Title:  Extended release acetaminophen particles

United States Patent:  6,126,967

Inventors:  Clemente; Emmett (Manchester, MA); Anaebonam; Aloysius O. (Burlington, MA); Mendes; Robert W. (Dedham, MA); Fawzy; Abdel A. (Dracut, MA); Morrel; Eric M. (Medfield, MA)

Appl. No.:  146248

An extended release acetaminophen composition comprises a plurality of discrete particles containing acetaminophen which, when contained within a gelatin capsule and assayed in a USP Apparatus I rotating basket at 50 rpm in 900 mL of phosphate buffer at pH 5.8 and 37^oC., exhibits about 40 percent to about 53 percent acetaminophen dissolution at one-half hour, about 50 percent to about 68 percent dissolution at 45 minutes, about 57 percent to about 77 percent acetaminophen dissolution at one hour, and about 82 percent to about 92 percent acetaminophen dissolution at two hours. After six hours, the contemplated extended release acetaminophen composition exhibits substantially complete dissolution. A process for treating a human patient with the extended release acetaminophen composition is also disclosed.

SUMMARY OF THE INVENTION

The present invention contemplates an extended release composition of acetaminophen in the form of generally spherical particles. The particles can be packaged in a gelatin capsule or a blister, and the contents administered in the gelatin capsule to adults that can swallow such capsules or the contents of the capsule or blister can be emptied therefrom and dispersed in an edible medium such as applesauce that can be swallowed by patients such as children that cannot swallow or have difficulty swallowing tablets, caplets or capsules.

The extended release acetaminophen composition comprises a plurality of discrete particles containing acetaminophen which, when contained within a gelatin capsule and assayed in a USP Apparatus I rotating basket at 50 rpm in 900 milliliters (mL) of phosphate buffer at pH 5.8 and 37^oC. exhibits about 40 percent to about 53 percent acetaminophen released at one-half hour, about 50 percent to about 68 percent released at 45 minutes, about 57 percent to about 77 percent acetaminophen released at one hour, and about 82 percent to about 92 percent acetaminophen released at two hours. After six hours, the contemplated extended release acetaminophen exhibits substantially complete release.

Even though there appears to be overlap of the dissolution values at various times and subsequent, adjacent times, it is to be understood that a dissolution value within a stated range of values at a particular time increases from that dissolution value at a later time. As a consequence, even though the upper limit for a previously recited time frame can overlap with a lower limit from a subsequent time frame, an individual sample exhibits greater dissolution values until substantially complete dissolution is achieved.

Advantageously, a contemplated extended release acetaminophen composition provides an extended or sustained release profile in a particle-or prill- containing gelatin capsule or blister. A contemplated composition can thus be dispersed or sprinkled on, for example, food such as applesauce, so that it can be administered to a patient that, otherwise has difficulty taking, or could not take a "solid" tablet or caplet. Thus, the present extended release composition now provides long term analgesic administration for patients who otherwise could not obtain such relief.

It is to be understood that reference herein to gelatin capsule, capsule or blister is made only for the purpose of describing or providing various alternate packaging or "containing" vehicles for the composition of the present invention, and is not intended to limit the scope of the present invention. All such packaging or "containing" vehicles are thus within the scope of the present invention.

One exemplary composition comprises particles containing acetaminophen coated on sugar/starch seeds. All of these particles are free of a wicking agent and an erosion promoter as required and utilized in U.S. Pat. No. 4,820,522. The particles are present as a blend of both an immediate release and a controlled release form.

Preferably, the controlled release particles comprise a sugar/starch seed particle coated with a plurality of layers of acetaminophen and magnesium stearate that are bound with povidone. Most preferably, the acetaminophen-containing layers are coated with a plurality of layers of a mixture of povidone and magnesium stearate. In a contemplated composition, the weight ratio of acetaminophen to magnesium stearate in the controlled release particles is about 5:1 to about 10:1, and acetaminophen comprises about 70 to about 80 weight percent of the controlled release particles.

In a preferred composition, the immediate release particles also comprise sugar/starch seed particles, which seeds are coated with a plurality of layers of a mixture of acetaminophen, starch and cross-linked carboxymethyl cellulose bound with povidone. A preferred cross-linked carboxymethyl cellulose is croscarmellose NF. In a preferred composition, the immediate release particles contain acetaminophen, starch and cross-linked carboxymethyl cellulose in a weight ratio of about 13-16:1:1.5-2, respectively, and acetaminophen constitutes about 60-70 weight percent of the particles.

A preferred blend of the composition includes immediate release particles and controlled release particles in a weight ratio of about 1:1 to about 1:1.5, respectively.

The blend can also contain coated sugar/starch seeds that are free of acetaminophen. In one such blend, the immediate release particles, the controlled release particles and the coated sugar/starch seeds are present in a weight ratio of about 1:1-1.5:0.1-0.25.

Another exemplary composition comprises acetaminophen particles coated with each of a first, second and third layer, the first and third layers being hydroxypropyl cellulose and the second layer being ethylcellulose. Preferably, the weight ratio of each the first, second and third layers on a bead is about 1:4-6:1, respectively, and the acetaminophen constitutes about 92 to about 94 weight percent of each bead.

Most preferably, the beads are sized so that about 90 percent by weight pass through a 20 mesh sieve screen and about 90 percent by weight are retained on an 80 mesh sieve screen.

A process for treating a human patient that has difficulty swallowing acetaminophen in tablet, caplet or capsule form includes the steps of distributing an effective amount of the particles in a pharmaceutically acceptable palatable medium to form an acetaminophen particle-containing medium and administering the acetaminophen particle-containing medium to the human patient.

The present process is particularly contemplated for administering the composition to human patients that are about three months to about 14 years old, and particularly to children 2 to about 11 years old, including children that are febrile. However, the composition can be used by others that may have difficulty swallowing a tablet, caplet or capsule, or it can be used by those that do not have difficulty taking such "solid" non-dispersible medication forms.

Claim 1 of 18 Claims

What is claimed is:

1. An extended release acetaminophen composition comprising a plurality of discrete particles containing acetaminophen which, when contained within a gelatin capsule and assayed in a USP 23/NF 18 Apparatus I rotating basket at 50 rpm in 900 mL of phosphate buffer at pH 5.8 and 37^oC. exhibits about 40 percent to about 53 percent acetaminophen dissolution at one-half hour, about 50 percent to about 68 percent dissolution at 45 minutes, about 57 percent to about 77 percent acetaminophen dissolution at one hour, about 82 percent to about 92 percent acetaminophen dissolution at two hours and about 100 percent dissolution at six hours.

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