WO1997037641A1 - Medicaments actifs enrobes a administration orale - Google Patents

Medicaments actifs enrobes a administration orale Download PDF

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Publication number
WO1997037641A1
WO1997037641A1 PCT/US1997/005800 US9705800W WO9737641A1 WO 1997037641 A1 WO1997037641 A1 WO 1997037641A1 US 9705800 W US9705800 W US 9705800W WO 9737641 A1 WO9737641 A1 WO 9737641A1
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WO
WIPO (PCT)
Prior art keywords
unit
stomach
active drug
intestine
receptor antagonist
Prior art date
Application number
PCT/US1997/005800
Other languages
English (en)
Inventor
Colin R. Gardner
Mandana Asgharnejad
Original Assignee
Merck & Co., Inc.
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
Priority claimed from GBGB9608929.7A external-priority patent/GB9608929D0/en
Priority claimed from GBGB9619063.2A external-priority patent/GB9619063D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU24470/97A priority Critical patent/AU2447097A/en
Priority to EP97920223A priority patent/EP0914099A1/fr
Priority to JP9536446A priority patent/JPH11510514A/ja
Publication of WO1997037641A1 publication Critical patent/WO1997037641A1/fr

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • 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
    • A61K31/42—Oxazoles
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

  • the present invention relates to a coated solid active drug composition having releasability of the active drug in the small or large intestine or, more particularly, to a coated solid fibrinogen receptor antagonist composition which, when orally administered, passes unaffected through the stomach but is disintegrated when it reaches the small or large intestine so as to release the therapeutically active drug contained therein only in the small or large intestine.
  • Platelet activation and aggregation are involved in unstable angina and acute myocardial infarction, in reocclusion following thrombolytic therapy and angioplasty, in transient ischemic attacks and in a variety of other vaso-occlusive disorders.
  • thrombolytic therapy and angioplasty in transient ischemic attacks and in a variety of other vaso-occlusive disorders.
  • platelets When a blood vessel is damaged either by acute intervention such as angioplasty, or, more chronically, by the pathophysiological processes of atherosclerosis, platelets are activated to adhere to the disrupted surface and to each other. This activation, adherence and aggregation may lead to occlusive thrombus formation in the lumen of the blood vessel.
  • Antiplatelet therapy has been used in a wide variety of cardiovascular disease states and in conjunction with interventional therapy such as coronary artery or peripheral bypass grafting, cardiac valve replacement, and percutaneous transluminal coronary angioplasty (PTCA).
  • interventional therapy such as coronary artery or peripheral bypass grafting, cardiac valve replacement, and percutaneous transluminal coronary angioplasty (PTCA).
  • Available drugs such as aspirin and ticlopidine, have shown efficacy in syndromes involving vascular occlusion, presumably due to sustained inhibition of platelet function.
  • the inhibitory effects of aspirin and ticlopidine are dependent upon the agonist which activates the platelet.
  • aspirin is effective in blocking platelet aggregation induced by agonists such as collagen that are dependent upon the cylooxygenase pathway.
  • thrombin which can act by cyclooxygenase independent pathways.
  • ticlopidine 's inhibitory effects can be overcome by combinations of agonists.
  • an efficacious inhibitor of platelet aggregation that acts independently of the agonist and the pathway activating the platelet could be an important therapeutic advance providing greater efficacy than aspirin or ticlopidine in a broader spectrum of thrombotic events.
  • the final obligatory step in platelet aggregation is the binding of fibrinogen to an activated membrane -bound glycoprotein complex, GP Ilb/IIla (oc ⁇ 3).
  • Platelet activators such as thrombin, collagen, epmephrine or ADP, are generated as an outgrowth of tissue damage.
  • GP IltylUa undergoes changes in conformation that results in exposure of occult binding sites for fibrinogen.
  • fibrinogen can potentially act as a hexavalent ligand to crossing GP Ilb/IIla molecules on adjacent platelets.
  • a deficiency in either fibrinogen or GP Ilb ITJa prevents normal platelet aggregation regardless of the agonist used to activate the platelets. Since the binding of fibrinogen to its platelet receptor is an obligatory component of normal aggregation, GP Ilb/ ⁇ ia is an attractive target for an antithrombotic agent.
  • Orally active agents include SC54684, which is a prodrug (i.e., it requires biotransformation in vivo to its active form) with high oral bioavailability and R043-8857, GR144053, and DMP728, which are themselves the active inhibitors (Cook et al. ibid.; and Cox et al. ibid.).
  • SC54684 is a prodrug (i.e., it requires biotransformation in vivo to its active form) with high oral bioavailability and R043-8857, GR144053, and DMP728, which are themselves the active inhibitors (Cook et al. ibid.; and Cox et al. ibid.).
  • Oral fibrinogen receptor antagonists are readily absorbed when a patient consumes them on an empty stomach.
  • absorption and bioavailability of oral fibrinogen receptor antagonists when taken with food, may be reduced by the presence of food in the stomach.
  • Food is digested in the stomach, by mixing with digestive aids such as secreted acid and digestive enzymes, to form a material referred to as chyme.
  • Chyme is a thick semifluid mass of partly digested food that is passed from the stomach to the duodenum
  • the present invention provides a means for allowing the active drug to remain in the stomach in the presence of food.
  • the invention is an oral, coated pharmaceutical composition suitable for administration to a patient .
  • the coated compositions comprise an active drug, suitable solid oral dosage form pharmaceutical excipients, and a suitable protective enteric coating surrounding the active drug and pharmaceutical excipients.
  • the suitable coating prevents release from the composition of active drug while the coated composition is located in the stomach, and provides for release of the active drug following transfer of the composition from the stomach to the intestine.
  • the compositions have sufficient effective diameter to prevent gastric emptying of the composition from the stomach into the duodenum until gastric emptying of chyme from the stomach is completed.
  • compositions are specifically designed to prevent interaction of the active drug with food. While the compositions remain in the stomach, food is converted in the stomach to chyme and then transported to the duodenum. Only after gastric emptying of the chyme does the composition leave the stomach and enter the duodenum. The active drug is then released from the coated composition into the intestine.
  • compositions include a coated medicament having releasability of the active drug only in the intestine having an inner core and an outer coating, wherein the inner core comprises active drug and one or more suitable pharmaceutically acceptable excipients, and wherein the outer coating does not substantially dissolve in the stomach and does substantially dissolve in the intestine.
  • the invention also includes a method for preventing interaction between food and an active drug whose absorption is affected by the presence of food, which comprises administering to the patient an oral, coated pharmaceutical composition of the invention which releases the active drug into the intestine after food has been digested.
  • the active drug can be a fibrinogen receptor antagonist suitable for administration to a patient in need of therapy for inhibiting platelet aggregation.
  • the coated compositions of the invention thus may comprise an inhibitor of fibrinogen binding to the GP Ilb/IUa receptor, suitable solid oral dosage form pharmaceutical excipients, and a suitable protective enteric coating surrounding the inhibitor and pharmaceutical excipients.
  • the suitable coating prevents release from the composition of the fibrinogen receptor antagonist while the coated composition is located in the stomach, and provides for release of the fibrinogen receptor antagonist following transfer of the composition from the stomach to the intestine. This only occurs after the food has been digested and eliminated from the stomach.
  • the invention also includes the use of a composition of the invention in the manufacture of a medicament for reducing the risk of acute coronary ischemic syndrome in patients at risk to acute coronary ischemic syndrome, in a mammal.
  • compositions are particularly useful for reducing the risk of acute coronary ischemic syndrome in patients at risk to acute coronary ischemic syndrome.
  • the compositions minimize the risk associated with oral fibrinogen receptor antagonists that interact with food, and provide a safer means for treating patients in need of fibrinogen receptor antagonists.
  • the invention also includes a composition in the manufacture of a medicament for preventing, in a patient, interaction between food and an active drug, the absorption rate of which drug is substantially affected by the coinciding presence of food in the stomach.
  • the invention is an oral drug dosage unit, for administration to a patient, having active drug, and an effective diameter and surface composition sufficient for the unit to be transported from the stomach into the duodenum following substantially complete emptying of chyme from the stomach into the duodenum and prior to release of active drug from the unit, wherein the active drug has an absorption rate that is affected by the coinciding presence of food in the stomach, the effective diameter of the unit prevents gastric emptying of the unit prior to gastric emptying of chyme, and the surface composition is an enteric coating which prevents release of the active drug in the stomach and allows release of the active drug in the intestine.
  • Active drugs having food interaction are those where drug absorption is affected by the presence of food, to such an extent that the medicinal benefit ordinarily provided by the drug (in the absence of food) is detrimentally altered.
  • Compositions within the scope of the invention, having releasability of the active drug only in the intestine, have an inner core and an outer enteric coating, wherein the inner core comprises an active drug and one or more suitable pharmaceutically acceptable excipients, and wherein the outer coating does not substantially dissolve in the stomach and does substantially dissolve in the intestine.
  • the invention also includes a method for preventing, in a patient, interaction between food and an active drug, the absorption rate of which drug is substantially affected by the coinciding presence of food in the stomach, which comprises administering to the patient an oral drug dosage unit having the active drug, an effective diameter sufficient for the unit to be transported from the stomach into the duodenum following substantially complete emptying of chyme from the stomach into the duodenum and prior to release of active drug from the unit, and an enteric coating surface composition which retains the active drug in the stomach and releases the active drug in the intestine.
  • the coating which delays release of the active drug is insoluble in pH environments such as those in the stomach, e.g. less than 4, but soluble in pH environments such as those in the intestine, e.g. about 5.5. or greater.
  • the effective diameter of the pharmaceutical composition of the invention is between about 3 mm and 20 mm, preferably between about 6 and 15 mm, e.g. 7, 8, 9, 10, 11 , 12, 13, and 14 mm.
  • Effective diameter for purposes of this invention refers to the dimension of the composition that is presented to the opening between the stomach and the duodenum and which limits entry of the composition into the duodenum.
  • the effective diameter of a spheroid is the diameter of the spheroid.
  • the effective diameter of a tablet is the diameter of the tablet face.
  • the effective diameter of a cylindrical capsule is the diameter of the narrow dimension of the cylinder.
  • compositions of the present invention may be prepared in any of a number of ways as long as the objective of preventing release of the active drug in the stomach and providing for release of the active drug in the intestine is achieved.
  • Such compositions are prepared with enteric coatings that are insoluble in gastric juices but readily soluble on passage into the intestine.
  • compositions of the invention may also be prepared by mixing the active drug with an excipient, and coating the mixture with a thin polymer film.
  • the active drug is mixed with microcrystalline cellulose to form a spheroid which is then coated with a film of hydroxypropyl methyl cellulose phthalate which may or may not contain a plasticizer which prevents any release of the drug in the stomach.
  • the composition reaches the intestine, the active drug is released.
  • compositions of the invention may also be prepared by mixing the active drug and an acid such as fumeric or tartaric acid which is compressed into a tablet or capsule shape and coated with lacquers that are insoluble in gastric juices and soluble in intestinal juices.
  • Compositions of the invention may also be prepared by mixing the active drug with materials for forming a gel capsule, inserting drug particles into a capsule, or inserting a liquid drug formulation into a capsule, which capsules are then coated with lacquers that are insoluble in gastric juices and soluble in intestinal juices.
  • lacquers include copolymers of acrylic acid and methacrylic acid esters.
  • the acidic matrix prevents quick dissolution early and yet promotes the drugs' bioavailability further downstream in the digestive tract.
  • compositions of the invention may also be prepared by coating a solid dosage form of the active drug with hydroxypropyl methyl cellulose phthalate or acidic succinyl and acetyl esters of hydroxypropyl methyl cellulose.
  • Triethyl citrate is added as a plasticizer which aids in the binding of the coating material to the core pellet. The coating resists dissolution in the stomach but completely dissolves in the small intestine.
  • Suitable materials for providing enteric coatings include, for example, hydroxypropyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose hexahydrophthalate, shellac, cellulose acetate, cellulose acetate phthalate, polyvinyl acetate phthalate, carboxymethyl ethyl cellulose, methacrylic acid copolymers, methacrylic ester copolymers and the like.
  • enteric coating system which contains polyvinyl acetate phthalate, talc, polyethylene glycol, titanium dioxide, sodium bicarbonate, triethyl citrate, purified stearic acid, sodium alginate, and colloidal silicon dioxide, may be used.
  • solid dosage forms comprising the active drug may be coated using conventional coating techniques such as conventional pan coating techniques or column spray coating techniques.
  • coating pans e.g. subglobular, pear shaped or hexagonal pans, which are inclined are set to rotate at an appropriate setting sufficient to allow uncoated tablets to be exposed to spray solutions of the polymer used to form the coat.
  • the pan is heated to a sufficient temperature to allow the coat to dry soon after contact with the outside of the tablet.
  • Some pans have a cylindrical shape, are rotated horizontally, and have at least some regions of the walls perforated by small holes or slots. This design permits a one-way air flow through the pan. In other designs the flow of air is through the tablet bed and out through the perforated wall of the pan. In others the air flows from the perforated pan wall through the tablet bed into the central region, i.e., countercurrent to the coating spray direction. Still others permit either co- or counter- current air flow to suit particular products.
  • the coating is sprayed in one of several methods.
  • One method relies entirely on hydraulic pressure to produce a spray when material is forced through a nozzle (airless spraying).
  • atomization of the spray is assisted by turbulent jets of air. This method tends to produce a more easily controlled spray pattern and is therefore better for small-scale operations, although both are capable of giving the flat jet profile preferred for pan operation.
  • the thickness of coating required on the granules depends on the dissolution profile of the particular coating materials.
  • the coating can contain a plasticizer and possibly other coating additives such as coloring agents, gloss producers, talc and/or magnesium stearate.
  • Active drugs useful in the present invention include fibrinogen receptor antagonists such as those described in United States Patents 5,470,849, 5,463,011, 5,455,243, 5,451,578, 5,446,056, 5,441,952, 5,422,249, 5,416,099, 5,405,854, 5,397,791, 5,393,760, 5,389,631 , 5,380,713, 5,374,622, 5,358,956, 5,344,783, 5,340,798, 5,338,7235,334,596, 5,321 ,034, 5,318,899,5,312,923, 5,294,616,
  • Glycoprotein Ilb/IIIa receptor antagonists and their pharmaceutically acceptable salts are useful in the present invention.
  • pharmaceutically acceptable salts means non-toxic salts of the compounds which include, but are not limited to, acetate, benzenes u If onate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide,
  • glycoprotein Ilb/IIIa receptor antagonists are suitable for use in the compositions and methods of the present invention.
  • pharmaceutically effective amount means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
  • the methods of the present invention are useful in combination with procedures for treating patients with other anticoagulants (e.g. heparin and warfarin), thrombolytic agents (e.g. streptokinase and tissue plasminogen activator), and platelet antiaggregation agents (e.g. aspirin and dipyridamole).
  • glycoprotein Ilb/IIla receptor antagonists can be administered to the patient in one oral composition, such as a tablet or capsule, or in several oral compositions.
  • Suitable oral compositions include tablets, compressed capsules, gel capsules containing drug integrated into the gel matrix forming the gel capsule, gel capsules containing drug particles, or gel capsules containing liquid drug composition (each of which may include sustained release or timed release formulations), which are coated with an enteric coating.
  • the coated composition may be a tablet comprising the active drug with other excipients and an enteric coat, a non-tablet solid complex comprising the active drug with other excipients and an enteric coat contained in a capsule (e.g. wherein the non-tablet solid complex is loaded into the capsule) which is coated with an enteric coat, or other form, with the condition being that the active drug is protected from release in the stomach but not from release in the intestine.
  • the active drug may be administered to patients where prevention of thrombosis by inhibition of binding of fibrinogen to the platelet membrane glycoprotein complex Ilb/IIIa receptor is desired. Such administration is useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption.
  • the aggregated platelets may form thrombi and thromboemboli.
  • the active drugs may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
  • Other applications include prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty or coronary artery bypass procedures.
  • the methods may also be used to prevent myocardial infarction.
  • the dosage regimen utilizing the active drug is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
  • Oral dosages of active drug when used for the indicated effects will range between about 0.005 mg per kg of body weight per day (mg/kg/day) to about 50 mg/kg/day and preferably 0.005-20 mg/kg/day and most preferably 0.005-10 mg/kg/day.
  • Suitable oral tablets contain between 0.1 mg and 500 g, preferably between 1.0 mg and 250 g, most preferably between 1.0 mg and 150 g, e.g. 1 mg, 50 mg, 100 mg, 150 mg, 250 mg, or 500 mg.
  • Oral administration may be in one or divided doses of two, three, or four times daily.
  • the active drug can be administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, and the like, and consistent with convention pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non- toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, microcrystalline cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • an oral, non- toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, microcrystalline cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn -sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, stearic acid, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrants include, without limitation, starch and derivatives thereof, microcrystalline cellulose, methyl cellulose, agar, bentonite, croscarmellose sodium, xanthan gum and the like.
  • compositions are useful for treating patients where inhibition of human or mammalian platelet aggregation or adhesion is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endaterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and potential formation of thrombi and thromboemboli. Methods of the invention may be used to prevent the formation of thrombi and thromboemboli.
  • the present invention is demonstrated in a study of patients with acute coronary ischemic syndromes who are undergoing early coronary revascularization with percutaneous coronary angioplasty or atherectomy.
  • compositions are administered to patients who are evaluated at 30 days for acute coronary ischemic syndrome and the need for follow-up intervention associated with acute coronary ischemic syndrome, including coronary artery bypass grafting, repeat percutaneous intervention for acute ischemia, and insertion of a coronary endovascular stent.
  • Aspirin is administered in a dose of 325 mg at least two hours before angioplasty, and daily thereafter. Heparin is given intravenously in an initial bolus dose of 10,000 to 12,000 units followed by incremental bolus doses of up to 3000 units at 15-minute intervals, but no more than 20,000 units is given during the procedure. The goal is to keep the activated clotting time between 300 and 350 seconds during the operation. Heparin is continued by constant infusion for at least 12 hours to maintain the activated partial- thromboplastin time at 1.5 to 2.5 times the control value. Aspirin is required at discharge in a dose of 325 mg per day.
  • Hydroxypropyl methyl 10 cellulose phthalate Compound 1-1 microcrystalline cellulose, dicalcium phosphate and croscarmellose sodium are mixed and then lubricated with magnesium stearate and the resulting mixture is then compressed into tablets having diameter of 8 mm.
  • the tablets are coated in a coating pan with hydroxypropyl methyl cellulose phthalate in a coating amount of 10 mg per tablet.
  • Coated tablets containing 15 mg of the fibrinogen receptor gp Ilb/IIIa antagonist 2(S)-[(p-Toluenesulfonyl)amino]-3-([ (5,6,7,8- tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[l,5- aJ[l ,4]diazepin-2-yl]carbonyl]-amino]propionic acid (compound 1-1) are prepared as illustrated below:
  • Compound 1-1 , microcrystalline cellulose, and a portion of the corn starch are mixed and granulated into 10% co starch paste.
  • the resulting granulation is sieved, dried and blended with the remainder of the com starch and the magnesium stearate.
  • the resulting granulation is then compressed into tablets having diameter of 8 mm.
  • the tablets are coated in a coating pan with hydroxypropyl methyl cellulose phthalate in a coating amount of 20 mg per tablet. - 15 -
  • Capsules containing the fibrinogen receptor gp Ilb/IIIa antagonist 2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5, 6,7, 8-tetrahydro-4- oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[l,5-a][ l ,4]diazepin-2- yljcarbonylj-aminojpropionic acid (compound 1-1 ) are prepared as illustrated below:
  • Compound 1 -1 microcrystalline cellulose, disodium phosphate and croscarmellose sodium are mixed in a blender. The resulting mixture is granulated and dried prior to milling. Milled granules are lubricated and filled into a standard pharmaceutical capsule, having a narrow dimension of 4 mm, which is then coated with hydroxypropyl methyl cellulose phthalate.
  • Compound 1-1 microcrystalline cellulose, calcium phosphate dibasic, croscarmellose sodium were combined in a conventional manner to form the core tablet. Tablets were then coated with a pre-coat solution of 2.4 mg hydroxypropylmethylcellulose, 2.4 mg hydroxypropylcellulose, 0.96 mg titanium dioxide, and 60 microliters of water. After the pre-coat solution was applied, the enteric coat was added The enteric coat was made using Colorcon's Sureteric TAE- 6-18107 aqueous based enteric coating system. A 15% solution of Sureteric was made by suspending the powder in water. Dow Coming's antifoam AF emulsion was added to prevent foaming (weight equal to 0.334% of the weight of the Sureteric in the suspension). The solution was added until a 10% weight gain (based on core tablet weight of 300 mg) was achieved.
  • Example 5 The tablet prepared in Example 5 was prepared. After the enteric coating was applied, an additional pre-coat solution of 2.4 mg hydroxypropylmethylcellulose, 2.4 mg hydroxypropylcellulose, 0.96 mg titanium dioxide, and 60 microliters of water was added to achieve a 3% weight gain.

Abstract

Dose unitaire de médicaments à administration par voie orale constituée d'un médicament actif présentant un diamètre efficace et d'une composition superficielle permettant le transport de cette dose de l'estomac au duodenum une fois que le chyme se trouve pratiquement entièrement déversé de l'estomac dans l'intestin et avant que le médicament actif ne soit libéré de la dose. Le médicament actif présente un rythme d'absorption qui est considérablement affecté par la présence concomitante d'aliments dans l'estomac. Le diamètre efficace de la dose empêche sa libération dans l'estomac avant le transfert du chyme gastrique, tandis que la composition superficielle est constituée d'un revêtement entérique empêchant la libération du médicament actif dans l'estomac mais permettant cette libération dans l'intestin.
PCT/US1997/005800 1996-04-10 1997-04-07 Medicaments actifs enrobes a administration orale WO1997037641A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU24470/97A AU2447097A (en) 1996-04-10 1997-04-07 Oral coated active drugs
EP97920223A EP0914099A1 (fr) 1996-04-10 1997-04-07 Medicaments actifs enrobes a administration orale
JP9536446A JPH11510514A (ja) 1996-04-10 1997-04-07 経口被覆活性薬物

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US1517696P 1996-04-10 1996-04-10
US60/015,176 1996-04-10
GBGB9608929.7A GB9608929D0 (en) 1996-04-29 1996-04-29 Oral coated firbrinogen receptor antagonist composition
GB9608929.7 1996-04-29
US2399996P 1996-08-12 1996-08-12
US60/023,999 1996-08-12
GBGB9619063.2A GB9619063D0 (en) 1996-09-12 1996-09-12 Oral coated active drugs
GB9619063.2 1996-09-12

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WO1997037641A1 true WO1997037641A1 (fr) 1997-10-16

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EP (1) EP0914099A1 (fr)
JP (1) JPH11510514A (fr)
AU (1) AU2447097A (fr)
CA (1) CA2251022A1 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2352172A (en) * 1999-05-11 2001-01-24 West Pharm Serv Drug Res Ltd Orally administered dose unit comprising a drug with an outer coating of an enteric polymer, which allows co-administered food to separate from the dose unit
WO2004073747A1 (fr) * 2003-02-24 2004-09-02 Lg Life Sciences Ltd. Compositions pharmaceutiques a administration orale et procedes pour empecher l'interaction aliment / medicament
US11458104B1 (en) * 2018-06-21 2022-10-04 Mission Pharmacal Company Enteric coated tiopronin tablet

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5374430A (en) * 1986-09-18 1994-12-20 London School Of Pharmacy Pharmaceutical formulation
US5446056A (en) * 1993-11-24 1995-08-29 The Du Pont Merck Pharmaceutical Company Isoxazoline compounds useful as fibrinogen receptor antagonists

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5374430A (en) * 1986-09-18 1994-12-20 London School Of Pharmacy Pharmaceutical formulation
US5446056A (en) * 1993-11-24 1995-08-29 The Du Pont Merck Pharmaceutical Company Isoxazoline compounds useful as fibrinogen receptor antagonists

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2352172A (en) * 1999-05-11 2001-01-24 West Pharm Serv Drug Res Ltd Orally administered dose unit comprising a drug with an outer coating of an enteric polymer, which allows co-administered food to separate from the dose unit
WO2004073747A1 (fr) * 2003-02-24 2004-09-02 Lg Life Sciences Ltd. Compositions pharmaceutiques a administration orale et procedes pour empecher l'interaction aliment / medicament
US11458104B1 (en) * 2018-06-21 2022-10-04 Mission Pharmacal Company Enteric coated tiopronin tablet

Also Published As

Publication number Publication date
JPH11510514A (ja) 1999-09-14
CA2251022A1 (fr) 1997-10-16
EP0914099A1 (fr) 1999-05-12
AU2447097A (en) 1997-10-29

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