Oral tablets comprising roller compacted particles of naproxen sodium and methods of making and using same

Abstract

The present disclosure relates to oral naproxen sodium tablets containing roller compacted particles, methods of making the same, and methods of using the same. Naproxen sodium tablets are formulated and prepared by dry granulation, in particular roller compaction. The naproxen sodium tablet is produced by combining a dry granulation compatible excipient with a roller compaction method, and compared with commercially available oral naproxen sodium tablets prepared by a standard wet granulation method, the naproxen sodium tablet has the advantages that the dissolution rate general situation is enhanced, and the disintegration time is shortened.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a divisional application of the invention patent application with application date of December 18, 2020 and application number 202080088723.5.

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 950,196, filed December 19, 2019, which is incorporated herein by reference in its entirety. Technical Field

[0004] The present invention generally relates to oral tablets prepared by dry granulation methods, and more particularly, to naproxen sodium tablets with enhanced dissolution profiles and disintegration times, dry granulation methods for preparing the naproxen sodium tablets, and methods of using the naproxen sodium tablets. Background Art

[0005] Naproxen sodium is a nonsteroidal anti-inflammatory drug (NSAID) used to treat inflammation associated with a variety of conditions and provide long-lasting relief of mild to moderate pain. Although naproxen sodium is most commonly sold as an immediate-release oral tablet, immediate-release formulations of naproxen sodium exhibit a delayed onset of therapeutic effect (e.g., up to one hour) after administration. Naproxen sodium tablets have improved properties, such as a faster initial dissolution rate and / or a shorter disintegration time, resulting in a more rapid onset of action. The earlier onset of therapeutic effect of naproxen sodium tablets, followed by more rapid reduction of inflammation and pain, is desirable to consumers.

[0006] The composition of commercially available naproxen sodium tablets has remained essentially unchanged for decades due to their compatibility with wet granulation, which produces tablets with consistent, recognized physicochemical properties. However, despite its reproducibility, wet granulation involves numerous process steps that, unless optimized for the operating equipment and conditions specific to an individual manufacturing plant, can lead to significant inefficiencies and material losses throughout the production process. Furthermore, the various stages and procedures associated with wet granulation often involve significant costs associated with installing new or upgrading equipment to increase efficiency or production capacity.

[0007] The growing global demand for naproxen sodium has rekindled interest in improved formulations and alternative processes that can improve production capacity and efficiency compared to existing methods. The challenge in developing new methods and / or formulations is that the new process for manufacturing the formulation must be as cost-effective and reliable as the existing process, while the new formulation must exhibit the same or better drug release and bioavailability profile as the existing formulation. Although alternative formulations and manufacturing processes for naproxen sodium tablets have been investigated in the past, none have successfully replaced the existing formulation and associated wet granulation process on a commercial scale.

[0008] The difficulty in designing cost-effective alternative methods for manufacturing naproxen sodium tablets has hindered the development of new fixed-dose combinations that may include naproxen as a key active pharmaceutical ingredient. The preparation of oral tablets containing naproxen sodium and other active ingredients imposes additional excipient constraints based on physical and chemical compatibility requirements, further complicating cost and manufacturing considerations. Consumers also expect fixed-dose combinations to provide equivalent or better drug release and bioavailability profiles for the other active ingredients compared to stand-alone formulations. Identifying a viable formulation that meets these drug release and bioavailability criteria for active ingredients with varying dissolution and disintegration properties and / or storage stability requirements is a significant task, despite any manufacturing constraints. For tablets containing naproxen sodium, manufacturing considerations are significant, resulting in even less flexibility in adjusting excipients to achieve a satisfactory fixed-dose combination formulation.

[0009] Therefore, there remains a need for improved formulations of oral tablets containing naproxen sodium as the sole active pharmaceutical ingredient or in combination with other active pharmaceutical ingredients, as well as improved methods for producing the same. Summary of the Invention

[0010] The present invention provides naproxen sodium tablets having an enhanced dissolution profile (e.g., faster initial dissolution rate) and a shorter disintegration time compared to existing formulations. The improved performance of naproxen sodium tablets is achieved through a unique excipient composition combined with dry roller compaction to provide granules within the tablet that are more permeable to the dissolution medium (e.g., water) than existing formulations. The faster dissolution and shorter disintegration time of the naproxen sodium tablets result in a faster onset of therapeutic effects, reducing inflammation and pain.

[0011] In addition to improving the properties of naproxen sodium tablets, the methods for preparing naproxen sodium tablets provided herein can also achieve simpler and more efficient manufacturing than existing wet granulation methods by using less excipient material and reducing the total number of required process steps, thereby producing tablets with consistent dissolution and disintegration profiles across a range of different process parameters. These processes can be used to prepare oral tablets containing naproxen sodium as the sole active ingredient or in combination with other active pharmaceutical ingredients.

[0012] In one aspect, provided herein is a naproxen sodium tablet comprising:

[0013] Granules containing naproxen sodium;

[0014] Mannitol;

[0015] colloidal silica;

[0016] one or more lubricants; and

[0017] one or more superdisintegrants,

[0018] wherein the tablet has a dissolution profile of at least 80% of the naproxen sodium dissolved in 10 minutes and 100% of the naproxen sodium dissolved in 20 minutes as determined by dissolution testing in USP Apparatus-2 at 37°C ± 0.5°C in pH 7.4 phosphate buffer.

[0019] In another aspect, provided herein is a naproxen sodium tablet comprising:

[0020] Granules containing naproxen sodium;

[0021] Mannitol;

[0022] colloidal silica;

[0023] stearic acid;

[0024] Sodium starch glycolate; and

[0025] magnesium stearate,

[0026] wherein the tablet has a dissolution profile of at least 80% of the naproxen sodium dissolved in 10 minutes and 100% of the naproxen sodium dissolved in 20 minutes as determined by dissolution testing in USP Apparatus-2 at 37°C ± 0.5°C in pH 7.4 phosphate buffer.

[0027] In yet another aspect, provided herein is a method for preparing the naproxen sodium tablets described herein, comprising:

[0028] combining naproxen sodium, mannitol, colloidal silicon dioxide, one or more lubricants, and one or more superdisintegrants to provide a blended mixture;

[0029] compacting the blended mixture by roller compaction to form a ribbon;

[0030] grinding the ribbon to obtain granules;

[0031] combining the granules with mannitol, one or more lubricants, one or more superdisintegrants, and optionally colloidal silicon dioxide to provide a tableting mix; and

[0032] The tableting mixture is compressed to obtain naproxen sodium tablets.

[0033] In yet another aspect, provided herein is a method for preparing the naproxen sodium tablets described herein, comprising:

[0034] combining naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, and sodium starch glycolate to obtain a blended mixture;

[0035] compacting the blended mixture by roller compaction to form a ribbon;

[0036] grinding the ribbon to obtain granules;

[0037] combining the granules with mannitol, sodium starch glycolate, magnesium stearate, and optionally colloidal silicon dioxide to provide a tableting mixture; and

[0038] The tableting mixture is compressed to obtain naproxen sodium tablets.

[0039] In yet another aspect, provided herein is a method of treating pain in a subject in need thereof, comprising administering to the subject a naproxen sodium tablet as described herein.

[0040] In yet another aspect, provided herein is a method of reducing fever in a subject in need thereof, the method comprising administering to the subject a naproxen sodium tablet as described herein.

[0041] The present invention also provides bilayer naproxen sodium tablets that combine naproxen sodium with one or more other active pharmaceutical ingredients (e.g., acetaminophen). More specifically, the present invention provides fixed-dose composite bilayer tablets comprising roller-compacted granules of naproxen sodium in a primary layer and acetaminophen in a secondary layer. The bilayer tablets provided herein pair the complementary disintegration mechanisms of naproxen sodium and acetaminophen with the unique composition of roller-compacted granules comprising naproxen sodium to provide formulations that can surprisingly exhibit shorter disintegration times than existing tablet formulations comprising naproxen sodium as the sole active drug.

[0042] In another aspect, provided herein is a double-layer naproxen sodium tablet comprising:

[0043] The primary layer includes:

[0044] Granules containing naproxen sodium;

[0045] Mannitol;

[0046] colloidal silica;

[0047] one or more adhesives;

[0048] one or more lubricants; and

[0049] one or more superdisintegrants; and

[0050] The secondary layer includes:

[0051] one or more other active pharmaceutical ingredients;

[0052] colloidal silica;

[0053] one or more adhesives;

[0054] one or more lubricants; and

[0055] one or more superdisintegrants,

[0056] wherein the tablet has a disintegration time of less than 5 minutes as determined by the USP disintegration test conducted in water at 37°C ± 0.5°C using a basket assembly with disks.

[0057] In yet another aspect, provided herein is a double-layer naproxen sodium tablet comprising:

[0058] A naproxen sodium layer, the naproxen sodium layer comprising:

[0059] Granules containing naproxen sodium;

[0060] Mannitol;

[0061] colloidal silica;

[0062] Sodium starch glycolate;

[0063] starch and / or partially pregelatinized starch;

[0064] stearic acid or magnesium stearate; and

[0065] Croscarmellose sodium; and

[0066] An acetaminophen layer, the acetaminophen layer comprising:

[0067] Acetaminophen;

[0068] colloidal silica;

[0069] starch and / or partially pregelatinized starch;

[0070] stearic acid or magnesium stearate; and

[0071] Croscarmellose sodium,

[0072] wherein the tablet has a disintegration time of less than 5 minutes as determined by the USP disintegration test conducted in water at 37°C ± 0.5°C using a basket assembly with disks.

[0073] In another aspect, provided herein is a method of treating pain in a subject in need thereof, comprising administering to the subject a bilayer naproxen sodium tablet as described herein.

[0074] In yet another aspect, provided herein is a method of reducing fever in a subject in need thereof, the method comprising administering to the subject a bilayer naproxen sodium tablet as described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0075] The present application may be understood by referring to the following description in conjunction with the accompanying drawings.

[0076] Figure 1 An exemplary process for preparing the naproxen sodium tablets described herein is described.

[0077] Figure 2 Shown is the dissolution profile of naproxen sodium tablets (with two different film coatings) prepared by dry roller compaction method compared to the dissolution profile of commercially available naproxen sodium film-coated oral tablets prepared by wet granulation method, as determined by dissolution testing conducted in USP Apparatus-2 at 37°C ± 0.5°C in pH 7.4 phosphate buffer.

[0078] Figure 3 Shown is the dissolution profile of naproxen sodium tablets (with two film coatings) prepared by dry roller compaction method compared to the dissolution profile of commercially available naproxen sodium film-coated oral tablets prepared by wet granulation method, as determined by dissolution testing conducted in USP Apparatus-2 at 37°C ± 0.5°C in pH 5.8 phosphate buffer.

[0079] Figure 4 An exemplary process for preparing the bi-layer naproxen sodium tablets described herein is shown.

[0080] Figures 5A-5E Shown are composite monolayer and bilayer tablets containing naproxen sodium and acetaminophen at various time points during a comparative disintegration study. Figure 5AShown are photographs of a monolayer oral tablet comprising naproxen sodium granules (prepared by dry roller compaction) and acetaminophen granules (commercially available) (left), and a photograph of an oral bilayer tablet comprising naproxen sodium granules (prepared by dry roller compaction) in the primary layer and acetaminophen granules in the secondary layer (right). Figure 5B-5E Shown at 0 seconds ( Figure 5B ), 10 seconds( Figure 5C )、35 seconds( Figure 5D ) and 3 minutes and 3 seconds ( Figure 5E ) were taken to show the disintegration time of each formulation in the disintegration device.

[0081] Figure 6A-6B A graph comparing the disintegration times of various tablet formulations of naproxen sodium and acetaminophen is shown. DETAILED DESCRIPTION

[0082] The present invention provides naproxen sodium tablets prepared by dry granulation, and more specifically, provides naproxen sodium tablets comprising roller-compacted granules, wherein the naproxen sodium tablets can have an enhanced dissolution profile and a shorter disintegration time than existing formulations. In one aspect of the present invention, the naproxen sodium tablets of the present invention comprise: granules comprising naproxen sodium; mannitol; colloidal silicon dioxide; stearic acid; sodium starch glycolate; and magnesium stearate.

[0083] Compared to commercially available naproxen sodium tablets, naproxen sodium tablets comprising naproxen sodium granules and specific excipients described herein can exhibit superior dissolution profiles. Specifically, the naproxen sodium tablets of the present invention can exhibit approximately 80% dissolution of naproxen sodium after 10 minutes and nearly complete or complete (95% or more) dissolution of naproxen sodium within 20 minutes, whereas naproxen sodium tablets prepared using existing wet granulation methods require at least 20 minutes to achieve 80% dissolution and 30 minutes or more to achieve complete dissolution.

[0084] The dissolution and disintegration properties of the tablets provided herein can be improved by using selected intragranular and extragranular excipients in the tablets. Naproxen sodium has been observed to disintegrate according to a surface erosion mechanism; its disintegration is not significantly affected or accelerated by increasing the concentration of the superdisintegrant present. However, for the tablets of the present invention, the specific selection and combination of extragranular excipients (mannitol, sodium starch glycolate, and optionally colloidal silicon dioxide) is believed to promote the absorption and transport of the dissolution medium (e.g., water) into the tablet core. Similarly, the use of a selected combination of intragranular excipients (mannitol, sodium starch glycolate, stearic acid, and colloidal silicon dioxide) may produce particles that can be compacted into tablets but still have sufficient porosity to promote the dissolution medium to pass through the tablet and penetrate larger particles. The combination of extragranular excipients and dry roller compaction can produce naproxen sodium tablets that penetrate the dissolution medium more easily than existing formulations, thereby enhancing dissolution and disintegration properties.

[0085] In addition to a specific naproxen sodium tablet formulation with enhanced properties, a dry granulation method for preparing the naproxen sodium tablet is also provided herein. The method of the present invention relates to dry granulation, particularly dry granulation by roller compaction, in contrast to commercially available oral tablets prepared by wet granulation. Both wet granulation and dry granulation involve agglomeration or densification of powdered materials to facilitate downstream processing. However, dry granulation achieves densification through direct physical compression, while wet granulation utilizes a granulation solvent or fluid to induce aggregation. The dry granulation-based method for preparing the naproxen sodium tablet of the present invention includes first mixing naproxen sodium with the above-mentioned intragranular excipients to form a blended mixture. The blended mixture is passed through a roller compactor and the compacted material is ground into porous granules. The granules are then combined with the above-mentioned extragranular excipients and compressed into a final tablet dosage form.

[0086] By using less excipient material overall, reducing the number of production steps, improving production time, and optimizing the production of tablets with consistent dissolution and disintegration characteristics with minimal process parameters, the roller compaction method provided herein can ultimately achieve more efficient production than existing wet granulation methods. For example, roller compaction can be easily adapted to a continuous process or a batch process, unlike wet granulation methods that are primarily performed in batches. Wet granulation methods typically use batch processing to allow sufficient residence time to achieve the desired particle size distribution and residual moisture content. Other benefits of roller compaction can include reduced upfront installation costs, flexibility to expand and / or reduce production batches, and reduced operating costs.

[0087] Furthermore, it was unexpectedly observed that the enhanced dissolution profile of naproxen sodium tablets can be achieved using the specific excipient combinations described herein for a range of process parameter values during dry granulation (roller speed, roller compaction, milling speed, etc.) and tableting (compression force). It has been observed that the dry granulation method described herein is not only compatible with the selected combination of excipients described herein, but also can form a porous structure within the granules with surprisingly consistent porosity and particle size distribution levels despite changes in roller compaction parameters. Therefore, the excipient composition of naproxen sodium tablets can be described as highly compatible with roller compaction and will result in tablets with enhanced dissolution, with high reproducibility under a range of process parameters.

[0088] In another aspect, the present invention provides a naproxen sodium tablet comprising granules comprising naproxen sodium and one or more other active pharmaceutical ingredients. Fixed-dose compositions comprising naproxen sodium and other active pharmaceutical ingredients may provide additional or supplemental therapeutic benefits due to different mechanisms of therapeutic effect, different onset times of therapeutic effect, and different pharmacokinetic half-lives. For example, a fixed-dose composition comprising naproxen sodium and acetaminophen (or other analgesics) may provide supplemental analgesic and / or antipyretic effects. Naproxen sodium is a nonsteroidal anti-inflammatory drug (NSAID) widely used as a long-acting analgesic (half-life between 8 and 12 hours), but has a relatively slow onset of action. In contrast, acetaminophen is a non-NSAID analgesic with a rapid onset of action (within 15 minutes) but a shorter half-life (4 hours), resulting in a much shorter overall duration of analgesic effect. The combination of naproxen sodium and acetaminophen offers consumers the dual advantages of rapid and long-lasting pain relief in a single dosage form.

[0089] In one aspect, the present invention provides a bilayer naproxen sodium tablet comprising a naproxen sodium layer comprising: granules comprising naproxen sodium as described herein, mannitol; colloidal silicon dioxide; sodium starch glycolate; starch and / or partially pregelatinized starch; stearic acid or magnesium stearate; and croscarmellose sodium, and an acetaminophen layer, wherein the acetaminophen layer comprises: acetaminophen; colloidal silicon dioxide; starch and / or partially pregelatinized starch; stearic acid or magnesium stearate, and croscarmellose sodium.

[0090] Unexpectedly, it was observed that composite tablets containing the roller-compacted granules of naproxen sodium described herein and acetaminophen in a bilayer tablet configuration exhibited shorter disintegration times than tablets containing naproxen sodium alone, whether in the form of commercially available naproxen sodium tablets prepared by wet granulation or in the form of naproxen sodium tablets prepared by dry granulation (roller compaction) as described herein.

[0091] Without being bound by theory, the observed shorter disintegration times in bilayer naproxen sodium tablets containing naproxen sodium granules and acetaminophen compared to active naproxen sodium tablets alone are attributed to the complementary disintegration mechanisms of naproxen sodium and acetaminophen, as well as the confinement of naproxen sodium in a single half-layer. In contrast to the erosive disintegration of naproxen sodium, the disintegration of acetaminophen is directly related to the amount of superdisintegrant present. Due to the presence of the superdisintegrant in the bilayer tablet, the acetaminophen layer was observed to disintegrate within tens of seconds. The rapid disintegration of the acetaminophen layer resulted in an increase in the surface area of the remaining naproxen sodium half-layer exposed to the disintegration medium, which is believed to enable faster disintegration of the naproxen sodium layer and result in a shorter overall disintegration time for the bilayer tablet.

[0092] The following description sets forth exemplary methods, parameters, etc. However, it should be understood that these descriptions are not intended to limit the scope of the invention, but rather to describe exemplary embodiments.

[0093] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter itself. For example, description of "about X" includes description of "X."

[0094] It should be understood that the aspects and variations described herein also include "comprising" and / or "consisting essentially of" aspects and variations.

[0095] Oral monolayer and bilayer tablets containing roller-compacted granules

[0096] In one aspect of the present invention, provided herein is an oral tablet comprising roller-compacted granules and extragranular excipients, wherein the roller-compacted tablet comprises an active pharmaceutical ingredient and an intragranular excipient. In some embodiments, the active pharmaceutical ingredient is naproxen sodium, and the roller-compacted granules comprise naproxen sodium.

[0097] In some embodiments, provided herein are naproxen sodium tablets comprising roller-compacted granules comprising naproxen sodium; mannitol; colloidal silicon dioxide; one or more lubricants, and a superdisintegrant. In other embodiments, provided herein are naproxen sodium tablets comprising roller-compacted granules comprising naproxen sodium; mannitol; colloidal silicon dioxide; stearic acid; sodium starch glycolate; and magnesium stearate. In some variations, the naproxen sodium tablets have a dissolution profile of at least 80% (±5%) of the naproxen sodium dissolved at 10 minutes and 100% (±5%) of the naproxen sodium dissolved at 20 minutes, as determined by dissolution testing in USP Apparatus-2 (paddle) in pH 7.4 phosphate buffer.

[0098] Roller compaction of particles

[0099] As described herein, the present invention provides oral tablets prepared by dry granulation using a roller compaction process. Accordingly, the present invention provides oral tablets comprising roller-compacted granules.

[0100] The naproxen sodium tablets of the present invention have an enhanced dissolution profile compared to commercially available naproxen sodium tablets prepared by a wet granulation process. Furthermore, the enhanced dissolution profile appears to be primarily a result of the unique composition of the tablets, namely, naproxen sodium combined with the selection and amount of excipients inside (intragranular) and outside (extragranular) the roller-compacted granules, while being minimally affected by process parameters during roller compaction and tableting. As described herein, the unique composition and structural characteristics of the roller-compacted granules, including their particle size distribution and porosity, contribute to a consistent physical profile, including, but not limited to, dissolution rate and disintegration time.

[0101] The term "granule" as used herein may be defined as a solid aggregate or agglomerated particle comprising two or more finely divided powder materials in a single mass. The term "roller-compacted granule" as used herein is understood to refer to a granule produced by roller compaction.

[0102] The roller-compacted granules of the present invention comprise at least one active pharmaceutical ingredient, such as naproxen sodium, and an intragranular excipient. In some embodiments where the active ingredient is naproxen sodium, provided herein is a naproxen sodium tablet comprising the roller-compacted granules, wherein the roller-compacted granules comprise naproxen sodium.

[0103] In some embodiments, the naproxen sodium tablet comprises at least 75 weight % (or % w / w), at least 80% w / w, at least 85% w / w, or at least 90% w / w of roller-compacted granules, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 95% w / w, less than or equal to 92% w / w, or less than or equal to 90% w / w of roller-compacted granules, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 75-95% w / w, 75-92% w / w, 75-90% w / w, 80-95% w / w, 80-92% w / w, 80-90% w / w, 85-95% w / w, 85-92% w / w, 85-90% w / w, 90-95% w / w, or 90-92% w / w of roller-compacted granules based on the total weight of the naproxen sodium tablet.

[0104] Active pharmaceutical ingredients

[0105] As described above, the present invention provides an oral tablet comprising roller-compacted granules, wherein the roller-compacted granules comprise at least one active pharmaceutical ingredient. In some embodiments, provided herein are oral tablets comprising roller-compacted granules comprising naproxen sodium as the active pharmaceutical ingredient. It should be appreciated that the oral tablets of the present invention comprising naproxen sodium may also be referred to as "naproxen sodium tablets." A "naproxen sodium tablet" may also be characterized as a single-layer naproxen sodium tablet or a double-layer naproxen sodium tablet.

[0106] Naproxen sodium is an active compound in a class of nonsteroidal anti-inflammatory drugs (NSAIDs), which are widely used to treat inflammation-related conditions. In addition to its anti-inflammatory properties, naproxen sodium also has antipyretic and analgesic properties and is used to treat a variety of ailments, including but not limited to minor aches and pains such as arthritis, dysmenorrhea, muscle pain, back pain, headaches, toothaches, and the common cold.

[0107] In some embodiments, the naproxen sodium tablet comprises at least 50 mg or at least 100 mg of naproxen sodium. In other embodiments, the naproxen sodium tablet comprises less than or equal to 300 mg, less than or equal to 250 mg, less than or equal to 200 mg, or less than or equal to 150 mg of naproxen sodium. In some embodiments, the naproxen sodium tablet comprises 50 mg to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 150 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, 150 mg to 300 mg, 150 mg to 250 mg, 150 mg to 200 mg, 200 mg to 300 mg, 200 mg to 250 mg, or 250 mg to 300 mg of naproxen sodium. In certain embodiments, the naproxen sodium tablet comprises 100 mg, 110 mg, 150 mg, 200 mg, 220 mg, 250 mg, or 300 mg of naproxen sodium. In certain other embodiments, the naproxen sodium tablet comprises 220 mg of naproxen sodium.

[0108] In some embodiments, the naproxen sodium tablets described herein comprise at least 40% w / w, at least 50% w / w, at least 60% w / w, or at least 70% w / w naproxen sodium, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablets described herein comprise less than or equal to 95% w / w, less than or equal to 90% w / w, less than or equal to 85% w / w, or less than or equal to 80% w / w naproxen sodium, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 40-95% w / w, 40-90% w / w, 40-85% w / w, 40-80% w / w, 50-95% w / w, 50-90% w / w, 50-85% w / w, 50-80% w / w, 60-95% w / w, 60-90% w / w, 60-85% w / w, 60-80% w / w, 70-95% w / w, 70-90% w / w, 70-85% w / w, or 70-80% w / w of naproxen sodium, based on the total weight of the naproxen sodium.

[0109] In other embodiments, the roller-compacted granules comprise at least 50% w / w, at least 60% w / w, or at least 70% w / w naproxen sodium, based on the total weight of the roller-compacted granules. In some embodiments, the roller-compacted granules comprise less than or equal to 90% w / w, less than or equal to 80% w / w, or less than or equal to 75% w / w naproxen sodium, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 50-90% w / w, 50-80% w / w, 50-75% w / w, 60-90% w / w, 60-80% w / w, 70-90% w / w, 70-80% w / w, or 70-75% w / w naproxen sodium, based on the total weight of the roller-compacted granules.

[0110] However, it should be recognized that the dry granulation method of the present invention and its compatible excipients may also be applicable to the preparation of oral tablets containing other drugs similar to naproxen sodium in terms of analgesic effect, mechanism of action, chemical structure, physicochemical properties, or any combination thereof, which replace naproxen sodium as the primary active ingredient. Alternatively, it should be recognized that the oral tablets and dry granulation method of the present invention may be applicable to pharmaceutical combinations containing multiple active pharmaceutical ingredients, wherein naproxen sodium may be one such ingredient. In some embodiments, the oral tablet comprising roller-compacted granules comprising naproxen sodium may include one or more other active pharmaceutical ingredients. In certain embodiments, the oral tablet comprises a single layer comprising roller-compacted granules of naproxen sodium and one or more other active pharmaceutical ingredients. Suitable other active ingredients may include, but are not limited to, active pharmaceutical ingredients used to treat pain, fever, and / or colds and flu, such as acetaminophen, phenylephrine, pseudoephedrine, doxylamine, dextromethorphan, and / or guaifenesin, or any pharmaceutically acceptable salts thereof.

[0111] Intragranular excipients

[0112] In addition to the active pharmaceutical ingredient, the roller-compacted granules of the oral tablets described herein may also contain excipients, such as fillers, lubricants, dispersants, superdisintegrants, etc., to provide any desired physical properties, such as for downstream manufacturing and use. Such excipients contained within the roller-compacted granules may be referred to as intragranular excipients. In some embodiments, the naproxen sodium tablets having roller-compacted granules of the present invention further contain intragranular excipients. As described above, the combination of naproxen sodium and intragranular excipients can form a porous structure within the resulting granules containing naproxen sodium described herein and impart enhanced dissolution properties to the resulting naproxen sodium tablets.

[0113] In some embodiments, the roller-compacted granules comprising naproxen sodium comprise mannitol. As another aspect, in some embodiments, the naproxen sodium tablet comprising roller-compacted granules comprises mannitol as an intragranular excipient. Mannitol is a water-soluble sugar alcohol used as a diluent, filler, and disintegrant in many formulations. Mannitol is also known by various commercial trade names, including but not limited to Ludiflash ® 、Mannogem ® and Pearlitol ®. In some embodiments, the mannitol is spray-dried mannitol. In some of the foregoing embodiments, the mannitol has an average particle size of at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, or at least 150 μm. In other embodiments, the mannitol has an average particle size of less than or equal to 300 μm, less than or equal to 275 μm, less than or equal to 250 μm, less than or equal to 225 μm, or less than or equal to 200 μm. In certain embodiments, the mannitol has an average particle size of 50 μm to 300 μm, 50 μm to 250 μm, 50 μm to 200 μm, 100 μm to 300 μm, 100 μm to 250 μm, 100 μm to 200 μm, 150 μm to 300 μm, 150 μm to 250 μm, or 50 μm to 200 μm.

[0114] In some embodiments, the roller-compacted granules comprise at least 5% w / w, at least 10% w / w, or at least 15% w / w mannitol, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 30% w / w, less than or equal to 25% w / w, or less than or equal to 20% w / w mannitol, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 5-30% w / w, 5-25% w / w, 5-20% w / w, 10-30% w / w, 10-25% w / w, 10-20% w / w, 15-30% w / w, 15-25% w / w, or 15-20% w / w mannitol, based on the total weight of the roller-compacted granules.

[0115] It should be appreciated that mannitol in the granules as described above can be substituted by other suitable disintegrants (e.g., polyols) or combined with other suitable disintegrants (e.g., polyols). In some embodiments, the roller compacted granules comprise one or more polyols. The polyols used in the tablets provided herein may include but are limited to sugar alcohols, such as sorbitol, erythritol, xylitol, mannitol, and lactitol. In certain embodiments, the one or more polyols are one or more sugar alcohols. In other embodiments, the roller compacted granules comprise mannitol, sorbitol, lactitol, or xylitol, or a combination thereof.

[0116] In some embodiments, the roller-compacted granules comprise at least 5% w / w, at least 10% w / w, or at least 15% w / w of the polyol, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 30% w / w, less than or equal to 25% w / w, or less than or equal to 20% w / w of the polyol, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 5-30% w / w, 5-25% w / w, 5-20% w / w, 10-30% w / w, 10-25% w / w, 10-20% w / w, 15-30% w / w, 15-25% w / w, or 15-20% w / w of the polyol, based on the total weight of the roller-compacted granules.

[0117] In some embodiments, the roller-compacted granules comprise colloidal silicon dioxide. In some embodiments, naproxen sodium tablets comprising roller-compacted granules comprise colloidal silicon dioxide as an intragranular excipient. Colloidal silicon dioxide (also known as Cab-O-Sil ® ) is a glidant that enhances the flowability of the powder mixture during the manufacturing process and reduces friction. In some embodiments, the roller-compacted granules comprise at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of colloidal silicon dioxide, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 10% w / w, less than or equal to 5% w / w, or less than or equal to 2% w / w of colloidal silicon dioxide, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of colloidal silicon dioxide, based on the total weight of the roller-compacted granules.

[0118] In some embodiments, the roller-compacted granules comprise one or more lubricants. In some of the foregoing embodiments, the roller-compacted granules comprise stearic acid. As another approach, in some embodiments, naproxen sodium tablets comprising roller-compacted granules comprise stearic acid as an intragranular excipient. Stearic acid is both a lubricant and a solubilizer, helping to achieve the desired powder mixture flowability during manufacturing, as well as the desired dissolution profile during actual tablet use. In some embodiments, the roller-compacted granules comprise at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of stearic acid, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 10% w / w, less than or equal to 5% w / w, or less than or equal to 2% w / w of stearic acid, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of stearic acid, based on the total weight of the roller-compacted granules.

[0119] In other embodiments, sodium stearyl fumarate can be used as a lubricant instead of stearic acid. In some embodiments, the roller-compacted granules comprise sodium stearyl fumarate. As stated another way, in some embodiments, naproxen sodium tablets comprising roller-compacted granules comprise sodium stearyl fumarate as an intragranular excipient. Similar to stearic acid, sodium stearyl fumarate is also a lubricant that can be used to adjust the flowability of the granules. In some embodiments, the roller-compacted granules comprise at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of sodium stearyl fumarate, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 10% w / w, less than or equal to 5% w / w, or less than or equal to 2% w / w of sodium stearyl fumarate, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of sodium stearyl fumarate, based on the total weight of the roller-compacted granules.

[0120] In other embodiments, the roller-compacted granules comprise magnesium stearate. Similar to stearic acid and sodium stearyl fumarate, magnesium stearate also acts as a lubricant. In some embodiments, the roller-compacted granules comprise at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of magnesium stearate, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 10% w / w, less than or equal to 5% w / w, or less than or equal to 2% w / w of magnesium stearate, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of magnesium stearate, based on the total weight of the roller-compacted granules.

[0121] In other embodiments, stearic acid, sodium stearyl fumarate, and magnesium stearate may be used in combination as lubricants.

[0122] In some embodiments, the roller-compacted granules comprise stearic acid and sodium stearyl fumarate. In other embodiments, the naproxen sodium tablet comprises stearic acid and sodium stearyl fumarate as intragranular excipients. In some embodiments where both stearic acid and sodium stearyl fumarate are used as intragranular excipients, the roller-compacted granules comprise at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of the combination of stearic acid and sodium stearyl fumarate, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 10% w / w, less than or equal to 5% w / w, or less than or equal to 2% w / w of the combination of stearic acid and sodium stearyl fumarate, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of a combination of stearic acid and sodium stearyl fumarate, based on the total weight of the roller-compacted granules.

[0123] In some embodiments, the roller-compacted granules comprise stearic acid and magnesium stearate. In other embodiments, the naproxen sodium tablet comprises stearic acid and magnesium stearate as intragranular excipients. In some embodiments where both stearic acid and magnesium stearate are used as intragranular excipients, the roller-compacted granules comprise at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of the combination of stearic acid and magnesium stearate, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 10% w / w, less than or equal to 5% w / w, or less than or equal to 2% w / w of the combination of stearic acid and magnesium stearate, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise a combination of stearic acid and magnesium stearate at 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of the total weight of the roller-compacted granules.

[0124] In some embodiments, the roller-compacted granules comprise one or more superdisintegrants. In some embodiments of the foregoing, the roller-compacted granules comprise sodium starch glycolate. In an alternative description, in some embodiments, naproxen sodium tablets comprising roller-compacted granules comprise sodium starch glycolate as an intragranular excipient. Sodium starch glycolate, sodium salt of carboxymethyl ether, also commercially known as Explotab ® or Primogel ® — is commonly used as a superdisintegrant in pharmaceutical dosage forms. Sodium starch glycolate, as a highly hygroscopic porous material, can promote the conduction and penetration of water throughout the dosage form, thereby shortening dissolution and disintegration times. In some embodiments, the roller-compacted granules comprise at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of sodium starch glycolate, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 10% w / w, less than or equal to 5% w / w, or less than or equal to 3% w / w of sodium starch glycolate, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 0.1-10% w / w, 0.1-5% w / w, 0.1-3% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-3% w / w, 1-10% w / w, 1-5% w / w, or 1-3% w / w of sodium starch glycolate, based on the total weight of the roller-compacted granules.

[0125] In other embodiments, the roller-compacted granules comprise at least 5% w / w, at least 10% w / w, at least 15% w / w, or at least 20% w / w of intragranular excipients, based on the total weight of the roller-compacted granules. In other embodiments, the roller-compacted granules comprise less than or equal to 40% w / w, less than or equal to 35% w / w, less than or equal to 30% w / w, or less than or equal to 25% w / w of intragranular excipients, based on the total weight of the roller-compacted granules. In certain embodiments, the roller-compacted granules comprise 5-40% w / w, 5-35% w / w, 5-30% w / w, 5-25% w / w, 10-40% w / w, 10-35% w / w, 10-30% w / w, 10-25% w / w, 15-40% w / w, 15-35% w / w, 15-30% w / w, 15-25% w / w, 20-40% w / w, 20-35% w / w, 20-30% w / w, or 20-25% w / w / w of intragranular excipients based on the total weight of the roller-compacted granules.

[0126] In some embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, and sodium starch glycolate. In other embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, sodium stearyl fumarate, and sodium starch glycolate. In some embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, magnesium stearate, and sodium starch glycolate. In yet other embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, sodium stearyl fumarate, and sodium starch glycolate. In some embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, magnesium stearate, and sodium starch glycolate. In some embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, magnesium stearate, and sodium starch glycolate. In yet other embodiments, the naproxen sodium tablet comprises a combination of mannitol, colloidal silicon dioxide, stearic acid, and sodium starch glycolate as intragranular excipients. In some embodiments, the naproxen sodium tablet comprises a combination of mannitol, colloidal silicon dioxide, sodium stearyl fumarate, and sodium starch glycolate as an intragranular excipient. In other embodiments, the naproxen sodium tablet comprises a combination of mannitol, colloidal silicon dioxide, stearic acid, sodium stearyl fumarate, and sodium starch glycolate as an intragranular excipient. In other embodiments, the naproxen sodium tablet comprises a combination of mannitol, colloidal silicon dioxide, stearic acid, magnesium stearate, and sodium starch glycolate as an intragranular excipient.

[0127] Extragranular excipients

[0128] As described herein, oral tablets comprising roller-compacted granules may comprise an active pharmaceutical ingredient and intragranular excipients within the granules and extragranular excipients outside the granules. Other excipients (extragranular excipients) may be added to the roller-compacted granules to help bind the granules together, provide the granules with volume for compression, and provide structural stability to the final tablet. Suitable extragranular excipients may include, but are not limited to, excipients such as binders, lubricants, dispersants, superdisintegrants, and the like. In some embodiments, the naproxen sodium tablets of the present invention having roller-compacted granules further comprise extragranular excipients.

[0129] In some embodiments, the naproxen sodium tablet comprises mannitol as an extragranular excipient. As described above, mannitol is a sugar alcohol that can function as a variety of excipients (e.g., a diluent, a filler, and a disintegrant). In some embodiments, the naproxen sodium tablet comprises at least 0.5% w / w, at least 0.75% w / w, at least 1% w / w, at least 2% w / w, or at least 3% w / w of extragranular mannitol, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, less than or equal to 7% w / w, or less than or equal to 5% w / w of extragranular mannitol, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.75-10% w / w, 0.75-7% w / w, 0.75-5% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, 2-10% w / w, 2-7% w / w, 2-5% w / w, 3-10% w / w, 3-7% w / w, or 3-5% w / w of extragranular mannitol, based on the total weight of the naproxen sodium tablet.

[0130] In some embodiments, certain properties or types of mannitol may be particularly suitable for the extragranular mannitol described herein. In some embodiments, the mannitol is spray-dried mannitol. In some of the aforementioned embodiments, the mannitol has an average particle size of at least 50 μm, at least 75 μm, at least 100 μm, at least 125 μm, or at least 150 μm. In other embodiments, the mannitol has an average particle size of less than or equal to 300 μm, less than or equal to 275 μm, less than or equal to 250 μm, less than or equal to 225 μm, or less than or equal to 200 μm. In certain embodiments, the mannitol has an average particle size of 50 µm to 300 µm, 50 µm to 250 µm, 50 µm to 200 µm, 100 µm to 300 µm, 100 µm to 250 µm, 100 µm to 200 µm, 150 µm to 300 µm, 150 µm to 250 µm, or 50 µm to 200 µm.

[0131] As with the above-mentioned intragranular mannitol, it should also be recognized that the above-mentioned extragranular mannitol can also be replaced by other suitable disintegrants (e.g., polyols) or combined with other suitable disintegrants (e.g., polyols). In some embodiments, the naproxen sodium tablet comprises one or more polyols as extragranular excipients. The polyols used in the tablets provided herein may include but are limited to sugar alcohols, such as sorbitol, erythritol, xylitol, mannitol, and lactitol. In certain embodiments, the one or more polyols are one or more sugar alcohols. In other embodiments, the naproxen sodium tablet comprises mannitol, sorbitol, lactitol, or xylitol, or a combination thereof, as extragranular excipients.

[0132] In some embodiments, the naproxen sodium tablet comprises a polyol as an extragranular excipient. In some embodiments, the naproxen sodium tablet comprises at least 0.5% w / w, at least 0.75% w / w, at least 1% w / w, at least 2% w / w, or at least 3% w / w of the extragranular polyol, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, less than or equal to 7% w / w, or less than or equal to 5% w / w of the extragranular polyol, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.75-10% w / w, 0.75-7% w / w, 0.75-5% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, 2-10% w / w, 2-7% w / w, 2-5% w / w, 3-10% w / w, 3-7% w / w, or 3-5% w / w of the extragranular polyol, based on the total weight of the naproxen sodium tablet.

[0133] In yet other embodiments, the naproxen sodium tablet comprises one or more extragranular superdisintegrants. In some embodiments, the naproxen sodium tablet comprises sodium starch glycolate as an extragranular excipient. As described above, sodium starch glycolate can be used as a superdisintegrant in pharmaceutical formulations to facilitate conduction and penetration of the dissolution medium throughout the naproxen sodium tablet. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, at least 1% w / w, or at least 2% w / w of extragranular sodium starch glycolate, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, 7% w / w, 5% w / w, or 3% w / w of extragranular sodium starch glycolate, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-3% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-3% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, 1-3% w / w, 2-10% w / w, 2-7% w / w, 2-5% w / w, or 2-3% w / w of extragranular sodium starch glycolate, based on the total weight of the naproxen sodium tablet.

[0134] In yet other embodiments, the naproxen sodium tablet comprises one or more extragranular lubricants. In some embodiments, the naproxen sodium tablet comprises magnesium stearate as an extragranular excipient. Magnesium stearate is an excipient used as a lubricant in various dosage forms to reduce the adhesion of powdered material to processing equipment and to facilitate discharge of the tablet from the tablet press. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular magnesium stearate, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, 7% w / w, 5% w / w, or 2% w / w of extragranular magnesium stearate, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of extragranular magnesium stearate, based on the total weight of the naproxen sodium tablet.

[0135] In other embodiments, the naproxen sodium tablet comprises colloidal silicon dioxide as an extragranular excipient. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular colloidal silicon dioxide, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, 7% w / w, 5% w / w, or 2% w / w of extragranular colloidal silicon dioxide, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of extragranular colloidal silicon dioxide, based on the total weight of the naproxen sodium tablet.

[0136] In some embodiments, the naproxen sodium tablet comprises stearic acid as an extragranular excipient. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular stearic acid, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, 7% w / w, 5% w / w, or 2% w / w of extragranular stearic acid, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of extragranular stearic acid, based on the total weight of the naproxen sodium tablet.

[0137] In other embodiments, the naproxen sodium tablet comprises sodium stearyl fumarate as an extragranular excipient. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular sodium stearyl fumarate, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, 7% w / w, 5% w / w, or 2% w / w of extragranular sodium stearyl fumarate, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of extragranular sodium stearyl fumarate, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises a combination of stearic acid and sodium stearyl fumarate as an extragranular excipient. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of a combination of stearic acid and sodium stearyl fumarate as an extragranular excipient, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises a combination of stearic acid and sodium stearyl fumarate as an extragranular excipient at 10% w / w, 7% w / w, 5% w / w, or 2% w / w of the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of the total weight of the naproxen sodium tablet. In yet other embodiments, the naproxen sodium tablet comprises a combination of stearic acid and sodium stearyl fumarate as an extragranular excipient. In some embodiments, the naproxen sodium tablet comprises as an extragranular excipient a combination of stearic acid and sodium stearyl fumarate at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises as an extragranular excipient a combination of stearic acid and sodium stearyl fumarate less than or equal to 10% w / w, 7% w / w, 5% w / w, or 2% w / w of the total weight of the naproxen sodium tablet.In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of extragranular sodium stearyl fumarate, based on the total weight of the naproxen sodium tablet. In further embodiments, the naproxen sodium tablet comprises a combination of stearic acid and sodium stearyl fumarate as an extragranular excipient. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of a combination of stearic acid and sodium stearyl fumarate as an extragranular excipient, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises as an extragranular excipient less than or equal to 10% w / w, 7% w / w, 5% w / w, or 2% w / w of the combination of stearic acid and sodium stearyl fumarate, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises as an extragranular excipient 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of the combination of stearic acid and sodium stearyl fumarate, based on the total weight of the naproxen sodium tablet.

[0138] In some embodiments, the naproxen sodium tablet comprises mannitol, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, stearic acid, sodium stearyl fumarate, or any combination thereof as an extragranular excipient. In some embodiments, the naproxen sodium tablet comprises mannitol, sodium starch glycolate, magnesium stearate, and optionally colloidal silicon dioxide as an extragranular excipient. In further embodiments, the naproxen sodium tablet comprises mannitol, sodium starch glycolate, and magnesium stearate as an extragranular excipient. In yet further embodiments, the naproxen sodium tablet comprises mannitol, sodium starch glycolate, magnesium stearate, and colloidal silicon dioxide as an extragranular excipient.

[0139] In yet other embodiments, the oral tablet comprising roller-compacted granules comprising naproxen sodium may comprise one or more additional active pharmaceutical ingredients external to the roller-compacted granules. In certain embodiments, the oral tablet comprises a single layer comprising roller-compacted granules of naproxen sodium and one or more additional extragranular active pharmaceutical ingredients. Suitable additional extragranular active ingredients may include, but are not limited to, active pharmaceutical ingredients used to treat pain, fever, and / or colds and flu, such as acetaminophen, phenylephrine, pseudoephedrine, doxylamine, dextromethorphan, and / or guaifenesin, or any pharmaceutically acceptable salt thereof (e.g., pseudoephedrine hydrochloride or pseudoephedrine sulfate).

[0140] Intragranular and extragranular excipients

[0141] As described herein, the naproxen sodium tablet may contain one or more excipients as intragranular and extragranular excipients. The excipients of the present invention may be suitable for use as intragranular excipients, extragranular excipients, or both, and may include, but are not limited to, mannitol, colloidal silicon dioxide, and sodium starch glycolate.

[0142] For example, in some embodiments, the naproxen sodium tablet comprises mannitol as both an intragranular excipient and an extragranular excipient. In some embodiments where the naproxen sodium tablet comprises intragranular mannitol and extragranular mannitol, the naproxen sodium tablet comprises at least 5% w / w, at least 10% w / w, or at least 15% w / w mannitol, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 40% w / w, less than or equal to 30% w / w, or less than or equal to 20% w / w mannitol, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 40% w / w, less than or equal to 30% w / w, or less than or equal to 20% w / w mannitol, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 5-40% w / w, 5-30% w / w, 5-20% w / w, 10-40% w / w, 10-30% w / w, 10-20% w / w, 15-40% w / w, 15-30% w / w, or 15-20% w / w of mannitol, based on the total weight of the naproxen sodium tablet.

[0143] In yet other embodiments where the tablet comprises one or more polyols (e.g., sorbitol, erythritol, xylitol, mannitol, and lactitol) as intragranular and extragranular excipients, the naproxen sodium tablet comprises at least 5% w / w, at least 10% w / w, or at least 15% w / w of the one or more polyols, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 40% w / w, less than or equal to 30% w / w, or less than or equal to 20% w / w of the one or more polyols, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 5-40% w / w, 5-30% w / w, 5-20% w / w, 10-40% w / w, 10-30% w / w, 10-20% w / w, 15-40% w / w, 15-30% w / w, or 15-20% w / w of one or more polyols, based on the total weight of the naproxen sodium tablet.

[0144] In some embodiments where the naproxen sodium tablet comprises sodium starch glycolate as both an intragranular and an extragranular excipient, the naproxen sodium tablet comprises at least about 1% w / w, at least about 2% w / w, at least about 3% w / w, or at least about 4% w / w of sodium starch glycolate. In other embodiments where the naproxen sodium tablet comprises both intragranular and extragranular sodium starch glycolate, the naproxen sodium tablet comprises less than or equal to 10% w / w, less than or equal to 9% w / w, less than or equal to 8% w / w, less than or equal to 7% w / w, less than or equal to 6% w / w, or less than or equal to 5% w / w of sodium starch glycolate. In certain embodiments where the naproxen sodium tablet comprises sodium starch glycolate as both an intragranular and an extragranular excipient, the naproxen sodium tablet comprises 1-10% w / w, 1-7% w / w, 1-5% w / w, 1-3% w / w, 2-10% w / w, 2-8% w / w, 2-6% w / w, 2-4% w / w, 3-10% w / w, 3-9% w / w, 3-7% w / w, 3-5% w / w, 4-10% w / w, 4-8% w / w, 4-6% w / w, or 4-5% w / w of sodium starch glycolate.

[0145] In yet other embodiments, the naproxen sodium tablet comprises colloidal silicon dioxide as an intragranular and extragranular excipient. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of colloidal silicon dioxide, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, 7% w / w, 5% w / w, or 2% w / w of colloidal silicon dioxide, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of colloidal silicon dioxide, based on the total weight of the naproxen sodium tablet.

[0146] In some embodiments, the naproxen sodium tablet comprises stearic acid as an intragranular and extragranular excipient. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of stearic acid, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, 7% w / w, 5% w / w, or 2% w / w of stearic acid, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of stearic acid, based on the total weight of the naproxen sodium tablet.

[0147] In some embodiments, the naproxen sodium tablet comprises sodium stearyl fumarate as an intragranular and extragranular excipient. In some embodiments, the naproxen sodium tablet comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of sodium stearyl fumarate, based on the total weight of the naproxen sodium tablet. In other embodiments, the naproxen sodium tablet comprises less than or equal to 10% w / w, 7% w / w, 5% w / w, or 2% w / w of sodium stearyl fumarate, based on the total weight of the naproxen sodium tablet. In certain embodiments, the naproxen sodium tablet comprises 0.1-10% w / w, 0.1-7% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-7% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-7% w / w, 1-5% w / w, or 1-2% w / w of sodium stearyl fumarate, based on the total weight of the naproxen sodium tablet.

[0148] It should be noted that the dry granulation (roller compaction) method of the present invention differs from the more commonly used wet granulation method in the production of naproxen sodium tablets because no liquid granulation liquid is used. Therefore, in some embodiments, the naproxen sodium tablets do not contain water and / or ethanol.

[0149] In other embodiments, the naproxen sodium tablets of the present invention do not include certain ingredients as intragranular or extragranular excipients that can be used to enhance intragranular binding during wet granulation. For example, in some embodiments, the naproxen sodium tablets described herein do not include microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), or other cellulose derivatives. In some embodiments, the naproxen sodium tablets do not contain polyvinylpyrrolidone (povidone) or derivatives such as cross-linked polyvinylpyrrolidone (crospovidone) or polyvinylpyrrolidone-vinyl acetate copolymer (copovidone). In other embodiments, the naproxen sodium tablets do not contain croscarmellose sodium. In some embodiments, the naproxen sodium tablets do not contain polyethylene glycol. In yet other embodiments, the naproxen sodium tablets do not contain corn starch or talc.

[0150] coating

[0151] In some embodiments, the naproxen sodium tablet further comprises a film coating. In some variations, the film coating comprises polyvinyl alcohol. In certain embodiments, the film coating is an immediate-release coating.

[0152] In other embodiments, the film coating further comprises a colorant, a flavoring agent, or a combination thereof.

[0153] Tablet dissolution, disintegration and other characteristics

[0154] By carefully selecting excipients in combination with roller compaction, the naproxen sodium tablets of the present invention have a drug release profile in which the tablets disintegrate in a relatively short period of time and the active pharmaceutical ingredient dissolves in solution faster than existing naproxen sodium tablets.

[0155] Naproxen and naproxen sodium are insoluble in acidic media (including gastric pH). In vivo absorption of naproxen sodium occurs primarily in the small intestine. Therefore, the drug release profile of naproxen tablets (including naproxen sodium tablets) can be characterized under conditions that better reflect the environment provided by various parts of the small intestine (e.g., pH 7.4 and / or pH 5.8).

[0156] In one aspect, provided herein is a naproxen sodium tablet comprising roller-compacted granules comprising naproxen sodium, wherein the naproxen sodium tablet has an enhanced dissolution profile. Dissolution refers to a measure of the amount of active ingredient released from a given dosage form into solution over time under standardized conditions. The United States Pharmacopoeia provides a standardized protocol for the dissolution evaluation of naproxen sodium tablets (USP34-NF29, Chapter 10). <711> Dissolution, Stage 6 Harmonization Bulletin dated December 1, 2011; and Naproxen Sodium monograph USP41-NF36, Interim Revision Announcement dated May 1, 2018, 0.1 M phosphate buffer of pH 7.4, 900 mL, 37°C ± 0.5°C, apparatus 2, 50 rpm, 45 min). As used herein, the term "about" when referring to the percentage of the active pharmaceutical ingredient (naproxen sodium) dissolved should be understood to include a variation of ± 5%.

[0157] In some embodiments, the naproxen sodium tablet has a dissolution profile of at least about 70%, at least about 75%, or at least about 80% of the naproxen sodium dissolved in 10 minutes as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 7.4 phosphate buffer. In other embodiments, the naproxen sodium tablet has a dissolution profile of less than or equal to about 95%, less than or equal to about 90%, or less than or equal to about 85% of the naproxen sodium dissolved in 10 minutes as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 7.4 phosphate buffer. In certain embodiments, the naproxen sodium tablet has a dissolution profile of 70% to 95%, 70% to 90%, 70% to 85%, 75% to 95%, 75% to 90%, 75% to 85%, 80% to 95%, 80% to 90%, or 80% to 85% naproxen sodium dissolved in 10 minutes as determined by dissolution testing conducted in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 7.4 phosphate buffer.

[0158] In other embodiments, the naproxen sodium tablet has a dissolution profile of at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the naproxen sodium dissolved in 20 minutes as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 7.4 phosphate buffer.

[0159] In yet other embodiments, the naproxen sodium tablet has a dissolution profile of at least 70%, at least 75%, or at least 80% of the naproxen sodium dissolved at 10 minutes, and at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the naproxen sodium dissolved at 20 minutes, as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 7.4 phosphate buffer. In certain embodiments, the naproxen sodium tablet has a dissolution profile of at least about 80% of the naproxen sodium dissolved at 10 minutes, and about 100% of the naproxen sodium dissolved at 20 minutes, as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 7.4 phosphate buffer.

[0160] Surprisingly, it was also observed that, when evaluated at pH 5.4, the naproxen sodium tablets of the present invention exhibited a dissolution profile similar to that observed at pH 7.4. The observation of similar dissolution profiles for the naproxen sodium tablets described herein was compared to the dissolution profile of naproxen sodium tablets prepared by a conventional wet granulation process. To evaluate the dissolution profile of the naproxen sodium tablets under acidic conditions, the USP standardized dissolution protocol for naproxen sodium tablets was employed, using a pH 5.8 phosphate buffer instead of a pH 7.4 weakly alkaline buffer, with all other parameters remaining the same (900 mL, apparatus 2, 50 rpm, 45 minutes, 37°C ± 0.5°C).

[0161] In certain embodiments, the naproxen sodium tablet has a dissolution profile of at least about 70%, at least about 75%, or at least about 80% of the naproxen sodium dissolved in 10 minutes as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37° C.±0.5° C. in pH 5.8 phosphate buffer. In other embodiments, the naproxen sodium tablet has a dissolution profile of less than or equal to about 95%, less than or equal to about 90%, or less than or equal to about 85% of the naproxen sodium dissolved in 10 minutes as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37° C.±0.5° C. in pH 5.8 phosphate buffer. In certain embodiments, the naproxen sodium tablet has a dissolution profile of 70% to 95%, 70% to 90%, 70% to 85%, 75% to 95%, 75% to 90%, 75% to 85%, 80% to 95%, 80% to 90%, or 80% to 85% naproxen sodium dissolved in 10 minutes as determined by dissolution testing conducted in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 5.8 phosphate buffer.

[0162] In other embodiments, the naproxen sodium tablet has a dissolution profile of at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the naproxen sodium dissolved in 20 minutes as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 5.8 phosphate buffer.

[0163] In yet other embodiments, the naproxen sodium tablet has a dissolution profile of at least 70%, at least 75%, or at least about 80% of the naproxen sodium dissolved at 10 minutes and at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the naproxen sodium dissolved at 20 minutes, as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 5.8 phosphate buffer. In other embodiments, the naproxen sodium tablet has a dissolution profile of at least about 80% of the naproxen sodium dissolved at 10 minutes and 100% of the naproxen sodium dissolved at 20 minutes, as determined by dissolution testing in USP Apparatus-2 (Paddles) at 37°C ± 0.5°C in pH 5.8 phosphate buffer.

[0164] In other embodiments, the naproxen sodium tablets of the present invention have enhanced disintegration characteristics. Complete disintegration is defined as any unit residue (excluding insoluble coating or capsule shell fragments) remaining on the test device screen or adhering to the lower surface of the disc (if used) is a soft mass with no apparent solid inner core. The disintegration of the tablet can be determined using USP-NF (USP43-NF38, Chapter <701> Disintegration is determined using the protocol described in the Disintegration, Stage 4 Harmonization Bulletinized April 26, 2019; uncoated tablet procedure, basket-rack assembly at 37°C ± 0.5°C. Briefly, this protocol involves immersing six identical uncoated or plain-coated tablets in individual test tubes (e.g., basket-rack assemblies with trays) containing water or a designated medium for a specific active ingredient at a fixed temperature (e.g., 37°C ± 0.5°C) for a specified period of time. Tablet disintegration is assessed visually.

[0165] The disintegration time of the naproxen sodium tablets of the present invention can be determined by the USP disintegration test performed in water at 37°C ± 0.5°C using a basket assembly with discs. For example, in some embodiments, the disintegration time of the naproxen sodium tablets is less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, or less than about 4 minutes, as determined by the USP disintegration test performed in water at 37°C ± 0.5°C using a basket assembly with discs. In other embodiments, the disintegration time of the naproxen sodium tablets is at least about 1 minute, at least about 2 minutes, or at least about 3 minutes, as determined by the USP disintegration test performed in water at 37°C ± 0.5°C using a basket assembly with discs. In certain embodiments, the naproxen sodium tablet has a disintegration time of 1 minute to 8 minutes, 1 minute to 7 minutes, 1 minute to 6 minutes, 1 minute to 5 minutes, 1 minute to 4 minutes, 2 minutes to 8 minutes, 2 minutes to 7 minutes, 2 minutes to 6 minutes, 2 minutes to 5 minutes, 2 minutes to 4 minutes, 3 minutes to 8 minutes, 3 minutes to 7 minutes, 3 minutes to 6 minutes, 3 minutes to 5 minutes, 3 minutes to 4 minutes as determined by the USP disintegration test performed in water at 37°C ± 0.5°C using a basket assembly with disks. In other embodiments, the naproxen sodium tablet is not an orally disintegrating tablet.

[0166] In addition to its pharmacokinetic properties, the naproxen sodium tablets of the present invention may also have other properties, such as physical durability and structural integrity. Physical durability and structural integrity are other considerations in evaluating the commercial viability of a pharmaceutical dosage form.

[0167] Tablet hardness (or tablet breaking force) is a property that can be used to quantify the structural integrity of a tablet under various conditions to which it may be exposed during storage, shipping, and handling prior to use. Hardness can be determined by compression testing methods known in the art, such as USP No. <1217> Chapter "Tablet Breaking Force" (USP35-NF30 Chapter <1217> Tablet Breaking Force, dated May 1, 2012), and a suitable measuring instrument, such as a tablet (hardness) tester placed inside. Hardness refers to the mechanical force required to cause the tablet to break (tablet breaking force). In some embodiments, the hardness of the naproxen sodium tablet is at least 2 kilograms force (kp), at least 3 kp, at least 4 kp, at least 5 kp, or at least 6 kp, as determined by a tablet tester according to the USP Tablet Breaking Force Test. In other embodiments, the hardness of the naproxen sodium tablet is less than or equal to 18 kp, less than or equal to 17 kp, less than or equal to 16 kp, less than or equal to 15 kp, less than or equal to 14 kp, less than or equal to 13 kp, or less than or equal to 12 kp, as determined by a tablet tester according to the USP Tablet Breaking Force Test. In certain embodiments, the naproxen sodium tablet has a hardness of 2 to 18 kp, 2 to 16 kp, 2 to 14 kp, 2 to 12 kp, 4 to 18 kp, 4 to 16 kp, 4 to 14 kp, 4 to 12 kp, 6 to 18 kp, 6 to 16 kp, 6 to 14 kp, or 6 to 12 kp as determined by a tablet tester according to the USP Tablet Breaking Force Test.

[0168] Friability is another common property that can be used to assess the durability of tablets and their tendency to break into small pieces under light compression or frictional contact. <1216> Chapter "Tablet Friability" (USP35-NF30, Chapter <1216> Friability, dated May 1, 2012) describes a method and test instrument (friability tester) for measuring friability. In brief, a pre-weighed, compressed, uncoated tablet to be evaluated is placed in a drum with an internal diameter between 283 and 291 mm and a depth between 36 and 40 mm. The drum is made of a transparent synthetic polymer, has a polished inner surface, and is subjected to a minimum static load. The drum is connected to the horizontal axis of a device rotating at 25 ± 1 rpm (rpm), and the enclosed tablet is turned over by a curved protrusion (internal diameter between 75.5 and 85.5 mm) extending from the middle of the drum to the outer wall in the drum body. The compressed tablet is tumbled in the drum for a fixed number of revolutions, for example, a total of 100 or 200 revolutions. The tablet is then removed from the drum, weighed, and inspected for cracks, ruptures, or fractures. Tablet friability refers to the percentage of mass loss of the tablet during the crushing process.

[0169] In some embodiments, the naproxen sodium tablet has a friability of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, or at least 0.5%, as determined by the USP friability test after 200 revolutions. In other embodiments, the naproxen sodium tablet has a friability of less than or equal to 1%, less than or equal to 0.9%, less than or equal to 0.8%, less than or equal to 0.7%, less than or equal to 0.6%, or less than or equal to 0.5%, as determined by the USP friability test after 200 revolutions. In certain embodiments, the naproxen sodium tablet has a friability of 0.1% to 1%, 0.1% to 0.9%, 0.1% to 0.7%, 0.1% to 0.5%, 0.3% to 1%, 0.3% to 0.9%, 0.3% to 0.7%, 0.3% to 0.5%, 0.5% to 1%, 0.5% to 0.9%, or 0.5% to 0.7%, as determined by the USP friability test after 200 revolutions.

[0170] Composite oral bilayer tablets containing roller-compacted naproxen sodium granules

[0171] In yet another aspect, provided herein are composite bi-layer oral tablets comprising roller-compacted granules comprising naproxen sodium and one or more other active pharmaceutical ingredients. Suitable other active pharmaceutical ingredients that may be combined with the roller-compacted granules comprising naproxen sodium may include, but are not limited to, acetaminophen, phenylephrine, pseudoephedrine, doxylamine, dextromethorphan, and / or guaifenesin, or any pharmaceutically acceptable salts thereof. In one aspect, provided herein are bi-layer oral tablets comprising roller-compacted granules comprising naproxen sodium and acetaminophen.

[0172] As described above, oral tablets containing granules comprising naproxen sodium can be combined with one or more other active pharmaceutical ingredients to provide a pharmaceutical complex dosage form, wherein naproxen sodium can be one such ingredient. For example, acetaminophen is an antipyretic and analgesic drug that, based on its onset of efficacy and half-life, may be suitable as a supplemental active ingredient for naproxen sodium.

[0173] Surprisingly, it was observed that a bilayer tablet construction combining roller-compacted granules of naproxen sodium in one layer with acetaminophen as the other active ingredient in a separate secondary layer had a significantly shorter disintegration time compared to a control monolayer tablet comprising naproxen sodium alone or a monolayer tablet comprising naproxen sodium and acetaminophen.

[0174] The primary (or naproxen sodium) layer of a bilayer tablet

[0175] In some embodiments, the bilayer naproxen sodium tablet comprises a primary layer (or naproxen sodium layer), wherein the primary (or naproxen sodium) layer comprises granules comprising naproxen sodium. The intragranular composition of the roller-compacted granules comprising naproxen sodium can be used for the granules used in the bilayer naproxen sodium tablet relative to the intragranular excipients and amounts described herein.

[0176] In some embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, and sodium starch glycolate. In other embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, sodium stearyl fumarate, and sodium starch glycolate. In some embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, magnesium stearate, and sodium starch glycolate. In still other embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, sodium stearyl fumarate, and sodium starch glycolate. In some embodiments, the roller-compacted granules comprise naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, magnesium stearate, and sodium starch glycolate.

[0177] In yet other embodiments, the bilayer naproxen sodium tablet comprises a combination of mannitol, colloidal silicon dioxide, stearic acid, and sodium starch glycolate as an intragranular excipient. In some embodiments, the bilayer naproxen sodium tablet comprises a combination of mannitol, colloidal silicon dioxide, sodium stearyl fumarate, and sodium starch glycolate as an intragranular excipient. In other embodiments, the bilayer naproxen sodium tablet comprises a combination of mannitol, colloidal silicon dioxide, stearic acid, sodium stearyl fumarate, and sodium starch glycolate as an intragranular excipient. In other embodiments, the bilayer naproxen sodium tablet comprises a combination of mannitol, colloidal silicon dioxide, stearic acid, magnesium stearate, and sodium starch glycolate as an intragranular excipient.

[0178] In some embodiments, the bilayer naproxen sodium tablet comprises at least 50 mg or at least 100 mg of naproxen sodium. In other embodiments, the bilayer naproxen sodium tablet comprises less than or equal to 300 mg, less than or equal to 250 mg, less than or equal to 200 mg, or less than or equal to 150 mg of naproxen sodium. In some embodiments, the bilayer naproxen sodium tablet comprises 50 mg to 300 mg, 50 mg to 250 mg, 50 mg to 200 mg, 50 mg to 150 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, 150 mg to 300 mg, 150 mg to 250 mg, 150 mg to 200 mg, 200 mg to 300 mg, 200 mg to 250 mg, or 250 mg to 300 mg of naproxen sodium. In certain embodiments, the bilayer naproxen sodium tablet comprises 100 mg, 110 mg, 150 mg, 200 mg, 220 mg, 250 mg, or 300 mg of naproxen sodium. In certain other embodiments, the bilayer naproxen sodium tablet comprises 110 mg or 150 mg of naproxen sodium.

[0179] In some embodiments, the primary (or naproxen sodium) layer comprises at least 10% w / w, at least 12% w / w, at least 15% w / w, at least 17% w / w of naproxen sodium, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the primary (or naproxen sodium) layer comprises less than or equal to 30% w / w, less than or equal to 27% w / w, less than or equal to 25% w / w, or less than or equal to 22% w / w of naproxen sodium, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the primary (or naproxen sodium) layer comprises 10-30% w / w, 10-27% w / w, 10-25% w / w, 10-22% w / w, 10-20% w / w, 10-17% w / w, 10-15% w / w, 10-12% w / w, 12-30% w / w, 12-27% w / w, 12-25% w / w, 12-22% w / w, 12-20% w / w, 12-17% w / w, 12-15% w / w, 15-30% w / w, 15-27% w / w, 15-25% w / w, 15-22% w / w, 15-20% w / w, 15-17% w / w, 17-30% w / w, w / w, 17-27% w / w, 17-25% w / w, 17-22% w / w, 17-20% w / w, 20-30% w / w, 20-27% w / w, 20-25% w / w, 20-22% w / w, 22-30% w / w, 22-27% w / w, 22-25% Naproxen sodium w / w, 25-30% w / w, 25-27% w / w or 27-30% w / w.

[0180] In some embodiments, the primary (or naproxen sodium) layer of the bilayer tablet comprises extragranular excipients including, but not limited to, lubricants, glidants, binders, and superdisintegrants.

[0181] In some embodiments, the primary (or naproxen sodium) layer comprises one or more extragranular lubricants. In some embodiments, the one or more extragranular lubricants include stearic acid, sodium stearyl fumarate, magnesium stearate, or any combination thereof. In some embodiments, the primary (or naproxen sodium) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular lubricant, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the primary (or naproxen sodium) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of extragranular lubricant, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the primary (or naproxen sodium) layer comprises 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of extragranular lubricant, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the primary (or naproxen sodium) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular magnesium stearate, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the primary (or naproxen sodium) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of extragranular magnesium stearate, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the primary (or naproxen sodium) layer comprises 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of extragranular magnesium stearate, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the primary (or naproxen sodium) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular stearic acid, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the primary (or naproxen sodium) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of extragranular stearic acid, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the primary (or naproxen sodium) layer comprises 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of extragranular stearic acid based on the total weight of the bi-layer naproxen sodium tablet.

[0182] In some embodiments, the primary (or naproxen sodium) layer comprises one or more glidants. In some embodiments, the primary (or naproxen sodium) layer comprises extragranular colloidal silicon dioxide. In some embodiments, the primary (or naproxen sodium) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular colloidal silicon dioxide, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the primary (or naproxen sodium) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of extragranular colloidal silicon dioxide, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the primary (or naproxen sodium) layer comprises 0.1-5% w / w, 0.1-2% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-5% w / w, or 1-2% w / w of extragranular colloidal silicon dioxide, based on the total weight of the bilayer naproxen sodium tablet.

[0183] In some embodiments, the primary (or naproxen sodium) layer comprises one or more binders. Binders may be included in the primary (or naproxen sodium) layer to help maintain adhesion between the granules and other extragranular excipients in the same layer. Suitable binders may include, but are not limited to, starch or starch derivatives (e.g., partially pregelatinized starch) or any combination thereof. In some embodiments, the primary (or naproxen sodium) layer comprises starch and / or partially pregelatinized starch. In some embodiments, the primary (or naproxen sodium) layer comprises starch. In some embodiments, the primary (or naproxen sodium) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular starch, based on the total weight of the double-layer naproxen sodium tablet. In other embodiments, the primary (or naproxen sodium) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of extragranular starch, based on the total weight of the double-layer naproxen sodium tablet. In certain embodiments, the primary (or naproxen sodium) layer comprises 0.1-5% w / w, 0.1-2% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-5% w / w, or 1-2% w / w of extragranular starch, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the primary (or naproxen sodium) layer comprises partially pregelatinized starch. In some embodiments, the primary (or naproxen sodium) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular partially pregelatinized starch, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the primary (or naproxen sodium) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of extragranular partially pregelatinized starch, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the primary (or naproxen sodium) layer comprises 0.1-5% w / w, 0.1-2% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-5% w / w, or 1-2% w / w of extragranular partially pregelatinized starch based on the total weight of the bi-layer naproxen sodium tablet.

[0184] In other embodiments, the primary (or naproxen sodium) layer comprises one or more superdisintegrants as extragranular excipients. In some embodiments, the primary (or naproxen sodium) layer in the double-layer naproxen sodium tablet comprises microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), or other cellulose derivatives. In some embodiments, the primary (or naproxen sodium) layer comprises croscarmellose sodium. In some embodiments, the primary (or naproxen sodium) layer comprises an extragranular superdisintegrant. In some embodiments, the primary (or naproxen sodium) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of the extragranular superdisintegrant, based on the total weight of the double-layer naproxen sodium tablet. In other embodiments, the primary (or naproxen sodium) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of the extragranular superdisintegrant, based on the total weight of the double-layer naproxen sodium tablet. In certain embodiments, the primary (or naproxen sodium) layer comprises 0.1-5% w / w, 0.1-2% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-5% w / w, or 1-2% w / w of an extragranular superdisintegrant, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the primary (or naproxen sodium) layer comprises extragranular croscarmellose sodium. In some embodiments, the primary (or naproxen sodium) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of extragranular croscarmellose sodium, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the primary (or naproxen sodium) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of extragranular croscarmellose sodium, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the primary (or naproxen sodium) layer comprises 0.1-5% w / w, 0.1-2% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-5% w / w, or 1-2% w / w of extragranular croscarmellose sodium, based on the total weight of the bi-layer naproxen sodium tablet.

[0185] In some embodiments, the primary (or naproxen sodium) layer comprises a colorant.

[0186] Secondary (or acetaminophen) layer of a bilayer tablet

[0187] In some embodiments, the bilayer naproxen sodium tablets provided herein comprise a secondary layer comprising one or more other active pharmaceutical ingredients. In some embodiments, the secondary layer may or may not further comprise naproxen sodium. In some embodiments, the secondary layer comprises naproxen sodium. In other embodiments, the secondary layer does not comprise naproxen sodium.

[0188] In some embodiments, the secondary layer comprises one or more other active pharmaceutical ingredients, wherein the one or more other active pharmaceutical ingredients include acetaminophen. In some embodiments where the secondary layer comprises acetaminophen, the secondary layer may also be referred to as an acetaminophen layer.

[0189] In some embodiments where the secondary layer comprises acetaminophen, the bilayer naproxen sodium tablet comprises at least 50 mg, at least 100 mg, at least 200 mg, or at least 300 mg of acetaminophen. In other embodiments, the bilayer naproxen sodium tablet comprises less than or equal to 500 mg, or less than or equal to 400 mg of acetaminophen. In some embodiments, the bilayer naproxen sodium tablet comprises 50 mg to 500 mg, 50 mg to 400 mg, 50 mg to 325 mg, 50 mg to 200 mg, 50 mg to 100 mg, 100 mg to 500 mg, 100 mg to 400 mg, 100 mg to 325 mg, 100 mg to 200 mg, 200 mg to 500 mg, 200 mg to 400 mg, 200 mg to 325 mg, 325 mg to 500 mg, 325 mg to 400 mg, or 400 mg to 500 mg of acetaminophen. In certain embodiments, the bilayer naproxen sodium tablet comprises 100 mg, 250 mg, 325 mg, or 500 mg of acetaminophen. In certain other embodiments, the bilayer naproxen sodium tablet comprises 325 mg of acetaminophen.

[0190] In some embodiments, the secondary (or acetaminophen) layer comprises at least 45% w / w, at least 47% w / w, at least 50% w / w, at least 52% w / w, or at least 55% w / w acetaminophen, based on the total weight of the bi-layer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 70% w / w, less than or equal to 65% w / w, less than or equal to 60% w / w, or less than or equal to 57% w / w acetaminophen, based on the total weight of the bi-layer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises 45-70% w / w, 45-65% w / w, 45-60% w / w, 45-57% w / w, 45-55% w / w, 45-52% w / w, 45-50% w / w, 45-47% w / w, 47-70% w / w, 47-65% w / w, 47-60% w / w, 47-57% w / w, 47-55% w / w, 47-52% w / w, 47-50% w / w, 50-70% w / w, 50-65% w / w, 50-60% w / w, 50-57% w / w, 50-55% w / w, 50-52% w / w, 52-70% w / w, w / w, 52-65% w / w, 52-60% w / w, 52-57% w / w, 52-55% w / w, 55-70% w / w, 55-65% w / w, 55-60% w / w, 55-57% w / w, 57-70% w / w, 57-65% w / w, 57-60% Acetaminophen w / w, 60-70% w / w, 60-65% w / w or 65-70% w / w.

[0191] It will be appreciated that such other active pharmaceutical ingredients may be suitable for use as one or more other active pharmaceutical ingredients in the secondary layer of the bilayer naproxen sodium tablet, in place of or in combination with acetaminophen. It will also be appreciated that active pharmaceutical ingredients that exhibit a similar disintegration mechanism to acetaminophen or that exhibit a relatively faster disintegration time than that observed for the acetaminophen layer described herein may also provide a final bilayer naproxen sodium tablet having a shorter disintegration time.

[0192] In some embodiments, the secondary (or acetaminophen) layer comprises one or more adhesives. An adhesive may be included in the secondary (or acetaminophen) layer to help maintain adhesion between the active pharmaceutical ingredient (e.g., acetaminophen) and the excipients in the same layer. Suitable adhesives may include, but are not limited to, starch or a starch derivative (e.g., partially pregelatinized starch) or any combination thereof.

[0193] In some embodiments, the secondary (or acetaminophen) layer comprises starch. In some embodiments, the secondary (or acetaminophen) layer comprises at least 2% w / w, at least 3% w / w, at least 4% w / w, or at least 5% w / w of starch, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 15% w / w, less than or equal to 12% w / w, or less than or equal to 10% w / w of starch, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises 2-15% w / w, 2-12% w / w, 2-10% w / w, 2-7% w / w, 2-5% w / w, 2-4% w / w, 2-3% w / w, 3-15% w / w, 3-12% w / w, 3-10% w / w, 3-7% w / w, 3-5% w / w, 3-4% w / w, 4-15% w / w, 4-12% w / w, 4-10% w / w, 4-7% w / w, 4-5% w / w, 5-15% w / w, 5-12% w / w, 5-10% w / w, 5-7% w / w, 7-15% w / w, 7-12% w / w, 7-10% w / w, w / w, 10-15% w / w, 10-12% w / w or 12-15% w / w starch.

[0194] In some embodiments, the secondary (or acetaminophen) layer comprises partially pregelatinized starch. In some embodiments, the secondary (or acetaminophen) layer comprises at least 2% w / w, at least 3% w / w, at least 4% w / w, or at least 5% w / w of partially pregelatinized starch, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 15% w / w, less than or equal to 12% w / w, or less than or equal to 10% w / w of partially pregelatinized starch, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises 2-15% w / w, 2-12% w / w, 2-10% w / w, 2-7% w / w, 2-5% w / w, 2-4% w / w, 2-3% w / w, 3-15% w / w, 3-12% w / w, 3-10% w / w, 3-7% w / w, 3-5% w / w, 3-4% w / w, 4-15% w / w, 4-12% w / w, 4-10% w / w, 4-7% w / w, 4-5% w / w, 5-15% w / w, 5-12% w / w, 5-10% w / w, 5-7% w / w, 7-15% w / w, 7-12% w / w, 7-10% w / w, w / w, 10-15% w / w, 10-12% w / w or 12-15% w / w partially pregelatinized starch.

[0195] In some embodiments, the secondary (or acetaminophen) layer comprises starch and partially pregelatinized starch. In some embodiments, the secondary (or acetaminophen) layer comprises at least 2% w / w, at least 3% w / w, at least 4% w / w, or at least 5% w / w of starch and partially pregelatinized starch, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 15% w / w, less than or equal to 12% w / w, or less than or equal to 10% w / w of starch and partially pregelatinized starch, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises 2-15% w / w, 2-12% w / w, 2-10% w / w, 2-7% w / w, 2-5% w / w, 2-4% w / w, 2-3% w / w, 3-15% w / w, 3-12% w / w, 3-10% w / w, 3-7% w / w, 3-5% w / w, 3-4% w / w, 4-15% w / w, 4-12% w / w, 4-10% w / w, 4-7% w / w, 4-5% w / w, 5-15% w / w, 5-12% w / w, 5-10% w / w, 5-7% w / w, 7-15% w / w, 7-12% w / w, 7-10% w / w, w / w, 10-15% w / w, 10-12% w / w or 12-15% w / w starch and partially pregelatinized starch.

[0196] As described herein, acetaminophen exhibits disintegration behavior that is directly related to the presence of disintegrants and / or superdisintegrants. In the bilayer naproxen sodium tablets described herein, the incorporation of a disintegrant in the secondary (acetaminophen) layer significantly contributes to the rapid disintegration time observed for the bilayer tablet as a whole. In other embodiments, the secondary (or acetaminophen) layer comprises one or more superdisintegrants. In some embodiments, the secondary (or acetaminophen) layer comprises at least 1% w / w, at least 2% w / w, or at least 3% w / w of superdisintegrant, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 6% w / w, less than or equal to 5% w / w, or less than or equal to 4% w / w of superdisintegrant, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises 1-6% w / w, 1-5% w / w, 1-4% w / w, 1-3% w / w, 1-2% w / w, 2-6% w / w, 2-5% w / w, 2-4% w / w, 2-3% w / w, 3-6% w / w, 3-5% w / w, 3-4% w / w, 4-6% w / w, 4-5% w / w, or 5-6% w / w of a superdisintegrant, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises at least 1% w / w, at least 2% w / w, or at least 3% w / w of croscarmellose sodium, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 6% w / w, less than or equal to 5% w / w, or less than or equal to 4% w / w of croscarmellose sodium, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises 1-6% w / w, 1-5% w / w, 1-4% w / w, 1-3% w / w, 1-2% w / w, 2-6% w / w, 2-5% w / w, 2-4% w / w, 2-3% w / w, 3-6% w / w, 3-5% w / w, 3-4% w / w, 4-6% w / w, 4-5% w / w, or 5-6% w / w of croscarmellose sodium, based on the total weight of the bilayer naproxen sodium tablet.

[0197] In some embodiments, the secondary (or acetaminophen) layer comprises one or more glidants. In some embodiments, the secondary (or acetaminophen) layer comprises colloidal silicon dioxide. In some embodiments, the secondary (or acetaminophen) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of colloidal silicon dioxide, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of colloidal silicon dioxide, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the secondary (or acetaminophen) layer comprises 0.1-5% w / w, 0.1-2% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-5% w / w, or 1-2% w / w of colloidal silicon dioxide, based on the total weight of the bilayer naproxen sodium tablet.

[0198] In some embodiments, the secondary (or acetaminophen) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of lubricant, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of lubricant, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the secondary (or acetaminophen) layer comprises 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of lubricant, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of magnesium stearate, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of magnesium stearate, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the secondary (or acetaminophen) layer comprises 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of magnesium stearate, based on the total weight of the bilayer naproxen sodium tablet. In some embodiments, the secondary (or acetaminophen) layer comprises at least 0.1% w / w, at least 0.5% w / w, or at least 1% w / w of stearic acid, based on the total weight of the bilayer naproxen sodium tablet. In other embodiments, the secondary (or acetaminophen) layer comprises less than or equal to 5% w / w, or less than or equal to 2% w / w of stearic acid, based on the total weight of the bilayer naproxen sodium tablet. In certain embodiments, the secondary (or acetaminophen) layer comprises 0.1-10% w / w, 0.1-5% w / w, 0.1-2% w / w, 0.5-10% w / w, 0.5-5% w / w, 0.5-2% w / w, 1-10% w / w, 1-5% w / w, or 1-2% w / w of stearic acid, based on the total weight of the bilayer naproxen sodium tablet.

[0199] In some embodiments, the secondary (or acetaminophen) layer comprises a colorant.

[0200] In some embodiments, the one or more extragranular lubricants in the primary (or naproxen sodium) layer are the same as the one or more lubricants in the secondary (or acetaminophen) layer. In some embodiments, the one or more extragranular superdisintegrants in the primary (or naproxen sodium) layer are the same as the one or more superdisintegrants in the secondary (or acetaminophen) layer.

[0201] In some embodiments, the bilayer naproxen sodium tablet further comprises a film coating. In some variations, the film coating comprises polyvinyl alcohol. In certain embodiments, the film coating is an immediate-release coating. In other embodiments, the film coating further comprises a colorant, a flavoring, or a combination thereof.

[0202] Dissolution, disintegration and other characteristics of bilayer tablets

[0203] In some embodiments, the bilayer naproxen sodium tablets provided herein can be characterized by their disintegration and / or dissolution properties. As described herein, the bilayer naproxen sodium tablets have unexpectedly short disintegration times.

[0204] The disintegration time of the bilayer naproxen sodium tablet of the present invention can be determined by the USP disintegration test performed in water at 37°C ± 0.5°C using a basket assembly with discs. For example, in some embodiments, the disintegration time of the bilayer naproxen sodium tablet is less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, or less than about 4 minutes, as determined by the USP disintegration test performed in water at 37°C ± 0.5°C using a basket assembly with discs. In other embodiments, the disintegration time of the bilayer naproxen sodium tablet is at least about 1 minute, at least about 2 minutes, or at least about 3 minutes, as determined by the USP disintegration test performed in water at 37°C ± 0.5°C using a basket assembly with discs. In certain embodiments, the disintegration time of the bilayer naproxen sodium tablet is 1 minute to 8 minutes, 1 minute to 7 minutes, 1 minute to 6 minutes, 1 minute to 5 minutes, 1 minute to 4 minutes, 2 minutes to 8 minutes, 2 minutes to 7 minutes, 2 minutes to 6 minutes, 2 minutes to 5 minutes, 2 minutes to 4 minutes, 3 minutes to 8 minutes, 3 minutes to 7 minutes, 3 minutes to 6 minutes, 3 minutes to 5 minutes, 3 minutes to 4 minutes as determined by the USP disintegration test performed in water at 37°C ± 0.5°C using a basket assembly with disks. In other embodiments, the bilayer naproxen sodium tablet is not an orally disintegrating tablet.

[0205] The bilayer naproxen sodium tablet can also be characterized by its dissolution profile as determined by the USP Apparatus-2 dissolution test as described herein. As described above for the single-layer naproxen sodium tablet, the bilayer naproxen sodium tablet can also be characterized by a number of properties related to its physical durability and structural integrity.

[0206] In some embodiments, the hardness of the bilayer naproxen sodium tablet is at least 2 kilograms force (kp), at least 3 kp, at least 4 kp, at least 5 kp, or at least 6 kp, as determined by a tablet tester according to the USP Tablet Breaking Force Test. In other embodiments, the hardness of the bilayer naproxen sodium tablet is less than or equal to 18 kp, less than or equal to 17 kp, less than or equal to 16 kp, less than or equal to 15 kp, less than or equal to 14 kp, less than or equal to 13 kp, or less than or equal to 12 kp, as determined by a tablet tester according to the USP Tablet Breaking Force Test. In certain embodiments, the hardness of the bilayer naproxen sodium tablet is 2 to 18 kp, 2 to 16 kp, 2 to 14 kp, 2 to 12 kp, 4 to 18 kp, 4 to 16 kp, 4 to 14 kp, 4 to 12 kp, 6 to 18 kp, 6 to 16 kp, 6 to 14 kp, or 6 to 12 kp as determined by a tablet tester according to the USP Tablet Breaking Force Test.

[0207] In some embodiments, the bilayer naproxen sodium tablet has a friability of at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, or at least 0.5%, as determined by the USP friability test after 200 revolutions. In other embodiments, the bilayer naproxen sodium tablet has a friability of less than or equal to 1%, less than or equal to 0.9%, less than or equal to 0.8%, less than or equal to 0.7%, less than or equal to 0.6%, or less than or equal to 0.5%, as determined by the USP friability test after 200 revolutions. In certain embodiments, the bilayer naproxen sodium tablet has a friability of 0.1% to 1%, 0.1% to 0.9%, 0.1% to 0.7%, 0.1% to 0.5%, 0.3% to 1%, 0.3% to 0.9%, 0.3% to 0.7%, 0.3% to 0.5%, 0.5% to 1%, 0.5% to 0.9%, or 0.5% to 0.7%, as determined by the USP friability test after 200 revolutions.

[0208] Preparation method of oral tablets

[0209] As described herein, the oral tablets of the present invention, more particularly the naproxen sodium tablets of the present invention, are prepared by dry granulation rather than wet granulation. In one aspect, the present invention provides a method for preparing the oral tablets described herein comprising roller-compacted granules.

[0210] Granulation is a process by which individual powder ingredients are combined and converted into preformed aggregates or agglomerated particles (granules) containing two or more powder components with a well-defined size distribution to help ensure consistency during tableting and / or other mechanical processing later in the manufacturing process. Roller compaction dry granulation is a process in which a mixture of active pharmaceutical ingredients and dry excipients is passed through a pair of roller compactors to compress the powders into sheets or ribbons, which are then milled into granules. Following granulation, the granules are combined with other excipients and compressed into tablet form. Dry granulation does not require the use of a "wet" granulation liquid to combine the excipients during the granulation stage, so there is no need for a downstream drying step to remove residual moisture from the granulation liquid.

[0211] Dry granulation can be a complex process due to the variety of excipients that can be mixed with the active pharmaceutical ingredient, as well as the different adjustment parameters during roller compaction that can affect the final product properties. For example, the choice of excipient, roller speed, roller gap / intrusion angle, and feed rate are several variables that can affect the density of the compacted ribbon. The production of consistent, uniform ribbons with a specific ribbon density can affect the ability to obtain reproducible granules (size distribution, porosity). The reproducibility of the granulation production process can further affect the uniformity, compressibility, and compactability of the materials used in downstream mixing and tableting processes, thereby affecting the dissolution profile, disintegration time, and hardness of the tablets. Therefore, controlling process parameters and other variables in methods involving dry granulation can be important to ensure tablet quality and reproducibility.

[0212] The naproxen sodium formulations containing the pharmaceutically acceptable excipients described herein were found to be uniquely compatible with roller compaction and tableting in terms of flowability, compressibility, and minimal material loss (due to sticking / picking). Furthermore, the composition of the intragranular excipients was found to be readily formable under a range of process parameters while still producing roller-compacted granules with consistent porosity and particle size distribution, and ultimately, highly reproducible naproxen sodium tablets with enhanced dissolution and disintegration properties.

[0213] In one aspect, provided herein is a method for preparing naproxen sodium tablets, the method comprising: combining naproxen sodium, mannitol, colloidal silicon dioxide, one or more lubricants, and one or more superdisintegrants to obtain a blended mixture; compacting the blended mixture by roller compaction to form ribbons; milling the ribbons to obtain granules; combining the granules with mannitol, one or more lubricants, one or more superdisintegrants, and optionally colloidal silicon dioxide to obtain a tableting mixture; and compressing the tableting mixture to obtain naproxen sodium tablets.

[0214] refer to Figure 1, process 100 is an exemplary process for preparing naproxen sodium tablets. In step 102, naproxen sodium is combined with intragranular excipients (e.g., mannitol, colloidal silicon dioxide, stearic acid, and sodium starch glycolate) to form a blended mixture. The naproxen sodium and intragranular excipients are provided in dry powder form. The resulting blended mixture is processed in steps 104 and 106 to produce granulated naproxen sodium. In step 104, the blended mixture comprising naproxen sodium and intragranular excipients is compacted by roller compaction to produce ribbons. In step 106, the ribbons are milled to produce roller-compacted granules. Then, in step 108, the roller-compacted granules are combined with extragranular excipients (e.g., mannitol, sodium starch glycolate, and magnesium stearate, and optionally colloidal silicon dioxide) to produce a tableting mixture. Then, in step 110, the tableting mixture is compressed to produce naproxen sodium tablets.

[0215] In another aspect, provided herein is a method for preparing naproxen sodium tablets, the method comprising: combining naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, and sodium starch glycolate to provide a blended mixture; compacting the blended mixture by roller compaction to form ribbons; milling the ribbons to provide granules; combining the granules with mannitol, sodium starch glycolate, magnesium stearate, and optionally colloidal silicon dioxide to provide a tableting mixture; and compressing the tableting mixture to provide naproxen sodium tablets.

[0216] Notably, the components for naproxen sodium tablets described herein are compatible with dry granulation by roller compaction and subsequent compression to provide tablets with enhanced dissolution and minimal material loss throughout the manufacturing process. The specific selection of intragranular and extragranular excipients for the naproxen sodium tablets described herein also surprisingly yields tablets with an enhanced dissolution profile that remains consistent even when processing parameters are adjusted.

[0217] For example, the step of compacting the blended mixture by roller compaction typically produces a roller-compacted ribbon whose properties vary depending on the conditions under which the blended mixture is compacted. Process parameters for roller compaction may include, but are not limited to, the feed rate of the blended mixture into the roller compactor, the type of rollers used (smooth rollers and / or serrated rollers), roller speed, roller gap, and roller pressure. Properties of the resulting ribbon affected by these variables include, but are not limited to, porosity, solid fraction, hardness, and / or thickness.

[0218] After the blended mixture is prepared, the blended mixture is roller compacted as described in the previous method. Figure 1, step 104, in some embodiments, the blended mixture is compacted by roller compaction under variable process settings, the variable process settings including, for example, the applied pressure of the rollers (e.g., 18 to 30 bar), the roller speed (e.g., 4 to 9 rpm), and the roller gap (e.g., 1.0 to 4.0 mm).

[0219] The applied pressure, roller speed, and roller gap can all affect the hardness, thickness, and porosity of the resulting roller-compacted material. In some embodiments of the foregoing methods, the blended mixture is compacted by roller compacting at an applied force of at least 10 bar, at least 15 bar, or at least 18 bar. In other embodiments, the blended mixture is compacted by roller compacting at an applied force of less than or equal to 40 bar, less than or equal to 35 bar, or less than or equal to 30 bar. In certain embodiments, the blended mixture is compacted by roller compacting at an applied force of 10 to 40 bar, 10 to 35 bar, 10 to 30 bar, 15 to 40 bar, 15 to 35 bar, 15 to 30 bar, 18 to 40 bar, 18 to 35 bar, or 18 to 30 bar.

[0220] In some embodiments, the blended mixture is compacted by roller compaction at a roller speed of at least 1 rpm, at least 2 rpm, at least 3 rpm, or at least 4 rpm. In other embodiments, the blended mixture is compacted by roller compaction at a roller speed of less than or equal to 12 rpm, less than or equal to 11 rpm, less than or equal to 10 rpm, or less than or equal to 9 rpm. In certain embodiments, the blended mixture is compacted by roller compacting at a roller speed of 1 rpm to 12 rpm, 1 rpm to 11 rpm, 1 rpm to 10 rpm, 1 rpm to 9 rpm, 2 rpm to 12 rpm, 2 rpm to 11 rpm, 2 rpm to 10 rpm, 2 rpm to 9 rpm, 3 rpm to 12 rpm, 3 rpm to 11 rpm, 3 rpm to 10 rpm, 3 rpm to 9 rpm, 4 rpm to 12 rpm, 4 rpm to 11 rpm, 4 rpm to 10 rpm, or 4 rpm to 9 rpm.

[0221] In yet other embodiments, the blended mixture is compacted by roller compaction at a roller gap of at least 0.5 mm, or at least 1 mm, or at least 1.5 mm. In yet other embodiments, the blended mixture is compacted by roller compaction at a roller gap of less than or equal to 6 mm, less than or equal to 5 mm, or less than or equal to 4 mm. In certain embodiments, the blended mixture is compacted by roller compaction at a roller gap of 0.5 to 6 mm, 0.5 to 5 mm, 0.5 to 4 mm, 1 to 6 mm, 1 to 5 mm, 1 to 4 mm, 1.5 to 6 mm, 1.5 to 5 mm, or 1.5 to 4 mm.

[0222] In addition to the above roller parameters, it should be recognized that the blended mixture can also be compacted by roller compaction using smooth and / or serrated rollers. In some embodiments, the rollers used to roller compact the blended mixture are smooth rollers, serrated rollers, or a combination thereof.

[0223] It should be understood that roller compaction of the powder mixture in step 104 results in a compacted or densified material whose shape can vary depending on the roller surface profile. In some embodiments, the compacted or densified powder mixture can form a rectangular sheet, which can be referred to as a ribbon or roller-compacted ribbon. The resulting ribbon can be characterized, for example, by solid fraction, porosity, hardness, and / or thickness.

[0224] In some embodiments, the roller-compacted ribbons can be characterized by their solid fraction (or relative density). The solid fraction is a measure of the percentage of a material's volume that is solid material rather than voids or pores. The solid fraction can be calculated as the material envelope density (P e ) and the true density of the material (P o ) ratio (SF = P e / P o ). Envelope density is measured as the displacement of a solid medium that conforms to the surface of the material under investigation but does not insert into voids or pores; true density is measured by gas displacement and reflects the solid volume of the material, including voids and pores. In some embodiments, the solid phase fraction of the roller-compacted ribbon is at least 0.4, at least 0.45, at least 0.5, at least 0.55, or at least 0.6. In other embodiments, the solid phase fraction of the roller-compacted ribbon is less than or equal to 0.9, less than or equal to 0.85, less than or equal to 0.8, less than or equal to 0.75, or less than or equal to 0.7. In certain embodiments, the solid phase fraction of the roller-compacted ribbon is 0.4 to 0.9, 0.4 to 0.8, 0.4 to 0.7, 0.5 to 0.9, 0.5 to 0.8, 0.5 to 0.7, 0.6 to 0.9, 0.6 to 0.8, or 0.6 to 0.7.

[0225] The roller-compacted ribbon of the above method can also be characterized by its porosity. Porosity is a measure of the void space within a material (space not occupied by solids). Porosity can be calculated from the solid fraction (SF) using the following equation: Porosity = [1-SF] x 100%. In some embodiments, the porosity of the roller-compacted ribbon is at least 10%, at least 15%, at least 20%, at least 25%, or at least 30%. In other embodiments, the porosity of the roller-compacted ribbon is less than or equal to 60%, less than or equal to 55%, less than or equal to 50%, less than or equal to 45%, or less than or equal to 40%. In certain embodiments, the porosity of the roller-compacted ribbon is 10% to 60%, 10% to 50%, 10% to 40%, 20% to 60%, 20% to 50%, 20% to 40%, 30% to 60%, 30% to 50%, or 30% to 40%.

[0226] The roller-compacted ribbon can also be characterized by its hardness and / or thickness, which can be determined by methods known in the art. The thickness of the roller-compacted ribbon can be determined by measurement with a vernier caliper. The thickness of the ribbon can be measured using a correspondingly configured hardness measuring instrument, utilizing snap, bend, and / or break test methods. For example, a suitable method for measuring hardness may involve an instrument with a three-point bending setup or configuration. In a three-point setup, a section of ribbon to be evaluated is placed on top of two supporting "fulcrums" at either end of the ribbon segment; a third, central "fulcrum" is positioned above the ribbon segment and manipulated to induce bending / breaking by applying a downward force.

[0227] It will be appreciated that the roller compacted ribbon of the above-described method may have a combination of one or more of the above-described features.

[0228] After the roller-compacted ribbon is produced, the dry granulation process is completed by a grinding step to convert the ribbon into a plurality of roller-compacted granules. In some embodiments, the ribbon is ground at a grinding speed of at least 40 rpm, 60 rpm, 80 rpm, or 100 rpm. In other embodiments, the ribbon is ground at a grinding speed of less than or equal to 160 rpm, less than or equal to 140 rpm, less than or equal to 120 rpm, or less than or equal to 100 rpm. In certain embodiments, the ribbon is milled at a milling speed of 40 to 160 rpm, 40 to 140 rpm, 40 to 120 rpm, 40 to 100 rpm, 60 to 160 rpm, 60 to 140 rpm, 60 to 120 rpm, 60 to 100 rpm, 80 to 160 rpm, 80 to 140 rpm, 80 to 120 rpm, 80 to 100 rpm, 100 to 160 rpm, 100 to 140 rpm, or 100 to 120 rpm.

[0229] In some embodiments of the aforementioned methods, the method further comprises screening the roller-compacted particles to obtain roller-compacted particles having a specific particle size distribution. However, in the methods of the present invention, the roller-compacted particles produced by the milling step are observed to have consistent particle size distribution, bulk density, and tap density over a range of roller compaction parameters and / or milling speeds.

[0230] As the name implies, dry granulation does not use a "wet" granulation fluid, such as water or ethanol, to help mix and compact the active ingredient and excipients to form granules. Therefore, roller-compacted granules do not require a drying step to remove excess water before tableting.

[0231] As described above, a particle can be characterized as a solid aggregate or agglomerated particles formed from two or more fine powder materials into a single mass. Although a particle is characterized as an aggregate, it should be understood that a particle can be characterized as a particle, and a plurality of particles can be further characterized by a particle (or particle) size distribution or other particle size attributes.

[0232] Thus, the particles prepared in this method and comprising naproxen sodium and an intragranular excipient as described herein can be characterized by their particle size properties to distinguish them from the unmixed original fine powder form of naproxen sodium and / or the intragranular excipient. In still other embodiments of the foregoing method, the particles can be characterized by their particle size properties (e.g., average particle size, particle size distribution, particle size range, etc.).

[0233] The particle size distribution of the roller-compacted particles can be determined by methods known in the art, including, for example, sieve analysis using a mechanical sieving (e.g., sequential application of a series of sieves or screen materials) or a laser diffraction particle size analyzer to quantify the amount of material within a given particle size range (i.e., mass percent distribution). In some embodiments, the roller-compacted particles have a particle size distribution such that at least 20%, at least 30%, at least 40%, or at least 50% of the particles have a particle size greater than or equal to 250 μm. In other embodiments, the roller-compacted particles have a particle size distribution such that less than or equal to 90%, less than or equal to 80%, or less than or equal to 70% of the particles have a particle size greater than or equal to 250 μm. In certain embodiments, the roller-compacted particles have a particle size distribution such that 20% to 90%, 20% to 80%, 20% to 70%, 30% to 90%, 30% to 80%, 30% to 70%, 40% to 90%, 40% to 80%, 40% to 70%, 50% to 90%, 50% to 80%, or 50% to 70% of the particles have a particle size greater than or equal to 250 μm.

[0234] In addition to particle size distribution, the bulk density and tap density of roller-compacted particles can also indicate the material's ability to settle, flow, and / or be compressible. The bulk density and tap density can be determined by methods known in the art. For example, a given mass of material can be placed in a cylindrical volumetric measuring container, allowed to settle, the volume occupied measured, and the resulting density calculated as the bulk density. The same mass of material can then be tapped using a slight mechanical force, for example, by dropping it from a specified controlled height, and the resulting density calculated as the tap density. In some embodiments, the bulk density of the roller-compacted particles is at least 0.3 g / cc, at least 0.4 g / cc, or at least 0.5 g / cc. In other embodiments, the bulk density of the roller-compacted particles is less than or equal to 0.9 g / cc, less than or equal to 0.8 g / cc, or less than or equal to 0.7 g / cc. In certain embodiments, the roller-compacted granules have a bulk density of 0.3 to 0.9 g / cc, 0.3 to 0.8 g / cc, 0.3 to 0.7 g / cc, 0.4 to 0.9 g / cc, 0.4 to 0.8 g / cc, 0.4 to 0.7 g / cc, 0.5 to 0.9 g / cc, 0.5 to 0.8 g / cc, or 0.5 to 0.7 g / cc.

[0235] In yet other embodiments, the roller-compacted granules have a tap density of at least 0.5 g / cc, at least 0.6 g / cc, at least 0.7 g / cc. In some embodiments, the roller-compacted granules have a tap density of less than or equal to 0.95 g / cc, less than or equal to 0.9 g / cc, or less than or equal to 0.8 g / cc. In certain embodiments, the roller-compacted granules have a tap density of 0.5 to 0.95 g / cc, 0.5 to 0.9 g / cc, 0.5 to 0.8 g / cc, 0.6 to 0.95 g / cc, 0.6 to 0.9 g / cc, 0.6 to 0.8 g / cc, 0.7 to 0.95 g / cc, 0.7 to 0.9 g / cc, or 0.7 to 0.8 g / cc.

[0236] The roller-compacted particles can also be characterized by their compressibility, which can be calculated as compressibility = (tap density - bulk density / tap density) x 100. In some embodiments of the above methods, the roller-compacted particles have a compressibility of at least 5%, at least 10%, or at least 15%. In other embodiments, the roller-compacted particles have a compressibility of less than or equal to 30%, less than or equal to 25%, or less than or equal to 20%. In certain embodiments, the roller-compacted particles have a compressibility of 5% to 30%, 5% to 25%, 5% to 20%, 10% to 30%, 10% to 25%, 10% to 20%, 15% to 30%, or 15% to 25%.

[0237] The tableting mixture of the above method can have many measurable characteristics, including but not limited to particle size distribution, bulk density, tap density, compressibility and / or flowability. These characteristics may affect the dissolution and disintegration characteristics of the resulting tablet. The particle size distribution, bulk density and tap density of the final tableting mixture can be determined according to the method of the above-mentioned roller compacted granules.

[0238] The particle size distribution of the tableting mixture can be determined by methods similar to those described above for evaluating the particle size distribution of roller compacted granules, for example, by sequentially applying a series of sieves or mesh materials. In some embodiments, the particle size distribution of the tableting mixture is such that at least 20%, at least 30%, or at least 40% of the granules have a particle size greater than or equal to 250 μm. In other embodiments, the particle size distribution of the tableting mixture is such that less than or equal to 90%, less than or equal to 80%, or less than or equal to 70% of the granules have a particle size greater than or equal to 250 μm. In certain embodiments, the particle size distribution of the tableting mixture is such that 20% to 90%, 20% to 80%, 20% to 70%, 30% to 90%, 30% to 80%, 30% to 70%, 40% to 90%, 40% to 80%, or 40% to 70% of the granules have a particle size greater than or equal to 250 μm.

[0239] As described above, the bulk density and tap density of the tableting mixture can be similarly measured by methods known in the art. In some embodiments, the bulk density of the tableting mixture is at least 0.3 g / cc, at least 0.4 g / cc, or at least 0.5 g / cc. In some embodiments, the bulk density of the tableting mixture is less than or equal to 0.9 g / cc, less than or equal to 0.8 g / cc, or less than or equal to 0.7 g / cc. In certain embodiments, the bulk density of the tableting mixture is 0.3 to 0.9 g / cc, 0.3 to 0.8 g / cc, 0.3 to 0.7 g / cc, 0.4 to 0.9 g / cc, 0.4 to 0.8 g / cc, 0.4 to 0.7 g / cc, 0.5 to 0.9 g / cc, 0.5 to 0.8 g / cc, or 0.5 to 0.7 g / cc.

[0240] In further embodiments, the tableting mixture has a tap density of at least 0.5 g / cc, at least 0.6 g / cc, at least 0.7 g / cc. In some embodiments, the tableting mixture has a tap density of less than or equal to 0.95 g / cc, less than or equal to 0.9 g / cc, or less than or equal to 0.8 g / cc. In certain embodiments, the tableting mixture has a tap density of 0.5 to 0.95 g / cc, 0.5 to 0.9 g / cc, 0.5 to 0.8 g / cc, 0.6 to 0.95 g / cc, 0.6 to 0.9 g / cc, 0.6 to 0.8 g / cc, 0.7 to 0.95 g / cc, 0.7 to 0.9 g / cc, or 0.7 to 0.8 g / cc.

[0241] In some embodiments of the above methods, the compressibility of the tableting mixture is at least 5%, at least 10%, or at least 15%. In some embodiments, the compressibility of the tableting mixture is less than or equal to 30%, less than or equal to 25%, or less than or equal to 20%. In certain embodiments, the compressibility of the tableting mixture is between 5% and 30%, between 5% and 25%, between 5% and 20%, between 10% and 30%, between 10% and 25%, between 10% and 20%, between 15% and 30%, or between 15% and 25%.

[0242] In the above method, the step of compressing the tableting mixture can be carried out by any suitable tablet press. In some embodiments, the compression force applied to the tableting mixture can be changed. For example, in some embodiments, the tableting mixture is compressed with a compression force of at least 6 kN, or at least 10 kN, or at least 15 kN. In other embodiments, the tableting mixture is compressed with a compression force of less than or equal to 30 kN, less than or equal to 25 kN, or less than or equal to 20 kN. In certain embodiments, the tableting mixture is compressed with a compression force of 6 to 30 kN, 6 to 25 kN, 6 to 20 kN, 10 to 30 kN, 10 to 25 kN, 10 to 20 kN, 15 to 30 kN, 15 to 25 kN or 15 to 20 kN to obtain naproxen sodium tablets.

[0243] In some embodiments of the foregoing methods, the method further comprises coating the naproxen sodium tablet to provide a coated naproxen sodium tablet.

[0244] In some embodiments, one or more steps of the foregoing methods can be performed as a continuous process or a batch process.

[0245] In yet another aspect, provided herein are methods for preparing a bilayer naproxen sodium tablet comprising granules comprising naproxen sodium and one or more other active pharmaceutical ingredients, as described herein. In some embodiments, the method for preparing a bilayer naproxen sodium tablet comprises similar intragranular excipients and similar steps as described above for preparing roller-compacted granules comprising naproxen sodium to form the primary (or naproxen sodium) layer of the bilayer tablet. The method for preparing the bilayer naproxen sodium tablet described herein also combines the preparation of the roller-compacted granules and tableting mixture for the naproxen sodium layer with the parallel preparation of one or more other active pharmaceutical agents (e.g., acetaminophen) and excipients (including a superdisintegrant) as the tableting mixture to form the secondary layer of the bilayer tablet.

[0246] In one aspect, provided herein is a method for preparing a bilayer naproxen sodium tablet, the method comprising: combining naproxen sodium, mannitol, colloidal silicon dioxide, one or more lubricants, and one or more superdisintegrants to obtain a blended mixture; compacting the blended mixture by roller compaction to form ribbons; milling the ribbons to obtain granules; combining the granules with mannitol, one or more binders, one or more lubricants, one or more superdisintegrants, and optionally colloidal silicon dioxide to obtain a primary tableting mixture; combining one or more other active pharmaceutical ingredients, colloidal silicon dioxide, one or more lubricants, one or more superdisintegrants, and optionally one or more binders or compression aids to obtain a secondary tableting mixture; and compressing the primary tableting mixture and the secondary tableting mixture to obtain a bilayer naproxen sodium tablet.

[0247] refer to Figure 4 Process 200 is an exemplary process for preparing a bilayer naproxen sodium tablet. In step 202, naproxen sodium is combined with an intragranular excipient (e.g., mannitol, colloidal silicon dioxide, stearic acid or magnesium stearate, and sodium starch glycolate) to form a blended mixture. The naproxen sodium and the intragranular excipient are provided in dry powder form. Similar to process steps 104 and 106 of process 100 described above, the resulting blended mixture is processed in steps 204 and 206 to produce granulated naproxen sodium. In step 204, the blended mixture comprising naproxen sodium and the intragranular excipient is compacted by roller compaction to form ribbons. In step 206, the ribbons are ground to produce roller-compacted granules. Then, in step 208, the roller-compacted granules are combined with extragranular excipients (e.g., mannitol, sodium starch glycolate, starch and / or partially pregelatinized starch, stearic acid or magnesium stearate, croscarmellose sodium, and optionally colloidal silicon dioxide) to produce a primary tableting mixture. In a parallel step 210, one or more other active pharmaceutical ingredients (e.g., acetaminophen), colloidal silicon dioxide, one or more lubricants, one or more superdisintegrants, and optionally one or more binders or compression aids are combined to produce a secondary tableting mixture. After the two tableting mixtures are prepared, the two tableting mixtures are transferred to a tablet press for compression. The tablet press can optionally be externally lubricated to facilitate tableting, as described in step 212. In step 214, the primary tableting mixture and the secondary tableting mixture are then compressed to produce a double-layer naproxen sodium tablet.

[0248] It should be appreciated that the exemplary process 200 may be adapted to accommodate alternative active pharmaceutical ingredients, cosolvents, and / or excipients as described herein. It should also be appreciated that in other variations, the process 200 may include other processing steps. In other variations, certain steps in the process 200 may be omitted.

[0249] In yet another aspect, provided herein is a method for preparing a naproxen sodium tablet, the method comprising: combining naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid or magnesium stearate, and sodium starch glycolate to obtain a blended mixture; compacting the blended mixture by roller compaction to form ribbons; milling the ribbons to obtain granules; combining the granules with mannitol, sodium starch glycolate, starch and / or partially pregelatinized starch, stearic acid or magnesium stearate, croscarmellose sodium, and optionally colloidal silicon dioxide to obtain a primary tableting mixture; combining acetaminophen, colloidal silicon dioxide, starch and / or partially pregelatinized starch, stearic acid or magnesium stearate, and croscarmellose sodium to obtain a secondary tableting mixture; and compressing the primary tableting mixture and the secondary tableting mixture to obtain a double-layer naproxen sodium tablet.

[0250] In some embodiments, the preparation of the roller-compacted granules of the double-layer naproxen sodium tablets described in steps 204 and 206 is similar to the preparation of the granules of the naproxen sodium tablets described in steps 104 and 106 of process 100. In addition, the characteristics of the roller-compacted granules of the double-layer naproxen sodium tablets described in steps 204 and 206 are similar to the preparation of the granules of the naproxen sodium tablets described in steps 104 and 106 of process 100.

[0251] For example, in some embodiments, the blended mixture provided in the preparation of a bilayer naproxen sodium tablet can be compacted by a tablet press under applied pressure, roller speed, and roller gap, as described herein. In some embodiments that may be combined with the preceding embodiments, the resulting roller-compacted ribbon can be characterized by its solid fraction, porosity, hardness, and / or thickness, as described herein. In yet other embodiments, the milling step of converting the ribbon material into granules can be characterized by the milling rate. In other embodiments that may be combined with any of the preceding embodiments, the roller-compacted granules produced by the milling step can be characterized by their particle size distribution, bulk density, and tap density, as described herein.

[0252] Further references Figure 4 In step 212, an external lubricant may be added to a tablet press or other tableting equipment before the two tableting mixtures are used to form a bilayer tablet. The use of an external lubricant can facilitate discharge of the final tablet by reducing material adhesion to the tablet press. In other embodiments of the foregoing, the method includes optionally applying one or more external lubricants to the tablet press prior to compression. In some embodiments, the one or more external lubricants include hydroxypropyl methylcellulose, zinc stearate, carnauba wax, or any combination thereof.

[0253] The process 200 for preparing a bilayer naproxen sodium tablet differs from the process 100 for preparing a (single-layer) naproxen sodium tablet in the parallel preparation of the secondary tableting mixture (shown as step 210) and the details of the compression step 214. Depending on the tablet press used, the compression of the two tableting mixtures in step 214 to form a bilayer naproxen sodium tablet can be performed in a single compression step or in a two-step process, which includes first (pre-)compressing one of the tableting mixtures to form a layer, then loading the remaining tableting mixture into the tablet press along with the prepared layer, and compressing the remaining tableting mixture and the prepared layer to form a bilayer tablet. It should be appreciated that when a two-step tableting process is used, the compression order can be sequenced, with the primary tableting mixture or the secondary tableting mixture being pre-compressed.

[0254] In some embodiments where the primary tableting mixture and the secondary tableting mixture are compressed in a single compression step, the primary tableting mixture and the secondary tableting mixture are compressed with a compression force of at least 1 kN, at least 2 kN, at least 3 kN, at least 4 kN, at least 5 kN, at least 10 kN, at least 15 kN, at least 20 kN, or at least 25 kN. In other embodiments, the primary tableting mixture and the secondary tableting mixture are compressed with a compression force of less than or equal to 45 kN, less than or equal to 40 kN, less than or equal to 35 kN, less than or equal to 30 kN, less than or equal to 25 kN, or less than or equal to 20 kN. In certain embodiments, the range of the present invention is from 5 kN to 45 kN, 5 kN to 40 kN, 5 kN to 35 kN, 5 kN to 30 kN, 5 kN to 25 kN, 5 kN to 20 kN, 5 kN to 15 kN, 5 kN to 10 kN, 10 kN to 45 kN, 10 kN to 40 kN, 10 kN to 35 kN, 10 kN to 30 kN, 10 kN to 25 kN, 10 kN to 20 kN, 10 kN to 15 kN, 15 kN to 45 kN, 15 kN to 40 kN, 15 kN to 35 kN, 15 kN to 30 kN, 15 kN to 25 kN, 15 kN to 20 kN, 20 kN to 45 kN, 20 kN to 40 kN, 20 kN to 35 kN, 20 kN to 30 The primary tableting mix and the secondary tableting mix are compressed with a compressive force between 100 kN and 200 kN, 150 kN and 300 kN, 150 kN and 400 kN, 150 kN and 300 kN, 150 kN and 400 kN, 150 kN and 300 kN, 150 kN and 400 kN, 150 kN and 300 kN, 150 kN and 400 kN, 150 kN and 300 kN, 150 kN and 400 kN, 150 kN and 400 kN, 150 kN and 400 kN, 150 kN and 400 kN, 150 kN and 400 kN, 150 kN and 400 kN,

[0255] In some embodiments in which the primary tableting mixture and the secondary tableting mixture are compressed in a two-step process, the primary tableting mixture or the secondary tableting mixture can be compressed with a first compression force to form a first layer, and then the secondary tableting mixture or the primary tableting mixture can be compressed onto the first layer with a second compression force to form the bilayer naproxen sodium tablet. As used herein, the terms "first layer" and "second layer" describe the order of layers prepared as part of the process of forming a bilayer tablet; the term "primary layer" as used herein can be used to refer to the "naproxen sodium layer," and the term "secondary layer" can be used to refer to the layer containing "one or more other active pharmaceutical ingredients" (e.g., acetaminophen) in the bilayer tablet.

[0256] In some embodiments, the method comprises compressing the primary tableting mixture to produce a first layer; and compressing the secondary tableting mixture onto the first layer to produce a bilayer naproxen sodium tablet. In certain embodiments, the method comprises compressing the primary tableting mixture with a first compressive force to produce a naproxen sodium layer; and compressing the secondary tableting mixture onto the naproxen sodium layer with a second compressive force to produce a bilayer naproxen sodium tablet. In other embodiments, the method comprises compressing the secondary tableting mixture to produce a first layer; and compressing the primary tableting mixture onto the first layer to produce a bilayer naproxen sodium tablet. In certain other embodiments, the method comprises compressing the secondary tableting mixture with a first compressive force to produce an acetaminophen layer; and compressing the primary tableting mixture onto the acetaminophen layer with a second compressive force to produce a bilayer naproxen sodium tablet.

[0257] In some embodiments, the first compressive force is at least 1 kN, at least 2 kN, at least 3 kN, at least 4 kN, at least 5 kN, at least 10 kN, at least 15 kN, at least 20 kN, or at least 25 kN. In other embodiments, the first compressive force is less than or equal to 45 kN, less than or equal to 40 kN, less than or equal to 35 kN, less than or equal to 30 kN, less than or equal to 25 kN, or less than or equal to 20 kN. In some embodiments, the second compressive force is at least 5 kN, at least 10 kN, at least 15 kN, at least 20 kN, or at least 25 kN. In other embodiments, the second compressive force is less than or equal to 45 kN, less than or equal to 40 kN, less than or equal to 35 kN, less than or equal to 30 kN, less than or equal to 25 kN, or less than or equal to 20 kN.

[0258] In some embodiments, the first compressive force and the second compressive force are the same. In other embodiments, the first compressive force and the second compressive force are different. In still other embodiments, the first compressive force is less than or equal to the second compressive force.

[0259] How to use

[0260] In yet another aspect of the present invention, provided herein are methods of using the naproxen sodium tablets described herein.

[0261] As described herein, naproxen sodium is used to treat inflammation associated with various conditions and to relieve mild to moderate pain.

[0262] In some embodiments, provided herein is a method of treating pain in a subject in need thereof, comprising administering to the subject a naproxen sodium tablet. In certain embodiments of the foregoing embodiments, the pain is associated with arthritis, headache, muscle pain, toothache, backache, the common cold, or dysmenorrhea. In yet other embodiments, provided herein is a method of reducing fever in a subject in need thereof, comprising administering to the subject a naproxen sodium tablet.

[0263] As described herein, a subject may include, but is not limited to, a mammal, or more specifically a human.

[0264] In certain embodiments of the above methods, the naproxen sodium tablet is administered orally. In further embodiments, the naproxen sodium tablet is formulated for oral administration.

[0265] In other aspects, the present invention provides an article of manufacture, such as a container, comprising a naproxen sodium tablet as described herein, and a label comprising instructions for use of the naproxen sodium tablet.

[0266] In yet other aspects, a kit is provided comprising the naproxen sodium tablets described herein; and a package insert comprising instructions for use of the naproxen sodium tablets.

[0267] In another aspect, methods of using the double-layer naproxen sodium tablets described herein are provided. Similar to the naproxen tablets described herein, the double-layer naproxen sodium tablets provided herein can be used to treat inflammation associated with various conditions and to relieve mild to moderate pain.

[0268] In some embodiments, provided herein are methods for treating pain in a subject in need thereof, comprising administering to the subject the bilayer naproxen sodium tablet. In certain embodiments of the aforementioned embodiments, the pain is associated with arthritis, headache, muscle pain, toothache, backache, the common cold, or dysmenorrhea. In further embodiments, provided herein are methods for reducing fever in a subject in need thereof, comprising administering to the subject the bilayer naproxen sodium tablet. In some embodiments of the aforementioned methods, the administering step comprises administering to the subject two bilayer naproxen sodium tablets in one dose.

[0269] In certain embodiments of the above methods, the bilayer naproxen sodium tablet is administered orally. In other embodiments, the bilayer naproxen sodium tablet is formulated for oral administration.

[0270] In other aspects, the present invention provides an article of manufacture, such as a container comprising the bi-layer naproxen sodium tablet described herein, and a label comprising instructions for use of the bi-layer naproxen sodium tablet.

[0271] In yet other aspects, the present invention provides a kit comprising the double-layer naproxen sodium tablet described herein; and a package insert comprising instructions for use of the double-layer naproxen sodium tablet.

[0272] List implementation plans

[0273] The embodiments listed below represent aspects of the invention.

[0274] 1. Naproxen sodium tablets, comprising:

[0275] Granules containing naproxen sodium;

[0276] Mannitol;

[0277] colloidal silica;

[0278] one or more lubricants; and

[0279] one or more superdisintegrants,

[0280] wherein the tablet has a dissolution profile of at least about 80% of the naproxen sodium dissolved in 10 minutes and 100% of the naproxen sodium dissolved in 20 minutes as determined by dissolution testing in USP Apparatus-2 at 37°C ± 0.5°C in pH 7.4 phosphate buffer.

[0281] 2. Naproxen sodium tablets, comprising:

[0282] Granules containing naproxen sodium;

[0283] Mannitol;

[0284] colloidal silica;

[0285] stearic acid;

[0286] Sodium starch glycolate; and

[0287] magnesium stearate,

[0288] wherein the tablet has a dissolution profile of at least about 80% of the naproxen sodium dissolved in 10 minutes and 100% of the naproxen sodium dissolved in 20 minutes as determined by dissolution testing in USP Apparatus-2 at 37°C ± 0.5°C in pH 7.4 phosphate buffer.

[0289] 3. The naproxen sodium tablet according to embodiment 1 or embodiment 2, wherein the tablet comprises 60-80% w / w naproxen sodium.

[0290] 4. The naproxen sodium tablet of any one of embodiments 1 to 3, wherein the naproxen sodium tablet comprises 10-20% w / w mannitol.

[0291] 5. The naproxen sodium tablet of any one of embodiments 1 to 4, wherein the granules comprise mannitol, colloidal silicon dioxide, stearic acid, and sodium starch glycolate.

[0292] 6. The naproxen sodium tablet of any one of embodiments 1 to 5, wherein the granules are at least 85% w / w of the total weight of the naproxen sodium tablet.

[0293] 7. The naproxen sodium tablet according to any one of embodiments 1 to 6, wherein the naproxen sodium tablet comprises mannitol, sodium starch glycolate and magnesium stearate as extragranular excipients.

[0294] 8. The naproxen sodium tablet of any one of embodiments 1 to 7, wherein the naproxen sodium tablet comprises colloidal silicon dioxide as an extragranular excipient.

[0295] 9. The naproxen sodium tablet of any one of embodiments 1 to 8, further comprising a film coating.

[0296] 10. The naproxen sodium tablet of any one of embodiments 1 to 9, wherein the naproxen sodium tablet has a disintegration time of less than 5 minutes as determined by the USP disintegration test conducted in water at 37°C ± 0.5°C using a basket assembly with disks.

[0297] 11. The naproxen sodium tablet of any one of embodiments 1 to 10, wherein the naproxen sodium tablet has a hardness of 2 to 14 kilogram-force (kp) as determined by a tablet tester according to the USP Tablet Breaking Force Test.

[0298] 12. The naproxen sodium tablet of any one of embodiments 1 to 11, wherein the naproxen sodium tablet has a friability of less than or equal to 1% as determined by the USP friability test performed after 200 revolutions.

[0299] 13. A method for preparing the naproxen sodium tablet according to embodiment 1, the method comprising:

[0300] combining naproxen sodium, mannitol, colloidal silicon dioxide, one or more lubricants, and one or more superdisintegrants to provide a blended mixture;

[0301] compacting the blended mixture by roller compaction to form a ribbon;

[0302] grinding the ribbon to obtain granules;

[0303] combining the granules with mannitol, one or more lubricants, one or more superdisintegrants, and optionally colloidal silicon dioxide to provide a tableting mix; and

[0304] The tableting mixture is compressed to obtain naproxen sodium tablets.

[0305] 14. A method for preparing the naproxen sodium tablet according to any one of embodiments 1 to 12, the method comprising:

[0306] combining naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid, and sodium starch glycolate to obtain a blended mixture;

[0307] compacting the blended mixture by roller compaction to form a ribbon;

[0308] grinding the ribbon to obtain granules;

[0309] combining the granules with mannitol, sodium starch glycolate, magnesium stearate, and optionally colloidal silicon dioxide to provide a tableting mixture; and

[0310] The tableting mixture is compressed to obtain naproxen sodium tablets.

[0311] 15. The method of embodiment 13 or embodiment 14, wherein the blended mixture is compacted by roller compaction at an applied force of 18 to 30 bar.

[0312] 16. The method of any one of embodiments 13 to 15, wherein the blended mixture is compacted by roller compaction at a roller speed of 4 to 9 rpm.

[0313] 17. The method of any one of embodiments 13 to 16, wherein the blended mixture is compacted by roller compaction with a roller gap of 1.0 to 4.0 mm.

[0314] 18. The method of any one of embodiments 13 to 17, wherein the ribbon has a porosity of 10% to 60%.

[0315] 19. The method of any one of embodiments 13 to 18, wherein the ribbon has a solid fraction of 0.4 to 0.9.

[0316] 20. The method of any one of embodiments 13 to 19, wherein the ribbon is milled at a milling speed of 40 to 160 rpm to obtain granules.

[0317] 21. The method of any one of embodiments 13 to 20, wherein the particles have a particle size distribution such that at least 50% w / w of the particles have a particle size greater than or equal to 250 μm.

[0318] 22. The method of any one of embodiments 13 to 21, wherein the particles have a bulk density of 0.3 to 0.9 g / cc.

[0319] 23. The method of any one of embodiments 13 to 22, wherein the particles have a tap density of 0.6 to 0.9 g / cc.

[0320] 24. The method of any one of embodiments 13 to 23, wherein the tableting mixture has a particle size distribution such that at least 40% w / w of the particles have a particle size greater than or equal to 250 μm.

[0321] 25. The method of any one of embodiments 13 to 24, wherein the tableting mixture has a bulk density of 0.3 g / cc to 0.9 g / cc.

[0322] 26. The method of any one of embodiments 13 to 25, wherein the tableting mixture has a tap density of 0.6 g / cc to 0.9 g / cc.

[0323] 27. The method of any one of embodiments 13 to 26, wherein the tableting mixture is compressed with a compression force of 6 to 30 kN to obtain naproxen sodium tablets.

[0324] 28. The method of any one of embodiments 13 to 27, further comprising coating the naproxen sodium tablet to obtain a coated naproxen sodium tablet.

[0325] 29. A naproxen sodium tablet obtained by the method of any one of embodiments 13 to 28.

[0326] 30. A method of treating pain in a subject in need thereof, comprising administering to the subject the naproxen sodium tablet according to any one of Embodiments 1 to 12 or Embodiment 29.

[0327] 31. The method of embodiment 30, wherein the pain is associated with arthritis, muscle pain, back pain, dysmenorrhea, headache, toothache, or the common cold.

[0328] 32. A method of reducing fever in a subject in need thereof, comprising administering to the subject the naproxen sodium tablet according to any one of Embodiments 1 to 12 or Embodiment 29.

[0329] 33. A double-layer naproxen sodium tablet comprising:

[0330] The primary layer includes:

[0331] Granules containing naproxen sodium;

[0332] Mannitol;

[0333] colloidal silica;

[0334] one or more adhesives;

[0335] one or more lubricants; and

[0336] one or more superdisintegrants, and

[0337] The secondary layer includes:

[0338] one or more other active pharmaceutical ingredients;

[0339] colloidal silica;

[0340] one or more adhesives;

[0341] one or more lubricants; and

[0342] one or more superdisintegrants,

[0343] wherein the tablet has a disintegration time of less than 5 minutes as determined by the USP disintegration test conducted in water at 37°C ± 0.5°C using a basket assembly with disks.

[0344] 34. The bi-layer naproxen sodium tablet of embodiment 33, wherein the one or more extragranular lubricants in the primary layer and the one or more lubricants in the secondary layer are the same.

[0345] 35. The bilayer naproxen sodium tablet of embodiment 33 or embodiment 34, wherein the one or more extragranular superdisintegrants in the primary layer and the one or more superdisintegrants in the secondary layer are the same.

[0346] 36. A double-layer naproxen sodium tablet comprising:

[0347] A naproxen sodium layer, the naproxen sodium layer comprising:

[0348] Granules containing naproxen sodium;

[0349] Mannitol;

[0350] colloidal silica;

[0351] Sodium starch glycolate;

[0352] starch and / or partially pregelatinized starch;

[0353] stearic acid or magnesium stearate; and

[0354] Croscarmellose sodium, and

[0355] An acetaminophen layer, the acetaminophen layer comprising:

[0356] Acetaminophen;

[0357] colloidal silica;

[0358] starch and / or partially pregelatinized starch;

[0359] stearic acid or magnesium stearate; and

[0360] Croscarmellose sodium,

[0361] wherein the tablet has a disintegration time of less than 5 minutes as determined by the USP disintegration test conducted in water at 37°C ± 0.5°C using a basket assembly with disks.

[0362] 37. The bilayer naproxen sodium tablet of any one of embodiments 33 to 36, wherein the tablet comprises 100 to 200 mg of naproxen sodium.

[0363] 38. The double-layer naproxen sodium tablet of any one of embodiments 33 to 37, wherein the naproxen sodium tablet comprises 150 mg of naproxen sodium.

[0364] 39. The bilayer naproxen sodium tablet of any one of embodiments 33 to 38, wherein the granules comprise mannitol, colloidal silicon dioxide, stearic acid or magnesium stearate, and sodium starch glycolate.

[0365] 40. The bi-layer naproxen sodium tablet of any one of embodiments 33 to 39, wherein the particles comprising naproxen sodium are at least 25% w / w of the total weight of the tablet.

[0366] 41. The naproxen sodium tablet of any one of embodiments 33 to 40, further comprising a film coating.

[0367] 42. The naproxen sodium tablet of any one of embodiments 33 to 41, wherein the bi-layer naproxen sodium tablet has a disintegration time of less than 4 minutes as determined by the USP disintegration test performed in water at 37°C ± 0.5°C using a basket assembly with disks.

[0368] 43. The naproxen sodium tablet of any one of embodiments 33 to 42, wherein the naproxen sodium tablet has a hardness of 2 to 14 kilograms force (kp) as determined by a tablet tester according to the USP Tablet Breaking Force Test.

[0369] 44. The naproxen sodium tablet of any one of embodiments 33 to 43, wherein the naproxen sodium tablet has a friability of less than or equal to 1% as determined by the USP friability test after 200 revolutions.

[0370] 45. A method for preparing the double-layer naproxen sodium tablet according to embodiment 33, the method comprising:

[0371] combining naproxen sodium, mannitol, colloidal silicon dioxide, one or more lubricants, and one or more superdisintegrants to provide a blended mixture;

[0372] compacting the blended mixture by roller compaction to form a ribbon;

[0373] grinding the ribbon to obtain granules;

[0374] combining the granules with mannitol, one or more binders, one or more lubricants, one or more superdisintegrants, and optionally colloidal silicon dioxide to provide a primary tableting mixture;

[0375] combining one or more other active pharmaceutical ingredients, colloidal silicon dioxide, one or more lubricants, and one or more superdisintegrants to form a secondary tableting mixture; and

[0376] The primary tableting mixture and the secondary tableting mixture are compressed to obtain double-layer naproxen sodium tablets.

[0377] 46. A method of preparing the naproxen sodium tablet according to any one of embodiments 33 to 44, the method comprising:

[0378] combining naproxen sodium, mannitol, colloidal silicon dioxide, stearic acid or magnesium stearate, and sodium starch glycolate to obtain a blended mixture;

[0379] compacting the blended mixture by roller compaction to form a ribbon;

[0380] grinding the ribbon to obtain granules;

[0381] combining the granules with mannitol, sodium starch glycolate, starch and / or partially pregelatinized starch, stearic acid or magnesium stearate, croscarmellose sodium, and optionally colloidal silicon dioxide to provide a primary tableting mixture; and

[0382] combining acetaminophen, colloidal silicon dioxide, starch and / or partially pregelatinized starch, stearic acid or magnesium stearate, and croscarmellose sodium to form a secondary tableting mixture; and

[0383] The primary tableting mixture and the secondary tableting mixture are compressed to obtain double-layer naproxen sodium tablets.

[0384] 47. The method of embodiment 45 or embodiment 46, wherein the blended mixture is compacted by roller compaction at an applied force of 18 to 30 bar.

[0385] 48. The method of any one of embodiments 45 to 47, wherein the blended mixture is compacted by roller compaction at a roller speed of 4 to 9 rpm.

[0386] 49. The method of any one of embodiments 45 to 48, wherein the blended mixture is compacted by roller compaction with a roller gap of 1.0 to 4.0 mm.

[0387] 50. The method of any one of embodiments 45 to 49, wherein the ribbon has a porosity of 10% to 60%.

[0388] 51. The method of any one of embodiments 45 to 50, wherein the ribbon has a solid fraction of 0.4 to 0.9.

[0389] 52. The method of any one of embodiments 45 to 51, wherein the ribbon is milled at a milling speed of 40 to 160 rpm to obtain granules.

[0390] 53. The method of any one of embodiments 45 to 52, wherein the particles have a particle size distribution such that at least 50% w / w of the particles have a particle size greater than or equal to 250 μm.

[0391] 54. The method of any one of embodiments 45 to 53, wherein the particles have a bulk density of 0.3 to 0.9 g / cc.

[0392] 55. The method of any one of embodiments 45 to 54, wherein the particles have a tap density of 0.6 to 0.9 g / cc.

[0393] 56. The method of any one of embodiments 45 to 55, wherein the tableting mixture has a particle size distribution such that at least 40% w / w of the particles have a particle size greater than or equal to 250 μm.

[0394] 57. The method of any one of embodiments 45 to 56, wherein the tableting mixture has a bulk density of 0.3 g / cc to 0.9 g / cc.

[0395] 58. The method of any one of embodiments 45 to 57, wherein the tableting mixture has a tap density of 0.6 g / cc to 0.9 g / cc.

[0396] 59. The method of any one of embodiments 45 to 58, wherein the primary tableting mixture and the secondary tableting mixture are compressed at a compression force of 6 to 30 kN to obtain a bi-layer naproxen sodium tablet.

[0397] 60. The method of any one of embodiments 45 to 59, wherein the step of compressing the primary tableting mixture and the secondary tableting mixture to form a bi-layer naproxen sodium tablet comprises:

[0398] compressing the primary tableting mixture at a first compression force to form a naproxen sodium layer; and

[0399] The secondary tableting mixture is compressed onto the naproxen sodium layer with a second compression force to form a double-layer naproxen sodium tablet.

[0400] 61. The method of any one of embodiments 45 to 59, wherein the step of compressing the primary tableting mixture and the secondary tableting mixture to form a bi-layer naproxen sodium tablet comprises:

[0401] compressing the secondary tableting mixture with a first compressive force to obtain a first layer; and

[0402] The primary tableting mixture is compressed onto the first layer with a second compression force to form a double-layer naproxen sodium tablet.

[0403] 62. The method of embodiment 60 or embodiment 61, wherein the first compressive force is 1 kN to 30 kN and the second compressive force is 5 kN to 30 kN.

[0404] 63. The method of any one of embodiments 45 to 62, further comprising coating the double-layer naproxen sodium tablet to obtain a coated double-layer naproxen sodium tablet.

[0405] 64. A double-layer naproxen sodium tablet obtained by the method of any one of embodiments 45 to 63.

[0406] 65. A method of treating pain in a subject in need thereof, comprising administering to the subject the bilayer naproxen sodium tablet of any one of Embodiments 33 to 44 or Embodiment 64.

[0407] 66. The method of embodiment 65, wherein the pain is associated with arthritis, muscle pain, back pain, dysmenorrhea, headache, toothache, or the common cold.

[0408] 67. A method of reducing fever in a subject in need thereof, comprising administering to the subject the bilayer naproxen sodium tablet of any one of Embodiments 33 to 44 or Embodiment 64.

[0409] Example

[0410] The presently disclosed subject matter will be better understood by reference to the following examples, which are provided by way of illustration and not limitation of the invention.

[0411] Example 1: Preparation of Naproxen Sodium Tablets

[0412] This example describes the preparation of naproxen sodium tablets by dry granulation using mannitol, anhydrous calcium hydrogen phosphate, or both as intragranular and extragranular diluents. Table 1A shows the three test blends used for roller compaction in this example. The three test blends were mixed in the mass proportions shown in Table 1A, passed through a roller compactor (roller compactor roller speed of 9 rpm, roller pressure of 20 bar, and roller gap of 4.0 mm), and the resulting compacted ribbon was milled (milling speed of 107 rpm).

[0413] Table 1A

[0414]

[0415] The roller-compacted granules produced from each of the three test blends were further mixed with the corresponding extragranular excipients in the mass proportions shown in Table 1B and compressed into tablets (compression force of 15 kN).

[0416] Table 1B

[0417]

[0418] The dissolution profile of naproxen sodium tablets prepared as described above was tested in comparison to commercially available naproxen sodium tablets prepared by fluid bed granulation ("Standard").

[0419] Commercially available naproxen sodium tablets ("Comparative Example") were prepared using the ingredients shown in Table 2. Commercially available naproxen sodium tablets can be prepared according to the general process detailed below. Naproxen sodium is first combined with microcrystalline cellulose, povidone, and water to obtain granules by wet granulation (high shear / fluidized bed granulation). The granules are then dried to a certain moisture content and ground to a certain particle size. The ground granules are further combined with microcrystalline cellulose, talc, and magnesium stearate to facilitate compression and discharge in the subsequent tableting step. The mixture is formed into tablets and coated with a suitable tableting coating to obtain the final naproxen sodium tablets.

[0420] Table 2

[0421]

[0422] *After drying, the remaining water in the particles

[0423] According to the United States Pharmacopoeia standardization scheme for the dissolution of naproxen sodium immediate release dosage forms (USP34-NF29 Chapter <711> Dissolution, Stage 6 Harmonization Bulletin dated December 1, 2011; and Naproxen Sodium monograph USP41-NF36, Interim Revision Announcement dated May 1, 2018), the dissolution profiles of the test and comparative tablets in the three tests were determined and are briefly summarized below.

[0424] Individual tablets were placed in a paddle apparatus (Apparatus 2) at 50 rpm containing 900 mL of 0.1 M phosphate buffer (pH 7.4), equilibrated to 37 ± 0.5°C. Aliquots of the phosphate buffer were removed at 10, 20, 30, and 45 minutes. The amount of naproxen sodium dissolved in the dissolution medium was determined by UV absorption spectroscopy at 332 nm. Dissolution measurements were performed on six tablets for each test.

[0425] The percentage of naproxen observed to be dissolved in pH 7.4 phosphate buffer at each time point is shown in Table 3 as the average of six measurements performed for each test. The overall dissolution rate was found to be fastest for the formulation containing mannitol as the primary diluent.

[0426] Table 3

[0427]

[0428] Example 2: Dissolution Profiles of Naproxen Sodium Tablets in Different Dissolution Media

[0429] This example describes the preparation of naproxen sodium tablets by dry granulation and the evaluation of their dissolution profiles in different dissolution media.

[0430] Combine USP grade naproxen sodium with mannitol (Mannogem ® EZ, spray drying), colloidal silicon dioxide (Cab-O-Sil ® ), stearic acid and sodium starch glycolate (Explotab ® ) were mixed in the proportions detailed in Table 4A (same as Test 1 in Table 1A) to prepare a blended mixture for subsequent roller compaction.

[0431] The blended mixture was passed through a roller compactor (roller compactor roller speed of 9 rpm; roller pressure of 20 bar; roller gap of 4.0 mm) to form roller-compacted ribbons, which were then milled through a screen of specified opening (milling speed of 107 rpm) to form free-flowing roller-compacted granules containing naproxen sodium.

[0432] Table 4A

[0433]

[0434] * is the weight of tablet core (Table 2)

[0435] The roller compacted granules were then mixed with other excipients mannitol (Pearlitol ® SD200, spray dried), sodium starch glycolate (Explotab ® ) and magnesium stearate were mixed in the proportions shown in Table 4B (same as Test 1 in Table 1B). The resulting final blend (tableting mixture) was compressed in a tablet press at a compression force of 15 kN to obtain uncoated naproxen sodium tablets.

[0436] Table 4B

[0437]

[0438] The uncoated tablets produced by this tableting step were then coated with one of two film coatings (Opadry® YS-1-4215 and Opadry® QX).

[0439] The dissolution profiles of the coated test and comparative tablets provided in Example 1 were determined according to the USP dissolution test described above in Example 1 (Table 2). Individual tablets were placed in a paddle apparatus (Apparatus 2) at 50 rpm containing 900 mL of 0.1 M phosphate buffer (pH 7.4), equilibrated to 37 ± 0.5°C. Aliquots of the phosphate buffer were removed at 10, 20, 30, and 45 minutes. The amount of naproxen sodium dissolved in the dissolution medium was determined by UV absorption spectroscopy at 332 nm.

[0440] Table 5 shows the percentage of naproxen dissolved in pH 7.4 phosphate buffer observed at each time point as the average of six tablets per test. Figure 2 A comparison of the dissolution profiles of naproxen sodium tablets in pH 7.4 phosphate buffer over time (ie, the percentage of naproxen sodium in solution as a percentage of the total amount of naproxen sodium in the initial tablet) is shown.

[0441] Table 5

[0442]

[0443] In addition, additional evaluations were conducted to determine the dissolution profile of naproxen sodium coated tablets prepared by dry granulation / roller compaction under acidic conditions. The USP dissolution protocol for naproxen sodium immediate-release tablets was adapted to replace the standard phosphate buffer at pH 7.4 with phosphate buffer at pH 5.8. Table 6 shows the percentage of naproxen dissolved in pH 5.8 phosphate buffer at each time point. Figure 3 A graph comparing the dissolution profile of naproxen sodium tablets in pH 5.8 buffer versus the dissolution profile of the same tablets in pH 7.4 buffer over time is shown. The results in Table 6 are the average percentages for each of the six tablets tested.

[0444] Table 6

[0445]

[0446] like Figure 2 As shown in Figure 2, the dissolution profile of naproxen sodium tablets prepared by dry granulation is better than that of naproxen sodium tablets prepared by wet granulation. Figure 3 As shown, naproxen sodium tablets prepared by dry granulation / roller compaction method showed the same dissolution profile in acidic medium.

[0447] Example 3: Process parameter evaluation

[0448] This example describes the effects of various parameters in the dry granulation / roller compaction process on the properties of the final processed materials (roller-compacted ribbons, granules, blends, and tableting mixes), as well as the evaluation of the dissolution profile, disintegration time, hardness, and friability of the final naproxen sodium tablets.

[0449] As shown in this example, the formulations of naproxen sodium tablets described herein produce process materials with consistent physical properties, and the final naproxen sodium tablets exhibit consistently enhanced dissolution even when initially subjected to variable roller compaction parameters.

[0450] Part I - Roller Compaction Parameters

[0451] A blend of naproxen sodium and intragranular excipients (mannitol, colloidal silicon dioxide, stearic acid, sodium starch glycolate) for roller compaction granulation was prepared according to the mass ratios detailed in Table 4A above. This blend was roller compacted thirteen times under the different roller compaction process conditions shown in Table 7 below.

[0452] Table 7

[0453]

[0454] Each of the thirteen roller compaction runs employed a different combination of roller speed, roller gap, roller pressure, and roller type to evaluate the effect of the aggregate on the final roller-compacted ribbon. The resulting roller-compacted ribbon was evaluated for hardness, thickness, true density, envelope density, solid fraction, and porosity. The results are shown in Table 8.

[0455] As shown in Table 8, the roller compacted ribbons produced under a range of roller compaction parameters exhibited fairly constant porosity.

[0456] Table 8

[0457]

[0458] Part II - Grinding Speed

[0459] Before the ribbons prepared in the above-mentioned Part I were ground, a brief assessment was made of the impact of grinding speed on particle size. Prepare the blended mixture according to the mass ratio in Table 4A above. Use a roller compactor with a feed rate of 80%, a roller speed of 7 rpm, a roller pressure of 20 bar, and a roller gap compaction of 2.0 mm. Grind by a grinder with a kind of in three different grinding speeds (60 rpm, 85 rpm, and 108 rpm) to obtain particles.

[0460] The resulting granules were sequentially sieved through seven sieves of different mesh sizes (and their corresponding nominal mesh openings): No. 20 (841 µm), No. 40 (420 µm), No. 60 (250 µm), No. 80 (177 µm), No. 100 (149 µm), No. 200 (74 µm), and No. 325 (44 µm). The mass of material remaining on each sieve was recorded. The total mass remaining on each sieve was calculated as a percentage of the total mass of material passing through the seven sieves to determine the particle size distribution of the roller-compacted granules. The particle size distributions of the granules obtained from the three different grinding speeds are shown in Table 9.

[0461] Table 9

[0462]

[0463] The particle size distribution of particles produced at three different grinding speeds does not change much.

[0464] Part III—Particle Size Distribution of Granules and Tableting Blends

[0465] After evaluating the ribbon properties, the ribbons from each of the 13 roller compactions in Part I were ground (at a grinding speed of 85 rpm) into granules, and the granules were sieved to determine the particle size distribution. The granules were sieved sequentially through seven sieves with different mesh sizes (and corresponding nominal mesh openings): No. 20 (841 µm), No. 40 (420 µm), No. 60 (250 µm), No. 80 (177 µm), No. 100 (149 µm), No. 200 (74 µm), and No. 325 (44 µm), and the mass of material remaining on each sieve was recorded. The total mass remaining on each sieve was calculated as a percentage of the total mass of material passing through the seven sieves to determine the particle size distribution of the roller-compacted granules. The particle size distribution of the granules obtained from these 13 roller compactions is shown in Table 10.

[0466] Table 10

[0467]

[0468] The granules obtained from the thirteen roller compactions were then mixed with extragranular excipients (mannitol, sodium starch glycolate, magnesium stearate and colloidal silicon dioxide) to obtain a tableting mix (according to the proportions in Table 11).

[0469] Table 11

[0470]

[0471] However, prior to tableting, the tableting blend was sieved to determine its particle size distribution. Similar to the analysis of the granules described above, each roller-compacted tableting blend was sieved sequentially through seven sieves of varying mesh sizes (and corresponding nominal mesh openings): No. 20 (841 µm), No. 40 (420 µm), No. 60 (250 µm), No. 80 (177 µm), No. 100 (149 µm), No. 200 (74 µm), and No. 325 (44 µm), and the mass of material remaining on each sieve was recorded. The total mass remaining on each sieve was calculated as a percentage of the total mass of material passing through the seven sieves to determine the particle size distribution of the final tableting blend, as shown in Table 12. The particle size distribution of the final tableting blend was very similar to that of the roller-compacted granules.

[0472] Table 12

[0473]

[0474] The bulk density, tap density and Carr's index (compressibility) of the roller compacted granules and the mixture for tableting (final blend) were also determined and are shown in Table 13.

[0475] Table 13

[0476]

[0477] Part III - Production

[0478] The thirteen tableting blends from Part II were compressed in a tablet press at six different compression forces (6 kN, 10.8 kN, 15.5 kN, 20.8 kN, 25 kN, and 30 kN). The final weight, thickness, and hardness of the tablets obtained from these thirteen blends at these six compression forces were measured using a semi-automatic tablet tester (SotaxPharmatest ST50). The thickness and hardness of the tablets compressed at each compression force are shown in Tables 14 and 15.

[0479] Table 14

[0480]

[0481] Table 15

[0482]

[0483] Still in water, in a basket stand assembly with discs, disintegrate according to the USP disintegration test (USP43-NF38, Chapter <701> Disintegration of 78 tablets (13 roller compactions × compression force) was evaluated using the Disintegration, Stage 4 Harmonization Bulletin dated April 26, 2019; uncoated tablet procedure, basket-rack assembly. The results are shown in Table 16.

[0484] Table 16

[0485]

[0486] The tablets produced in each of the thirteen roller compactions were further characterized for hardness and friability using a tablet tester according to the USP tablet breaking force test and the USP friability test. The observed hardness and friability are shown in Tables 17 and 18 below.

[0487] Table 17

[0488]

[0489] Table 18

[0490]

[0491] For comparison, the hardness, friability, and disintegration time of commercially available naproxen sodium tablets prepared by wet granulation (as described in Example 1 above) were also measured. Tablets produced using the wet granulation process had a hardness of 6-16 kp and a friability of 0.3%. These tablets were found to disintegrate in water within approximately 8 minutes.

[0492] The dissolution profiles of coated tablets obtained from each of 13 roller compactions at a compression force of 15.5 kN were determined. ® YS-1-4215 (“YS”) and Opadry ® QX ("QX") was evaluated on each of the 13 roller compaction cycles. The dissolution test was performed according to the USP dissolution test (Apparatus 2, paddle, pH 7.8 phosphate buffer, at 37°C ± 0.5°C) (USP34-NF29 Chapter <711> Tablet dissolution profiles were determined using the Naproxen Sodium Monograph (USP41-NF36, Interim Revision Announcement, May 1, 2018) and the Dissolution, Stage 6 Harmonization Bulletin (Date: December 1, 2011). Six tablets of each coating type (six "YS"-coated tablets and six "QX"-coated tablets) were evaluated at each roller compaction run, and the percentage dissolved was measured at each time point. Table 19 below shows the average dissolution profiles (average of six tablets at each time point) for the two types of coated tablets and one commercially available tablet (Comparative Tablet, Table 2).

[0493] Table 19

[0494]

[0495] Example 4: Preparation of Naproxen Sodium and Acetaminophen Double-Layer Composite Tablets

[0496] This example describes the preparation and disintegration profiles of oral tablets containing naproxen sodium granules in combination with acetaminophen in either monolayer or bilayer form. The disintegration characteristics of various tablets containing either naproxen sodium or acetaminophen alone were also evaluated for comparison with the composite tablets.

[0497] As shown in this example, combining roller-compacted naproxen sodium granules with acetaminophen in a monolayer tablet resulted in a significantly longer disintegration time compared to the disintegration time of tablets containing either naproxen sodium or acetaminophen as the active pharmaceutical ingredients alone. Unexpectedly, the disintegration time of a bilayer tablet consisting of roller-compacted naproxen sodium granules in one layer and acetaminophen in the second layer was observed to be significantly shorter than the monolayer tablet and disintegrated faster than a tablet containing naproxen sodium alone.

[0498] Part I—Evaluation of Monolayer and Bilayer Composite Tablets

[0499] Table 20 shows the compositions of three tablet formulations prepared according to the present invention, including an oral tablet comprising roller-compacted naproxen sodium granules, a composite single-layer tablet comprising roller-compacted naproxen sodium granules and acetaminophen, and a bilayer composite tablet comprising roller-compacted naproxen sodium granules and acetaminophen in a single layer. The naproxen sodium granules used in this example were prepared by roller compaction as described in Example 1 above; the granules in this example differ from those in Example 1 in that magnesium stearate was used as a lubricant instead of stearic acid. The average particle size (d90) of the prepared naproxen sodium granules was 1694 μm for at least 90% of the granules. Acetaminophen granules (comprising acetaminophen and starch) were obtained from a commercial supplier; the average particle size (d90) of the acetaminophen granules was 1537 μm.

[0500] The naproxen sodium tablets shown in Table 20 were prepared using the granules prepared in this example (magnesium stearate), but according to the protocol described in Example 1.

[0501] For both single-layer and bi-layer composite tablets, the same roller-compacted granulation components were used for the naproxen sodium tablets. The amount of naproxen sodium granules added to each tablet formulation was adjusted to the desired mass shown in Table 20; the naproxen sodium content provided by the granules was calculated based on the original composition and weight of the added granules. The naproxen sodium content in the composite tablets (150 mg) was lower than the naproxen sodium content in the single-active naproxen sodium tablets (220 mg) because the composite tablets were prepared for the desired two-tablet single dose.

[0502] The amount of croscarmellose sodium was kept constant in both the monolayer and bilayer tablets to ensure that the different amounts and types of superdisintegrants in the two formulations did not affect the observed disintegration times. The amounts of other ingredients used in both the monolayer and bilayer tablets were kept constant to ensure that the excipients had the same effect on disintegration.

[0503] Table 20

[0504]

[0505] Table 21

[0506]

[0507] The two composite tablet formulations described in Table 20 were compressed in a tablet press. A single compression force of 8 kN was used to prepare the monolayer tablets; for the bilayer tablets, the initial compression force for the first layer (acetaminophen layer) was 1 kN, and the second layer (naproxen sodium layer) was added with a final compression force of 8 kN to form the bilayer tablets.

[0508] Tablets produced from each formulation were further characterized for hardness and friability using a tablet tester according to the USP Tablet Breaking Force Test and the USP Friability Test. As shown in Table 21, the monolayer tablets showed similar hardness and friability. Also in water, in a basket rack assembly with a disc, the tablets were disintegrated according to the USP Disintegration Test (USP43-NF38, Chapter 21). <701> The tablets were evaluated using the Disintegration, Stage 4 Harmonization Bulletin dated April 26, 2019; uncoated tablet procedure, basket-rack assembly. As shown in Table 21, the composite bilayer tablet disintegrated in less than 4 minutes, while the monolayer tablet disintegrated in more than 10 minutes, almost four times the time of the bilayer tablet.

[0509] Figure 5A Photographs of a monolayer tablet comprising a combination of naproxen sodium (roller-compacted granules) and acetaminophen (left panel) and a bilayer tablet comprising naproxen sodium (roller-compacted granules) in the first layer and acetaminophen in the second layer (right panel) are shown. Figure 5B-5E A photograph showing exemplary comparative disintegration times of three tablets each of a single-layer composite tablet and a double-layer composite tablet over time is shown. Figure 5B ), 10 seconds( Figure 5C )、35 seconds( Figure 5D ) and 3 minutes and 3 seconds ( Figure 5E ) are photographs of the disintegration time of each formulation in the disintegration apparatus. The setup and samples shown in the photographs were not used for the disintegration time measurements provided in Table 21; the plastic discs required for the standard USP disintegration test were removed from the standard disintegration apparatus to improve the visibility of the photographic documentation. Figure 5B-5E As shown, in the disintegration times collected in Table 21, the bilayer tablets comprising naproxen sodium and acetaminophen granules showed faster disintegration time compared to the single-layer combination tablets.

[0510] Because the monolayer and bilayer tablets were similar in formulation, shape, size, and other physical properties, the difference in disintegration time was attributed to the influence of naproxen sodium and acetaminophen matrix effects on tablet disintegration. The acetaminophen layer in the bilayer tablet was observed to burst and disintegrate at 40 seconds, while the naproxen sodium layer decreased in thickness and size and disintegrated at 3 minutes and 40 seconds. These observations suggest that acetaminophen disintegrates via a burst release mechanism, while naproxen sodium disintegrates via a surface erosion mechanism. On the other hand, the monolayer tablet decreased in size and disintegrated at 13 minutes and 45 seconds.

[0511] In a further comparison, the observed disintegration times were plotted against the disintegration times of single active formulations of naproxen sodium and acetaminophen, as determined according to the USP disintegration test. Figure 6A and Figure 6B The disintegration time curves are shown for (1) a commercially available naproxen sodium tablet (a comparative example as described in Table 2); (2) a commercially available acetaminophen tablet (pregelatinized starch, magnesium stearate powder, cellulose powder, corn starch, sodium starch glycolate); (3) a disintegration time of a tablet comprising roller-compacted granules of naproxen sodium (the naproxen sodium tablet described in Table 20); (4) a disintegration time of a composite bilayer tablet comprising roller-compacted granules of naproxen sodium and acetaminophen (the composite bilayer tablet in Table 20); (5) a disintegration time of a composite monolayer tablet comprising roller-compacted granules of naproxen sodium and acetaminophen (the combined monolayer tablet in Table 20); and (6) a disintegration time of a half-layer tablet comprising acetaminophen (the first layer of the bilayer composite tablet in Table 20, compressed at 1 kN).

[0512] like Figure 6A and Figure 6B As shown in Figure 3, the disintegration time of the composite bilayer tablet is shorter than that of the commercial naproxen sodium tablet and the single active tablet prepared using naproxen sodium roller-compacted granules.

[0513] The reduced disintegration time of naproxen sodium in the bilayer tablet is attributed to the relative sizes of the naproxen sodium tablet and the naproxen sodium half-layer in the bilayer tablet. The thickness of the naproxen sodium half-layer in the bilayer tablet construction was 2.1 mm, compared to 4.3 mm for a commercially available standard naproxen tablet (entry #1) and a tablet containing roller-compacted naproxen sodium granules (entry #3). Following the rapid disintegration of acetaminophen in the bilayer tablet, the exposed surface area to volume ratio of the naproxen sodium half-layer was greater than that of the tablet containing only naproxen sodium, contributing to the reduced disintegration time.

[0514] In contrast, the disintegration time of the monolayer composite tablet was observed to be much longer than that of naproxen sodium alone (conventional tablets or granules) and acetaminophen alone. The increased disintegration time of the monolayer tablet relative to the single-active tablet was attributed to the matrix effect caused by the interaction between naproxen sodium and acetaminophen in the monolayer tablet.

Claims

1. Naproxen sodium tablets, comprising: Granules containing naproxen sodium; Mannitol; one or more lubricants; and one or more superdisintegrants, wherein the tablet comprises 60-80% w / w naproxen sodium and further comprises a film coating; The granules comprise mannitol, colloidal silicon dioxide, stearic acid and sodium starch glycolate.

2. Naproxen sodium tablets, comprising: Granules containing naproxen sodium; Mannitol; Sodium starch glycolate; and magnesium stearate, wherein the tablet comprises 60-80% w / w naproxen sodium and further comprises a film coating; The granules comprise mannitol, colloidal silicon dioxide, stearic acid and sodium starch glycolate.

3. The naproxen sodium tablet according to claim 1 or 2, wherein the naproxen sodium tablet comprises 10-20% w / w mannitol.

4. The naproxen sodium tablet of claim 1 or 2, wherein the particles are at least 85% w / w of the total weight of the naproxen sodium tablet.

5. The naproxen sodium tablet according to claim 1 or 2, wherein the naproxen sodium tablet comprises mannitol, sodium starch glycolate and magnesium stearate as extragranular excipients.

6. The naproxen sodium tablet according to claim 1 or 2, wherein the naproxen sodium tablet comprises colloidal silicon dioxide as an extragranular excipient.

7. The naproxen sodium tablet of claim 1 or 2, wherein the naproxen sodium tablet has a disintegration time of less than 5 minutes as determined by the USP disintegration test conducted in water at 37°C ± 0.5°C using a basket assembly with disks.

8. The naproxen sodium tablet of claim 1 or 2, wherein the naproxen sodium tablet has a hardness of 2 to 14 kilogram-force (kp) as determined by a tablet tester according to the USP Tablet Breaking Force Test.

9. The naproxen sodium tablet of claim 1 or 2, wherein the naproxen sodium tablet has a friability of less than or equal to 1% as determined by the USP friability test after 200 revolutions.

10. The naproxen sodium tablet of claim 1 or 2, wherein the tablet has a dissolution profile wherein at least 80% of the naproxen sodium is dissolved at 10 minutes and 100% of the naproxen sodium is dissolved at 20 minutes as determined by USP Apparatus-2 dissolution testing conducted in pH 7.4 phosphate buffer at 37°C ± 0.5°C.

11. Use of the naproxen sodium tablet according to any one of claims 1 to 10 in the preparation of a medicament for treating distress or pain.

12. The use according to claim 11, wherein the suffering or pain is associated with arthritis, muscle pain, back pain, dysmenorrhea, headache, toothache or the common cold.

13. Use of the naproxen sodium tablet according to any one of claims 1 to 10 in the preparation of a medicament for reducing fever.

14. A double-layer naproxen sodium tablet comprising: A naproxen sodium layer, the naproxen sodium layer comprising: Granules containing naproxen sodium; colloidal silica; starch and / or partially pregelatinized starch; stearic acid or magnesium stearate; and Croscarmellose sodium, and An acetaminophen layer, the acetaminophen layer comprising: Acetaminophen; colloidal silica; starch and / or partially pregelatinized starch; stearic acid or magnesium stearate, and Croscarmellose sodium, The granules comprise mannitol, colloidal silicon dioxide, stearic acid or magnesium stearate and sodium starch glycolate.

15. The double-layer naproxen sodium tablet of claim 14, wherein the tablet comprises 100 to 200 mg of naproxen sodium.

16. The double-layer naproxen sodium tablet of claim 14, wherein the naproxen sodium tablet comprises 150 mg of naproxen sodium.

17. The bi-layer naproxen sodium tablet of claim 14, wherein the particles comprising naproxen sodium are at least 25% w / w of the total weight of the tablet.

18. The double-layer naproxen sodium tablet of claim 14, further comprising a film coating.

19. The bi-layer naproxen sodium tablet of claim 14, wherein the bi-layer naproxen sodium tablet has a disintegration time of less than 5 minutes as determined by the USP disintegration test conducted in water at 37°C ± 0.5°C using a basket assembly with disks.

20. The bi-layer naproxen sodium tablet of claim 14, wherein the bi-layer naproxen sodium tablet has a disintegration time of less than 4 minutes as determined by the USP disintegration test conducted in water at 37°C ± 0.5°C using a basket assembly with disks.

21. The bi-layer naproxen sodium tablet of claim 14, wherein the naproxen sodium tablet has a hardness of 2 to 14 kilogram-force (kp) as determined by a tablet tester according to the USP Tablet Breaking Force Test.

22. The bilayer naproxen sodium tablet of claim 14, wherein the naproxen sodium tablet has a friability of less than or equal to 1% as determined by the USP friability test after 200 revolutions.

23. Use of the double-layer naproxen sodium tablet according to any one of claims 14 to 22 in the preparation of a medicament for treating distress or pain.

24. The use of claim 23, wherein the distress or pain is associated with arthritis, muscle pain, back pain, dysmenorrhea, headache, toothache or the common cold.

25. Use of the double-layer naproxen sodium tablet according to any one of claims 14 to 22 in the preparation of a medicament for reducing fever.

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