Transdermal delivery system

A method of treating pain in a patient by applying a transdermal therapeutic system for the transdermal administration of buprenorphine base for 7 days on the skin of a patient, said transdermal therapeutic system comprising a buprenorphine base-containing self-adhesive layer structure comprising

• A) a buprenorphine base-impermeable backing layer, and
• B) a buprenorphine base-containing matrix layer on said buprenorphine base-impermeable backing layer, the matrix layer comprising
• a) a polymer-based pressure-sensitive adhesive comprising polysiloxane,
• b) buprenorphine base, and
• c) levulinic acid, in an amount sufficient so that said buprenorphine base is solubilized therein to form a mixture, and the levulinic acid buprenorphine base mixture forms dispersed deposits in the said pressure-sensitive adhesive, and
• C) a skin contact layer on said buprenorphine base-containing matrix layer comprising a polymer-based pressure-sensitive adhesive comprising polyacrylate,
• and optionally wherein the buprenorphine base-containing self-adhesive layer structure contains said buprenorphine base in an amount of less than 0.8 mg/cm2.

A transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from:

• a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 4.8 cm2 to about 8 cm2 and providing a mean AUCt of more than 7,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population;
• and
• a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 9.5 cm2 to about 15 cm2 and providing a mean AUCt of more than 14,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population;
• and
• a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 19 cm2 to about 30 cm2 and providing a mean AUCt of more than 28,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population;
• and
• a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 28.5 cm2 to about 45 cm2 and providing a mean AUCt of more than 42,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population;
• and
• a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 38 cm2 to about 60 cm2 and providing a mean AUCt of more than 62,000 pg·hr/ml over about 168 hours of administration after a single-dose administration to a subject population.

A transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from:

• a first transdermal therapeutic system containing an amount of said buprenorphine ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 4.8 cm2 to about 8 cm2 and providing a nominal mean release rate of about 5 μg/hr over about 168 hours of administration;
• and
• a second transdermal therapeutic system containing an amount of said buprenorphine ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 9.5 cm2 to about 15 cm2 and providing a nominal mean release rate of about 10 μg/hr over about 168 hours of administration;
• and
• a third transdermal therapeutic system containing an amount of said buprenorphine ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 19 cm2 to about 30 cm2 and providing a nominal mean release rate of about 20 μg/hr over about 168 hours of administration;
• and
• a fourth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 28.5 cm2 to about 45 cm2 and providing a nominal mean release rate of about 30 μg/hr over about 168 hours of administration;
• and
• a fifth transdermal therapeutic system containing an amount of said buprenorphine ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a size of the area of release ranging from more than 38 cm2 to about 60 cm2 and providing a nominal mean release rate of about 40 μg/hr over about 168 hours of administration.

A transdermal therapeutic system for the transdermal administration of buprenorphine comprising a buprenorphine-containing self-adhesive layer structure comprising

• A) a buprenorphine-impermeable backing layer, and
• B) a buprenorphine-containing matrix layer on said buprenorphine-impermeable backing layer, the matrix layer comprising
• a) a polymer base,
• b) buprenorphine, and
• c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the polymer base, and
• C) a skin contact layer on said buprenorphine-containing matrix layer comprising a polymer-based pressure-sensitive adhesive,
• and optionally wherein the buprenorphine-containing self-adhesive layer structure contains said buprenorphine in an amount of less than 0.8 mg/cm2 buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof,
• for use in a method of treating pain in a patient by applying the transdermal therapeutic system for 7 days on the skin of a patient.

A set of two to five different transdermal therapeutic systems for the transdermal administration of buprenorphine selected from five different transdermal therapeutic systems, a first, a second, a third, a fourth and a fifth transdermal therapeutic system, each of the five different transdermal therapeutic systems comprising a buprenorphine-containing self-adhesive layer structure comprising

• A) a buprenorphine-impermeable backing layer, and
• B) a buprenorphine-containing matrix layer on said buprenorphine-impermeable backing layer, the matrix layer comprising
• a) a polymer base,
• b) buprenorphine, and
• c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the polymer base, and
• C) a skin contact layer on said buprenorphine-containing matrix layer comprising a polymer-based pressure-sensitive adhesive,
• and optionally wherein the buprenorphine-containing self-adhesive layer structure contains said buprenorphine in an amount of less than 0.8 mg/cm2 buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, and wherein
• the first transdermal therapeutic system provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 4.8 cm2 to about 8 cm2;
• and
• the second transdermal therapeutic system provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 9.5 cm2 to about 15 cm2;
• and
• the third transdermal therapeutic system provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 19 cm2 to about 30 cm2;
• and
• the fourth transdermal therapeutic system provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 28.5 cm2 to about 45 cm2;
• and
• the fifth transdermal therapeutic system provides a size of said buprenorphine-containing matrix layer providing the area of release ranging from more than 38 cm2 to about 60 cm2,
• wherein the five different transdermal therapeutic systems have increasing areas of release from the first to the fifth transdermal therapeutic system.