AU623868B2 - Improved method for treatment of gastrointestinal disorders - Google Patents

Description

i OPI DATE 02/05/89 WORLD AOJP DATE 15/06/89 APPLN. ID 25405 88 PCT PCT NUMBER PCT/AU88/00379 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 A61K 33/24, 31/29 (11) International Publication b Al (43) International Publication Date: er: WO 89/ 03219 20 April 1989 (20.04.89) (21) International Application Number: PCT/AU88/00379 (22) International Filing Date: 29 September 1988 (29.09.88) (31) Priority Application Numbers: PI 4838 PI 5985 PI7513 (32) Priority Dates: (33) Priority Country: 12 October 1987 (12.10.87) 18 December 1987 (18.12.87) March 1988 (30.03.88) (8 esiated, p atent), AU, BE (Euprdian pent op patent), DE (European patent), FR (European patent), GB (European patent), IT (European patent), JP, LU (European patent), NL (European patent), SE (European patent),

US.

Published With international search report.

AUSTRALIAN

2 MAY 1989 PATENT OFFICE (71)(72) Applicant and Inventor: BORODY, Thomas, Julius [AU/AU]; 144 Great North Road, Five Dock, NSW 2046 (AU).

(74) Agent: SPRUSON FERGUSON; G.P.O. Box 3898, Sydney, NSW 2001 (AU).

(54) Title: IMPROVED METHOD FOR TREATMENT OF GASTROINTESTINAL DISORDERS (57) Abstract The present invention provides a method for eradicating and/or preventing recurrence of gastrointestinal disorders associated with Campylobacterpylori infections, which involves the administration of a pharmaceutical composition, comprising a pharmaceutically acceptable bismuth compound with a first antibiotic and a second antibiotic. There is also provided a pharmaceutical composition for the treatment of gastrointestinal disorders associated with C. pylori, and pharmaceutical compositions for said treatment in the form of a sequential pack.

-1- IMPROVED METHOD FOR TREATMENT OF GASTRO INTESTINAL

DISORDERS

TECHNICAL FIELD This invention relates to pharmaceutical compositions and therapeutic methods for eradication and/or prevention of recurrence of gastrointestinal disorders associated with infection by Campylobacterpy!ori. C. pylori is now known as Helicobacterpylori as of November 1989.

BACKGROUND ART H. pylori is a recently described bacterium found to cause chronic histological gastritis. Its causal role in peptic ulceration is less clear and even less so in non-ulcer dyspepsia. Its role could be more effectively studied if effective therapy for its eradication were devised.

Until recent times, H. pylori has been found to be difficult to eradicate using known chemotherapeutic agents. Although many antibiotics can suppress H. pylori growth in vitro, in vivo the mucosal concentration appears to be inadequate and penetration of the usual gastric mucus layer poor. Hence, development of an adequate in vivo eradication method for chronic H. pylori infection has been difficult. Moreover, adequate prediction of in vivo results cannot be predicted from in vitro work.

European Patent Application No. 206,625 and Australian Patent Application No.

59026/86 describe the use of bismuth together with a single antibiotic for the treatment of H. pylori. However, bismuth alone achieves low (30 to 70%) initial clearance rates for H. pylori and recurrence of the infection approaches 100% by twelve months post therapy. Bismuth together with a single antibiotic, namely amoxicillin, appears to be relatively effective as a short term means of reducing the symptoms but it is now clear that the use of bismuth together with a single antibiotic frequently fails to eradicate the infection and has a high rate of infection recurrence (Rauws, Erik A. J. et al; Gastroenterology, 1988; 94: 33-40).

DISCLOSURE OF THE INVENTION 3 0 The present inventor has now found that the use of a multi antibiotic therapy not S 30 only results in a high initial clearance rate of H. pylori, of the order of greater than "but also leads to a high eradication rate where most patients remain free of infection for .more than twelve to eighteen months. It now seems that therapeutic success measured at S eight weeks biopsy (post treatment) should be termed as clearance only whilst the term "eradication" should be used in the context of patients who remain free of H. pylori infection for more than twelve months post treatment.

The present inventor has also found that H. pylori is not only associated with gastritis but is also causally associated with peptic ulcer including duodenal, pre-pyloric, gastric, oesophageal and marginal ulcer and consequently the novel therapy for eradication of H. pylori described in the present invention is useful in the treatment of ©,04k A peptic ulcer. Moreover, the novel therapy of the present invention is useful in the Ua WP1183VV.DOC T r -2treatment of oesophageal reflux, reflux oesophagitis as well as asymptomatic carrier states.

In a first embodiment, the invention provides a method for the eradication and/or prevention of recurrence of gastrointestinal disorders associated with Helicobacter pylori infections, other than non-ulcer dyspepsia, in a patient requiring said eradication and/or prevention which method comprises administering to said patient sequentially or simultaneously, a therapeutically effective amount of at least one pharmaceutically acceptable bismuth compound, a therapeutically effective amount of at least one first antibiotic or antibacterial agent and a therapeutically effective amount of at least one second antibiotic or antibacterial agent.

The invention also provides a pharmaceutical composition for the treatment of gastrointestinal disorders associated with H. pylori infections, comprising a therapeutically effective amount of at least one pharmaceutically acceptable bismuth compound, a therapeutically effective amount of at least one first antibiotic or antibacterial agent and a therapeutically effective amount of at least one second antibiotic or antibacterial agent.

The invention also provides a sequential pack for the administration of at least two pharmaceutical compositions comprising a first composition which comprises a pharmaceutically acceptable bismuth compound, a first antibiotic or antibacterial agent and a second antibiotic or antibacterial agent, in unit dosage form adapted and presented for a first administration period of 3 to 36 days, together with a second pharmaceutical composition which comprises an acid suppressant for ulcer treatment in unit dosage form adapted and presented for a second administration period of 3 to 36 days prior to or overlapping with the initial part of said first administration period.

Preferably, the first antibiotic or antibacterial agent is selected from one or more of tetracyclines, penicillins, quinolones, cephalosporins, furazolidones, lincosamides, nitrofurantoins and/or polypeptides. Preferably, the second antibiotic or antibacterial agent is selected from one or more of quinolones, furazolidones, nitrofurantoins, and/or metronidazoles.

t y More preferably the first antibiotic or antibacterial agent is selected from Stetracyclines and/or penicillins and the second antibiotic or antibacterial agent is a metronidazole. The first and second antibiotics or antibacterial agents are not the same, although they may be selected from the same class.

I"' The tetracyclines include tetracycline, oxytetracycline, doxycycline, demeclocycline, methacycline and minocycline.

The penicillins include penicillin G, penicillin V, oxacillin, nafcillin, ampicillin, amoxicillin, cloxacillin and carbenicillin.

The metronidazoles include metronidazole and tinidazole.

Rifanpin, trimethoprim and/or nalidixic acid may also be used.

SA 40 The cephalosporins include cephalexin, cefaclor, cephapirin, cephradine and WP1183VV.DOC jvi cefadroxil as well as second and third generation cephalosporins.

The polypeptide antibiotics include polymyxin B, bacitracin, colisin sulfate and/or spectinomycin HCi.

Quinolones include ciprofloxacin, norfloxacin and ofloxacin.

Lincosamides include lincomycin and clindamycin.

Whilst it is preferred that the first and second antibiotics or antibacterial agents are selected from different classes, they may be selected from within the one class.

Moreover, a third or more antibiotics may be included in the methodology and compositions of the invention; eg amoxicillin, tetracycline and metronidazole, together with bismuth, in situations where patients are resistant to lesser therapy, triple therapy.

Bismuth compounds suitable in the present invention include those selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgallate, bismuth subnitrate, bismuth tartrate, bismuth salicylate, bismuth subsalicylate, and mixtures thereof. Bismuth citrate, bismuth subcitrate, tripotassium dicitrato bismuthate, bismuth I tartrate, bismuth subsalicylate, and mixtures thereof are preferred bismuth salts for use in i this invention. The bismuth useful herein may be administered alone, or in combination with other pharmaceuticallyacceptable components, in a bismuth-containing composition.

l 20 A variety of such compositions containing bismuth salts are commercially-available, including, for example, DeNol, containing tripotassium dicitrato bismuthate (sold by Gist-Brocades Noralac, containing bismuth aluminate, alginic acid, and magnesium carbonate (manufactured by North American Pharmaceuticals), Roter bismuth, containing bismuth subnitrate (sold by Roter Laboratories), Fensobar Polvo, containing bismuth subcarbonate among other materials (manufactured by USV S. Pharmaceutical Corporation), and Pepto-Bismol, containing bismuth subsalicylate (sold by The Procter Gamble Company).

In a preferred form of the present invention there is provided a method of treating gastro intestinal infections associated with H. pylori which comprises administering an effective amount of a pharmaceutically acceptable bismuth compound in combination with a tetracycline and/or a penicillin and a metronidazole.

j The bismuth compound, the first antibiotic or antibacterial agent and the second antibiotic or antibacterial agent are generally chosen as to interact synergistically in the eradication and/or prevention of infections associated with H. pyloni.

In a further aspect of the present invention there is provided a capsule for oral administration to patients suffering from gastro intestinal infections associated with H.

pylori wherein said capsule includes a pharmaceutically acceptable bismuth compound together with a first antibiotic and a second antibiotic wherein said capsule is adapted to release said bismuth within the stomach of the recipient and wherein at least said first A,1 40 antibiotic and preferably also said second antibiotic is microencapsulated so that said first 1 f WP1 183VV.DOC AA L -4and optionally said second antibiotic is released within the gastro intestinal tract after said stomach.

In a preferred form of this aspect of the invention there is provided a capsule containing an effective amount of a pharmaceutically acceptable bismuth compound together with coated micro-spherules of an antibiotic of the tetracycline class or penicillin class which capsule also contains an effective amount of a second antibiotic selected from the metronidazole class which second antibiotic is optionally provided in coated micro-spherule form.

The micro-spherules may be coated with a coating or a non-reactive coating.

Substances that by their nature prevent reactions between the micro-spheres of actives e.g. oils or Polyethylene Glycol (PEG) Lecithin etc..

The preferred treatment regimen involves therapy with a capsule containing the three separate compounds, four times daily, for an average of fourteen days. Treatment ranges from three to twenty-eight days. It is not essential to pre-administer or post-administer any of the three components. Simplification of the treatment and increase of compliance is obtained when all the components are ingested in a pre-formed tablet or the described capsule.

In a further aspect of the present invention the methodology uses the treatment Sregimen comprising the combination of pharmaceutically acceptable bismuth compound in combination with a first antibiotic and a second antibiotic for between three to twenty-eight days. Preferably the treatment is combined with the administration of an acid suppressant such as a histamine 2 antagonist such as cimetidine, ranitidine or famotidine to effect symptomatic relief and ulcer epithelialization. This is followed by the combination of the bismuth and first and second antibiotic therapy. Preferably the histamine2 antagonist is administered for three to twenty-eight days followed by a three to twenty-eight day therapy of the bismuth/antibiotics combination. Other acid suppressants may be used instead of a histamine 2 antagonist such as benzimidazole or prostaglandins. Alternatively, the histamine2 blocker or other acid suppressant can be combined with the pharmaceutical composition of the present invention.

The present invention also provides a sequence presented pack suitable for therapy for gastro intestinal disorders associated with H. pylori infection which combines a pharmaceutically acceptable bismuth compound together with a first antibiotic and a second antibiotic and optionally further antibiotics so that said treatment regimen can be Sadapted for individual patient needs. Optionally the sequence presented pack may also include an initial therapy comprising an acid suppressant such as a histamine 2 antagonist or a K/Na ATP-ase inhibitor such as omeperazole and may be combined with mucus disrupting agents such as carbocysteine, n-acetylcysteine, corticosteroids or bisolvon (bromhexine hydrochloride). It should be noted that the pharmaceutical composition comprises at least two antibiotics but further antibiotics may be selectively added in ,40 difficult cases or where resistant strains and/or multiple strains present a more resistant WP1 183VV.DOC problem.

The triple therapy capsule may be combined with another antibiotic in patients in whom resistance has occurred or the bacteria have entered a nitch which requires an agent which penetrates cells effectively to enter the micro-organelles of the mucosal cells. Patients have, in the past, been treated by some antibiotics and, hence, multiple strains which may have multiple resistances not able to be picked up by simple culture, need to be addressed by adding further antibiotics.

The "effective amount" may be defined as the amount of therapeutic agents which results in a high initial clearance rate of H. pylori, of the order of greater than 90%, and also leads to a high eradication rate for more than twelve months.

In the composition and methodology of the present invention, preferably from to 5000mg, more preferably 50 to 250mg of a pharmaceutically acceptable bismuth compound is used together with from 5 to 10000mg, more preferably 50 to 500mg of a first antibiotic together with from 5 to 10000mg, more preferably 50 to 250mg of a second antibiotic.

Preferably the invention provides a pharmaceutical composition containing from to 250mg of a bismuth suspension in pharmaceutically acceptable form, 50 to 500mg of tetracycline doxycycline, minocycline) or a penicillin (eg amoxicillin) type antibiotic and 50 to 250mg of a metronidazole type antibiotic such as metronidazole or tinidazole. The "effective amount" of the therapeutic agents generally contains about 250mg colloidal bismuth or bismuth subsalicylate; 250mg metronidazole; and 500mg tetracycline per capsule and administered four times a day. These amounts may be reduced per capsule if the capsule is used more frequently during the day. Preferably the tetracycline or penicillin is microencapsulated to prevent bismuth chelation at high pH.

In a further aspect the invention provides a sequential pack comprising an I antibacterial pharmaceutical composition in unit dosage form adapted for an administration period of three to thirty-six days, said antibacterial composition comprising a pharmaceutically acceptable bismuth compound, at least a first antibiotic and at least a second antibiotic, together with a palliative pharmaceutical composition in 30 unit dosage form adapted and presented for a three to thirty-six day administration period prior to, or overlapping with the initial part of the administration period of said antibacterial pharmaceutical composition wherein said palliative pharmaceutical composition comprises a therapeutic agent such as an acid suppressant, adapted for ulcer t T treatments.

In a further aspect the invention provides a sequential pack comprising a first pharmaceutical composition in unit dosage form adapted for an administration period of three to thirty-six days, said composition comprising a pharmaceutically acceptable bismuth compound and at least a first antibiotic, together with a second pharmaceutical composition in unit dosage form comprising a second antibiotic adapted for '/.An4/t40 administration for a period different to said administration period of said first p/U) WP1183VV.DOC a: 71l.W.OC T 0;, pharmaceutical composition. Preferably the pack further comprises a palliative pharmaceutical composition in unit dosage form presented in said pack in a 3 to 36 day administration period which is prior to or overlaps with the initial part of the administration period of said first pharmaceutical composition wherein said palliative pharmaceutical composition comprises a therapeutic agent, such as an acid suppressant, adapted for ulcer treatment.

BEST MODES OF CARRYING OUT THE INVENTION The methodology and treatment described above is useful in the treatment of disorders associated with H. pylori which include duodenal ulcer, pre-pyloric ulcer, gastric ulcer, oesophageal ulceration, reflux oesophagitis with or without ulceration, bile-reflux "gastritis", and/or asymptomatic carrier state.

Whilst tablets or capsules of the pharmaceutical composition of the present invention are preferred, sachets or syrups or other orally ingestible forms of the compositions are also included within the scope of the present invention.

A sachet may be manufactured containing micro-encapsulated bismuth and micro-encapsulated antibiotics, as described above. The micro-encapsulation would allow segregation of the antibiotics with prevention of cross-reaction within the sachet.

Doses could be equivalent to those in a tablet or capsule form. A coating would prevent blackening of teeth and tongue where bismuth otherwise would cause this in a tablet. A syrup may be prepared for children. This would contain an acceptable bismuth such as bismuth subsalicylate, amoxycillin and metronidazole. Sequential packs may be constructed so that patients would not forget the frequent, four times daily, ingestion.

Labelling for days and times during the day may be allowed for in the packing.

The components of the pharmaceutical composition may be separated by microencapsulation of one or more of the components. When the components are separated by microencapsulation, at least two of the active ingredients are microencapsulated. For example, the first antibiotic or antibacterial agent and the second antibiotic or antibacterial agent are microencapsulated separately. The j ,microcapsules of both type and the bismuth compound are packed into capsules.

30 Alternately, each active ingredient is microencapsulated separately. Any combination of components can be microencapsulated.

Another means of separation is by coating each of the components and then placing each coated component within the one capsule, tablet or pill or any other form of medication. Another means of separating the components include a multi-layered tablet wherein each layer contains one of the components. Alternatively, each layer is F prepared such that each component occupies a certain area on the tablet. This technique is generally used for a single-dose preparation from which each layer is released separately, after differing intervals of time, giving a prolonged action.

The invention will be further described with reference to the following test :1 40 procedure of the Example and accompanying Figures wherein Figure 1 shows the results U WP1 1B3VV.DOC

I

1 r -7of treatment of the present invention in 64 out of 100 patients at an average of 19.3 months post treatment and Figure 2 shows the histologic grading pre and post treatment with the treatment of the present invention.

EXAMPLE

Test Procedure Patients aged 19 to 79 years (M:F 47:53) with symptoms of dyspepsia lasting three months or more referred for endoscopy, were entered. Only patients positive for H. pylori with duodenal ulcer were entered into the study. Patients with duodenal ulcer were entered into the treatment protocol only after ulcer treatment with either four weeks of ranitidin, (300mg/day) or cimetidine (800mg/day), known not to influence H. pyloi.

Exclusion criteria included coagulopathy, antibiotic use within two weeks of endoscopy, presence of oesophageal varices, previous gastrectomy, neoplasm, systemic disease or allergy preventing use of the medications. Gastric ulcer patients were excluded to form a separate study. Of 122 patients entered in the study, 112 completed the triple chemotherapy adequately. Of these, 100 consecutive re-endoscoped patients became available for analysis of results at eight weeks after commencement of treatment and constitutes the short term follow up groups. Ten patients did not complete the treatment due to failure to follow up nausea clostridium difficile-positive diarrhoea allergy and oral moniliasis At 12 to 37 months after H. pylon eradication therapy CP-negative patients at eight weeks from the pilot studies and the abovementioned group were invited for re-examination by gastroscopy. Of the entire cohort 64 patients returned for examination and constitute the long term follow up group.

Gastroscopy All examinations were carried out by the same endoscopist. Two biopsy specimens were taken from the gastric antrum and one from the body. One antral speciman was placed in a microtitre tray containing buffered urea and an indicator to detect rapidly presence of H. pylori urease activity. The other specimens were placed in 10% buffered formalin for histological examination. No bacterial cultures were carried out.

30 Histological Assessment Paraffin sections of tissues fixed in formalin were stained with haematoxylin and eosin to grade severity of histological gastritis and with Warthin-Starry silver stain to grade H. pylori density. Grading was based on density of lymphocyte/plasma cell (chronic), neutrophil (active) infiltration, or presence of H. pylori from O to III as previously described.

Specimens were graded by the same consultant histopathologist without knowledge of patients' details.

Medication Except for eight patients allergic to tetracycline, all subjects received a combination of colloid bismuth substrate (108mg chew-tablets tetracycline HC1 WP1183VV.DOC 44 4 4 C1 44 4 4 44a 4 r.4 c 4 44,4 C 4 4r 4 C I 44 44 4 C C 4 4.4' p4,,u *1 _1 -8- (500mg for four weeks, together with metronidazole (200rg for the first ten days. Amoxicillin (500mg was substituted for tetracycline in the eight allergic patients. Patients and endoscopist were not blinded to the treatment regiment.

Patients were asked if they had completed the medication as requested but no tablet count was attempted.

The medications were administered as tablets and capsules in the majority of the patients. In ten patients a combined preparation was administered containing bismuth subsalicylate 260mg, together with metronidazole 250mg in the same capsule.

Tetracycline HC1 500mg was administered in a separate capsule concurrently four times daily. The patients took these medications with water. They were then re-examined four weeks after cessation of treatment.

Assessment of Symptoms In duodenal ulcer patients symptom improvement or disappearance was recorded.

RESULTS

Clearance of H. pylori at eight weeks Of the 100 consecutive available patients treated for H. pylori, 94 were negative on urease testing and histology at eight weeks after commencement of chemotherapy (See Table The six patients remaining positive at eight weeks claimed to have taken their medication as directed.

Long Term Clearance of H. pylori Follow up gastroscopic biopsies were obtained in 64 patients (M:F 36:28) at 12 to 37 months after original triple chemotherapy (mean 19.3 months), and results shown in Fig. 1. These patients were drawn from the 94 who remained HP negative at eight weeks post therapy and from a small pilot study carried out some months earlier.

Of these 64, paid recalled volunteers who resubmitted to gastroscopic biopsy, 28 had endoscopically-proven duodenal ulcer. At follow up overall 60 or 94% remained free of H. pylori infection at the 19.3 months. Three of 31 patients originally with duodenal ulcer were HP positive. In the latter three patients, two again had re-ulcerated while the other patient had pronounced duodenitis. All 28 patients who remained free of H. pylori S 30 maintained their ulcers endoscopically healed. They were on no maintenance therapy Sand were free of ulcer-like symptoms.

An unexpected finding in four of 15 patients who initially had linear oesophageal Si. ulceration, was total healing and disappearance of the ulcers after H. pylor eradication.

No appreciable weight change had occurred in these patients and the improvement could not be ascribed to any other medical therapy.

Pe Table 1 Patient Age M/F H. pylori at start of H. pylori 8 wks treatment past therapy 1 D.U. 59 M +ve -ve S2 P.P.U 74 F +ve -ve ISP WP1183VV.DOC y i-g ii i i

I

i:r r i ::i t ii

B

i i: :4 ii g "x i 1.

i 3G.U3 4 D.U 52D.U 6D.U 7 P.P.U 8 P.P.U 9 D.U 11 D.U 12 D.U 13 D.U 14 D.U 15 P.P.U 16 D.U 17D.U 18 D.U 19 D.U 20 G.U/D.U 21 D-.U 22 P.P.U 23 O.U 24 PREV G.U

P.P.U

26 D.U 27 D.U 28 D.U +ve +ve +ve +ve +ve +ve +ve +ve +ve +ve +ve +ve +ve +ve +ve +ve +ve +ve -ve* -ve -ve +ve* -ve -ve -ve -ve -ve -ve +ve* -ve -ve -ve -ve -ve -ve -ve F +ve -ve M +ve -ve M +ve -ve M +ve -ve F +ve -ve F +ve -ve M +ve -ve M +ve -ve indicates failure to cure infection.

l ulcer O.U Oesophageal ulcer D.U Duodena P.P.U Pre-pyloric ulcer G.U Gastric ulcer Histological Changes S 5 The effects of therapy on histological grading of H. pylori density as well as lymphocyte and neutrophil infiltration are summarized in Figure 2.

i Histological scores have been arbitrarily assigned to show graphically the time-course of inflammation resolution. All patients presented initially with high scores for both chronic and active gastritis. Neutrophil infiltration disappeared rapidly S 10 parallelling H. pylori clearance. Lymphocyte infiltration, on the other hand, persisted for a much longer time.

This study has demonstrated that high 90%) initial "clearance" of gastric H.

pylori is possible with a combination of available antibacterial agents. Such a high level i i of initial clearance has not been previously achieved. It is also clear that therapeutic SA/A1 P/ WP1183VV.DOC

I.*

S0O success measured at the eight week biopsy, should for the present be termed "clearance".

The term "eradication" should be reserved for patients remaining free of HP beyond six months. In this study most of those patients cleared of HP at eight weeks remained clear of the infection for more than twelve months.

Although H. pylori is susceptible to numerous antibiotics in vitro, such agents notoriously fail to eradicate it in vivo. Bismuth appears to be an important component in the combination chemotherapy. While it is not clear why several antibacterials are required to improve eradication of HP, antibiotic access to the bacteria may be a problem. The bismuth compound may be required locally within the gastric pits and mucus whereas the antibiotics could be required to be carried systemically to reach bacteria deep in gastric pits and within endocytotic vacuoles. Presence of multiple strains of H. pylori with varying antibiotic susceptibility spectra could provide another explanation for the need to employ multiple antibiotics. In view of the multiplicity of strains, it is in fact surprising that such a high HP clearance rate could be achieved employing only two systemic antibacterials and one locally-acting agent (CBS). Perhaps the success can be further explained by prevention of the development of resistant strains seen after short courses of single systemic antibiotics.

A clinically useful method for successful long term H. pylori eradication has not di previously been described. Twelve month follow up figures of 51% and 35% have been ij 20 reported using bismuth plus a single antibiotic. Such therapy would clearly be unsatisfactory for patients and may lead to creation of resistant H. pylori strains. It is also desirable to have an effective eradication therapy for H. pylori before embarking upon a double-blind trial designed to demonstrate the relevance of the organism in a particular disease.

Although it is known that bismuth can decrease tetracycline bioavailability, the antibiotic combination as used here achieved its desired effect in spite of presumed chelation. It would appear that adequate bismuth and tetracycline remained post-chelation to reach the infected targets. It is known also that chelation is in part pH dependent and low pH protects against chelation. As some patients with H. pylori 30 infection will have impaired gastric acid secretion, elevated pH may have contributed to treatment failures. Other sources of treatment failure could include reduction in tetracycline bioavailability by ingestion of milk, antacids, iron or food, or simply non-compliance.

Rauws, Eric A.J. et al, Gastroenterology 1988, Vol. 94; 33-40, have shown how CBS (bismuth) alone results in a 15% 12-month cure rate, amoxycillin in a 23% cure rate and CBS plus amoxycillin in a 35 cure rate. These results are shown in Table 2.

t t U3I -11- Table 2 Follow-up Culture Results of the 233 C. pyloridis Culture-Positive Patients With Chronic Active Gastritis After Various Therapeutic Regimens Still Negative after Treatment n Negative 1 month 3 months 6 months 12 months Immediately after treatment Cimetidine 53 0 Sucralfate 13 0 CBS 67 30 12 10 10 10(15%) Amoxicillin 22 15 5 5 5 5 (23%) CBS+ 20 18 8 8 8 7(35%) amoxicillin No treatment 58 0 Total 233 63 25 23 23 22 CBS, colloidal bismuth subcitrate.

from Rauws E.A.J. et al Gastroenterology 1988 94 33-40.

This is further substantiated by Tytgat G.N.J. et al Working Party Reports (1990) 36-45. Tytgat et al state that colloidal bismuth subcitrate (CBS) alone eradicated H.

pylori in 20% of individuals. CBS or bismuth subsalicylate (BSS) is very useful in combination with antibiotics, not only increasing the eradication rate but also inhibiting the emergence of resistant organisms. A combination of amoxycillin with tinidazole eradicated H. pylori in 43% of individuals and was associated with the emergence of acquired resistance in 25% of individuals. CBS or BSS combined with nitroimidazole eradicates H. pylori in 67% the combination of CBS or BSS with amoxycillin was shown to be disappointing. The working party recommended triple therapy consisting of 15 CBS or BSS, tetracycline and metronidazole because it was shown to eradicate H. pylori infection in 91% of individuals.

.oo Lambert J.R. et al Rev. Esp. Enf. Digest 1990 78:115-116 discloses CBS plus metronidazole which is a bismuth plus class 2 antibiotic and gives about a 64% cure rate.

Triple therapy was also shown to have a 90% cure rate. These results are shown in Table 3.

t a t l a 0 i ii~-i R -12- Table 3 Treatment Duration Post-therapy 1. CBS 4 Weeks 5/20 2. CBS 4 Weeks 19/30 Amoxicillin 2 Weeks 3. CBS 2 Weeks 12/30 Amoxicillin 1 Week 4. CBS 2 Weeks 7/11(64%)+ Metronidazole 1 Week CBS 2 Weeks 18/20 Amoxicillin 1 Week Metronidazole 1 Week +P 0.01 cf CBS alone; P 0.05.

from Lambert J.R. et al Rev. Esp. Enf. Digest 1990 78:115-116.

George L.L. et al The Medical Journal of Australia 1990 153:145-149 discloses triple therapy with four year follow-up again giving about a 90% effective cure rate.

Resistant strains of H. pylori seem to be eradicated quite readily by adding Omeperazole. Ranitidine an H2-antagonist, when added to triple therapy, may be used not only to reduce pain, but it also appears to aid with the eradication. Lamouliatte H et al Rev. Esp. Ent. Digest 1990 78:101 found that the association of an antisecretory drug such as Omeperazole or ranitidine with amoxycillin and tinidazole resulted in a 81.5% rate of eradication of H. Pylori.

Dosage Forms The combination of the bismuth preparation bismuth subcitrate or bismuth subsalicylate, or any acceptable bismuth form) can take the form of 2 capsules, being administered for 3-28 days in a twice-daily thrice-daily or four times daily manner.

Metronidazole or tinidazole e.g. 250 mg is packed into a small capsule, and this capsule is then placed into a larger capsule e.g. 500mg capsule, and is surrounded by the bismuth preparation. The second capsule consists of the second antibiotic e.g. penicillin, tetracycline or erythromycin. Both these can then be placed into a blister-pack to be 20 taken e.g. four-times daily, or boxed in a double-chamber dispenser.

Abj'S 5' WP1183VV.DOC

Claims (39)

1. A method for the eradication and/or prevention of recurrence of gastrointestinal disorders associated with Helicobacter pylori infections, other than non-ulcer dyspepsia, in a patient requiring said eradication and/or prevention which method comprises administering to said patient sequentially or simultaneously, a therapeutically effective amount of at least one pharmaceutically acceptable bismuth compound, a therapeutically effective amount of at least one first antibiotic or antibacterial agent and a therapeutically effective amount of at least one second antibiotic or antibacterial agent.

2. The method of claim 1, wherein said bismuth compound is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, colloidal bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgallate, bismuth subnitrate, bismuth tartrate, bismuth salicylate, bismuth subsalicylate, and mixtures thereof.

3. The method of claim 1 or claim 2, wherein said first antibiotic or antibacterial agent is selected from one or more of tetracyclines, penicillins, quinolones, cephalosporins, furazolidones, lincosamides, nitrofurantoins, and/or polypeptides.

4. The method of any one of claims 1 to 3, wherein said second antibiotic or antibacterial agent is selected from one or more of quinolones, furazolidones and/or metronidazoles.

The method of claim 3, wherein said first antibiotic or antibacterial agent is a penicillin or tetracycline.

6. The method of claim 5, wherein said tetracycline is selected from doxycycline or minocycline.

7. The method of claim 4, wherein said second antibiotic or antibacterial agent is a metronidazole.

8. The method of any one of claims 1 to 7, further comprising administering to said patent a therapeutically effective amount of a third antibiotic or antibacterial agent.

9. The method of any one of claims 1 to 8, which further comprises administering a therapeutically effective amount of an acid suppressant Swhen used with any or all antibiotic or antibacterial agents.

10. The method of claim 9, wherein said acid suppressant is a histanine2 antagonist when used with any or all antibiotic or antibacterial agents.

11. The method of claim 10, wherein said histamine 2 antagonist is a 35 cimetidine, ranitidine or famotidine or a benzimidazole or prostaglandins when used with any or all antibiotic or antibacterial agents.

12. The method of claim 9, wherein said acid suppressant is a K/Na ATP-ase inhibitor when used with any or all antibiotic or antibacterial agents.

13. The method of claim 12, wherein said K/Na ATP-ase inhibitor is O0 omeperazole when used with any or all antibiotic or antibacterial agents. 0 4 0 0*# 000.i 1 0 0 *I LI I IO I #0 lot WP1183VV.DOC 7 -14-

14. The method of any one of claims 1 to 13, which further comprises administering a therapeutically effective amount of a mucus disrupting agent.

The method of claim 14, wherein said mucus disrupting agent is carbocysteine, n-acetylcysteine, corticosteroids or bromhexine hydrochloride.

16. The method of any one of claims 1 to 14, wherein said gastrointestinal disorder is gastritis, peptic ulcer, oesophageal reflux, reflux oesophagitis with or without ulceration, duodenal ulcer, pre-pyloric ulcer, gastric ulcer, oesophageal ulceration, bile reflux gastritis, and/or asymptomatic carrier state.

17. A pharmaceutical composition for the treatment of gastrointestinal disorders associated with H. pylori infections, comprising a therapeutically effective amount of at least one pharmaceutically acceptable bismuth compound, a therapeutically effective amount of at least one first antibiotic or antibacterial agent and a therapeutically effective amount of at least one second antibiotic or antibacterial agent.

18. The composition of claim 17, wherein said bismuth compound is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, colloidal bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgallate, bismuth subnitrate, bismuth tartrate, bismuth salicylate, bismuth subsalicylate, and mixtures thereof.

19. The composition of claim 17 or claim 18, wherein said first antibiotic or antibacterial agent is selected from one or more of tetracyclines, penicillins, quinolones, cephalosporins, furazolidones, lincosamides, nitrofurantoins, and/or polypeptides.

The composition of any one of claims 17 to 19, wherein said second antibiotic or antibacterial agent is selected from one or more of quinolones, furazolidones, metronidazoles, and/or cephalosporins with the proviso that where the first antibiotic or antibacterial agent is of the same class as the second antibiotic or antibacterial agent, the first antibiotic or antibacterial agent is different from the second antibiotic or antibacterial agent.

21. The composition of claim 19, wherein said first antibiotic or antibacterial agent is a penicillin or tetracycline. S 30

22. The composition of claim 21, wherein the tetracycline is selected from doxycycline or minocycline.

23. The composition of claim 20, wherein said second antibiotic or antibacterial agent is a metronidazole.

24. The composition of any one of claims 17 to 23, which further comprises a S 35 therapeutically effective amount of an acid suppressant used with any or all antibiotic or antibacterial agents. V'

25. The composition of claim 24, wherein said acid suppressant is a histamine 2 antagonist.

26. The composition of claim 25, wherein said histamine 2 antagonist is a S 40 cimetidine, ranitidine or famotidine or a benzimidazole or prostaglandins. 7 WP1183VV.DOC

27. The composition of claim 24, wherein the acid suppressant is K/Na ATP-ase inhibitor or omeperazole used with any or all antibiotic or antibacterial agents.

28. The composition of any one of claims 17 to 27, which further comprises a therapeutically effective amount of a mucus disrupting agent.

29. The composition of claim 28, wherein said mucus disrupting agent is carbocysteine, n-acetylcysteine, corticosteroids or bisolvon.

A sequential pack for the administration of at least two pharmaceutical compositions comprising a first composition which comprises a pharmaceutically acceptable bismuth compound, a first antibiotic or antibacterial agent and a second antibiotic or antibacterial agent, in unit dosage form adapted and presented for a first administration period of 3 to 36 days, together with a second pharmaceutical composition which comprises an acid suppressant for ulcer treatment in unit dosage form adapted and presented for a second administration period of 3 to 36 days prior to or overlapping with the initial part of said first administration period.

31. The sequential pack of claim 30, wherein said bismuth compound is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, colloidal bismuth subcitrate, bismuth citrate, tripotassium dicitritobismuthate, bismuth subgallate, bismuth subnitrate, bismuth tartrate, bismuth salicylate, bismuth subsalicylate and mixtures thereof.

32. The sequential pack of claim 30 or claim 31, wherein said first antibiotic or antibacterial agent is selected from one or more of tetracyclines, penicillins, quinolones, cephalosporins, furazolidones, lincosamides, nitrofurantoins and/or polypeptides.

33. The sequential pack of any one of claims 30 to 32, wherein said second antibiotic or antibacterial agent is selected from one or more of quinolones, furazolidones, nitrofurantoins and/or metronidazoles.

34. The sequential pack of claim 3J2. wherein said first antibiotic or antibacterial agent is a penicillin or tetracycline. i

35. The sequential pack of claim 34, wherein said tetracycline is selected from doxycycline or minocycline. S 30

36. The sequential pack of claim 33, wherein said second antibiotic or antibacterial agent is a metronidazole. S.

37. The sequential pack of claim 34, wherein said penicillin or tetracycline is microencapsulated.

38. The sequential pack of any one of claims 30 to 37, wherein said acid S 35 suppressant is a histamine2 antagonist or K/Na ATP-ase inhibitor when used with any or all antibiotic or antibacterial agents.

39. A pharmaceutical composition for the treatment of gastrointestinal disorders associated with H. pylori infectons, substantially as hereinbefore described with reference to the Example but excluding any comparative examples. LU WP1183VV.DOC V t 0- ^Vr6 3 D -7 -16- DATED this FOURTH day of MARCH 1992 Thomas Julius Borody Patent Attorneys for the Applicant SPRUSON ]FERGUSON WP1 183VV.DOC