Elan Corporation, Plc

Elan Transdermal Limited

Athpharma Limited

501 Elan Corporation Plc.

Eland Corporation P.l.c.

Edward J Geoghegan

Donald E Panoz

Seamus Mulligan

Randall T Sparks

Owen I Corrigan

John Corish

Joseph G Masterson

Yvonne B Bannon

Mary Margaret Foynes

Isosorbide mononitrate formulations and methods of treatment are disclosed. The formulations and treatments provide for subtherapeutic levels of the mononitrate in a washout period to prevent nitrate tolerance.

Pharmaceutical formulations for preventing drug tolerance

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 controlled release powder containing discrete micro-particles for use in edible, pharmaceutical and other controlled release compositions is disclosed. The micro-particles have an average size in the range of from 0.1 to 125 .mu.m. Each of the micro-particles is in the form of a micromatrix of an active ingredient uniformly distributed in at least one non-toxic polymer. The micro-particles have a predetermined release of active ingredient when the dissolution rate thereof is measured according to the Paddle Method of U.S. Pharmacopoeia XX at 37.degree. C. and 75 r.p.m.

Controlled release powder and process for its preparation

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 preparation for the once-daily, percutaneous administration of nicotine comprises nicotine uniformly distributed in a solid, semi-solid or mucilaginous medium which can be placed in intimate contact with the skin, the solid, semi-solid or mucilaginous medium is formed by adding a given amount of nicotine to a solution of a solidifying or gel-forming agent or mixture thereof in a suitable solvent or mixture of solvents and mixing or heating the mixture thereby obtained so as to form the solid, semi-solid or mucilaginous medium. The preparation can be used in a method of treating withdrawal symptoms associated with smoking cessation and for combating the psychological dependence that occurs through frequent smoking.

Method for the treatment of withdrawal symptoms associated with smoking

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

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 controlled release powder containing discrete micro-particles for use in edible, pharmaceutical and other controlled release compositions is disclosed. The micro-particles have an average size in the range of from 0.1 to 125 .mu.m. Each of the micro-particles is in the form of a micromatrix of an active ingredient uniformly distributed in at least one non-toxic polymer. The micro-particles have a predetermined release of active ingedient when the dissolution rate thereof is measured according to the Paddle Method of U.S. Pharmacopoeia XX at 37.degree. C. and 75 r.p.m.

A preparation for the once-daily, percutaneous administration of nicotine comprises nicotine uniformly distributed in a solid, semi-solid or mucilaginous medium which can be placed in intimate contact with the skin, the solid, semi-solid or mucilaginous medium is formed by adding a given amount of nicotine to a solution of a solidifying or gel-forming agent or mixture thereon in a suitable solvent or mixture of solvents and mixing or heating the mixture thereby obtained so as to form the solid, semi-solid or mucilaginous medium. The preparation can be used in a method of treating withdrawal symptoms associated with smoking cessation and for combating the psychological dependence that occurs through frequency smoking.

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.

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Athlone, Ireland

Edward J Geoghegan