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WO1992018111A2 - Pharmaceutical composition for the treatment of gastritis - Google Patents

Pharmaceutical composition for the treatment of gastritis Download PDF

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Publication number
WO1992018111A2
WO1992018111A2 PCT/GB1992/000551 GB9200551W WO9218111A2 WO 1992018111 A2 WO1992018111 A2 WO 1992018111A2 GB 9200551 W GB9200551 W GB 9200551W WO 9218111 A2 WO9218111 A2 WO 9218111A2
Authority
WO
WIPO (PCT)
Prior art keywords
chloride
antimicrobial agent
hexetidine
hydrochloride
pharmaceutical composition
Prior art date
Application number
PCT/GB1992/000551
Other languages
French (fr)
Other versions
WO1992018111A3 (en
Inventor
Philip Lea
Mark Coke
Kim Morwood
Andrew William Smith
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP4506927A priority Critical patent/JPH06506919A/en
Publication of WO1992018111A2 publication Critical patent/WO1992018111A2/en
Publication of WO1992018111A3 publication Critical patent/WO1992018111A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A61K31/055—Phenols the aromatic ring being substituted by halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A61K31/79—Polymers of vinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to pharmaceutical compositions of antimicrobial agents active against Helicobacter pylori and their use in the treatment of gastrointestinal disorders associated with Helicobacter pylori infection.
  • Helicohacter pylori (formerly known as CaiPPytobacter 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.
  • the organism may be a pathogen which causes, or at least exacerbates, gastritis, and may also be important in the aetiology of peptic ulceration.
  • Reviews on the state of the art include those by C.A.M. McNulty in _I. Infection. 1986, 12, 107-113, and by C.S. Goodwin fit al. in -L £_____. £a___h__ ., 1986, 2SL, 353-365.
  • H.pylori is known to be susceptible to a large number of antimicrobial agents in vitro. Furthermore, several workers have shown that treatment of gastritis with antimicrobial agents, for example ⁇ -lactam antibiotics such as amoxycillin, or bismuth salts, leads to eradication of the associated H.pylori organisms in vivo.
  • antimicrobial agents for example ⁇ -lactam antibiotics such as amoxycillin, or bismuth salts
  • GB 2 243 549 A (Reckitt & Colman), published November 6, 1991, 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 -y ⁇ sa ⁇ . infection.
  • the medicament may be formulated as a gastric sustained release composition having prolonged residence time within the stomach and continuously releasing triclosan during that time.
  • Triclosan compositions formulated so as to produce floating alginate rafts within the stomach, or as muco-adherent coated granules or spheroids, are identified as suitable sustained release compositions.
  • GB 2 243 549 A further describes, for tablets, a co-formulation and, for tablet or liquid presentations, co-administration with a pharmaceutically acceptable solid carboxylic acid, or salt thereof, in order to overcome the tendency for elevated stomach pH, observed with certain patients suffering from Helicobacter pylori infections, to reduce the ability for alginate rafts to float.
  • Citric acid is referred to as a suitable acid for this purpose.
  • GB 2 243 549 A discloses the in vitro testing of 11 antimicrobial compounds in addition to triclosan versus Helicobacter pylori. based on methods described by McNulty et al. ( Antimicrobial Agents & Chemotherapy, 2_ 837-838, 1985). MIC results for triclosan, tinidazole, cetalkonium chloride, cetyl pyridinium chloride, clioquinol, hexetidine, dichlorophen, halquinol, 4-hexyl recor ⁇ nol, hibitane (chlorhexidine gluconate), PCMX (chorloxylenol), and guaiacol are disclosed.
  • antimicrobial agents respectively defined as cationic antimicrobial agents, benzene derivatives, phenols, and amines, and certain naturally occuring substances, for example certain plant extracts.
  • cationic antimicrobial agents include pyridinium and isoquinolinium compounds, guanides, for example bis- biguanides, and a range of quaternary ammonium salts.
  • a number of cationic antimicrobial agents have shown activity against human oral bacteria which has promoted their use in the treatment or prophylaxis of periodontal diseases and dental caries.
  • benzene derivatives such as benzoic acid, benzyl alcohol, dibromopropamidine isethionate, 2,4-dichlorobenzyl alcohol, and hyroxy benzoates including methy-, ethyl-, propyl- 8 n-butyl-, n-heptyl- and benzyl-p-hydroxy benzoates; phenols such as amylmetacresol, chlorochresol, phenol, trichlorophenol and creosote; amines such as hexamine; bis-biguanides such as chlorhexidine hydrochloride; quaternary ammonium compounds such as benzalkonium chloride, dequilinium chloride, domiphen bromide and cetrimide; pyrimidines such as hexetidine citrate; glycerol esters such as glycerol m ⁇ nolaurate; dyclonine hydrochloride; miconazole; mupir
  • the present invention provides the use of these substances hereinbefore identified in the manufacture of a medicament for the treatment of gastric disorders associated with Helicobacter pylori.
  • substances 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
  • 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.
  • EP-A-0 403 048 (Warner-Lambert) describes medicated compositions comprising sucralfate and a therapeutically effective amount of a medicament which is, a) substantially water insoluble, or b) a mixture of a water-soluble medicament and a release-delaying material which on admixture forms a substantially water-insoluble medicament.
  • a sucralfate benzoic acid composition against Escherichia coli is described.
  • US 4,615 697 discloses a controlled release composition
  • a treating agent which may be a medicament
  • 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.
  • the present invention relies on the combination or co-administration of an antimicrobial agent which is active against H.pylori selected from the group consisting of cationic antimicrobial agents, for example benzene derivatives such as benzoic acid, benzocaine, hexylresorcinol, benzyl alcohol, dibromopropamidine isethionate, 2,4- dichlorobenzyl alcohol, and hyroxy benzoates including methy-, ethyl-, propyl-, n-butyl-, n-heptyl- and benzyl-p-hydroxy benzoates; phenols such as amylmetacresol, chlorochresol, chloroxylenol, clioquinol, phenol, trichlorophenol and creosote; amines such as hexamine; bis-biguanides such as chlorhexidine gluconate and chlorhexidine hydrochloride; quaternary
  • 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.
  • the antimicrobial agent may for example be co-formulated, suitably by intimate admixture, with a muco-adherent or bioadhesive substance to form a bioadhesive complex.
  • a bioadhesive 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.
  • 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 POLYCARBOPHIL.
  • Antimicrobial agents effective against H.pylori may alternatively be formulated to produce a floating alginate raft within the stomach.
  • Such formulations may include sohd 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.
  • beadlets or granules are coated, layered, or form an intimate, homogeneous matrix with release-delaying materials.
  • dosage forms may be prepared using conventional techniques known in the art.
  • 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.
  • 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.
  • 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.
  • the release of the antimicrobial agent may be altered by changing its 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 ⁇ udragit') 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.
  • Preferred antimicrobial agents for use in the treatment of gastrointestinal disorders associated with H. pylori are cationic antimicrobial agents, in particular hexetidine and hexetidine citrate, chlorhexidine gluconate and chlorhexidine hydrochloride, benzalkonium chloride, dequilinium chloride, cetyl pyridinium chloride, cetrimide, and domiphen bromide.
  • the antimicrobial agent is present in compositions of the invention in an appropriate amount to provide an effective dose, which will depend on the pharmacological properties of the corn-pound employed. Normally a single dose used to treat an adult human will provide from 0.0 lmg to lOOmg, generally 0.1 to 15mg of antimicrobial agent.
  • a suitable single dose of chlorhexidine hydrochloride lies in the range of 0.1 to 100 mg, typically 1.0 to 15mg.
  • a suitable single dose for cetylpyridinium chloride lies in the range 0.01 to 100 mg, typically 0.1 to lOmg.
  • compositions containing sucralfate as muco adherent a suitable single dose lies in the range 0.5 to 20g, typically 1.0 to 8.0g.
  • 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.
  • the activity of the antimicrobial agents 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.
  • antimicrobial agents and compositions containing antimicrobial agents 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.
  • EDTA ethylenediaminetetraacetic acid
  • CaEDTA CaEDTA
  • CaNa2EDTA CaNa2EDTA
  • Suitable surfactants include ionic and non-ionic surfactants.
  • 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.
  • compositions of the invention may be prepared by conventional pharmaceutical techniques.
  • 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.
  • MIC Minimum Inhibitory Concentration
  • cetyl pridinium chloride 3mg citric acid (anhydrous) 2.2g sodium bicarbonate 2.3g sodium carbonate 0.5g

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Abstract

A pharmaceutical composition for use in the treatment of gastric disorders associated with Helicobacter pylori comprising an antimicrobial agent optionally co-administered with a release-delaying substance.

Description

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF GASTRITIS
The present invention relates to pharmaceutical compositions of antimicrobial agents active against Helicobacter pylori and their use in the treatment of gastrointestinal disorders associated with Helicobacter pylori infection.
Helicohacter pylori (formerly known as CaiPPytobacter 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 ulceration. Reviews on the state of the art include those by C.A.M. McNulty in _I. Infection. 1986, 12, 107-113, and by C.S. Goodwin fit al. in -L £_____. £a__h__ ., 1986, 2SL, 353-365.
H.pylori is known to be susceptible to a large number of antimicrobial agents in vitro. Furthermore, several workers have shown that treatment of gastritis with antimicrobial agents, for example β-lactam antibiotics such as amoxycillin, or bismuth salts, leads to eradication of the associated H.pylori organisms in vivo.
GB 2 243 549 A (Reckitt & Colman), published November 6, 1991, 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 -y^saά. infection. According to GB 2 243 549 A, the medicament may be formulated as a gastric sustained release composition having prolonged residence time within the stomach and continuously releasing triclosan during that time. Triclosan compositions formulated so as to produce floating alginate rafts within the stomach, or as muco-adherent coated granules or spheroids, are identified as suitable sustained release compositions.
GB 2 243 549 A further describes, for tablets, a co-formulation and, for tablet or liquid presentations, co-administration with a pharmaceutically acceptable solid carboxylic acid, or salt thereof, in order to overcome the tendency for elevated stomach pH, observed with certain patients suffering from Helicobacter pylori infections, to reduce the ability for alginate rafts to float. Citric acid is referred to as a suitable acid for this purpose.
For comparative purposes, GB 2 243 549 A discloses the in vitro testing of 11 antimicrobial compounds in addition to triclosan versus Helicobacter pylori. based on methods described by McNulty et al. ( Antimicrobial Agents & Chemotherapy, 2_ 837-838, 1985). MIC results for triclosan, tinidazole, cetalkonium chloride, cetyl pyridinium chloride, clioquinol, hexetidine, dichlorophen, halquinol, 4-hexyl recorάnol, hibitane (chlorhexidine gluconate), PCMX (chorloxylenol), and guaiacol are disclosed.
J. Pediatr. Gastroenterol. Nutr., 9(1), 46-8, (1989), describes Helicobacter pylori as being extremely sensitive to the anti-infective activity of benzocaine, a commonly used topical anaesthetic.
It has now been found that activity against Helicobacter pylori is also conferred by a range of readily available substances, in particular substances which already have utililty as antimicrobial agents.
Included within this range of substances are groups of antimicrobial agents respectively defined as cationic antimicrobial agents, benzene derivatives, phenols, and amines, and certain naturally occuring substances, for example certain plant extracts.
Included within the group known as cationic antimicrobial agents are pyridinium and isoquinolinium compounds, guanides, for example bis- biguanides, and a range of quaternary ammonium salts. A number of cationic antimicrobial agents have shown activity against human oral bacteria which has promoted their use in the treatment or prophylaxis of periodontal diseases and dental caries.
Examples of substances which have now been found to have in vitro activity against sixains of Helicobacter pylori resident in the gastric and duodenal mucosa, and hence to have potential utility for the in vivo treatment of gastric disorders associated with Helicobacter pylori. include benzene derivatives such as benzoic acid, benzyl alcohol, dibromopropamidine isethionate, 2,4-dichlorobenzyl alcohol, and hyroxy benzoates including methy-, ethyl-, propyl-8 n-butyl-, n-heptyl- and benzyl-p-hydroxy benzoates; phenols such as amylmetacresol, chlorochresol, phenol, trichlorophenol and creosote; amines such as hexamine; bis-biguanides such as chlorhexidine hydrochloride; quaternary ammonium compounds such as benzalkonium chloride, dequilinium chloride, domiphen bromide and cetrimide; pyrimidines such as hexetidine citrate; glycerol esters such as glycerol mόnolaurate; dyclonine hydrochloride; miconazole; mupiroώn; polynoxylin; povidone iodine; sorbate; and natural products such as garlic and tea tree oil.
Accordingly, the present invention provides the use of these substances hereinbefore identified in the manufacture of a medicament for the treatment of gastric disorders associated with Helicobacter pylori.
It has been found that treatment of H.pylori associated gastritis with antimicrobial agents given by a conventional oral dosing regimen may require a prolonged course of therapy to be effective. Furthermore, follow-up of patients cleared of H-i_y____i infection by antimicrobial treatment has shown that relapse (rather than reinfection) can be a problem.
In another aspect of the invention, substances 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 antiacid 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.
EP-A-0 403 048 (Warner-Lambert) describes medicated compositions comprising sucralfate and a therapeutically effective amount of a medicament which is, a) substantially water insoluble, or b) a mixture of a water-soluble medicament and a release-delaying material which on admixture forms a substantially water-insoluble medicament. The in-vitro testing of a sucralfate benzoic acid composition against Escherichia coli is described.
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 relies on the combination or co-administration of an antimicrobial agent which is active against H.pylori selected from the group consisting of cationic antimicrobial agents, for example benzene derivatives such as benzoic acid, benzocaine, hexylresorcinol, benzyl alcohol, dibromopropamidine isethionate, 2,4- dichlorobenzyl alcohol, and hyroxy benzoates including methy-, ethyl-, propyl-, n-butyl-, n-heptyl- and benzyl-p-hydroxy benzoates; phenols such as amylmetacresol, chlorochresol, chloroxylenol, clioquinol, phenol, trichlorophenol and creosote; amines such as hexamine; bis-biguanides such as chlorhexidine gluconate and chlorhexidine hydrochloride; quaternary ammonium compounds such as benzalkonium chloride, cetalkonium chloride, cetyl pyridinium chloride, dequilinium chloride, domiphen bromide and cetrimide; pyrimidines such as hexetidine and hexetidine citrate; glycerol esters such as glycerol monolaurate; dyclonine hydrochloride; miconazole; mupiroάn; polynoxylin; povidone iodine; sorbate; and natural products such as garlic and tea tree oil, with one or more substances providing a sustained release and/or prolonged retention of the antimicrobial agent in the stomach, so as to overcome, or at least mitigate, the disadvantages associated with conventionally formulated antimicrobial agents and provide an effective treatment for H.pylori infections of the gastric and duodenal mucosa in humans and domestic animals. In this further aspect, the present invention also provides a pharmaceutical composition comprising one or more such antimicrobial agents effective against H.pylori organisms, and one or more substances providing a sustained release and/or prolonged retention of the antimicrobial agent in the stomach.
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.
The antimicrobial agent 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 POLYCARBOPHIL.
Antimicrobial agents effective against H.pylori may alternatively be formulated to produce a floating alginate raft within the stomach. Such formulations may include sohd 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 antimicrobial agent may be altered by changing its 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 Εudragit') 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.
Preferred antimicrobial agents for use in the treatment of gastrointestinal disorders associated with H. pylori are cationic antimicrobial agents, in particular hexetidine and hexetidine citrate, chlorhexidine gluconate and chlorhexidine hydrochloride, benzalkonium chloride, dequilinium chloride, cetyl pyridinium chloride, cetrimide, and domiphen bromide.
The antimicrobial agent is present in compositions of the invention in an appropriate amount to provide an effective dose, which will depend on the pharmacological properties of the corn-pound employed. Normally a single dose used to treat an adult human will provide from 0.0 lmg to lOOmg, generally 0.1 to 15mg of antimicrobial agent.
For example, a suitable single dose of chlorhexidine hydrochloride lies in the range of 0.1 to 100 mg, typically 1.0 to 15mg. A suitable single dose for cetylpyridinium chloride lies in the range 0.01 to 100 mg, typically 0.1 to lOmg.
For compositions containing sucralfate as muco adherent, a suitable single dose lies in the range 0.5 to 20g, typically 1.0 to 8.0g.
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 antimicrobial agents 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, antimicrobial agents and compositions containing antimicrobial agents 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 invention will now be illustrated by the following examples.
Examnle 1
Activity of Cationic Antimicrobial Agents against Helicobacter Pvlori
The Minimum Inhibitory Concentration (MIC) of representative antimicrobial agents of the invention against human strains ofH.pylori (H.pylori NCTC 11916 & 11637) were assessed using a spiral plater and automatic agar plate pourer, according to the method of Wallace A.S. and Corkill J.E. (J. Microbiol. Methods, KL 303-310, 1989).
MIC values were calculated according to the equation for the Archimedes spiral.
Figure imgf000011_0001
A. A tablet prepared according to standard methods including chlorhexidine hydrochloride (5mg) and sucralfate (lOOOmg). B. A tablet prepared according to standard methods including cetylpyridinium chloride (3mg) and sucralfate (lOOOmg).
C. An effervescent powder containing per 5g dose:
cetyl pridinium chloride 3mg citric acid (anhydrous) 2.2g sodium bicarbonate 2.3g sodium carbonate 0.5g
D. An effervescent powder containing per 5g dose:
domiphen bromide 6mg citric acid (anhydrous) 2.2g sodium bicarbonate 2.3g sodium carbonate 0.5g
E. An effervescent powder containing per 5g dose:
chloriiexidine HCL 5mg citric acid (anhydrous) 2.2g sodium bicarbonate 2.3g sodium carbonate 0.5g
F. A tablet containing cetyl pyridinium chloride (3mg) and alginate (1.5g).
(Dosage : 2 tablets t.i.d.)
G. A tablet containing domiphen bromide (6mg) and alginate (1.5g). (Dosage : 2 tablets 6.i.d.)
H. A tablet containing chlorhexidine HCl (5mg) and alginate (1.5g). (Dosage : 2 tablets t.i.d.)

Claims

1. The use of an antimicrobial agent selected from benzoic acid, benzyl alcohol, dibromopropamidine isethionate, 2,4-dichlorobenzyl alcohol, a hyroxy benzoate, amylmetacresol, chlorochresol, phenol, trichlorophenol, creosote, hexamine, chlorhexidine hydrochloride, benzalkonium chloride, dequilinium chloride, domiphen bromide, ∞trimide, hexetidine citrate, glycerol monolaurate, dyclonine hydrochloride, miconazole, mupirodn, polynoxylin, povidone iodine, sorbate, garlic and tea tree oil, for the manufacture of a medicament for the treatment of gastric disorders associated with H__liΩ__2____t__cι_ ____i.
2. The use of an antimicrobial agent selected from benzoic add, benzocaine, hexylresorcinol, benzyl alcohol, dibromopropamidine isethionate, 2,4-dichlorobenzyl alcohol, a hyroxy benzoate, amylmetacresol, chlorochresol, chloroxylenol, dioquinol, phenol, trichlorophenol, creosote, hexamine, chlorhexidine gluconate, chlorhexidine hydrochloride, benzalkonium chloride, cetalkonium chloride, cetyl pyridinium chloride, dequilinium chloride, domiphen bromide, cetrimide, hexetidine, hexetidine dtrate, glycerol monolaurate, dyclonine hydrochloride, miconazole, mupirodn, polynoxylin, povidone iodine, sorbate, garlic and tea tree oil, for the manufacture of a medicament for the treatment of gastric disorders associated with Helicobacter jyifi∑ characterised in that the antimicrobial agent is combined with one or more substances providing a sustained release and/or prolonged retention time of the antimicrobial agent in the stomach.
3. The use of an antimicrobial agent selected from benzoic add, benzocaine, hexylresorcinol, benzyl alcohol, dibromopropamidine isethionate, 2,4-dichlorobenzyl alcohol, a hyroxy benzoate, tridosan, amylmetacresol, chlorochresol, chloroxylenol, dioquinol, phenol, trichlorophenol, creosote, hexamine, chlorhexidine gluconate, chlorhexidine hydrochloride, benzalkonium chloride, cetalkonium chloride, cetyl pyridinium chloride, dequilinium chloride, domiphen bromide, cetrimide, hexetidine, hexetidine dtrate, glycerol monolaurate, dyclonine hydrochloride, miconazole, mupirodn, polynoxylin, povidone iodine, sorbate, garlic and tea tree oil, for the manufacture of a medicament for the treatment of gastric disorders assodated with Helicobacter pylori. characterised in that the antimicrobial agent is combined with at least one of a chelating agent or a surfactant. 4. A pharmaceutical composition comprising an antimicrobial agent selected from benzoic add, benzocaine, hexylresorcinol, benzyl alcohol, dibromopropamidine isethionate, 2,
4-dichlorobenzyl alcohol, a hyroxy benzoate, amylmetacresol, chlorochresol, chloroxylenol, dioquinol, phenol, trichlorophenol, creosote, hexamine, chlorhexidine gluconate, chlorhexidine hydrochloride, benzalkonium chloride, cetalkonium chloride, cetyl pyridinium chloride, dequilinium chloride, domiphen bromide, cetrimide, hexetidine, hexetidine dtrate, glycerol monolaurate, dydonine hydrochloride, miconazole, mupirodn, polynoxylin, povidone iodine, sorbate, garlic and tea tree oil, and one or more substances providing a sustained release and/or prolonged retention time of the antimicrobial agent in the stomach.
5. A pharmaceutical composition as daimed in claim 4 wherein the one or more substances providing a sustained release and/or prolonged retention time of the antimicrobial agent in the stomach is a muco-adherent or bioadhesive substance.
6. A pharmaceutical composition as daimed in claim 5 wherein the one or more substances providing a sustained release and/or prolonged retention time of the antimicrobial agent in the stomach is a natural gum, a plant extract, sucralfate, a cellulose derivative, or an acrylic add or methacrylic add derivative,
7. A pharmaceutical composition as daimed in clai 6 wherein the antimicrobial agent and the muco-adherent or bioadhesive substance are co- formulated as an intimate mixture.
8. A pharmaceutical composition comprising an antimicrobial agent selected from benzoic add, benzocaine, hexylresorcinol, benzyl alcohol, dibromopropamidine isethionate, 2,4-dichlorobenzyl alcohol, a hyroxy benzoate, triclosan, amylmetacresol, chlorochresol, chloroxylenol, dioquinol, phenol, trichlorophenol, creosote, hexamine, chlorhexidine gluconate, chlorhexidine hydrochloride, benzalkonium chloride, cetalkonium chloride, cetyl pyridinium chloride, dequilinium chloride, domiphen bromide, cetrimide, hexetidine, hexetidine dtrate, glycerol monolaurate, dydonine hydrochloride, miconazole, mupirodn, polynoxylin, povidone iodine, sorbate, garlic and tea tree oil, and at least one of a chelating agent or a surfactant.
9. A pharmaceutical composition as daimed in claim 8 wherein the chelating agent is ethylenediaminetetraacetic add (EDTA), CaEDTA, and CaNa2EDTA, EGTA or dtrate.
10. A process for preparing a pharmaceutical composition as daimed in any one of daims 5 to 9 comprising the admixture of the antimicrobial agent with one or more substances providing a sustained release and/or prolonged retention time of the antimicrobial agent in the stomach, and/or at least one of a chelating agent or a surfactant, and a pharmaceutically acceptable carrier.
PCT/GB1992/000551 1991-04-15 1992-03-25 Pharmaceutical composition for the treatment of gastritis WO1992018111A2 (en)

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