PHARMACEUTICAL COMPOSITION CONTAINING AN ANTIMICROBIAL AGENT AND AN ANTIBIOTIC

Abstract: A pharmaceutical composition for use in the treatment of gastric disorders comprising an antimicrobial agent and an antibiotic, optionally co-administered with a release-delaying and/or retention-prolonging substance.

Description: PHARMACEUTICAL COMPOSITION CONTAINING AN ANTIMICROBIAL AGENT AND AN ANTIBIOTIC The present invention relates to pharmaceutical compositions active against Helicobacter pylori and their use in the treatment of gastrointestinal disorders associated with Helicobacter pylori infection. Helicobacter pylori (formerly known as Campylobacter pyloridis') is a spiral-shaped Gram-negative organism which appears to live beneath the mucus layer of the stomach. Many recent studies have shown an association between the presence of H.pylori in the gastric mucosa and histologically confirmed gastritis. In the light of these results, it has been suggested that the organism may be a pathogen which causes, or at least exacerbates, gastritis, and may also be important in the aetiology of peptic and duodenal ulceration. Reviews on the state of the art include those by C.A.M. McNulty in J. Infection. 1986, 12, 107-113, and by C.S. Goodwin ei al. in J. Clin. Pathol. 1986, 22, 353-365. H.pylori is known to be susceptible to a large number of antimicrobial agents in vitro. It has however proven considerably more difficult to achieve in vivo eradication of the organism. Indeed, monotherapy with a wide range of drugs is largely unsuccessful in achieving significant levels of in vivo eradication of H. pylori. Therapy now typically relies upon what is known as Triple Therapy consisting of co- administration of three separate drugs. Triple Therapy currently consists of a combination of a bismuth salt and two antibiotics. Even Triple Therapy is not entirely successful in achieving long-term eradication of H. pylori. Follow-up of patients cleared of H. pylori infection has shown that relapse (rather than reinfection) can be a problem. Treatment of H. pylori associated gastric disorders with antimicrobial agents given by conventional oral dosing regimens may thus require a prolonged course of therapy to be effective. Long-term treatment with current therapies is not however recommended in view of side-effects, the build-up of drug resistance and, in particular, the inherent toxicity risk associated with bismuth compounds. Accordingly, there is a need for a safe and effective treatment which does not depend on administration of bismuth agents. GB 2 243 549 A claims the use of the non-antibiotic antimicrobial agent triclosan for the preparation of a medicament for the treatment of gastrointestinal disorders associated with Helicobacter pylori infection. For comparative purposes, GB 2243 549 A discloses the in vitro testing of a number of antimicrobial compounds in addition to triclosan versus Helicobacter pylori, based on methods described by McNulty et al. (Antimicrobial Agents & Chemotherapy, 2S, 837- 838, 1985). These include cetyl pyridinium chloride and hexetidine. WO 92/18111 discloses that activity against Helicobacter pylori is conferred by a range of readily available substances which already have utililty as antimicrobial agents, including cationic antimicrobial agents, benzene derivatives, phenols, amines, and certain naturally occuring substances, for example certain plant extracts. Included in this range of antimicrobial agents are the compounds cetyl pyridinium chloride, hexetidine and miconazole. It has now been found that a combination of a selected antimicrobial agent and one or more antibiotics provides a safe and effective therapy for eradication of H.pylori in mammals. These compositions are advantageous when compared with current Triple Therapy in that a bismuth agent is not required. The risk associated with the administration of bismuth agents is hence avoided. Accordingly, the present invention provides a pharmaceutical composition comprising an antimicrobial agent and an antibiotic, characterised in that the antimicrobial agent is miconazole, cetyl pyridinium chloride, hexetidine or hexetidine citrate. Suitable antibiotics for combination with antimicrobial agents according to the present invention include orally administrable antibiotics belonging to the classes of β-lactam antibiotics, tetracyclines, imidazoles and macrolide antibiotics. Preferred antibiotics include amoxycillin, tetracycline, metronidazole and clindomycin. In a preferred embodiment of the invention a composition having utility for the treatment of gastric disorders associated with H. pylori comprises an antimicrobial agent as hereinbefore defined in combination with one antibiotic agent. A therapy comprising an antimicrobial agent and two antibiotics is not however precluded. A preferred composition according to the invention comprises a combination of hexetidine and amoxycillin or a combination of cetyl pyridinium chloride and amoxycillin. In a further aspect, the invention provides a pharmaceutical composition as hereinbefore defined for use in therapy, in particular for use in the treatment of gastric disorders associated with Helicobacter pylori. The invention also provides a method of treatment of gastric disorders associated with Helicobacter pylori in mammals, comprising orally administering an effective amount of a pharmaceutical composition comprising an antimicrobial agent selected from cetyl pyridinium chloride, miconazole, hexetidine or hexetidine citrate and an antibiotic. In another aspect of the invention, compositions comprising an antimicrobial agent and an antibotic having activity against H. pylori may be formulated as gastric controlled release compositions, more especially as compositions which prolong residence time of the antimicrobial agent within the stomach. Bioadhesive materials have received considerable attention as platforms for controlled drug delivery. They can be targetted to specific drug administration sites, prolong the residence time and ensure an optimal contact with the absorbing surface. Many different types of bioadhesive materials, both natural and synthetic, can be used in the design of controlled drug delivery systems. Sucralfate, a basic aluminium sulphate sucrose complex, is an ulcer-preventing agent having anti-pepsin and antacid properties. It has muco-adherent properties such that when administered orally it reacts with gastric juice to form a sticky paste which protects the mucosa by coating, and also binds to ulcer-affected sites. The preparation and use of sucralfate is described in for example US patent No.3432489 and "The Merck Index" 11th edition (1989) pl400 entry No 8853. US 4,615 697 (Robinson et al.) discloses a controlled release composition comprising an effective amount of a treating agent, which may be a medicament, and a bioadhesive material which is a water-swellable and water-insoluble, fibrous, cross-linked carboxy- functional polymer. The controlled release compositions are described as adhering to the skin or the mucous membranes in the presence of water. Accordingly, in this further aspect, the present invention provides a pharmaceutical composition as hereinbefore defined, further comprising one or more substances providing a sustained release and/or prolonged retention of the active components in the stomach, so as to overcome, or at least mitigate, the disadvantages associated with conventionally formulated H. pylori treatment and provide an effective treatment for H.pylori infections of the gastric and duodenal mucosa in humans and domestic animals. The present invention extends to these compositions for use in therapy and to the use of these compositions in the manufacture of a medicament for the treatment of gastric disorders associated with Helicobacter pylori. A combination of antimicrobial agent and antibiotic may for example be co-formulated, suitably by intimate admixture, with a muco-adherent or bioadhesive substance to form a bioadhesive complex. Such a complex confers the additional benefit of locally targetting the antimicrobial agent to the mucus layer of the stomach wall. Bioadhesive materials suitable for use in compositions of the present invention include materials, both natural and synthetic, which are capable of adhering to biological surfaces such as mucus membranes. Examples of bioadhesive materials include natural gums and plant extracts and synthetic materials such as sucralfate, cellulose derivatives, acrylic acid and methacrylic acid derivatives, for example cross-linked acrylic and methacrylic acid copolymers available under the Trade Names CARBOPOL and POLYCARBOPHTJL. Compositions effective against H.pylori may alternatively be formulated to produce a floating alginate raft within the stomach. Such formulations may include solid and liquid dosage forms, and may be prepared according to processes known to persons skilled in the art, for example as described in GB 2 243 549 A. Controlled release dosage forms, for example beadlets or granules, optionally encapsulated or compressed to form tablets, also form part of the invention. Advantageously, beadlets or granules are coated, layered, or form an intimate, homogeneous matrix with release-delaying materials. Such dosage forms may be prepared using conventional techniques known in the art. The composition of the invention may be made up in the form of a swallow tablet, a chewable tablet or a water dispersible tablet. Alternatively it may be supplied as a water-dispersible powder, either for dispersion immediately prior to administration or for dispensing in liquid form, as a suspension or as a liquid emulsion. Suitable water- dispersible formulations include soluble effervescent or non-effervescent powders. The compositions of the present invention may also contain appropriate additives, for example preservatives, buffering agents, suspending agents, flavourings, bulking agents, binders, adhesives, lubricants, disintegrants, colouring agents, sweeteners, adsorbents, thickeners, suspending agents, and diluents including water, appropriate to their form. If desired, the release of the active components of the composition may be altered by changing particle size, or by applying a suitable coating particularly to tablet forms. Coatings able to retard the release of pharmaceuticals are well known in the art of pharmaceutical formulation, and include polymers such as acrylic resins (for example the material sold by Rohm Pharma under the trade name 'Eudragit') and cellulose esters (for example ethyl cellulose). An encapsulated or delayed release formulation according to the invention may be any such form well known in the art. Suitable coating materials include water-based coatings, solvent-based coatings and colloidal dispersions. Lipids may also be used to form liposome-type formulations. Antimicrobial and antibiotic agents are present in compositions of the invention in appropriate amounts to provide an effective dose, which will depend on the pharmacological properties of the active compounds and the formulation employed for any given treatment. For example, for compositions containing cetylpyridinium chloride, a suitable daily dose lies in the range 0.01 to 100 mg, more suitably 0.1 to 20mg, and typically 7.5 to 15mg. For compositions containing hexetidine, a suitable daily dose lies in the range 0.01 to 100 mg, more suitably 0.1 to 20mg, and typically 5 to lOmg. For compositions containing miconazole, a suitable daily dose lies in the range 100 to 3000mg, more suitably 1000 to 2000mg, and typically 1400 to 1600mg. For compositions containing amoxycillin, a suitable daily dose lies in the range 500 to 5000mg, more suitably 1000 to 3000mg and typically 1200 to 1800mg. For compositions containing metronidazole, a suitable daily dose lies in the range 100 to 2000mg, more suitably 400 to 1500mg and typically 600 to lOOOmg. For compositions containing tetracycline, a suitable daily dose lies in the range 100 to 2000mg, more suitably 300 to 1500mg and typically 500 to 1200mg. The compositions of the present invention may also include additional therapeutic agents useful in the treatment of peptic ulcers and gastritis, and agents which delay gastric emptying, for example methylcellulose, guar gum, fats such as triglyceride esters, and triethanolamine myristate. Compositions of the invention may be administered as often as a physician directs, having regard to the severity of the H.pylori infection. Normally, it is recommended to take a dose two or three times daily, advantageously after meals. Surprisingly, it has also been found that the activity of the compositions hereinbefore identified against Helicobacter pylori may be enhanced if these agents are administered in combination with various materials which are not recognised as antimicrobial agents per se, for example chelating agents, surfactants and mixtures thereof. Accordingly, pharmaceutical compositions as hereinbefore described for use in the treatment of Helicobacter pylori, further comprising a chelating agent, a surfactant or mixtures thereof also form part of the invention. Suitable chelating agents include alkyldiamine tetraacetates, for example ethylenediaminetetraacetic acid (EDTA), CaEDTA, and CaNa2EDTA, EGTA and citrate. Suitable surfactants include ionic and non-ionic surfactants. Examples of non-ionic surfactants include glycerides and the materials commercially available under the Trade Names Tweens and Tritons. Ionic surfactants include fatty acids and quaternary compounds, the anionic surfactant sodium dodecyl sulphate, and amphoteric surfactants such as cocamidopropyl betaine and emulsifiers. The compositions of the invention may be prepared by conventional pharmaceutical techniques. Thus the composition may, for example, be prepared by mixing together the required ingredients with stirring or grinding to ensure adequate dispersion. Alternatively, some of the ingredients may be mixed together before other ingredients are added. Granulation and/or coating techniques may be used at a convenient stage in the process if required. The following example is illustrative of pharmaceutical compositions of the invention.

Claims: Claims 1. A pharmaceutical composition comprising an antimicrobial agent and an antibiotic, characterised in that the antimicrobial agent is cetyl pyridinium chloride, hexetidine, hexetidine citrate or miconazole. 2. A composition as claimed in claim 1 wherein the antibiotic is a b-lactam antibiotic, a tetracycline, an imidazole or a macrolide antibiotic. 3. A composition as claimed in claim 2 wherein the antibiotic is amoxycillin, tetracycline, metronidazole or clindamycin. 4. A composition as claimed in any one of claims 1 to 3 further comprising one or more substances providing a sustained release and or prolonged retention of the active components in the stomach. 5. A composition as claimed in claim 4 wherein the one or more substances providing a sustained release and/or prolonged retention of the active components in the stomach is a muco-adherent or bioadhesive substance or a material effective in producing a floating raft comprising the active components. 6. A composition as claimed in claim 5 wherein the one or more substances providing a sustained release and/or prolonged retention in the stomach is a natural gum, a plant extract, sucralfate, a cellulose derivative, or an acrylic acid or methacrylic acid derivative. 7. A composition as claimed in any one of claims 1 to 6 further comprising at least one of a chelating agent or a surfactant. 8. A composition as claimed in any one of claims 1 to 7 wherein the antimicrobial agent, the antibiotic and, where present, the one or more substances providing a sustained release and/or prolonged retention of the active components in the stomach and the chelating agent and/or surfactant are co-formulated as an intimate mixture. 9. A process for preparing a pharmaceutical composition as claimed in any one of claims 1 to 8 comprisng the admixture of the antimicrobial agent and the antibiotic, with a pharmaceutically acceptable carrier and, where present, the one or more substances providing a sustained release and/or prolonged retention of the active components in the stomach, and the chelating and/or surfactant. 10. A pharmaceutical composition as defined in any one of claims 1 to 8 for use in therapy. 11. The use of a pharmaceutical composition as defined in any one of claims 1 to 8 for the manufacture of a medicament for the treatment of gastric disorders associated with Helicobacter pylori.

Inventors: COKE MARK, LEA PHILIP, COKE, MARK, LEA, PHILIP
Applicants: COKE MARK, LEA PHILIP, SMITHKLINE BEECHAM PLC
Application year: 1993
Main classification: A61K31
IPC codes: A61K31, A61P31