Elan Corporation, Plc

501 Elan Corporation Plc.

Eland Corporation P.l.c.

Donald E Panoz

Edward J Geoghegan

Seamus Mulligan

Gilbert Corneille

Owen I Corrigan

A diltiazem pellet formulation for oral administration comprises a core of diltiazem or a pharmaceutically acceptable salt thereof in association with an organic acid, and a multi-layer membrane surrounding the core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble synthetic polymer and a minor proportion of a pharmaceutically acceptable film-forming, water soluble synthetic polymer. The number of layers in the membrane and the ratio of the water soluble to water insoluble polymer being effective to permit release of the diltiazem from the pellet at a rate allowing controlled absorption thereof over a twenty four hour period following oral administration.

Controlled absorption diltiazen formulation for once-daily administration

Controlled absorption diltiazem formulation for once daily administration

A diltiazem pellet formulation for oral administration comprises a core of diltiazem or a pharmaceutically acceptable salt thereof in association with an organic acid, and a multi-layer membrane surrounding the core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble synthetic polymer and a minor proportion of a pharmaceutically acceptable film-forming, water soluble synthetic polymer. The number of layers in the membrane and the ratio of the water soluble to water insoluble polymer being effective to permit release of diltiazem from the pellet at a rate allowing controlled absorption thereof over a twelve hour period following oral administration. The pellet has a dissolution rate in vitro which when measured in a dissolution apparatus (Paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KC1 at pH 7.0 results in not more than 35% of the total diltiazem being released after 2 hours of measurement. Not more than 80% of the total diltiazem is released after six hours of measurement and not less than 85% of the total diltiazem is released after 13 hours of measurement.

Diltiazem formulations and methods of treatment

A diltiazem pellet formulation for oral administration comprises a core of diltiazem or a pharmaceutically acceptable salt thereof in association with an organic acid, and a multi-layer membrane surrounding the core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble synthetic polymer and a minor proportion of a pharmaceutically acceptable film-forming, water soluble synthetic polymer. The number of layers in the membrane and the ratio of the water soluble to water insoluble polymer being effective to permit release of diltiazem from the pellet at a rate allowing controlled absorption thereof over a twelve hour period following oral administration. The pellet has a dissolution rate in vitro which when measured in a dissolution apparatus (Paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 results in not more than 35% of the total diltiazem being released after 2 hours of measurement. Not more than 80% of the total diltiazem is released after six hours of measurement and not less than 85% of the total diltiazem is released after 13 hours of measurement.

Methods of treatment with diltiazem formulations

Specifically, the present invention relates to processes for preparing delayed action galenic forms. The process is characterized in that the application solutions of excipients, coatings and active constituents are adjusted to a desired pH. The independence of the rate of dissolution of a controlled release or sustained action oral pharmaceutical form is increased by admixing a pH adjusting agent with every application solution of medicament, excipeint or coating, throughout the course of formulation of the pharmaceutical form.

Processes for the preparation of delayed action and programmed release

A controlled absorption diltiazem pellet formulation for oral administration comprises a core of diltiazem or a pharmaceutically acceptable salt thereof in association with an organic acid, and a multi-layer membrane surrounding the core and containing a major proportion of a pharmaceutically acceptable film-forming water insoluble synthetic polymer and optionally a minor proportion of a pharmaceutically acceptable film-forming, water soluble synthetic polymer. The number of layers in the membrane and the ratio of the water soluble to water insoluble polymer, when said water soluble polymer is present, being effective to permit release of diltiazem from the pellet at a rate allowing controlled absorption thereof over not less than a twelve hour period following oral administration. The pellet has a dissolution rate in vitro which when measured in a dissolution apparatus (paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KCl at pH 7.0 results in not more than 35% of the total diltiazem being released after 2 hours of measurement. Not more than 60% of the total diltiazem is released after four hours of measurement and 100% of the diltiazem is released no earlier than after 8 hours of measurement in said apparatus.

Controlled absorption diltiazem formulations

A diltiazem pellet formulation for oral administration comprises a core of diltiazem or a pharmaceutically acceptable salt thereof in association with an organic acid and a lubricant, and a membrane surrounding the core comprising a multiplicity of sequentially applied and dried layers, each layer containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble, naturally occurring polymer and a minor proportion of a pharmaceutically acceptable film-forming, water soluble polymer. The number of layers in the membrane and the ratio of the water soluble to water insoluble polymer being effective to permit release of the diltiazem from the pellet at a rate allowing controlled absorption thereof over a twelve hour period following oral administration.

Controlled absorption diltiazem formulation

A sustained absorption propranolol-containing pellet for oral administration comprises a core of propranolol or a pharmaceutically acceptable salt thereof and an organic acid embedded in a polymeric material in a multi-layer arrangement and an outer membrane which permits release of the propranolol at a controlled rate in an aqueous medium. The pellet has a dissolution rate in vitro in an aqueous medium, which when measured in a basket assembly according to U.S. Pharmacopoeia XX at 37.degree. C. and 75 r.p.m., is not more than 15% of the total propranol after 2 hours of measurement in a buffer solution at pH 7.5. Not more than 30% of the total propranolol is released after a total of 4 hours of measurement and not more than 63% of the total propranolol is released after a total of 6 hours.

Controlled absorption pharmaceutical composition

Controlled absorption diltiazem formulation for once-daily administration

Diltiazem formulation

A controlled absorption verapamil containing pellet formulation for oral adminstration comprises a core of a powder mixture containing verapamil or a pharmaceutically acceptable salt thereof and an organic acid and a polymeric material, said core comprising layers of said powder mixture and said polymeric material superimposed one upon the other and said polymeric material being present in an amount effective to ensure that all of said powder mixture is coated into said core and a multi-layer membrane surrounding said core, the number of layers in said membrane and the ratio of the various polymers comprising the membrane being effective to permit release of the verapamil from the pellet at a rate allowing controlled absorption thereof over a 24 hour period following oral administration, said rate being measured in vivo and having a Tmax between 6 and 16 hours.

A controlled absorption quinidine formulation for oral administration comprises a pellet having a core of quinidine or a pharmaceutically acceptable salt thereof in association with an organic acid and optionally other excipients, and an outer membrane which permits release of quinidine in an aqueous medium at a controlled rate which is substantially pH independent. The pellet has a dissolution rate in vitro, which when measured in a Basket Assembly according to U.S. Pharmacopoeia XXI at 37.degree. C. and 75 r.p.m. is not more than 15% after one hour of measurement. Not more than 50% of the total quinidine is release after a total of 4 hours of measurement, not more than 80% is released after a total of 8 hours of measurement and not less than 90% release is achieved after a total of 24 hours.

Controlled absorption pharmaceutical formulation

A device for the unidirectional transdermal administration of a drug in an ointment, cream or jelly-like carrier comprising a laminar applicator adapted to receive a predetermined quantity of the drug on a skin-contacting surface thereof, the applicator including a drug-impervious lamina such as a layer of aluminum foil, overlying said skin-contacting surface, such that in use a unidirectional transfer of the drug from the carrier to the skin surface is ensured. The device is especially suitable for the transdermal administration of nitroglycerin, clonidine, methadone and scopolamine or any drug that is skin-permeable. The drug receiving surface may be embossed, pressed, or stamped to define one or more mini-recesses or receptacles for receiving the drug to be administered.

Drug delivery device

A sustained absorption theophylline-containing pellet for oral administration comprises a core of theophylline or a pharmacological equivalent thereof and an organic acid embedded in a polymeric material in a multi-layer arrangement and an outer membrane which permits release of the theophylline at a controlled rate in an aqueous medium. The pellet has a dissolution rate in vitro in an aqueous medium, which when measured in a basket assembly according to U.S. Pharmacopoeia XX at 37.degree. C. and 75 r.p.m., is not more than 15% of the total theophylline after 2 hours of measurement in a buffer solution at pH 7.5. Not more than 35% of the total theophylline is released after a total of 7 hours of measurement and not more than 65% of the total theophylline is released after a total of 13 hours.

Sustained absorption pharmaceutical composition

The present invention relates to medicaments with a high degree of dissolution rate and solubility. These medicaments are characterized in that they are in amorphous form produced by spraying in the presence of a stabilizer and of an agent inhibiting the formation of crystals.

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Tuckerstown, Bermuda

Donald E Panoz