Sustained-release theophylline formulation

Claim 2

A pharmacologically-acceptable sustained-release theophylline formulation, which comprises matrix pellets in which theophylline particles are embedded in a matrix of water-insoluble plastic and which are enclosed by a membrane of water-insoluble plastic containing embedded particles of lactose.

Claim 3

A sustained-release theophylline formulation as claimed in claim 1, wherein the matrix pellets are built up from inert carrier pellets onto which the matrix containing the theophylline is applied.

Claim 4

A sustained-release theophylline formulation as claimed in claim 2, wherein the inert carrier pellets are sugar beads.

Claim 5

A sustained-release theophylline formulation as claimed in claim 1, wherein the theophylline particles have a particle size of less than 50 μm.

Claim 6

A sustained-release theophylline formulation as claimed in claim 1, wherein the water-insoluble plastic which forms the membrane is not swellable in water.

Claim 7

A sustained-release theophylline formulation as claimed in claim 5, wherein the water-insoluble plastic is a cellulose ether or a cellulose ester.

Claim 8

A sustained-release theophylline formulation as claimed in claim 1, wherein the particles of lactose embedded in the membrane have a particle size of less than 20 μm.

Claim 9

A sustained-release theophylline formulation as claimed in claim 1, which contains half a daily dose of theophylline.

Claim 10

A sustained-release theophylline formulation as claimed in claim 1, wherein a plastic in which lactose is insoluble is the p astic which forms the membrane.

Claim 11

A sustained-release theophylline formulation as claimed in claim 1, wherein some of the matrix pellets are in a slow form and some of the matrix pellets are in a rapid form.

Claim 12

A theophylline formulation as claimed in claim 10, wherein the matrix pellets of the slow form release more than 90%, of the theophylline present in the course of from 10 to 14 hours, preferably 11 to 13 hours in a USP paddle apparatus at pH 7.4, and the matrix pellets of the rapid form release more than 90%, of the theophylline present in the course of 4 to 8, hours in a USP paddle apparatus at pH 7.4.

Claim 13

A theophylline formulation as claimed in either claim 10 or claim 11, wherein 30 to 70 % of the theophylline is in the form of matrix pellets of the slow form.

Claim 14

A theophylline formulation as claimed in claim 11, which contains 50% of the theophylline as matrix pellets which release more than 95% of the theophylline present in the course of 12 hours in a USP paddle apparatus at pH 7.4, and 50% of the theophylline as matrix pellets which release more than 95% of the theophylline present in the course of 6 hours in a USP paddle apparatus at pH 7.4.

Claim 15

A process for the preparation of a sustained-release theophylline formulation, which comprises shaping micronized theophylline into matrix pellets together with a water-insoluble plastic and coating the matrix pellets with a membrane of water-insoluble plastic containing embedded particles of lactose.

Claim 16

A process for the preparation of a sustained-release theophylline formulation, which comprises shaping micronized theophylline into matrix pellets together with a water-insoluble plastic and coating the matrix pellets with a membrane of water-insoluble plastic containing embedded particles of lactose.

Claim 17

A process as claimed in claim 14, which comprises spraying a suspension of micronized theophylline in a solution of a water-insoluble plastic in an organic solvent onto carrier pellets to prepare the matrix pellets.

Claim 18

A process as claimed in claim 14, which comprises spraying the matrix pellets with a suspension of lactose in an organic-solvent solution of a water-insoluble plastic to coat said pellets.

Claim 19

A process as claimed in any one of claims 14, 15 and 16 for the preparation of a sustained-release theophylline formulation, wherein the membrane is a dialysis membrane, and which further comprises preparing the formulation in unit-dosage form.

Claim 20

A process as claimed in claim 17, which comprises combining matrix pellets which release the theophylline within 10 to 14 hours with matrix pellets which release the theophylline within 4 to 8 hours.

Claim 21

Enclosed-matrix theophylline pellets having 12-hour theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the ranges in the following table: __________________________________________________________________________ Hour 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th Percent 7-9 8-9 9-10 7-9 7-9 7-9 7-8 6-8 6-7 5-7 4-7 3-5 __________________________________________________________________________ and averaging from about 6.5 to 7.5 percent release per hour over a 12-hour period.

Claim 22

Enclosed-matrix theophylline pellets having 12-hour theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the ranges in the following table: __________________________________________________________________________ Hour 1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th Percent 7-9 8-9 9-10 7-9 7-9 7-9 7-8 6-8 6-7 5-7 4-7 3-5 __________________________________________________________________________ and averaging from about 6.5 to 7.5 percent release per hour over a 12-hour period.

Claim 23

Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative ranges in the following table: ______________________________________ Hour 1st 3rd 6th 9th Percent 8-16 30-50 65-85 >85. ______________________________________

Claim 24

Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative ranges in the following table: ______________________________________ Hour 1st 3rd 6th 9th Percent 8-16 30-50 65-85 >85. ______________________________________

Claim 25

Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative values in the following table: ______________________________________ Hour 1st 3rd 6th 9th Percent 12 38 73 >90. ______________________________________

Claim 26

Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative values in the following table: ______________________________________ Hour 1st 3rd 6th 9th Percent 12 38 73 >90. ______________________________________

Claim 27

Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative ranges in the following table: ______________________________________ Hour 1st 3rd 6th Percent 28-40 72-92 >95. ______________________________________

Claim 28

Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative ranges in the following table: ______________________________________ Hour 1st 3rd 6th Percent 28-40 72-92 >95. ______________________________________

Claim 29

Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative values in the following table: ______________________________________ Hour 1st 3rd 6th Percent 34 82 100. ______________________________________

Claim 30

Enclosed-matrix theophylline pellets having theophylline release properties, determined in the paddle model according to USP XX at 100 revolutions per minute at a pH of 7.4 (buffer), approximating the cumulative values in the following table: ______________________________________ Hour 1st 3rd 6th Percent 34 82 100. ______________________________________

Claim 31

A process for establishing and maintaining plasma theophylline levels in the therapeutic range over an extended period of time by orally administering a sustained-release formulation, as claimed in claim 1, to a patient in need of such therapy.

Claim 32

A sustained-release theophylline formulation as claimed in claim 7, wherein the particles of lactose embedded in the membrane have a particle size of less than 10 μm.

Claim 33

A theophylline formulation as claimed in claim 10, wherein the matrix pellets of the slow form release more than 95% of the theophylline present in the course of from 11 to 13 hours in a USP paddle apparatus at pH 7.4, and the matrix pellets of the rapid form release more than 95% of the theophylline present in the course of from 5 to 7 hours in a USP paddle apparatus at pH 7.4.

Claim 34

A theophylline formulation according to claim 12 wherein from 40 to 60% of the theophylline is in the form of matrix pellets of the slow form.

Claim 35

A pharmacologically-acceptable sustained-release theophylline formulation as claimed in claim 1, wherein the membrane comprises as claimed in claim 1, wherein the membrance comprises a weight ratio of plastic to lactose within a range of from about 2:1 to 1:3.