Controlled absorption naproxen formulation for once-daily administration

Claim 2

A naproxen formulation according to Claim 1, characterised in that said first portion is in pellet form, said pellet comprising a core of naproxen or a pharmaceutically acceptable salt thereof in association with an organic acid, the naproxen component and the organic acid being present in a ratio of from 20:1 to 1:1, and a multi-layer membrane surrounding said core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble polymer and optionally a minor proportion of a pharmaceutically acceptable film-forming, water soluble polymer, the number of layers in said membrane and the ratio of said water soluble to water insoluble polymer being effective to permit release of said naproxen from said pellet at a rate allowing controlled absorption thereof at therapeutically effective blood levels over a 24 hour period following each daily oral administration.

Claim 3

A pellet formulation according to Claim 2, characterised in that the pellet has a dissolution rate which when measured in vitro in a type 1 dissolution basket apparatus according to U.S. Pharmacopoeia XXII in phosphate buffer at pH 7.2 and at 75 r.p.m. substantially corresponds to the following dissolution pattern: a) from 0 to 50% of the total naproxen is released after 1 hour of measurement in said apparatus; b) from 20 to 70% of the total naproxen is released after 2 hours of measurement in said apparatus; and c) not less than 50% of the total naproxen is released after 4 hours of measurement in said apparatus.

Claim 4

A pellet formulation according to Claim 2, characterised in that the pellet has a dissolution rate which when measured in vitro in a type 2 dissolution basket apparatus according to U.S. Pharmacopoeia XXII in phosphate buffer at pH 7.4 and at 50 r.p.m. the dissolution rate substantially corresponds to the following dissolution pattern: a) from 20 to 70% of the total naproxen is released after 1 hour of measurement in said apparatus; b) not less than 50% of the total naproxen is released after 2 hours of measurement in said apparatus; and c) not less than 75% of the total naproxen is released after 4 hours of measurement in said apparatus.

Claim 5

A pellet formulation according to any one of Claims 2 to 4, characterised in that the core comprises naproxen or a pharmaceutically acceptable salt thereof and the associated organic acid embedded in a polymeric material.

Claim 6

A pellet formulation according to Claim 5, characterised in that the polymeric material is insoluble in water or slightly permeable to naproxen and water.

Claim 7

A pellet formulation according to any preceding claim, characterised in that the core comprises: a) a powder mixture containing naproxen or a pharmaceutically acceptable salt thereof and an organic acid selected from adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid; and b) a polymeric material containing a proportion of a pharmaceutically acceptable water soluble polymer and a proportion of a pharmaceutically acceptable water insoluble polymer, 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.

Claim 8

A pellet formulation according to any one of Claims 2 to 7, characterised in that the water insoluble polymer of the membrane is selected from ethyl cellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) or polyurethane or a mixture thereof or from a naturally occurring polymer selected from shellac, chitosan, gumjuniper or a mixture thereof.

Claim 9

A pellet formulation according to any one of Claims 2 to 8, characterised in that the water soluble polymer of the membrane is selected from polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose, agar, carrageenan, xanthan, hydroxypropylmethyl cellulose or polyethylene glycol or a mixture thereof.

Claim 10

A pellet formulation according to any one of Claims 2 to 8, characterised in that the water insoluble polymer of the membrane is replaced as appropriate by a proportion of a polymer which is slightly permeable to naproxen and in that water and the water soluble polymer of the membrane is replaced by a proportion of a polymer which is freely permeable to naproxen and water.

Claim 11

A process for the production of a formulation according to any one of Claims 2 to 10, which comprises forming a core of naproxen or a pharmaceutically acceptable salt thereof and an organic acid and enclosing the core in a membrane of a film-forming polymer or mixture thereof as defined in Claim 2 which permits release of the naproxen or the pharmaceutically acceptable salt thereof in the manner set out in any one of Claims 2 to 4.

Claim 12

A controlled absorption naproxen formulation for oral administration, characterised in that it comprises pellets according to any one of Claims 2 to 10, said formulation including a sufficient quantity of a rapid release form of naproxen to ensure prompt achievement of analgesically effective blood levels together with therapeutically effective blood levels over a 24 hour period following each daily oral administration.

Claim 13

A controlled absorption naproxen formulation according to Claim 12, characterised in that it has a dissolution rate which when measured in a type 1 dissolution basket apparatus according to U.S. Pharmacopoeia XXII in phosphate buffer at pH 7.2 and at 75 r.p.m. substantially corresponds to the following dissolution pattern: a) from 15 to 50% of the total naproxen is released after 0.5 hours of measurement in said apparatus; b) from 25 to 75% of the total naproxen is released after 1 hour of measurement in said apparatus; and c) not less than 65% of the total naproxen is released after 4 hours of measurement in said apparatus.

Claim 14

A controlled absorption naproxen formulation according to Claim 12, characterised in that it has a dissolution rate which when measured in vitro in a type 2 dissolution paddle apparatus according to U.S. Pharmacopoeia XXII in phosphate buffer at pH 7.4 and at 50 r.p.m. the dissolution rate substantially corresponds to the following dissolution pattern: a) from 25 to 60% of the total naproxen is released after 0.5 hours of measurement in said apparatus; b) from 35 to 75% of the total naproxen is released after 1 hour of measurement in said apparatus; and c) not less than 65% of the total naproxen is released after 4 hours of measurement in said apparatus.

Claim 15

A capsule or tablet comprising a formulation according to any one of Claims 1 to 10 or 12 to 14.