MXPA01002220A - Extended release acetaminophen - Google Patents

Abstract

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°C, 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.

Description

ACETAMINOFEN WITH PROLONGED RELEASE FIELD OF THE INVENTION This invention relates to the administration of a medicament with prolonged release. More specifically, the invention relates to an acetaminophen composition that has particular characteristics of acetaminophen release in vitro and is adapted for use in human patients who have difficulty swallowing acetaminophen tablets or capsules.

BACKGROUND OF THE INVENTION Medications with coating are well known to effect a prolonged or controlled release administration profile. Drug manufacturers have used such methods to provide oral administration of drugs that enter the body for a period of time. predetermined time, prolonged. Controlled release administration provides multiple benefits to a patient, for example, administration with prolonged release can reduce the number of times a patient requires self-administration of the medication, thereby reducing the possibility that the patient will forget Take your medication during the day: Analgesics and antipyretics, such as acetaminophen, are usually self-administered over the course of a day to help relieve pain or fever from which a person suffers. However, it is not necessary for the symptoms to affect the daily life of a person, so the person may not remember to take their medication due to other daily activities, as a result it has become advantageous to provide an analgesic medication with prolonged or controlled release for self-administration.This administration with controlled release can at the same time reduce Circulate the number of times a patient takes the medication during the day. The controlled release properties also facilitate overnight administration in that it is possible to provide a coating for controlled release in order to sufficiently extend over the period during which the person sleeps. For the preparation and application of a coating for controlled or prolonged release, as is known, the medicament is prepared as a quantity of small granules, non-pareils or globules, which are small, generally spherical in shape of the medicament. The granules are coated with, for example, a film coating product based on aqueous ethylcellulose, which dissolves when subjected to moisture or liquid aqueous medium. The granules may be contained within a gelatin capsule or ampoule. The capsule, like the ethylcellulose coating, dissolves when subjected to wet conditions or a liquid aqueous medium. The ampoule is not normally administered to a patient, but rather is opened or separated and the content of the ampule is emptied for its use. A method of applying the coating to the granulates uses a technique known as drum. This technique was originally developed to coat sugar and is described by SC Porter in "Coating of Pharmaceutical Dosage Forms", Remington's Pharmaceutical Sciences, 18th ed., AR Gennaro ed., Chapter 90, Mack Publishing Co., Easton PA (1990). ) pages 1666-1675. U.S. Patent No. 4,820,522 teaches the preparation of acetaminophen with prolonged release which includes hydroxyethyl cellulose as an excipient and povidone (polyvinyl pyrrolidone) as a granulating agent to form a molded and compressed medicament. The resulting compressed medicament is provided in the form of a compressed tablet or as a layer of a multilayer tablet. In this composition, povidone, hydroxyethyl cellulose and other ingredients bind to acetaminophen in a solid matrix for prolonged release. A composition of this patent is established to further require the inclusion of a "wicking agent", such as microcrystalline cellulose to cause fluids to enter the matrix and also an "erosion enhancer" such as pregelatinized starch. Although a composition of this patent provides sustained release of acetaminophen to normal adultsSuch a composition is tabletted and as such, can not provide the medication to a patient who has difficulty swallowing a tablet. Another method of coating application is to coat the granulate in a fluidized bed coating system. A normal type of system is the Wurster type coater. In this system, the container for fluidized bed coating includes an air intake nozzle at the bottom and an air outlet nozzle at the top. The container normally has a middle, divergent body expansion section. In approximately the expansion section, an air distributor plate covers the container. The distributor plate defines a top reactor section and a lower or full air intake section. The distributor plate includes holes in it to effect a relatively uniform air distribution through the plate. A column for the cylindrical lining, partition type extends upwards from above the distributor plate towards the reactor section. The space between the lining column and the walls of the container define a downflow bed. The coating column is located above the distributor plate to define a space between them. The space has the dimension to allow the inflow of material from the descending flow bed; through space, and towards the column. A spray nozzle extends from the feed section to the coating column from below the distributor plate. The spray nozzle is configured to provide a spray for the coating material towards the column. During operation, the container is charged with an amount of the granulate to be coated. The granulator rests in the downflow bed, above the distributor plate, and surrounding the coating column.

Air is supplied to the container through the air intake nozzle to the intake plenum. The air flow rate is selected to fluidize the downflow bed. In a common arrangement, the air flow is selected to establish an incipient fluidized bed in the region surrounding the coating column. In the incipient fluidized bed, the pressure drop across the bed is equal to the gravitational force acting on the granulated particles. Thus, the bed is minimally fluidized, and no gaps or channels are formed in it.

The coating material is fed to the coating column through the spray nozzle. The upward flow of material and air through the column creates a low pressure zone in the lower part of the column that drags the granulate from the downflow bed through the space between the distributor plate and the column. As the granulate enters the column, it is accelerated upwards by the spray and the air flow. In the coating column and the space above it, the intimate mixing of the granulate and the coating material takes place. As the granulated coating rises in the column and loses energy, it is pushed out, away from the updraft stream above the column. When the granulate loses enough energy to be overcome by the gravitational forces, it falls back on the bed of downward flow. The process is continued until the entire batch of loaded granulate is coated. When the process is complete, the granulate is removed from the container for further processing. In some fluidized bed coating systems, a significant amount of drying of the granulate occurs within the upper areas of the reactor vessel before the granulate falls back into the downflow column.

The particular process controls, flow rates and pressures are usually determined, among other things, by the particle size and density, the type of coating and the desired coating thickness, the conditions of the air fed and the drying requirements. . The particular process control parameters for a given system will be recognized by those skilled in the art. Although the Wurster-type coater has been used to provide coatings of all kinds for the drug industry, it is desirable to be able to more accurately predict the release rates over time or the dissolution profiles of such coated drugs. Due to the nature of the arrangement of the distributor plate, it has been observed that the granulate can agglomerate in the coating column. The agglomeration of the granulate can cause irregular coating of this, which in turn, can produce less predictable dissolution rates. Accordingly, there is still a need for a prolonged release acetaminophen composition which can be used to treat children and adults having difficulty swallowing tablets or capsules, and which presents a predictable profile for the prolonged release of acetaminophen over a period of time.

SUMMARY OF THE INVENTION The present invention contemplates a composition of acetaminophen with prolonged release in the form of generally spherical particles. The S-particles can be packaged in a gelatin capsule or ampoule, and the contents can be administered in the gel capsule to adults who can swallow such capsules or the contents of the capsule or ampoule can be emptied from them and dispersed in the capsule. an edible medium such as apple juice that can be swallowed by patients as children who can not swallow or have difficulty swallowing tablets, capsules or lozenges. The prolonged release acetaminophen composition contains a plurality of small particles containing acetaminophen that, when they are contained within a gelatin capsule and are evaluated in a rotating basket of USP Apparatus I at 50 rpm in 900 milliliters (ml) of phosphate buffer at pH 5.8 and 37 ° C, it presents approximately 40% to approximately 53% acetaminophen released in half an hour, approximately 50% to approximately 68% released at 45 minutes, approximately 57% to approximately 77% acetaminophen released in one hour, and approximately 82% to approximately 92% acetaminophen released in 2 hours . After 6 hours, the prolonged release acetaminophen contemplated presents almost complete release. Although there seems to be superposition of the dissolution values at different subsequent adjacent times and times, it should be understood that a dissolution value within a set interval of values at a particular time increases the dissolution value at a later time. As a consequence, although the upper limit for a previously mentioned time frame can be superimposed with a lower limit of a subsequent time frame, a single sample presents higher dissolution values until the practically complete dissolution is obtained. For convenience, a contemplated prolonged release acetaminophen composition provides a prolonged or sustained release profile in a gelatin capsule or ampule containing the particles or granules. A contemplated composition can thus be dispersed or powdered in, for example, foods such as applesauce, so that it can be administered to a patient who otherwise has difficulty taking, or could not take a "solid" tablet or lozenge. " Thus, the extended-release composition present now provides long-term analgesic administration to patients otherwise "unable to obtain such assistance." It is to be understood that the reference herein to the gelatin, capsule or blister capsule or ampoule is made solely for the purpose of describing or providing different alternative packaging or "containment" vehicles for the composition of the present invention, and is not intended to limit the scope of the present invention Such packaging or "containment" vehicles in this way An exemplary composition consists of acetaminophen-containing particles coated on sugar / starch seeds All of these particles are free of a wicking agent and an erosion promoter as required and used in US Pat. 4,820,522 The particles are present as a mixture of a release form i Immediate and a controlled release form. Preferably, the particles for controlled release contain a sugar / starch seed particle coated with a plurality of layers of acetaminophen and magnesium stearate which bind with povidone. More 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 contains about 70 to about 80% by weight in controlled release particles. In a preferred composition, the immediate release particles also contain sugar / starch seed particles, the seeds of which are coated with a plurality of layers of a mixture of acetaminophen, starch and cross-linked carboxymethyl cellulose agglutinated with povidone. A preferred cross-linked carboxymethyl cellulose is croscarmellose NF. In a preferred composition, the immediate release particles contain acetaminophen, starch and crosslinked carboxymethyl cellulose in a weight ratio of about 13-16: 1: 1.5-2, respectively, and acetaminophen constitutes about 60-70% by weight of the particles. A preferred mixture 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 mixture may also contain coated sugar / starch seeds that are free of acetaminophen. In one of these mixtures, 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 contains 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 of the first, second and third layers in a bead is approximately 1: 4-6: 1, respectively, and acetaminophen constitutes approximately 92 to approximately 94% by weight of each bead. More preferably, the beads are sized so that approximately 90% by weight passes through a 20 mesh screen and approximately 90% by weight is retained on an 80 mesh screen. A process for treating a human patient who has difficulty swallowing acetaminophen in the form of a tablet, dragee or capsule includes the steps of: distributing an effective amount of the particles in a palatable, pharmaceutically acceptable medium to form a medium containing acetaminophen particles and administering the medium containing the acetaminophen particles to a human patient. The present process is particularly contemplated for administering the composition to human patients who are approximately three months to approximately 14 years of age, and, particularly, to children of two to approximately 11 years of age, including children suffering from fever. However, the composition may be used by others who may have difficulty swallowing a tablet, capsule or lozenge, or may be used by those who have no difficulty in taking these "solid" non-dispersible forms of medication. Other features and advantages of the present invention will be apparent from the following detailed description, the accompanying drawings and the accompanying clauses.

BRIEF DESCRIPTION OF THE DRAWINGS In the figures forming a part of this description: Figure 1 is an illustration of a fluidized bed coating system for preparing an exemplary extended release acetaminophen composition incorporating the principles of the present invention; Figure 2 is a graphic illustration of the overall results of a randomized trial comparing the composition of acetaminophen present and an Immediate Release Elixir Tylenol® for children in children with hyperthermia, showing the average temperature in degrees Fahrenheit as a function of time, in which circles represent data for an acetaminophen composition contemplated and the triangles represent the data for the product Elixir Immediate Release Tylenol®; Figure 3 is a graphic illustration of the data of Figure 2 in which data are segregated by the concomitant use and non-use of an antibiotic. In this case, the full and empty circles represent data for an acetaminophen composition contemplated with and without, respectively, the concomitant use of an antibiotic, while the full and empty triangles represent data for the product Elixir ae Immediate Release Tylenol® with and without, respectively, the concomitant use of an antibiotic; and Figure 4 is a graphic illustration of the data of Figure 2 in which the data is segregated by high and low base temperatures. In this figure, the full and empty circles represent data for an acetaminophen composition contemplated at high and low base temperatures, respectively, and the full and empty triangles represent data for the Elixir product of Immediate Release Tylenol® at high and low base temperatures, respectively.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention contemplates acetaminophen prolonged release. Acetaminophen is present as a composition of coated beads or particles (also known herein as pellets, granules or beads). In a first exemplary form, the composition is a mixture of beads or particles of an immediate release form and a controlled or sustained release form. In a second exemplary form, the beads are generally spherical particles that are coated to provide prolonged release. The composition, when contained within a gelatin capsule and tested in vitro using the rotating basket protocol of USP Apparatus I in 900 ml of phosphate buffer at a pH value of about 5.8 and at a temperature of about 37 ° C, it presents about 40% to about 53% of acetaminophen released in half an hour, about 50% to about 68% of acetaminophen released in 45 minutes, about 57% to about 77% of acetaminophen released in one hour and about 82 % to approximately 92% of acetaminophen released in 2 hours. After 6 hours, the prolonged release acetaminophen, contemplated, presents practically complete release. Exemplary data for dissolution (eg, release) and contemplated compositions are illustrated below. Although there seems to be superposition of the dissolution values at different subsequent, adjacent times and times, it should be understood that a dissolution value within a set interval of values at a particular time increases from this dissolution value at a later time. As a consequence, although the upper limit for a previously established time frame may overlap with a lower limit of a subsequent time frame, an individual sample presents higher dissolution values until nearly complete dissolution is obtained. A composition prepared according to the present invention has surprising and significant advantages over the known acetaminophen preparations. Specifically, the composition exhibits substantial temperature depression in hyperthermic children, and particularly in periods of time after approximately 2-1 / 2 hours after administration, as compared to equally administered amounts of known, immediate release acetaminophen preparations. Most surprisingly, a prolonged release acetaminophen composition prepared in accordance with the present invention exhibited depressed sustained temperature compared to the commercial known acetaminophen preparation, in a time interval between about 4 hours and 6 hours , even after the subsequent administration of the commercial preparation 4 hours after the initial administration. Those skilled in the art will recognize that sustained temperature depression, i.e., relief of fever, has extreme benefits when administered to young children. Medical professionals, as well as parents and caregivers of young children, know well that it is difficult, if not impossible, to have a small child swallow a pill or tablet. As such, the use of a prolonged-release acetaminophen composition in a child was previously unknown. The present extended release acetaminophen composition provides such long-term relief in a palatable form. The present composition allows administration of the drug to a child so that the child can benefit from the prolonged release formulation. This single-dose administration can be extremely beneficial during the night, when it may now be possible for a child to rest or sleep comfortably for a sufficient time, 8 hours or more, while under the effects of the analgesic, compared with having to wake up the child to provide a second administration. Parents know very well that a "very good night's sleep" can be beneficial for the comfort and recovery of a sick child.

A. The composition The contemplated composition is contained within an ampoule (or a gelatin capsule that can be administered orally as a capsule), which can be opened and the particles mixed with, for example, food such as applesauce, tapioca, pudding with flavor or yogurt for those patients who have difficulty or can not swallow a capsule, tablet or lozenge. Two exemplary compositions and methods for preparing these compositions are described below. It should be understood that the following descriptions are for illustrative purposes only and are not intended to limit the present invention to the exemplary compositions and methods for preparing the compositions provided herein. The profiles or specifications for dissolution have been developed for the preparation of acetaminophen present based on two accepted test techniques, namely, the rotary basket and rotary bottle methods, which are described in more detail below. The specifications include particularly preferred dissolution values based on the regulatory requirements, that is, the FDA, and the "internal" requirements as determined by the rotating basket method and the "internal" requirements as determined by the the rotary bottle Particularly preferred dissolution profiles are as shown in the following Tables 1 and 2.

TABLE 1 DISSOLUTION PROFILE PARTICULARLY PREFERRED FOR THE PREPARATION OF PROLONGED RELEASE ACETAMINOFEN PRESENT AS MEASURED BY THE ROTATING BASKET METHOD TABLE 2 DISSOLUTION PROFILE PARTICULARLY PREFERRED FOR THE PREPARATION OF PROLONGED RELEASE ACETAMINOFEN, PRESENT, AS MEASURED BY THE ROTATING BOTTLE METHOD Some of the ranges of dissolution values presented in the above are superimposed, so that an upper limit of an interval er. a specific time may have a greater percentage isolated than a lower limit of an interval in a subsequent subsequent time. This does not imply that the dissolution value is constant or reversed as time progresses. Instead, the solution follows a substantially smooth curve with the total amount of acetaminophen being dissolved increasing with time until virtually all of the acetaminophen is dissolved. i. First Extractable Composition A first exemplary composition is a mixture of beads or particles of an immediate release form and a controlled or sustained release form containing acetaminophen coated on sugar / starch seeds. A preferred composition further includes inactive particles, without acetaminophen or nonpareils (also known herein as "placebo beads"), such as coated sugar / starch seeds. The first exemplary prolonged release acetaminophen composition includes a distribution of controlled release particles and immediate release particles that are prepared to effect a desired dissolution profile, which is dependent on the results of the tests in process. The batch quantities of the particles that are used to prepare the distribution are about 110 kg to about 140 kg of the controlled release particles, about 90 kg to about 115 kg of immediate release particles and about 0 kg to about 50 kg of particles. placebo particles. Those skilled in the art will appreciate that the weights of the different particles in each dose, for example, the ampoule or capsule, may vary depending on the specific dose desired, however, the weights of the immediate release and release particles. Controlled relative to each other usually remain relatively constant, to obtain that desired distribution and thus the desired dissolution profile. Also, those skilled in the art will realize that the particular "dosage" provided in a given ampoule or capsule may vary depending on the desired dosage. The anticipated desired dosages are 160 mg, 240 mg, 325 mg, and 650 mg of the blisters. The controlled release particles include acetaminophen, magnesium stearate, and povidone arranged on a seed or sugar / starch core. A preferred sugar / starch seed is NF sugar spheres of mesh between about 45 and 50, containing not less than 62.5% and not more than 91.5% sucrose, calculated on the anhydrous basis, the remainder consisting mainly of starch. (USP NF 1995 2313). In a preferred form, the controlled release particles include a plurality of layers of acetaminophen and magnesium stearate on the sugar / starch seeds, the layers of which are bound with povidone. More preferably, the acetaminophen-containing layers are coated with a plurality of layers of a mixture of povidone and magnesium stearate. A preferred preparation of the controlled release particles includes acetaminophen in a weight ratio to magnesium stearate of between about 5: 1 and about 10: 1, and acetaminophen is about 70 to about 80% by weight of the controlled release particles . A batch formula contemplated for controlled release particles includes "starter beads" having a batch formula of approximately 100 kg of acetaminophen, approximately 5.3 kg of magnesium stearate NF, approximately 21.6 kg of NF sugar spheres (40 to 50 mesh) about 17 kg to about 30 kg of a standard 15% solution of povidone / isopropyl alcohol (IPA), and about 47 kg to about 80 kg of isopropanol. A batch of 130.2 kg of the "starter beads" that are used to prepare the controlled release particles then has added thereto as additional coatings, about 5.85 kg to about 15.6 kg of magnesium stearate NF, about 2.4 about 6.4 1 isopropanol and about 2.4 1 to about 6.4 1 of 15% standard solution of povidone / IPA. The amount (ie the weight) of magnesium stearate, isopropanol and the povidone / IPA solution applied as the coating depends on the number of coatings required to meet the specifications; that is, the desired dissolution profile, as determined during the trials in the process. The immediate release particles are likewise formed from sugar / starch seeds having a plurality of layers of a mixture of acetaminophen, starch and a crosslinked carboxymethyl cellulose, preferably, croscarmellose sodium NF, which are bound with povidone. Preferably, acetaminophen is present in a weight ratio to the starch and sodium carboxymethyl cellulose of about 13-16: 1: 1.5-2, respectively, and the acetamotrophen is about 60-70% by weight of the particle of immediate release. The batch formula contemplated for the immediate release beads includes approximately 100 kg of acetaminophen, approximately 7.1 kg of crosslinked carboxymethyl cellulose, preferably croscarmellose NF, approximately 11.9 kg of NF starch, approximately 25.6 kg of NF sugar spheres (40 mesh a). 50) about 19 kg to about 34 kg of 15% standard solution povidone / IPA, and about 53 kg to about 91 kg of isopropanol. The composition may further include, as part of the mixture, placebo particles of coated sugar / starch seeds that do not contain acetaminophen. Preferably, the coated sugar spheres have a mesh size between about 30 and about 35. A batch formula contemplated for the placebo particles includes about 10 kg of ethylcellulose 7-FP, about 50 kg of NF sugar spheres (30 mesh). -35), approximately 1.2 kg of methylcellulose E-5, and purified water as needed. A final distribution of the immediate release particles, the controlled release particles and the placebo particles is made to effect a predetermined dissolution profile, and can be done to effect the particularly preferred dissolution profiles that are provided in Tables 1 and 2. The valuation techniques are described below. ii. Preparation of the first exemplary composition The different particles forming the first exemplary composition, i.e., the immediate release particles, the controlled release particles and the placebo particles each are prepared in separate processes as presented below, and subsequently they mix together to form the extended-release acetaminophen composition, present. to. Preparation of immediate release particles The immediate release particles are prepared in two batches. An amount of 100 kilograms (kg) of acetaminophen, an amount of 7.1 kg of croscarmellose sodium NF, and an amount of 11.9 kg of starch NF, is each divided in half, and the three constituents are mixed together to form two identical lots. Each of the lots is sifted through an 80 mesh screen using a mill such as a Fitzpatrick Mili mill. The two sifted lots are then mixed together to form a mixture, which is tested for composition according to accepted quality assurance test methods that are well known to those skilled in the art. The mixture of acetaminophen is subsequently divided into three equal parts, with a first part remaining as a whole, and the second and third parts each divided into lots of 50%, 30% and 20%. An amount of 25.6 kg of sugar seeds / 40-50 mesh starch, for example, NF sugar spheres, is placed in a stainless steel lining container. An amount of 80 liters (1) of 5% povidone / IPA solution is prepared for spraying on the particles. The container for the coating or drum is ripped off with the sugar spheres, onto which an application (approximately 0.173 kc per application) of the povidone-alcohol solution is sprayed, and on which an application is screened (approximately 0.32. g of the mixture of acetaminophen from the first part (that part that remained complete) The sieving is done using a normal sieve The spraying and sieving steps are continued until the first part of the mixture has been applied to the spheres sugar to form a batch of partially coated spheres.The partially coated spheres are then divided into two equal batches, each batch being placed in a container for coating.Separate for each of the two batches, the spraying of the povidone / solution IPA and the sieving of the acetamincfen mixture as it was divided into the 50% batches continues until the batches of 50% have been applied to the spheres. Application of batches at 50%, the spheres can be screened using a 25 mesh screen if necessary. The spraying of the povidone / IPA solution and the sieving of the acetaminophen mixture as it was divided in the 30% batches starts and continues until the batches of 30% have been applied to the spheres. The coated spheres can be screened again using a 25 mesh screen. Spraying the povidone / IPA solution and sieving the acetaminophen mixture, continues using the mixture as it was divided into batches of 20% have been applied to the spheres . At this point in the process, the entire amount of the acetaminophen mixture has been applied to the spheres, and approximately 50 kg of the 5% povidone / IPA solution has been applied to the spheres. A 7.5% povidone / IPA solution is prepared and applied to the spheres as a sealant. The sealed spheres are drum dried for about an hour, weighed and placed in an oven at approximately 122 ° F (68 ° C) for 24 hours. After drying, the spheres are screened through a 20 mesh screen and a 38 mesh screen to form the immediate release particles. Those skilled in the art will recognize that different mixtures and solutions must be weighed, tested and analyzed in the stages selected during the process.

Those skilled in the art will also recognize that the isopropanol as well as the isopropyl alcohol component of the povidone / IPA solution evaporates during the production process, and as such, its weights should not be considered in the total weight of the particles of the final immediate release particles. b. Preparation of controlled release particles The controlled release particles are prepared in a process similar to that used to prepare the immediate release particles, using a process of spraying and repeated sieving. First, "starter beads" are prepared using an amount of 100 kg of acetaminophen and an amount of 5.3 kg of magnesium stearate which are each divided in half, and the two constituents are mixed together to form two identical batches. Each of the lots is sifted through an 80 mesh screen using a mill such as Fitzpatrick Mili mill. The two sifted lots are then combined together to form a mixture, which is tested for composition according to the accepted quality assurance assessment methods. The acetaminophen mixture is then divided into three equal parts, with a first part remaining complete, and a second and third parts each divided into batches of 50%, 30% and 20%. An amount of 21.6 kg of 40-50 mesh sugar / starch seeds, such as the NF sugar spheres, is placed in a stainless steel lining container. An amount of 80 liters (L) of a 5% povidone / IPA solution is prepared for spraying on the particles. The coating container is ripped off with the sugar spheres, onto which an application (approximately 0.16 kg per application) of the povidone / IPA solution is sprayed, and onto which an application (approximately 0.3 kg) of the mixture is sieved. of acetaminophen from the first part (that part that remained complete). The sieving is done using a normal sieve. The spraying and sieving steps continue until the first part of the mixture has been applied to the sugar spheres to form a batch of partially coated spheres. The partially coated spheres are then divided into two equal batches, each batch being placed in a coating pan. Separately for each of the two batches, the spraying of the povidone / IPA solution and the screening of the acetaminophen mixture in 50% batches continues until 50% batches have been applied to the spheres. After the application of the batches of 50%, the spheres can be sieved 3o using a 25 mesh screen, if necessary. The spraying of the povidone / IPA solution and the sieving of the acetaminophen mixture as it was divided in the 30% batches starts and continues until the batches of 30% have been applied to the spheres. The coated spheres can be screened again through a 25 mesh screen, if necessary. The spraying of the povidone / IPA solution and the screening of the acetaminophen mixture begins and continues using the mixture divided into batches of 20% until the batches of 20% have been applied to the spheres. At this point in the process, the entire amount of the acetaminophen mixture has been applied to the spheres, and approximately 50 kg of the 5% povidone / IPA solution has been applied to the spheres. A 7.5% solution of povidone / IPA is prepared and applied to the spheres as a sealant, the sealed spheres are drum dried for one hour, weighed and placed in an oven at approximately 122 ° F (68 ° C) for 24 hours. hours. After drying, the spheres are screened using a 20 mesh screen and a 38 mesh screen, whose sieved beads form the "starter beads". An additional 7.5% povidone / IPA solution is prepared, and the "starter beads" are divided into two equal charges. An amount of magnesium stearate necessary to coat the particles is then prepared. The pearls are moistened by applying a quantity (approximately 0.7 1) of the povidone / IPA solution and coated by applying approximately 0.8 kg of magnesium stearate. The coated starter beads are dried for approximately 15 minutes. The wetting steps with povidone / IPA solution and the magnesium stearate coating continue until a desired number of "layers" is obtained. The coated beads are tested and a release pattern is obtained during the tests in the process. The "coating" can then be repeated until a desired release pattern is obtained, that is, until it is released. Pearls are within specifications. After the coating is "complete, the beads are placed in an oven and dried at room temperature for about 16 to about 24 hours." The beads, which are now the controlled release particles, are sampled, analyzed and sieved using a 20 mesh screen. c. Preparation of the placebo particle The placebo particles also prepare in a process of "Aspersion and sieving", similar to controlled and intermediate release particles. Two quantities of 2.5 kg and an amount of 5 kg of ethylcellulose (Ethocel® 7-FP) are dosed. An amount of 1.2 kg of methylcellulose (Methocel® E-5) and 50 kg of sugar seeds / 30-35 mesh starch, such as the NF sugar spheres are also prepared. The methylcellulose is prepared as a suspension for coating according to the instructions of the manufacturers and is allowed to stand for at least 8 hours before use. The sugar spheres are placed in a stainless steel lining container, and the container is peeled off, and the spheres are moistened with the methylcellulose suspension (approximately 0.211 kg per application) using a pressure gun. The ethylcellulose powder (approximately 0.37 kg per application) is then sieved over the wetted spheres using a normal sieve. The humidification and sieving steps are continued until the first portion (5 kg) of ethylcellulose is applied. The spheres are then screened using a 24 mesh screen and the wetting and sieving steps continue until the spheres reach a 24 mesh or 30 mesh screen. The spheres are rotated in a coating pan, weighed and analyzed in accordance with Accepted quality assurance analysis methods that are well known to those skilled in the art. After the test, the spheres are placed in an oven and dried at approximately 122 ° F (68 ° C) for at least 24 hours. After drying, the spheres (now particles or placebo beads) are screened using 20 mesh and 30 mesh screens. iii. Second exemplary composition In a second exemplary composition, acetaminophen is present as generally spherical particles that are coated to provide prolonged release. The generally spherical acetaminophen used in the present has a relatively narrow range of sizes. As an example, about 1% of the particles are retained on a 40 mesh screen, while at least about 88% are retained on an 80 mesh screen. The sizes of the EU series of sieves are used here for the sizes of sieve mesh. More preferably, about 90% or more of the acetaminophen particles pass through a 40 mesh screen and is retained on an 80 mesh screen. A standard lot of acetaminophen granules available from Mallinckrodt Chemical of St. Louis, Mo, under the designation acetaminophen USP Special Granular Code 1617, according to manufacturer information, is retained at approximately 0.1% on a 40 mesh screen, approximately 80% on a 60 mesh screen and approximately 98% is retained on an 80 mesh screen. These acetaminophen particles are preferred, but It is possible to obtain suitable material from other commercial sources or it can be prepared by sieving. The acetaminophen particles constitute the nuclei of the extended release composition, and those core particles are each coated with three separate coating layers which in the present are known as the first, second and third layers, respectively, proceeding from the surface of the acetaminophen particle outwardly in the order mentioned. The first layer is hydroxypropyl methylcellulose, the second is ethylcellulose and the third is hydroxypropyl methylcellulose again. The individual coated particles are also generally spherical in shape. These three layers homogeneously cover the surface of the particle as well as each previous coating layer so that each coating is evenly distributed over the surface it covers. The coatings are applied from the aqueous medium as described below to provide weight additions in a ratio of about 1: 4-6: 1, respectively, in their order of application. These weight ratios with each other are also the percentages of approximate weight additions of each coating for the final weight of the composition, so that a contemplated sustained release acetaminophen composition contains about 4 to about 6% by weight of the second layer. , or about 5% by weight of the total composition as solids. Hydroxypropyl methylcellulose can be obtained from different commercial sources. A particularly useful and preferred hydroxypropyl cellulose is available with the OPADRY® brand from the Colorcon Division of Berwind Pharmaceutical Serives, Inc. of West Point, PA (Colorcon). The material marketed under the designation "YS-1-7472 clear" is particularly preferred herein, and is a powder which is said to contain hydroxypropyl methylcellulose and polyethylene glycol. Ethylcellulose can also be obtained from a number of commercial sources. Particularly useful and preferred material for use herein is available under the trademark SURELEASE® E-7-19010 from Colorcon. This material is a turbid whitish liquid dispersion which is said to contain water, ethylcellulose, fractionated coconut oil, oleic acid and ammonium hydroxide with a pH value of 9.5-11.5. This product is said to contain 24-26% solids. The acetaminophen is, thus, present in about 92 to about 94% by weight of the composition, with the second coating being present at about 4 to about 6% by weight. The first and second coatings are present in approximately 1% by weight each. The coated acetaminophen particles have sizes such that more than 90% passes through a 20 mesh screen, and about 90% is retained on a 60 mesh screen. An exemplary screening result for a contemplated composition is shown below, in where a minus sign (-) indicates the passage through the mesh and a plus sign (+) indicates retention.

Sieve Percentage +18 0.0 -18 + 20 0.9 -20 + 40 33.6 -40 + 50 43.6 -50 + 60 13.6 -60 + 80 6.4 -80 1.8 The preferred coating materials noted above have been used together, alone in some combinations to coat powdered medicaments such as theophylline and acetaminophen. However, none of the amounts used here, nor their sequenced combination of the layers, nor the unexpected results obtained using these quantities in this sequence of layers have been reported. Thus, for example, the Technical Data Sheet PTA-96 (10-88) of Colorcon reports the use of a 10% by weight addition of SURELEASE® 0601-96 to form theophylline with controlled release produced using two different reactors. of fluidized bed. The Colorcon Technical Data Sheet PT-35 (10-92) describes the use of a single 80/20 coating (based on the dry solids of SURELEASE® / OPADRY® to coat tablets in a container coating technique. Similarly, the technical data sheet of Colorcon PT-38 (10-92) describes the use of a SURELEASE® layer, followed by an 80/20 layer of SURELEASET / OPADRY® (as above) and then a SURELEASE® layer / sodium lauryl sulfate (93.5: 6.5 solids) to provide an addition of 15% by weight and masking the flavor for acetaminophen granules, with the coated granules being mixed with other ingredients up to more than three times their original weight to finally form compacted tablets Technical data sheet PT-30 (10-92) from Colorcon describes a controlled release phenylpropanolamine hydrochloride composition.In this case, the drug was first coated with a 12% addition of OPADRY® (YS-3-7065), followed by 1% of OPADRY® (YS-1-7472), 10% of SURELEASE® (E-7-7050), and another 1% of OPADRY® (YS-1-7472). iv. Preparation of the second exemplary composition Figure 1 illustrates a fluidized bed coating system 10 for preparing the coated particles of the second exemplary acetaminophen composition. The fluidized bed system 10 includes a fluidized bed container 12 defining an air intake or plenum region 14 and a coating region. 16. The intake plenum 14 and the coating region 16 are separated by an air distribution plate 18 that spans the body of the container 18. The intake plenum 14 is in communication with a nozzle for air intake through which air is supplied to the container 12.

In the upper portion (as indicated at 22) of the coating region 16, the container 12 includes an air outlet 24. The body of the container 12 has a generally diverging or expanding region (indicated at 26) starting above of the air distributor plate 18 and extends to the coating region 16. The diverging region 26 defines a volume to accommodate a downflow bed B of the acetaminophen particles. The container 12 includes a coating column 28 which is defined by an upwardly extending cylindrical partition 30 extending upwardly from the distributor plate 18. The coating column 28 provides a region for coating the acetaminophen particles, and in addition provides a weir-type arrangement for retaining the acetaminophen particles within the downflow bed B, segregated from the particles in the coating column 28. A spray nozzle 32 extends to the coating column 28 from below the distributor plate 18. The distributor plate 18 has a hole 34 therein to accommodate penetration into the nozzle 32. The opening 34 defines a nozzle space 36 between the inner edge 38 of the plate 18 and the body of the nozzle 32. The nozzle 32 extends upwards, through the hole 34, with a tip 40 of this almost coplanar with the distributor plate 18. The container 1 2 includes a turbulence accelerator 42 extending downward from the distributor plate 18, until near the orifice of the intake nozzle 20. The accelerator 42 extends towards the intake plenum 14. The turbulence accelerator 42 has a generally frusto-conical shape that reduces its inward section toward the distributor plate 18. Near the junction of the accelerator 42 and the distributor plate 18, the accelerator 42 includes a director element that reduces its inward section 44. The accelerator 42 also includes a diverter plate 46 extending downwardly therefrom to divert and distribute the affluent air through the plenum 14. The coating system 10 is operated in a batch mode. In use, the container 12 is charged with a quantity of particles resting in the downflow bed B. Air is introduced into the air intake plenum 14 and flows up through the distributor plate 18 through the bed of acetaminophen particles. The upward flow of the air fluidizes the particles in the downflow bed B. Although the upward flow of air through the plate 18 is sufficient to fluidize the bed of particles, it is not so large as to create a void space on the bed. distributing plate 18 or through the bed. In practice, the air flow rate is selected to establish an incipiently fluidized bed, in which the pressure drop across the bed B is equal to the gravitational force in the acetaminophen particles. In such a process, bed B is minimally fluidized. Those skilled in the art will appreciate that the fluidized bed often has fluid type properties. That is, the "bed" takes the form of the container in which it is placed and tends to flow in a fluid type. A spray of coating material in an aqueous medium is injected from the spray nozzle 32 to the coating column 28. The spray consists of a quantity of material for coating, as well as a predetermined amount of hot air.The hydrodynamic strength of the coating which emerges from the spray nozzle 32 creates a region of low pressure at the sides and behind the nozzle 32, near the distributor plate 18. The low pressure region draws air from the intake plenum 14 to the accelerator 42, more beyond the nozzle 32, and towards the facing column 28. The accelerator 42 imparts a turbulent movement to the air that is drawn through it.The turbulence movement imparts additional rotational speed and turbulence to the affluent air. together with the air entrained in it is forced upward to the coating column 28. Acetaminophen particles that have been fluidized in the downflow bed B are drawn into and through the space 36 between the column 28 and the distributor plate 18. In the space 36, the particles are drawn towards. the flowing stream in the column 28 by the forces exerted on the particles by the low pressure region surrounding the nozzle 32. As the particles enter the coating column 28, they are accelerated upward to the fluid stream. Essentially, the particles have a jet-like flow condition in the coating column 28. As the spray from the coating material and the particles travel upward in the coating column 28, intimate mixing occurs. The intimate mixing between the air, the coating material and the particles provides an easily predetermined thickness, uniformly coated with the coating on the particles. As the coated, "wet" particles rise through the expansion region 26, they are subjected to intimate contact with hot, relatively dry, upwelling air from bed B, and to conditions of reduced pressure in the portions top of the container. The combination of air contact and low pressure removes moisture from the coating and thus facilitates the drying of the particles and minimizes the formation of lumps or aggregates of coated particles that might otherwise occur. It has been observed that in the present system 10, the acetaminophen particles are dragged individually to the coating column 28 and upwardly through it. This is very different from the known coating systems in which the particles tend to agglomerate as they are drawn into the coating column. This is partly due to the rotational speed and additional turbulence imparted by the turbulence accelerator on the affluent air. Furthermore, it has also been observed that in known systems, the flow patterns within the coating column, and thus the coating characteristics on the acetaminophen particles, are dominated by the flow of the particles. This is due, in part, to the agglomeration of the particles as they flow up the coating column. In contrast, in the present system 10, the particles are individually entrained to the coating column 28. Thus, the flow patterns within the coating column 28, and the resulting coating characteristics in the particles are dominated by the air flow through the column 28. Conveniently, due to the air flow patterns, instead of the flow patterns of the particles that dominate the current in the coating column, the coating of the particles is controlled more finely . The finely controlled coating process tends to facilitate the ability to produce acetaminophen particles with more uniform and predictable coating whose rate of dissolution in an aqueous medium can, by this means, be controlled in a relatively easy manner. In a preferred embodiment, the coating of the acetaminophen particles is carried out in a fluidized bed coating system brand PRECISION COATER®, manufactured by Aeromatic-Fielder Ltd. of Eastleigh, Hampshire UK and available from GEA Niro, Inc. of Columbia, Maryland.

Physical-chemical studies and efficacy Physical-chemical studies and efficacy were carried out to determine dissolution rates and to determine the effectiveness of the present extended-release composition. The physical and chemical studies were carried out in vi tro and included tests in a rotating basket. Once the suitable in vitro rates for these solutions were obtained, the dissolution of the exemplary extended release acetaminophen compositions, prepared according to the present invention, was then compared with a commercially available acetaminophen product, namely, with the first Tylenol® Prolonged Release Tablets (in 650 mg dose) as an external standard. Efficacy studies were conducted in vivo to determine the comparative effectiveness for producing long-term depression or temperature relief of the acetaminophen composition present in relation to a commercially available acetaminophen product, known, namely, immediate release Elixir. Tylenol® for children. to. Dissolution studies in vi The dissolution studies included comparative studies of the dissolution rates of two exemplary acetaminophen compositions of the present invention with the dissolution rates of Tylenol® Prolonged Release Dragees (650 mg). The studies included tests in a rotating basket that were performed in accordance with accepted methods, such as those contained in ÜSP 23 / NF 18, United States Pharmacopeial Convention, Inc. Rockville, Maryland 1791 (1994). b. Rotary basket tests Rotary basket tests were carried out in accordance with the accepted procedures of USP 23 / NF 18. The test apparatus for each of the samples, ie, the Tylenol® Prolonged Release Tablets and the composition of acetaminophen of the present invention was an Apparatus I of USP, with rotation at 50 rpm, using a medium of 900 ml of phosphate buffer at pH 5.8 and a temperature of 37 ° C. Six samples of each batch of the products (ie, the product Tylenol® Prolonged Release Dragees and the first exemplary acetaminophen composition contemplated) were evaluated at times of 10, 20, 30, 45, 60, 120, 360, 480 and in some cases 720 minutes. The filters used were Hanson Probé of 10 μM. The test medium was analyzed for UV absorbance of the test solution compared to standard acetaminophen (APAP), USP at 244 nm. The samples (indicated as Smpl in the following Tables 3-6) tested included the first exemplary acetaminophen composition in a dose of 650 mg (Table 3), and two series of Tylenol® Prolonged Release Dragee product samples (lot # MFM437 ) and lot # PEM910, in Tables 4 and 5, respectively). The results of the rotary basket evaluations are shown below in Tables 3, 4 and 5. Two samples of the second exemplary composition of acetaminophen (lot N) were evaluated. The results of the batch N tests are given in Table 6, as a range of the determined dissolution values, together with a summary of the comparison of the results of one of the batches (Lot # PEM910) of the Release Dragees product. Prolonged Tylenol® from the samples and the first exemplary preparation of acetaminophen (lot # EXPT9236).

TABLE 3 PERCENT OF DISSOLUTION OF THE COMPOSITION OF ACETAMINOFEN OF PROLONGED RELEASE PRESENT (650 mg, Lot # EXPT 9236) TABLE 4 PERCENT OF DISSOLUTION OF THE LIBERATION GRAINS PROLONGED TYLENOL® (ONE GRAGEA @ 650 mg, Lots # MFM437] TABLE 5 PERCENT OF DISSOLUTION OF PROLONGED RELEASE GRAGEA TYLENOL® (ONE GRAGEA @ 650 mg, Lot # PEM910) TABLE 6 CONDENSED SUMMARY OF THE RESULTS OF COMPARISON IN DISSOLUTION IN ROTARY BASKET OF THE FIRST (Lot # EXPT9632) AND AN INTERVAL FOR THE SECOND (Lot N) EXEMPLARY COMPOSITIONS OF ACETAMINOFEN OF RELEASE PROLONGADA AND TYLENOL® PROLONGED RELEASE GRAGEAS (Lot # PEM910) IN DISSOLVED PERCENT As can be seen from the data in Tables 3-6, the acetaminophen preparations contemplated showed slower controlled and sustained release, particularly in the early periods, which did not present the product Tylenol® Prolonged Release Dragee. Approximately 20 minutes after the start of the test, 50% of the product Tylenol® Prolonged Release Tablets had dissolved. After one hour, almost two thirds of the Tylenol® Extended Release Dragee product had dissolved, and about 75% in two hours. In contrast, a contemplated acetaminophen preparation, when contained within a gelatin capsule had achieved approximately 40% to approximately 53% acetaminophen solution at half an hour, approximately 50% to approximately 68% dissolution at 45 minutes , about 57% to about 77% dissolution of acetaminophen in one hour and about 82% to about 92% dissolution of acetaminophen in two hours. After six hours, the prolonged release acetaminophen composition, contemplated, practically obtained complete dissolution. The dissolution rates in vi tro were measured in vitro in 900 ml of phosphate buffer at pH 5.8 and at a temperature of 37 ° C in a rotary basket of apparatus I of the USP at 50 rpm. Although there seems to be superposition of the dissolution values of the acetaminophen composition contemplated, present, at different adjacent subsequent times and times, it must be understood that a dissolution value within a range of values established at a specific time increases from this dissolution value at a later time. As a consequence, although the upper limit for a previously mentioned time frame can be superimposed with a lower limit of a subsequent time frame, a single sample presents higher dissolution values until the substantially complete dissolution is obtained. Surprisingly, the rate of in vitro dissolution of a contemplated sustained release composition is substantially the same as that observed for the sorption rate in vi tro for the same composition.

Rotary bottle titration technique The rotary bottle tests were carried out to establish the dissolution profiles, such as the particularly preferred dissolution profiles as illustrated in Table 2, for the composition of acetaminophen contemplated. The rotary bottle tests were carried out according to a variant of the NF XIV procedure, American Pharmaceutical Association, Washington, D.C. 985 (1974). The test apparatus was a rotary bottle apparatus, rotating at 30 rpm, using a 60 ml medium of modified gastric fluid prepared according to the aforesaid NF XIV. The test conditions varied from the accepted NF XIV procedure in that the pH of fluid used (gastric fluid) differed from the NF XIV procedure, and the duration of the test that was performed (one hour) differed from the time in the NF XIV procedure. NF XIV.

In vivo studies Randomized trials were conducted to determine whether a contemplated acetaminophen composition administered as a single dose over a period of eight hours was as effective in reducing fever as Tylenol® Immediate Release Elixir for children administered in two doses, in children with fever between the ages of 2 and 11 years having initial temperatures of > 101.0 ° F (39 ° C). Administration was performed using an acetaminophen composition contemplated at an initial administration time and a placebo four hours after the initial administration, and the Elixir Immediate Release product Tylenol® in the initial administration and four hours after the initial administration. It is observed that the labeling of the product Elixir Immediate Release Tylenol® establishes that four hours must elapse between administrations. The study group included 120 children; 59 received the product Elixir Immediate Release Tylenol® and 61 received an acetaminophen composition contemplated. Some of the children were also treated, at the same time, with antibiotics. The temperature measurements were recorded before the dose, half an hour, 1, 1-1 / 2, 2, 3, 4, 5, 6, 7 and 8 hours after the initial administration. Temperatures were measured using an Exergen LighTouch Infrared Ear thermometer, which uses a method of arterial heat balance. The results of the studies are shown in Figures 2-4. In all the figures, the circles (full and empty) represent the data for a composition of acetaminophen contemplated (preparation) and the triangles (full and empty) represent the data for the product Immediate Release Elixir Tylenol®. Figure 2 shows the general results on the average temperature as a result of time, and includes all results, including children with moderate and severe initial fevers (low and high baseline temperatures, respectively), as well as children at the same time were administered with antibiotics. Figure 3 shows the average temperature over time and is segregated by antibiotic use. Figure 4 shows the average temperature over time and is segregated by high and low baseline temperatures. As can be seen from the results, in each case, the effect of the Elixir Immediate Release product Tylenol® began to decrease after approximately two hours, as indicated by the decrease in the rate of temperature reduction after two hours and a increase in temperature levels after approximately three hours. It is important to note that, even after the new administration at four hours after the initial administration (shown by the dotted vertical line in four hours), the temperature reducing effect of the Elixir Immediate Release product Tylenol® required approximately two hours until it reached an effect that approached it or an effect equivalent to that of the composition of acetaminophen contemplated. That is, an acetaminophen composition contemplated had a significantly higher capacity to reduce and maintain reduced temperatures in a single dose compared to an equivalent amount of the Tylenol® Immediate Release Elixir product. This result was very unexpected because the bioavailability of both materials was equivalent. With reference to Figure 3, where the filled circles and triangles indicate the data for the concomitant use of antibiotic for an acetaminophen composition contemplated and the product Elixir Immediate Release Tylenol®, respectively, in the empty circles and triangles indicate the data for non-use of antibiotic for an acetaminophen composition contemplated and the product Elixir Immediate Release Tylenol®, respectively, it is quite evident that the use of the composition of acetaminophen contemplated, with or without the concomitant use of antibiotic, presented reduction of increased fever and prolonged compared to an equivalent amount of the Tylenol® Immediate Release Elixir product. This result was also unexpected. Surprisingly, in view of the concomitant antibiotic data of the Tylenol® Immediate Release Elixir product, compared to an acetaminophen composition contemplated, a contemplated composition showed an increase in the reduction of fever with the concomitant use of antibiotics, whereas the Product Immediate Release Elixir Tylenol® showed a minor effect when used with antibiotics. For example, with respect to Figure 3, at three hours after the initial administration, an acetaminophen composition contemplated when used with antibiotics showed an average temperature reduction of approximately 2.4 ° F (-16 ° C). [sic] (from about 102.5 ° F to about 101.1 ° F), while the Elixir Immediate Release product Tylenol® exhibited a temperature reduction of only about 2.1 ° F (-16.67 ° C) (from about 102.7 ° C). F at approximately 100.6 ° F). This difference is more drastic at four hours after administration (at the time of the second administration of the Tylenol® Immediate Release Elixir product), where it can be seen that the effectiveness of Elixir Immediate Release Tylenol® decreased, while the effectiveness of an acetaminophen composition contemplated increased, and the differences in average temperature reduction were approximately 2.5 ° F (from approximately 102.5 ° F to approximately 100.0 ° F) for the contemplated acetaminophen composition and approximately 1.9 ° F (from approximately 102.7 ° F to approximately 100.8 ° F) for Tylenol® Immediate Release Elixir product. It is interesting to note that at all times during the study, regarding the concomitant use of antibiotics, the average temperature data for an acetaminophen composition contemplated was lower than that of the Tylenol® Immediate Release Elixir product. The data illustrated in Figure 4 are segregated by the high and low baseline temperatures for a contemplated acetaminophen composition and the Elixir product, Tylenol® Immediate Release (illustrated as full circles for a contemplated acetaminophen composition and triangles filled for the Tylenol® Immediate Release Elixir product, at high baseline temperatures and as empty circles for a contemplated acetaminophen composition and empty triangles for the Tylenol® Immediate Release Elixir product, at low baseline temperatures). As can be seen from the data, an acetaminophen composition contemplated showed a significantly higher temperature reduction in children with high baseline temperatures at 3 and 4 hours after administration, of approximately 3.2 ° F (from approximately 104 ° F to approximately 100.8 ° F) compared to the Immediate Release Elixir product Tylenol®, which exhibited a temperature decrease of only approximately 2.6 ° F and 2.2 ° F, respectively at 3 and 4 hours (from approximately 103.8 ° F at approximately 101.2 ° F at 3 hours, which subsequently increased to approximately 101.6 ° E at 4 hours), thus, an acetaminophen composition contemplated showed considerable efficacy in reducing the baseline high temperatures reductions compared to the product Elixir of Immediate Release Tylenol®. Again, this was an unexpected result. At lower temperatures of the baseline, an acetaminophen preparation contemplated had a greater temperature reduction, with a larger difference at four hours, where the acetaminophen preparation present had a temperature reduction of about 2.1 ° F (from about 102 ° C). ° F at approximately 99.9 ° F) compared to the Tylenol® Immediate Release Elixir product, which showed a temperature reduction of about 1.6 ° F (from about 101.9 ° F to about 100.3 ° F). The results of the in vivo study data were statistically assessed using the Fisher exact test for categorical data and using the Wilcoxon rank sum test for continuous variables. The extremes of efficacy were compared using the Wilcoxon Range Sum Test and a linear regression model was used to assess the treatment effect adjusted for potential confounders. The statistically significant differences in average temperatures between an acetaminophen composition contemplated (single dose) and the Elixir Immediate Release product Tylenol® (two doses) were shown at 4 and 5 hours after the initial administration that favored the composition of acetaminophen contemplated. There was generally a greater magnitude of temperature reduction in patients who received a de-acetaminophen composition contemplated compared to those who received the product Elixir Immediate Release Tylenol® with high temperatures in the baseline compared to those of low temperatures in the line base. However, the temperature reduction patterns in patients with high and low baseline temperatures were similar to each other and similar to the patterns observed in the analyzes in general. The average values of the area under the curve (AUC) from the initial administration at 4 hours after administration for all patients; that is, the total results were generally greater for an acetaminophen composition contemplated of those for the Elixir product of Immediate Release Tylenol®. As provided herein, the present extended release acetaminophen composition offers prolonged long-term relief in a pleasing manner. An acetaminophen composition contemplated allows the drug to be administered to a child so that the child can benefit from a prolonged-release formulation. This can be extremely beneficial at night, so that a child can rest or sleep comfortably for a sufficiently long time, 8 hours or more, while under the effects of the painkiller if the child has pain, or under the effects of the antipyretic if the child has a fever Parents know very well that a "good night's rest" can be beneficial for the comfort and recovery of a sick child. Further studies were conducted to determine the efficacy of an acetaminophen composition contemplated in comparison with a known analgesic (prolonged release tablets Tylenol®), and a placebo, over a period of 8 hours, for the relief of pain from surgery orally, specifically, the surgical removal of impacted third molars. In this study, 125 patients were randomly administered with 1300 mg of a contemplated acetaminophen composition, Tylenol® prolonged-release capsules of 1300 mg or a placebo. The results of this study indicate that the patients who were given the contemplated acetaminophen composition and the prolonged-release lozenge product Tylenol® experienced differences in average pain intensity that were significantly greater than those patients who were given placebo. There were no observed differences in pain between the composition of acetaminophen contemplated and the prolonged-release lozenge product Tylenol®. From the foregoing it will be noted that numerous modifications and variations may be made without departing from the true spirit and scope of the novel concepts of the present invention. It should be understood that limitations are not suggested or inferred with respect to the specific modalities illustrated. The description is proposed to cover through the attached clauses all these modifications that fall within the scope of the clauses.

Claims (15)

1. A prolonged release acetaminophen composition containing a plurality of small particles containing acetaminophen that, when contained within a gelatin capsule and titrated in a rotating basket of USP Apparatus I at 50 rpm in 900 ml of phosphate buffer at pH 5.8 and 37 ° C, it presents approximately 40% to approximately 53% acetaminophen solution at half an hour, approximately 50% at approximately 68% solution at 45 minutes, approximately 57% to approximately 77% acetaminophen solution at the hour, approximately 82% to approximately 92% acetaminophen solution at 2 hours and approximately 100% solution at 6 hours.

2. The prolonged release acetaminophen composition according to claim 1, which contains particles containing acetaminophen coated on sugar / starch seeds, the particles are presented as a mixture of an immediate release form and a controlled release form.

3. The sustained release acetaminophen composition according to claim 2, wherein the controlled release particles contain a sugar starch / starch particle, coated with a plurality of acetaminophen and magnesium stearate layers that are bound with povidone. , and the layers containing acetaminophen are coated with a plurality of layers of a mixture of povidone and magnesium stearate. The prolonged release acetaminophen composition according to claim 3, wherein the weight ratio of acetaminophen to magnesium stearate in the controlled release particles is about 5: 1 to about 10: 1, and the acetaminophen comprises about 70 to about 80% by weight of the controlled release particles. The prolonged release acetaminophen composition according to claim 2, wherein the immediate release particles comprise a sugar / starch seed particle coated with a plurality of layers of a mixture of acetaminophen, starch and cross-linked carboxymethylcellulose bound with povidone . The prolonged release acetaminophen composition according to claim 5, wherein the immediate release particles contain acetaminophen, starch and crosslinked carboxymethylcellulose in a weight ratio of about 13-16: 1: 1.5-2, respectively, and Acetaminophen constitutes approximately 60-70% by weight of the particles. The sustained release acetaminophen composition according to claim 2, wherein the immediate release particles and the controlled release particles are present in the mixture in a weight ratio of from about 1: 1 to about 1: 1.5, respectively. 8. The prolonged release acetaminophen composition according to claim 2, wherein the mixture also contains coated sugar / starch seeds that are without acetaminophen. The prolonged release acetaminophen composition according to claim 8, wherein the immediate release particles, the controlled release particles and the coated sugar / starch seeds which are present in the mixture in a weight ratio of about 1: 1-1.5.0.1-0.25. The prolonged release acetaminophen composition according to claim 1, wherein the beads consist of an acetaminophen particle coated with each of a first, second and third layer, wherein the first and third layers are composed of hydroxypropylcellulose and the second layer is ethylcellulose. The prolonged release acetaminophen composition according to claim 10, wherein the weight ratio of each of the first, second and third layers in a bead is approximately 1: 4-6: 1, respectively, and the Acetaminophen constitutes approximately 92 to approximately 94% by weight of each bead. 12. The prolonged release acetaminophen composition according to claim 10, wherein the beads have sizes such that approximately 90% by weight passes through a 20 mesh screen and approximately 90% by weight is retained in an 80 mesh screen. 13. A process for treating a human patient having difficulty for swallowing acetaminophen in the form of a tablet, dragee or capsule, comprising the steps of: (a) distributing an effective amount of acetaminophen-coated particles of claim 1 in an appetizing medium to form a medium containing acetaminophen particles.; and (b) administering the medium containing acetaminophen particles to a human patient. The process according to claim 13, wherein the human patient is a child from about 3 months to about 14 years of age. 15. The process according to claim 14, wherein the child presents hyperthermia.