Acetaminophen and naproxen for treating pain

Abstract

The present disclosure is directed to an improved method of treating mild pain in humans using a pharmaceutical dosage form comprising acetaminophen in admixture with naproxen.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application Nos. 63 / 422,547 (filed November 4, 2022) and 63 / 504,237 (filed May 25, 2023), which are incorporated by reference herein in their entireties.

[0002] FIELD OF THE INVENTION The present disclosure is directed to an improved method of treating mild pain in humans using a pharmaceutical dosage form comprising acetaminophen in admixture with naproxen. [Background technology]

[0003] Acetaminophen is an over-the-counter analgesic. Naproxen sodium is an over-the-counter nonsteroidal anti-inflammatory drug (NSAID). Each has been individually described as a safe and effective over-the-counter (OTC) treatment for mild pain. Acetaminophen has been combined with opioids, such as narcotics, e.g., hydrocodone, codeine, and oxycodone, to enhance pain relief, but these combination products may be contraindicated for certain patient populations. However, there remains a need for safe and effective OTC treatments that can induce pain relief. Summary of the Invention [Means for solving the problem]

[0004] The present disclosure is directed to methods for inducing mild pain relief in a human in need thereof. According to these methods, the human is administered a pharmaceutical dosage form comprising acetaminophen mixed with naproxen sodium, wherein the weight ratio of acetaminophen to naproxen sodium is from about 2:1 to about 4:1. Pharmaceutical dosage forms useful in these methods and methods for their preparation are described herein. DETAILED DESCRIPTION OF THE INVENTION

[0005] The present disclosure may be more fully understood by reference to the following description, including the following definitions and examples. Additionally, certain features of the compositions and methods of the present disclosure that are described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the compositions and methods of the present disclosure that are described for brevity in the context of a single aspect may also be provided separately or in any subcombination. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terms used herein are used only to describe particular embodiments and are not intended to limit the present disclosure.

[0006] In this disclosure, unless expressly stated otherwise, the singular forms "a," "an," and "the" include plural references and a reference to a particular numerical value includes at least that particular value. Thus, for example, a reference to "a material" is a reference to at least one of such material and equivalents and similar known to those skilled in the art.

[0007] When values ​​are expressed as approximations by use of the descriptor "about," it is understood that the particular value forms another embodiment. Generally, use of the term "about" indicates an approximation that may vary depending on the desired properties sought to be obtained by the disclosed subject matter and should be interpreted in the specific context in which it is used based on its function. Those of ordinary skill in the art can interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the term "about." In other cases, the gradations used in a series of values ​​can be used to determine the intended range available to the term "about" for each value. In some cases, the descriptor "about" is understood to mean up to ±10%, e.g., ±10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%. When present, all ranges are inclusive and combinable; that is, reference to values ​​stated in ranges includes all values ​​within that range.

[0008] When lists are presented, it is to be understood that each individual element of that list and every combination of that list is to be construed as a separate embodiment unless otherwise specified. For example, a list of embodiments presented as "A, B, or C" should be construed to include the embodiments "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."

[0009] It is understood that certain features of the invention, which are described herein for clarity in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless expressly incompatible or excluded, each individual embodiment is deemed compatible with any other embodiment, and such combinations are considered to be separate embodiments. Conversely, different features of the invention that are described in the context of a single embodiment for ease of explanation may also be provided separately or in any subcombination. It is further noted that the claims may be drafted to exclude optional elements. Accordingly, this description is intended to serve as a basis for prior limitation on the use of exclusive language such as "only" in connection with the recitation of claim elements, or the use of a "negative" limitation. Finally, while an embodiment may be described as part of a series of steps or as part of a more general structure, each step may be considered an independent embodiment in itself.

[0010] The present disclosure is directed to methods of inducing pain relief in a human, e.g., a human at least 12 years of age, at least 16 years of age, or at least 18 years of age, experiencing mild pain, by orally administering a pharmaceutical dosage form comprising acetaminophen (i.e., paracetamol) mixed with naproxen, wherein the naproxen is preferably in the form of a pharmaceutically acceptable salt of naproxen, such as naproxen sodium.

[0011] "Pharmaceutical dosage form" refers to any orally ingestible form, e.g., solid, semi-solid, or liquid. In some embodiments, the dosage form is solid, but may contain liquid or semi-solid components. A preferred dosage form is a tablet (e.g., a compressed or molded solid dosage form of any shape or size), preferably a film-coated tablet. Other dosage forms include capsules and powders.

[0012] As used herein, "mild pain" includes, for example, headache, back pain, arthritis pain (e.g., osteoarthritis pain, rheumatoid arthritis pain), bursitis pain, pain from a gout attack, dental pain (e.g., toothache), surgical incision pain (e.g., tooth extraction), muscle pain, premenstrual and menstrual cramps, tendonitis, sore throat, acute traumatic pain, and the like.

[0013] As used herein, pain relief and pain intensity are determined using clinical assessment scales known to those skilled in the art. Examples of such assessments include, for example, the time-weighted sum of pain intensity difference (SPID), the Pain-Intensity-Numerical Rating Scale (PI-NRS), the pain intensity difference (PID), the time-weighted total pain relief (TOTPAR), and the Pain Relief Numerical Rating Scale (PR-NRS). PI-NRS and PR-NRS are scales used to measure pain intensity and pain relief, while SPID and TOTPAR are assessments calculated using the data collected from PI-NRS and PR-NRS to evaluate pain intensity or pain relief over a specific period of time.

[0014] Differences in pain intensity and / or pain relief can be assessed at baseline (at or immediately prior to administration of the dosage form) and compared to pain intensity and / or pain relief assessments at time points or time intervals after administration of the dosage form. For example, assessments can be made at about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes after administration. In other embodiments, assessments can be made at about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours after administration.

[0015] The pharmaceutical dosage forms of the present disclosure contain acetaminophen mixed with a salt of naproxen (e.g., naproxen sodium). Examples of various forms of acetaminophen are disclosed in WO 1998027931. In preferred embodiments, the pharmaceutical dosage form contains acetaminophen and naproxen sodium in the same granulation product. In some embodiments, the pharmaceutical dosage form contains acetaminophen and naproxen sodium in a single granulation product.

[0016] In some embodiments, the pharmaceutical dosage form and one or more tablets comprise acetaminophen and naproxen sodium in a single layer of one or more tablets. These dosage forms exclude multi-layer (e.g., bi-layer) tablets in which the active ingredients are not mixed with each other. For example, in a multi-layer tablet containing two or more active ingredients, each active ingredient is contained within its own layer, with minimal (or no) mixing of the active ingredients.

[0017] Exemplary pharmaceutical dosage forms of the present disclosure include acetaminophen mixed with naproxen sodium. In these dosage forms, the weight ratio of acetaminophen to naproxen sodium is about 2:1 to about 4:1, e.g., about 2:1, 2.5:1, 3:1, 3.5:1, or 4:1. In one embodiment, the weight ratio of acetaminophen to naproxen sodium is about 3:1.

[0018] In some embodiments of the present disclosure, the pharmaceutical dosage form contains about 600 mg to about 700 mg of acetaminophen, e.g., about 600, 625, 650, 675, or 700 mg of acetaminophen. In some embodiments, the pharmaceutical dosage form contains about 650 mg of acetaminophen.

[0019] In some embodiments of the present disclosure, the pharmaceutical dosage form contains about 150 mg to about 350 mg of naproxen sodium, e.g., about 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, or 350 mg of naproxen sodium. In some embodiments, the pharmaceutical dosage form contains about 220 mg of naproxen sodium.

[0020] In some embodiments, the pharmaceutical dosage forms of the present disclosure contain about 650 mg of acetaminophen and about 220 mg of naproxen sodium, e.g., 650 mg ± 10% acetaminophen and 220 mg ± 10% naproxen sodium. In other embodiments, the pharmaceutical dosage forms of the present disclosure contain 650 mg ± 5% acetaminophen and 220 mg ± 5% naproxen sodium, 650 mg ± 4% acetaminophen and 220 mg ± 4% naproxen sodium, 650 mg ± 3% acetaminophen and 220 mg ± 3% naproxen sodium, 650 mg ± 2% acetaminophen and 220 mg ± 2% naproxen sodium, or 650 mg ± 1% acetaminophen and 220 mg ± 1% naproxen sodium.

[0021] Also within the scope of this disclosure are pharmaceutical dosage forms, e.g., unit pharmaceutical dosage forms containing about 325 mg of acetaminophen and about 110 mg of naproxen sodium, e.g., 325 mg ± 10% of acetaminophen and 110 mg ± 10% of naproxen sodium. In other embodiments, pharmaceutical dosage forms of the present disclosure include 325 mg ± 5% of acetaminophen and 110 mg ± 5% of naproxen sodium, 325 mg ± 4% of acetaminophen and 110 mg ± 4% of naproxen sodium, 325 mg ± 3% of acetaminophen and 110 mg ± 3% of naproxen sodium, 650 mg ± 2% of acetaminophen and 220 mg ± 2% of naproxen sodium, or 325 mg ± 1% of acetaminophen and 110 mg ± 1% of naproxen sodium.

[0022] The pharmaceutical dosage forms of the present disclosure include a core tablet containing a mixture of acetaminophen and naproxen sodium. The core tablet can also contain about 35% to about 45% by weight, e.g., about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45% by weight, of acetaminophen. These core tablets can also contain about 10% to about 15% by weight, e.g., about 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15% by weight of naproxen sodium.

[0023] The core tablet of the present disclosure includes other pharmaceutically acceptable excipients. The core tablet of the present disclosure can include microcrystalline cellulose, for example, in an amount ranging from about 14% to about 18% by weight of microcrystalline cellulose. In some embodiments, the core tablet of the present disclosure includes about 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, or 18% by weight of microcrystalline cellulose.

[0024] The core tablets of the present disclosure can include lactose, such as lactose monohydrate. In those core tablets that include lactose monohydrate, the lactose monohydrate can be present in an amount ranging from about 4% to about 8% by weight of lactose monohydrate. In some embodiments, the core tablets of the present disclosure include about 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or about 8% by weight of lactose monohydrate.

[0025] The core tablet of the present disclosure can contain crospovidone. In those core tablets containing crospovidone, the total amount of crospovidone in the core tablet can be about 3% to about 7% by weight of crospovidone. In some embodiments, the core tablet of the present disclosure contains about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7% by weight of crospovidone.

[0026] In some embodiments, the core tablet of the present disclosure comprises naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, and crospovidone. In some embodiments, the core tablet comprises about 10% to about 15% by weight of naproxen sodium, about 35% to about 45% by weight of acetaminophen, about 14% to about 18% by weight of microcrystalline cellulose, about 4% to about 8% by weight of lactose monohydrate, and 3% to about 7% by weight of crospovidone.

[0027] In other embodiments, the core tablet consists essentially of naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, and crospovidone. In some embodiments, the core tablet consists essentially of about 10% to about 15% by weight of naproxen sodium, about 35% to about 45% by weight of acetaminophen, about 14% to about 18% by weight of microcrystalline cellulose, about 4% to about 8% by weight of lactose monohydrate, and 3% to about 7% by weight of crospovidone.

[0028] The core tablets of the present disclosure can further comprise, in addition to naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, and crospovidone, a starch, such as pregelatinized starch. In those core tablets comprising pregelatinized starch, the pregelatinized starch can be present in an amount of about 7% to about 12% by weight of pregelatinized starch. In some embodiments, the core tablets of the present disclosure comprise about 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12% by weight of pregelatinized starch.

[0029] The core tablet of the present disclosure can further comprise silicified microcrystalline cellulose in addition to naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, and crospovidone. In other embodiments, the core tablet of the present disclosure can further comprise silicified microcrystalline cellulose in addition to naproxen sodium, acetaminophen, silicified microcrystalline cellulose, lactose monohydrate, crospovidone, and pregelatinized starch. In those core tablets containing silicified microcrystalline cellulose, the silicified microcrystalline cellulose is present in an amount of about 7% to about 12% by weight of silicified microcrystalline cellulose. In some embodiments, the core tablet of the present disclosure contains about 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12% by weight of silicified microcrystalline cellulose.

[0030] The core tablet of the present disclosure can further comprise magnesium stearate in addition to naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, and crospovidone. In another embodiment, the core tablet of the present disclosure can further comprise magnesium stearate in addition to naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, crospovidone, and pregelatinized starch. In another embodiment, the core tablet of the present disclosure can further comprise magnesium stearate in addition to naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, crospovidone, pregelatinized starch, and silicified microcrystalline cellulose. In those core tablets containing magnesium stearate, the magnesium stearate is present in an amount of about 0.5% to about 1.5% by weight of magnesium stearate. In some embodiments, the core tablet of the present disclosure comprises about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, or 1.5% by weight of magnesium stearate.

[0031] In some embodiments, the core tablet of the present disclosure comprises about 10% to about 15% by weight naproxen sodium, about 35% to about 45% by weight acetaminophen, about 14% to about 18% by weight microcrystalline cellulose, about 4% to about 8% by weight lactose monohydrate, about 3% to about 7% by weight crospovidone, about 2% to about 5% by weight pregelatinized starch, about 7% to about 12% by weight silicified microcrystalline cellulose, and 0.5% to about 1.5% by weight magnesium stearate.

[0032] In some embodiments, the core tablet of the present disclosure consists essentially of about 10% to about 15% by weight naproxen sodium, about 35% to about 45% by weight acetaminophen, about 14% to about 18% by weight microcrystalline cellulose, about 4% to about 8% by weight lactose monohydrate, about 3% to about 7% by weight crospovidone, about 2% to about 5% by weight pregelatinized starch, about 7% to about 12% by weight silicified microcrystalline cellulose, and 0.5% to about 1.5% by weight magnesium stearate.

[0033] The pharmaceutical dosage forms of the present disclosure may further comprise one or more active ingredients other than acetaminophen and naproxen. For example, the pharmaceutical dosage forms of the present disclosure may further comprise a decongestant (e.g., phenylephrine, pseudoephedrine), an antihistamine (e.g., cetirizine, diphenhydramine, fexofenadine, loratadine), a mucolytic (e.g., guaifenesin), a sleep aid (e.g., diphenhydramine, doxylamine, melatonin), an antitussive (e.g., dextromethorphan), or a mixture thereof.

[0034] According to the methods of the present disclosure, the pharmaceutical dosage form is administered as one or more tablets, e.g., one or more film-coated tablets. In those embodiments in which the pharmaceutical dosage form is administered as a single tablet, the tablet contains about 600 mg to about 700 mg of acetaminophen and about 150 mg to about 250 mg of naproxen sodium, e.g., 650 mg of acetaminophen and 220 mg of naproxen sodium.

[0035] In those embodiments in which the pharmaceutical dosage form is administered as two tablets, each tablet contains about 300 mg to about 350 mg of acetaminophen and about 75 mg to about 125 mg of naproxen sodium. In some of these embodiments, each tablet contains about 325 mg of acetaminophen and about 110 mg of naproxen.

[0036] In some methods of the present disclosure, the pharmaceutical dosage form is administered once a day to induce mild pain relief in a person in need of mild pain relief. In other embodiments, the pharmaceutical dosage form is administered twice a day to induce mild pain relief in a person in need of mild pain relief. In some embodiments, the pharmaceutical dosage form is administered every 6 hours to induce mild pain relief in a person in need of mild pain relief. In some embodiments, the pharmaceutical dosage form is administered every 8 hours to induce mild pain relief in a person in need of mild pain relief. In some embodiments, the pharmaceutical dosage form is administered every 12 hours to induce mild pain relief in a person in need of mild pain relief. In some embodiments, the pharmaceutical dosage form is administered every 24 hours to induce mild pain relief in a person in need of mild pain relief.

[0037] In some methods of the present disclosure, the pharmaceutical dosage forms are administered at about 6 hour time intervals. In some methods of the present disclosure, the pharmaceutical dosage forms are administered at about 8 hour time intervals. In some methods of the present disclosure, the pharmaceutical dosage forms are administered at about 12 hour time intervals. In some methods of the present disclosure, the pharmaceutical dosage forms are administered at variable time intervals, including 6 hours, 8 hours, 12 hours, or a combination thereof. In some methods of the present disclosure, the pharmaceutical dosage forms are administered at variable time intervals, including 6 hours, 8 hours, 12 hours, 24 hours, or a combination thereof.

[0038] Those skilled in the art can prepare the core tablets described herein using granulation methods. In some embodiments, a granulation product, e.g., an intragranular portion, is prepared by granulating naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, and crospovidone with a binder solution containing purified water and pregelatinized starch. The granulation product can be combined with silicified microcrystalline cellulose, additional crospovidone, and magnesium stearate to form a product blend. The product blend can be compressed into a core tablet using a tablet compression method known in the art. The resulting core tablet can be coated, e.g., film-coated, using a method known in the art.

[0039] In some embodiments, the granulated product, e.g., the intragranular portion, is prepared by granulating naproxen sodium (about 10% to about 15% by weight), acetaminophen (about 35% to about 45% by weight), microcrystalline cellulose (about 14% to about 18% by weight), lactose monohydrate (about 4% to about 8% by weight), and crospovidone (about 0.5% to about 2.5% by weight) with a binder solution, e.g., a binder spray, comprising purified water and pregelatinized starch (about 7% to about 12% by weight). The weight percentages referenced for preparing the granulated product exclude purified water.

[0040] In some embodiments, the weight ratio of acetaminophen to naproxen sodium in the intragranular portion is about 2:1 to about 4:1, e.g., about 2:1, 2.5:1, 3:1, 3.5:1, or 4:1. In one embodiment, the weight ratio of acetaminophen to naproxen sodium in the intragranular portion is about 3:1.

[0041] Preferably, the acetaminophen, naproxen sodium, microcrystalline cellulose, lactose monohydrate, and crospovidone are sieved before being combined with the binder solution. In some embodiments, the granulation product is screened, milled, rescreened (e.g., to about 0.062 inches), and blended using techniques known in the art.

[0042] In some embodiments, the granulated product is combined with silicified microcrystalline cellulose (about 7% to about 12% by weight) and additional crospovidone (an additional about 2% to about 5% by weight) in an extragranular process. Magnesium stearate (0.5% to about 1.5% by weight) can also be added and blended in the extragranular process. The extragranular process produces a product blend. The product blend can be compressed into one or more core tablets. Administration of one or more core tablets to a human induces mild pain relief. The one or more core tablets can be film coated using methods known in the art. Administration of one or more film-coated tablets to a human induces mild pain relief.

[0043] In some embodiments, the intragranular portion is combined with an extragranular portion comprising a binder, a lubricant, a superdisintegrant, or a combination thereof. In some embodiments, the intragranular portion is combined with an extragranular portion comprising a binder. In some embodiments, the intragranular portion is combined with an extragranular portion comprising a lubricant. In some embodiments, the intragranular portion is combined with an extragranular portion comprising a superdisintegrant. In some embodiments, the intragranular portion is combined with an extragranular portion comprising a binder and a lubricant. In some embodiments, the intragranular portion is combined with an extragranular portion comprising a lubricant and a superdisintegrant. In some embodiments, the intragranular portion is combined with an extragranular portion comprising a binder and a superdisintegrant. In some embodiments, the intragranular portion is combined with an extragranular portion comprising a binder, a lubricant, and a superdisintegrant. An exemplary binder is silicified microcrystalline cellulose. An exemplary lubricant is magnesium stearate. An exemplary superdisintegrant is crospovidone.

[0044] The combination of the intragranular and extragranular portions can be compressed into one or more core tablets. One or more core tablets can be film-coated using methods known in the art. When one or more core tablets are administered to a human, mild pain relief is induced. When one or more film-coated tablets are administered to a human, mild pain relief is induced.

[0045] Acetaminophen and naproxen each contain reactive functional groups, e.g., -OH, -COOH, -NHC(O)CH. It is notable that little or no acetaminophen-naproxen by-product was observed in core tablets produced according to the methods described herein.

[0046] [ka]

[0047] [ka]

[0048] The pharmaceutical dosage forms of the present disclosure can be provided as part of an over-the-counter (OTC) pharmaceutical pack, e.g., a blister pack. In other embodiments, the pharmaceutical dosage forms of the present disclosure are provided in an OTC bottle containing, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, or 500 units of the pharmaceutical dosage form.

[0049] Surprisingly, the pharmaceutical dosage form has been demonstrated to induce more rapid pain relief and / or reduce pain intensity more rapidly in humans experiencing mild pain.

[0050] The pharmaceutical dosage form of the present disclosure has been shown to provide greater pain relief in a shorter time compared to placebo, as measured by pain relief score.For example, according to the disclosed method, the pain relief score of a person who needs mild pain relief is evaluated 15 minutes after administration of the described pharmaceutical dosage form (for example, comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) is greater than the pain relief score of a person who needs mild pain relief 15 minutes after administration of placebo.

[0051] The pharmaceutical dosage forms of the present disclosure have been shown to provide greater pain relief in a shorter time, as measured by pain relief scores, compared to dosage forms containing 1000 mg of acetaminophen and 440 mg of naproxen sodium. For example, according to the disclosed methods, the pain relief scores of a person requiring mild pain relief assessed 15 minutes after administration of the described pharmaceutical dosage forms (e.g., containing about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) are greater than the pain relief scores of a person requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form not of the present disclosure (e.g., containing about 1000 mg of acetaminophen and about 440 mg of naproxen sodium).

[0052] The greater pain relief effect of the described dosage forms over those dosage forms containing about 1000 mg of acetaminophen and about 440 mg of naproxen sodium is also observed as measured by pain intensity difference scores. According to the disclosed methods, the pain intensity difference score of a person requiring mild pain relief assessed 15 minutes after administration of the described pharmaceutical dosage forms (e.g., containing about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) is greater than the pain intensity difference score of a person requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form not of the present disclosure (e.g., containing about 1000 mg of acetaminophen and about 440 mg of naproxen sodium). According to the disclosed methods, the pain intensity difference score of a person needing mild pain relief assessed 30 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) is greater than the pain intensity difference score of a person needing mild pain relief 30 minutes after administration of a pharmaceutical dosage form other than that disclosed herein (e.g., comprising about 1000 mg of acetaminophen and about 440 mg of naproxen sodium). According to the disclosed methods, the pain intensity difference score of a person needing mild pain relief assessed 45 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) is greater than the pain intensity difference score of a person needing mild pain relief 45 minutes after administration of a pharmaceutical dosage form other than that disclosed herein (e.g., comprising about 1000 mg of acetaminophen and about 440 mg of naproxen sodium). According to the disclosed methods, the pain intensity difference score of a person requiring mild pain relief assessed 60 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) is greater than the pain intensity difference score of a person requiring mild pain relief 60 minutes after administration of a pharmaceutical dosage form not of the present disclosure (e.g., comprising about 1000 mg of acetaminophen and about 440 mg of naproxen sodium).

[0053] Pharmaceutical dosage forms of the present disclosure have unexpectedly been shown to provide greater mild pain relief in a shorter time as measured by pain relief scores compared to a dosage form containing about 440 mg of naproxen sodium in the absence of acetaminophen. For example, according to the disclosed methods, a person in need of mild pain relief will have a greater pain relief score 15 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to a person in need of mild pain relief 15 minutes after administration of a pharmaceutical dosage form not of the present disclosure (e.g., comprising about 440 mg of naproxen sodium in the absence of acetaminophen). According to the disclosed methods, a person in need of mild pain relief will have a greater pain relief score 30 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to a person in need of mild pain relief 30 minutes after administration of a pharmaceutical dosage form not of the present disclosure (e.g., comprising about 440 mg of naproxen sodium in the absence of acetaminophen). According to the disclosed methods, a person in need of mild pain relief will have a greater pain relief score 45 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to a person in need of mild pain relief 45 minutes after administration of a pharmaceutical dosage form other than that of the present disclosure (e.g., comprising about 440 mg of naproxen sodium in the absence of acetaminophen). According to the disclosed methods, a person in need of mild pain relief will have a greater pain relief score 60 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to a person in need of mild pain relief 60 minutes after administration of a pharmaceutical dosage form other than that of the present disclosure (e.g., comprising about 440 mg of naproxen sodium in the absence of acetaminophen).

[0054] The greater mild pain relief effect of the described dosage forms than those dosage forms containing about 440 mg of naproxen sodium in the absence of acetaminophen is also observed as measured by pain intensity difference scores. According to the disclosed method, the pain intensity difference score of a person in need of mild pain relief assessed 15 minutes after administration of the described pharmaceutical dosage forms (e.g., containing about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) is greater than the pain intensity difference score of a person in need of mild pain relief 15 minutes after administration of a pharmaceutical dosage form not of the present disclosure (e.g., containing about 440 mg of naproxen sodium in the absence of acetaminophen). According to the disclosed methods, a person in need of mild pain relief will have a greater pain intensity difference score assessed 30 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to a person in need of mild pain relief 30 minutes after administration of a pharmaceutical dosage form other than that disclosed herein (e.g., comprising about 440 mg of naproxen sodium in the absence of acetaminophen). According to the disclosed methods, a person in need of mild pain relief will have a greater pain intensity difference score assessed 45 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to a person in need of mild pain relief 45 minutes after administration of a pharmaceutical dosage form other than that disclosed herein (e.g., comprising about 440 mg of naproxen sodium in the absence of acetaminophen). According to the disclosed methods, a pain intensity difference score for a person in need of mild pain relief assessed 60 minutes after administration of a described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) is greater than a pain intensity difference score for a person in need of mild pain relief 60 minutes after administration of a pharmaceutical dosage form not of the present disclosure (e.g., comprising about 440 mg of naproxen sodium in the absence of acetaminophen).

[0055] Surprisingly, the pharmaceutical dosage forms of the present disclosure have also been shown to provide greater mild pain relief in a shorter time, as measured by pain relief scores, compared to dosage forms containing about 650 mg of acetaminophen and about 10 mg of hydrocodone. For example, surprisingly, according to the disclosed methods, the pain relief scores of individuals in need of mild pain relief assessed 15 minutes after administration of the described pharmaceutical dosage forms (e.g., containing about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) are greater than the pain relief scores of individuals in need of mild pain relief 15 minutes after administration of a pharmaceutical dosage form other than that disclosed herein (e.g., containing about 650 mg of acetaminophen and about 10 mg of hydrocodone).

[0056] The greater mild pain relief effect of the described dosage forms over those dosage forms containing about 650 mg of acetaminophen and about 10 mg of hydrocodone is also observed as measured by pain intensity difference scores. According to the disclosed methods, the pain intensity difference scores of a person in need of mild pain relief assessed 15 minutes after administration of the described pharmaceutical dosage forms (e.g., containing about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) are greater than the pain intensity difference scores of a person in need of mild pain relief 15 minutes after administration of a pharmaceutical dosage form not of the present disclosure (e.g., containing about 650 mg of acetaminophen and about 10 mg of hydrocodone).

[0057] Also, according to the described methods, the time-weighted sum of pain intensity difference scores from baseline to 6 hours is greater in humans in need of mild pain relief who are administered the described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to the time-weighted sum of pain intensity difference scores from baseline to 6 hours in humans in need of mild pain relief who are administered a pharmaceutical formulation not of the present disclosure (e.g., comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone).

[0058] Also, according to the described methods, the time-weighted sum of pain intensity difference scores from baseline to 8 hours is greater in humans in need of mild pain relief who are administered the described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to the time-weighted sum of pain intensity difference scores from baseline to 8 hours in humans in need of mild pain relief who are administered a pharmaceutical formulation not of the present disclosure (e.g., comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone).

[0059] Also, according to the described methods, the time-weighted sum of pain intensity difference scores from baseline to 12 hours is greater in humans in need of mild pain relief who are administered the described pharmaceutical dosage forms (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to the time-weighted sum of pain intensity difference scores from baseline to 12 hours in humans in need of mild pain relief who are administered a pharmaceutical formulation not of the present disclosure (e.g., comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone).

[0060] Also, according to the described methods, the time-weighted sum of total pain relief scores from baseline to 6 hours is greater in humans in need of mild pain relief who are administered the described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to the time-weighted sum of total pain relief scores from baseline to 6 hours in humans in need of mild pain relief who are administered a pharmaceutical formulation not of the present disclosure (e.g., comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone).

[0061] Also, according to the described methods, the time-weighted sum of total pain relief scores from baseline to 8 hours is greater in humans in need of mild pain relief who are administered the described pharmaceutical dosage form (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to the time-weighted sum of total pain relief scores from baseline to 8 hours in humans in need of mild pain relief who are administered a pharmaceutical formulation not of the present disclosure (e.g., comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone).

[0062] Also, according to the described methods, the time-weighted sum of total pain relief scores from baseline to 12 hours is greater in humans in need of mild pain relief who are administered the described pharmaceutical dosage forms (e.g., comprising about 650 mg of acetaminophen mixed with about 220 mg of naproxen sodium) compared to the time-weighted sum of total pain relief scores from baseline to 12 hours in humans in need of mild pain relief who are administered a pharmaceutical formulation not of the present disclosure (e.g., comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone). [Example]

[0063] Example 1: Granulation

[0064] [Table 1]

[0065] The binder spray is prepared by combining purified water and pregelatinized starch in a high-shear propeller mixer at ambient temperature for approximately 30 minutes, or until the suspension is visually uniform and lump-free. Pre-sieved acetaminophen, naproxen sodium, microcrystalline cellulose, lactose monohydrate, and crospovidone are combined, and the mixture is granulated with the binder spray. The resulting granules are screened, milled, rescreened (0.062 inches), and blended.

[0066] Example 2: Extragranular

[0067] [Table 2]

[0068] The granules of Example 1 are combined with the silicified microcrystalline cellulose and crospovidone and blended for approximately 30 minutes. Magnesium stearate is added and the mixture is blended for approximately an additional 5 minutes.

[0069] Example 3: Core tablet Core tablets prepared via compression of the product blend of Example 2

[0070] [Table 3]

[0071] The core tablet preferably has the following characteristics:

[0072] [Table 4]

[0073] Example 4: Coated tablets The core tablets of Example 3 are spray coated with the coating solution (11% w / w solids).

[0074] [Table 5]

[0075] Coated tablets containing 325 mg of acetaminophen and 110 mg of naproxen sodium are prepared according to these methods.

[0076] Example 5: Dissolution Dissolution of coated tablets prepared as described herein was analyzed using the paddle method (USP Apparatus II) set at 50 RPM. Samples were analyzed using HPLC (flow rate 1.0 ml / min and injection volume 10 μL) equipped with a YMC Hydrosphere C18, 50 mm x 4.6 mm, 2 μm particle size column, and a UV detector switched to 280 nm and 332 nm at 2.5 minutes. Mobile phase A: 40 mM ammonium acetate / 0.1% TFA in water. Mobile phase B: 40 mM ammonium acetate / 0.1% TFA in methanol:water:acetonitrile (75:15:10). The dissolution medium was 0.1 M sodium phosphate buffer at pH 7.4. Dissolution criteria were Q = 80 (% released) at 45 minutes for acetaminophen (APAP) and Q = 80 (% released) at 45 minutes for naproxen.

[0077] Example 6: Stability Stability studies conducted at 25°C, 60% relative humidity and 40°C, 75% relative humidity were performed on coated tablets prepared as described herein. Data after 1 and 3 months showed good stability at both temperature / relative humidity conditions.

[0078] Example 7: Phase 2 Clinical Trial and Results: NCT03879408 This was a randomized, double-blind, placebo- and active-controlled, parallel-group study to evaluate the analgesic efficacy and safety of naproxen sodium 440 mg co-administered with acetaminophen 1000 mg and naproxen sodium 220 mg co-administered with acetaminophen 650 mg compared with fixed combinations of hydrocodone 10 mg / acetaminophen 650 mg, naproxen sodium 440 mg, and placebo over 12 hours after surgical extraction of four third molars.

[0079] Primary endpoint 1. Time-weighted sum of pain intensity difference scores from baseline (hour 0) to 6 hours (SPID0-6) [Time frame: baseline (hour 0) to 6 hours post-dose]. The time-weighted sum of pain intensity difference (SPID) score was measured using the Pain Intensity Numerical Rating Scale (PI-NRS), ranging from 0 to 10 (0 = no pain, 10 = very severe pain). The possible range of SPID from 0 to 6 hours was -60 to 60. Higher SPID values ​​indicated greater pain relief. The PID was the difference between baseline pain intensity and pain intensity at the time of assessment. The time-weighted sum of pain intensity difference scores was derived by first multiplying each PID score by the time since the previous time point and then adding these time-weighted PID scores together over the 0-6 hour interval.

[0080] 2. Time-weighted sum of pain intensity difference scores from baseline (hour 0) to 12 hours (SPID0-12) [Time frame: baseline (hour 0) to 12 hours post-dose]. The time-weighted sum of pain intensity difference scores was measured using the PI-NRS, which ranges from 0 to 10 (0 = no pain, 10 = very severe pain). The possible range of SPID from 0 to 12 hours was -120 to 120. Higher SPID values ​​indicated greater pain relief. The PID was the difference between baseline pain intensity and pain intensity at the time of assessment (hour 12). The time-weighted sum of pain intensity difference scores was derived by first multiplying each PID score by the time since the previous time point and then adding these time-weighted PID scores together over the 0-12 hour interval.

[0081] Secondary endpoints 1. Time-weighted sum of total pain relief scores from baseline (hour 0) to 6 hours (TOTPAR0-6) [Time frame: baseline (hour 0) to 6 hours post-dose]. Time-weighted total pain relief (TOTPAR) was measured using the Pain Relief Numerical Rating Scale (PR-NRS), ranging from 0 to 10 (0 = no relief, 10 = complete relief). The total pain relief score (TOTPAR) was calculated by multiplying the pain relief score at each post-dose time point by the duration (in hours) from the preceding time point and then summing these values. The minimum value was 0 and the maximum value was 60. Higher scores indicated greater pain relief.

[0082] 2. Time-weighted sum of total pain relief scores from baseline (hour 0) to 8 hours (TOTPAR0-8) [Time frame: baseline (hour 0) to 8 hours post-dose]. TOTPAR was measured using the PR-NRS, which ranges from 0 to 10 (0 = no relief, 10 = complete relief). The total pain relief score (TOTPAR) was calculated by multiplying the pain relief score at each post-dose time point by the duration (in hours) from the preceding time point and then summing these values. The minimum value was 0 and the maximum value was 80. Higher scores indicated greater pain relief.

[0083] 3. Time-weighted sum of total pain relief scores from baseline (hour 0) to 12 hours (TOTPAR0-12) [Time frame: baseline (hour 0) to 12 hours post-dose]. TOTPAR was measured using the PR-NRS, which ranges from 0 to 10 (0 = no relief, 10 = complete relief). The total pain relief score (TOTPAR) was calculated by multiplying the pain relief score at each post-dose time point by the duration (in hours) from the preceding time point and then summing these values. The minimum value was 0 and the maximum value was 120. Higher scores indicated greater pain relief.

[0084] 4. Time-weighted sum of pain intensity difference scores from baseline (hour 0) to 8 hours (SPID0-8) [Time frame: baseline (hour 0) to 8 hours post-dose]. The time-weighted sum of pain intensity difference scores was measured using the PI-NRS, which ranges from 0 to 10 (0 = no pain, 10 = very severe pain). The possible range of SPID from 0 to 8 hours was -80 to 80. Higher SPID values ​​indicated greater pain relief. The PID was the difference between baseline pain intensity and pain intensity at the time of assessment (hour 8). The time-weighted sum of pain intensity difference scores was derived by first multiplying each PID score by the time since the previous time point and then adding these time-weighted PID scores together over the 0-8 hour interval.

[0085] 5. Pain Relief (PAR) scores at individual time points [time frames: 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.25 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, and 12 hours]. Participants answered the question "How much relief from initial pain?" at each time point on the 11-point PR-NRS. The scale ranged from 0 = no relief to 10 = complete relief. Higher scores indicated greater improvement in pain.

[0086] 6. Pain Intensity Difference (PID) scores at individual time points [time frames: 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 1.25 hours, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, and 12 hours]. Pain intensity was self-reported over 12 hours using a pain rating of 0 to 10 on the PI-NRS, with scores ranging from 0 to 10 (0 = no pain, 10 = worst imaginable pain). Pain intensity differences were calculated relative to baseline at each time point after study drug administration.

[0087] 7. Participant's overall assessment of the study drug or overall impression of the study drug according to participant's overall assessment [Time frame: up to 12 hours]. Participants were asked to rate their overall impression of the study drug using the following scale: poor (0), fair (1), good (2), excellent (3), and excellent (4), where higher scores represented better results.

[0088] Inclusion Criteria: 1. Male or female, aged 17 to 50 2.Weight ≥ 100 lbs and a body mass index (BMI) of 18.5 to 35 (including borderline values) at screening 3. Up to four third molars have been surgically removed (two of which must be impacted mandibular molars) 4. Meet the postoperative pain level requirements 5. Women and men of childbearing potential agree to the study's contraceptive requirements. 6. Have a negative urine drug screen at screening and on the day of the surgical procedure

[0089] Exclusion criteria: 1. Pregnant women, women who are breastfeeding, women who are trying to conceive, or men whose partners are pregnant or currently trying to conceive 2. Known allergy or hypersensitivity to naproxen or other NSAIDs (including aspirin), or to acetaminophen, tramadol, hydrocodone, or other opioids 3. Inability to swallow large tablets or capsules 4. History of any condition that, in the opinion of the investigator, may jeopardize the subject's safety, health, and integrity of the study 5. Use painkillers more than five times a week 6. History of long-term tranquilizer use, heavy alcohol use, or substance abuse within the past 5 years as determined by the investigator's on-site staff 7. Use of immunosuppressants within 2 weeks of screening 8. History of peptic ulcer disease or gastrointestinal bleeding or hemorrhage within the past two years

[0090] [Table 6]

[0091] [Table 7]

[0092] Time-weighted sum of pain intensity difference scores from baseline (hour 0) to 6 hours (SPID0-6): The time-weighted sum of pain intensity difference (SPID) score was measured using the Pain Intensity Numerical Rating Scale (PI-NRS), ranging from 0 to 10 (0 = no pain, 10 = very severe pain). The possible range of the SPID from 0 to 6 hours was -60 to 60. Higher SPID values ​​indicated greater pain relief. The PID was the difference between baseline pain intensity and the pain intensity at the time of assessment. The time-weighted sum of pain intensity difference scores was derived by first multiplying each PID score by the time since the previous time point and then adding these time-weighted PID scores together over the 0-6 hour interval.

[0093] [Table 8]

[0094] Time-weighted sum of pain intensity difference scores from baseline (0 hours) to 12 hours (SPID0-12): The time-weighted sum of pain intensity difference scores was measured using the PI-NRS, which ranges from 0 to 10 (0 = no pain, 10 = very severe pain). The possible range of SPID from 0 to 12 hours was -120 to 120. Higher SPID values ​​indicated greater pain relief. The PID was the difference between baseline pain intensity and the pain intensity at the time of assessment (12 hours). The time-weighted sum of pain intensity difference scores was derived by first multiplying each PID score by the time since the previous time point and then adding these time-weighted PID scores together over the 0-12 hour interval.

[0095] [Table 9]

[0096] Time-weighted sum of total pain relief scores from baseline (hour 0) to 6 hours (TOTPAR0-6): Time-weighted total pain relief (TOTPAR) was measured using the Pain Relief Numerical Rating Scale (PR-NRS), ranging from 0 to 10 (0 = no relief, 10 = complete relief). The total pain relief score (TOTPAR) was calculated by multiplying the pain relief score at each post-dose time point by the duration (in hours) from the preceding time point and then summing these values. The minimum value was 0 and the maximum value was 60. Higher scores indicated greater pain relief.

[0097] [Table 10]

[0098] Time-weighted sum of total pain relief scores from baseline (hour 0) to 8 hours (TOTPAR 0-8): TOTPAR was measured using the PR-NRS, which ranges from 0 to 10 (0 = no relief, 10 = complete relief). The total pain relief score (TOTPAR) was calculated by multiplying the pain relief score at each post-dose time point by the duration (in hours) from the preceding time point and then summing these values. The minimum value was 0 and the maximum value was 80. Higher scores indicated more pain relief.

[0099] [Table 11]

[0100] Time-weighted sum of total pain relief scores from baseline (0 hours) to 12 hours (TOTPAR 0-12): TOTPAR was measured using the PR-NRS, which ranges from 0 to 10 (0 = no relief, 10 = complete relief). The total pain relief score (TOTPAR) was calculated by multiplying the pain relief score at each post-dose time point by the duration (in hours) from the preceding time point and then summing these values. The minimum value was 0 and the maximum value was 120. Higher scores indicated more pain relief.

[0101] [Table 12]

[0102] Time-weighted sum of pain intensity difference scores from baseline (0 hours) to 8 hours (SPID0-8): The time-weighted sum of pain intensity difference scores was measured using the PI-NRS, which ranges from 0 to 10 (0 = no pain, 10 = very severe pain). The possible range of the SPID from 0 to 8 hours was -80 to 80. Higher SPID values ​​indicated greater pain relief. The PID was the difference between baseline pain intensity and the pain intensity at the time of assessment (8 hours). The time-weighted sum of pain intensity difference scores was derived by first multiplying each PID score by the time since the previous time point and then adding these time-weighted PID scores together over the 0-8 hour interval.

[0103] [Table 13]

[0104] Participant's overall rating of the study drug or overall impression of the study drug according to participant's overall rating: Participants were asked to rate their overall impression of the study drug using the following scale: poor (0), fair (1), good (2), excellent (3), and excellent (4), where higher scores represented better results.

[0105] [Table 14]

[0106] Pain relief at time points (PAR) score: Participants answered the question "How much relief from the initial pain?" at each time point on the 11-point PR-NRS. The scale ranged from 0 = no relief to 10 = complete relief. Higher scores indicated greater improvement in pain.

[0107] [Table 15]

[0108] Pain Intensity Difference (PID) scores at individual time points: Pain intensity was self-reported over a 12-hour period using a pain rating of 0-10 on the PI-NRS, with scores ranging from 0 to 10 (0 = no pain, 10 = worst imaginable pain). Pain intensity difference was calculated relative to baseline at each time point after study drug administration.

[0109] [Table 16]

[0110] No serious adverse events were reported.

[0111] [Embodiment] (1) A method for inducing mild pain relief in a human in need thereof, comprising: 10. A method comprising administering to the human a pharmaceutical dosage form comprising acetaminophen in admixture with naproxen sodium, wherein the weight ratio of the acetaminophen to the naproxen sodium is from about 2:1 to about 4:1. (2) The method of embodiment 1, wherein the weight ratio of acetaminophen to naproxen sodium is about 3:1. (3) The method of any one of claims 1 to 2, wherein the pharmaceutical dosage form comprises about 650 mg of acetaminophen and about 220 mg of naproxen sodium. (4) The method of embodiment 1, wherein the pain relief is induced within 15 minutes of the administration. (5) The method according to any one of embodiments 1 to 4, wherein the pain relief score of the human 15 minutes after administration is greater than the pain relief score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form comprising 1000 mg of acetaminophen and 440 mg of naproxen sodium.

[0112] (6) The method according to any one of embodiments 1 to 5, wherein the pain relief score of the human after 15 minutes of administration is greater than the pain relief score of a human requiring mild pain relief after 15 minutes of administration of a pharmaceutical dosage form comprising about 440 mg of naproxen sodium in the absence of acetaminophen. (7) The method according to any one of embodiments 1 to 6, wherein the pain relief score of the human 15 minutes after administration is greater than the pain relief score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone. (8) The method according to any one of embodiments 1 to 7, wherein the pain intensity difference score of the human 15 minutes after administration is greater than the pain intensity difference score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form comprising about 1000 mg of acetaminophen and 440 mg of naproxen sodium. (9) The method according to any one of embodiments 1 to 8, wherein the pain intensity difference score of the human after 15 minutes of administration is greater than the pain intensity difference score of a human requiring mild pain relief after 15 minutes of administration of a pharmaceutical dosage form comprising about 440 mg of naproxen sodium in the absence of acetaminophen. (10) The method according to any one of embodiments 1 to 9, wherein the pain intensity difference score of the human 15 minutes after administration is greater than the pain intensity difference score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone.

[0113] (11) The method of any one of embodiments 1 to 10, wherein the time-weighted sum of pain intensity difference scores from baseline to 6 hours for the human is greater than the time-weighted sum of pain intensity difference scores from baseline to 6 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone. (12) The method of any one of embodiments 1 to 11, wherein the time-weighted sum of pain intensity difference scores from baseline to 8 hours for the human is greater than the time-weighted sum of pain intensity difference scores from baseline to 8 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone. (13) The method of any one of embodiments 1 to 12, wherein the time-weighted sum of pain intensity difference scores from baseline to 12 hours for the human is greater than the time-weighted sum of pain intensity difference scores from baseline to 12 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone. (14) The method of any one of embodiments 1 to 13, wherein the time-weighted sum of total pain relief scores from baseline to 6 hours for the human is greater than the time-weighted sum of total pain relief scores from baseline to 6 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone. (15) The method of any one of embodiments 1 to 14, wherein the time-weighted sum of total pain relief scores from baseline to 8 hours for the human is greater than the time-weighted sum of total pain relief scores from baseline to 8 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone.

[0114] (16) The method of any one of embodiments 1 to 15, wherein the time-weighted sum of total pain relief scores from baseline to 12 hours for the human is greater than the time-weighted sum of total pain relief scores from baseline to 12 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone. (17) The method according to any one of the preceding claims, wherein the pharmaceutical dosage form is one or more tablets. (18) The method of embodiment 17, wherein the one or more tablets each comprise a core tablet. (19) The core tablet is about 10% to about 15% by weight of naproxen sodium; about 35% to about 45% by weight of acetaminophen; about 14% to about 18% by weight of microcrystalline cellulose; About 4% to about 8% by weight of lactose monohydrate; and 3% to about 7% by weight of crospovidone. (20) The core tablet is about 10% to about 15% by weight of naproxen sodium; about 35% to about 45% by weight of acetaminophen; about 14% to about 18% by weight of microcrystalline cellulose; About 4% to about 8% by weight of lactose monohydrate; 20. The method of embodiment 18 or 19, consisting essentially of about 3% to about 7% by weight of crospovidone.

[0115] (21) The method of any one of embodiments 18 to 20, wherein the core tablet further comprises about 7% to about 12% by weight of pregelatinized starch. (22) The method of any one of embodiments 18 to 21, wherein the core tablet form further comprises about 7% to about 12% by weight of silicified microcrystalline cellulose. (23) The method according to any one of embodiments 18 to 22, wherein the core tablet further comprises about 0.5% by weight to about 1.5% by weight of magnesium stearate. (24) The core tablet is about 10% to about 15% by weight of naproxen sodium; about 35% to about 45% by weight of acetaminophen; about 14% to about 18% by weight of microcrystalline cellulose; About 4% to about 8% by weight of lactose monohydrate; about 3% to about 7% by weight of crospovidone; about 2% to about 5% by weight of pregelatinized starch; about 7% to about 12% by weight of silicified microcrystalline cellulose; 24. The method of any of embodiments 18-23, comprising 0.5% to about 1.5% by weight of magnesium stearate. (25) The core tablet is about 10% to about 15% by weight of naproxen sodium; about 35% to about 45% by weight of acetaminophen; about 14% to about 18% by weight of microcrystalline cellulose; About 4% to about 8% by weight of lactose monohydrate; about 3% to about 7% by weight of crospovidone; about 7% to about 12% by weight of pregelatinized starch; about 7% to about 12% by weight of silicified microcrystalline cellulose; 25. The method of any of embodiments 18-24, consisting essentially of about 0.5% to about 1.5% by weight of magnesium stearate.

[0116] (26) The method according to any one of embodiments 17 to 25, wherein the one or more tablets are one or more coated tablets. (27) The method according to any one of embodiments 17 to 26, wherein the one or more tablets are one or more film-coated tablets. (28) The method of any one of embodiments 1 to 27, wherein the pharmaceutical dosage form comprises two tablets, each of which contains about 325 mg of acetaminophen and about 110 mg of naproxen sodium. (29) A method for preparing a core tablet, comprising: granulating naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, and crospovidone with purified water and a binder solution comprising pregelatinized starch to form a granulated product; combining the granulated product with silicified microcrystalline cellulose, crospovidone, and magnesium stearate to form a product blend; compressing the product blend to provide the core tablet. (30) The core tablet is about 10% to about 15% by weight of naproxen sodium; and about 35% to about 45% by weight of acetaminophen.

[0117] (31) The method of any one of claims 29 to 30, wherein the core tablet comprises about 14% to about 18% by weight of microcrystalline cellulose. (32) The method of any one of embodiments 29 to 31, wherein the core tablet comprises about 4% to about 8% by weight of lactose monohydrate. (33) The method of any one of embodiments 29 to 32, wherein the core tablet comprises about 3% to about 7% by weight of crospovidone. (34) The method of any one of embodiments 29 to 33, wherein the core tablet comprises about 2% to about 5% by weight of pregelatinized starch. (35) The method of any one of embodiments 29 to 34, wherein the core tablet comprises about 7% to about 12% by weight of silicified microcrystalline cellulose.

[0118] (36) The method according to any one of embodiments 29 to 35, wherein the core tablet comprises about 0.5% by weight to about 1.5% by weight of magnesium stearate. (37) The method of any one of embodiments 29 to 36, wherein the core tablet comprises about 220 mg of naproxen sodium and 650 mg of acetaminophen. (38) The method of any one of embodiments 29 to 37, further comprising coating the core tablet with a coating to form a coated tablet. (39) A core tablet produced according to any one of the methods described in embodiments 29 to 38. (40) A core tablet comprising: an intragranular portion comprising acetaminophen and naproxen sodium, wherein the weight ratio of the acetaminophen to the naproxen sodium is from about 2:1 to about 4:1; an extragranular portion comprising a binder, a lubricant, a superdisintegrant, or a combination thereof.

[0119] (41) A method for inducing mild pain relief in a human in need thereof, comprising administering to said human the core tablet of embodiment 40.

Claims

1. 1. A method for making a core tablet, comprising: granulating naproxen sodium, acetaminophen, microcrystalline cellulose, lactose monohydrate, and crospovidone with purified water and a binder solution comprising pregelatinized starch to form a granulated product; combining the granulated product with silicified microcrystalline cellulose, crospovidone, and magnesium stearate to form a product blend; compressing the product blend to provide the core tablet.

2. The core tablet is about 10% to about 15% by weight of naproxen sodium; about 35% to about 45% by weight of acetaminophen; Optionally, The core tablet is about 14% to about 18% by weight of microcrystalline cellulose, or about 4% to about 8% by weight of lactose monohydrate, or about 3% to about 7% by weight of crospovidone, or about 2% to about 5% by weight of pregelatinized starch, or about 7% to about 12% by weight of silicified microcrystalline cellulose, or 10. The method of claim 1 comprising about 0.5% to about 1.5% by weight of magnesium stearate.

3. 3. The method of claim 1 or 2, wherein the core tablet comprises about 220 mg of naproxen sodium and 650 mg of acetaminophen.

4. A core tablet produced according to the method of claim 2.

5. A core tablet comprising: an intragranular portion comprising acetaminophen and naproxen sodium, wherein the weight ratio of said acetaminophen to said naproxen sodium is from about 2:1 to about 4:1; an extragranular portion comprising a binder, a lubricant, a superdisintegrant, or a combination thereof.

6. 1. A method of inducing mild pain relief in a human in need thereof, comprising: administering to the human a pharmaceutical dosage form comprising acetaminophen in admixture with naproxen sodium, wherein the weight ratio of said acetaminophen to said naproxen sodium is from about 2:1 to about 4:1, preferably about 3:

1.

7. 7. The method of claim 6, wherein the pharmaceutical dosage form comprises about 650 mg of acetaminophen and about 220 mg of naproxen sodium.

8. 8. The method of claim 6 or 7, wherein the pain relief is induced within 15 minutes of the administration.

9. the human's pain relief score 15 minutes after administration is greater than the pain relief score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form containing 1000 mg of acetaminophen and 440 mg of naproxen sodium; or the human's pain relief score 15 minutes after administration is greater than the pain relief score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form comprising about 440 mg of naproxen sodium in the absence of acetaminophen; or the human's pain relief score 15 minutes after administration is greater than the pain relief score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone; or the human's pain intensity difference score 15 minutes after administration is greater than the pain intensity difference score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form comprising about 1000 mg of acetaminophen and 440 mg of naproxen sodium; or the human's pain intensity difference score 15 minutes after administration is greater than the pain intensity difference score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form comprising about 440 mg of naproxen sodium in the absence of acetaminophen; or the human's pain intensity difference score 15 minutes after administration is greater than the pain intensity difference score of a human requiring mild pain relief 15 minutes after administration of a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone; or the time-weighted sum of pain intensity difference scores from baseline to 6 hours for said human is greater than the time-weighted sum of pain intensity difference scores from baseline to 6 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone; or the time-weighted sum of pain intensity difference scores from baseline to 8 hours for said human is greater than the time-weighted sum of pain intensity difference scores from baseline to 8 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone; or the time-weighted sum of pain intensity difference scores from baseline to 12 hours for said human is greater than the time-weighted sum of pain intensity difference scores from baseline to 12 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone; or the time-weighted sum of total pain relief scores from baseline to 6 hours for said human is greater than the time-weighted sum of total pain relief scores from baseline to 6 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone; or the time-weighted sum of total pain relief scores from baseline to 8 hours for said human is greater than the time-weighted sum of total pain relief scores from baseline to 8 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone; or 7. The method of claim 6, wherein the time-weighted sum of total pain relief scores from baseline to 12 hours for the human is greater than the time-weighted sum of total pain relief scores from baseline to 12 hours for a human in need of mild pain relief who is administered a pharmaceutical dosage form comprising about 650 mg of acetaminophen and about 10 mg of hydrocodone.

10. 7. The method of claim 6, wherein the pharmaceutical dosage form is one or more tablets.

11. 11. The method of claim 10, wherein the one or more tablets each comprise a core tablet.

12. The core tablet is about 10% to about 15% by weight of naproxen sodium; about 35% to about 45% by weight of acetaminophen; about 14% to about 18% by weight of microcrystalline cellulose; about 4% to about 8% by weight of lactose monohydrate; 3% to about 7% by weight of crospovidone; Optionally, the core tablet further comprises about 7% to about 12% by weight of pregelatinized starch; or the core tablet form further comprises about 7% to about 12% by weight of silicified microcrystalline cellulose; or 12. The method of claim 11, wherein the core tablet further comprises about 0.5% to about 1.5% by weight of magnesium stearate.

13. The core tablet is about 10% to about 15% by weight of naproxen sodium; about 35% to about 45% by weight of acetaminophen; about 14% to about 18% by weight of microcrystalline cellulose; about 4% to about 8% by weight of lactose monohydrate; about 3% to about 7% by weight of crospovidone; about 2% to about 5% by weight of pregelatinized starch; about 7% to about 12% by weight of silicified microcrystalline cellulose; 0.5% to about 1.5% by weight of magnesium stearate.

14. the one or more tablets are one or more coated tablets; or 11. The method of claim 10, wherein the one or more tablets are one or more film-coated tablets.

15. 7. The method of claim 6, wherein the pharmaceutical dosage form comprises two tablets, each of the tablets comprising about 325 mg of acetaminophen and about 110 mg of naproxen sodium.

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