AU2008243202A1 - Oral antimicrobial pharmaceutical compositions - Google Patents

Description

AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION Standard Patent Applicant (a): Cosmo Technologies Ltd Invention Title: Oral antimicrobial pharmaceutical compositions The following statement is a full description of this invention, including the best method for performing it known to me/us: P79501.AU PetStFling Applcation 2005-11-11.doc (M) -2 Title Oral antimicrobial pharmaceutical compositions Description 5 Intestinal infections are common diseases caused by the colonization of the intestine by foreign pathogenic agents of various origins, or caused by intestinal microorganisms that are normally present becoming virulent. 10 It is known that the intestine is divided into two distinct portions: the proximal portion, called the "small intestine", which is formed, in the craniocaudal direction, by the duodenum, the jejunum and the ileum, and 15 the distal portion, called the "large intestine", which is formed by the colon and the recto-anus (Fatter A, Scevola G. Anatomia e Fisiologia del Corpo Umano (Anatomy and Physiology of the Human Body). VoI I. Edizioni Minerva Medica, Turin, 1973, pp. 235-254). The two portions, the 20 small intestine and the large intestine, are completely separated anatomically by the ileocaecal valve which permits the passage of the intestinal contents from the small intestine to the large intestine but not vice versa. 25 Besides from the anatomical-structural point of view, the large intestine is quite different from the small intestine also, and above all, from the functional point of view (Braga PC. Enteric microflora and its regulation. In Drugs in Gastroenterology. Raven Press, New York, 1991, 30 pp. 501-508). While the small intestine is assigned to the digestion of the majority of the food, to the absorption thereof, to N:\Melbourne\Cases\Patent\79000-79999\P79501.AU\Specis\P79501 AU.GHSPECI Idoc 11/108 -3 the production of B-complex vitamins and vitamin K, to the metabolism of biliary acids and various other organic substances and to the rapid transfer of the alimentary bolus to the sections further downstream, the large 5 intestine provides for the absorption of water, for the digestion of vegetable fibres and for the completion of some digestive processes initiated in the small intestine. In addition, the large intestine differs from the small 10 intestine by the presence of an extremely rich bacterial flora, the balance of which is of fundamental importance in regulating the ambient pH, motility, the production of gas and ammonia, the formation of faeces, and the production of metabolites essential for maintain the good 15 functioning of the large intestine. These many differences between the small intestine and the large intestine explain the distinctive nature of some pathologies which occur at the expense of the large 20 intestine and in particular the colon. The colon is the portion of the large intestine that is host to the majority of the bacterial strains and that offers conditions of pH, anaerobiosis, humidity and 25 slowness of transit that are particularly suitable for the permanent flora potentially becoming virulent or for the proliferation of and colonization by pathogenic bacteria. For those reasons, the colon is the sector of the intestine most susceptible to infection; in feet, 30 infections located in the colon (infectious colites, bacillary dysentery, diarrhoea, pseudomembranous colitis, diverticulitis, etc.) constitute an important and autonomous chapter in the gastroenterological monograph N:\Melboune\Cases\Patent\79000-79999\P79501.AU\Specis\P79501AU.GHSPECII.doc 11/1 I/08 - 4 (Sorice F., Vullo V. Intossicazioni alimentari e infezioni del tubo digerente. (Food Poisoning and Infections of the Alimentary Canal). In: Medicina Clinica (Clinical Medicine). Edizione Medico Scientifiche, Turin, 2002). 5 In addition, the increased endoluminal pressure, linked with the production of gas and associated with predisposing local factors, can promote the occurrence of diverticular which are susceptible to infection and 10 inflammation and which are located exclusively in the colon (Jackson BT. Diverticular disease. In: Inflammatory Bowel Diseases Churchill Livingston, New York, 1997, pp. 443- 447). 15 Currently, the oral therapy of intestinal infections, and in particular colon infections, uses substances having antibacterial activity which must have specific characteristics such as: broad spectrum of activity on Gram+ and Gram- bacteria, resistance to strongly acidic 20 environments, such as the gastric environment, anti infectious activity independent of the presence of the intestinal biomass, residence inside the intestine for an appropriate period of time, good penetrability into the infecting host cell and good tolerability [beta]raga PC. 25 Interaction of antibiotics on enteric microflora. In: Drugs in Gastroenterology. Raven Press, New York, 1991, pp. 509-517). Therapy with antibacterial agents administered in the oral 30 preparations employed today has at least two limitations. In the first place, the antibacterial agents, if not suitably protected, may lose their efficacy owing to the enzymatic or degradative inactivation which occurs during N:\Melbourne\Cases\Patent\79000-79999\P79501.AU\Specis\P79501AU.GHSPECII.doc 11 /11/08 -5 their passage through the stomach or through the small intestine. In addition, the pharmaceutical forms nowadays used, 5 although they permit the administration of the active ingredient in discrete doses, release it too rapidly in relation to the time taken to pass through the digestive tract, so that the active ingredient performs its anti infectious activity in an indiscriminate manner along the 10 entire gastro-intestinal tract. This leads to the disappearance of the non-pathogenic bacterial flora living in the small intestine (duodenum, jejunum and the ileum), which flora, since it is not 15 normally the seat of infection, should be protected and not subjected to the sterilizing action characteristic of the formulations used today. For it is known that this bacterial flora is important in fundamental biological processes, such as, for example, the digestion and 20 absorption of alimentary nutritive components, the production and absorption of vitamins (vitamin K and B complex vitamins), the metabolism of biliary acids and of steroid hormones, the activation and inactivation of various substances, the protection of the organism from 25 xenobiotics, (Braga PC. Ibidem). In particular, the usual oral antibacterial therapies for the treatment of pathologies located in the colon have often given a contradictory result, probably owing to the 30 excessive dilution of the active ingredients in the intestinal lumen; this dilution is caused by the premature release of the antimicrobial agent from the pharmaceutical form containing it, which takes place as early as in the N:\Melbourne\Cases\Patent\79000-79999\P79501.AU\Specis\P79501 AU.GHSPECI l.doc 11/11/08 -6 stomach and in the immediate vicinity of the patient's pyloric valve. In addition, although the antimicrobial agents used for the disinfection of the digestive tract often do not have a high rate of metabolism, in order to 5 maintain unaltered the therapeutic possibility connected with the administration of a traditional form containing antimicrobial agents, no phenomenon of metabolic degradation should occur, in order to avoid any weakening of the therapeutic efficacy associated with the presence 10 of the antimicrobial agent. Therefore, in such cases, in order to ensure the real efficacy of the anti-infectious therapy, it is felt that there is a need for the possibility of a controlled and site- specific form of administration. For the release of the antimicrobial/anti 15 infectious active ingredient in the immediate vicinity of the region where a diverticulum or a generic infection becomes established, leads to the formation of a much higher concentration gradient than in the case of a conventional form of oral administration, with the 20 consequent greater possibility that the antimicrobial agent will succeed in penetrating to the inside of the diverticulum. In that situation, particular importance is attached to 25 the possibility of the remission also of infectious pathologies which are not widespread but which are of considerable socio-epidemiological importance, such as bacillary dysentery and pseudomembranous colitis, and also of infectious complications in surgical operations at the 30 expense of the large intestine and in particular the colon. Rifamicin SV, which has been known since the 1960s, is a semi-synthetic active ingredient which is derived from rifamicin S and which has a strong antimicrobial N:\Melboume\Cascs\Patent\7900-79999\P79501.AU\Specis\P79501AU.GHSPECII.doc Il/11/08 - 7 and/or anti-infectious activity both locally and parenterally. Its activity has also been evaluated in vitro at minimum concentrations (mcg/ml) on Gram+ bacteria, such as Staphylococcus aureus or Enterococcus 5 faecalis, as well as at higher concentrations on Gram bacteria, such as Escherichia coli, Salmonella, Enterobacter aerogenes, Enterobacter cloacae or Pseudomonas aeruginosa. Rifamicin SV, in the form of its sodium salt, is currently marketed under the name Rifocin 10 (R) both for external topical use and for injection. In particular, the topical use, indicated for the local treatment of infectious processes, is limited to external use by means of a solution of the active ingredient which is to be diluted at the time of use. 15 Patent application WO01/11077, which is incorporated herein by reference, describes the use of antimicrobial agents, including the generic rifamicin, for the preparation of pharmaceutical compositions that can be 20 used in the treatment of pathologies caused by anomalous bacterial growth (Small Intestine Overgrowth - SEBO) at the expense of the small intestine. Those compositions are formulated in such a manner as to release the active ingredient rapidly in the proximal portion of the 25 intestine, that is to say, solely in the small intestine (duodenum, jejunum and ileum). Metronidazole is a nitroimidazole chemotherapeutic agent having powerful antimicrobial activity and a broad 30 spectrum of action both on Gram+ bacteria and Gram bacteria. In addition, metronidazole is known to have a proven antiprotozoan activity (Tracy J.W. et ah, Metronidazole, in: Goodmen & Gilman 's, The N \Melbourne\Cascs\Patcnt\79000-79999\P79501.AU\Specis\P79501AU.GHSPECI I .doc 1l/l/08 -8 Pharmacological Bases of Therapeutics, IX Ed., 1996, pp 995- 998). Current therapy with metronidazole is supported with tablets (Flagyl (R) ) that contain 250 mg of active ingredient and that are formulated for immediate release. 5 It has now surprisingly been found that the efficacy of antimicrobial/anti- infectious active ingredients, such as rifamicin SV and/or metronidazole, in the treatment of infections of the large intestine, and in particular of the colon, can be substantially potentiated thanks to the 10 elimination of the undesired effects described above (aviteminosis, destruction of non-pathogenic bacterial flora, etc.) which are caused by the premature release of the active ingredients in the first portions of the digestive canal, such as the stomach, the duodenum and the 15 jejunum, and thanks to the protection from the metabolic enzymatic inactivation of the active ingredients which is brought about before the ingredients can reach the site of infection. 20 In particular, the efficacy of rifamicin SV was verified by means of an evaluation of the MIC (Minimum Inhibiting Concentration) on specific pathogenic bacterial strains, such as, for example, Escherichia coli, Enterobacter faecalis, Proteus vulgaris, Pseudomonas aeruginosa, 25 Salmonella typhi and Enterobacter cloacae as shown in the following Table A. TABLE A Bacterial species MIC (mcg/ml) The present invention therefore relates to oral pharmaceutical compositions containing an active 30 ingredient having antimicrobial/anti-infectious activity, such as rifamicin SV, characterized in that they are formulated in such a manner as to release the active substances substantially in the portion of the large N:\Melboume\Cases\Patent\79000-79999\P79501.AU\Specis\P795OiAU.GHSPECII.doc 11/11/08 -9 intestine where their specific sterilizing action is required, but leaving unaltered the non-pathogenic bacterial flora present in the portions of the small intestine which are not affected by the infection. 5 In particular, the formulations according to the present invention are capable of releasing the active ingredient solely in the colon, thus ensuring localized and restricted anti-infectious efficacy. 10 Consequently, the advantage of the formulations of the invention is the particular site-specificity in the large intestine, and in particular in the colon, which permits a greater concentration of the active substance in the 15 infected distal intestinal region with complete preservation of the healthy proximal regions. This advantage is displayed mainly during the treatment of specific pathological situations in the colon region, such as infectious colites, bacillary dysentery, diverticular 20 disease and diverticulitis where the site-specificity and the tolerability of the formulations play a key role in the resolution of the pathology. A further advantageous application of the formulations of the invention is their use during preparation for surgical operations on the 25 large intestine, in ileocolic anastomoses, and in the sterilization of the ammonia-producing colonic flora in order to prevent and/or treat hyperammonaemias. In these last-mentioned cases, the site-specificity of treatment and the consequent concentration of the activity of the 30 active ingredient may lead to a significant resolution of cases which would otherwise involve substantial complications. N:\Melbour\Cases\Patent\79000-79999\P79501 AU\Specis\P79501AU.GHSPECI1 doc 11/11/08 - 10 In the formulations of the invention, the substances having antimicrobial/anti- infectious activity are contained in an amount of from 10 to 90% by weight; in particular rifamicin SV is contained in an amount of from 5 20 % to 60% by weight. The oral formulations of the invention are selected from tablets, capsules, granules and/or microgranules. A preferred embodiment of the present invention comprises 10 a system for controlled release which is characterized by the presence of a first, amphiphilic, matrix in which the active ingredient is incorporated and which is in turn dispersed in a second, lipophilic, matrix. The form so obtained is again in turn dispersed in a third, 15 hydrophilic, matrix before producing the final oral pharmaceutical form. The lipophilic matrix of the present invention is represented by substances having a melting point lower 20 than 90 0 C, such as, for example, beeswax, carnauba wax, stearic acid, stearin and the like; the amphiphilic matrix is represented by substances selected, for example, from phospholipids, ceramides, sphingomyelins, lecithins, alkyl block copolymers, salts of sulphated alkyl acids, 25 polyoxyethylenated alkyl, derivatives of sorbitan and the like, while the hydrophilic matrix is represented by generally cross-linked or linear polymeric or copolymeric substances, which are known as hydrogels, that is to say, substances capable of increasing their mass and their 30 weight, owing t6 the polar groups present in the main or side polymer chains, when they come into contact with molecules of water. N:\Melboume\Cases\Patent\79OO-79999\P79501.AU\Specis\P79501 AU.GHSPECI.doc 11/11/08 - 11 In particular, the hydrophilic matrix corresponds to substances selected, for example, from cellulose derivatives, such as hydroxyalkylcelluloses, alkylcelluloses, carboxyalkylcelluloses and their salts or 5 derivatives, polyvinyl alcohols, carboxyvinyl derivatives, polysaccharide derivatives of anionic or cationic nature, such as, for example, hyduronic acid, glucuronic acid, or glucosamines, pectins and/or their derivatives. 10 In this preferred embodiment, the matrices are dispersed in one another in succession together with the active ingredient, thus bringing about the formation of a homogeneous structure responsible for the site-specificity of release. 15 In a further embodiment of the present invention, the tablets obtained are finally subjected to a coating process using gastroresistant substances, such as, for example, polymers of acrylic and methacrylic acids 20 (Eudragit) and/or derivatives of cellulose phthalate. Systems of controlled and/or programmed release suitable for the present invention are described in EP 1183014, GB 2245492 and EP572942, which are also incorporated herein 25 by reference. The following Examples describe the invention in detail without limiting the content thereof in any way. 30 EXAMPLE 1 200 g of rifamicin SV are mixed with 5 g of stearic acid, 7 g of carnauba wax, 8 g of sodium dioctyl sulphosuccinate, 100 g of lactose and 10 g of sodium N:\Melbournc\Cases\Patent\79000-79999\P7950i AU\Specis\P79501AU.GHSPEC11.doc 11/1I1/08 - 12 edetate and granulated with a solution containing 25 g of low-viscosity polyvinylpyrrolidone in 0.2 litre of purified water. When the granulate has been dried, it is mixed with 100 g of sodium carboxymethylcellulose, 25 g of 5 silica, 5 g of glycerol palmitostearate and 10 mg of talcum before being subjected to compression to the unit weight of 495 mg/tablet. The cores so obtained are then film-coated with a hydroalcoholic dispersion of acrylic and methacrylic acid esters, titanium dioxide, talcum and 10 triethyl citrate, which confers on the product resistance to disintegration in a strongly acidic environment, simulating the environment of the stomach and the small intestine. The dissolution of the tablets is practically zero in pH conditions of less than 7 and is progressive in 15 an enteric buffer at pH 7.2 with the following percentage quotas: less than 20% after 1 hour's residence, less than 50% after 3 hours' residence, more than 70% after 8 hours' residence. 20 EXAMPLE 2 500 g of rifamicin SV are mixed with 10 g of stearic acid, 10 g of beeswax, 10 g of sodium lauryl sulphate, 200 g of mannitol and 10 g of sodium edetate and granulated with a solution containing 50 g of hydroxypropylcellulose in 0.5 25 litre of water. When the granulate has been dried, it is mixed with 150 g of sodium hydroxypropyhnethylcellulose, 25 g of silica, 5 g of glycerol palmitostearate and 10 mg of talcum before being subjected to compression to the unit weight of 490 mg/tablet. The cores so obtained are 30 then film-coated with an aqueous dispersion of acrylic and methacrylic acid esters, iron oxide, talcum and triethyl citrate, with confers on the product resistance to disintegration in an acidic environment, simulating the N:\Melbourne\Caes\Patent\79000-79999\P79501.AU\Spccs\P79501AU.GHSPECII.doc 1l/ U08 - 13 environment of the stomach and the small intestine. The dissolution of the tablets is practically zero in pH conditions of less than 7 and is progressive in an enteric buffer at pH 7.2 with the following percentage quotas: 5 less than 30% after 1 hour's residence, - less than 60% after 3 hours' residence, more than 80% after 8 hours' residence. EXAMPLE 3 10 20 kg of Rifamicin Sodium, expressed as anhydrous substance, have been mixed with 2 kg of ascorbic acid, 1 kg of lecithin, 2 kg of gliceryl distearate and 10 kg of mannitol till an homogeneous mixture was obtained. Then the core composition is completed by adding 45 kg of 15 mannitol, 15 kg of the methacrylate copolymer known under the trade mark Eudragit RS PO*, 1.5 kg of colloidal silicon dioxide and 1.5 kg of magnesium stearate. After mixture for 15 minutes, the powders are compacted as slugs with a tabletting unit and granulated on a screen of 20 suitable opening meshes. After the final addition of further 1 kg of magnesium stearate, the powder blend is tabletted in the final core shape, designed to contain unitarily 200 mg of Rifamycin 25 Sodium. The cores are then coated in a pan coat using a suspension obtained by pouring and dispersing in the suitable quantity of ethyl alcohol 2.3 kg of methacrylic acid 30 copolymer type B, 0.2 kg of titanium dioxide, 0.6 kg of yellow ferric oxide, 0.25 kg of triethylcitrate and 1.5 kg of talc. The coating operation are carried out maintaining the product at a temperature ranging between 35 and 45*C. N:\Melbourne\Cases\Patent\790O0-79999\P79501.AU\Specis\P79501 AU GHSPECil.doc 11/11/08 - 14 At the end of coating process, the tablets are polished by using 100 g of polyethylenglycol 6000. The tablets are packaged in Aluminium/Aluminium blister and HDPE bottles. 5 EXPERIMENTAL PART The tablets of example 3 have been used to test the pharmacokinetic characteristics and to assess the clinical efficacy of Rifamycin SV administered by oral, intestinal 10 route: - in health volunteers the single and repeated daily administration of 3 tablets didn't produce any detectable absorption in the blood and urines, so that this product could be defined unabsorbable (< 1% 15 of the administered dose) by oral route of administration; - in patients suffering of infectious colitis sustained mainly, but not only, by Escherichia Coli, Enterobacter or Citrobacter microbial strains, the 20 tablets promoted a fast relief of the diarrhea symptoms and disease remission depending on the daily doses. In fact, the 400mg/day regimen shown a median value of TLUS (Time to the Last Unformed Stools) of 57.7 hours whereas the 800mg/day regimen 25 shown a TLUS median value of 36.7 hours. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary 30 implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but N:\Melbourne\Cases\Patent\79000-79999\P7950.AU\Specis\P79501AU.GHSPECI I.doc 1/11/08 - 15 not to preclude the presence or addition of further features in various embodiments of the invention. It is to be understood that, if any prior art publication 5 is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country. N:\Melbourne\Cases\Patenm\79000-79999\P79501.AU\Specis\P7950 AU.GHSPECI I doc I 1/11/08

Claims (13)

1. Controlled and/or delayed release oral pharmaceutical compositions containing Rifamicin SV in association with 5 one or more pharmacologically acceptable excipient(s), wherein the controlled and/or delayed release is given by a multi-matrix structure comprising: - a) an amphiphilic matrix in which the active ingredient is incorporated; 10 - b) a lipophilic matrix which is formed by substances having a melting point of less than 900 C and in which a) is dispersed; - c) a hydrophilic matrix, characterized in that the controlled and/or delayed 15 release of the active ingredient takes place in the large intestine.

2. Pharmaceutical compositions according to claim 1, wherein the release of the active ingredient takes place 20 in the colon.

3. Pharmaceutical compositions according to the preceding claims, wherein the rifamicin SV is contained in an amount of from 10 to 90% by weight. 25

4. Pharmaceutical compositions according to the preceding claims, wherein the rifamicin SV is contained in an amount of from 20 to 60% by weight. 30

5. Pharmaceutical compositions according to the preceding claims, wherein the amphiphilic matrix is selected from lecithin, polyoxyethylenated sorbitan monooleate, sodium lauryl sulphate, sodium dioctyl sulphosuccinate and/or N:\Melbourne\Cases\Patent\79000-79999\P79501.AUJ\Specis\P79501AU.GHSPECII.doc 11/11/08 - 17 ethylene and/or propylene block copolymers.

6. Pharmaceutical compositions according to the preceding claims, wherein the lipophilic matrix is selected from 5 stearic acid, beeswax, carnauba wax, palmitic acid and/or palmitostearate esters.

7. Pharmaceutical compositions according to the preceding claims, wherein the hydrophilic matrix is selected from 10 hydroxypropylcellulose, hydroxypropybnethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, carboxyvinyl polymers, polyvinyl alcohol, vinyl polymers, alginic acid and its salts and/or polysaccharide polymers. 15

8. Pharmaceutical compositions according to the preceding claims, comprising a gastro-protective coating.

9. Pharmaceutical compositions according to claim 8, wherein the gastro- protective coating is selected from 20 acrylic and methacrylic acid esters and/or cellulose acetate phthalate.

10. Pharmaceutical compositions according to the preceding claims for the treatment of pathologies of the large 25 intestine.

11. Pharmaceutical compositions according to the preceding claims for the treatment of pathologies of the colon. 30

12. Pharmaceutical compositions according to the preceding claims for the treatment of infectious colites, bacillary dysentery, pseudomembranous colitis, travellers' diarrhoea, diverticular disease and/or diverticulitis. N:\Mclboume\Cases\Paicnt\790O0-79999\P79501.AU\Specis\P79501AU.GHSPECII.doc l1/l1/08 - 18

13. Pharmaceutical compositions according to the preceding claims for preparation treatment for surgical operations on the colon and/or for support treatment in the therapy of ammonaemias or hyperammonaemias N.\MclbournC\Cases\Patent\79OO-79999\P79501 AU\Specis\P79501 AUGHSPECI I.doc 11/11/08