Novel ibuprofen and acetaminophen composition

Abstract

To provide novel compositions, tablet formulations, methods of treatment and methods of manufacture of large scale, commercially viable ibuprofen and acetaminophen tablets.SOLUTION: Provided is an oral pharmaceutical composition suitable for tableting comprising ibuprofen and acetaminophen being active pharmaceutical ingredients, the ibuprofen being present in an amount of 100 to 300 mg and acetaminophen being present in an amount of 150 to 600 mg, a ratio of ibuprofen to acetaminophen being 1:3 to 1:1 by weight; and the composition further comprising intragranular and extragranular components, the intragranular component comprising the active ingredients, a binding agent, a disintegrating agent and a glidant; and the extragranular components comprising a disintegrating agent, a glidant and a lubricant, and the composition being essentially free of unmodified starch.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel ibuprofen and acetaminophen compositions. [Background technology]

[0002] Ibuprofen (IBU) and acetaminophen (APAP) are among the most widely used analgesic / antipyretic medications in the United States and worldwide. Their effectiveness and safety as non-prescription treatments for mild pain and fever in adults and children is well established (e.g., Dickman A., “Choosing over-the-counter analgesics,” Pharm J. 2008;281:631; Perrott DA, et al., “Efficacy and safety of acetaminophen vs ibuprofen for treating children's pain or fever: a meta-analysis,” Arch Pediatr Adolesc Med. 2004;158:521-526; Goldman RD et al., “Antipyretic efficacy and safety of ibuprofen and acetaminophen in children,” Ann Pharmacother. 2004;38:146-150; and Pierce CA and Voss B., “Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review,” Ann Pharmacother. 2010;44:489-506).

[0003] Ibuprofen, a propionic acid derivative nonsteroidal anti-inflammatory drug (NSAID), has been used in the treatment of pain, injuries, and illnesses due to its analgesic, anti-inflammatory, and antipyretic effects. It is taken for, for example, arthritis, sports injuries, soft tissue trauma, dysmenorrhea, migraines, tension headaches, and toothache. Ibuprofen is one of the most extensively studied and widely used drugs. It is estimated that ibuprofen has been used to treat more than 100 million patients in at least 100 countries worldwide. Acetaminophen, N-(4-hydroxyphenyl)acetamide or referred to herein as APAP, was first used in medicine by Van Mering in 1893, but it was not until 1949 that it became popular as an effective alternative to aspirin for over-the-counter analgesic use.

[0004] However, for many patients taking over-the-counter (OTC) analgesics, it can be difficult to achieve complete pain or fever relief with a single analgesic or antipyretic agent. Unfortunately, further single dose increases above 400 mg for IBU or above 1000 mg for APAP (i.e., the maximum recommended single-dose OTC strength) provide little, if any, additional therapeutic benefit but may incur a higher risk of adverse events (AEs).

[0005] The concept of multimodal analgesia, a method of achieving adequate pain control using different procedures, techniques, and / or medications with different mechanisms of action, first emerged in the 1990s to improve post-surgical recovery. This strategy has gradually become more commonplace and has been associated with improved patient satisfaction and shorter hospital stays.

[0006] It stands to reason that operationalizing this same concept in the OTC analgesic environment could lead to better pain control compared to that achieved with a single OTC analgesic, and similarly for fever reduction.

[0007] Ibuprofen and APAP are two such drugs that act through different mechanisms. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenase (COX)-1 and COX-2 isoenzymes, blocking the subsequent synthesis of proinflammatory prostanoids in both the peripheral and central nervous systems. APAP is thought to act through the inhibition of a subclass of COX enzyme isoforms in the central nervous system (Tanner T et al., "The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol," BMC Clin Pharmacol. 2010;10:10). Other proposed mechanisms of action of APAP include activation of central serotonergic pain inhibitory pathways descending from the brain and inhibition of the L-arginine nitric oxide pathway mediated by substance P or N-methyl-D-aspartate (NMDA). Additionally, effects on cannabinoid receptors via acetaminophen metabolites have been proposed (Anderson BJ, "Paracetamol (acetaminophen): mechanisms of action," Paediatr Anaesth. 2008;18:915-921). Investigations have been conducted to determine whether specific combinations are more effective than either drug alone (Mehlisch DR, "The efficacy of combination analgesic therapy in relieving dental pain," J Am Dent Assoc. 2002;133:861-871; Beaver WT, "Combination analgesics," Am J Med. 1984;77:38-53).

[0008] IBU and APAP do not share a common metabolic pathway, reducing the potential for drug-drug interactions (Tanner T et al., "The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol," BMC Clin Pharmacol. 2010;10:10; Wright CE et al., "Ibuprofen and acetaminophen kinetics when taken concurrently," Clin Pharmacol Ther. 1983;34:707-710). Previous pharmacokinetic studies have demonstrated the lack of drug-drug interactions between IBU and APAP. IBU and APAP also have different side effect profiles. At higher doses and longer treatment durations, IBU and other NSAIDs are associated with potential gastrointestinal, cardiovascular, and renal side effects, while APAP overdoses are associated with hepatotoxicity. Thus, a combination product containing IBU and APAP would allow for the use of lower doses of both agents, reducing safety concerns associated with higher doses of either drug, such as gastrointestinal bleeding or hepatotoxicity (Moore N and Scheiman JM, “Gastrointestinal safety and tolerability of oral non-aspirin over-the-counter analgesics,” Postgrad Med. 2018;130:188-199), while fulfilling the unmet need for more convenient non-prescription analgesics / antipyretics with a desirable safety profile.

[0009] Previous studies of a fixed-dose combination (FDC) of IBU 200 mg and APAP 500 mg in postoperative dental pain found that the FDC provided significantly better analgesia than APAP 1000 mg alone and numerically better analgesia than IBU 400 mg alone, without any emerging safety concerns (Mehlisch DR et al., "Comparison of the analgesic efficacy of concurrent ibuprofen and paracetamol with ibuprofen or paracetamol alone in the management of moderate to severe acute postoperative dental pain in adolescents and adults: a randomized, double-blind, placebo-controlled, parallel-group, single-dose, two-center, modified factorial study," Clin Ther. 2010;32:882-895; Mehlisch DR et al., "A single-tablet fixed-dose combination of racemic ibuprofen / paracetamol in the management of moderate to severe acute postoperative dental pain in adolescents and adults: a randomized, double-blind, placebo-controlled, parallel-group, single-dose, two-center, modified factorial study," Clin Ther. 2010;32:882-895; Postoperative dental pain in adult and adolescent patients: a multicenter, two-stage, randomized, double-blind, parallel-group, placebo-controlled, factorial study,” Clin Ther. 2010;32:1033-1049; and Doherty M et al., A randomized controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen / paracetamol in community-derived people with knee pain,” Ann Rheum Dis. 2011;70:1534-1541).

[0010] Additionally, certain combinations of IBU and APAP have been investigated for fever reduction (Malya RR, "Does combination treatment with ibuprofen and acetaminophen improve fever control?" Ann Emerg Med. 2013;61:569-570; Paul IM et al., "Efficacy of standard doses of ibuprofen alone, alternating, and combined with acetaminophen for the treatment of febrile children," Clin Ther. 2010;32:2433-2440; Purssell E., "Systematic review of studies comparing combined treatment with paracetamol and ibuprofen, with either drug alone," Arch Dis Child. 2011;96:1175-1179).

[0011] WO 2007 / 034135 (Reckitt Benckiser Healthcare (UK) Ltd) discloses a fixed-dose combination product containing 200 mg ibuprofen and 500 mg paracetamol (acetaminophen). Such a product is sold by Reckitt Benckiser as Nuromol® for the temporary relief of mild to moderate pain associated with migraines, headaches, backaches, menstrual cramps, toothaches, rheumatic and muscular pain, non-severe arthritis pain, cold and flu symptoms, sore throat, and fever. The dosing regimen is one or two tablets taken up to three times per day, with at least six hours between doses, up to a maximum of six tablets (3000 mg paracetamol, 1200 mg ibuprofen) in any 24-hour period. The tablets are shown to contain croscarmellose sodium, microcrystalline cellulose, colloidal anhydrous silica, magnesium stearate, and stearic acid, along with a film coating containing polyvinyl alcohol, titanium dioxide, talc, macrogol, potassium aluminum silicate (E555), and polysorbate.

[0012] U.S. Patent No. 10,532,036 (Atkinson) discloses a fixed dose combination pharmaceutical product for the treatment of pain, comprising about 125 mg to about 150 mg ibuprofen and about 475 mg to about 500 mg paracetamol, the ratio of paracetamol:ibuprofen in the single therapeutic dose being about 50:15.

[0013] U.S. Patent Application Publication No. 2019 / 0350883 (Chau) describes solid dosage forms, such as a single tablet containing about 1000 mg of acetaminophen and 400 mg of ibuprofen or a single tablet containing about 650 mg of acetaminophen and about 400 mg of ibuprofen.

[0014] Additionally, certain processing steps are utilized to accurately formulate and / or manufacture solid dosage products. The "wet granulation" method can be used when a compound, such as an active pharmaceutical ingredient ("API"), has poor flow properties that would result in content uniformity issues when formulated as a dry blend. Wet granulation is commonly used to improve the processing characteristics of powder blends, including improved flow, content uniformity, and more uniform particle size. Wet granulation is used to improve the flow, compressibility, bioavailability, homogeneity, electrostatic properties, and stability of solid dosage forms. Granulation is often required to improve the flow of powder mixtures and the mechanical properties of tablets. Granules are usually obtained by adding a liquid (binder or solvent solution). A higher amount of granulation liquid results in a narrower particle size range, producing coarser, harder granules, i.e., a lower proportion of fine granule particles. The particle size of the granules is determined by the amount and feed rate of the granulation liquid.

[0015] Wet granulation can be used when a compound, such as an active pharmaceutical ingredient ("API"), has poor flow properties that would result in content uniformity problems when formulated as a dry blend. Wet granulation is commonly used to improve the processing characteristics of powder blends, including improved flow, content uniformity, and more uniform particle size. The use of water and heat in wet granulation can cause chemical degradation or physical form transformation.

[0016] The variables encountered in granule processing can lead to significant tableting problems. The properties of the granules formed can be affected by the viscosity of the granulation solution, the rate of addition of the granulation solution, the type of mixer used and the duration of the mixing method, and the dry and wet blending speeds. The above variables can change the density and particle size of the resulting granules, which can have a significant impact on the fill weight and compression properties. Summary of the Invention

[0017] The present invention provides novel compositions, tablet formulations, methods of treatment, and methods of large-scale manufacture of commercially viable ibuprofen and acetaminophen tablets. The unique characteristics and synergistic effects resulting from the disclosed formulations, methods of treatment, and methods of manufacture demonstrate products with optimal analgesia, safety profiles, and the potential for large-scale manufacturing. The invention described herein surprisingly demonstrates unique formulations and methods of manufacture for large-scale commercial batches of novel ibuprofen and acetaminophen tablets. In particular, in contrast to teachings in the art, the use of water and heat processes in the disclosed multi-step blending, wet granulation steps did not result in the expected chemical degradation or physical form transformation.

[0018] In a further aspect, the present invention provides an oral pharmaceutical composition suitable for compression tableting comprising active ingredients ibuprofen in an amount of 100 mg to 300 mg and acetaminophen in an amount of 150 mg to 600 mg, wherein the ratio of ibuprofen to acetaminophen is 1:3 to 1:1 by weight, Provided is an oral pharmaceutical composition, wherein the composition comprises intragranular and extragranular components, the intragranular component comprising an active ingredient; a binding agent selected from the group consisting of pregelatinized starch, cellulose, such as microcrystalline cellulose and hypromellose, gelatin, sugar, polyethylene glycol, wax, natural and synthetic gums, synthetic polymers, and mixtures thereof; a disintegrant; and a glidant, and the extragranular component comprising a disintegrant, a glidant, and a lubricant.

[0019] In another aspect, the present invention provides an oral pharmaceutical composition suitable for tableting, comprising the active ingredients ibuprofen and acetaminophen, the ibuprofen is present in an amount of 100-300 mg and the acetaminophen is present in an amount of 150-600 mg, and the ratio of ibuprofen to acetaminophen is 1:3 to 1:1 (e.g., 1:2) by weight; the composition further comprises intragranular and extragranular components, the intragranular component comprising an active ingredient, a binder, a disintegrant and a glidant, and the extragranular component comprising a disintegrant, a glidant and a lubricant; An oral pharmaceutical composition is provided, wherein the composition is essentially free of unmodified starch.

[0020] By "essentially free" is meant about 1% or less, preferably about 0.5% or less, and most preferably 0%, based on the composition.

[0021] In a further aspect, the present invention provides a method of treating a mammalian subject in need thereof for relief of pain and / or inflammation, comprising the step of orally administering to the subject a pharmaceutical composition comprising the active ingredients ibuprofen in an amount of 250 mg and acetaminophen in an amount of 500 mg; the composition further comprises intragranular and extragranular components, the intragranular component comprising an active ingredient, a binder, a disintegrant and a glidant, and the extragranular component comprising a disintegrant, a glidant and a lubricant, the composition being essentially free of unmodified starch; the composition is administered in a single or divided dose; The administration is optionally repeated at 8 hour intervals until the subject achieves relief of pain and / or inflammation.

[0022] In a preferred embodiment, the invention includes a method wherein the composition is administered in a split dose, the split dose consisting of two tablets each containing 125 mg ibuprofen and 250 mg acetaminophen.

[0023] The methods of the present invention also contemplate total daily ibuprofen doses of 750 mg and total daily acetaminophen doses of 1500 mg, both of which are much lower than the currently approved OTC maximum daily doses of the drugs (1200 mg and 4000 mg, respectively).

[0024] In a further aspect, the invention includes a method of reducing fever in a mammalian subject in need thereof, comprising administering to the subject an oral pharmaceutical composition comprising the active ingredients ibuprofen in an amount of 250 mg and acetaminophen in an amount of 500 mg, in single or divided doses, said administration optionally being repeated until the subject achieves reduction in fever.

[0025] In a further aspect, the composition comprises intragranular and extragranular components, the intragranular component comprising an active ingredient, a binder, a disintegrant and a glidant, the extragranular component comprising a disintegrant, a glidant and a lubricant, and the composition is essentially free of unmodified starch.

[0026] In one embodiment, the antipyretic composition is orally administered in divided doses each comprising ibuprofen in an amount of 125 mg and acetaminophen in an amount of 250 mg.

[0027] In yet a further aspect, the invention includes a method wherein the composition is administered in a split dose, the split dose consisting of two tablets each containing ibuprofen in an amount of 125 mg and acetaminophen in an amount of 250 mg.

[0028] The present invention also contemplates a method for making the tablets of the present invention.

[0029] The embodiments are described with reference to the following figures, in which like numerals represent like elements throughout: [Brief explanation of the drawings]

[0030] [Figure 1A-1B] 1A and 1B are bar graphs showing the particle size distribution (PSD) of milled granulations prepared from prototypes A-C and D-F, respectively, except for A, which was not milled (Example 2). [Figure 2] FIG. 2 is a graph showing the cumulative mass distribution of prototype formulations A through F (Example 2). [Figure 3A-3B] 3A and 3B show the compression profiles of prototypes A to C and D to F, respectively (Example 2). [Figure 4] FIG. 4 is a flow chart of the manufacturing process for the exemplary ibuprofen 125 mg / acetaminophen 250 mg tablets of Example 3. [Figure 5]Figure 5 summarizes the course of pain relief over time in Study 1 using fixed dose combinations (FDCs) of IBU 200 mg and APAP 500 mg, IBU 250 mg and APAP 500 mg, IBU 300 mg and APAP 500 mg, IBU 400 mg, and placebo (Example 4a). [Figure 6] Figure 6 shows SPID

[11] 0-8 scores from single-dose study 2 (Example 4b). [Figure 7A] Figure 7A shows Kaplan-Meier estimates of time to meaningful relief. [Figure 7B] FIG. 7B shows Kaplan-Meier estimates of duration of pain relief from Study 2 (Example 4c). [Figure 8] FIG. 8 shows the numerical pain intensity difference scores over time from Multiple Dose Study 3 (Example 4c). [Figure 9] FIG. 9 shows the mean oral temperatures for each study group after treatment with FDC (IBU 250 mg / APAP 500 mg), IBU 250 mg, APAP 500 mg, or placebo (Example 5). [Figure 10] FIG. 10 presents the time-weighted sum of the temperature difference from baseline over 0 to 8 hours, calculated as the treatment difference (first treatment minus second treatment) and 95% confidence interval based on the least squares mean difference (aP=0.002 vs. placebo, bP<0.05 vs. placebo) (Example 5). [Figure 11] Figure 11 shows the overall assessment of FDC IBU 250 mg / APAP 500 mg. a P<0.05 vs. placebo (from an ANCOVA model when analyzed as a continuous variable, with a term for treatment group and time from first full dose of RSE to randomization and baseline temperature as covariates), and b P=0.05 vs. placebo (by chi-square test when analyzed as a categorical variable). Results are presented as percentages (Example 5). DETAILED DESCRIPTION OF THE INVENTION

[0031] Applicants have surprisingly discovered compositions of ibuprofen and APAP that synergistically provide effective pain treatment, minimize adverse events, minimize degradants and contaminants, and minimize manufacturing-related problems, especially in large-scale commercial batch manufacturing.

[0032] Furthermore, compositions described herein containing a 250 mg dosage of ibuprofen and a 500 mg dosage of acetaminophen, suitably delivered in split doses (e.g., as two tablets containing 125 mg ibuprofen and 250 mg acetaminophen, respectively), have been found to provide effective antipyretic treatment, providing a faster onset of longer-lasting fever reduction than the same doses of ibuprofen and acetaminophen alone. In particular, the compositions have been demonstrated to provide a statistically significant reduction in fever from 0 to 2 hours post-administration compared to placebo, which is not seen with ibuprofen or acetaminophen alone. In addition, co-administration of 250 mg ibuprofen and 500 mg acetaminophen was found to reduce fever significantly better than placebo over a period of 0 to 8 hours, with the combination being numerically better than either active agent individually over this period.

[0033] The tablets of the present invention may be uncoated or coated. Coated tablets may be polished or unpolished. The most preferred form of tablet for the disclosed invention is film-coated and polished.

[0034] One aspect of the present invention is a granule, i.e., a material that has been adapted and preprocessed by suitable means, e.g., aqueous or non-aqueous granulation, to form a granule. For purposes herein, the components of the granule will be referred to as "intragranular" or "intragranular components," while the components that are outside the granule and preferably mixed with it will be referred to as "extragranular" or "extragranular components." The granule comprises acetaminophen, ibuprofen, a binder, a disintegrant, and a glidant. The intragranular component may contain one or more additional ingredients, including, but not limited to, a processing aid, a diluent or filler, a colorant, a dye, a sweetener, or mixtures thereof. The granule may optionally be combined (preferably mixed or blended) with one or more suitable extragranular components to form a pharmaceutical composition.

[0035] The compositions of the present invention are preferably in the form of swallow tablets, i.e., tablets intended to be swallowed whole, without being chewed or otherwise dispersed in the mouth, or dissolved or suspended in water prior to administration.

[0036] The term "tablet" as used herein includes tablets of any shape, including caplets, which are capsule-shaped tablets. Suitably, tablets according to the present invention have a hardness of 80 to 200 N, a disintegration time of about 30 to about 240 seconds, and a friability value of less than about 1.0% after 500 revolutions.

[0037] Tablets according to the present invention contain ibuprofen. Ibuprofen as referred to herein is 2-(4-isobutylphenyl)propionic acid or a pharmaceutically acceptable salt thereof, such as the sodium, arginine, lysine, or histidine salt of ibuprofen. The most preferred form of ibuprofen for the disclosed invention is the free acid form. Suitably, ibuprofen is present in tablets according to the present invention in an amount ranging from 15% to 30% by weight of the tablet, for example, from 20% to 28% by weight of the tablet. In some embodiments, tablets according to the present invention contain ibuprofen in an amount of 100 mg to 150 mg, for example, 110 mg to 140 mg, e.g., about 125 mg, per tablet. In alternative embodiments, ibuprofen may be present in an amount of, for example, 250 mg.

[0038] The tablet according to the present invention comprises acetaminophen. As referred to herein, acetaminophen includes any pharmaceutically acceptable isomer, ester, polymorph, or salt thereof. Suitably, acetaminophen is present in the tablet according to the present invention in an amount ranging from 40% to 60% by weight of the tablet, for example, from 45% to 55% by weight of the tablet. In one embodiment, acetaminophen is present in an amount of 200 mg to 300 mg, for example, from 230 mg to 270 mg, for example, about 250 mg. In an alternative embodiment, acetaminophen may be present in an amount of, for example, 500 mg.

[0039] Suitably the ratio of ibuprofen to acetaminophen is in the range 1:3 to 1:1.5, for example about 1:2.

[0040] All amounts recited herein relate to ibuprofen free acid or acetaminophen. Pharmaceutically acceptable salts or esters or other derivatives may optionally be used in dose-adjusted amounts equivalent to the doses recited herein for free ibuprofen or acetaminophen.

[0041] It is also contemplated that one or more non-pharmaceutically active excipients may be included in the compositions of the present invention, including, but not limited to, controlled release agents, diluents, binders, disintegrants, surface active agents, glidants, lubricants, colorants, coating materials, surfactants, and many other ingredients that impart various properties to the final solid dosage product.

[0042] The tablet according to the present invention contains a binder. A binder or binding agent is an agent that imparts cohesiveness to a powdered substance. The binder imparts cohesiveness to the tablet formulation, which ensures that the tablet remains intact after compression and improves free flow by blending granules of the desired hardness and size. Suitable binders for use in the present invention are selected from the list consisting of pregelatinized starch, cellulose, such as microcrystalline cellulose and hypromellose, gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums, such as acacia, tragacanth, sodium alginate, and synthetic polymers, such as polymethacrylate and polyvinylpyrrolidone, and mixtures thereof.

[0043] Unexpectedly, despite its widespread use as a tablet binder, it has been found that unmodified starch, such as corn (maize) starch, results in excessively fine granules with poor compressibility and is therefore unsuitable for use as a binder in the present compositions.In comparison, it has now been found, and is an aspect of this invention, that the selection of a binder comprising or consisting essentially of pregelatinized starch (optionally containing a cellulose, such as hypromellose) results in ibuprofen- and acetaminophen-containing granules with desirable properties, including granulation performance, compression blending performance, and tablet strength, that could not be achieved using unmodified starch.

[0044] As understood by those skilled in the art, the term "unmodified starch" (alternatively referred to in the art as "common" or "normal" or "native" starch) refers to carbohydrates (generally composed of linear amylose and branched amylopectin) derived without chemical modification from corn (maize) kernels or other natural sources, such as potato or rice, generally by the process of wet-milling and drying (see "Corn Starch," published by the Corn Refiners Association, 11th ed., 2006). Such unmodified starches, which are insoluble in cold water, are typically prepared in the form of a paste using hot water.

[0045] In comparison, pregelatinized starch is derived from natural sources, such as corn (maize) starch, potato, or rice, but is chemically and / or mechanically processed to cause all or part of the granules to rupture in the presence of water, i.e., the product is gelatinized and then dried. An example of a suitable pregelatinized starch is that produced from dent corn (common corn), which has a range of about 22-28% amylose and the remainder amylopectin. Some types of pregelatinized starch can be further modified to enhance their compressible and flowable properties (USP 37-NF32).

[0046] Fully pregelatinized starch is characterized by being soluble in cold water, eliminating the need to prepare a heated starch paste for wet granulation applications and by eliminating the pre-solubilization step, the starch can be added directly to the granulation equipment along with other actives and excipients, and water can then be used as the granulation fluid.

[0047] Partially pregelatinized starch (PPS) contains a soluble (gelatinized) and an insoluble fraction. In most cases, the insoluble fraction contains intact starch granules. (See Pharmaceutical Excipients - Properties, Functionality, and Applications in Research and Industry, edited by OMY Koo, John Wiley & Sons, 2016; C. Cunningham, C, "Starch Contrasts," Colorcon.)

[0048] Suitable examples of pregelatinized starches useful herein have a cold water solubility (ie, at about 25° C.) of at least 50%, preferably at least 75%, and more preferably about 90% or greater.

[0049] Commercially available fully or partially pregelatinized starch excipients include Unipure WG 220 (Ingredion), National Starch 1551, Ingredion WG220, Colorcon Starch 1500, Rocket Lycatab PGS, and Seppic PC-10 Starch.

[0050] It is preferred to use fully pregelatinized starch in the compositions of the present invention, such as Unipure WG 220 (Ingredion).

[0051] The compositions of the present invention are "essentially free of raw starch" in that raw starch (e.g., corn or maize starch) is not provided to the compositions as an excipient during their preparation. Thus, the compositions of the present invention preferably lack, or have 1% or less, raw starch other than any amount of raw starch that remains as an intrinsic component of the fully or partially pregelatinized starch excipient.

[0052] In one embodiment of the invention, the binder comprises or consists essentially of pregelatinized starch, optionally together with a cellulose, such as hypromellose.

[0053] In one embodiment, pregelatinized starch (optionally containing hypromellose) is the only binder.

[0054] Generally, the binder is present in an amount of about 1% to about 25% by weight of the tablet. While the binder is present as an intragranular component, it is recognized that a moderate amount of binder may also be present extragranularly, e.g., up to about 5% to 10% by weight of the intragranular binder. Typically, when present in tablets of the present invention, the pregelatinized starch is present intragranularly in an amount of about 4% to 25% by weight of the tablet, typically about 5% to 20% by weight, e.g., about 8% to 15% by weight.

[0055] Hypromellose (also referred to in the art as hydroxypropyl methylcellulose or HPMC) is a mixed methyl and hydroxypropyl ether of cellulose. Suitably, the hypromellose used in the present invention contains, on a dry basis, methoxy and hydroxypropoxy groups according to the following limits:

[0056] TIFF2025134843000001.tif29161

[0057] Furthermore, hypromellose as used herein suitably has a low nominal viscosity in the range of 2 to 70 mPa·s, such as 3 to 25 mPa·s, for example 10 to 20 mPa·s, as determined by standard viscosity methods used in the art (e.g. using an Ubbelhode viscometer, e.g. measured at 20°C using a 2% solution).Suitably, the hypromellose comprises a weight average molecular weight in the range of 20,000 to 100,000, for example 30,000 to 70,000, for example about 52,000.

[0058] An example of a suitable commercially available grade of hypromellose is known as hypromellose "E" type, e.g., E3, E5, E15, E50, available from Ashland Inc, Covington, KY USA, and has the following properties:

[0059] TIFF2025134843000002.tif44162

[0060] Typically, when present in tablets of the present invention, hypromellose is present intragranularly in an amount of 2.5% or less by weight of the tablet, for example, from about 1% to about 2% by weight of the tablet.

[0061] In one embodiment, the tablet of the present invention comprises a first binder and a second binder. Suitably, pregelatinized starch is the first binder and hypromellose is the second binder. Advantageously, the incorporation of a small amount of hypromellose (relative to pregelatinized starch) as the second binder has a slight but positive effect on tablet hardness. Suitably, the weight ratio of pregelatinized starch to hypromellose is about 7:1 to about 12:1, e.g., 7:1 to 11:1, e.g., about 10:1. In one embodiment, the pregelatinized starch is present as the first binder in an amount ranging from about 8% to about 15% by weight of the tablet, and the hypromellose is present as the second binder in an amount ranging from about 1% to about 2% by weight of the tablet.

[0062] Although used as a binder, it is recognized that pregelatinized starch may also serve as a disintegrant in the compositions of the present invention.

[0063] The tablet according to the present invention contains a component that functions as a disintegrant, e.g., one or more disintegrants. A disintegrant or disintegrating agent is a substance, mixture of substances, or combination of substances added to a tablet formulation to facilitate the breakage or disintegration of the tablet after administration. Substances that act as disintegrants are chemically classified as starches, clays, celluloses, aligns, gums, and cross-linked polymers. Suitable disintegrants include non-super disintegrants, super disintegrants, or a combination of both. Suitable non-super disintegrants for use in the present invention are selected from pregelatinized starch, microcrystalline cellulose, or powdered cellulose. In one embodiment, the non-super disintegrant is pregelatinized starch. It is recognized in the art that some excipients can fulfill more than one role in a given pharmaceutical formulation. For example, certain excipients, such as pregelatinized starch and microcrystalline cellulose (previously defined as binders), function as both binders and disintegrants. It is therefore understood that the same excipient can act as both a binder and a disintegrant. In such cases, the inclusion of a disintegrant in addition to a binder is entirely optional.Similarly, in such cases, the inclusion of a binder in addition to a disintegrant is entirely optional.

[0064] Suitably, the non-super disintegrant is present intragranularly or extragranularly, or both, in an amount ranging from about 4% to about 25% by weight of the tablet, such as from 5% to 20% by weight, for example from 8% to 15% by weight.

[0065] "Superdisintegrants" refer to a type of disintegrant that can be commonly used in pharmaceutical preparations in reduced amounts compared to conventional disintegrants. Examples of superdisintegrants include modified celluloses, e.g., croscarmellose, sodium salt of carboxymethylcellulose; sodium starch glycolate, and cross-linked polyvinylpyrrolidone. In one embodiment, the disintegrant comprises a superdisintegrant that is croscarmellose. The superdisintegrant may be present intragranularly, extragranularly, or both intragranularly and extragranularly. In one embodiment, the superdisintegrant is present both intragranularly and extragranularly. Suitably, the superdisintegrant is present intragranularly, extragranularly, or both intragranularly and extragranularly in an amount of about 0.5% to about 5% by weight of the tablet, e.g., about 1.5% to about 3.5% by weight. Suitably, the combined amount of superdisintegrant present intragranularly and extragranularly is about 1% to about 10% by weight of the tablet, e.g., about 3% to about 7% by weight.

[0066] The tablets of the present invention contain a glidant. A glidant is a substance that improves the flow characteristics of a powder mixture. Examples of glidants include, but are not limited to, silicon dioxide (e.g., colloidal silicon dioxide), talc, or mixtures thereof. The most preferred glidant for the disclosed invention is colloidal silicon dioxide. Suitably, the glidant is present intragranularly, extragranularly, or both intragranularly and extragranularly. Generally, the glidant is present in an amount of about 0.1% to about 10% of the tablet weight, more particularly about 1% to about 5% of the tablet weight. The most preferred amount of glidant for the disclosed invention is about 2% to about 3% of the tablet weight. For example, the glidant is present intragranularly, extragranularly, or both intragranularly and extragranularly in an amount of about 0.5% to about 2% by weight of the tablet, e.g., about 1% by weight of the tablet. For example, the combined amount of glidant present intragranularly and extragranularly is about 1% to about 4% by weight of the tablet, e.g., about 2% by weight.

[0067] The tablets according to the present invention contain a lubricant. Lubricants have several functions in tablet production. They can prevent adhesion of tablet material to the surfaces of the die and punches, reduce interparticle friction, facilitate ejection of the tablet from the die cavity, and improve the flow rate of the tablet granulation. Examples of suitable lubricants include magnesium stearate, calcium stearate, stearic acid, glyceryl dibehenate, talc, sodium lauryl sulfate, sodium stearyl fumarate, polyethylene glycol, or mixtures thereof. Glyceryl dibehenate includes mixtures of various esters of behenic acid and glycerol, including glyceryl (mono)behenate. In one embodiment, the lubricant includes glyceryl dibehenate.

[0068] A common problem that can arise with the tableting of certain active substances, such as ibuprofen, is the problem of "picking and sticking." Sticking occurs when granules adhere to the face of the tablet press punch. Picking is a more specific term that describes the product of skimming into letters, logos, or designs on the punch face. Advantageously, the use of glycerin and a mono-, di-, or triester of a saturated aliphatic carboxylic acid having 18 to 24 carbon atoms, e.g., 22 carbon atoms, results in the formation of good tablets with little or no sticking and picking and low ejection force from the press.

[0069] Typically, the lubricant is present in an amount of about 0.25% to about 3% by weight of the tablet, e.g., about 0.5% to about 2% by weight. The most preferred amount of lubricant for the disclosed invention is about 1% to about 1.5% by weight of the tablet. The lubricant is generally present extragranularly.

[0070] Preferably, the milled granules of the present invention comprise a population of granules having a d50 of 100 or more (e.g. as described in Example 2), for example a d50 of about 100-200, or about 110-180, for example about 150.

[0071] As used herein, the term "about" (or "approximately") means that a particular value may have a range that is acceptable to one of ordinary skill in the art, given the nature of the value and the method by which it was determined. Preferably, when the term "about" is considered in the context of an amount of a component, "about" means plus or minus 5% of the component. Most preferably, when the term "about" is considered in the context of an amount of a component, "about" means plus or minus 2% of the component's amount.

[0072] If desired, other ingredients conventionally used in pharmaceutical formulations may be included in the formulation, such as diluents, stabilizers, and anti-adherents. Optional ingredients include coloring and flavoring agents well known in the art.

[0073] Among its various embodiments, the present invention includes the following. (i) the active ingredients ibuprofen and acetaminophen present within the granules; (ii) 5% to 20% by weight of pregelatinized starch present in the granules; (iii) 0.5% by weight to 2.5% by weight of hypromellose present within the granules; (iv) 0.5% to 3% by weight of extragranular glyceryl dibehenate; (v) 1% by weight to 10% by weight of croscarmellose present intragranularly and extragranularly; (vi) 1% to 5% by weight of silicon dioxide present intragranularly and extragranularly Including, the composition being essentially free of unmodified starch; A composition suitable for tableting.

[0074] (i) the active ingredients ibuprofen and acetaminophen present within the granules; (ii) 8% to 15% by weight of pregelatinized starch present in the granules; (iii) 1% by weight to 2% by weight of hypromellose present within the granules; (iv) 1% to 2% by weight of extragranular glyceryl dibehenate; (v) 5% to 8% by weight of croscarmellose present intragranularly and extragranularly; (vi) 2% to 4% by weight of silicon dioxide present intragranularly and extragranularly Including, the composition being essentially free of unmodified starch; Composition suitable for tableting (all weight percentages based on total composition).

[0075] In a preferred embodiment, the compositions of the invention comprise ibuprofen in an amount of 100 mg to 200 mg (e.g., 110 mg to 140 mg, e.g., 125 mg) and acetaminophen in an amount of 200 mg to 300 mg (e.g., 230 mg to 270 mg, e.g., 250 mg); or alternatively, ibuprofen is present in an amount of 200 mg to 300 mg (e.g., 230 mg to 270 mg, e.g., 250 mg) and acetaminophen is present in an amount of 400 mg to 600 mg (e.g., 500 mg), in either case the ratio of ibuprofen to acetaminophen is about 1:3 to 1:1.5 (e.g., 1:2) by weight.

[0076] Thus, in a specific embodiment of the composition, 125mg ibuprofen, 250 mg of acetaminophen, 5% to 20% by weight of pregelatinized starch; 0.5% to 2.5% by weight of hypromellose, 0.5% to 3% by weight of glyceryl dibehenate, 1% to 10% by weight of croscarmellose, and 1% to 5% by weight colloidal silicon dioxide Including, The composition is essentially free of unmodified starch.

[0077] Another embodiment of the composition of the present invention comprises: 125mg ibuprofen, 250 mg of acetaminophen, 8% to 15% by weight of pregelatinized starch; 1% to 2% by weight of hypromellose, 1% to 2% by weight of glyceryl dibehenate, 5% to 8% by weight of croscarmellose, and 2% to 4% by weight colloidal silicon dioxide Including, The composition is essentially free of unmodified starch (all weight percentages are based on the total composition).

[0078] The present invention provides a compressed tablet for oral administration, comprising: 125mg ibuprofen, 250 mg of acetaminophen, about 12% by weight of pregelatinized starch; about 2% by weight of hypromellose, about 1% by weight of glyceryl dibehenate, about 7% by weight of croscarmellose, and Approximately 3% by weight colloidal silicon dioxide Including, All weight percentages are based on uncoated tablet cores.

[0079] An example of such a tablet is one whose uncoated tablet core consists of the following excipients: Ibuprofen, 125 mg; Acetaminophen, 250 mg; Hypromellose, approximately 8 mg; Croscarmellose sodium, approximately 33 mg; colloidal silicon dioxide, approximately 14 mg; Pregelatinized starch, approximately 60 mg; and Glyceryl dibehenate, approximately 7 mg.

[0080] As used herein, large-scale batch manufacturing refers to the production of commercially viable batches of tablets in quantities greater than 300,000 tablets per single batch or sub-batch. Preferably, the batch or sub-batch ranges from 300,000 tablets to 4,000,000 tablets. Most preferably, the batch is comprised of one or more sub-batches. Most preferably, the sub-batch ranges from 500,000 to 750,000 tablets.

[0081] In another aspect of the invention, there is provided a process for the preparation of tablets, which process comprises the steps of preparing granules as described above, mixing the granules with any desired extragranular components to create a masterblend, and compressing the masterblend into tablets.

[0082] In another aspect, the present invention provides a process for producing a tablet according to the present invention, comprising the steps of: (a) adding a binder to water in a mixing tank and mixing to form a granulation liquid; (b) adding and blending an intragranular flow promoter and a disintegrant in a blending tank to form a preblend; (c) forming a wet granulate by combining the granulation liquid, preblend, ibuprofen, acetaminophen, and intragranular disintegrant; (d) optionally wet-milling the wet granules; (e) forming a tablet blend by drying the wet granules in a dryer until the fluid content of the wet granules is below 2.0%; (f) converting the tablet blend into tablets in a tablet press by applying a force of at least 15 kN (i.e., a hardness of 80 N); (g) optionally coating the tablets It is a process that includes:

[0083] In a further aspect, the present invention provides a method of treating a mammalian subject in need thereof for the relief of pain and / or inflammation and / or fever, comprising the step of orally administering to the subject a pharmaceutical composition; said composition comprising active ingredients ibuprofen in an amount of 250 mg and acetaminophen in an amount of 500 mg; said composition further comprising intragranular and extragranular components, wherein the intragranular component comprises the active ingredients, a binder, a disintegrant, and a glidant, and the extragranular component comprises the disintegrant, glidant, and lubricant, and wherein the composition is essentially free of unmodified starch; said composition is administered in a single or divided dose; The administration is optionally repeated at 8 hour intervals until the subject achieves relief of pain and / or inflammation.

[0084] The composition may be administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen.

[0085] The composition may be administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen, said divided dose consisting of two tablets.

[0086] An appropriate treatment regimen is oral administration of two tablets every eight hours until the subject achieves pain relief, resulting in a total daily IBU dose of 750 mg and a total daily APAP dose of 1500 mg, both of which are much lower than the currently approved OTC maximum daily doses of the drug (1200 mg and 4000 mg, respectively).

[0087] Generally, no more than 6 tablets should be taken in a 24-hour period.

[0088] The compositions of the present invention are administered for the temporary relief of mild aches and pains due to one or more conditions selected from headache, toothache, backache, menstrual pain, muscle pain, and mild arthritic pain.

[0089] In one aspect there is provided a composition as defined above for use in therapy.

[0090] In one aspect there is provided a composition as defined above for use in the treatment of pain and / or inflammation, or for antipyresis (reduction of fever).

[0091] In one aspect there is provided the use of a composition as defined above in the manufacture of a medicament for the treatment of pain and / or inflammation, or for reducing fever.

[0092] Accordingly, the present invention also includes a method of reducing fever in a mammalian subject in need thereof, comprising orally administering to the subject, in single or divided doses, a pharmaceutical composition comprising the active ingredients ibuprofen in an amount of 250 mg and acetaminophen in an amount of 500 mg, said administration optionally being repeated until the subject achieves reduction in fever.

[0093] The composition may be administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen.

[0094] The composition can further comprise intragranular and extragranular components, wherein the intragranular component comprises an active ingredient, a binder, a disintegrant, and a glidant, and the extragranular component comprises a disintegrant, a glidant, and a lubricant, and wherein the composition is essentially free of unmodified starch.

[0095] The composition may be administered in a split dose containing 125 mg ibuprofen and 250 mg acetaminophen, said split dose consisting of two tablets.

[0096] In one aspect, there is provided a composition as defined above for use in reducing fever.

[0097] In one aspect there is provided the use of a composition as defined above in the manufacture of a medicament for the reduction of fever.

[0098] Unless otherwise indicated, all weight percentages recited herein referring to components or ingredients of the composition are based on the composition as a whole. If the composition is a tablet, all weight percentages recited herein are based on the weight of the tablet (i.e., tablet core) without any film coating, unless otherwise indicated. The present invention encompasses, for example, the following embodiments: [1] An oral pharmaceutical composition suitable for tableting, comprising the active pharmaceutical ingredients ibuprofen and acetaminophen, wherein the ibuprofen is present in an amount of 100-300 mg and the acetaminophen is present in an amount of 150-600 mg, and wherein the ratio of ibuprofen to acetaminophen is 1:3 to 1:1 by weight; the composition further comprises intragranular and extragranular components, the intragranular component comprising an active ingredient, a binder, a disintegrant and a glidant, and the extragranular component comprising a disintegrant, a glidant and a lubricant; An oral pharmaceutical composition, wherein said composition is essentially free of unmodified starch. [2] The pharmaceutical composition according to [1], wherein the intragranular binder comprises pregelatinized starch and optionally hypromellose. [3] The pharmaceutical composition according to [2], wherein pregelatinized starch and optionally hypromellose are the only intragranular binders. [4] The pharmaceutical composition according to [2] or [3], wherein the pregelatinized starch is present in an amount of 4% to 25% by weight of the composition. [5] The pharmaceutical composition according to [1], [2], [3] or [4], wherein the intragranular binder further comprises hypromellose. [6] The pharmaceutical composition according to [5], wherein hypromellose is present in an amount of 1% to 2% by weight of the composition. [7] The pharmaceutical composition according to [5], wherein the pregelatinized starch is present as a first binder in an amount ranging from 8 to 15% by weight, and the hypromellose is present as a second binder in an amount ranging from 1% by weight to 2% by weight of the composition. [8] The pharmaceutical composition according to [5], [6] or [7], wherein the weight ratio of pregelatinized starch to hypromellose is about 7:1 to about 12:1. [9] The pharmaceutical composition according to any one of [1] to [8], wherein the disintegrant comprises a super disintegrant present intragranularly, extragranularly, or both intragranularly and extragranularly.

[10] The pharmaceutical composition according to [9], wherein the super disintegrant is present both intragranularly and extragranularly.

[11] The pharmaceutical composition according to [9] or

[10] , wherein the super disintegrant is cross-linked carboxymethyl cellulose.

[12] The pharmaceutical composition according to

[10] or

[11] , wherein the super disintegrant is present intragranularly in an amount of 0.5% to 5% by weight of the composition and extragranularly in an amount of 0.5% to 5% by weight of the composition.

[13] The pharmaceutical composition of any of [1] to

[12] , wherein the glidant comprises colloidal silicon dioxide.

[14] The pharmaceutical composition according to

[13] , wherein the colloidal silicon dioxide is present intragranularly in an amount of 0.5% to 2% by weight of the composition and extragranularly in an amount of 0.5% to 2% by weight of the composition.

[15] The pharmaceutical composition according to any one of [1] to

[14] , wherein the lubricant comprises glyceryl behenate.

[16] The pharmaceutical composition according to

[15] , wherein glyceryl behenate is present extragranularly in an amount of 0.5% by weight to 2% by weight.

[17] The pharmaceutical composition according to any one of [1] to

[16] , wherein the intragranular components are present as a group of granules having a d50 of about 100 to about 200.

[18] The pharmaceutical composition according to any one of [1] to

[17] , wherein ibuprofen is present in an amount of 110 mg to 140 mg and acetaminophen is present in an amount of 230 mg to 270 mg.

[19] The pharmaceutical composition of

[18] , wherein ibuprofen is present in an amount of 125 mg and acetaminophen is present in an amount of 250 mg.

[20] The pharmaceutical composition of any one of [1] to

[17] , wherein ibuprofen is present in an amount of 250 mg and acetaminophen is present in an amount of 500 mg.

[21] The pharmaceutical composition according to any one of [1] to

[20] , which is in the form of a tablet.

[22] (i) the active ingredient present in the granule; (ii) 5% to 20% by weight of pregelatinized starch present in the granule; (iii) 0.5% by weight to 2.5% by weight of hypromellose present within the granules; (iv) 0.5% to 3% by weight of glyceryl dibehenate present extragranularly; (v) 1% by weight to 10% by weight of croscarmellose present intragranularly and extragranularly, and (vi) 1% to 5% by weight of colloidal silicon dioxide present intragranularly and extragranularly The pharmaceutical composition according to [1],

[23] (i) the active ingredient present in the granule; (ii) 8% to 15% by weight of pregelatinized starch present in the granule; (iii) 1% by weight to 2% by weight of hypromellose present within the granules; (iv) 1% by weight to 2% by weight of glyceryl dibehenate present extragranularly; (v) 5% to 8% by weight of croscarmellose present intragranularly and extragranularly, and (vi) 2% to 4% by weight of colloidal silicon dioxide present intragranularly and extragranularly The pharmaceutical composition according to [1],

[24] The pharmaceutical composition of

[22] or

[23] , wherein ibuprofen is present in an amount of 125 mg and acetaminophen is present in an amount of 250 mg; or wherein ibuprofen is present in an amount of 250 mg and acetaminophen is present in an amount of 500 mg.

[25] The pharmaceutical composition according to any one of

[22] to

[24] , which is in the form of a tablet.

[26] A compressed tablet for oral administration, the core of which consists of the following excipients: Ibuprofen, 125 mg Acetaminophen, 250 mg Hypromellose, approximately 8 mg Croscarmellose sodium, approximately 33 mg Colloidal silicon dioxide, approximately 14 mg, Pregelatinized starch, approximately 60 mg, and Glyceryl dibehenate, approximately 7 mg.

[27] A method of treating a mammalian subject in need thereof for the relief of pain and / or inflammation, comprising orally administering to the subject a pharmaceutical composition comprising the active ingredients ibuprofen in an amount of 250 mg and acetaminophen in an amount of 500 mg; the composition further comprises intragranular and extragranular components, the intragranular component comprising an active ingredient, a binder, a disintegrant and a glidant, and the extragranular component comprising a disintegrant, a glidant and a lubricant, the composition being essentially free of unmodified starch; the composition is administered in a single or divided dose; The administration is optionally repeated at 8 hour intervals until the subject achieves relief of pain and / or inflammation.

[28] The method of

[27] , wherein the composition is administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen.

[29] The method of

[27] , wherein the composition is administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen, said divided dose consisting of two tablets.

[30] A method of treating fever in a mammalian subject in need thereof, comprising administering to the subject an antipyretic composition comprising the active ingredients ibuprofen in an amount of 250 mg and acetaminophen in an amount of 500 mg, wherein the composition is administered in a single or divided dose, and wherein the administration is optionally repeated until the subject achieves relief from fever.

[31] The method of

[30] , wherein the composition is administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen.

[32] The method of

[30] or

[31] , wherein the composition further comprises intragranular and extragranular components, the intragranular component comprising an active ingredient, a binder, a disintegrant and a glidant, and the extragranular component comprising a disintegrant, a glidant and a lubricant, and the composition is essentially free of unmodified starch.

[33] The method of

[30] or

[32] , wherein the composition is administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen, the divided dose consisting of two tablets.

[34] A method as described in

[30] that produces a statistically significant faster onset of action over 0-2 hours compared to placebo.

[35] A method for preparing a tablet from the composition of [1], comprising the steps of preparing a granule, mixing the granule with any desired extragranular components to form a masterblend, and compressing the masterblend into a tablet.

[36] The composition according to any one of [1] to

[26] , which is used in the treatment of pain and / or inflammation or for reducing fever.

[37] A composition according to any one of [1] to

[26] in the manufacture of a medicament for treating pain and / or inflammation, or for reducing fever.

[0099] The following examples illustrate the invention.

[0100] [Example 1] Prototype tablet formulation. One embodiment of the ibuprofen 125 mg / acetaminophen 250 mg tablet is an immediate release yellow film-coated capsule-shaped tablet printed in black ink on one side.

[0101] [Table 1]

[0102] Excipients: All of the excipients utilized in the 125 mg ibuprofen / 250 mg acetaminophen tablets are compendial and considered "Generally Recognized As Safe" (GRAS) except for the Opadry II yellow film coat and Opcode black ink. Subcomponents of the film coat and ink are compendial and considered safe for use in the United States and Canada. The Opcode black ink used in this product is included in the FDA Inactive Ingredients Database.

[0103] Tablet core components: Croscarmellose sodium was added as both an intragranular and extragranular disintegrant. Hypromellose was added as an intragranular binder. Glyceryl dibehenate was added as an extragranular lubricant. Purified water was added as an intragranular binder but is essentially removed during processing. Colloidal silicon dioxide was added as both an intragranular and extragranular glidant. Pregelatinized starch was added as an intragranular binder and disintegrant.

[0104] Based on initial formulation testing, intragranular pregelatinized starch demonstrated superiority over corn starch, either alone or in combination with microcrystalline cellulose. The addition of hypromellose (at low levels) to pregelatinized starch prototypes slightly improved tablet hardness. Therefore, pregelatinized starch in combination with hypromellose was used as the intragranular binder for further formulation development.

[0105] Additionally, 150 mg ibuprofen / 250 mg acetaminophen prototypes were successfully compressed. Hardness profiles indicated tablet hardnesses of 80-200 (e.g., 98-196) N. Tablet cores compressed at compression forces between 15 kN and 30 kN (e.g., 20-24 kN) had disintegration times ranging from 41 seconds to 192 seconds and friability values ​​of less than 1.0% after 500 revolutions.

[0106] Film Coating Components: Opadry II Yellow was used to form a decorative film coat on the cores. Purified water was the film coating dispersant and was essentially removed during processing. The film coated cores were polished with carnauba wax. Other coatings and film coats are known in the art and are contemplated herein.

[0107] Printing Components. Opacode black ink was used for printing using isopropyl alcohol as the printing solvent. The alcohol was essentially removed during processing. Other inks are known in the art and are contemplated herein.

[0108] [Example 2] To evaluate corn starch versus pregelatinized starch as a binder / disintegrant in IBU / APAP tablets, a series of prototype granulations A-C (corn starch, microcrystalline cellulose) and D-F (pregelatinized starch), as shown in Table 2, were prepared by high-shear wet granulation with HPMC binder solution, followed by drying in a GPGC-1 fluid bed dryer and milling using a hammer mill, number 1A screen (0.04 inch).

[0109] [Table 2]

[0110] Results and Discussion: Prototype A could not be formed into granules and was compressed without being crushed, and accordingly, prototypes B to C were prepared so as to also contain crystalline cellulose.

[0111] Particle Size Distribution. As shown in Figure 1A, the particle size distribution (PSD) of granules A-C was found to be skewed toward finer particles, with only minor levels of larger particles formed. However, formulations with high levels of fines are not viable on high-speed tablet presses due to poor flow and compression issues (e.g., capping / lamination, picking / sticking, weight variation, segregation). In comparison, granules D-F demonstrated better granule formation with desirable PSD (Figure 1B).

[0112] The d50 refers to the midpoint in the particle size distribution such that half of the particles in a population of granules are larger than the d50 and half are smaller. The d50 is the 50% midpoint of each curve in Figure 2. Table 3 summarizes the d50 for each prototype granulation.

[0113] [Table 3]

[0114] The d50 of corn starch granules A-C are all <100 microns. In comparison, pregelatinized starch formulations D-F have higher d50 of approximately 110 μm (D), 171 μm (E), and 151 μm (F).

[0115] Compression results and discussion Compression tests were performed on an instrumented benchtop rotary tablet press equipped with capsule-shaped dies. A force transducer captured the average main compression force; no precompression force was used. Qualitative observations of powder flow during the compression runs were captured, and the powder flow of pregelatinized starch blends (D–F) was significantly improved compared to corn starch blends (A–C), consistent with the higher PSD of blends D–F.

[0116] The compression profiles (compression force vs. hardness) of B-F are shown in Figures 3A and 3B, respectively. The raw data for these figures are presented in Table 4.

[0117] [Table 4]

[0118] Corn starch prototypes B and C were found to have a limited compression range, which in turn imposes a limit on the compression force that can be applied to increase tablet hardness. As compression force increases, the compression profiles A-C tend to flatten out, so applying a compression force in the flattened range (referred to in the art as the "capping limit") can result in capping, a tablet defect.

[0119] In comparison, pregelatinized starch prototypes D-F all had significantly improved compaction profiles compared to B-C. For D-F, there was no sign of a capping limit, higher hardness was generally achieved at lower compaction forces, and all had wider compaction windows, making them suitable for large-scale batch manufacturing.

[0120] [Example 3] Embodiments of manufacturing processes and process controls. The 125 mg ibuprofen / 250 mg acetaminophen tablets can be manufactured by a process including wet granulation, optional wet milling, drying, dry milling, blending, compressing, film coating, and printing. The actual equipment and operating parameters are representative of those of a production batch and may vary based on the size of the batch, but the operation and design class remain the same.

[0121] The active pharmaceutical ingredients (APIs) ibuprofen and APAP are known to have poor compressibility. In the example product, the API constitutes approximately 75% of the tablet weight (uncoated). These characteristics must be considered to create a commercially viable composition that can withstand the manufacturing process. This is particularly relevant in large-batch manufacturing settings. Ibuprofen and acetaminophen can present challenges during multiple stages of the manufacturing process. First, ibuprofen has a relatively low melting point (75°C-78°C); therefore, processing steps that expose the product to high temperatures (e.g., drying and coating) should be minimized. Also, from a safety perspective, both ibuprofen and acetaminophen are known to raise explosive concerns during granulation and blending. Therefore, equipment must be properly grounded, and the use of high-energy mills, such as hammer mills, should be avoided unless operated under an inert atmosphere. Finally, ibuprofen has a well-known tendency to adhere to tablet punch die faces, which can lead to tablet defects such as picking, sticking, or filming. These defects are particularly noticeable at lower tablet compression forces.

[0122] Exemplary batch formulations and sizes are shown in Table 5.

[0123] [Table 5]

[0124] A flow diagram describing exemplary commercial-scale operations involved in the production of 125 mg ibuprofen / 250 mg acetaminophen tablets is shown in Figure 7. This is a flow chart of the manufacturing process for 125 mg ibuprofen / 250 mg acetaminophen tablets.

[0125] As shown in Figure 4, the steps of such a process are as follows:

[0126] 1. Add hypromellose and purified water to a suitable stainless steel mixing tank equipped with a mixer. Mix until dissolved.

[0127] 2. Add colloidal silicon dioxide and pregelatinized starch to a drum blender. Blend for a minimum of 2 minutes.

[0128] 3. Add ibuprofen, preblend from Step 2, acetaminophen, and croscarmellose sodium through a sieve equipped with a #4 mesh stainless steel screen to a wet high shear granulator. Allow the mix to dry at low speed for a minimum of 2 minutes. Add the granulating solution from Step 1 and mix at low speed for a minimum of 2 minutes. Increase the speed to high and mix until the granulation endpoint is determined by the change in power consumption. In-process control: Change in power consumption: Endpoint is achieved between 6 and 12 kW.

[0129] 4. Wet Milling: Pass the wet granulation through a screening mill (rotating impeller) fitted with a 0.25 inch screen directly into the fluid bed dryer bowl.

[0130] 5. Dry with an inlet air temperature set point of 55-65°C and an air flow of 6000-8000 cfm. After 20 minutes, adjust the air flow to 4600-6600 cfm. Dry until the exhaust air temperature reaches 32-52°C. Take a sample and determine the moisture content by Karl Fischer method. In-process control: The moisture content of the dried granulation should be 2.0% w / w or less (NMT). Note: If the moisture level exceeds 2.0% w / w, additional drying time may be applied.

[0131] 6. Mill the dried granulation from Step 5 using a screening mill (vibrating bar) equipped with a #16 mesh stainless steel screen directly into the diffusion bin blender.

[0132] 7. Add colloidal silicon dioxide and croscarmellose sodium to a drum blender. Blend for a minimum of 2 minutes. Pass the preblend through a #20 mesh screen and place in a suitable container.

[0133] 8. Add the pre-blend from step 7 to the diffusion bin blender from step 6. Pass the glyceryl dibehenate through a #20 mesh screen and add it to the diffusion bin blender. Blend for a minimum of 9 minutes. Empty the final blend into a suitable container.

[0134] 9. Compress tablets in a rotary tablet press (gravity) with capsule-shaped tablet dies (0.590 in x 0.291 in x 0.038 in). Set the tablet press speed within the range of 30-55 rpm. In-process controls: Individual tablet weight: 471-521 mg; Average tablet weight (n=10): 486-506 mg; Tablet hardness: 98-196 N.

[0135] 10. Add the required amount of purified water and Opadry II Yellow to a suitable stainless steel mixing tank equipped with a mixer to prepare a 20% solids coating suspension. Mix until the solids are dispersed.

[0136] 11. Place the tablet cores from step 9 into the perforated coating system. Run the preheat cycle until the minimum required temperature is achieved. Dispense the appropriate amount of coating solution to achieve an approximate theoretical weight gain of 3%. After coating is complete, reduce the inlet temperature and cool the coated tablets.

[0137] 12. Rub the tablets with screened carnauba wax #1 yellow powder. After polishing is complete, empty the coated tablets into a suitable container.

[0138] 13. Print the tablets using an offset press with pharmaceutical ink (Opacode black NS-78-17821 diluted in isopropyl alcohol).

[0139] 14. Package tablets with an approved container closure system.

[0140] Testing of Composition Embodiments Here we present results from three tests of the composition illustrated in Example 1.

[0141] Example 4a Clinical trials for analgesic efficacy - Study 1. The objective of Study 1 was to determine the overall analgesic efficacy and tolerability of three different FDCs of IBU and APAP, each with different amounts of IBU, compared to IBU 400 mg, to demonstrate the advantage of FDC IBU / APAP 250 mg / 500 mg (e.g., tablets exemplified in Table 1 and manufactured as disclosed herein) administered as two tablets containing 125 mg ibuprofen, 250 mg acetaminophen.

[0142] Study 1 was a phase 2, 12-hour, 5-arm, randomized, double-blind, parallel-group, inpatient, placebo-controlled study designed to determine the overall analgesic efficacy of three different FDCs of IBU / APAP compared with IBU 400 mg and placebo.

[0143] All study procedures adhered to ethical principles originating from or derived from the Declaration of Helsinki and complied with all International Council for Harmonization Good Clinical Practice Guidelines and local regulatory requirements. All patients provided written informed consent. Eligible patients were healthy men or women aged 16 to 40 years, inclusive, who underwent extraction of three third molars (at least two of which were partially or completely impacted in the mandible) and experienced at least moderate pain within 5 hours of oral surgery. Other inclusion criteria included use of only the following preoperative / anesthetic medications: topical benzocaine, short-acting parenteral local anesthetics (mepivacaine or lidocaine) with or without vasoconstrictors and / or nitrous oxide; no contraindications to study or rescue medications; and sufficient reliability, cooperation, and intelligence to record the requested information on an analgesia questionnaire.

[0144] Once they experienced at least moderate pain, patients were randomized 1:3:3:3:3 to receive a single oral dose of placebo, IBU 400 mg, FDC IBU / APAP 200 mg / 500 mg, FDC IBU / APAP 250 mg / 500 mg, or FDC IBU / APAP 300 mg / 500 mg.

[0145] Patients who did not experience sufficient pain relief from the study medication were allowed to take rescue medication consisting of immediate-release tramadol 50-100 mg or codeine phosphate 15-60 mg. Patients could receive two additional doses of rescue medication at the study site. Patients were allowed to take the rescue medication at any time but were encouraged to wait at least one hour after taking the study medication to allow time for the medication to take effect. Patients who took rescue medication remained at the study site and continued to be evaluated for the entire duration of the study.

[0146] Assessment and Endpoints of Study 1. At baseline, patients rated their pain severity using categorical and numeric Pain Severity Rating (PSR) scales. The categorical PSR was a 4-point scale (none, mild, moderate, severe), with each category assigned a value of 0 to 3. Achievement of moderate pain at baseline was confirmed by a score of >50 mm on a 100 mm visual analog pain scale. In addition, pain was assessed using an 11-point numeric PSR (0 to 10, with 0 = none to 10 = worst possible pain).

[0147] After administration of study medication, patients were followed and assessed in situ for 12 hours, during which time study participants submitted self-ratings of pain severity (both categorical and numeric PSR scales as described above) and pain relief using a 5-point categorical Pain Relief Rating (PRR) scale (0=none, 1=little, 2=moderate, 3=quite a lot, and 4=complete) at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after the procedure, after taking study medication, immediately before taking rescue medication, or at study withdrawal (if any).

[0148] Additional patient assessments included time to first perceptible relief (TFPR) and time to meaningful pain relief (TMPR) using a double-stopwatch method, with one stopwatch pressed by the patient when pain relief was first perceived and the second when relief became meaningful. Duration of pain relief was measured by time to treatment failure (i.e., time to first administration of rescue medication or dropout due to lack of efficacy). At 12 hours or immediately prior to taking rescue medication for the first time, patients also provided a patient global assessment based on a 6-point categorical scale ranging from 0 (very poor) to 5 (excellent).

[0149] The primary endpoint was the time-weighted sum of pain relief and pain intensity difference (PID) scores from baseline (time 0) to 8 hours after dosing based on the PRR and categorical PSR (SPRID[4] 0~8 The secondary endpoint was the SPRID[4]0~2 ,SPRID[4] 0~6 , and SPRID[4] 0~12 TFPR and TMPR; Cumulative proportion of patients achieving FPR and MPR at each time point; 0-2 hours (TOTPAR 0~2 ), 0-6 hours (TOTPAR 0~6 ), 0-8 hours (TOTPAR 0~8 ), and 0-12 hours (TOTPAR 0~12 ) time-weighted sum of PRR scores over the same intervals (SPID[4] and SPID

[11] ); time-weighted sum of categorical and numerical (PID) scores over the same intervals (SPID[4] and SPID

[11] ); duration of remission (measured by time to treatment failure or patient discontinuation); cumulative proportion of treatment failures at each time point; and patient global assessment of study drug.

[0150] Patients were monitored for any AEs during the study. All AEs reported through 14 days after administration of study drug were reported, regardless of relatedness.

[0151] The primary analysis set (full analysis set) included all randomized patients who received study drug and provided a baseline pain assessment. The safety analysis set included all patients who received at least one dose of study drug.

[0152] Based on the results of a previous similarly designed study, the SPRID study compared IBU 400 mg with any FDC group [4]. 0~8 Based on this assumption, with a sample size of 90 patients per group, this SPRID between treatments was predicted at a 5% significance level (two-sided). 0~8 This would provide approximately 80% power to detect a difference in the mean mean square error (RMS) of 14.0 units (observed in previous studies). Therefore, a total of 390 patients were required to complete the study. A 5% dropout rate was assumed, resulting in a total of 410 patients being enrolled. No statistical comparisons were made between individual FDCs.

[0153] The PID (both scales), PRR, and their sum (PRID) at each time point, as well as the corresponding summary scales, SPID, TOTPAR, and SPRID, were analyzed using an analysis of variance model with treatment group, gender, baseline category PSR, and treatment-baseline category PSR interaction terms. For each comparison, treatment differences based on least squares means and the associated P-values were calculated. TMPR, TFPR, and time to treatment failure were analyzed using a proportional hazards regression model with terms for treatment, baseline category PSR, and gender. The 95% confidence intervals for each pairwise treatment difference were calculated using the hazard ratio and the associated 95% Wald confidence intervals. The cumulative percentages of patients with MPR, FPR, complete remission, and treatment failure at each specified time point were compared using the Cochran-Mantel-Haenszel row mean score test using the table scores with baseline category PSR and gender as controls. The overall patient assessment was analyzed using the Cochran-Mantel-Haenszel row mean score test using the modified ridit scores with baseline category PSR and gender as targets (controlling for).

[0154] All treatment differences were considered statistically significant at the P ≤ 0.05 level (all tests were two-sided), and marginally significant when 0.05 < P ≤ 0.10. Since this was a proof-of-concept trial, no correction for multiple comparisons was made.

[0155] Study 1 Results. A total of 576 patients were screened and 394 were randomized. The baseline characteristics in each treatment cohort were well balanced between groups. Approximately 50% of the patients were female, the majority (>95%) were white, and the mean age was 18.1 years. Overall, 61.9% of the patients ranked their pain as severe on the category PSR scale at study enrollment.

[0156] Study 1 - Efficacy. The course of pain relief over time with FDC, IBU 400 mg, and placebo is shown in Figure 5 (*P ≤ 0.001 vs. placebo, †P ≤ 0.01 vs. placebo, ‡P ≤ 0.05 vs. placebo,§ P ≤ 0.01 for 400 mg IBU; || P ≤ 0.05 for 400 mg IBU; ¶ P ≤ 0.05 for FDC IBU / APAP 200 mg / 500 mg).

[0157] Significantly better pain relief was observed with all FDC formulations versus placebo from the 0.25 hour time point through the 10 or 11 hour time point, but IBU 400 mg was significantly better than placebo from 0.50 hour through the end of the study. The FDC formulations provided significantly better pain relief than IBU 400 mg at earlier time points, but IBU 400 mg tended to be better than some of the FDC formulations, and some of these differences achieved statistical significance.

[0158] All active treatments were performed to achieve the primary endpoint of SPRID[4] 0~8 The efficacy of IBU 400 mg in patients with bronchial asthma was significantly higher than placebo (P<0.001 for all comparisons). There were no significant differences between any of the FDC formulations and IBU 400 mg for the primary endpoint.

[0159] Similar results were observed for the secondary endpoint of SPRID[4] 0~2 ,SPRID[4] 0~6 , and SPRID[4] 0~12 However, SPRID[4] 0~2 For schizophrenia, FDC IBU / APAP 200 mg / 500 mg and FDC IBU / APAP 300 mg / 500 mg were significantly better than IBU 400 mg (P < 0.05). A similar pattern was seen for time-weighted SPID[4] and SPID

[11] scores over the same time interval (data not shown).

[0160] All active treatment groups provided significantly better pain relief than placebo for all comparisons, as measured by TOTPAR (Table 6). In addition, FDC IBU / APAP 200 mg / 500 mg and FDC IBU / APAP 300 mg / 500 mg provided superior pain relief compared to IBU 400 mg for the 0-2 hour interval (TOTPAR). 0~2 , P = 0.031 and P = 0.011, respectively).

[0161] TFPR ranged from 18.5 to 22.8 minutes with IBU / APAP FDC compared with 24.9 minutes with IBU 400 mg and >720 minutes with placebo (Table 7). TFPR was significantly faster in all active treatment groups versus placebo (P<0.001).

[0162] Additionally, FDC IBU / APAP 200mg / 500mg and FDC IBU / APAP 300mg / 500mg had significantly faster TFPR than IBU 400mg (P=0.012 and P=0.030, respectively). A significantly higher percentage of patients reported FPR versus placebo from the first assessment point at 0.25 hours (P=0.031) to the end of the study (P<0.001 for all time points from 0.5 to 12 hours).

[0163] Median TMPR with the FDC IBU / APAP combination ranged from 44.5 to 54.1 minutes compared with 56.2 minutes with IBU 400 mg and >720 minutes with placebo (Table 5). All of the active treatment regimens resulted in significantly faster TMPR than placebo (P<0.001). FDC IBU / APAP 200 mg / 500 mg also had a significantly faster median TMPR than IBU 400 mg (44.5 minutes vs. 56.2 minutes, P=0.014); no other FDC reached statistical significance for this comparison. The median time to treatment failure for placebo was 1.6 hours, while the median times to treatment failure for FDC IBU / APAP 200 mg / 500 mg, FDC IBU / APAP 250 mg / 500 mg, and FDC IBU / APAP 300 mg / 500 mg were 9.7, 10.1, and 11.1 hours, respectively. Results for FDC were not significantly different from IBU 400 mg (10.4 hours, Table 7).

[0164] For patient global assessment, all of the FDC formulations and IBU 400 mg produced scores significantly better than placebo (P<0.001 for all comparisons), but there were no significant differences between any of the FDCs and IBU 400 mg.

[0165] Study 1—Safety. The overall incidence of AEs was comparable among all treatment groups, with no significant differences observed for any system organ class. A total of 256 treatment-emergent AEs were reported by 127 patients (32.2%). The majority of AEs were mild or moderate in severity, and none were determined to be treatment-related. There were no serious AEs. Nausea, vomiting, and dizziness were the most commonly reported AEs (Table 8). The incidence of nausea was higher in the placebo group compared with the active treatment group. No differences were observed between the FDC and IBU 400 mg groups. Two patients (one each in the FDC IBU / APAP 200 mg / 500 mg and FDC IBU / APAP 250 mg / 500 mg groups) discontinued study drug due to vomiting within 1 hour of receiving the study drug; both events were considered related to the surgical procedure rather than the treatment.

[0166] Study 1 - Discussion. This dose-ranging study demonstrated that the FDCs of IBU and APAP (200 mg / 500 mg, 250 mg / 500 mg, and 300 mg / 500 mg) provided significantly better pain relief than placebo and equivalent to IBU 400 mg over 8 hours. There was also no difference between the FDC and IBU 400 mg over 0-6 and 0-12 hours. However, each of the FDC doses provided significantly better pain relief than IBU 400 mg at 30 minutes post-dose (all P < 0.01), suggesting a faster onset of action.

[0167] TMPR and duration of relief are other important indicators of acute analgesia. Time to onset of pain relief was significantly faster with FDC than with placebo. There was also a trend toward faster TMPR compared with IBU 400 mg alone, but this only reached statistical significance with FDC IBU / APAP 200 mg / 500 mg (44.5 minutes vs. 56.2 minutes, P=0.014). This faster TMPR seen with FDC is consistent with that seen in a previous dental pain study comparing FDC IBU / APAP 200 mg / 500 mg with IBU 400 mg. 0~2 Statistically significant differences in pain relief between FDC IBU / APAP 200mg / 500mg and IBU 400mg, and between FDC IBU / APAP 300mg / 500mg and IBU 400mg, further supported a faster onset of action; FDC IBU / APAP 250mg / 500mg did not reach statistical significance compared to IBU 400mg, but showed a similar trend. This is likely expected because the APAP tablet has a faster time to maximum concentration than IBU. TFPR followed a similar pattern. Another trend based on the data, as shown in Figure 2, was that FDC IBU / APAP 250mg / 500mg surprisingly and relatively demonstrated the highest mean pain relief score at 8 hours.

[0168] Duration of relief, as measured by time to treatment failure, was significantly longer with FDC than with placebo. There was no significant difference between FDC and IBU 400 mg, but the duration of action increased directionally with the amount of IBU in the combination.

[0169] The most common AEs were nausea, vomiting, and dizziness. These AEs commonly occur after wisdom tooth extraction and may be related to the surgical procedure and / or anesthesia. These AEs occurred most frequently in the placebo group and may have been due to greater pain and the use of rescue opioid medication in this group. Overall, the AE profile of FDC was comparable to that of IBU 400 mg and placebo. There were no unexpected AEs, and the safety profile of FDC was consistent with that seen in previous studies.

[0170] This study demonstrates that all three IBU / APAP FDCs were as effective as IBU 400 mg for most of the primary and secondary efficacy endpoints, with a similar safety profile.

[0171] However, there was some suggestion that the FDC may have a more rapid onset of action than IBU alone. Overall, none of the combinations were substantially different from each other or from 400 mg IBU, so no conclusions can be drawn from this study regarding which FDC dose combination is superior. However, it can be concluded that the FDCs of IBU and APAP evaluated in this study provide pain relief at least as effectively as 400 mg IBU, with exposures lower than the maximum OTC doses of IBU (400 mg) and APAP (1000 mg). Because multiple studies have demonstrated that 400 mg IBU is superior to 1000 mg APAP, and previous studies have demonstrated that FDC IBU / APAP 200 mg / 500 mg is superior to 1000 mg APAP, all of the FDCs evaluated herein are also expected to be superior to the maximum dose of APAP.

[0172] [Table 6]

[0173] [Table 7]

[0174] [Table 8]

[0175] The proposed dosing regimen of FDC IBU / APAP 250 mg / 500 mg is every 8 hours (TID), resulting in a total daily IBU dose of 750 mg and a total daily APAP dose of 1500 mg, both of which are much lower than the currently approved over-the-counter (OTC) maximum daily doses of the drugs (1200 mg and 4000 mg, respectively).

[0176] [Examples 4b-c] Clinical trials in analgesic efficacy - Studies 2 and 3. Two additional tests (Tests 2 and 3) were conducted to demonstrate the performance of the compositions contemplated by the inventors. The objectives of the two tests described herein were to: 1) whether FDC IBU / APAP 250 mg / 500 mg provided superior analgesia to its individual components (Study 2); 2) whether the FDC had a rapid onset of analgesia (within 1 hour) (Studies 2 and 3); 3) whether the 8-hour dosing interval was appropriate (Studies 2 and 3), and 4) Whether analgesic efficacy was sustained across multiple doses (Study 3) The purpose was to decide.

[0177] Two studies were conducted, both single-center, phase 3, randomized, double-blind, parallel-group, placebo-controlled trials conducted in the United States. Study 2 was a single-dose study, while Study 3 was a multiple-dose study. The studies were conducted in accordance with ethical principles originating or derived from the Declaration of Helsinki, in accordance with all International Council for Harmonization Good Clinical Practice Guidelines, and all local regulatory requirements.

[0178] In Study 2, patients experiencing moderate to severe pain after the extraction of ≥3 third molars, at least two of which were partially or completely impacted, were randomized 3:3:3:1 under double-blind conditions to receive a single dose of FDC IBU / APAP 250 mg / 500 mg (administered as two tablets of 125 mg IBU / 250 mg APAP), 250 mg IBU alone, 650 mg APAP alone, or placebo. Patients self-rated their pain severity and pain relief for 12 hours after administration of the study medication.

[0179] Study 3 had a similar design, except that it was a multiple-dose study. Patients with at least moderate pain after the extraction of ≥3 third molars, at least two of which were partially or completely impacted, were randomized 2:1 to receive FDC IBU / APAP 250 mg / 500 mg or placebo. Patients received study medication every 8 hours for 40 hours, and pain severity and relief were self-assessed up to 48 hours after the procedure.

[0180] In both Studies 2 and 3, patients who did not experience adequate pain relief were allowed to take rescue medication. Rescue medication consisted of tramadol hydrochloride 50-100 mg or codeine sulfate 15-60 mg, both immediate-release, with patients able to take additional doses every 4-6 hours as needed up to the maximum labeled daily dose. Patients who received rescue medication remained at the study site and continued to be evaluated for the entire duration of each study (12 or 48 hours, respectively).

[0181] Studies 2 and 3—Patients. In both Studies 2 and 3, patients were healthy adult males or females, aged 18 to 40 years, including both ends, who underwent surgical extraction of ≥3 third molars (≥2 had to be partially or completely impacted in the mandible). Other important enrollment criteria included moderate to severe pain confirmed by a rating of ≥50 mm on a 100 mm visual analog pain severity rating (PSR) scale within approximately 5 hours after completion of surgery and use of the following preoperative / anesthetic agents only: topical benzocaine, short-acting parenteral local anesthetic (mepivacaine or lidocaine) with or without vasoconstrictors and / or nitrous oxide, and no contraindications to study or rescue medications.

[0182] In Study 2, enrolled patients received one of four treatments: 1) placebo (administered as two tablets), 2) FDC IBU / APAP 250mg / 500mg (administered as two caplets of 125mg IBU / 250mg APAP), 3) IBU 250mg (administered as two caplets of 125mg IBU), or APAP 650mg (administered as two tablets of 325mg APAP).

[0183] In Study 3, enrolled patients received one of two treatments: 1) placebo (administered as two tablets), or 2) FDC IBU / APAP 250 mg / 500 mg (administered as two tablets of IBU 125 mg / APAP 250 mg). All patients in both studies received two tablets of study drug under double-blind conditions. Patients were blinded during study drug administration, which was performed by study site personnel not involved in any other aspect of the study.

[0184] Studies 2 and 3 - Assessment and Endpoints. At baseline, patients provided self-ratings of pain severity using both categorical and numeric PSR scales. The categorical PSR used a 4-point scale (none, mild, moderate, severe), with each category assigned a number from 0 (none) to 3 (severe). Patients reporting at least moderate pain on the categorical PSR at baseline completed a 100-mm visual analog scale. A score of at least 50 mm confirmed study eligibility. In addition, pain was assessed using an 11-point (0–10, 0 = none to 10 = worst imaginable pain) numeric PSR scale.

[0185] After administration of the study treatment, pain and pain relief were assessed at designated assessment times by obtaining categorical PSR, numeric PSR, and a 5-point categorical pain relief rating scale (0=none, 1=a little, 2=somewhat, 3=a lot, 4=complete). In Study 2 (the single-dose study), these assessments were made at 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 hours after treatment. In Study 3 (the multiple-dose study), these assessments were also made at the same time points as in Study 2, up to 12 hours, and at 16, 24, 32, 40, and 48 hours after treatment. Additional assessments included patient assessments of the time to first perceptible pain relief (TFPR), defined as the time when the patient first begins to feel any pain-relieving effects of the medication, and the time to meaningful pain relief (TMPR), defined as the time when the patient experiences pain relief that is meaningful to that individual, using a double stopwatch (see Mehlisch DR et al., 2010, ibid.). In Study 2, these assessments were made over the 12-hour study period or until the first use of rescue medication. In Study 3, stopwatch assessments were made from the first 8 hours after the first dose of study medication until the second dose or the first use of rescue medication, whichever occurred first. In both studies, a patient global assessment asked patients to rate the study medication as a pain reliever on a 6-point categorical scale ranging from 0 (very poor) to 5 (excellent). This assessment was completed at the end of Study 2 (12 hours), at 24 and 48 hours in Study 3, or immediately before the first rescue medication dose (if applicable) in both studies.

[0186] The pain intensity difference (PID

[11] ) at each time point was obtained by subtracting the numeric PSR at that time point from the numeric PSR at baseline. The primary endpoint in Study 2 was the time-weighted sum of the PID

[11] score based on the 11-point numeric PSR scale over the 8-hour interval from baseline (SPID

[11] ). 0~8 Other endpoints were the time-weighted sum of PID

[11] scores over 6 to 8 hours (SPID

[11] 6~8 ), time-weighted sum of pain relief rating scores over 0-8 hours and 6-8 hours (TOTPAR0~8 and TOTPAR 6~8 ), TFPR (confirmed by TMPR), TMPR, duration of pain relief (cumulative rates of procedural failure at 6 and 8 hours as measured by time to procedural failure (defined as time to first rescue medication use or withdrawal due to AE or lack of efficacy), and patient global assessment score.

[0187] In the multiple-dose study 3, the primary endpoint was the time-weighted sum of the PID

[11] score based on the 11-point numeric PSR scale from 0 to 24 hours (SPID

[11] 0~24 ). The other endpoints are SPID

[11] 0~8 , SPID

[11] 6~8 , time-weighted sum of PID

[11] scores from 0 to 16 hours (SPID

[11] 0~16 ), time-weighted sum of PID

[11] scores from 8 to 16 hours (SPID

[11] 8~16 ), time-weighted sum of PID

[11] scores from 0 to 48 hours (SPID

[11] 0~48 ), TFPR, TMPR, duration of pain relief after first dose (time to first use of rescue medication or second dose of study drug, or withdrawal due to AE or lack of efficacy), rates of procedural failure within the intervals of first dose (0-8 hours) and overall (0-48 hours), and patient global assessment of study drug. In both studies, patients were closely monitored for any AEs during surgery and the pain assessment period. AEs were recorded when they occurred or were reported.

[0188] Studies 2 and 3 - Statistics. For Study 2, with a sample size of 168 patients in each active treatment group and 56 in the placebo group, the FDC combination treatment group and the IBU 250 mg and APAP 650 mg treatment groups were compared for SPID

[11] . 0~8 It was estimated that the system would have at least 85% power (5% significance level, two-sided) to detect a difference of 6.1 and 7.9 between the FDC formulation and placebo, respectively, and a difference of 8.5 between the FDC formulation and placebo. These differences were comparable to those observed in SPID

[11] . 0~8We assumed a root mean square error (RMSE) of 18.26 for the mean mean square error (mRSE). We planned to enroll approximately 588 patients, allowing for a 5% dropout rate.

[0189] For Study 3, the sample size of 68 patients in the FDC combination treatment group and 34 patients in the placebo group was used to evaluate the risk of SPID

[11] . 0~24 It was estimated that the system would have at least 85% power (5% significance level, two-sided) to detect at least 33 differences in the SPIDs

[11] over 2, 8, and 12 hours. This was estimated based on the RMSE for the SPIDs

[11] . 0~24 An RMSE of approximately 52 was assumed for . A 10% dropout rate was assumed, and approximately 112 patients were to be enrolled. Sample size calculation assumptions for both studies were based on data from a single-dose pilot toothache study.

[0190] SPID endpoints in both studies were analyzed using an analysis of covariance model with treatment group, sex, and baseline categorical and numerical PSR in the model. For each comparison, treatment differences based on least squares means and P values ​​and associated 95% confidence intervals based on the primary model are presented.

[0191] Duration of pain relief, TFPR, and TMPR were analyzed using the Gehan-Wilcoxon test with the effects of treatment, sex, and baseline category PSR as terms. These endpoints (except TFPR) are graphically represented using survival curves based on Kaplan-Meier estimates. Median survival times and their corresponding 95% CIs are presented and estimated using the method of Simon and Lee (Simon R and Lee YJ, "Nonparametric confidence limits for survival probabilities and median survival time," Cancer Treat Rep. 1982;66:37-42). Total pain relief (TOTPAR) was analyzed using a main-effects analysis of variance model with terms for treatment, baseline category PSR, and sex in the model.

[0192] The cumulative proportions of treatment failures at 6 and 8 hours post-dose in Study 2 and the proportions of treatment failures over the first dosing interval (0-8 hours) and overall (0-48 hours) in Study 3 were analyzed with the Cochran-Mantel-Haenszel (CMH) general association test using the table scores for baseline categorical PSR and gender. Patient global assessments in both studies were analyzed with the CMH row mean score test using modified ridit scores, stratifying by gender and baseline categorical PSR.

[0193] To protect the primary endpoint in Study 2 against type I error due to multiple comparisons, two-sided treatment group comparisons at 5% significance were performed in the following order: FDC vs. placebo, FDC vs. IBU and FDC vs. APAP, IBU vs. placebo, APAP vs. placebo, and IBU vs. APAP.

[0194] Tests 2 and 3 - Results. Participants and Baseline Characteristics. A total of 722 patients were screened and 568 randomized in Study 2, and a total of 203 were screened and 123 randomized in Study 3. Baseline characteristics in each of Studies 2 and 3 were well balanced between treatment groups. In both studies, approximately 40% to 45% of patients were male, and the majority (>90%) were white. The mean ages were 19.5 and 21.8 years in Studies 2 and 3, respectively. Based on the 4-point categorical PSR scale, 44.9% had moderate pain and 55.1% had severe pain at baseline in Study 2, whereas 53.7% of patients had moderate pain and 46.3% had severe pain in Study 3.

[0195] Efficacy: Single-dose study 2. Figure 6 shows SPID from study 2

[11] . 0~8 The single-dose study met its primary endpoint: FDC IBU / APAP 250 mg / 500 mg significantly reduced the risk of developing SPID

[11] . 0~8The results were significantly better than placebo, IBU alone, and APAP alone (P<0.001, P=0.008, and P<0.001, respectively, Table 7). 6~8 The results were also significantly better than both placebo and APAP alone (both P<0.001), but this difference was not related to the FDC SPID

[11] . 6~8 The difference was not statistically significant compared to IBU alone (P = 0.053). Figure 6 shows the difference between time 0 and 8 hours in single-dose study 2 (SPID

[11] 0~8 ) shows the time-weighted sum of PID

[11] scores.

[0196] Figures 8A and 8B show Kaplan-Meier estimates of 1) time to meaningful relief and 2) duration of pain relief, respectively, in Single-Dose Study 2. Time to meaningful relief was measured from the time of dosing until the patient pressed a second stopwatch to indicate that meaningful relief had been achieved. Duration of pain relief was defined as the time to treatment failure, which was measured as the time from the first dose to the first use of rescue medication or withdrawal due to an adverse event or lack of efficacy ( * P<0.05 vs. placebo; † P < 0.05 for 250 mg IBU; ‡ P<0.05 vs. APAP 650 mg).

[0197] Kaplan-Meier estimates for TMPR are shown in Figure 8A. TMPR was significantly faster with all three active treatments compared with placebo (P<0.001). TMPR for FDC IBU / APAP 250 mg / 500 mg was 47.9 minutes, significantly faster than that observed for IBU 250 mg (65.9 minutes, P=0.003), APAP 650 mg (56.6 minutes, P=0.031), and placebo (not applicable [N / A], P<0.001; Table 10).

[0198] TFPR results are shown in Table 11. All active treatment groups achieved significantly faster FPR than placebo (P<0.001 for all comparisons), but there were no significant differences between active treatment groups (median TFPR: FDC IBU / APAP 250mg / 500mg, 21.3 min; IBU 250mg, 24.6 min; APAP 650mg, 24.2 min).

[0199] All active treatment groups were assessed in the 0-8 hour interval (TOTPAR 0~8 , all P<0.001) and the 6-8 hour period (TOTPAR 6~8 In addition, FDC IBU / APAP 250 mg / 500 mg provided significantly better pain relief than placebo in the 0-8 hour interval (TOTPAR) compared with IBU 250 mg and APAP 650 mg alone. 0~8 , P=0.002 and P<0.001, respectively) and the 6-8 hour interval (TOTPAR 6~8 , P=0.013 and P<0.001, respectively).

[0200] Figure 8B shows Kaplan-Meier estimates for duration of pain relief as measured by time to treatment failure. All active treatments were significantly superior to placebo (P<0.001, Table 12). The median duration of pain relief (determined using the median time to treatment failure) was approximately 10.5 hours for FDC IBU / APAP 250mg / 500mg, compared with 10.1 hours for IBU 250mg alone, 7.5 hours for APAP 650mg alone, and 1.8 hours for placebo. Duration of pain relief was significantly longer with FDC than with placebo and APAP 650mg alone (both P<0.001), but did not reach statistical significance versus IBU 250mg alone (P=0.069).

[0201] The cumulative rates of procedural failure after 8 hours were 69.6%, 24.4%, 33.1%, and 51.5% in the placebo, FDC IBU / APAP 250 mg / 500 mg, IBU alone, and APAP alone groups, respectively. The FDC group had significantly fewer procedural failures than the placebo and APAP groups (P<0.001), but this difference was not significant compared with the IBU alone group (P=0.064).

[0202] For patient global assessment of study medication, all active treatment groups were significantly better than placebo (P<0.001 for all comparisons). In addition, the FDC IBU / APAP 250mg / 500mg treatment group was significantly better than both IBU 250mg (P=0.004) and APAP 650mg (P<0.001) alone.

[0203] Efficacy: Multiple-dose study 3. FIG. 9 shows the numeric pain intensity difference scores over time in multiple-dose study 3 (*P<0.05 vs. placebo).

[0204] As shown in Figure 9, FDC IBU / APAP 250mg / 500mg was significantly superior to placebo at all time points tested for PID

[11] . Study 3 met its primary endpoint: FDC IBU / APAP 250mg / 500mg was significantly superior to placebo at all time points tested for SPID

[11] . 0~24 FDC IBU / APAP 250 mg / 500 mg was significantly better than placebo for SPID

[11] 6-8 (SPID

[11] 6-s) (P<0.001).

[0205] The median TMPR in this study was 59.2 minutes for FDC IBU / APAP 250 mg / 500 mg compared with 165.9 minutes for placebo (P<0.001, Table 10). The TFPR (median: 28.2 minutes) in the FDC IBU / APAP 250 mg / 500 mg group was significantly faster than in the placebo group (N / A, P<0.001, Table 11). In total, 87.8% of patients receiving FDC IBU / APAP 250 mg / 500 mg achieved an FPR compared with 29.3% of patients receiving placebo.

[0206] For TOTPAR, FDC provided significantly better pain relief than placebo for all intervals assessed over 48 hours (P<0.001 for all interval comparisons).

[0207] A lower percentage of patients in the FDC / APAP 250 mg / 500 mg group, 36.6%, took at least one dose of rescue medication between the first and second doses (or withdrew early due to an AE) compared with placebo (87.8%). Duration of relief was significantly longer for the FDC group compared with the placebo group (median: 82.0 minutes, P<0.001, Table 12).

[0208] In the patient global assessment of study medication, the FDC IBU / APAP 250mg / 500mg treatment group was rated significantly better than placebo at both 24 and 48 hours post-dose (P≦0.001 for both comparisons).

[0209] Trials 2 and 3 - Safety. FDC IBU / APAP 250 mg / 500 mg was generally well tolerated, and no unexpected AEs were observed. In both studies, the most commonly reported AEs were nausea, vomiting, dizziness, and headache, all of which occurred more frequently in the placebo group than in the active treatment group (Table 13). The incidence of these AEs was lowest for FDC IBU / APAP 250 mg / 500 mg in both studies.

[0210] Tests 2 and 3 - Discussion. The studies described herein evaluating the efficacy and tolerability of a new FDC, IBU 250 mg / APAP 500 mg, met their respective primary endpoints. Single-dose studies demonstrated that the FDC IBU / APAP 250 mg / 500 mg provided significantly better analgesia than placebo, IBU 250 mg alone, and APAP 650 mg alone over a 0-8 hour period. Multiple-dose studies demonstrated that the FDC IBU / APAP 250 mg / 500 mg was significantly better than placebo over the entire study period and demonstrated sustained efficacy over 2 days with multiple doses at an 8-hour dosing interval. These results are consistent with previous studies of different FDCs of IBU and APAP. Previous studies of the IBU / APAP 200 mg / 500 mg FDC demonstrated superior analgesic efficacy compared to placebo or either agent alone. In addition, Study 1 above found that FDC IBU / APAP 250 mg / 500 mg provided similar efficacy to IBU 400 mg. The onset of pain relief, as determined using TFPR and TMPR, is an additional important indicator for assessing analgesic efficacy in acute pain. The TFPR was 21 and 28 minutes for FDC in Studies 2 and 3, respectively, and was numerically better than either IBU or APAP alone in Study 2. The TMPR of 48 and 59 minutes for FDC in Studies 2 and 3 was consistent with the 39-74 minutes reported in previous studies of FDC IBU / APAP 200 mg / 500 mg and the 54 minutes reported for FDC IBU / APAP 250 mg / 500 mg in a pilot study. The TMPR for FDC in Study 2 was also significantly faster than IBU or APAP alone. These data demonstrate that FDC provides rapid onset of pain relief, occurring within one hour, an important attribute for any analgesic used for acute pain.

[0211] The median duration of pain relief with the FDC was approximately 10.5 hours in the single-dose study, longer than the 8 hours in the multiple-dose study (data were censored for all patients at 8 hours after taking the second dose of study drug). This duration of pain relief was significantly longer with the FDC IBU / APAP 250 mg / 500 mg than the approximately 7.5 hours observed with APAP 650 mg in single-dose study 1. The results of this study are again consistent with a previous study 1, which also reported a median duration of pain relief of over 10 hours with this FDC. This longer duration of pain relief with the FDC compared with placebo and APAP 650 mg is consistent with the SPID

[11] . 6~8 This finding was further supported by the significantly better analgesia observed in the 6-8 hour interval as measured by FDC (P<0.001 for FDC vs. APAP 650 mg and placebo). The 8-hour dosing interval was confirmed in a multiple-dose study in which the FDC demonstrated superior pain relief compared to placebo over a 2-day evaluation period and demonstrated no loss of efficacy with the 8-hour dosing regimen. Collectively, these data indicate that the Ibu / APAP 250 mg / 500 mg FDC can be administered at 8-hour intervals, i.e., three times daily, without loss of efficacy. This 8-hour dosing interval corresponds to the 4-6 hour dosing interval for currently available single-entity IBU and APAP products.

[0212] AEs occurred most frequently in the placebo group. Nausea, vomiting, and dizziness are fairly common events after oral surgery and may be related to postoperative pain and / or the greater use of rescue opioid medications in that group. The AE profile of the FDC was comparable to or better than that of the two components alone. No unexpected AEs were observed with the combination, and the safety profile of the FDC was consistent with that seen in previous studies.

[0213] These studies demonstrate that FDC IBU / APAP 250mg / 500mg is a more effective analgesic than the same dose of each agent alone and is well tolerated. Importantly, these studies also demonstrate rapid onset of analgesia within one hour and sustained analgesia over an eight-hour dosing interval. The maximum combined daily dose of IBU and APAP for the FDC (750mg IBU / 1500mg APAP) is substantially less than the recommended maximum daily dose of either component administered alone (1200mg and 4000mg, respectively); therefore, FDC IBU / APAP 250mg / 500mg is expected to have a desirable safety profile. Thus, this FDC may offer consumers another non-opioid pain relief option with reduced exposure to both IBU and APAP compared to standard OTC dosing of either agent alone.

[0214] [Table 9]

[0215] [Table 10]

[0216] [Table 11]

[0217] [Table 12]

[0218] [Table 13]

[0219] [Example 5] Antipyretic efficacy of FDC in endotoxin-induced fever model. Objective: This study evaluated the antipyretic efficacy, onset of effect, and tolerability of a single dose of FDC IBU / APAP 250 mg / 500 mg compared with placebo and the same dose of each single component.

[0220] Methods: This was a single-center, randomized, double-blind, placebo-controlled, full factorial study in healthy men aged 18 to 55 years in whom fever was induced by intravenous administration of reference standard endotoxin (RSE). After RSE administration and achievement of an oral temperature ≥ 100.5°F (38.1°C), subjects were randomized 3:3:3:1 in a double-blind manner to receive a single oral dose of FDC IBU / APAP 250mg / 500mg, APAP 500mg, IBU 250mg, or placebo. Oral temperatures were then measured every 10 minutes for the first 2 hours, then every 30 minutes for up to 8 hours after administration. The time-weighted sum of temperature differences from baseline to 8 hours after study drug administration (WSTD) was used. 0~8 ) was the primary efficacy endpoint. Secondary endpoints included WSTD scores at 0-2, 0-4, 0-6, and 6-8 hours, time to return to "normal" temperature, time to use of rescue medication, and global drug assessment. Safety was monitored and assessed by adverse events (AEs).

[0221] Findings: 290 subjects were randomized, and 273 were included in the primary efficacy analysis population. 0~8 was significantly better for FDC IBU / APAP 250 mg / 500 mg (P = .002), IBU 250 mg (P = .030), and APAP 500 mg (P = .023) versus placebo, with no significant differences between active treatments. 0~2 For FDC, the effect was statistically significant versus placebo (P = .004), but its single components were not.

[0222] All active treatments were compared to placebo for WSTD. 0~4 and WSTD 0~6 The difference in WSTD between groups was significantly better (P<.05). 6~8There were no differences in temperature. Temperatures returned to normal during the 8-hour treatment period in approximately 50% of subjects in each treatment group. Rescue medication was taken by only one subject (IBU group). Post-hoc analysis of WSTD at early time points showed that WSTD 50~110 FDC will clarify the significant treatment differences desired for placebo and IBU, and WSTD 80~110 For FDC, there was a significant treatment difference versus placebo and both single components. Overall, 223 / 290 (76.9%) subjects experienced an AE related to RSE, and only 2 subjects experienced a treatment-related AE (rash with FDC, ear pain with placebo).

[0223] Impact: FDC IBU / APAP 250mg / 500mg provides an effective antipyretic treatment option that provides a faster onset of fever reduction that lasts longer than the same dose of IBU and APAP alone.

[0224] Participants and Methods Study design: This was a single-center, randomized, double-blind, placebo-controlled, fully factorial, single-dose study in subjects in whom fever was induced by intravenous (IV) administration of reference standard endotoxin (RSE). In this standardized model, fever was induced by endotoxin (a gram-negative bacterial lipopolysaccharide) derived from Escherichia coli O113, which was developed as a national biological reference standard in 1976 by the National Institute of Allergy and Infectious Diseases and the U.S. Food and Drug Administration. The RSE used in this study was supplied by List Biological Laboratories, Inc. (Campbell, CA, USA).

[0225] Subject eligibility was determined at a screening visit within 28 days prior to study drug treatment, and eligible subjects were assigned consecutive subject numbers by the investigator. Subjects were required to have a normal, stable body temperature, 17.5-37.0 kg / m at screening and on day 0. 2Participants were healthy males aged 18 to 55 years, inclusive, with a body mass index of ≥ 1.0 and total body weight ≥ 50 kg at screening, a clearly suitable vein for IV catheter insertion, and willing and able to comply with all study procedures. Subjects of childbearing potential had to agree to use highly effective contraception throughout the study and for at least 28 days after the last dose of treatment. Female subjects were not enrolled due to concerns about potential teratogenicity associated with the use of RSE. Important exclusion criteria were the presence or history of significant medical or laboratory abnormalities that could have increased the subject's risk, including the presence or history of gastrointestinal disorders or excessive bleeding; a history of recurrent acute or chronic infections of any kind or any findings suggestive of occult infection; cold or flu symptoms within 2 weeks prior to the first dose of study treatment; screening supine blood pressure ≤ 90 or ≥ 140 mmHg (systolic) or ≤ 50 or ≥ 90 mmHg (diastolic) after at least 5 minutes of supine rest; screening supine 12-lead electrocardiogram (ECG) showing a corrected QT > 450 msec or a QRS interval > 120 msec at screening and on Day 1; Deemed to be at high risk for syncope and / or hypotension in the investigator's judgment; a heart rate (HR) decrease to ≦50 beats per minute or after carotid sinus massage; a positive urine drug screen or alcohol breath test during screening or on day 0; a history of habitual alcohol consumption; an unwillingness to abstain from tobacco or nicotine-containing products; treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug; use of prescription, non-prescription, or dietary supplements within 7 days or 5 half-lives (whichever is longer); administration of endotoxin within 3 months; or a history of heparin sensitivity or heparin-induced thrombocytopenia.

[0226] Subjects entered the study facility on Day 0 to confirm eligibility, i.e., afebrile status defined as a mean oral temperature of 97.4°F to 98.8°F with no variation of more than 0.4°F over three repeated measurements over 30 minutes, and that they still met the inclusion / exclusion criteria. Subjects who remained eligible for the study remained in the facility until after the completion of all study procedures.

[0227] Subjects received prophylactic ondansetron 8 mg intravenously approximately 30 minutes before RSE administration to reduce the likelihood of nausea and vomiting. Prior to RSE administration, changes to pretreatment were recorded, blood pressure and heart rate were measured, and a 12-lead ECG was obtained. Oral temperature was recorded, and each subject's "normal" was the temperature recorded immediately before RSE administration.

[0228] judgement Subject eligibility assessment included physical examination, vital sign measurements, ECG evaluation, and clinical laboratory tests (hematology, blood chemistry, and urinalysis). Baseline oral temperature was defined as the temperature reading obtained immediately before administration of study drug after the subject achieved an RSE-induced oral temperature of ≥ 100.5°F (38.1°C), required for randomization. After randomization and study drug administration, oral temperature was measured using a standard electronic digital thermometer every 10 minutes for the first 2 hours and then every 30 minutes until 8 hours post-dose. Subjects were assessed for the occurrence of AEs at each temperature assessment. Respiratory rate and blood pressure were measured hourly, an ECG was performed after 8 hours, and subjects were discharged if appropriate. Clinic personnel conducted safety follow-up by calling all subjects within 24 hours of discharge and 14 days after the last dose of study drug.

[0229] Study endpoints. The primary efficacy endpoint was the time-weighted sum of the temperature difference from baseline to 8 hours (WSTD). 0~8 ), and the weighting was equal to the time elapsed between each two consecutive time points. Secondary endpoints were baseline to 2 hours (WSTD 0~2 ), baseline ~ 4 hours (WSTD 0~4 ), baseline ~ 6 hours (WSTD 0~6 ), and 6 to 8 hours (WSTD 6~8) included a weighted sum of the temperature difference between baseline and rescue medications. Temperature difference from baseline at each post-dose assessment, as well as time to fever clearance as measured by time to reach normal temperature (the temperature immediately before administration of RSE) and time to administration of rescue medication, were also assessed. The proportion of subjects requiring rescue medication by 2, 3, 4, 5, 6, 7, and 8 hours was also reported. An overall assessment of study medication was performed at the end of the 8-hour study period or at the time of rescue administration by asking subjects, "How would you rate this medication as an antipyretic?" using a 6-point categorical scale ranging from 0 (very poor) to 5 (excellent). Safety and tolerability were monitored throughout the study by assessment of AEs, discontinuations due to AEs, serious AEs (SAEs), vital signs, laboratory results, and ECG recordings.

[0230] A post-hoc analysis was performed to analyze the effect of FDC treatment on distinct WSTD across early post-treatment time points where FDC demonstrated significantly superior efficacy over single-component IBU and APAP. This analysis was performed using an ANCOVA model with terms for treatment and covariates of time from first full dose of RSE to randomization and baseline temperature. Two WSTD endpoints were analyzed: WSTD from baseline in the 50-110 minute post-treatment window using temperature values ​​at 60, 70, 80, 90, 100, and 110 minutes (WSTD). 50~110分 ), and WSTD from baseline in the 80-110 min post-treatment window using temperature values ​​at 90, 100, and 110 min (WSTD 80~110分 ).

[0231] result. Participants and Baseline Characteristics. A total of 607 subjects were screened, and 290 were randomized. Of these, 273 subjects (94.1%) were included in the primary efficacy analysis population (mITT), and 290 subjects comprised the safety analysis population. Of the 23 subjects who discontinued the study in the safety analysis population, 21 (including the 11 mentioned above) did so due to RSE-related AEs. Baseline characteristics were well balanced between groups (Table 14). Per study design, all subjects were male, as indicated. The majority of the study population (78.0%) was Caucasian, with a mean age of 32.2 years.

[0232] [Table 14]

[0233] The mean time from ingestion of the full dose of RSE to randomization (i.e., oral temperature ≥ 100.5°F [38.1°C]) ranged from 124.3 to 140.4 minutes.

[0234] Effectiveness Primary Endpoint. Mean oral temperatures for each study group over the course of the study are shown in Figure 10. (Baseline (point 0) LSM was calculated from an ANCOVA model with terms for treatment group and the covariates of time from first full dose of RSE to randomization. Post-baseline LSM was calculated from an ANCOVA model with terms for treatment group and the covariates of time from first full dose of RSE to randomization and baseline temperature.) a P ≤ .05 vs. placebo; b P ≤ .01 vs. placebo; c P ≤ .001 vs. placebo; d P ≤ .05 for 250 mg IBU; e P ≤ .05 vs. APAP 500 mg. (P: significantly better than placebo at the 0.05 level; I: significantly better than IBU 250 mg at the 0.05 level; A: significantly better than APAP 650 mg at the 0.05 level).

[0235] For the primary efficacy parameter, LSM(SE)WSTD in the placebo, FDC, IBU 250 mg, and APAP 500 mg groups 0~8 The sigma-positive (SNR) scores were 9.42 (0.89), 12.55 (0.51), 11.65 (0.51), and 11.77 (0.51), respectively. The difference between FDC and placebo was statistically significant (P = .002), with FDC numerically, but not statistically, better than either the IBU or APAP components (Table 15). Both the IBU 250 mg and APAP 500 mg doses were significantly better than placebo (P < .05).

[0236] Secondary endpoints. WSTD results for other time intervals are summarized in Table 15. FDC was significantly better than placebo in the 0-2 hour interval (WSTD 0~2 , P = .004), and there was no difference between IBU and APAP and placebo. 0~4 and WSTD 0~6 showed a similar pattern to the primary endpoint, with FDC, IBU 250 mg, and APAP 500 mg all significantly better than placebo. 6~8 showed no differences between either group and placebo.

[0237] [Table 15]

[0238] FDC was significantly better than placebo in the 0-2 hour interval (WSTD 0~2 , P = .004), and there was no difference between IBU and APAP and placebo. 0~4 and WSTD 0~6 showed a similar pattern to the primary endpoint, with FDC, IBU 250 mg, and APAP 500 mg all significantly better than placebo. 6~8 showed no differences between either group and placebo.

[0239] Other Evaluations. In an analysis of temperature changes at different time points during the study, FDC significantly reduced subject temperatures relative to placebo, beginning 60 minutes after treatment administration. The difference relative to placebo remained significant at each subsequent assessment over 5.5 hours (P<0.05 for each assessment). In contrast, significant temperature reductions were observed for IBU 250 mg at 100 and 110 minutes and 2, 2.5, and 3 hours (P<0.05 for each), and for APAP 500 mg at 100 and 110 minutes and 2, 2.5, 3, 4, and 4.5 hours relative to placebo. Endotoxin-induced fever was significantly reduced at 60, 90, and 110 minutes with FDC relative to IBU 250 mg, and at 90 minutes with FDC relative to APAP 500 mg.

[0240] For the a priori global assessment of the study drug, subjects were asked to rate the study drug on a 6-point scale from 0 to 5 (0 = very poor to 5 = excellent) in response to the question, "How would you rate this drug as an antipyretic?" Results are presented as percentages in Figure 11. a P<0.05 vs. placebo (from an ANCOVA model when analyzed as a continuous variable, using treatment group as a term and time from first full dose of RSE to randomization and baseline temperature as covariates). b P = .05 versus placebo (by chi-square test when analyzed as a categorical variable).

[0241] The majority of subjects in all groups rated their study medications as "good" or "very good" antipyretics. In chi-square analysis, IBU 250 mg was rated significantly higher than placebo (P = .050). In ANCOVA analysis, both the FDC and IBU 250 mg treatment groups rated their treatments significantly higher than those in the placebo group (P < .05 for each), but the APAP 500 mg group did not.

[0242] Post-hoc WSTD analysis. To identify early time intervals (0-2 hours) where the FDC shows statistical significance over a single component, a post-hoc analysis was performed to determine the WSTD between treatment groups for the 50-110 minute and 80-110 minute post-baseline time intervals. Results from this analysis are presented in Table 16.

[0243] [Table 16]

[0244] As shown in the table, FDC significantly improved WSTD compared with placebo (P<.001) and IBU (P=.042). 50~110分 Results showed a statistically significant treatment difference of 0.05, with a trend toward significance for FDC versus APAP (P = .076). For the 80-110 minute post-baseline comparison, FDC was statistically superior to placebo (P < .001), IBU (P = .045), and APAP (P = .049).

[0245] Safety and Tolerability Treatment-emergent AEs (TEAEs) during the endotoxin administration period. A total of 290 subjects (100%) reported TEAEs attributable to RSE during the RSE administration period. The most common AEs were chills in 281 subjects (96.9%) and tremor in 236 subjects (81.4%), and these AEs were generally similar between treatment groups. Other TEAEs included headache in 181 subjects (62.4%), pain in 117 subjects (40.3%), increased HR in 80 subjects (27.6%), nausea in 66 subjects (22.8%), fatigue in 49 subjects (16.9%), and myalgia in 35 subjects (12.1%), which were reported at similar rates between treatment groups. Only one subject (0.3%) reported a TEAE not attributable to RSE during the RSE administration period (IBU 250 mg group, infusion-related reaction).

[0246] TEAEs During Study Drug Treatment. A total of 223 of 290 subjects (76.9%) reported AEs considered related to RSE during study drug treatment. The most common of these AEs were increased HR in 129 subjects (44.5%), pyrexia in 100 subjects (34.5%), hypotension in 62 subjects (21.4%), nausea in 32 subjects (11.0%), and headache in 31 subjects (10.7%), none of which were serious. Fever was reported by a higher percentage of subjects in the placebo and IBU 250 mg treatment groups (41.4% in each group) than in the FDC or APAP 500 mg groups (29.9% each). Nausea and headache due to RSE, reported by 32 (11.0%) and 31 (10.7%) subjects, respectively, were also reported in higher percentages in participants treated with placebo (20.7% and 24.1%, respectively) and IBU 250 mg (12.6% and 14.9%, respectively) compared with the FDC (8.0% and 6.9%, respectively) and APAP 500 mg (9.2% and 5.7%, respectively) treatment groups. A total of 21 (7.2%) of 290 subjects reported TEAEs (vomiting and pyrexia) due to RSE that led to withdrawal from the study (4 [13.8%], 6 [6.9%], 5 [5.7%], and 6 [6.9%] subjects in the placebo, FDC, IBU, and APAP treatment groups, respectively).

[0247] Consideration. The study compared placebo to the primary endpoint of WSTD 0~8 The statistical significance of a single oral dose of FDC IBU / APAP 250mg / 500mg was demonstrated for fever-reducing symptoms, confirming the efficacy of FDC as an antipyretic. IBU 250mg and APAP 500mg alone were also statistically superior to placebo for this outcome.

[0248] FDC did not demonstrate statistical significance for the primary endpoint compared with each single component alone, but did demonstrate numerical superiority over each single component.

[0249] WSTD, a secondary endpoint 0~2 For WSTD, FDC was statistically superior to placebo, but neither IBU 250 mg nor APAP 500 mg were. Additional analyses found that FDC treatment significantly reduced subject temperatures compared to placebo from 60 minutes to 5.5 hours after administration, compared to 100 minutes to 3 hours for IBU 250 mg and 100 minutes to 4.5 hours for APAP 500 mg. Post-hoc analyses determining separate early WSTD time intervals showed that FDC was superior to IBU 250 mg from 50 to 110 minutes and superior to both IBU and APAP from 80 to 110 minutes.

[0250] Combined with previous studies of combined IBU and APAP in children (see Malya RR, “Does combination treatment with ibuprofen and acetaminophen improve fever control?” Ann Emerg Med. 2013;61:569-570; Paul IM et al., “Efficacy of standard doses of ibuprofen alone, alternating, and combined with acetaminophen for the treatment of febrile children,” Clin Ther. 2010;32:2433-2440; and Purssell E, “Systematic review of studies comparing combined treatment with paracetamol and ibuprofen, with either drug alone,” Arch Dis Child. 2011;96:1175-1179), these results suggest that FDC has a faster onset of fever reduction, is more effective in reducing fever, and has a longer duration of action than either single component.

[0251] In this study, an induced fever model was used to determine the antipyretic activity of FDC IBU / APAP 250 mg / 500 mg (see Suffredini AF and Noveck RJ, “Human endotoxin administration as an experimental model in drug development,” Clin Pharmacol Ther. 2014;96:418-422). The use of RSE results in fever that can be reproduced in a clinical setting for testing purposes. Indeed, RSE was developed by the National Institute of Allergy and Infectious Diseases and the U.S. Food and Drug Administration to assist pharmaceutical companies and biomedical researchers, particularly in standardizing study designs. While naturalistic fever studies may be preferable, there are several logistical barriers to conducting such studies, primarily recruiting febrile adult subjects, because individuals are more likely to treat themselves than to report for enrollment in a clinical trial. Other challenges include seasonal variations in the incidence and severity of viral and bacterial infections and the fact that subjects may be at different stages of their illness and have illnesses of different origins at the time of randomization to treatment. All of these factors can confound the results and / or increase the number of subjects required for testing due to increased variability.

[0252] A limitation of this study is that the more conservative approach used to administer a RSE batch that appeared more potent than those used in previous studies (as evidenced by the frequency and earlier onset of RSE-related adverse events) may have resulted in a lower and shorter duration of fever that did not persist over the 8-hour posttreatment observation period, as evidenced by the fact that 51.9% of subjects in the placebo group returned to normal temperature during the observation period. This, in turn, may have limited the model sensitivity with respect to observing the statistical separation of the active treatment from placebo (lower sensitivity) and the statistical separation of each of the active treatments (upper sensitivity). Due to the restrictive criteria used for study enrollment, these results cannot be generalized to febrile patients with medical complications, those younger than 18 years or older than 55 years, and women. Nevertheless, the data indicate that FDC is an effective antipyretic that results in a more rapid reduction in fever than the individual components at the same dose.

[0253] The majority of AEs reported in this study were attributable to RSE. All of these events were mild to moderate in intensity. Overall, the FDC formulation was shown to be safe and generally well-tolerated in otherwise healthy subjects with induced fever, and no new safety concerns for FDC were identified in this study.

[0254] Conclusion. This study demonstrated that the IBU 250 mg / APAP 500 mg FDC reduced fever significantly better than placebo over the 0-8 hour period. Additionally, the FDC was numerically better than both single components over this period, but did not reach statistical significance for this primary endpoint. Similar trends were observed across most of the pre-determined efficacy endpoints. The FDC was statistically significantly superior to placebo over the 0-2 hour period, whereas IBU and APAP alone were not, suggesting that the FDC may result in a faster onset of fever reduction. This conclusion is supported by the results of a post-hoc analysis, which showed that the FDC was superior to IBU 250 mg over the 50-110 minute period and to both IBU 250 mg and APAP 500 mg over the 80-110 minute period. The incidence of TEAEs in this study was very low, indicating that the FDC was safe and generally well tolerated. FDC IBU / APAP 250mg / 500mg may provide another effective treatment option for fever with a more rapid onset and longer duration than comparable doses of IBU and APAP single components.

[0255] Thus, FDC and each single component provided superior fever reduction compared to placebo. In induced fever, faster and longer defervescence occurred with FDC versus monotherapy.

[0256] TIFF2025134843000019.tif253158

Claims

1. 1. An oral pharmaceutical composition suitable for tableting, comprising the active pharmaceutical ingredients ibuprofen and acetaminophen, wherein the ibuprofen is present in an amount of 100 to 300 mg and the acetaminophen is present in an amount of 150 to 600 mg, the ratio of ibuprofen to acetaminophen being 1:3 to 1:1 by weight; the composition further comprises intragranular and extragranular components, the intragranular component comprising an active ingredient, a binder, a disintegrant and a glidant, and the extragranular component comprising a disintegrant, a glidant and a lubricant; An oral pharmaceutical composition, wherein said composition is essentially free of unmodified starch.

2. 10. The pharmaceutical composition of claim 1, wherein the intragranular binder comprises pregelatinized starch and optionally hypromellose.

3. 3. The pharmaceutical composition of claim 2, wherein the pregelatinized starch and optionally hypromellose are the only intragranular binders.

4. 4. The pharmaceutical composition of claim 2 or 3, wherein the pregelatinized starch is present in an amount of from 4% to 25% by weight of the composition.

5. 5. The pharmaceutical composition of claim 1, 2, 3, or 4, wherein the intragranular binder further comprises hypromellose.

6. 6. The pharmaceutical composition of claim 5, wherein the hypromellose is present in an amount of 1% to 2% by weight of the composition.

7. 6. The pharmaceutical composition of claim 5, wherein the pregelatinized starch is present as a first binder in an amount ranging from 8 to 15% by weight and the hypromellose is present as a second binder in an amount of 1% to 2% by weight of the composition.

8. 8. The pharmaceutical composition of claim 5, 6 or 7, wherein the weight ratio of pregelatinized starch to hypromellose is from about 7:1 to about 12:

1.

9. 9. The pharmaceutical composition of claim 1, wherein the disintegrant comprises a superdisintegrant that is intragranular, extragranular, or both intragranular and extragranular.

10. 10. The pharmaceutical composition of claim 9, wherein the superdisintegrant is present both intragranularly and extragranularly.

11. 11. The pharmaceutical composition of claim 9 or 10, wherein the super disintegrant is cross-linked carboxymethyl cellulose.

12. 12. The pharmaceutical composition of claim 10 or 11, wherein the super disintegrant is present intragranularly in an amount of 0.5% to 5% by weight of the composition and extragranularly in an amount of 0.5% to 5% by weight of the composition.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the glidant comprises colloidal silicon dioxide.

14. 14. The pharmaceutical composition of claim 13, wherein the colloidal silicon dioxide is present intragranularly in an amount of 0.5% to 2% by weight of the composition and extragranularly in an amount of 0.5% to 2% by weight of the composition.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, wherein the lubricant comprises glyceryl behenate.

16. 16. The pharmaceutical composition of claim 15, wherein the glyceryl behenate is present extragranularly in an amount of 0.5% to 2% by weight.

17. 17. The pharmaceutical composition of any one of claims 1 to 16, wherein the intragranular component is present as a population of granules having a d50 of about 100 to about 200.

18. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein ibuprofen is present in an amount from 110 mg to 140 mg and acetaminophen is present in an amount from 230 mg to 270 mg.

19. 19. The pharmaceutical composition of claim 18, wherein the ibuprofen is present in an amount of 125 mg and the acetaminophen is present in an amount of 250 mg.

20. 18. The pharmaceutical composition of any one of claims 1 to 17, wherein ibuprofen is present in an amount of 250 mg and acetaminophen is present in an amount of 500 mg.

21. 21. The pharmaceutical composition of any one of claims 1 to 20, in the form of a tablet.

22. (i) the active ingredient present within the granules; (ii) 5% to 20% by weight of pregelatinized starch present in the granule; (iii) 0.5% to 2.5% by weight of hypromellose present within the granules; (iv) 0.5% to 3% by weight of extragranular glyceryl dibehenate; (v) 1% to 10% by weight of intragranular and extragranular croscarmellose; and (vi) 1% to 5% by weight of intragranular and extragranular colloidal silicon dioxide 2. The pharmaceutical composition of claim 1, comprising:

23. (i) the active ingredient present within the granules; (ii) 8% to 15% by weight of pregelatinized starch present in the granule; (iii) 1% to 2% by weight of hypromellose present within the granules; (iv) 1% to 2% by weight of extragranular glyceryl dibehenate; (v) 5% to 8% by weight of croscarmellose present intragranularly and extragranularly; and (vi) 2% to 4% by weight of colloidal silicon dioxide present intragranularly and extragranularly 2. The pharmaceutical composition of claim 1, comprising:

24. 24. The pharmaceutical composition of claim 22 or 23, wherein ibuprofen is present in an amount of 125 mg and acetaminophen is present in an amount of 250 mg; or wherein ibuprofen is present in an amount of 250 mg and acetaminophen is present in an amount of 500 mg.

25. 25. The pharmaceutical composition of any one of claims 22 to 24, in the form of a tablet.

26. Compressed tablets for oral administration whose core consists of the following excipients: Ibuprofen, 125 mg Acetaminophen, 250 mg Hypromellose, approximately 8 mg Croscarmellose sodium, approximately 33 mg Colloidal silicon dioxide, approximately 14 mg, Pregelatinized starch, approximately 60 mg, and Glyceryl dibehenate, approximately 7 mg.

27. 1. A method of treating a mammalian subject in need thereof for the relief of pain and / or inflammation, comprising orally administering to the subject a pharmaceutical composition comprising the active ingredients ibuprofen in an amount of 250 mg and acetaminophen in an amount of 500 mg; the composition further comprises intragranular and extragranular components, the intragranular component comprising an active ingredient, a binder, a disintegrant and a glidant, and the extragranular component comprising a disintegrant, a glidant and a lubricant, the composition being essentially free of unmodified starch; the composition is administered in a single or divided dose; The administration is optionally repeated at 8 hour intervals until the subject achieves relief of pain and / or inflammation.

28. 28. The method of claim 27, wherein the composition is administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen.

29. 28. The method of claim 27, wherein the composition is administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen, said divided dose consisting of two tablets.

30. 1. A method of treating fever in a mammalian subject in need thereof, comprising administering to the subject an antipyretic composition comprising the active ingredients ibuprofen in an amount of 250 mg and acetaminophen in an amount of 500 mg, wherein the composition is administered in a single or divided dose, and wherein the administration is optionally repeated until the subject achieves relief from fever.

31. 31. The method of claim 30, wherein the composition is administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen.

32. 32. The method of claim 30 or 31, wherein the composition further comprises intragranular and extragranular components, the intragranular component comprising the active ingredient, a binder, a disintegrant and a glidant, and the extragranular component comprising the disintegrant, a glidant and a lubricant, and the composition is essentially free of unmodified starch.

33. 33. The method of claim 30 or 32, wherein the composition is administered in divided doses each containing 125 mg ibuprofen and 250 mg acetaminophen, said divided dose consisting of two tablets.

34. 31. The method of claim 30, which provides a statistically significant faster onset of action over 0-2 hours compared to placebo.

35. 10. A method for preparing a tablet from the composition of claim 1, comprising the steps of preparing a granule, mixing the granule with any desired extragranular components to form a masterblend, and compressing the masterblend into a tablet.

36. 27. A composition according to any one of claims 1 to 26 for use in the treatment of pain and / or inflammation or for reducing fever.

37. 27. A composition according to any one of claims 1 to 26 in the manufacture of a medicament for the treatment of pain and / or inflammation, or for reducing fever.

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