Patent Description:
Naproxen is a propionic acid derivative. It is a nonsteroidal anti-inflammatory drug and a potent inhibitor of the cyclooxygenase responsible for the biosynthesis of prostaglandins Naproxen has anti-inflammatory, analgesic and antipyretic activity in man. Naproxen and salts of naproxen are indicated for the reduction of fever and the treatment of pain, e.g. arthritis pain, pain of inflammation, muscular ache, backache, headache, migraine pain, pain of menstrual cramps, toothache, and pains associated with common cold.

<NPL>) reports that following oral administration, naproxen is rapidly and completely absorbed, and the extent of absorption results in similar exposure, as measured by area under the concentration-time curve, compared with intravenous administration. The rapidity but not the extent of absorption is affected by the presence of food in the stomach. Maximum plasma concentration is typically achieved within <NUM>-<NUM> hours after administration of naproxen sodium.

Speed to the onset of pain relief is an important unmet need in the pain care space. Improving the rate and extent of absorption of oral formulations of compounds has been and continues to be researched. Once an immediate release solid swallow composition reaches the stomach, it undergoes disintegration and/or dissolution and passes into the small intestine where the active ingredient is absorbed across the intestinal walls into the circulatory system via the portal vein and liver before reaching the site of action. For drugs where absorption is not rate limited, such as naproxen, fast disintegration and fast dissolution of the active ingredient will promote fast absorption in vivo. <CIT>) discloses formulations manufactured as immediate release solid dosage forms intended to be swallowed intact, which achieve fast dissolution and fast absorption of an active ingredient, including naproxen.

However, naproxen does have pH related solubility. In pH above <NUM>, naproxen stays in solution. At lower acidic pH conditions, naproxen sodium dissolves but immediately precipitates out into a fine colloidal particulate matter of naproxen. If naproxen precipiates in the stomach, the naproxen must pass into the small intestine before it solubilizes and re-dissolves. This may create a delay in absorption.

Patent application publication <CIT> describes this phenomenon and discloses a non-effervescent form of sodium naproxen comprising sodium hydrogen carbonate. It describes the formation of agglomerates of precipitated naproxen to larger, poorly soluble naproxen crystal agglomerates, and proposes formulations to minimize potential poor solubility and bioavailability.

Applicants have now discovered an improved immediate release solid dosage form with a certain particle size distribution for the intragranular portion, and a certain particle size distribution for the carbonate portion which allows for naproxen to remain in solution and achieves faster dissolution and faster absorption of naproxen in humans. In particluar, applicants have discovered a naproxen dosage form that when administered to a human in a fasted state provides an average blood plasma naproxen concentration of at least <NUM>-<NUM>µg/ml in <NUM> minutes or less. Applicants have further discovered a naproxen dosage form that when administered to a human in a fed state provides an average blood plasma naproxen concentration of at least <NUM>-<NUM>µg/ml in <NUM> minutes or less for compositions comprising <NUM> to <NUM> of a carbonate compound. Applicants have further discovered a naproxen dosage form that when administered to a human in a fed state provides an average blood plasma naproxen concentration of at least <NUM>-<NUM>µg/ml in <NUM> minutes or less for compositions comprising <NUM> of a carbonate compound.

The present invention provides an improved immediate release solid dosage form of naproxen sodium that achieves fast dissolution in the stomach, allows naproxen to remain in solution and achieves fast absorption of naproxen. Particularly, the present invention provides an immediate relase naproxen sodium dosage form for use in a method of treating pain, which method comprising administering said dosage form toa human in a fasted state to provide an average blood plasma naproxen concentration of at least <NUM>-<NUM>µg/ml in <NUM> minutes or less, wherein said dosage form comprises an intragranular portion comprising an effective amount of naproxen sodium and an extragranular portion comprising a carbonate compound in an amount from about <NUM> to <NUM>. The present invention also provides an immediate release naproxen dosage form for use in a method of treating pain, said method comprising administering said dosage formto a human in a fed state to provide an average blood plasma naproxen concentration of at least <NUM>-<NUM>µg/ml in <NUM> minutes or less, wherein said dosage form comprises an intragranular portion comprising an effective amount of naproxen, salts thereof and combinations thereof, and an extragranular portion comprising a carbonate compound in an amount from <NUM> to <NUM> of a carbonate compound.

In one embodiment, the immediate release solid dosage form of naproxen sodium has an intragranular particle size distribution of about <NUM>-<NUM> microns. In another embodiment, the immediate release solid dosage form of naproxen has a carbonate particle size distribution of about <NUM>-<NUM> microns.

The drawings described herein are for illustrative purposes only of selected embodiments, and are not intended to limit the scope of the present disclosure.

The present invention is directed to the use of a composition which delivers a time to a specific average blood plasma (therapeutic) concentration in mammalian subjects which correlates to pain relief. This minimum effective therapeutic plasma concentration (MEC) for naproxen is defined herein as between <NUM> to <NUM>µg/mL. In one embodiment this is regarded as administration in a fasted condition with a resulting time to the MEC of a range of <NUM> minutes to <NUM> minutes. In one embodiment the time to MEC in a fasted condition is less than <NUM> minutes, or less than <NUM> minutes, or less than <NUM> minutes. In another embodiment the time to minimum effective therapeutic concentration in a fed condition is in a range of <NUM> minutes to <NUM> minutes. In another embodiment, the time to MEC in a fed condition is less than <NUM> minutes, or less than <NUM> minutes, or less than <NUM> minutes, or less than <NUM> minutes, or less than <NUM> minutes, or less than <NUM> minutes.

The present invention can be further defined as the time to maximum plasma concentration. In one embodiment the time to maximum plasma concentration is less than <NUM> minutes, or less than <NUM> minutes or less than <NUM> minutes.

The composition of the present invention contains an intragranular portion and an extragranular portion. The intragranular portion may contain naproxen sodium, compression fillers, binders and disintegrants. Compressible fillers include but are not limited to microcrystalline cellulose, directly compressible microcrystalline cellulose, celluloses,water insoluble celluloses, starch, cornstarch and modified starches. Suitable fillers include but are not limited to starch and modified starches. The filler may be added at a range of about <NUM> percent to about <NUM> percent, or from about <NUM> percent to about <NUM> percent by weight of the tablet. Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and mixtures thereof. Disintegrants may be added at a range from about <NUM> percent to about <NUM> percent, or from about <NUM> percent to about <NUM> percent by weight of the tablet. In one embodiment the disintegrant is added in the intragranular portion at a range of from about <NUM> percent to about <NUM> percent and in the extragranular portion at a range from about <NUM> percent to about <NUM> percent by total weight of the tablet.

Extragranular materials include carbonates, compression fillers, lubricants, flow aids, and disintegrants. Suitable carbonates include potassium bicarbonate and sodium bicarbonate. Suitable lubricants include magnesium stearate and stearic acid. The lubricant or flow aid may be added at a range of from about <NUM> percent to about <NUM> percent, of from about <NUM> percent to about <NUM> percent by weight of the tablet. Suitable flow aids include silicon dioxide. In certain embodiments, the tablet comprises less than <NUM> percent magnesium stearate, or less than <NUM> percent magnesium stearate. In one embodiment the compression filler in the extragranular portion is microcrystalline cellulose. In this embodiment the microcrystalline cellulose has a mean particle size of less than <NUM> microns, or less than <NUM> microns.

In one embodiment the extrangraular portion comprises a "pH modulating agent" and includes one or more than one pH modulating agents which alter the pH of an aqueous solution. These may include acids, bases or a combination of one or more acids and/or bases.

The carbonate may be any pharmaceutically acceptable soluble carbonate or a mixture thereof and includes bicarbonate. Reference to a "bicarbonate" or a "carbonate" includes a single agent or multiple (i.e. two or more) agents. Preferred carbonates include but are not limited to sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium bicarbonate, calcium carbonate, magnesium bicarbonate, magnesium carbonate, ammonium bicarbonate, ammonium carbonate, sodium glycine carbonate, disodium glycine carbonate, arginine carbonate, lysine carbonate and/or other pharmaceutically acceptable carbonates or homologs or functional equivalents thereof and combinations thereof. The carbonate may be added at a range of from about <NUM> percent to about <NUM> percent, or from about <NUM> percent to about <NUM> percent by weight of the tablet. In one embodiment the intragranular portion is substantially free of the carbonate. By substantially free, as used herein, the intragranular portion comprises less than <NUM> percent of carbonate by weight of the tablet.

The carbonates of the present invention have a mean particle size range of from about <NUM> microns to about <NUM> microns, or from about <NUM> microns to about <NUM> microns. The particle size of the carbonate portion of the present invention contributes to the dissolution of the composition. It was found that the higher the particle size of the carbonate, the slower the dissolution profile of the composition.

The intragranular portion of the present invention also comprises physical characteristics which contribute to the dissolution of the composition. In one embodiment the mean particle size of the intragranular portion is from about <NUM> microns to about <NUM> microns, or from about <NUM> microns to about <NUM> microns.

Naproxen sodium has pH related solubility. In pH above <NUM>, naproxen sodium stays in solution. At lower acidic pH, naproxen sodium dissolves but immediately precipitates out into a fine colloidal particulate matter. If the naproxen precipiates in the stomach, the naproxen must pass into the small intestine before it re-dissolves creating a delay in absorption. The particle size of the intragranular and carbonate portions of the invention help keep the active ingredient naproxen in solution as it dissloves in the acidic pH of the stomach. The carbonate portion of the dosage form dissolves at a rate such that it raises the pH of the milieu in the micro and macro environment of the stomach which facilitates the dissolution of naproxen and allows the naproxen to remain in solution and allows absorption of naproxen to begin in the stomach.

In certain embodiments bulk density of the intragranular portion is from about <NUM> to about <NUM>/cc, or from about <NUM> to about <NUM>/cc. In certain embodiments, the tablet of the present invention is compressed at specific compression force ranges, including from about <NUM> kilonewtons to about <NUM> kilonewtons, for a hardness of from about <NUM> kiloponds to about <NUM> kiloponds. In embodiments where <NUM> of bicarbonate is incorporated into the tablet blend, the tablet comprises a hardness of about <NUM> kiloponds to about <NUM> kiloponds. In embodiments where <NUM> of carbonate is used, the tablet comprises a hardness of about <NUM> kiloponds to about <NUM> kiloponds.

Hardness is a term used in the art to describe the diametral breaking strength as measured by conventional pharmaceutical hardness testing equipment, such as a Schleuniger Hardness Tester. In order to compare values across different size tablets, the breaking strength must be normalized for the area of the break. This normalized value, expressed in kp/cm2, is sometimes referred in the art as tablet tensile strength. A general discussion of tablet hardness testing is found in <NPL>.

In other embodiments the tablets of the present invention disintegrate in water. In this case the disintegration time is measured using the Disintegration test and apparatus in USP <NUM>, Section <NUM> using deionized water at <NUM>. The disintegration time for tablets of the present invention are less than <NUM> minutes, or less than <NUM> minutes and <NUM> seconds. In other embodiments the granulation (intragranular portion) is granulated and passed as a wet material through a mill prior to drying. In other embodiments, the dosage form may be a tablet, capsule, powder or other unit presentation. These dosage forms may also comprise an intragranular and extragranular portion.

Preferably, the carbonate is present in an amount from about <NUM>% to about <NUM>% by weight of swallow formulation and in an amount that will neutralise between about <NUM> and <NUM> millimoles of hydrochloric acid. More preferably the carbonate is present in an amount from about <NUM>% to about <NUM>% by weight in the swallow formulation and in an amount that will neutralise between about <NUM> and <NUM> millimoles of hydrochloric acid. The carbonate component of the pH modulating agent is present in an amount from about <NUM> to about <NUM> in the swallow formulation, or from about <NUM> to <NUM>. Examples of other particular amounts of carbonate include <NUM> to <NUM> per swallow formulation. More preferably the carbonate is present in an amount from about <NUM> to <NUM>.

In one swallow formulation embodiment, the carbonate is sodium bicarbonate and/or potassium bicarbonate and is present in an amount from about <NUM>% to <NUM>% by weight of the swallow formulation.

The water uptake agent may be present in an amount from <NUM>% to <NUM>%, or <NUM>% to <NUM>% or more preferably from <NUM>% to <NUM>% by weight of the swallow formulation and more preferably between <NUM>% and <NUM>% by weight of the swallow formulation.

Preferably, the ratio of water uptake agent to pH modulating agent is between <NUM>:<NUM> and <NUM>:<NUM>. More preferably the ratio of water uptake agent to pH modulating agent is between <NUM>:<NUM> and <NUM>:<NUM> or even more preferably between <NUM>:<NUM> and <NUM>:<NUM> by weight.

Typically, at least <NUM>% of the therapeutic compound is dissolved from the swallow formulation within <NUM> seconds in USP dissolution apparatus <NUM> with <NUM> <NUM> N hydrochloric acid at <NUM> rpm and <NUM>° C. In a preferred embodiment at least <NUM>% of the therapeutic compound is dissolved from the swallow formulation within <NUM> seconds in USP dissolution apparatus <NUM> with <NUM> <NUM> N hydrochloric acid at <NUM> rpm and <NUM>° C. In another embodiment, at least <NUM>% is dissolved in <NUM> seconds. In another embodiment, at least <NUM>% is dissolved from the swallow formulation within <NUM> seconds in USP dissolution apparatus <NUM> with <NUM> of pH <NUM> phosphate buffer at <NUM> rpm and <NUM>° C. In a preferred embodiment at least <NUM>% is released within <NUM> seconds in USP dissolution apparatus <NUM> with <NUM> of pH <NUM> phosphate buffer at <NUM> rpm and <NUM>° C.

This study which was conducted was an open-label, single-dose, randomized, crossover study design conducted in three parts and five separate treatment periods. Thirty healthy subjects, ages <NUM> to <NUM> years were enrolled. No less than approximately <NUM>% of either gender were represented in the study population.

Part <NUM> of the study was a fasted, three-way crossover design in which all subjects were randomized to six sequences of Treatments A, B and C over consecutive periods, combined with one of treatments D and E in Part <NUM>, and one of treatments F, G and H in part <NUM>.

In Part <NUM>, the treatments consisted of a single dose of naproxen sodium as test <NUM> tablet formulation <NUM> (Treatment A), test <NUM> tablet formulation <NUM> (Treatment B) and Aleve® <NUM> tablet (Treatment C), that were administered with approximately <NUM> water after an overnight fast of at least <NUM> hours.

In Part <NUM>, the treatments were a single dose of naproxen sodium as Nalgesin S® <NUM> tablet (Treatment D) or Aleve <NUM> Liquid Gels® (Treatment E). In Part <NUM>, the treatments were a single dose of naproxen sodium as test <NUM> tablet formulation <NUM> (Treatment F), test <NUM> tablet formulation <NUM> (Treatment G), or Aleve® <NUM> tablet (Treatment H) approximately <NUM> minutes after the start of a high-fat breakfast. The dose was swallowed with approximately <NUM> water.

A washout period of at least <NUM> days separated the treatment administration. In each study period, <NUM> blood samples for pharmacokinetic analysis were taken within <NUM> hour before and at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> minutes, as well as at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>, <NUM>, and <NUM> hours after drug administration. Plasma was harvested and quantified for naproxen using a validated analytical method. Subjects were monitored to report any adverse events that may occur.

Part <NUM>. To compare the bioavailability of naproxen sodium from single doses of:.

Part <NUM>. To compare bioavailability of naproxen sodium from single dose of:.

Part <NUM>. To assess potential food effects by comparing the bioavailability of naproxen sodium from single doses of:.

Test products, dosage, and mode of administration:.

Reference product, dosage, and mode of administration:.

Duration of Study: The study duration was about nine weeks, which includes duration for eligibility screening (between one and <NUM> days before first dose administration) and five separate treatment periods. Subjects remained at the study site for the duration of each treatment period.

The following pharmacokinetic (PK) parameters were determined by means of non-compartmental analysis for each subject and treatment:
Cmax (maximum plasma concentration), Tmax (time to maximum concentration), and plasma naproxen concentrations at <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM> minutes (Cp5MIN Cp10MIN, Cp20MIN, Cp40MIN, Cp60MIN and Cp80MIN), λZ (rate constant) and Thalf (half life).

The proposed sample size calculations are for part <NUM> of the study. Assuming an intra-subject coefficient of variation (CV) of <NUM>% for CMAX, a sample size of <NUM> subjects were provided at least <NUM>% power to ensure the two-sided <NUM>% confidence interval for the ratio will be between <NUM>-<NUM>% of the reference product, should the true mean ratio of Test to Reference product be between <NUM> and <NUM>. The estimate of <NUM>% intra-subject CV was observed in previous Naproxen bioequivalence study. See <NPL>; and <NPL>).

Analysis for Cmax, as well as the naproxen plasma concentrations at <NUM>, <NUM> and <NUM> minutes (Cp<NUM>, Cp<NUM>, and Cp<NUM>) were as follows:
Statistical comparisons of pairs of treatment (A versus B, A versus C, B versus C) were based on log transformed (natural log) pharmacokinetic parameter data. A mixed-effect analysis of variance model that includes treatment, period, and treatment sequence as fixed effects, and subject within sequence as a random effect, were used to estimate the least squares means and intra-subject variance. Model-based <NUM>% confidence intervals for the geometric mean ratio of Cmax corresponding to the reference.

During each study period, blood samples (<NUM>) for pharmacokinetic analysis were collected into appropriately labeled K2EDTA vacutainer® blood collection tubes. The tube labels included the following information (at a minimum): protocol number, subject identification number, sampling time, study period, and any applicable site specific sample identification code.

Blood samples were collected before dosing (predose) and at specific times following each designated dose. The pharmacokinetic samples were collected at the exact nominal time relative to dosing. Samples collected outside of <NUM>-minute window for postdose time points up to <NUM> minutes or outside of <NUM>-minute window for time points after <NUM> minutes will be captured as protocol deviations. The exact time of the sample collection were noted on the source document and data collection tool (e.g. CRF).

After drawing the blood, the tube was gently inverted approximately eight times after collection and immediately placed in an ice bath for transport to a centrifuge. Samples were kept on ice and processed into plasma within <NUM> minutes. Any deviations regarding the pharmacokinetic blood sample and handling process were recorded on the appropriate log.

Samples were centrifuged at high speed (~<NUM> revolutions per minute) for approximately <NUM> minutes at approximately <NUM> nominal. As soon as the centrifuge stops, the samples were returned to an ice bath. Plasma was withdrawn into two equally divided aliquots in an appropriately labeled polypropylene transfer tube (polypropylene push- cap tube) (which can hold approximately <NUM> plasma). The tubes were labeled with freezer-safe labels and/or marked by permanent marker, and the labels were filled out and affixed to the tube before placing plasma into the tube.

Samples were placed in the freezer (approximately -<NUM> nominal) within <NUM> minutes from the time of collection and stored until shipped. The time samples were placed in the freezer will be recorded in a sample accountability record. Samples were analyzed using a validated analytical method in compliance with the standard operating procedures of the bioanalytical laboratory. The range of validated method was <NUM>µg/mL to <NUM>µg/mL.

The following single-dose pharmacokinetic parameters for naproxen sodium in plasma were estimated using noncompartmental methods:.

Cmax parameters for Nalgesin S® <NUM> tablet (E) were presented with dose normalized and without dose normalized data.

Comparisons were assessed of potential food effects by comparing the bioavailability of naproxen sodium from single doses of:.

Statistical comparisons of pairs of treatment fed versus fasted states (F versus A, G versus B, H versus C) for set <NUM> PK parameters were analyzed using paired t test for log transformed (natural log) pharmacokinetic parameter. <NUM>% confidence intervals for the geometric mean ratio of Cmax corresponding to the reference treatment (F versus A, G versus B, H versus C) will be calculated in each case.

The following formulations were prepared for use in the PK study.

Granulation and Tableting Procedure (for Formulation <NUM> (Table <NUM>) & Formulation <NUM> (Table <NUM>)):.

The formulations in Table <NUM> were tested for dissolution using a USP dissolution apparatus <NUM> with <NUM> of <NUM> N hydrochloric acid at <NUM> rpm and <NUM>° C. Samples were pulled at respective timepoints and analyzed via a high pressure liquid chromatography (HPLC) apparatus equipped with a Phenomenex Kinetex C18 column (<NUM> X <NUM>); with a mobile phase of <NUM>:<NUM> Water: Methanol plus <NUM>% trifluoroacetic acid; a flow rate of <NUM>/min; an injection volume of <NUM>µL; a UV detector set at <NUM>; and a column temperature of <NUM>.

The formulations in Table <NUM> were also tested for dissolution using a USP dissolution apparatus <NUM> with <NUM> of <NUM> phosphate buffer at <NUM> rpm and <NUM>° C. The data is shown in Table <NUM>. The dissolution method (media, apparatus, speed, temperature) was the same as for naproxen sodium tablets as defined by USP <NUM>-NF <NUM>. The method for analyzing the pulled dissolution samples was the same as those for Table <NUM>.

Claim 1:
An immediate release naproxen sodium formulation for use in a method for the treatment of pain,
which method comprises administering said formulation to a fasted subject in need thereof so that the blood plasma concentration levels of naproxen range from and include at least <NUM>-<NUM>µg/ml in <NUM> minutes or less,
wherein said formulation comprises an intragranular portion comprising naproxen sodium, and an extragranular portion comprising a carbonate compound in an amount from about <NUM> to <NUM>,
wherein the mean particle size of the carbonate is from about <NUM> microns to about <NUM> microns, and
wherein the mean particle size of the intragranular portion is from about <NUM> microns to about <NUM> microns.