Pharmaceutical composition comprising meloxicam

Abstract

This invention relates to a novel pharmaceutical composition comprising meloxicam for the treatment of acute pain, wherein the composition comprises at least one hydrophilic polymer and one or more alkalizing agents or combinations thereof.

Description

Technical Field

[0001] This invention relates to a novel pharmaceutical composition comprising meloxicam or a pharmaceutically acceptable salt, solvate, mirror isomer, or mixture thereof having improved solubility, soluble properties, and pharmacokinetic properties. Prior Technology

[0002] The absorption of orally administered drugs is a crucial physiological process that delivers the active pharmaceutical ingredient (API) into the bloodstream and facilitates its distribution, metabolism, and excretion throughout the body. Solubility and permeability are two physical properties that affect the absorption of orally administered drugs. Therefore, the U.S. Food and Drug Administration (FDA) classifies orally administered APIs in the Biopharmaceutical Classification System (BCS) based on solubility and permeability. Consequently, significant efforts have been invested in improving drug solubility during pharmaceutical development, with particular focus on APIs exhibiting poor solubility profiles.

[0003] Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities, and is classified as a Class II drug under the BCS. Like other NSAIDs, meloxicam's main mechanism of action is through inhibition of the cyclooxygenase (COX-2) enzyme system, leading to a reduction in prostaglandin synthesis.

[0004] Meloxicam, an oxacin derivative, is a member of the enolic acid group of NSAIDs. Its chemical name is 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl-1)-2H-1,2-benzothiazine-3-carboxymethylamine-1,1-dioxide, and it is described by the following chemical structure:

[0005] Meloxicam was originally developed by Boehringer Ingelheim and marketed in Europe as an oral suspension under the name Meloxyl for the short-term treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. In the United States, it is marketed as MOBIC® for the relief of symptoms and signs of osteoarthritis. Meloxicam is manufactured as tablets (7.5 and 15 mg doses) or an oral suspension (7.5 mg / 5 ml dose). The meloxicam used in the commercially available product MOBIC® is pure meloxicam.

[0006] The absorption of meloxicam after administration via intramuscular, oral, and rectal routes has been studied. The bioavailability of a single 30 mg oral dose of meloxicam is 89% compared to a 30 mg intravenous injection. Meloxicam capsules have been shown to be bioequivalent to 15 mg tablets of MOBIC® (meloxicam). Following a single intravenous dose, dose-proportional pharmacokinetics are observed in the range of 5 mg to 60 mg. Following multiple oral doses of meloxicam, pharmacokinetics are dose-proportional in the range of 7.5 to 15 mg. The rate or extent of absorption is not affected by multiple doses. A mean Cmax is reached within 4 to 5 hours after administration of a 7.5 mg meloxicam tablet under fasting conditions, indicating prolonged drug absorption. A second peak concentration of meloxicam occurs approximately 12 to 14 hours after administration, indicating gastrointestinal recirculation.

[0007] Under steady-state feeding conditions in healthy adult men, the 7.5 mg tablet had a mean Cmax of 1.05 µg / mL, a Tmax of 4.9 hours, and a t1 / 2 of 20.1 hours. Under steady-state feeding conditions in older men and women, the 15 mg tablet had Cmax of 2.3 and 3.2 µg / mL, Tmax of 5 and 6 hours, and t1 / 2 of 21 and 24 hours, respectively. [See MOBIC® (Meloxicam): Prescribing Information and Medication Guide; FDA approved for osteoarthritis 04 / 13 / 2000]

[0008] Meloxicam is practically insoluble in water, but has been observed to have high solubility in strong acids and bases. It exhibits very slight solubility in methanol. Meloxicam has a significant partition coefficient (logP) app = 0.1 in n-octanol / pH 7.4 buffer. Meloxicam has pKa values ​​of 1.1 and 4.2. Specifically, the solubility of meloxicam varies depending on pH and the solvent polarity leading to the interconversion between its free and open states. Due to its low solubility under acidic conditions, orally administered meloxicam exhibits a Tmax (time to maximum concentration) of 4 to 6 hours in the human body.

[0009] When administered after breakfast, the maximum plasma concentration (Cmax) of meloxicam 15 mg tablets is reached 5 to 6 hours later (Tmax). Meloxicam begins to act well before Tmax. When meloxicam is administered on an empty stomach, Cmax occurs later (Tmax is doubled) [Turck D, Busch U, Heinzel G, Narjes H. Clinical pharmacokinetics of meloxicam. Eur J Rheumatol Inflamm 1995;15:22 to 34]. For long-term use, NSAIDs are generally administered after meals; therefore, Cmax (5 to 6 hours) is a more clinically relevant figure but is not suitable for treating acute pain.

[0010] Prior art methods for increasing the bioavailability of meloxicam include increasing its solubility by: forming a cyclodextrin complex of the drug [see U.S. Patent No. 6,284,269 ('269 Patent)] or forming a salt of meloxicam using an inorganic or organic base (see U.S. Patent Publication No. US 2002 / 0035107 A1). Further, the '269 Patent describes a method for manufacturing a pharmaceutical composition containing meloxicam and characterized by improved wettability and water solubility. Such compositions are prepared by modifying the crystal structure of the drug through dry or wet mechanical homogenization with additional components selected from the group consisting of oligosaccharides and alkalizing agents.

[0011] U.S. Patent No. 9,821,075 ('075 Patent) discloses a dosage form comprising a meloxicam encapsulation complex in cyclodextrin and a bicarbonate, wherein the complex is formed by mixing meloxicam and cyclodextrin in solution and drying the solution to form the complex. Furthermore, compared to dosage forms containing meloxicam but without cyclodextrin, antacids, or buffers (such as bicarbonates), this pharmaceutical composition results in an increased bioavailability of meloxicam from that dosage form (e.g., decreased Tmax, increased Cmax, increased AUC, etc.).

[0012] Enhancing the low water solubility of meloxicam has been a subject of numerous publications, achieved through the use of different solvents (Sreedhar et al., AAPS Pharma Sci. Tech. 2003), salt formation (Choi et al., EU J. Pharm and Biopharm. 65, 2007, 99-103), or metal complexation (Cini et al., J. Chem. Soc. Dalton Trans. 2002, 1888-1897). Preparation of different crystalline polymorphs of meloxicam is disclosed in the literature, see, for example, U.S. Patent No. 6,967,248 and U.S. Patent Publication No. 2006 / 0025408 A1. Furthermore, improvements in meloxicam solubility are also disclosed in U.S. Patent Nos. 6,869,948 and WO 99 / 09988.

[0013] Furthermore, the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer has been successfully used in combination with povidone and other excipients to enhance the solubility of the poorly soluble drug meloxicam (Noor et al., Pak. J. Pharm. Sci., 2017, pp. 407-414).

[0014] In addition, several methods exist for formulating poorly soluble active agents. One method involves preparing the active agent as a soluble salt, and when this method is not feasible, alternative (usually physical) methods are used to improve the solubility of the active agent. Alternative methods typically subject the active agent to physical conditions that alter its physical and / or chemical properties to improve its solubility. These include processes such as micronization, modification of crystalline or polymorphic structures, development of oil-based solutions, use of co-solvents, surface stabilizers, or complexing agents, microemulsions, supercritical fluids, and the generation of solid dispersions or solutions. Multiple of these processes can be combined to improve the formulation of specific therapeutic materials. Many of these methods often convert the drug into an amorphous state, which typically results in higher solubility. However, due to concerns related to stability and the possibility of material recrystallization, formulation methods that generate amorphous materials are not common in commercial formulations. Typically, these methods involve different compounding methods, different polymorphs and salt forms, and some solid formulations, which sometimes involve the generation of certain salt forms or compounding with metal ions.

[0015] Due to the limitations associated with meloxicam's low water solubility and high Tmax, there is a need to develop novel pharmaceutical formulations of meloxicam that offer improved solubility, rapid drug release, and increased absorption rates leading to lower Tmax. This would translate to greater clinical benefits in the treatment of acute pain. Summary of the Invention

[0016] One of the objectives of this invention is to provide a novel pharmaceutical composition for the treatment of acute pain, wherein the composition provides rapid drug release and has an increased absorption rate.

[0017] Another objective of the present invention is to provide a novel pharmaceutical composition comprising meloxicam for the treatment of acute pain, wherein the composition provides rapid drug release and has increased absorption in human subjects under fasting conditions.

[0018] Another objective of the present invention is to provide a novel pharmaceutical composition comprising meloxicam for the treatment of acute pain, wherein the composition is acyclodextrin and its derivatives.

[0019] Another object of the present invention is to prepare a novel pharmaceutical composition comprising meloxicam for the treatment of acute pain, wherein the composition comprises meloxicam, at least one hydrophilic polymer, and one or more alkalizing agents or combinations thereof.

[0020] Another object of the present invention is to prepare a novel pharmaceutical composition containing meloxicam for the treatment of acute pain, wherein the composition is prepared by a method comprising the step of encapsulating meloxicam in an alkaline environment.

[0021] The inventors of the novel pharmaceutical composition of the present invention for the treatment of acute pain have now surprisingly discovered that the solubility and bioavailability of meloxicam can be improved by encapsulating meloxicam in an alkaline environment with at least one hydrophilic polymer and one or more alkalizing agents or combinations thereof. Implementation

[0022] This article describes a novel pharmaceutical composition for the treatment of acute pain, wherein the composition comprises at least one hydrophilic polymer and one or more alkalizing agents or combinations thereof. Furthermore, the pharmaceutical composition has improved pharmacokinetic properties (such as Tmax, Cmax, and AUC).

[0023] Techniques used to increase drug solubility include chemical modifications (such as prodrugs or salt formation); physical modifications (such as solid dispersions, nanocrystals and nanoparticles, cocrystals, and loading onto porous structures); changes in solvent composition (such as pH adjustment, cosolvents, and wetting agents); and carrier systems (such as cyclodextrins, encapsulated complexes, liposomes, polymeric microcells, emulsions, microemulsions and amphiphilic polymers, surfactant dispersions, microparticles produced by colloid milling or jet milling, and the like). Solid dispersions have proven to be the most common technique for improving the solubility of poorly soluble active pharmaceutical ingredients due to their simplicity, cost-effectiveness, and advantages.

[0024] The term "solid dispersion" refers to a group of solid products containing at least two distinct components, typically a hydrophilic polymeric matrix and a hydrophobic drug. The matrix can be crystalline or amorphous. The drug can be dispersed molecularly within amorphous particles (clusters) or crystals.

[0025] The advantages of solid dispersions are due to the increased wettability of dispersions in hydrophilic carriers; reduced drug particle size and the resulting increased surface area in two-phase solid dispersions; and reduced crystallinity or the formation of amorphous systems.

[0026] Various methods for forming solid dispersions include spray drying, slow low-temperature evaporation, rotary evaporation, freeze drying, rotary drying, conventional melt cooling, hot stage extrusion, melt coagulation, and solvent evaporation (such as vacuum drying, hot plate drying, and supercritical fluid drying).

[0027] In this invention, a novel pharmaceutical composition for treating acute pain, meloxicam, comprises a meloxicam solid dispersion having at least one hydrophilic polymer and one or more alkalizing agents or combinations thereof. During solid dispersion, the drug transforms from a crystalline form to an amorphous form.

[0028] In one preferred embodiment of the present invention, the novel meloxicam pharmaceutical composition is prepared by a method comprising the step of encapsulating meloxicam in an alkaline environment.

[0029] Meloxicam is encapsulated in an alkaline environment to maintain the pH of the microenvironment towards the alkaline side, ensuring that the dissolved drug does not immediately precipitate in the acidic dissolution medium. This ensures very rapid absorption of meloxicam in vivo, resulting in a higher Cmax and a shorter Tmax curve compared to the reference product MOBIC® (meloxicam) 15 mg tablets.

[0030] In one embodiment of the invention, a novel pharmaceutical composition comprising meloxicam is provided for treating acute pain. This composition comprises a hydrophilic polymer used to prepare a solid dispersion of meloxicam. Suitable hydrophilic polymers include, but are not limited to, copovidone, hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, hydroxyethyl cellulose, PEG 6000, PEG 8000, PEG 20000, Lutrol F-127, or any combination thereof. Any other hydrophilic polymer known to those skilled in the art and found suitable for pharmaceutical compositions according to the invention may also be used in pharmaceutical compositions according to the invention.

[0031] In a further embodiment of the present invention, a novel pharmaceutical composition for treating acute pain, wherein the release rate and absorption of meloxicam can be improved with the assistance of an alkalizing agent. The alkalizing agent may include, but is not limited to, ammonium hydroxide, sodium phosphate, sodium acetate, sodium carbonate, sodium bicarbonate, meglumine, ethylamine, triethylamine, ethylenediamine, glycerol, lysine, arginine, histidine, sodium hydroxide, or any combination thereof. Any other alkalizing agent known to those skilled in the art and found suitable for pharmaceutical compositions according to the present invention may also be used in pharmaceutical compositions according to the present invention.

[0032] In one embodiment of the invention, a novel pharmaceutical composition comprising meloxicam for treating acute pain, the composition comprising an alkalizing agent of less than about 400 mg; preferably about 100 to 400 mg; or any amount within the range defined by any of such equivalents, or any amount between any of such equivalents.

[0033] The novel meloxicam pharmaceutical composition of this invention may be in tablet or capsule form, or any other oral dosage form comprising meloxicam, a hydrophilic polymer, and one or more alkalizing agents or combinations thereof, to reduce or eliminate pain or inflammation in a patient upon administration of one or more of the unit dosage forms. The components of the novel pharmaceutical composition may be in an immediate-release dosage form.

[0034] Novel pharmaceutical compositions containing meloxicam for the treatment of acute pain may be prepared by any method known to a person skilled in the art.

[0035] Novel pharmaceutical compositions containing meloxicam for the treatment of acute pain are preferably oral pharmaceutical compositions as of the present invention, which further comprise one or more pharmaceutically acceptable excipients.

[0036] A novel pharmaceutical composition comprising meloxicam for the treatment of acute pain is a composition comprising meloxicam and at least one pharmaceutically acceptable excipient, wherein the composition is acyclodextrin and its derivatives.

[0037] The excipients preferred for use in the compositions of the present invention are preferably selected from the group consisting of: diluents, binders, hydrophilic polymers, lubricants, slip agents, disintegrants, alkalizing agents, coating materials, and solvents. Any other excipients known and found suitable for the compositions according to the present invention by those skilled in the art may also be used in the compositions according to the present invention.

[0038] The novel meloxicam pharmaceutical composition of the present invention may comprise one or more suitable inert pharmaceutical diluents selected from the group consisting of: sucrose, glucose, lactose, mannitol, microcrystalline cellulose, fructose, xylitol, sorbitol, starch, and the like, and mixtures thereof.

[0039] One or more adhesives according to the invention are preferably selected from the group consisting of polyvidone (used as a synonym for polyvidone), methylcellulose, hydroxypropyl methylcellulose (HPMC) / hydroxypropyl methylcellulose, starch, gelatin, and hydroxymethylcellulose. Any other adhesives known and found suitable for compositions according to the invention by those skilled in the art may also be used in compositions according to the invention.

[0040] The novel meloxicam pharmaceutical composition of this invention may also include one or more disintegrants selected from the group consisting of croscarmellose sodium, carboxymethyl starch sodium, pregelatinized starch, and croscarmellose. Any other disintegrant known and found suitable for the composition according to the invention by those skilled in the art may also be used in the composition according to the invention.

[0041] The novel meloxicam pharmaceutical composition of this invention may also include one or more lubricants, which are selected from the group consisting of magnesium stearate, calcium stearate, glyceryl docosanoate, polyethylene glycol, stearic acid, and talc. Any other lubricant known and found suitable for the composition according to the invention by those skilled in the art may also be used in the composition according to the invention.

[0042] The novel meloxicam pharmaceutical composition according to the present invention may also contain one or more lubricating agents, including but not limited to calcium phosphate, calcium silicate, powdered cellulose, magnesium trisilicate, silica, talc, colloidal silica, anhydrous colloidal silica, and the like.

[0043] The novel meloxicam pharmaceutical composition according to the present invention may also include one or more solvents, including but not limited to isopropanol, methanol, ethanol, dichloromethane, acetone, and the like. Other suitable solvents may also be selected from dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), 1-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-2-imidazolone (DMI), acetone, tetrahydrofuran (THF), dimethylformamide (DMF), propylene carbonate (PC), glycerol, isosorbide dimethyl ether, and mixtures thereof. Aqueous solvents include water. Combinations of aqueous and non-aqueous solvents may also be used.

[0044] The novel meloxicam pharmaceutical composition according to the present invention may also include one or more coating materials, including but not limited to film-forming substances (e.g., hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol). Optionally, other excipients (such as plasticizers and colorants) may be present. Preferred plasticizers are polyethylene glycol (Macrogols, such as Macrogol 6000), triethyl citrate, and glyceryl triacetate. The coating may also contain excipients (such as excipients for better film adhesion, preferably lactose and / or stearic acid), release agents / anti-adhesion agents (preferably talc and / or glyceryl monostearate), and colorants (pigments and precipitating pigments). A preferred blend of hydroxypropyl methylcellulose, plasticizers, and colorants is commercially available under the trade name Opadry®.

[0045] The present invention relates, more preferably, to a novel pharmaceutical composition comprising meloxicam for the treatment of acute pain. More preferably, the composition contains 1 to 50 mg or 5 to 50 mg of meloxicam. Even more preferably, the composition contains 1 to 20 mg of meloxicam, or 1.25 to 15 mg of meloxicam, or 7.5 to 15 mg of meloxicam. Most preferably, the composition contains 1 mg, 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg of meloxicam.

[0046] In some embodiments of the invention, novel meloxicam medical compositions may be administered to relieve arthritis pain. In some embodiments, the pharmaceutical composition may be administered to relieve other symptoms and / or signs of arthritis. Examples of arthritis include, but are not limited to, pain associated with osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, erosive arthritis, seronegative (non-rheumatoid) joint lesions, non-articular rheumatism, periarticular diseases, neuropathic joint lesions (including Charcot's foot), midaxial spondyloarthritis (including ankylosing spondylitis), and SAPHO syndrome. In other embodiments, arthritis pain may be chronic or acute. In some embodiments, a medical composition may be administered to relieve symptoms and / or signs of arthritis including, but not limited to, osteoarthritis.

[0047] In some embodiments of the invention, the novel meloxicam medical composition may be used to treat or alleviate inflammatory diseases, pain brought about by inflammatory diseases or symptoms thereof, persistent pain after tooth extraction, sore throat, ear pain, joint pain, low back pain, myalgia, headache, shoulder muscle stiffness, pain from muscle strain or sprain, muscle Pain from tight flesh, pain from swelling, contusion pain, fracture pain, sprain or bruise pain, pain from burns, menstrual pain (painful menstruation), trauma pain, chills, febrile reactions, and / or colds and various cold symptoms (e.g., sore throat, chills, fever or fever, joint pain, and muscle pain).

[0048] The term Acute pain refers to sudden pain of a specific cause (injury, infection, inflammation, etc.) that lasts for a limited period of time (relative to chronic pain). “Chronic pain” refers to a persistent state of pain. Chronic pain is often associated with long-term incurable or refractory conditions or diseases. “Procedure pain” means pain triggered by a medical, dental procedure, or other disposition, wherein the disposition may be planned or associated with acute trauma.

[0049] The term "pain" in this document refers to all types of pain, ranging from moderate to severe. Pain includes neuropathic pain, postoperative pain, chronic lower back pain, cluster headaches, herpetic neuralgia, phantom limb pain, central pain, toothache, visceral pain, surgical pain, bone and joint pain, labor and delivery pain, burn pain, postpartum pain, migraine, angina, genitourinary pain (including cystitis), and nociceptive pain. In some cases, pain is acute. Postoperative pain or post-surgical pain, as used herein, refers to pain experienced by the subject after surgery. In some cases, this document provides methods for treating pain in human subjects, which involve administering a pharmaceutical composition containing meloxicam to human subjects in need, wherein the human subject experiences enhanced pain relief compared to human subjects administered a commercially available formulation.

[0050] Measurement of bioavailability is well known in the field of the art and includes the area under the plasma concentration-time curve (AUC), the maximum concentration (Cmax), and the time to reach Cmax (Tmax).

[0051] AUC is the area under the plasma concentration-time curve and represents the amount of drug absorbed after a single dose (Remington: The Science and Practice of Pharmacy, (Alfonso R. Gennaro ed. 2000), p. 999).

[0052] Cmax is the maximum plasma concentration achieved after oral administration of the drug (Remington, p. 999).

[0053] Tmax is the time required to reach Cmax after oral administration of a drug, and it relates to the drug's absorption rate (Remington, p. 999).

[0054] The terms "about" or "approximately" refer to an acceptable margin of error for a given value, as determined by someone of ordinary skill in the art, in part depending on the method of measurement or determination, i.e., the limitations of the measurement system, i.e., the precision required for a particular purpose (such as a pharmaceutical preparation). For example, according to convention in the art, "about" may mean within one (1) or more (1) standard deviations. Alternatively, "about" may mean a range of up to 20%, preferably up to 10%, of a given value. [Example I:] [] [Table 1: Composition of Meloxicam Tablets 15 mg] [] [Element] [Example 1] [Example 2] [Example 3] [Example 4] [Example 5] [Example 6] [Example 7] [Alkaliizing agent solution 1] [mg / ] [piece] [mg / ] [piece] [mg / ] [piece] [mg / ] [piece] [mg / ] [piece] [mg / ] [piece] [mg / ] [piece] 1 Sodium bicarbonate (Part 1) 50,000 50,000 50,000 50,000 50,000 50,000 10.000 2 Hydroxypropyl methylcellulose E3LV (Part 1) 5.000 5.000 5.000 5.000 5.000 5.000 1.000 3 Purified water qs qs qs qs qs qs qs [Dry mixing] 4 Microcrystalline cellulose PH101 270.00 220.000 220.000 220.000 220.00 220.000 220.000 5 Cross-linked polyvinylpyrrolidone (Polyplasdone XL 10) 30,000 30,000 30,000 30,000 30,000 30,000 30,000 6 Colloidal silicon dioxide (Aerosil 200) 25,000 15,000 15,000 15,000 15,000 15,000 15,000 7 Sodium bicarbonate (Part 2) 130,000 70,000 70,000 70,000 70,000 70,000 10.000 [Drug adhesive solution] 8 Meloxicam API 15,000 15,000 15,000 15,000 15,000 15,000 15,000 9 Sodium bicarbonate (Part 3) 60,000 60,000 60,000 60,000 60,000 60,000 60,000 10 Plasdone S 630 105.000 95,000 95,000 95,000 95,000 95,000 95,000 11 Purified water qs qs qs qs qs qs qs 12 Isopropanol qs qs qs qs qs qs qs [Alkaliizing agent solution 2] 13 Sodium bicarbonate (Part 4) 150,000 150,000 150,000 120.000 30,000 120.000 20,000 14 Hydroxypropyl methylcellulose E3LV (Part 2) 15,000 15,000 15,000 12.000 3.000 12.000 2.000 15 Purified water qs qs qs qs qs qs qs [External particles] 16 Cross-linked polyvinylpyrrolidone (Polyplasdone XL) 110.000 205.00 107.000 100.000 109.000 100.000 104.000 17 Sodium carbonate --- 50.00 --- --- --- --- --- 18 Colloidal silicon dioxide (Syloid 244FP) 50,000 40.00 10.000 10.000 10.000 10.000 10.000 20 Melamine --- --- --- --- --- ---- 50.00 twenty one magnesium stearate 10.000 10.00 8.000 8.000 8.000 8.000 8.000 [Core tablet weight] [1025.00] [1030.00] [850,000] [810.000] [720.00] [810.00] [650,000] twenty two opadry yellow 03F82657 30.750 --- --- 20.250 --- --- --- twenty three Isopropanol qs --- --- qs --- --- --- twenty four Purified water qs --- --- qs --- --- --- [Weight of coated tablets] [1055.75] [---] [---] [830.25] [--] [---] [---] *Evaluate changes in the concentration of alkalizing agents such as sodium bicarbonate, sodium carbonate, and meropenem. The total amount of sodium bicarbonate in each tablet varied from 100 mg to 400 mg, and very rapid dissolution was observed. [] [Brief Manufacturing Process:] []

[0055] 1. A solution of alkalizing agent-1 is prepared by dissolving sodium bicarbonate (part 1) and hydroxypropyl methylcellulose E3LV (part 1) in purified water. 2. Microcrystalline cellulose PH101, crospovidone, colloidal silicon dioxide, and sodium carbonate are sieved and granulated together with the solution of alkalizing agent-1 in the first step to obtain alkalizing agent-based particles. 3. Sodium carbonate (Part 3) and copovidone are dissolved in purified water, and meloxicam is added to this solution to form a dispersion. Isopropanol is added to the dispersion with stirring to obtain a meloxicam solution. 4. The alkalized particles are further granulated using the meloxicam suspension from the third step in the fluid bed processor. 5. Alkalizing agent solution-2 was prepared by dissolving sodium bicarbonate (part 4) and hydroxypropyl methylcellulose E3LV (part 2) in purified water. 6. The drug particles are further granulated using the solution of alkalizing agent-2 from step 5 to obtain drug particles. Particle exterior 7. Cross-linked polyvinylpyrrolidone (Polyplasdone XL) and colloidal silicon dioxide (Syloid 244FP) are sieved through a suitable screen and blended with drug particles in a blender. The blend is lubricated with magnesium stearate in the blender. 8. The lubricated blend is compressed using a suitable tool on a rotary compressor. The core tablet is finally coated in an automated coating disc using an Opadry hydrolactic dispersion. [Example II:] [] [surface] [2] [Meloxicam tablets] [15 mg] [The components-] [MUPS] [preparation] [] [Element] [Example] [7] [Alkaliizing agent solution] [1] [mg / ] [piece] 1 Sugar Balls (60 / 80) 100.00 2 Hydroxypropyl methylcellulose E5LV (Part 1) 20.00 3 Sodium bicarbonate (Part 1) 100.00 4 Purified water qs [Drug adhesive solution] 5 Meloxicam API 15,000 6 Sodium bicarbonate (Part 2) 60,000 7 Plasdone S 630 95,000 8 Purified water qs 9 Isopropanol qs [Alkaliizing agent solution] [2] 10 Sodium bicarbonate (Part 3) 170,000 11 Hydroxypropyl methylcellulose E5LV (Part 2) 40,000 12 Purified water qs [External particles] 13 Cross-linked polyvinylpyrrolidone (Polyplasdone XL) 20,000 14 Microcrystalline cellulose pH 102 (Avicel pH 102) 365.000 15 magnesium stearate 10.000 [Core tablet weight] [995.00] 16 Opadry White 03F58750 25,000 17 Purified water qs [Weight of coated tablets] [1020.00] *The alkalizing agent and drug binder solution are sprayed onto the sugar beads. The order of adding the alkalizing agent, drug binder solution, and then adding the alkalizing agent again remains the same. [Brief Manufacturing Process:] []

[0056] 1. A solution of alkalizing agent 1 is prepared by dissolving sodium bicarbonate (Part 1) and hydroxypropyl methylcellulose E5LV (Part 1) in purified water. 2. Coat the sugar balls (60 / 80) with the alkalizing agent solution-1 from the first step to obtain alkalized sugar balls. 3. Sodium carbonate (Part 2) and copovidone are dissolved in purified water, and meloxicam is added to this solution to form a dispersion. Isopropanol is added to the dispersion with stirring to obtain a meloxicam solution. 4. The meloxicam solution from step 3 is used in the fluid bed processor to further coat the alkalized sugar spheres. 5. Alkalizing agent solution 2 is prepared by dissolving sodium bicarbonate (Part 3) and hydroxypropyl methylcellulose E5LV (Part 2) in purified water. The solution of alkalizing agent 2 is then used to further coat drug-loaded pellets to obtain drug pellets. Particle exterior 6. Cross-linked polyvinylpyrrolidone (Polyplasdone XL), microcrystalline cellulose PH 102 (Avicel PH 102), and colloidal silicon dioxide (Syloid 244FP) are sieved through a suitable sieve and blended with drug-loaded pellets in a blending machine. 7. The blending system is lubricated with magnesium stearate in the blending machine. 8. The lubricated mixture is compressed using a suitable tool on a rotary compressor. 9. The core tablets are finally coated in an automated coating tray using Opadry's hydroalcoholic dispersion. The data reported in the table below show that rapid drug release was observed under the studied solubility conditions of 0.1N HCl and pH 4.5 acetate buffer. Drug release with these components was observed to be substantially higher than that of the currently marketed MOBIC® (meloxacin) 15 mg tablets. [Table 3: Dissolution data for meloxicam tablets 15 mg] [] [] [Dissolution conditions: 0.1 N HCl, 900 ml, USP Apparatus II (Paddle), 75 rpm] [] [] [Batch number and percentage of dissolved drug] [Time (minutes)] [Reference Product -] [MOBIC®] [15 mg tablets] [Example 1] [Example 2] [Example 3] [Example 4] [Example 5] [Example 6] [Example 7] [5] 1 88 73 92 92 80 82 48

[15] 3 88 84 93 93 91 90 65

[30] [5] 88 87 96 93 75 78 69

[60] 6 86 83 94 92 72 60 69 [*] The table presents solubility data for Examples 1 to 7 with different alkalizing agent concentrations. [] [Table 4: Dissolution data for meloxicam tablets 15 mg] [] [Dissolution conditions: pH 4.5 acetate buffer, 900 ml, USP Apparatus II (Paddle), 75 rpm] [] [Batch number and percentage of dissolved drug] [Time (minutes)] [Reference Product -] [MOBIC®] [15 mg tablets] [Example 1] [Example 2] [Example 4] [Example 7] [5] 4 94 94 78 79

[15] [7] 96 98 96 81

[30] 9 95 98 100 87

[60] 11 95 98 98 89

[0057] The above dissolution data indicate that, compared with the commercially available reference product MOBIC® (meloxicam) 15 mg tablets, the tablets prepared using the aforementioned invention have a faster dissolution rate. [Pharmacokinetic properties of meloxicam components:]

[0058] The pharmacokinetic profile of the meloxicam composition of this invention was substantially unaffected by the fasting status of human subjects ingesting the meloxicam composition. Furthermore, when compared to the reference product MOBIC® (meloxicam) 15 mg tablets, the composition of this invention substantially reduced T max and increased C max of the meloxicam composition. Therefore, it will be beneficial for the treatment of acute pain conditions.

[0059] Preferably, the Tmax of the administered dose of the meloxicam composition of the present invention is lower than that of the reference product MOBIC® (meloxicam) administered at the same dose. In comparative pharmacokinetic tests with the reference product MOBIC® (meloxicam) 15 mg tablets, the preferred meloxicam composition of the present invention, in the form of oral suspension, capsules, or tablets, exhibited a Tmax that was approximately 100%, approximately 90%, approximately 80%, approximately 70%, approximately 60%, approximately 50%, approximately 40%, approximately 30%, approximately 25%, approximately 20%, approximately 15%, and approximately 10% lower than that of the reference product MOBIC® (meloxicam) 15 mg tablets. Quick start working:

[0060] The meloxicam composition of the present invention exhibits a faster therapeutic effect. In one embodiment, administration of the meloxicam composition of the present invention containing meloxicam resulted in a Tmax that was approximately 4 hours, 3.5 hours, 3 hours, 2.75 hours, 2.5 hours, 2.25 hours, 2 hours, 1.75 hours, 1.5 hours, 1.25 hours, 1.0 hour, 50 minutes, 40 minutes, 30 minutes, 25 minutes, 20 minutes, and 15 minutes shorter than that of the reference product MOBIC® (meloxicam) 15 mg tablets. Increased bioavailability:

[0061] When compared to MOBIC® (meloxicam) 15 mg tablets administered at the same dose, the meloxicam composition of this invention exhibits an increased bioavailability (AUC). When administered in a fasting state, the absorption differential of the meloxicam composition of this invention is approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% greater than that of MOBIC® (meloxicam) 15 mg tablets. This is a particularly important feature when treating patients with acute pain who have difficulty maintaining a fasting state.

[0062] Furthermore, the Cmax of the meloxicam composition of the present invention is greater than that of the reference product MOBIC® (meloxicam) 15 mg tablet administered at the same dose. The preferred meloxicam composition of the present invention exhibits a Cmax that is approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, approximately 90%, approximately 100%, approximately 110%, approximately 120%, approximately 130%, approximately 140%, or approximately 150% higher than that of the reference product MOBIC® (meloxicam) 15 mg tablet.

[0063] In one embodiment, after administration of a novel pharmaceutical composition comprising meloxicam for the treatment of acute pain, the Cmax of meloxicam is between about 2000 ng / ml and about 3500 ng / ml; preferably between about 2200 ng / ml and about 3400 ng / ml; or any Cmax within the range defined by any of such equivalents, or any Cmax within the range between any of such equivalents.

[0064] Following a single oral dose of 15 mg under fasting conditions, a single-dose, randomized, two-phase, two-therapeutic, two-sequence, crossover bioequivalence study was conducted on the test product meloxicam tablets 15 mg according to the present invention (Example 4) against the reference product MOBIC® (meloxicam) tablets 15 mg distributed by Boehringer Ingelheim Pharmaceuticals, Inc.

[0065] Following a single oral dose of 15 mg of the study drug under fasting conditions, single-dose pharmacokinetics were characterized in 18 healthy adult subjects (2 subjects withdrew). To determine the pharmacokinetic dynamics of the formulation, a total of 50 blood samples were collected, representing a total of 200 mL of blood collected from each subject for pharmacokinetic analysis, assuming all blood collections were completed by the subjects. Dosings during the treatment period were spaced at least 12 days apart.

[0066] The bioequivalence of the test product meloxicam tablets 15 mg and the reference product MOBIC® (meloxicam) tablets according to the present invention was assessed by statistical comparison of various pharmacokinetic parameters obtained from plasma concentrations, as presented below. [surface] [5] Summary of meloxicam pharmacokinetics data [(n=16)] [dose:] [1 x 15 mg] [parameter] [] [Test Product (A): Meloxicam] [USP 15 mg tablets] [Reference Product (B): MOBIC®] [Meloxicam Tablets 15 mg] N Arithmetic Mean [±] [Standard deviation (coefficient of variation (%))] N Arithmetic Mean [±] [Standard deviation (coefficient of variation (%))] T max (hours) 16 0.750 (0.333-3.500) 16 4,000 (2,000-8,000) T1090 (hours)^ 16 0.333 (0.333-0.500) 16 3,000 (1,250-6,000) C max(ng / mL) 16 2786.072±558.429 (20.044) 16 1611.147±248.539 (15.426) AUCt (ng / mL)*(hours) 16 49700.363±16123.474 (32.441) 16 42834.546±11236.963 (26.233) AUCi (ng / mL)*(hours) 16 55910.213±24751.922 (44.271) 16 48233.472±17534.480 (36.353) T1090 = the time when the concentration first exceeds 1090 ng / mL (^) T1090 and Tmax are presented as median (range). [Table 6: Test (A) vs. Reference (B), 90% confidence interval and rates of use for meloxicam (n=16)] [Pharmacokinetic parameters] [90%] [Confidence Interval] [ratio(%)] C max(ng / mL) (159.92%-184.44%) 171.74% AUC t(ng / mL) (hours) (109.37%-119.24%) 114.20% AUC i(ng / mL) (hours) (108.02%-119.00%) 113.38%

[0067] Based on the results provided in Tables 5 and 6 above, compared with the reference product MOBIC® (meloxicam) 15 mg tablets distributed by Boehringer Ingelheim Pharmaceuticals, Inc., the median T max for the test product meloxicam 15 mg tablets was 5 times faster (0.75 hours vs. 4 hours, respectively). As expected for this meloxicam formulation designed for the treatment of acute pain, the test product exhibited faster absorption than MOBIC®, as evidenced by higher C max, higher pAUC, shorter T max, and a faster time to reach 1090 ng / mL (as supported by the review criteria for Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations established by the FDA's Center for Drug Evaluation and Research (CDER) in March 2003).

Claims

1. A solid oral medical tablet for the treatment of acute pain comprising an effective amount of amorphous meloxicam, at least one hydrophilic polymer, and one or more alkalizing agents for the treatment of acute pain, wherein the tablet provides a Tmax of less than 4 hours for meloxicam in a human subject under fasting conditions.

2. A solid oral medical pharmaceutical tablet of claim 1, wherein the tablet has rapid drug release and increased absorption rate.

3. A solid oral medical tablet of claim 2, wherein the tablet has a dissolution rate greater than 90% by weight within 15 minutes.

4. If the solid oral medical tablet of claim 1, wherein the acute pain is from a joint disease, or the pain is post-surgical pain; 5. As in the solid oral medical tablet of claim 4, wherein the joint disease comprises an arthritic or inflammatory condition.

6. As in the solid oral medical tablet of claim 5, wherein the arthritis or inflammatory condition comprises rheumatoid arthritis, osteoarthritis, ankylosing spondylitis.

7. As in the solid oral medical tablet of claim 1, wherein the tablet comprises 5 mg to 50 mg of meloxicam.

8. A solid oral medical tablet of claim 7, wherein the tablet comprises 7.5 mg to 15 mg of meloxicam.

9. If the solid oral medical tablet of claim 1, wherein the tablet further comprises a combination of one or more diluents, adhesives, lubricants, slip aids, disintegrating agents, coating materials, solvents, or the like.

10. As in the solid oral medical tablet of claim 1, wherein the hydrophilic polymer is selected from the group consisting of copovidone, hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, hydroxyethyl cellulose, or a combination thereof.

11. As in the solid oral medical tablet of claim 10, wherein the hydrophilic polymer is a conjugated vitriol.

12. As in the solid oral medical tablet of claim 1, wherein the alkalizing agent is selected from a combination of sodium carbonate, sodium bicarbonate, meglumine, calcium carbonate, and the like.

13. As in the solid oral medical tablet of claim 12, wherein the alkalizing agent is sodium bicarbonate.

14. As in the solid oral medical tablet of claim 13, wherein the sodium bicarbonate is present in a quantity from 100 mg to 400 mg.

15. As in the solid oral medical tablet of claim 14, wherein the amount of the sodium bicarbonate is 100 mg.

16. As in the solid oral medical tablet of claim 14, wherein the amount of the sodium bicarbonate is 200 mg.

17. As in the solid oral medical tablet of claim 14, wherein the amount of the sodium bicarbonate is 300 mg.

18. As in the solid oral medical tablet of claim 14, wherein the amount of the sodium bicarbonate is 400 mg.

19. The solid oral medical tablet of claim 1, wherein the oral tablet has a median of less than 90 minutes of one meloxicam Tmax in the body of a human subject in a fasted state.

20. A solid oral pharmaceutical tablet as claimed in claim 1, wherein the oral tablet has a median meloxicam Tmax of less than 60 minutes in a fasting human subject.

21. A solid oral pharmaceutical tablet for treating acute pain, the tablet comprising an effective amount of amorphous meloxicam for treating acute pain, at least one hydrophilic polymer, and one or more alkalizing agents, wherein the tablet provides a plasma concentration (Cmax) of meloxicam between 2000 ng / ml and 3500 ng / ml.

22. The solid oral pharmaceutical tablets as claimed in claim 21, wherein the Cmax of meloxicam is between 2200 ng / ml and 3400 ng / ml.

23. The solid oral pharmaceutical tablet of claim 1, wherein the tablet is prepared by a method comprising the step of encapsulating the meloxicam in an alkaline environment.

24. The solid oral pharmaceutical tablet of claim 21, wherein the one or more alkalizing agents are selected from ammonium hydroxide, sodium phosphate, sodium acetate, sodium carbonate, sodium bicarbonate, meglumine, ethylamine, triethylamine, ethylenediamine, glycerol, lysine, arginine, histidine, sodium hydroxide, and combinations thereof.