Classifications

• • 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
  • A61K31/425—Thiazoles
• • 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
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• • 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
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
  • A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
• • 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
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• This invention relates to the treatment of gastric disorders and pharmaceutical compositions for use therein. More particularly the invention relates to the local 5 treatment of gastric disorders, especially acute gastric disorders such as acid indigestion, heartburn and gastritis, and gastric and peptic ulcer, using orally administrable pharmaceutical compositions comprising a histamine H2-receptor antagonist contained within a drug delivery system. Compositions for use in the invention are specifically adapted to provide local delivery across the stomach wall to 0 the H2-receptor on the parietal cell.
• Histamine H2-receptor antagonists for example cimetidine, ranitidine, nizetidine and famotidine, reduce acid secretion by acting directly on the acid-secreting parietal cell located within the gastric gland of the stomach wall. Histamine H2-receptor 5 antagonists are widely used in the treatment of conditions where there is an advantage in lowering gastric acidity.
• Oral dosing is the preferred route for administration of histamine H2-receptor antagonists such as cimetidine and ranitidine.
• histamine H2-receptor antagonists such as cimetidine and ranitidine.
• these substances have a 0 pronounced bitter taste which is disadvantageous in promoting patient compliance.
• Various methods have been described for masking the bitter taste associated with drug substances, including histamine H2-receptor antagonists. These methods include the use of ion-exchange resins.
• JP 1 242 522-A (Fujisawa) describes the preparation of a taste-masking suspension 30 containing cimetidine adsorbed onto a cation exchange resin.
• histamine H2-receptor antagonists act systemically, i.e. the histamine H2-receptor antagonist is delivered to the parietal cell receptor from the blood. It has recently been shown that histamine H2-receptor antagonist compositions 35 can be formulated to promote local delivery of the histamine H2-receptor antagonist directly through the stomach wall.
• International Patent Application Publication No. WO 92/00102 (Beecham Group) describes oral treatment of gastric disorders using a histamine H2-receptor antagonist in combination with an antacid to promote local delivery of the histamine H2- receptor antagonist to the receptor of the parietal cell wall.
• stomach wall receptor site bioavailability of the histamine H2-receptor antagonist is beneficial in increasing the capacity of the histamine H2-receptor antagonist to reduce acid secretion compared with that of histamine H2-receptor antagonist alone.
• the approach of locally delivering H2-receptor antagonists via the stomach mucosa is of particular benefit in the self-medication of acute, self-limiting gastric disorders such as hyperacidity.
• Local delivery according to the invention which increases the concentration of drug at the H2-receptor of the parietal-cell and renders the histamine H2-receptor antagonist effective at low dosage levels, is regarded as of particular benefit in the treatment of these disorders.
• An increase in the capacity to reduce acid-secretion is advantageous in the treatment of ulcer patients, in particular hypersecreting patients, in the treatment of those patients diagnosed as histamine H2-receptor antagonist non-responders, and also to reduce the onset-phase of single-dose, self-medication for acute gastric disorders, for example gastric orders due to hyperacidity.
• sucralfate has been shown to act by forming a bioadhesive gel structure which is believed to provide a local protective barrier. It has been reported that sucralfate does not interfere with the absorption of histamine H2-receptor antagonists. Clinical studies have indicated a combination therapy to be of potential benefit.
• EP-A-0 286781 (Heumann Pharma) relates to pharmaceutical preparations with cytoprotective effect on the gastrointestinal tract containing a combination of a histamine H2-receptor antagonist and an antacid substance which is able to give functional cytoprotection.
• Sucralfate is identified as an example of the antacid substance. It is described as giving functional cytoprotection but having a comparatively low acid-netutralising effect.
• 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 medicament is selected from the group consisting of inter alia antacids and anti-ulcer medicaments.
• Compositions comprising sucralfate plus antacid and sucralfate plus an anti-ulcer medicament are described as cytoprotective compositions, useful in the treatment of peptic ulcers by forming an ulcer-adherent protective gel barrier.
• EP-A-0 193 400 (Reckitt and Colman) describes pharmaceutical compositions comprising mixtures of a histamine H2-receptor antagonist and sodium polyacrylate in the weight ratio 10 : 1 to 1 : 10.
• the compositions are described for use in the treatment of gastritis or of gastro-duodenal ulcers.
• the compositions may include an antacid. Use of antacid is described as resulting in a reduction in the viscosity of the liquid compositions, thereby providing some degree of viscosity control in the design of readily pourable liquid preparations.
• 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 to mucous membranes in the presence of water.
• Cimetidine is listed as an example of a medicament.
• WO 92/09286 (Beecham Group) describes an orally administrable pharmaceutical composition comprising a histamine H2-receptor antagonist adapted for local delivery of the histamine H2-receptor antagonist and formulated so as to adhere to the mucosal surface of the stomach wall.
• the application describes compositions comprising histamine H2-receptor antagonist and a bioadhesive material formulated as an intimate mixture and optimally buffered to confer a pH substantially equal to that of the pKa of the histamine H2-receptor antagonist.
• histamine H2-receptor antagonist/ion-exchange complex is not only effective in masking the bitter taste of the histamine H2-receptor antagonist in the mouth but also has utility as a dosage form for prolonging the residence time of the drug within the stomach by controlling the release of histamine H2-receptor antagonist in the stomach and thus enhancing local delivery of the histamine H2-receptor antagonist.
• the present invention provides the use of an orally administrable pharmaceutical composition comprising a drug/ion-exchange complex formed between a histamine H2-receptor antagonist and a cationic ion-exchange resin, for the manufacture of a medicament for the treatment of gastric disorders, characterised in that histamine H2-receptor antagonist is released from the complex in the stomach in a controlled manner whereby residence time of the histamine H2**receptor antagonist in the stomach is prolonged.
• Prolonged residence time of the histamine H2-receptor antagonist in the stomach has the effect of promoting local absorption of the drug through the stomach wall.
• the invention also provides a method of treatment of gastric disorders comprising administering to a sufferer an effective amount of a pharmaceutical composition comprising a drug/ion-exchange complex formed between a histamine H2-receptor antagonist and a cationic ion-exchange resin, whereby histamine H2-receptor antagonist is released from the complex in the stomach in a controlled manner and residence time of the histamine H2-receptor antagonist in the stomach is prolonged, such that absorption of the histamine H2-receptor antagonist locally through the stomach wall is promoted.
• the invention provides a pharmaceutical composition for use in the treatment of gastric disorders which comprises a drug/ion-exchange complex formed between a histamine H2-receptor antagonist and a cationic ion-exchange resin, whereby histamine H2-receptor antagonist is released from the complex in the stomach in a controlled manner and residence time of the histamine H2-receptor antagonist in the stomach is prolonged such that absorption of histamine H2-receptor antagonist through the stomach wall is promoted.
• Histamine H2-receptor antagonists for use in compositions of the invention include cimetidine, ranitidine and famotidine, preferably cimetidine and ranitidine, and especially cimeditine.
• a wide range of cationic ion-exchange resins is potentially available to form drug- resin complexes for use in the present invention.
• Suitable pharmaceutically acceptable cationic ion-exchange resins are commercially available and include a range of synthetic cationic ion-exchange resins with different polymeric matrices which may be cross-linked.
• a synthetic cationic ion-exchange resin may for example be a polymer of styrene, or acrylic or methacrylic acid, and the resin may derive its exchange activity from either weakly or strongly acidic groups such as carboxylic acid or sulphonic acid groups.
• Ion-exchange resins particularly suitable for use with histamine H2-receptor antagonists include strongly cationic resins having sulphonic acid groups on a polystryene polymer matrix, which resins are suitably cross-linked, preferably by a divinyl or polyvinyl compound such as divinylbenzene.
• T e proportion of cross- linking may vary from 1 to 20%, suitably from 1 to 12%, and preferably from 7 to
• Suitable resins are those commercially available under the trade names Amberlite and Duolite from Rohm and Haas Co. and Dowex from the Dow Chemical Co..
• the resin may be in either acid form or in the form of a salt with an alkali metal such as sodium or potassium.
• the histamine H2-receptor antagonist may be presented for complex formation in the form of a pharmaceuticaly acceptable acid addition salt, for example the hydro-chloride salt, in which case the chosen resin will be in its salt form.
• the histamine H2-receptor antagonist may presented as the free base in which case the resin will be in its acid form.
• drug-resin complexes for use in the present invention are those formed between a histamine H2-receptor antagonist salt, suitably the hydrochloride salt, and the sodium form of a sulphonated styrene-divinylbenzene resin, for example
• Amberlite IRP-69 or the potassium form of a methacrylic acid-divinylbenzene resin, for example Amberlite IRP-88.
• Further examples include those formed between a histamine H2-receptor antagonist free base and a methacrylic acid-divinybenzene resin in the free acid form, for example Amberlite IRP-64.
• the scope of invention is not limited to any particular ratios of the histamine H2- receptor antagonist to ion-exchange resin. It has however been found that optimal absorption and release of histamine H2-receptor antagonist is achieved when the histamine H2-receptor antagonist content of the drug-resin complex is up to 50% by weight, based on the histamine H2-receptor antagonist free base, preferably between 5% and 35% by weight.
• the particle size of the ion-exchange resin influences not only the diffusion rate of the histamine H2-receptor antagonist from the drug-resin complex but also the retention time of the resinate per se in the stomach.
• a number of commercially available ion-exchange resins have particle size distributions which favour prolonged gastric residence times and, unless otherwise indicated by the requirements of particular formulation types, these are preferred.
• Drug preparations based on ion-exchange complexes wherein the resinate particle size is greater than about 120 ⁇ m are known to impart a gritty texture which renders them unpalatable if formulated as liquid suspensions or as chewable tablets.
• resinates containing a significant proportion of particle sizes above 120 ⁇ m are contra-indicated, in order to provide a product for oral consumption having good mouth feel.
• Formulation types such as swallow- tablets, lozenges or pills are not however constrained with respect to particle size for reasons of mouth feel. It is however generally preferred to use a resinate with a maximum particle size no greater than 120 ⁇ m and particularly preferred to use a resinate with a maximum particle size no greater than 65 ⁇ m.
• Adsorption of histamine H2-receptor antagonist onto the ion-exchange resin may be carried out by standard procedures well known in the art, for example as described in US 2,990,332.
• a commercially available ion-exchange resin may be added directly to a solution of histamine H2-receptor antagonist in an appropriate solvent.
• Pre-conditioning of ion-exchange resins prior to complex formation may be desirable in order to remove any potentially toxic extractibles and/or to facilitate easier processing and analysis of the resulting resinate.
• the histamine H2-receptor antagonist/ion- exchange complex is formulated with a material which will further prolong the retention time of the histamine H2-receptor antagonist within the ⁇ stomach, for example by increasing the volume of solids in the stomach with a bulking agent, through floatation by formulation with, for example alginate materials to produce a floating raft, or through bioadhesion by incorporation of a bioadhesive material.
• the histamine H2-receptor antagonist/ion-exchange complex is formulated with a bioadhesive agent to form, in situ, a bioadhesive complex, locally targeting the histamine H2-receptor antagonist to the stomach wall.
• the invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a drug/ion-exchange complex formed between a histamine H2-receptor antagonist and a cationic ion-exchange resin, and a material which prolongs the residence time of the histamine H2-receptor antagonist within the stomach.
• Bioadhesive materials suitable for use compositions of the present invention for further prolonging residence time 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.
• compositions for use in the invention are buffered by incorporation of a buffering component.
• a buffering component will be present in an amount which confers a gastric pH of no less than about 3.5 or alternatively a gastric pH at or around no less than 4 pH units, preferably 2 to 3 pH units, below the pKa of the histamine H2-receptor antagonist.
• a suitable gastric pH lies in the range pH 3.5 to 7.5.
• the buffering component is suitably an antacid and preferably has equilibrium pH, acid neutralising capacity and gastric residence time values which provide a pH profile with time conferring a gastric pH no less than about 3.5 or alternatively a gastric pH at or around no less than 4 pH units below the pKa of the histamine H2-receptor antagonist.
• a pharmaceutical composition comprising a drug/ion-exchange resin complex formed between a histamine H2-receptor antagonist and a cationic ion-exchange resin, and a buffering component, also forms part of the invention.
• Local delivery of histamine H2-receptor antagonist through the stomach wall according to the present invention is particularly enhanced by oral administration of a pharmaceutical composition comprising a drug-resin complex formed between a histamine H2-receptor antagonist and a cationic ion-exchange resin, further comprising both a material which enhances the residence time of the histamine H2- receptor antagonist within the stomach and a buffering component.
• the invention therefore provides a composition
• a composition comprising a drug/ion-exchange resin complex formed between a histamine H2-receptor antagonist and a cationic ion-exchange resin, a residence time enhancing agent, suitably a bioadhesive material, and a buffering component, suitably an antacid.
• Suitable buffering agents for use in compositions of the invention include antacids, for example antacids such as aluminium hydroxide, magnesium hydroxide, aluminium hydroxide-magnesium carbonate co-dried gel, magnesium carbonate, magnesium oxide, magnesium aluminium silicate, magnesium trisilicate, sodium bicarbonate, calcium carbonate, bismuth carbonate, alkali metal salts of citric, tartaric, benzoic, sorbic and phosphoric acid, and combinations thereof.
• pKa values for known histamine H2-receptor antagonists are readily available from pharmacological publications.
• Conventional histamine H2-receptor antagonist therapies act systemically and drug is distributed to all parts of the body via the bloodstream. Hence, it will be appreciated that non-target body tissues are exposed to drug.
• An advantage of a locally targeted drug delivery system is that low doses may be used and thus pharmacologically relevant doses are not delivered to non-target tissues.
• An advantageous feature of the present invention is thus the potential for using reduced dose levels of histamine H2-receptor antagonist.
• the dose level of histamine H2-receptor antagonist may be selected according to the potency of the antagonist on a weight basis and according to the severity of the condition.
• the histamine H2-receptor antagonist is cimetidine or ranitidine it may be present in an amount from about 1 mg to 800 mg per dosage form, typically from about 5 mg to 400 mg, for example 20, 50, 100, 150, 200 or 400 mg.
• the histamine H2-receptor antagonist is famotidine it may be present in an amount from about 0.25mg to 20 mg per dosage form, typically from about 0.5mg to 10 mg.
• treatment with the present compositions provides a more rapid onset of action which renders them particularly suitable for the treatment of acute gastritis.
• a further aspect of the invention is that the amount of antacid present in any given composition is independent of the dose of histamine H2-receptor antagonist.
• a bioadhesive material where present, for example sucralfate, may be present in an amount from about 100 mg to 1500 mg per dosage form, typically from about 800 mg to 1200 mg, for example 1000 mg. It is a feature of an antacid buffering component that it serves a dual role. In one aspect, in the accepted mode of action of antacids, it brings about relief from the symptoms of excess stomach acidity by neutralisation. In a second aspect, and more importantly, it serves to act as an appropriate buffered vehicle to enhance the absorption of the histamine H2-receptor antagonist. The dose of antacid may be selected to achieve both effects.
• a suitable dose range for magnesium hydroxide or aluminuim hydroxide is from about 150 mg to 3000 mg, for example from about 360 mg to 1800 mg, such as from about 360 mg to 720 mg.
• a suitable dose range for sodium bicarbonate is from about 400mg to 8,000mg for example from about 800 mg to 4000mg, such as from about 800mg to 1600mg.
• compositions for use in the present invention may also-contain one or more pharmaceutically acceptable carriers or excipients.
• Compositions may be formulated for oral administration in solid or liquid form, for example as tablets, capsules, lozenges, granules, powders, suspensions or dispersions. Granules and powders may be ingested directly, or alternatively dispersed in water or other suitable vehicles prior to administration.
• Capsules may be of the hard or soft gelatin type, including chewable soft gelatin capsules.
• compositions may be formulated using conventional carriers or excipients and well established techniques.
• compositions may thus be formulated by admixture with pharmaceutically acceptable vehicles additionally containing, as desired, pharmaceutically acceptable adjuvants including inter alia thickeners, preservatives, and colouring and flavouring agents.
• pharmaceutically acceptable adjuvants including inter alia thickeners, preservatives, and colouring and flavouring agents.
• the present invention includes a pharmaceutical composition
• a pharmaceutical composition comprising a drug/ion-exchange complex formed between a histamine H2-receptor antagonist and a cationic ion-exchange resin, an optional residence time enhancing agent and/or buffering agent, and a pharmaceutically acceptable carrier; and extends to processes for the preparation thereof.
• sucralfate may not be a suitable bioadhesive agent in compositions buffered to pH values above that at which it is capable of forming a bioadhesive gel.
• Examples 1-3 are illustrative of tablet, liquid suspension and powder dosage forms. Tablet formulations may be swallowed for dispersal in the stomach, chewed in the mouth or dispersed in water before consumption. Each Example describes the quantity (in mg) of the representative components in a single dosage form.
• the histamine H2-receptor antagonist and ion-exchange resin are combined in the conventional manner to produce a histamine H2-receptor antagonist/ion-exchange resinate.
• the resinate, and where present, bioadheseive agent and granulated antacid are blended along with conventional ingredients as appropriate such as tabletting aids, fillers and palatability aids and (for tablet formulations) the blend is tabletted on a conventional machine.
• Cimetidine Ion-Exchange Resinate lOg of ion-exchange resin (Amberlite IRP69), milled to a maximum particle size of 63 ⁇ m, was suspended in 43ml of distilled water, to which 43ml of 160mg/ml cimetidine HCl was added. The mixture was agitated for thirty minutes at room temperature. The suspension was spun down in a benchtop centrifuge for ten minutes at 400rpm, and the supernatant was removed. The pellet was resuspended with distilled water and filtered through a GF/B filter. The resinate was dried in an oven at 60°C. The resinate was found to contain 336mg of cimetidine per gram of resinate.

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• 1992
  • 1992-05-26 GB GB929211148A patent/GB9211148D0/en active Pending
• 1993
  • 1993-05-20 JP JP6500295A patent/JPH07507293A/ja active Pending
  • 1993-05-20 CA CA002136623A patent/CA2136623A1/en not_active Abandoned
  • 1993-05-20 AU AU40827/93A patent/AU4082793A/en not_active Abandoned
  • 1993-05-20 EP EP93910246A patent/EP0642340A1/en not_active Withdrawn
  • 1993-05-20 WO PCT/GB1993/001041 patent/WO1993024124A1/en not_active Application Discontinuation
  • 1993-05-24 MX MX9303023A patent/MX9303023A/es unknown
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