro-duodenal mucosal barrier to protect against the digestive properties of the acid-pepsin complex. The discovery of a new bacterium, Helicobacter pylori by Warren and Marshall in 1982 has, however, revolutionized our view of the gastric environment, the disease associated with it and the appropriate treatment regimen. In most cases, peptic ulcer is now considered to be a consequence of H. Pylori infection and can be cured by the eradication of this enteric pathogen. With its emergence into clinical consciousness, exceptional attention is being devoted and vast amount of research is being carried out to unravel the biology of H.pylori. H. pylori is one of the most genetically diverse of the bacterial species and the important challenge is to elucidate its pattern of transmission in human population, it adaptation during long time colonization and its contribution to infection. Though H pylori infects about half of the world population, only 10 to 15% of those infected develop the disease. Of those infected, who will develop the disease is influenced by bacterial genotypes and the virulence of the infecting strains, the genetic susceptibility of the host and the environmental cofactors. Of these, bacterial genotypes have been the most intensively studied. (Simanti Data et al in the article entitled "Diversity in the genetic makeup of H. Pylori). H. Pylori is gram negative rods colonizing in mucous on the luminal surface of the gastric epithelium. H. Pylori has several genotypes and pathogenicity depends on virulence of these strains. These organisms are gram negative, spiral, microaerophilic bacteria specifically infecting the stomach and thus is the most prevalent infection of mankind in ulceration. It causes gastritis and is a putative contributor to peptic ulcer disease, gastric lymphoma, gastric carcinoma and adrenocarcinoma. (Ref : Blaster and Parsonnet, 1994 and Peterson, 1994, Symposium through Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9 th edition). A majority of patients with complaints of duodenal and gastric ulcers have presence of H. Pylori in antral samples taken and thus eradication of H. Pylori is correlated with reduction in recurrence of ulcers. Generally the treatment of ulcers caused by H. Pylori consists of the use of H2 Antagonist Receptors or Proton Pump Inhibitors and antibiotics like clarithromycin, amoxycillin, etc., and drugs like metronidazole, tinidazole, etc., which are active against non-specific anaerobic pathogens which are normally used in amoebiasis caused by Entamoeba histolytica and giardia lamblia. Drugs commonly used consist of metronidazole, tinidazole, ranitidine, cytoprotective drugs like sucralfate, colloidal bismuth derivatives, prostaglandin antagonists and antacids. Single drug therapy for H. Pylori is ineffective invivo and emergence of resistant strains is very common. Metronidazole and tinidazole as a therapy is also ineffective because of nitro reductase strains. Clarithromycin, amoxycillin, etc., are effective but because of emergent resistant strains, combination therapy along with metronidazole, bismuth salt, etc., are tried. Sometimes a combination of antibiotics, consisting of two or more antibiotics along with anti-secretory agents, is used for treatment of patients with H. Pylori. It is to be noted that multi drug regimens are difficult to manage and are cumbersome because of the number of tablets to be taken that too for a fairly long time to prevent any relapse. Hence the current therapy practiced suffers from the following drawbacks : a. Unsatisfactory patient compliance, which is absolutely necessary for permanent cure of ulcers caused by H Pylori. b. Cost of treatment because it is a combination of drugs often containing a costly antibiotic. It is rather difficult for patients in poor countries like developing countries to comply with the treatment regimen. c. Importantly, side effects because of longer use and use of a number of medicines at a time. This problem is further aggravated in the case of elderly patients and infants. It would be interesting to note the prevalence of peptic, gastric and duodenal ulcers is approximately 10% and some physicians opine that 50% of healthy individuals experience heart burn on a daily basis. Majority of patients, 70-90% with duodenal and gastric ulcers, have H. Pylori in antral samples taken. Cholera is another syndrome caused by strains of Vibrio.cholerae which causes acute secretory diarrhea. It can be associated with 2 serogroup of cholerae (l) 01 & (2) 0139 * . Serogroup 01 is further divided in to 2 biotypes, (classical and El Tor). Each has 3 serotypes. (Inaba, Oeawa and Hikojima). The genus vibrio includes a group of gram negative short and curved rods (comma Bacilli) having polar flagella. The pathogenecity is due to V. Cholerae and E 1 Tor vibrio species. It appears as epidemics in various parts of the globe. These organisms cause rice water stools with water and electrolyte imbalance in body. It enters the body through oral route and multiplies in intestine in alkaline environment. They multiply rapidly. It causes high mortality without proper treatment, death is caused because of dehydration and electrolyte imbalance, leading to irreversible shock. The treatment of Vibrocholerae is with antibiotics like Doxycycline, Ciprofloxacin or Ofloxacin, Sulphamethoxazole & Trimethoprim, Furazolidane, Erthyromycin, Chloramphenicol with Furazolidone. Drug resistance is a common feature for V. cholerae strains. Multiple drug resistance is often a problem, differing in sensitivity and resistance patterns. It is thus the basic objective of the present invention to provide for a novel formulation and cost effective short duration therapy regimen for treatment of widely prevalent diseases such as peptic/duodenal ulcers caused by H. Pylori. Another object of the present invention is to provide for novel formulation and cost effective short duration therapy regimen for treatment of cholera caused by strains of Vibrio.cholerae. In our co-pending application No. 467/BOM/99 (US Patent Application No. 09/363,338), there is described and claimed a compositional matter and method for preparation of feracrylum. In the same application the material, feracrylum, has been found to be not only haemostatic but also anti-infective against a number of gram positive and gram negative pathogenic, bacterial and fungus strains like Staphylococcus aureus, Streptococcus pyogenes, Corynebacterium diphtheriae, Salmonella typhi, Shigella dysentriae, Escherichia coli, Proteus Vulgaris, Pseudomanas aeruginosa, Trichoderma Viridae, Candida Albicans, Etc. Feracrylum when prepared by the novel process as described in our co- pending Application No. 467/BOM/99 could be processed to a solid form or solution in water. As mentioned this material is an excellent haemostatic and anti-infective. To our surprise we now find that feracrylum is also an excellent bactericidal for H. Pylori and also effective in treatment of cholera caused by strains of Vibrio.cholerae. Detailed description of the invention Thus the present invention relates to a pharmaceutical composition comprising feracrylum in an amount of 1% w/v to 10% w/v of the composition for use in the treatment of peptic and duodenal ulcers caused by the bacteria H. Pylori and/or cholera caused by the bacteria V.cholerae. The applicants have also found that the pharmaceutical composition of the invention comprising feracrylum shows increased benefits when the feracrylum used in the composition is prepared by the process developed by the applicants and disclosed in co-pending application No. 467/BOM/99. Thus according to a preferred aspect the process of preparation of the pharmaceutical composition of the invention comprises : partial polymarizing of an acrylic acid in the presence of iron salt and potassium persulphate to obtain a solution of feracrylum ; purifying the solution by removal of impurities by treating the solution with an ion exchange resin ; and vacuum drying the solution at a controlled temperature and micronising to obtain pitch colour particles of feracrylum. In the above process preferably the ratio of acrylic acid to initiator is 166 to 186 : 1.0, the ratio of acrylic acid to iron salt is 105- 115 : 1.0, the iron salt is ammonium ferrous sulphate, the ratio of acrylic acid to ammonium ferrous sulphate is 110 : 1. The present invention relates to the pharmaceutical composition comprising feracrylum and use of this composition for treatment of peptic/duodenal ulcers and/or cholera. The composition can be in form of oral liquid or in the form of tablets, capsules. The pH of the oral liquid composition is between 2.5 to 4.0 and preferably between 2.9 to 4.0. The concentration of the feracrylum may vary from 1% w/v to 10% w/v of an aqueous composition, and composition may optionally contain other adjuvants used in oral preparations and drugs like proton pump inhibitors, H2 antagonist receptors, anaerobic organism inhibitors, antibiotics and anti secretive agents. The feracrylum solution prepared using the feracrylum by the process has strong characteristics for suitability of treatment of peptic/ duodenal ulcers and cholera. The use of feracrylum solution for the above treatment can be made by administering the compound in syrup or by admixing its tablets/ capsules. The formulation can be administered alone or in conjunction with other adjuvants. Fercrylum may be prepared in solution form in various concentrations preferably from 1%-10% w/v or w/w depending on the formulation. This solution prepared is limpid, stable and safe. The amount of water can be upto 90% v/v to 99% v/v by volume of the composition. EXAMPLES The composition of the invention including its preparation and efficacy will be illustrated and demonstrated with the help of examples which are non- limiting: Example 1: 0.039 mole of potassium persulphate is taken in a vessel containing 14.3 L of distilled water and stirred for 3 minutes. 26.08 mole of acrylic acid solution is added which is previously dissolved in 1.2 L of distilled water. This is further mixed with 0.0592 mole of Ammonium Ferrous Sulphate dissolved in water. This is mixed thoroughly under continuous stirring for 3 to 4 hours. The mixture is diluted to 25 L and the whole mass is cooled to room temperature and kept for 2 hours. Resin is then added to remove impurities the mixture stirred for 30 minutes, filtered and evaporated under vacuum at 50°C to 60°C using rotary evaporator. The evaporated product is passed through a micronizer, which yields fine shining peach coloured crystals. These crystals have the characteristics of rapid solubility and meet the general pharmaceutical specifications. The feracrylum prepared by the applicant has the following specifications: 1. Water (by Karl Fischer) : 1%, max. 2. Colour Density of 1% aqueous solution at 420nm in 1 cm cell: 0.1, max. 3. Bulk density (g/ml) : min. 0.6 & max. 0.85 4. Particle size Av.particle size 500 micron The feracrylum thus prepared readily dissolves in water at 25°C, is easily filterable and can also be easily sterilized. Example 2: Preparation of feracrylum solution - feracrylum concentration 1% w/v In a glass vessel, which has an arrangement for stirring and temperature control, 800 ml of double distilled water is taken - temperature maintained at 25°C - in which 10 gms of feracrylum is slowly added under continuous stirring till all the material is dissolved. The mixture is made to 1 litre and then filtered through a 0.2 μ filter. The pH of the solution is measured potentiometrically and maintained between 2.5 to 4.5. The solution is filled in a suitable container and further terminal sterilization is carried out as is conventionally undertaken for sterile preparations. Example 3: Preparation of feracrylum solution - feracrylum concentration 10% w/v In a glass vessel, which has an arrangement for stirring and temperature control, 800 ml of double distilled water is taken - temperature maintained at 25°C - in which 100 gms of Feracrylum is slowly added under continuous stirring till all the material is dissolved. The mixture is made 1 litre and then filtered through a 0.2 μ filter. The pH of the solution is measured potentiometrically and maintained between 2.5 to 4.5. The solution is filled in a suitable container and further terminal sterilization is carried out as is conventionally undertaken for sterile preparations. Properties Of Feracrylum For Treatment Of Peptic /Duodenal Ulcer Caused By The Bacteria H. Pylori Agar dilution method was used to determine the minimal concentration of Feracrylum required to inhibit the growth of Helicobacter Pylori. The drug was dissolved in minimum volume of sterile distilled water to get different Feracrylum concentrations used in this drug sensitivity study. A total of 24 different H.pylori strains were selected for this study. The strains of category A are collected from the antral region of the stomach while those of category B are collected from the fundus region. The strains were collected from the Post Graduate Medical Institute (PGMI), Calcutta. The sample numbers were also generated by the PGMI. Blood agar plates were prepared with brain-heart infusion agar containing 10% defibrinated sheep blood and a particular dilution of the drug added to each plate. Control plates with no Feracrylum were simultaneously prepared. The drug- supplemented as well as the control blood-agar plates were streak- inoculated with ~ 10 4 CFU of each H.pylori strain. The inoculated plates were incubated at 37°C under 10% CO2 and 5% O2 and were observed for the presence of bacterial growth initially at 48 hours and then daily for upto 10 days. With all H.pylori strains, the following 3 drug concentrations were tested - 3.3 mg/ml, 4.0 mg/ml and 6.6 mg/ml. The results are represented in TABLE - I hereunder. TABLE - I H.pylori strains used : 109A, 114A, 100A, 86A, 115B, 91A, 62A, 77A, 222B, 278A, 286B, 291B, 105A, 331A, 353A, 324B, 41B, 56B, 60A, 17A, 2 IB, 78B, l l lA and 27B. Medium used Brain-heart infusion agar + 10% defibrinated sheep blood. Volume of medium/ plate : 25 ml. All the results indicated that 4.0 mg/ml Feracrylum could be considered the lowest diluted drug concentration that prevented visible bacterial growth. Properties of Feracrylum in use for Treatment of Cholera was tested using V.cholerae strains as detailed hereunder : Composition of Muller Hinton Agar Beef Infusion 300 gms Bactocosoamino acid 17.5 gms. (technical) Starch 1.5 gms Bacto agar 77.0 gms From this total mixture 38 gms is taken and made upto 1000 ml using boiled demineralised water. pH is adjusted to 7.4. Results of test carried out using strains of V.cholerae are represented hereunder in Table II. TABLE - II V. cholerae strains used : 181, 175, 272, 285, 219, 186, 211 (01 , Ogawa, E 1 Tor Biotype) Medium used : Mueller Hinton agar Volume of medium/plate : 25 ml. It would be evident from results of Table-II above that use of feracrylum inhibits the growth of strains at the level of 3.3 mg/ml and thus is suitable for treatment of cholera. The above findings of the present invention establish that feracrylum is an excellent agent for eradicating H.pylori bacteria which as mentioned hereinbefore is responsible for almost all cases of ulcers, peptic and duodenal. Also feracrylum is shown to be suitable for use in the treatment of cholera caused by Vibrio.cholerae. Further it has been observed that feracrylum does not cause any toxic effect in animal models or when given orally or by intra peritoneal route and even years of clinical experience in mammals has exhibited that it leaves no residual toxic effect. The animal model studies and other clinical studies further confirm that feracrylum when administered orally or intra peritoneally has no adverse effects in the systemic sense or in the physio-pathological sense and gives no adverse side effects whatsoever. As stated above, the formulations having feracrylum for treatment of peptic/duodenal ulcer and/or cholera can be administered as syrup or in the form of tablets/capsules. The formulation can be administered alone or in conjunction with other adjuvants drugs. The formulations are stable as per ICH guidelines. The tablets can be obtained in varying strength ranging from 50 mg. to 2 gms. as per the needs of the patient and the gravity of the treatment required. The invention thus makes the treatment of peptic ulcers, duodenal ulcers, whether bleeding or non-bleeding, and cholera simple and cost effective by use of the novel formulation comprising the feracrylum. The formulation comprising feracrylum as detailed above is simple to manufacture and does not require special technology. The product can be easily administered and is therefore beneficial and highly advantageous for treatment of ulcer and/or cholera as discussed above.

Claims: CLAIMS 1. A pharmaceutical composition for treatment of peptic /duodenal ulcer caused by Helicobacter Pylori and/or cholera caused by vibrio cholerae comprising feracrylum having a concentration of between 1% w/v to 10% w/v of the composition. 2. A pharmaceutical composition as claimed in claim 1, having a pH of between of 2.5 and 4.0. 3. A pharmaceutical composition as claimed in claim 1 comprising water wherein the amount of water is upto 90 to 99% by volume of said composition. 4. A pharmaceutical composition as claimed in anyone of claims 1 to 3, in the form of oral liquid wherein constituents selected from sugar, glycerol, propylene glycol, sorbitol, stabilizers, colourants and flavouring agents are incorporated. 5. A pharmaceutical composition as claimed in anyone of claims 1 to 4, wherein the composition is in the form of syrup, capsule or tablet. 6. A pharmaceutical composition as claimed in claim 5, wherein said syrup comprise 1% to 10% of feracrylum and said capsule/tablet comprise feracrylum 1% to 10% with other common excipients. 7. A pharmaceutical composition as claimed in anyone of claims 1 to 6, comprising other adjuvants. 8. A pharmaceutical composition as claimed in claim 7, wherein other adjuvants and drugs are selected from proton pump inhibitors, H2 Antagonist receptor, anaerobic organism inhibitor, antibiotics, antisecretive agents and excipients. 9. A pharmaceutical composition as claimed in claim 1 as liquid oral formulation having feracrylum concentration of 1%-10% w/v. 10. A pharmaceutical composition as claimed in claim 1 in the form of tablets/ capsules of varying strength ranging from 50 mg. to 2 gms. 1 l.A method of treatment of peptic /duodenal ulcer caused by H. Pylori and/or cholera caused by Vibrio.cholerae comprising administering to the patient a composition according to claim 1. 12. A method as claimed in claim 9, wherein the composition is administered in the form of anyone or more of oral formulation, tablets and capsules. 13. A process for manufacture of the pharmaceutical composition comprising feracrylum for use in treatment of peptic /duodenal ulcers and/or cholera as claimed in claim 1, comprising the steps of partial polimarizing an acrylic acid in the presence of iron salt and potassium persulphate to obtain a solution of feracrylum ; purifying the solution by removal of impurities by treating the solution with an ion exchange resine ; and vacuum drying the solution at a controlled temperature and micronising to obtain pitch colour particles of feracrylum. 14.A process as claimed in claim 11, wherein the ratio of acrylic acid to initiator is 166 to 186 : 1.0. 15. A process as claimed in claim 11, wherein the ratio of acrylic acid to iron salt is 105-115 : 1.0. 16. A process as claimed in claim 11, wherein the iron salt is ammonium ferrous sulphate. 17. A process as claimed in claim 12, wherein the ratio of acrylic acid to ammonium ferrous sulphate is 110 : 1. 18. Use of the pharmaceutical composition as claimed in claim 1 for treatment of peptic /duodenal ulcer caused by H.pylori and/or cholera caused by V.cholerae. AMENDED CLAIMS [received by the International Bureau on 03 August 2001 (03.08.01); original claims 14-18 replaced by new claims 14-19; remaining claims unchanged (1 page)] 14. A process as claimed in claim 1 1 , wherein the ratio of acrylic acid to initiator is 166 to 186 : 1.0. 15.A process as claimed in claim 1 1 , wherein the ratio of acrylic acid to iron salt is 105- 1 15 : 1.0. 16.A process as claimed in claim 11, wherein the iron salt is ammonium ferrous sulphate. lϋ 17.A process as claimed in claim 12, wherein the ratio of acrylic acid to ammonium ferrous sulphate is 110 : 1. 18. A pharmaceutical composition comprising feracrylum for use in treatment of peptic/ duodenal ulcers and /or cholera when obtained by 15 the process claimed in claim 13. 19. Use of the pharmaceutical composition as claimed in claim 1 for treatment of peptic/duodenal ulcer caused by H.pylori and/or cholera caused by V.cholerae. 0

Inventors: KURANI SHASHIKANT PRABHUDAS, PATEL DINESH SHANTILAL, KURANI, SHASHIKANT, PRABHUDAS, PATEL, DINESH, SHANTILAL
Applicants: KURANI SHASHIKANT PRABHUDAS, PATEL DINESH SHANTILAL, KURANI, SHASHIKANT, PRABHUDAS, PATEL, DINESH, SHANTILAL
Application year: 2000
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K33, A61P1, A61P31