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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • 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
  • A61K31/4164—1,3-Diazoles
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • 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
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• • 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
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • 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
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50

Definitions

• the present invention relates to a convenient oral dosage form.
• the invention relates to a convenient oral dosage form containing a drug that is loaded onto an ion-exchange resin and subsequently coated.
• Oral administration represents the preferred route of administration for a wide range of pharmaceutical agents. Particular advantages associated with oral administration include ease of administration and convenience for the patient, both of which can lead to improved patient compliance.
• US 5,032,393 (Glaxo Group Ltd.) teaches that the bitter taste of ranitidine may be masked by forming an adsorbate with a synthetic cation exchange resin. The adsorbate may then be incorporated into compositions for oral administration.
• the synthetic cation exchange resin is selected from copolymers of styrene and divinylbenzene which are sulphonated, and copolymers of methacrylic acid and divinylbenzene.
• US 5,188,825 (lies et al.) discloses a freeze- dried dosage form comprising a water-soluble active agent which is bonded to an ion-exchange resin to form a substantially water insoluble complex.
• the dosage form is prepared by mixing the water insoluble complex with a compatible carrier and freeze-drying the mixture. It is taught that these freeze-dried dosage forms reduce the undesirable odour and / or taste of active agents. Chlorpheniramine maleate and phenylephrine hydrochloride compositions are given as examples.
• an ion-exchange resin can be used as a vehicle onto which a drug compound may be adsorbed for release in a controlled or sustained fashion.
• a drug compound may be adsorbed for release in a controlled or sustained fashion.
• factors which affect the performance of such drug / resin formulations include choosing a suitable resin, optimising the drug load within the resin particles and ensuring that the structural integrity of the particles is maintained.
• the last point is of considerable importance in sustained release formulations since the drug loaded particles tend to swell in a liquid environment which can rupture any coating on the particles with the result that the drug load is dumped in an uncontrolled manner.
• US 4,221 ,778 (Pennwalt Corporation) teaches the use of an impregnating / solvating agent, which is added to the drug / resin particles prior to application of a diffusion barrier coating to retard swelling.
• US 5,186,930 (Schering Corporation) teaches the use of an inner wax coating, applied prior to enteric coating, to prevent swelling.
• an object of the present invention is directed towards the delivery of drug compounds for which sustained delivery may not be of value; for example drugs, such as proton pump inhibitors, that interact in an irreversible manner with the target molecule or receptor.
• an object of the present invention is to provide a controlled release palatable convenient dosage form for the effective delivery of such drugs including proton-pump inhibitors (hereinafter PPIs).
• PPIs proton-pump inhibitors
• PPIs proton-pump inhibitors
• a stable composition for PPIs as well as other acid labile active ingredients.
• a preparation containing a drug / resin complex which may be used to deliver the active ingredient to a region of specific pH. Disclosure of Invention
• One aspect of the invention is a convenient oral dosage form that includes a multiparticulate composition and each particle includes an active ingredient reversibly adsorbed onto an ion exchange material to form an active ingredient-resin complex and each core is coated with a polymeric coating material.
• the ion exchange resin can be either a cation exchange resin or an anion exchange resin.
• the active ingredient can be entrapped with the ion exchange material in the core.
• the active ingredient can be one with a strong and unpleasant taste or odour or an acid labile compound.
• the polymeric coating can be a pH dependent or independent polymer and can include a combination or two or more polymeric materials.
• the oral dosage form provides taste masking for an active ingredient having a strong and unpleasant taste or odour.
• the oral dosage form is a controlled release dosage form such as a delayed release dosage form.
• aspects of the invention include methods of manufacturing the oral dosage form as well as final oral dosage forms that can be either solid or liquid oral dosage forms.
• Convenient oral dosage forms such as suspensions, syrups, sprinkles, fast melt tablets, effervescent tablets and fast dissolving tablets are readily acceptable to patients resulting in increased patient compliance for a given therapeutic regimen.
• the present invention allows for the presentation of acid labile drugs and drugs of unpleasant odour or taste into a range of different palatable convenient dosage forms.
• the invention is based on loading the drug, be it acid labile or unpleasant tasting, onto an ion exchange resin of opposite charge, coating the discrete resin particles with either a taste masking or enteroprotective coating and incorporating the resulting coated drug loaded resin particles into the convenient oral dosage form.
• the oral dosage form of the present composition comprises a plurality of particles, each particle having a core containing an active ingredient or a pharmaceutically acceptable salt thereof and a coating material coated onto the core; wherein the core further comprises an ion exchange resin material, the active ingredient or a pharmaceutically acceptable salt thereof being reversibly adsorbed onto the ion exchange resin material to form an ion exchange resin drug complex.
• active ingredient or “drug”, used interchangeably herein, includes any drug compound that is either acid labile or which is characterised by an unpleasant odour or taste and which can be bound to an ion exchange resin may be used in the present invention.
• the combination of complexing the drug with an ion-exchange resin and coating the resultant drug-resin complex in accordance with the invention provides good taste masking and facilitates the incorporation of the drug into dosage forms for oral administration.
• Complexing the drug with an ion-exchange resin prevents leaching of drug from the formulation and thus the likelihood of a bitter taste in the case of a formulation such as a fast melt tablet or liquid formulation.
• Representative drugs of unpleasant taste or odour include, but are not limited to, H 2 receptor antagonists, antibiotics, analgesics, cardiovascular agents, peptides or proteins, hormones, anti-migraine agents, anti-coagulant agents, anti-emetic agents, anti-hypertensive agents, narcotic antagonists, chelating agents, anti-anginal agents, chemotherapy agents, sedatives, anti-neoplasties, prostaglandins, antidiuretic agents and the like.
• Typical drugs include, but are not limited to, nizatidine, cimetidine, ranitidine, famotidine, roxatidine, etinidine, lupitidine, nifentidine, niperitone, sulphotidine, tuvatidine, zaltidine, erythromycin, erythromycin derivatives such as for example ketolide ( 1 1 , 12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0-methyl- alpha-L-ribohexopyranosyl)oxy)-6-0-methyl-3-oxo- 12, 1 1 - (oxycarbony l(4-(4-(4-(3-pyridinyl)- 1 H-imidazol- 1 -yl)butyl)imino)) erythromycin), penicillin, ampicillin, roxithromycin, clarithromycin, psylium, ciprofloxacin, theophylline, nife
• the combination of complexing the drug with an ion-exchange resin and coating the resultant drug-resin complex in accordance with the invention provides protection for the drug from the acid environment of the stomach upon ingestion and facilitates the incorporation of the drug into dosage forms for oral administration.
• Acid labile drugs include those drug substances that are adversely affected by exposure to acidic media.
• Representative acid labile drugs include, but are not limited to proton pump inhibitors in general, including benzimidazole compounds, more particularly substituted 2- pyridyl methyl sulfinyl benzimidazoles, either substantially in the form of one optically pure enantiomer or, in the form of a mixture of enantiomers or racemate where applicable, and pharmaceutically acceptable salts thereof.
• Substituted 2-pyridyl methyl sulfinyl benzimidazoles may typically contain a chiral centre when the carbon atom of the methyl sulfinyl bridge between the benzimidazole and pyridyl moieties is bonded to four different substituent groups.
• the active ingredient is a substituted 2-pyridyl methyl sulfinyl benzimidazole compound. More preferably the active ingredient is selected from the group consisting of omeprazole, perprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole. Most preferably the active ingredient is omeprazole.
• Acid labile active ingredients other than PPIs may also benefit from the protection afforded by the adsorption of the active onto an ion exchange material and entrapment on or within coated resin particles.
• An example of such an acid labile active ingredient, which is not a PPI, is erythromycin which is known to loose its antibacterial activity at pH lower than 5.5.
• Ion-exchange resin materials suitable for use in accordance with the present invention include any ion-exchange resin which is capable of binding the drug, including, for instance, anionic and cationic resin materials.
• the ion- exchange resin is suitably a cation exchange resin material. That is to say, a resin having a predominantly negative charge along the resin backbone, or a resin having a pendant group suitable for cation exchange, and which has an affinity for positively charged ions or cationic species.
• Typical of such cation exchange resins include resins having polymer backbones comprising styrene - divinyl benzene colpolymers, methacrylic acid and divinyl benzene co-polymers, and resins with pendant functional groups suitable for cation exchange, such as sulphonate and carboxylate groups.
• Cation exchange resins suitable for use in the practice of the present invention include for example those sold under the trade names Amberlite IRP-64, Amberlite IRP-69 and Amberlite IRP 88 (Rohm and Haas, Frankfurt, Germany), Dowex 50WX2-400, Dowex 50WX4-400 and Dowex 50WX8-400 (The Dow Chemical Company, Midland, MI), Purolite Cl 15HMR and Purolite C102DR (Purolite International Ltd., Hounslow, Great Britain).
• the ion exchange resin is suitably an anion exchange resin material. That is to say, a resin having a predominantly positive charge along the resin backbone, or a resin having a pendant group suitable for anion exchange, and which has an affinity for negatively charged ions or anionic species.
• anion exchange resins include resins having polymer backbones comprising styrene, acrylic acid or phenol units, co-polymers thereof, styrene-divinyl benzene co-polymers and phenolic-based polyamine condensates and resins with pendant functional groups suitable for anion exchange, such as ammonium or tetraalkyl ammonium functional groups.
• Anion exchange resins suitable for use in the practice of the present invention include for example those sold under the trade names Amberlite IRP-58, Amberlite IRA-67, Amberlite IRA 68 (Rohm and Haas, Frankfurt, Germany), Dowex 1X2- 400, Dowex 1X4-400, Dowex 1X8-400 and Dowex 2X8-400 (The Dow Chemical Company, Midland, MI), Purolite A845, Purolite A500P and Purolite PCA-433 (Purolite International Ltd., Hounslow, Great Britain), Duolite API 4371092 and Duolite A 143/ 1093.
• Resins with various degrees of crosslinking and a range of binding capacities may also be used in the practice of the present invention.
• the oral dosage forms of the present invention can be prepared by contacting the ion exchange resin with the active ingredient to form an active ingredient or drug/ ion exchange resin core or complex.
• the individual cores can then be coated with the polymeric coating material.
• the ion-exchange resins suitable for use in the present invention are in the form of ion-exchange resin particles. Stirring the ion-exchange resin particles in a solution of the selected drug is usually sufficient to achieve binding of the drug onto the resin particles. Loading of the resin is suitably carried out at a pH that facilitates binding of the drug compound. Some ion-exchange resins may require "activation" by rinsing with a solution of acid or base, prior to loading with the drug. Such activation requirements will be well known to those skilled in the art of working with ion-exchange resin materials. Specific requirements for individual ion-exchange resin materials may be obtained from the resin manufactures. Preferably, the particles are spherical to enable substantially complete coating of the particle.
• a suitably spherical ion exchange resin can substantially but not wholly masks the taste or odour of an active ingredient and lend itself readily to complete coating with the taste masking polymer which eliminates any residual bitter taste upon ingestion.
• the use of a suitably spherical ion exchange resin can help minimise the interaction of the acid labile drug with the acidic enteroprotective coating while also facilitating the coating of the acid labile drug with the enteroprotective coating.
• An important aspect of the current invention is the ability to coat the drug loaded resin particles as discrete particles hence minimising the potential for a gritty aftertaste after ingestion of the drug.
• reversibly adsorb means that the drug binds to an ion exchange resin of opposite charge via an ionic interaction that can be reversed in suitable ionic conditions
• the active ingredient component of the composition may be present in any amount which is sufficient to elicit a therapeutic effect.
• the active ingredient is present at about 1 - 70 % by weight of the uncoated resin.
• the active ingredient ranges from 5 - 60 % by weight of the uncoated resin. More preferably the active ingredient ranges from 10 - 50 %, most preferably 10-40%, by weight of the uncoated resin.
• the polymer material used for coating the drug-resin complex can be a polymer that has properties which can prevent the release of the drug until it reaches a specific site in the gastrointestinal tract and only then the drug is released.
• the specific site in the gastrointestinal (“GI") tract includes any point in the GI tract including the oesophagus, the stomach and the intestine.
• the polymer coating material used in coating the drug-resin complex may comprise a pH independent or pH dependent coating material.
• pH independent coating materials suitable for use in the present invention include, for example, alkyl celluloses such as methyl cellulose, hydroxyalkyl alkyl celluloses such as hydroxy propyl methyl cellulose, hydroxy alkyl celluloses such as hydroxy propyl cellulose and hydroxy ethyl cellulose, polyvinyl alcohol, maltodextrin, polymethacrylates such as Eudragit® RL (Rohm-Pharma, Darmstadt, Germany).
• pH dependent coating materials suitable for use in the present invention include for example esters of at least one cellulose derivative such as an alkyl cellulose, a hydroxyalkyl cellulose, a hydroxyalkyl alkyl cellulose or a cellulose ester, with at least one polybasic acid such as succinic acid, maleic acid, phthalic acid, tetrahydrophthalic acid, hexahydrophthalic acid, trimellitic acid or pyromellitic acid.
• Suitable enteric coating materials include for example those selected from the group consisting of hydroxy propyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimillitate (CAT) and hydroxypropyl methylcellulose acetate succinate.
• enteric materials such as those selected from the group consisting of poly vinyl acetate phthalate (PVAP), poly vinyl acetaldiethylamino acetate, and shellac.
• enteric materials such as those selected from the group consisting of poly vinyl acetate phthalate (PVAP), poly vinyl acetaldiethylamino acetate, and shellac.
• Particularly useful in relation to the present invention are poly acrylic and methacrylic acids and poly acrylate and methacrylate based coatings, and mixtures thereof, such as those sold under the tradename Eudragit ® , for example Eudragit L ® and Eudragit S ® (Rohm-Pharma, GmbH, Darmstadt, Germany) to 50 - 250 % by weight of the drug loaded resin particles.
• Eudragit® E is an organic radicals, sodium bicarbonate
• a particularly useful pH independent polymer for use in accordance with the present invention is Eudragit® RD 100 (Rohm-Pharma,
• the polymeric coating may suitably comprise a combination of two or more polymer materials.
• Acid labile drugs in the composition according to the invention are substantially protected from the enteric coated material by adsorption onto the ion exchange resin material. Thus the need for a subcoating between the active ingredient and the enteric coating is eliminated.
• the coating may be applied to the drug loaded particles by any suitable technique. Such techniques will be apparent to those skilled in the art. Particularly useful for application of the coating is the technique of spray coating, carried out for instance using a fluidised bed coating apparatus. Suitable excipients and / or additives may be added to the coating formulations. For example it may be desirable to add plasticisers, glidants, anti-tacking agents, pigments and other excipients to the coating formulations. Suitable plasticisers include, for example, triethyl citrate and polyethylene glycol. Suitable glidants include, for example, talc, syloid, glycerol monostearate and magnesium stearate.
• the coating material may be applied to the drug loaded particles in any amount which is sufficient to give the desired taste-masking characteristics. Typically the coating material is applied in an amount equivalent to 10 - 300 % by weight of the drug-loaded resin particles. Preferably, the coating material is applied in an amount equivalent to 20 - 250 % by weight of the drug loaded resin particles.
• acid labile benzimidazole compounds such as omeprazole are capable of binding to an anion exchange resin (i.e. a resin having a positively charged backbone). This may involve the loss of a proton leaving the benzimidazole molecule with a formal negative charge which can interact ionically with the resin.
• the resultant drug / resin complex particles may then be coated with an enteric coating with additional excipients if so desired. Binding of the active ingredient to the resin particles protects the drug from degradation by the acidic enteric coating.
• the enteric coating protects the active ingredient from acid degradation.
• the enteric coating is compromised and the drug / resin complex is exposed to the surrounding environment.
• Exchange of negative ions, such as chloride ions, from the surrounding environment for the drug bound to the resin releases the drug, facilitating the onset of a therapeutic effect.
• exposure of the drug to an even slightly acidic environment will cause it to be protonated leaving the molecule electrically neutral.
• the composition of the present invention is designed to provide a relatively rapid release of active after an initial delay.
• the present invention facilitates the relatively rapid delivery of active once the drug / resin particles are exposed.
• the enteric coating protects the drug / resin particles until they have passed through the stomach where the strongly acidic conditions would degrade the benzimidazole active ingredient.
• adsorption of the active ingredient on to the resin protects it from the potentially detrimental effects of the enteric coating.
• the drug loaded resin compositions according to the present invention can be used as a final oral dosage form, they can also be adapted for a range of final oral dosage forms, including controlled release dosage forms.
• Suitable final dosage forms include, for example, suspension, syrup, capsule, tablet, sprinkle, sachet, effervescent tablet, fast melt tablet, fast dissolving tablet and disintegrating tablet forms.
• the drug loaded, coated ion-exchange resin particles may be formulated in a suspension and freeze-dried to form a fast dissolving or disintegrating tablet.
• the compositions according to the invention may also be formulated in solid form which is reconstituted as a suspension prior to administration without losing any taste masking or entero-protective property.
• Drug loaded, coated resin particles of any size suitable for incorporation into any one of the abovementioned final dosage forms may be used in the practice of the invention.
• drug loaded, coated resin particles making up the multiparticulate composition of the present invention have an average diameter (defined as D 50 o o ) of 20 - 750 ⁇ m.
• the drug loaded, coated resin particles have an average diameter (defined as D 50% ) of 30 - 300 ⁇ m.
• Conditions treatable by administration of a PPI and hence by an oral dosage form of the present include duodenal and gastric ulcers and reflux oesophagitis.
• a method for treating these conditions can include administering to a patient suffering from said conditions a therapeutically effective amount of a proton pump inhibitor in the form of an oral dosage form in which the proton pump inhibitor is adsorbed onto ion exchange resin material forming cores of an ion exchange resin drug complex which are subsequently coated with an enteric coating.
• the method of treatment inhibits gastric acid secretion by administering to mammals, including humans, suffering from acid secretion related conditions a therapeutically effective amount of a proton pump inhibitor in the form of an oral dosage form of the present invention.
• purified water relates to water which has been distilled and purified using an ion-exchange water purification apparatus. Omeprazole concentrations were determined using HPLC.
• Ketolide (1 1 , 12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-0-methyl- alpha-L-ribohexopyranosyl)oxy)-6-0-methyl-3-oxo- 12,1 1- (oxycarbonyl(4-(4-(3-pyridinyl)- 1 H-imidazol- 1 -yl)butyl)imino)) erythromycin), also referred to below as "the active ingredient” or "ketolide” composition.
• ketolide a taste-masked powder formulation would be attractive due to the unpleasant taste characteristics of the drug.
• the physicochemical properties of this compound are such that as the pH of the drug in solution is lowered the drug is completely ionised, each of three nitrogen atoms being protonated according to their respective pK a values.
• the protonated drug may then be loaded onto a cationic exchange resin (such as a cation exchange resin material as listed above) to form a drug-resin complex.
• a cationic exchange resin such as a cation exchange resin material as listed above
• binding of this active ingredient to the ion-exchange resin is not sufficient to completely mask the taste of the drug as judged by a panel of seven.
• coating the drug-resin complex with a coating polymer results in a composition possessing the required taste masked and organoleptic character.
• the formulation of a taste masked ketolide composition according to the invention is given below.
• the granulates were prepared as follows: the raw materials were dry mixed; purified water was added slowly until effective granulation was achieved and the granulate was left to tray-dry in an oven at ca 40 °C overnight. This resulting granulate was size-reduced through a 0.25 mm screen using an Erweka oscillating granulator to form a fine granulate.
• the peppermint oil was added prior to the addition of water.
• the peppermint oil was added to the fine granulate.
• Table 1 Composition of placebo granulate with peppermint flavour added intra-granularly and extra-granularly.
• the cation exchange resin (Dowex 50WX2-400, 2 Kg) was washed with purified water (5 L) for 15 min. The washed resin was recovered and loaded with the active ingredient to a potency of 400 mg drug / g drug loaded resin by mixing the resin in a solution of 8 % active ingredient in 1 N HC1 for 60 min. The loaded resin was recovered by filtration, washed with purified water and oven dried at 40 °C.
• the drug-resin complex was then mixed with the placebo granulate described above to form an uncoated drug-resin ketolide composition.
• Three different ratios of drug-resin complex to granulate were prepared using (i) the "intra-granular” and (ii) "extra-granular” placebo respectively in the following ratios: 75 : 25 (drug-resin complex : granulate); 50 : 50 (drug-resin complex : granulate); and 25 : 75 (drug- resin complex : granulate).
• the uncoated drug-resin ketolide compositions thus prepared were found to have improved taste characteristics compared to the raw drug, but still had an unpleasant after taste. The taste of the resin material itself may have contributed to this.
• ketolide (1 l , 12-dideoxy-3-de((2,6-dideoxy-3-C-methyl-3- 0-methyl-alpha-L-ribohexopyranosyl)oxy)-6-0-methyl-3-oxo- 12, 1 1 - (oxycarbonyl(4-(4-(3-pyridinyl)- lH-imidazol- 1 -yl)butyl)imino)) erythromycin), also referred to below as "the active ingredient” or "ketolide” composition.
• the cation exchange resin (Dowex 50WX2-400, 2 Kg) was washed with purified water (5 L) for 15 min. The washed resin was recovered and loaded with the active ingredient to a potency of 400 mg drug / g drug loaded resin by mixing the resin in a solution of 8 % the active ingredient in 1 N HCl for 60 min. The loaded resin was recovered by filtration, washed with purified water and dried in a Uniglatt (Glatt Air Techniques, ) at 40 °C.
• the uncoated drug-resin ketolide compositions prepared above was then coated in a Glatt GPCG1 , with a 15 % aqueous solution of Eudragit RD100 : Syloid 244 FP : Polysorbate 80 (5: 1 : 1) to a level of 50 % weight gain with Eudragit RD100, at a spray rate of 8 g / min and product temperature of 23-27 °C.
• the coated drug-resin complex was found to be essentially tasteless. Examples 3 and 4.
• Anion exchange resin PCA-433 (4,000 g) was added to a stainless steel container, washed by stirring in purified water (50 1) and subsequently activated by stirring in a solution of NaOH (1 M).
• the resin material particles were loaded with the active ingredient by stirring the resin in a 3.0 % solution of omeprazole (supplied by Reddy Cheminoir, Ridgewood, NJ) in NaOH ( 1 M) (4 1 total volume of omeprazole solution) to form drug loaded particle cores.
• the potency of the drug solution was determined prior to and after loading on to the resin.
• the loaded particle cores were washed with purified water to remove any surface uncomplexed omeprazole, recovered and dried at 40 °C. After loading, the potency of the drug loaded particles cores was determined to be 177 mg/g.
• a coating solution was prepared according to the formulation shown in Table 2.
• the coating solution was applied to the omeprazole loaded resin particles cores using a Vector FLM- 15 Fluid Bed (Vector Corp., Cranbury, NJ) coating apparatus equipped with a Wurster column.
• the coating solution was applied at a spray rate of 45-50 g/min, with the inlet and outlet temperatures set at 55 and 32 °C respectively and an atomisation pressure of 3 bar.
• the product temperature during the process was typically about 35 °C. 167 % solids with respect to the drug loaded resin particle weight was applied onto the drug loaded resin particles. Agglomeration was found to be negligible.
• the rate of release of the active ingredient under alkali conditions was determined by spectrophotometrically using an Hewlett Packard 8452A Diode Array UV spectrometer.
• Table 3 shows the dissolution data for the particles prepared according to the procedures detailed in (i) and (ii) (USP II paddles; 900 ml buffer pH 9.1 ; stirred at 100 rpm). From the data it can be seen that up to about 80 % of the active ingredient loaded on to the resin is release in under 60 mins under the test conditions. Time % Omeprazole released
• Example 3 Essentially the same procedure as detailed in Example 3 was used to prepare a second batch of omeprazole loaded resin particles.
• Anion exchange resin PCA-433 (4,000 g) was added to a stainless steel column, washed by passing purified water (80 1) through the column and subsequently activated using a solution of NaOH (1 M), (80 1).
• the resin material particles were loaded with the active ingredient by passing a 4.0 % solution of omeprazole in NaOH ( 1 M) through the column (40 1 total volume of omeprazole solution).
• the potency of the drug solution was determined spectrophotometrically prior to and after loading on to the resin.
• the loaded particles were washed with purified water to remove any surface uncomplexed omeprazole, recovered from the column and dried at 40 °C. After loading, the potency of the drug loaded particles cores was determined to be 370 mg/g.
• the loaded particles cores were coated using a coating solution made up in the same proportions as that detailed in Example 3 and the same coating conditions described in relation to Example 3. 200 % solids with respect to the drug loaded resin particle weight was applied onto the drug loaded resin particles. Agglomeration was found to be negligible.
• Example 4 The particles prepared according to Example 4 were tested according to the USP method for enteric protection modified as described above in Example 1 and showed no acid degradation of the omeprazole active ingredient over a period of greater than 1 hour, indicative of good enteric protection provided by the coating. Further, no degradation of the active ingredient was observed after 2 hours.
• Omeprazole loaded PCA-433 resin particles were prepared substantially according to the method described in Example 3. In this instance a 1.0 % omeprazole solution (same volume) was used in loading the resin particles and the potency of the drug / loaded particles was determined to be 91 mg/g.
• a coating solution was prepared according to the formulation shown in Table 5.
• the coating solution was applied to the omeprazole loaded resin particles using a Glatt CPCG5 Fluid Bed (Glatt Air Techniques, Inc., Ramsey, NJ)coating apparatus equipped with a Wurster column. is
• the coating solution was applied at a spray rate of 45-50 g/min, with the inlet and outlet temperatures set at 65 and 45 °C respectively and an atomisation pressure of 3 bar.
• the product temperature during the process was typically about 48 °C. 55 % solids was applied onto the drug loaded resin particles. Some agglomeration of particles was evident.
• a granulate comprising the components shown in Table 6, below, was prepared by spraying an aqueous PEG 6000 solution onto the remaining components listed in Table 6 in a Niro Aeromatic, Strea 1 granulator (Niro Aeromatic AG, Bubendorf, Switzerland) at a temperature of 27 °C and a spray rate of 10 ml/min. After spraying the material was dried for one hour in the fluidising chamber of the granulator.
• Niro Aeromatic, Strea 1 granulator Niro Aeromatic AG, Bubendorf, Switzerland
• omeprazole containing resin particles were blended with a performed granulate in Example 6 above
• a second batch of fast melt tablets was prepared in which the omeprazole containing resin particles were added prior to granulation.
• Mint flavour (7.5 g) and magnesium stearate (1.67 g) were added and the granulate, details of which are shown in Table 7, was pressed into tablets as described in the previous Example.
• the average tablet weight was 1 190 mg with an average hardness of 5.42 kPa.

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