# Patent

## Title
Method for delivering a pharmaceutical composition to patient in need thereof

## Abstract

The present disclosure is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof.

## Background
This application is a continuation application of U.S. patent application Ser. No. 12/553,107, filed Sep. 3, 2009, now U.S. Pat. No. 9,220,698, issued on Dec. 29, 2015, which claims priority to U.S. Provisional Patent Application No. 61/095,584, filed Sep. 9, 2008. The entire contents of the above-referenced disclosures are specifically incorporated herein by reference.


The present disclosure is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof.
Over 15 million Americans take nonsteroidal anti-inflammatory drugs (NSAIDs) each day as a treatment for pain or inflammation. Unfortunately, many of these NSAIDs are associated with a high incidence of gastrointestinal complications, including gastritis, dyspepsia, gastroduodenal ulcers, perforations, and bleeding. A major factor contributing to the development of gastrointestinal lesions appears to be the presence of acid in the stomach and upper small intestines.
During recent years, attempts have been made to reduce the gastrointestinal risk associated with taking NSAIDs by administering agents that inhibit stomach acid secretion, such as, for example, proton pump inhibitors with the NSAID. For example, U.S. Pat. No. 6,926,907 is directed to at least one drug dosage form comprising a proton pump inhibitor that raises the pH of a patient's gastrointestinal tract, followed by an NSAID. This, and similar, formulations can be effective in improving NSAID tolerability through dosages of esomeprazole and naproxen that produce the desired pharmacodynamic response and pharmacokinetic values. Parameters that may influence the desired pharmacodynamic response and pharmacokinetic values include, but are not limited to, for example, the dosage of each; extent of drug absorption; extent of drug distribution, and the duration of drug administration.
There is a need for a clinically effective therapy that delivers to a patient in need thereof a pharmaceutical composition in a unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, for a duration sufficient to achieve an instragastric pH of about 4 or greater and a plasma level of naproxen that is efficacious.
In one aspect, the disclosure is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%.
In another aspect, the disclosure is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of about 81 μg/ml and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of about 76.2 μg/ml and a median Tmax of from about 10 to about 14 hours; and
        
        
        ii) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) is about 850 hr*ng/mL, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) is about 650 hr*ng/mL.
        
        
    
    


Yet another aspect is directed to delivering a pharmaceutical composition in unit dose form that provides the pharmacodynamic response and/or pharmacokinetic values disclosed herein to a patient being treated for a disease or disorder selected from pain and inflammation.
A further aspect is directed to delivering a pharmaceutical composition in unit dose form that provides the pharmacodynamic response and/or pharmacokinetic values disclosed herein to a patient being treated for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or a combination thereof.
A still further aspect is directed to delivering a pharmaceutical composition in unit dose form that provides the pharmacodynamic response and/or pharmacokinetic values disclosed herein to an at risk patient.
Another aspect is directed to delivering a pharmaceutical composition in unit dose form that provides the pharmacodynamic response and/or pharmacokinetic values disclosed herein to an at risk patient being treated for a disease or disorder selected from pain and inflammation.
A further aspect is directed to delivering a pharmaceutical composition in unit dose form that provides the pharmacodynamic response and/or pharmacokinetic values disclosed herein to an at risk patient being treated for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or a combination thereof.
Yet another aspect is directed to delivering a pharmaceutical composition in unit dosage form that provides the pharmacodynamic response and/or pharmacokinetic values disclosed herein via a multilayer tablet comprising at least one core and at least a first layer and a second layer, wherein:

    
    
        i) said core comprises naproxen, or pharmaceutically acceptable salt thereof;
        ii) said first layer is a coating that at least begins to release the naproxen, or pharmaceutically acceptable salt thereof, when the pH of the surrounding medium is at about 3.5 or greater; and
        iii) said second layer is esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released at a pH of from about 0 or greater.
    
    





BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: Mean pH data over 24 hours on day 9 per protocol population. Treatment A=PN400/E30; B=PN400/E20; C=PN400/E10; D=EC E20+naproxen.
FIG. 2: Mean intragastric pH data over 24 hours on day 1 per protocol population. Treatment A=PN400/E30; B=PN400/E20; C=PN400/E10; D=EC E20+naproxen.
FIG. 3: Mean plasma esomeprazole concentration vs. time curves on day 1.
FIG. 4: Mean plasma esomeprazole concentration vs. time curves on day 9.
FIG. 5: Mean plasma naproxen concentration vs. time curves on day 1.
FIG. 6: Mean plasma naproxen concentration vs. time curves on day 9.
FIG. 7: Correlation of plasma exposure to esomeprazole with effect on intragastric pH on day 9.
FIG. 8A: Mean pH data and mean naproxen concentration vs. time profiles over a 24-hour period on day 9: Treatment B (PN 400/E20).
FIG. 8B: Mean pH data and mean naproxen concentration vs. time profiles over a 24-hour period on day 9: Treatment D (EC E20+naproxen).
FIG. 9: Time course of plasma naproxen concentration.
FIG. 10: Time course of plasma esomeprazole concentration.
FIG. 11: Time course of esomeprazole and naproxen concentrations.



Abbreviations and/or special terms that may be used herein are set forth in Table 1 and the text that follows.







TABLE 1







Abbreviations and Special Terms








Abbreviation
Explanation





ANOVA
analysis of variance


AUC
area under the plasma concentration-time curve


AUC0-10, am
AUC from time zero (time of AM dosing) to 10 hours after the AM dose


AUC0-14, pm
AUC from time zero (time of PM dosing) to 14 hours after the PM dose


AUC0-24
AUC from time zero (time of AM dosing) to 24 hours after the AM dose


AUC0-t, am
AUC from time zero to the last time point with measurable drug



concentration following AM dosing


AUC0-t, pm
AUC from time zero to the last time point with measurable drug



concentration following PM dosing


Bid
twice daily


BQL
below the lower limit of quantification


CBC
complete blood count


CI
confidence interval


Cmax. am
maximum plasma concentration after the AM dose


Cmax. pm
maximum plasma concentration after the PM dose


CV
coefficient of variation


GCP
Good Clinical Practice


EC
enteric-coated


ECG
electrocardiogram


eCRF
electronic case report form


Emax
maximal response or pharmacodynamic effect


GI
Gastrointestinal


GLSM
Geometric least-squares mean


HPLC/MS/MS
high pressure liquid chromatography tandem mass spectrometry


ITT
intent-to-treat


LLOQ
lower limit of quantification


LS
least square


MedDRA
Medical Dictionary for Regulatory Activities


MRM
multiple reaction monitoring


λz, am
apparent first-order elimination rate constant following AM dosing


λz, pm
apparent first-order elimination rate constant following PM dosing


Ln
natural log


PD
pharmacodynamic(s)


PDS
Phoenix Data Systems


PK
pharmacokinetic(s)


PP
per protocol


PPD
Pharmaceutical Product Development


PPI
proton pump inhibitor


QC
quality control


SD
standard deviation


SE
standard error


SOC
system organ class


SPE
solid phase extraction


tlag, am
time to the first measurable plasma concentration following the AM dose (tlag, am)


tlag, pm
time to the first measurable plasma concentration following the PM dose (tlag, am)


tlast
last time point with measurable drug concentration


tmax
time to maximum plasma concentration


t1/2, am
apparent plasma half-life following the AM dose


t1/2, pm
apparent plasma half-life following the PM dose









The term “at risk patient” refers to patient(s) at risk for NSAID associated ulcer due to age or a documented history of gastric ulcers, or receiving concomitant LDA (low dose aspirin). In one embodiment, the at risk patient is a patient at risk for NSAID associated ulcer due to age greater than or equal to 50 years.
The term “pharmaceutically-acceptable”, as employed herein, indicates the subject matter being identified as “pharmaceutically acceptable” is suitable and physiologically acceptable for administration to a patient/subject. For example, the term “pharmaceutically acceptable salt(s)” denotes suitable and physiologically acceptable salt(s).
The phrase “naproxen, or pharmaceutically acceptable salt thereof” refers to the free base of naproxen, pharmaceutically acceptable salt(s) of naproxen, and/or mixtures of the free base of naproxen and at least one pharmaceutically acceptable salt of naproxen.
The phrase “esomeprazole, or pharmaceutically acceptable salt thereof” refers to the free base of esomeprazole, pharmaceutically acceptable salt(s) of esomeprazole, and/or mixtures of the free base of esomeprazole and at least one pharmaceutically acceptable salt of esomeprazole.
The term “unit dosage form” (or “unit dose form”) as used herein refers to a single entity for drug administration. For example, a single tablet or capsule containing both esomeprazole and naproxen is a unit dosage form. Unit dosage forms of the present disclosure provide for sequential drug release in a way that elevates gastric pH and reduces the deleterious effects of naproxen on the gastroduodenal mucosa, i.e., the esomeprazole is released first and the release of naproxen is delayed until after the pH in the GI tract has risen to 3.5 or greater. A “unit dosage form” (or “unit dose form”) may also be referred to as a “fixed dosage form” (or “fixed dose form”) or fixed dosage combination (or fixed dose combination”) and are otherwise interchangeable.
For the values provided herein, the term “about” indicates a given number may vary by at least 5%, with variations of 10%, 15% or 20% being possible.
With regard to the pharmacokinetic and/or pharmacodynamic values provided herein, the degree of variation is reflected in SDs and % CV values. The % CV=SD/mean×100; the SD=(% CV×mean) divided by 100. It can be expected that approximately 68% of patients will be within one SD of the mean and approximately 95% of patients will be within two SDs of the mean. The pharmacokinetic and pharmacodynamic values presented herein are average values, rounded to the nearest whole number, and are based upon results obtained from multiple individuals. As a result, the values presented herein may vary from one patient to another. This variation is reflected in the term “about.”
With regard to the dosages of each of naproxen, or pharmaceutically acceptable salt thereof and/or esomeprazole, or pharmaceutically acceptable salt thereof the term “about” is intended to reflect variations from the specifically identified dosages that are acceptable within the art.
With regard to time periods referred to herein, the term “about” is intended to reflect variations from the specifically identified time periods that are acceptable within the art.
With regard to the numerical % coefficient of variation values and/or ranges used herein, the term “about” is intended to reflect variations above and below the stated numerical value and/or range that that may achieve substantially the same results as the stated number.
With regard to the pH values and/or ranges recited herein, the term “about” is intended to capture variations above and below the stated number that may achieve substantially the same results as the stated number.
With regard to the term numerical values used in conjunction with the phrase “substantially free”, the term is intended to capture variations above and below the stated number that may achieve substantially the same results as the stated number.
The phrase “substantially free” means from about 95% to about 99.99% free. In one embodiment, substantially free means about 95% free. In another embodiment, the term substantially free means about 96% free. In still another embodiment, the term substantially free means about 97% free. In yet another embodiment, the term substantially free means about 98% free. In a further embodiment, the term substantially free means about 99% free. In still a further embodiment, the term substantially free means about 99.99% free.
In the present disclosure, each of the variously stated ranges is intended to be continuous so as to include each numerical parameter between the stated minimum and maximum value of each range. For Example, a range of about 1 to about 4 includes about 1, 1, about 2, 2, about 3, 3, about 4, and 4.
One embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%.
In other embodiments, the mean % time at which intragastric pH remains at about 4.0 or greater for a 24 hour period is at least about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 71%, about 75%, about 77%, about 80%, about 85%, about 90%, or about 95%.
Another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41% and a pharmacokinetic (pk) profile having a mean maximum plasma concentration (Cmax) for naproxen of at least 76 μg/ml with a % coefficient of variation ranging from 17-23.
A further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41% and a pharmacokinetic (pk) profile having a mean maximum plasma concentration (Cmax) for naproxen of about 76 μg/ml.
Yet another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from 0 or greater to target: a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41% and a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of at least 1500 hr*ng/mL with a % coefficient of variation ranging from 40-80.
Yet a further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from 0 or greater to target: a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41% and a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of about 1500 hr*ng/mL.
Still yet another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%; and a pharmacokinetic (pk) profile having a mean maximum plasma concentration (Cmax) for naproxen of at least 76 μg/ml with a % coefficient of variation ranging from 17-23 and a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of at least 1500 hr*ng/mL with a % coefficient of variation ranging from 40-80.
Still even yet another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%; and a pharmacokinetic (pk) profile having a mean maximum plasma concentration (Cmax) for naproxen of about 76 μg/ml and a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of about 1500 hr*ng/mL.
A still even further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: a pharmacokinetic (pk) profile having a mean maximum plasma concentration (Cmax) for naproxen of at least 76 μg/ml with a % coefficient of variation ranging from 17-23.
Yet a further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: a pharmacokinetic (pk) profile having a mean maximum plasma concentration (Cmax) for naproxen of about 76 μg/ml.
A yet still further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: and a pharmacokinetic (pk) profile having mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of at least 1500 hr*ng/mL with a % coefficient of variation ranging from 40-80.
A yet even further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater to target: and a pharmacokinetic (pk) profile having mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of about 1500 hr*ng/mL.
A further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of at least 81 μg/ml with a % coefficient of variation ranging from 22-23 and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of at least 76.2 μg/ml with a % coefficient of variation ranging from 18-23 and a median Tmax of from about 10 to about 14 hours; and
        
        
        ii) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of at least 850 hr*ng/mL with a % coefficient of variation ranging from 45-70, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of at least 650 hr*ng/mL with a % coefficient of variation ranging from 50-85.
        
        
    
    


A yet further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of about 81 μg/ml and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of about 76.2 μg/ml and a median Tmax of from about 10 to about 14 hours; and
        
        
        ii) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of about 850 hr*ng/mL, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 650 hr*ng/mL.
        
        
    
    


A still further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of at least 81 μg/ml with a % coefficient of variation ranging from 22-23 and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of at least 76.2 μg/ml with a % coefficient of variation ranging from 18-23 and a median Tmax of from about 10 to about 14 hours.
        
        
    
    


A yet still further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of about 81 μg/ml and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of about 76.2 μg/ml and a median Tmax of from about 10 to about 14 hours.
        
        
    
    


A yet even still further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) is at least 850 hr*ng/mL with a % coefficient of variation ranging from 45-70, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) is at least 650 hr*ng/mL with a % coefficient of variation ranging from 50-85.
        
        
    
    


A further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) is about 850 hr*ng/mL, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 650 hr*ng/mL.
        
        
    
    


A yet still even further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of at least 81 μg/ml with a % coefficient of variation ranging from 22-23 and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of at least 76.2 μg/ml with % coefficient of variation ranging from 18-23 and a median Tmax of from about 10 to about 14 hours;
        
        
        ii) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) is at least 850 hr*ng/mL with a % coefficient of variation ranging from 45-70, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) is at least 650 hr*ng/mL with a % coefficient of variation ranging from 50-85; and
        
        
        iii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%.
    
    


A still even further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of about least 81 μg/ml and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of about 76.2 μg/ml and a median Tmax of from about 10 to about 14 hours;
        
        
        ii) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of about 850 hr*ng/mL, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 650 hr*ng/mL; and
        
        
        iii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%.
    
    


Still yet another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of at least 81 μg/ml with a % coefficient of variation ranging from 22-23 and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of at least 76.2 μg/ml with a % coefficient of variation ranging from 18-23 and a median Tmax of from about 10 to about 14 hours; and
        
        
        ii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%.
    
    


A still yet further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of about 81 μg/ml and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of about 76.2 μg/ml and a median Tmax of from about 10 to about 14 hours; and
        
        
        ii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%.
    
    


Even still yet a further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole is released from said unit dose form at a pH of from 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) is at least 850 hr*ng/mL with a % coefficient of variation ranging from 45-70, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) is at least 650 hr*ng/mL with a % coefficient of variation ranging from 50-85; and
        
        
        ii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%.
    
    


An even still further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole is released from said unit dose form at a pH of from 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of about 850 hr*ng/mL, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 650 hr*ng/mL; and
        
        
        ii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%.
    
    


A yet still even further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of at least 81 μg/ml with a % coefficient of variation ranging from 22-23 and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of at least 76.2 μg/ml with a % coefficient of variation of ranging from 18-23 and a median Tmax of from about 10 to about 14 hours;
        
        
        ii) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to 10 hours after the AM dose is administered (AUC0-10,am) is at least 850 hr*ng/mL with a % coefficient of variation ranging from 45-70, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) is at least 650 hr*ng/mL with a % coefficient of variation ranging from 50-85;
        
        
        iii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%; and
        iv) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of at least 1500 hr*ng/mL with a % coefficient of variation ranging from 40-80.
    
    


Another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of about least 81 μg/ml and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of about 76.2 μg/ml and a median Tmax of from about 10 to about 14 hours;
        
        
        ii) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of about 850 hr*ng/mL, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 650 hr*ng/mL;
        
        
        iii) a mean % time at which intragastric pH remains at about 4.0 or greater for a 24 hour period of at least about 41%; and
        iv) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of about 1500 hr*ng/mL.
    
    


A further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of at least 81 μg/ml with a % coefficient of variation ranging from 22-23 and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of at least 76.2 μg/ml with a % coefficient of variation ranging from 18-23 and a median Tmax of from about 10 to about 14 hours;
        
        
        ii) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) is at least 850 hr*ng/mL with a % coefficient of variation ranging from 45-70, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) is at least 650 hr*ng/mL with a % coefficient of variation ranging from 50-85; and
        
        
        iii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of at least 1500 hr*ng/mL with a % coefficient of variation ranging from 40-80.
    
    


A yet further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of about 81 μg/ml and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of about 76.2 μg/ml and a median Tmax of from about 10 to about 14 hours;
        
        
        ii) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of about 850 hr*ng/mL, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 650 hr*ng/mL; and
        
        
        iii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of about 1500 hr*ng/mL.
    
    


A still further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) is at least 850 hr*ng/mL with a % coefficient of variation ranging from 45-70, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) is at least 650 hr*ng/mL with a % coefficient of variation ranging from 50-85; and
        
        
        ii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is at least 1500 hr*ng/mL with a % coefficient of variation ranging from 40-80.
    
    


Still a further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of about 850 hr*ng/mL, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 650 hr*ng/mL; and
        
        
        ii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of about 1500 hr*ng/mL.
    
    


Yet another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of at least 81 μg/ml with a % coefficient of variation ranging from 22-23 and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of at least 76.2 μg/ml with a % coefficient of variation ranging from 18-23 and a median Tmax of from about 10 to about 14 hours; and
        
        
        ii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is at least 1500 hr*ng/mL with a % coefficient of variation ranging from 40-80.
    
    


Yet still another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of about 81 μg/ml and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of about 76.2 μg/ml and a median Tmax of from about 10 to about 14 hours; and
        
        
        ii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of about 1500 hr*ng/mL.
    
    


Yet a further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) is at least 850 hr*ng/mL with a % coefficient of variation ranging from 45-70, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) is at least 650 hr*ng/mL with a % coefficient of variation ranging from 50-85;
        
        
        ii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%; and
        iii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is at least 1500 hr*ng/mL with a % coefficient of variation ranging from 40-80.
    
    


Yet a still further embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for esomeprazole where:
        
            a) the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of about 850 hr*ng/mL, and
            b) the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 650 hr*ng/mL;
        
        
        ii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%; and
        iii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole of about 1500 hr*ng/mL.
    
    


Yet another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of at least 81 μg/ml with a % coefficient of variation ranging from 22-23 and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of at least 76.2 μg/ml with a % coefficient of variation ranging from 18-23 and a median Tmax of from about 10 to about 14 hours;
        
        
        ii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%; and
        iii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is at least 1500 hr*ng/mL with a % coefficient of variation ranging from 40-80.
    
    


Yet still another embodiment is directed to a method for delivering a pharmaceutical composition to a patient in need thereof, comprising: administering to said patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said unit dose form at a pH of from about 0 or greater, wherein one unit dose form is administered as an AM dose and a second dose administered about 10 hours later as a PM dose to target:

    
    
        i) a pk profile for naproxen where:
        
            a) the AM dose has a mean Cmax of about 81 μg/ml and a median time to maximum concentration (Tmax) of from about 2.5 to about 4 hours, and
            b) the PM dose has a mean Cmax of about 76.2 μg/ml and a median Tmax of from about 10 to about 14 hours;
        
        
        ii) a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period of at least about 41%; and
        iii) a pharmacokinetic (pk) profile having a mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is about 1500 hr*ng/mL.
    
    


In another embodiment, naproxen can be present as the free base in an amount of from about 500 mg.
In still another embodiment, naproxen can be present as the free base in an amount of about 500 mg.
In yet another embodiment, naproxen can be present in equivalent amounts of pharmaceutically acceptable salts of naproxen, e.g., sodium naproxen.
In a further embodiment, esomeprazole can be present as a magnesium salt.
In an even further embodiment, esomeprazole, or pharmaceutically acceptable salt thereof, can be present in an amount to provide from about 10 mg to about 30 mg of esomeprazole.
In a further embodiment, esomeprazole, or pharmaceutically acceptable salt thereof, can be present in an amount to provide about 15 mg of esomeprazole.
In yet an even further embodiment, esomeprazole, or pharmaceutically acceptable salt thereof, can be present in an amount to provide about 20 mg of esomeprazole.
In still yet another embodiment, esomeprazole, or pharmaceutically acceptable salt thereof, can be present in an amount to provide about 30 mg of esomeprazole.
In still another embodiment, the mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period is at least about 60%.
In yet another embodiment, the mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period is at least about 71%.
In still yet an even further embodiment, the mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period is at least about 77%.
In an even still further embodiment, the mean maximum plasma concentration (Cmax) for naproxen is at least 79 μg/ml with a % coefficient of variation ranging from 17-23.
In a further embodiment, the mean maximum plasma concentration (Cmax) for naproxen is about 79 μg/ml.
In yet an even still further embodiment, the mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is 2134 hr*ng/mL with a coefficient of variation of 74.
In another embodiment, the mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is about 2134 hr*ng/mL.
In yet another embodiment, the mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is about 2000 hr*ng/mL with a % coefficient of variation ranging from 40-80.
In yet another embodiment, the mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is about 2000 hr*ng/mL.
In still another embodiment, the mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is about 1500 hr*ng/mL.
In a still further embodiment, the mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is 4911 hr*ng/mL with a % coefficient of variation of 42.
In yet still a further embodiment, the mean area under the plasma concentration-time curve from time zero when first dose is administered to about 24 hours after the first dose is administered (AUC0-24) for esomeprazole is about 4911 hr*ng/mL.
In one embodiment, the pharmaceutical composition in unit dose form comprises about 500 mg of said naproxen, or pharmaceutically acceptable salt thereof, and about 20 mg of said esomeprazole, or pharmaceutically acceptable salt thereof.
In another embodiment, the pharmaceutical composition in unit dose form comprises about 500 mg of said naproxen, or pharmaceutically acceptable salt thereof, and about 30 mg of said esomeprazole, or pharmaceutically acceptable salt thereof.
In yet another embodiment, the unit dose form is administered twice a day for at least 6 days.
In still another embodiment, the unit dose form is administered twice a day for at least 9 days.
In still yet another embodiment, the patient in need thereof is an at risk patient.
In yet another embodiment, the at risk patient is being treated for a disease or disorder selected from pain and inflammation.
In a further embodiment, the at risk patient is being treated for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or a combination thereof.
In another embodiment, the patient in need thereof is being treated for a disease or disorder selected from pain and inflammation.
In yet another embodiment, the patient in need thereof is being treated for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, or a combination thereof.
In yet another embodiment, the mean Cmax for said AM dose of naproxen is 86.2 μg/ml with a % coefficient of variation of 22 and said median Tmax is about 3.0 hours; and the mean Cmax for said PM dose is 76.8 μg/ml with a % coefficient of variation of 18 and said median Tmax is about 10 hours.
In another embodiment, the mean Cmax for said AM dose of naproxen is about 86.2 μg/ml and said median Tmax is about 3.0 hours; and the mean Cmax for said PM dose is about 76.8 μg/ml and said median Tmax is about 10 hours.
In still another embodiment, the mean Cmax for said AM dose of naproxen is 80.9 μg/ml with a % coefficient of variation of 23 and said median Tmax is about 3.0 hours; and b) the mean Cmax for said PM dose is 76.2 μg/ml with a % coefficient of variation of 23 and said median Tmax is about 10.4 hours.
In still yet another embodiment, the mean Cmax for said AM dose of naproxen is about 80.9 μg/ml and said median Tmax is about 3.0 hours; and b) the mean Cmax for said PM dose is about 76.2 μg/ml and said median Tmax is about 10.4 hours.
In yet still another embodiment, the mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) for said AM dose of esomeprazole is 1216 hr*ng/mL with a % coefficient of variation of 69, and the mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) for said PM dose of esomeprazole is 919 hr*ng/mL with a % coefficient of variation of 84.
In a further embodiment, the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) is at least 900 hr*ng/mL with a % coefficient of variation ranging from 50-85.
In a still further embodiment, the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 900 hr*ng/mL.
In a still even further embodiment, the PM dose has a mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) of about 2100 hr*ng/mL.
In yet another embodiment, the mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) for said AM dose of esomeprazole is about 1216 hr*ng/mL, and the mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) for said PM dose of esomeprazole is about 919 hr*ng/mL.
In an even further embodiment, the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) is at least 1200 hr*ng/mL with a % coefficient of variation ranging from 45-70.
In a still even further embodiment, the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of about 1200 hr*ng/mL.
In a till even further embodiment, the AM dose has a mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) of about 2800 hr*ng/mL.
In still yet a further embodiment, the mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) for said AM dose of esomeprazole is 2779 hr*ng/mL with a % coefficient of variation of 45, and the mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) for said PM dose of esomeprazole is 2066 hr*ng/mL with a % coefficient of variation of 53.
In an even further embodiment, the mean area under the plasma concentration-time curve from time zero when the AM dose is administered to about 10 hours after the AM dose is administered (AUC0-10,am) for said AM dose of esomeprazole is about 2779 hr*ng/mL, and the mean area under the plasma concentration-time curve from time zero when the PM dose is administered to about 14 hours after the PM dose is administered (AUC0-14,pm) for said PM dose of esomeprazole is about 2066 hr*ng/mL.
In an even further embodiment, the pharmaceutical composition in unit dose form is a multilayer tablet comprising at least one core and at least a first layer and a second layer, wherein said core comprises naproxen, or pharmaceutically acceptable salt thereof; said first layer is a coating that at least begins to release the naproxen, or pharmaceutically acceptable salt thereof, when the pH of the surrounding medium of about 3.5 or greater; said second layer is esomeprazole, or pharmaceutically acceptable salt thereof, wherein said esomeprazole, or pharmaceutically acceptable salt thereof, is released at a pH of from about 0 or greater.
In an even further embodiment, esomeprazole, or pharmaceutically acceptable salt thereof, is released at a pH of from 0 or greater.
In another embodiment, esomeprazole, or pharmaceutically acceptable salt thereof, is released at a pH of from about 1 or greater.
In a further embodiment, esomeprazole, or pharmaceutically acceptable salt thereof, is released at a pH of from 1 or greater.
In still another embodiment, esomeprazole, or pharmaceutically acceptable salt thereof, is released at a pH of from about 0 to about 2.
In yet a further embodiment, esomeprazole, or pharmaceutically acceptable salt thereof, is released at a pH of from 0 to 2.
In yet still another embodiment, at least a portion of said esomeprazole, or pharmaceutically acceptable salt thereof, is not coated with an enteric coating.
In even yet still another embodiment, the first layer is an enteric coating.
In an even further embodiment, the pharmaceutical composition in unit dose form is a multilayer tablet comprising a core comprising naproxen, or pharmaceutically acceptable salt thereof, and a first layer comprising a coating that at least begins releasing the naproxen when the pH of the surrounding medium is about 3.5 or greater and a second layer comprising esomeprazole, or pharmaceutically acceptable salt thereof, wherein at least a portion of said esomeprazole, or pharmaceutically acceptable salt thereof, is not surrounded by an enteric coating.
In another embodiment, the first layer is a coating that at least begins to release the naproxen when the pH of the surrounding medium is about 4.0, 4.5, 5.0 or greater.
In still yet another embodiment, said first layer begins to release the naproxen when the pH of the surrounding medium is at about 4.0 or greater.
In a further embodiment, said first layer begins to release the naproxen when the pH of the surrounding medium is at about 4.5 or greater.
In yet a further embodiment, said first layer begins to release the naproxen when the pH of the surrounding medium is at about 5.0 or greater.
In one embodiment, at least about 95% of the esomeprazole, or pharmaceutically acceptable salt thereof, is not surrounded by an enteric coating.
In another embodiment, at least about 99% of the esomeprazole, or pharmaceutically acceptable salt thereof, is not surrounded by an enteric coating. In yet another embodiment, at least about 99.5% of the esomeprazole, or pharmaceutically acceptable salt thereof, is not surrounded by an enteric coating.
In yet another embodiment, the multilayer tablet is substantially free of sodium bicarbonate.
In still another embodiment, the multilayer tablet is completely (i.e., 100%) free of sodium bicarbonate.
In one embodiment, the dosing regimen is twice a day.
In another embodiment, the doses can be separated by a period of at least about 10 hours.
In another embodiment, the pharmaceutical composition in unit dose form is given about 1 hour before a patient ingests a meal.
In another embodiment, the pharmaceutical compositions of the present disclosure may be administered therapeutically to patients either short term or over a longer period of time, for example chronically.
In other embodiments, long term or chronic administration of the pharmaceutical compositions disclosed herein can result in intragastric pH being at least about 4.0 or greater a higher percentage of time per 24 hour period versus short-term administration. For example, administration of certain pharmaceutical compositions may result in a higher percentage time of intragastric pH being greater than about 4.0 on Day 9 versus Day 1 of treatment.
In another embodiment, the method for delivering a pharmaceutical composition to a patient in need thereof, comprises administering to the patient a pharmaceutical composition in unit dose form comprising naproxen, or pharmaceutically acceptable salt thereof, and esomeprazole, or pharmaceutically acceptable salt thereof, wherein intragastric pH is increased to at least about 4.0 within one hour of administration.
In another embodiment, intragastric pH is increased to at least about 4.0 or greater within 30 or 45 minutes of administration
The pharmaceutical compositions disclosed herein include, but are not limited to, for example, tablets and capsules that can be made in accordance with methods that are standard in the art (see, e.g., Remington's Pharmaceutical Sciences, 16th ed., A Oslo editor, Easton, Pa. (1980)).
Suitable carriers include, but are not limited to: water; salt solutions; alcohols; gum arabic; vegetable oils; benzyl alcohols; polyethylene glycols; gelatin; carbohydrates such as lactose, amylose or starch; magnesium stearate; talc; silicic acid; paraffin; perfume oil; fatty acid esters; hydroxymethylcellulose; polyvinyl pyrrolidone; etc.
The pharmaceutical compositions disclosed herein can be sterilized and, if desired, mixed with, for example, auxiliary agents, such as, for example, preservatives; stabilizers; buffers; coloring agents; and flavoring agents.
In one embodiment, at least one of the layers comprising the pharmaceutical compositions disclosed herein may be applied using standard coating techniques. The layer materials may be dissolved or dispersed in organic or aqueous solvents. The layer materials may include, but are not limited to, for example, one or more of the following materials: methacrylic acid copolymers, shellac, hydroxypropylmethcellulose phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl-cellulose trimellitate, carboxymethylethyl-cellulose, cellulose acetate phthalate, and/or other suitable polymer(s). The pH at which the first layer dissolves can be controlled by the polymer or combination of polymers selected and/or ratio of pendant groups. For example, dissolution characteristics of the polymer film can be altered by the ratio of free carboxyl groups to ester groups. The layers may also contain pharmaceutically acceptable plasticizers, such as, for example, triethyl citrate, dibutyl phthalate, triacetin, polyethylene glycols, polysorbates or other plasticizers. Additives, such as, for example, dispersants, colorants, anti-adhering, and anti-foaming agents may also be used.
In one embodiment, the pharmaceutical compositions disclosed herein can be in the form of a bi- or multi-layer tablet. In a bi-layer tablet, one portion/layer of the tablet contains the esomeprazole, or pharmaceutically acceptable salt thereof, in the required dose along with appropriate excipients, agents to aid dissolution, lubricants, fillers, etc.; and a second portion/layer of the tablet contains the NSAID in the required dose along with other excipients, dissolution agents, lubricants, fillers, etc.
In another embodiment, the naproxen portion/layer is surrounded by a polymeric coating that dissolves at a pH of at least about 3.5 or greater.
In yet another embodiment, the naproxen portion/layer is surrounded by a polymeric coating that dissolves at a pH of at least about 4 or greater.
The naproxen, or pharmaceutically acceptable salt thereof, may be granulated by methods such as slugging, low- or high-shear granulation, wet granulation, or fluidized-bed granulation. Of these processes, slugging generally produces tablets of less hardness and greater friability. Low-shear granulation, high-shear granulation, wet granulation and fluidized-bed granulation generally produce harder, less friable tablets.
EXAMPLE(S)
The invention is further defined in the following Example(s). It should be understood the Example(s) are given by way of illustration only. From the above discussion and the Example(s), one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative example(s) set forth hereinbelow, but rather defined by the claims appended hereto.
EXAMPLE 1
A randomized, open-label, 4-way cross-over study to evaluate the effect on days 1 and 9 of twice daily oral administration of three PN 400 formulations (enteric coated naproxen 500 mg combined with non-enteric coated esomeprazole 10, 20, or 30 mg) versus the effect of twice daily oral administration of a separate 500 mg non-enteric coated naproxen tablet and once daily oral administration of a separate EC esomeprazole (20 mg) capsule (Nexium® 20 mg capsule) on the 24-hour intragastric pH and pharmacokinetic parameters (i.e., Cmax, Tmax, AUC0-10,am, AUC0-14,pm, AUC0-24, AUC0-t,am, and AUC0-t,pm) of healthy volunteers. The PN400 tablet is a multilayer tablet comprising an inner core of naproxen surrounded by a first layer comprising an enteric coating and a second layer comprising non-enteric coated esomeprazole.
The study was designed to compare the pharmacodynamic (PD) measurements of intragastric pH (percent time of pH>4.0) on Day 9 of three PN 400 formulations following twice daily (BID) administration versus a combination of non-enteric coated naproxen taken BID and EC esomeprazole (20 mg) taken once daily.
The study was also designed to compare the PD measurement of intragastric pH (percent time of pH>4.0) on Day 1 of three PN 400 formulations following BID administration versus a combination of non-enteric coated naproxen taken BID and EC esomeprazole taken once daily; and assess the pharmacokinetics of esomeprazole and naproxen on Day 1 and Day 9 in each of the treatment groups.
This was a single-center study in 28 healthy adults. The study consisted of four 9-day treatment periods. The first, second and third treatment periods were followed by a washout period of at least 12 days. Eligible subjects reported to the Phase 1 unit in the PM of Day 0 for screening.
Screening procedures included procurement of informed consent, medical and drug history, physical examination, vital signs, 12-lead electrocardiogram (ECG), clinical laboratory testing, urine drug screen, pregnancy test for females of childbearing potential, and helicobacter pylori breath test. Clinical laboratory tests, physical examination, and measurement of vital signs were performed at Screening and the Final Visit. A 12-lead electrocardiogram (ECG) and 13C-urea breath test to screen for possible helicobacter pylori infection were performed at Screening. A urine drug screen for all subjects and a urine pregnancy test for women of childbearing potential were performed on Days 0 and 8 of each treatment period. On Days 1 and 9 of each treatment period, 24-hour blood sampling was performed for pharmacokinetic (PK) assessments. Subjects were instructed to report to the Phase 1 unit within 14 days of the initiation of screening procedures.
28 subjects were planned, randomized and treated, and data for 25 subjects were analyzed as the Per-Protocol (PP) population; the Intent-to-Treat (ITT), Safety and PK populations included all 28 subjects. Subjects were healthy males or non-lactating, non-pregnant females 18 to 55 years of age with a body mass index of 19-32 kg/m2, were helicobacter pylori (H. pylori) negative, and were generally in good health with no history of peptic ulcer disease or other acid-related gastrointestinal (GI) symptoms.
Subject enrollment and disposition are summarized in Table 2. Twenty-eight subjects were randomized and treated at one investigational center; these subjects comprised the PK population. One subject dropped out of the study for personal reasons after completing 3 treatment periods (Treatments A [PN 400/E30], B [PN 400/E20] and D [EC E20+naproxen]). The PP population included 25 subjects.







TABLE 2







Subject Enrollment and Disposition - All Subjects









Subjects (%) N = 28













Subjects Randomized and Treated
 28 (100)



Safety Population
 28 (100)



Intent-to-Treat Population
 28 (100)



Per Protocol Population
25 (89)



PK Population
 28 (100)



Subjects Completed
27 (96)



Subjects Withdrawn Prematurely
1 (4)



Adverse event
0



Withdrew consent
0



Lost to follow-up
0



Other
1 (4)









The demographic characteristics of the ITT population at Screening are summarized in Table 3. The study population was 68% male and had a mean age of approximately 25 years. All subjects were white and non-Hispanic.







TABLE 3







Demographic Characteristics - ITT Population









Total Subjects N = 28













Age (years)




n
28



Mean (SD)
24.9 (3.9)



Median
24



Range
18-34



Gender - n (%)




Males
 19 (68)



Females
 9 (32)



Race - n (%)




White
 28 (100)



Black/African American
 0



Asian
 0



Other
 0



Ethnicity - n (%)




Hispanic or Latino
 0



Not Hispanic or Latino
 28 (100)



Height (in)




n
28



Mean (SD)
70.1 (4.1)



Median
  70.0



Range
63-79



Weight (lb)




n
28



Mean (SD)
177.9 (34.6)



Median
 178.0



Range
112-250









At any time during Screening but at least prior to Day 1 of the first treatment period, subjects had their lower esophageal sphincter (LES) located to determine accurate placement of the pH probe.
Subjects were randomized on Day 1 of the first treatment period into 1 of 4 dosing sequences to receive a 9-day course of each one of the following daily treatment regimens in a crossover fashion:

    
    
        Treatment A: 1 tablet PN 400/E30 (EC naproxen 500 mg and non-EC esomeprazole 30 mg) BID.
        Treatment B: 1 tablet PN 400/E20 (EC naproxen 500 mg and non-EC esomeprazole 20 mg) BID.
        Treatment C: 1 tablet PN 400/E10 (EC naproxen 500 mg and non-EC esomeprazole 10 mg) BID.
        Treatment D: EC E20+naproxen (1 tablet non-EC naproxen 500 mg and 1 capsule EC esomeprazole 20 mg in the AM and 1 tablet non-EC naproxen 500 mg in the PM)
    
    


All treatments were administered by study personnel 60 minutes prior to meals (i.e. doses were taken 60 minutes prior to breakfast (after an over night fast, for the AM dose) and/or 60 minutes prior to dinner (for the PM dose) for 9 days). The study medications administered BID were administered approximately 10 hours apart. Prior to administration of the Day 1 AM dose of study drug, the pH probe was placed to monitor intragastric pH for a period of 24 hours. The distal electrode was placed 10 cm below the LES with the proximal electrode placed 5 cm above the LES using the LES locator and/or by use of formal esophageal manometry by the investigator. The position of the distance of the electrode from the nostrils was recorded to facilitate the 24-hour intragastric pH assessments.
In addition, a pre-AM dose blood sample was collected. Post-AM dose blood samples were drawn approximately: 10, 20, 30 and 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 (pre-PM dose blood sample), 10.17, 10.33, 10.5, 10.75, 11, 11.5, 12, 12.5, 13, 14, 16, 18, 20 and 24 hours for PK assessments. After AM dosing on Day 2, subjects were discharged from the Phase 1 unit and instructed to return for the next dosing in the PM of Day 2 and on Days 3-8 to receive the AM and PM doses. Subjects were confined to the Phase 1 unit in the PM of Day 8 in preparation for the 24-hour PK and pH assessments on Day 9. Monitoring of pH and blood sample collection on Day 9 was as described above for Day 1. The pH probe was removed in the AM on Day 10. Final PK samples were collected in the AM of Day 10.
Subjects were instructed to return to the Phase 1 unit for subsequent treatment periods and reminded of the timing for the next treatment period (i.e., the wash-out period of at least 12 days between treatments). In each subsequent treatment period, the same procedures were performed as during the first period, and final study procedures were performed on Day 10 of the last treatment period or whenever a subject discontinued from the study.
The PK measurements used in this study are assessments commonly used in Phase I studies.
Measuring Intragatric pH
The procedure used to measuring intragastric pH is standard commonly used in assessing the pharmacodynamic effect of acid-suppressing drugs. A Medtronics Digitrapper pH data logger (Medtronics, Minneapolis, Minn.) was used to record pH. The 24-hour pH assessments were performed on Days 1 and 9. The pH recording system measured the difference in potential between the recording and reference electrodes in the tip of the probe and stored this value every couple of seconds. The pH data was provided to a third party blinded to the assigned treatment groups. The third party evaluated the data to determine the validity of the pH recordings based on the following established criteria: At least 20 hours of valid pH data within a pre-specified reference range; No technical failures of the pH recording; and Less than 1 continuous hour with pH data outside the reference range.
Collection of Samples
PK blood samples were collected in 6 mL sodium heparin VACUTAINER tubes and stored on ice until centrifuged within 30 minutes of sample draw for approximately 10 minutes at 3000 rpm (approximately 1800×g) in a refrigerated centrifuge maintained at approximately 4° C. Plasma supernatant was withdrawn and frozen at −20° C. or colder within 60 minutes of collection. Samples were divided into 2 equal aliquots, with 1 tube being used for naproxen analysis and the other for esomeprazole analysis. Samples were kept frozen at −20° C. and shipped overnight to PPD Development, Richmond Va. for analysis at the end of the study.
Analysis of Esomeprazole in Plasma Assay Methods
Esomeprazole is optically stable and the degree of conversion from the S to the R enantiomer in humans is negligible. Thus sample analysis for esomeprazole was performed using the validated high performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) method for omeprazole. This method was developed and validated by PPD Development, Richmond, Va.
Assay methods were generally performed as essentially described hereinbelow: A 100 μL aliquot of human plasma containing the anti-coagulant (sodium heparin) and the analytes was fortified with the internal standard (deuterated analog of omeprazole). The analytes were isolated by solid phase extraction (SPE) using a Phenomenex Strata-X (10 mg) 96-well SPE plate. The final extract was analyzed by HPLC with MS/MS detection using a Micromass Quattro Micro, triple quadrupole instrument. Chromatographic retention and separation of the analytes were obtained on Betasil Silica-100 analytical column (3×50 mm, 5 μm particle size) using a gradient mobile phase program. Mobile phase A consisted of 0.1% formic acid in acetonitrile and mobile phase B consisted of 0.1% formic acid. The analytes were detected by MS/MS with positive electrospray ionization in the mode of multiple reaction monitoring (MRM), with ions monitored for omeprazole (m/z 346→□198) and deuterated omeprazole (m/z 349 □→□198).
Quantification was by analyte to internal standard peak area ratio. The linear range of quantitation was 1 to 1000 ng/mL in human plasma, with a lower limit of quantification (LLOQ) of 1 ng/mL. The assay was validated in terms of specificity, precision, accuracy, and sample stability.
Assay Performance
A set of 8 calibration standards ranging from 1.00 to 1000 ng/mL and quality control (QC) samples at 5 different concentrations (2.60, 8.00, 30.0, 130, and 750 ng/mL) of each analyte were prepared and stored at −20° C. Between-batch precision and accuracy for analysis of the QC samples were determined from batch analyses of clinical samples in this study. Precision was measured as the percent coefficient of variation (% CV) of the set of values obtained for each QC level. Accuracy was expressed as the percent difference of the mean value from the theoretical concentration at each QC level.
The inter-assay CV of the QCs for the omeprazole runs ranged from 3.44% to 5.88%, with mean percent differences from theoretical ranging from 0.329% to 1.80%. The differences of back-calculated calibration curve values from nominal values ranged from −2.87% to 1.54%. For the analytical runs, which contained diluted subject samples, the appropriate level quality control pool was diluted and analyzed in a similar manner to validate the dilution of study samples. The % CV of the diluted QCs for the run ranged from 0.599% to 2.74% with mean percent differences from theoretical ranging from −1.24% to 3.99%.
Analysis of Naproxen in Plasma Assay Methods
Concentrations of naproxen in human plasma were generally determined essentially as described hereinbelow using a validated HPLC method with fluorescence detection developed and validated at PPD Development, Richmond, Va.
A 100 μL aliquot of human plasma containing sodium heparin and the analytes was combined with the internal standard solution (2-naphthylacetic acid) and diluted with potassium chloride. The analyte and the internal standard were isolated using liquid-liquid extraction. Chromatographic retention and separation of the analytes was obtained on a Symmetry C18 column (4.6×150 mm, 5 μm particle size) using an isocratic mobile phase consisting of 45% acetonitrile: 55% 14.8 mM phosphate buffer. The analytes were detected by fluorescence using excitation and emission wavelengths of 230 nm and 370 nm, respectively.
Quantification was by analyte to internal standard peak height ratio. The nominal range of the method was 0.10 to 100 μg/mL for naproxen in human plasma with an LLOQ of 0.10 μg/mL.
Assay Performance
A set of 8 calibration standards ranging from 0.1 to 100 μg/mL and QC samples at 5 different concentrations (0.28, 0.80, 3.0, 12.0 and 76.0 μg/mL) of the analyte were prepared and stored at −20° C. Between-batch precision and accuracy for analysis of the QC samples were determined from batch analyses of clinical samples in this study. Precision was measured as the % CV of the set of values obtained for each QC level. Accuracy was expressed as the percent difference of the mean value from the theoretical concentration at each QC level.
The inter-assay CV of the QCs for the naproxen runs ranged from 2.22% to 9.59%, with mean percent differences from theoretical ranging from −3.59% to 0.933%. The differences of back-calculated calibration curve values from nominal values ranged from −4.73% to 3.79%. For the analytical run that contained diluted subject samples, the appropriate level of QC samples was diluted and analyzed in a similar manner to validate the dilution of study samples. The % CV of the diluted QCs for the run was 4.12% with a mean percent difference from theoretical of −1.54%.
Statistics and Analysis
Data were summarized by reporting the frequency and percentage of subjects in each category for categorical and ordinal measures, and means, standard deviation or standard error, medians, and ranges for continuous measures. All statistical analyses and data listings were completed using the SAS® system, version 8.2 or higher.
Three analysis populations were used for analysis:

    
    
        1) Intent-to-Treat (ITT) population: all randomized subjects who had valid pH data for at least 1 treatment period. A subject was considered to have valid pH data for each treatment period if the subject received all doses of study medication per protocol, had at least 20 hours of valid pH data determined by the clinical investigator, did not have technical failures of the pH recording, and did not have one continuous hour or more with pH data outside the reference range.
    
    


2) Per-Protocol (PP) population: all ITT subjects who had valid pH data for all four treatment periods and did not violate the protocol in a way that would have significantly impacted the evaluation of PD endpoints.
3) PK population: all randomized subjects who received all doses of study medication for at least one treatment period and had adequate blood sampling to determine the PK parameters of the study drugs.
Pharmacodynamic Endpoints
For each Digitrapper session, separate plots of the esophageal and intragastric pH readings for each subject were prepared and reviewed for non-valid pH data. Particular attention was paid to recorded pH values that were outside the range from 0.6 to 8.0. Values considered by the investigator to be unlikely to have occurred due to a reasonable expectation of method variability, and which persisted to such an extent as to suggest possible transient unreliability of the equipment, were identified and excised from the database. Other apparent ‘flat-lining’ of the pH readings could also result in a determination of non-valid data.
The PD endpoints were summarized by treatment and analyzed by Analysis of Variance (ANOVA). The ANOVA model included sequence, period, and treatment as fixed effects, and subject within sequence as a random effect. The least square (LS) means for each treatment, the difference of LS means between each of the PN 400 treatments and the active control, and 95% confidence intervals (CIs) for all treatment differences were calculated. Both ITT and PP populations were used for the PD analysis. The PP population was the primary analysis population. In addition, the percent time of pH>3.0 and >5.0 on Days 1 and 9 was analyzed in a similar fashion as the percent time of pH>4.0. Mean pH data over 24 hours on Days 1 and 9 were plotted by treatment.
From a previous study, the within-subject standard deviation (SD) of percent time of pH>4.0 was 10%. The current study planned to enroll 28 subjects with the aim to have 24 evaluable subjects for analysis. A total of 24 subjects provides 80% power to reject the null hypothesis that the difference between each of the PN 400 treatments and the active control in percent time of pH>4.0 over 24 hours is ≦−8% using a pairwise t-test with a one-sided significance level of 0.05.
Primary Pharmacodynamic Endpoint: Percent Time Intragastric pH>4.0 on Day 9
Results from Day 9 are set forth in Table 4. On Day 9, both PN 400/E30 and PN 400/E20 treatments resulted in a greater percent time with intragastric pH>4.0 than treatment with EC E20+naproxen. PN 400/E10 had the lowest percent time with intragastric pH>4.0 and was also the most variable treatment as evidenced by the high % CV in Table 4.







TABLE 4







Percent Time of pH Greater than 4.0 - Day 9 - Per-Protocol Population















D



A
B
C
EC E20 +



PN 400/E30
PN 400/E20
PN 400/E10
naproxen


% Time of pH > 4.0
N = 25
N = 25
N = 25
N = 25





Mean (SD)
 76.50 (12.26)
 71.35 (13.01)
40.85 (22.51)
56.85 (10.06)


Median
78.79
70.42
35.76
55.14


% Coefficient of variation
16  
18  
55  
18  


Range
49.79-95.32
51.76-97.61
10.30-85.26
40.63-75.51


LS Mean (SD)
76.75 (3.02)
71.46 (3.02)
41.09 (3.02) 
57.23 (3.02) 


LS Mean Difference (SE)
A vs. D
B vs. D
C vs. D
—



19.52 (3.25)
14.23 (3.25)
−16.14 (3.25) 



95% Confidence Interval
13.04-26.01
 7.75-20.71
−22.26-−9.66 
—









On Day 1, the LS mean percent time intragastric pH>4.0 ranged from 13% with PN 400/E10 to 28% with PN 400/E30. Treatment differences compared to EC E20+naproxen were small. Only PN 400/E30 (28%) had a statistically significant, greater percent time with pH>4.0 compared to EC E20+naproxen (21%).
As shown in FIG. 1, there were three increases in pH throughout the day which were associated with food intake at 1, 6 and 11 hours, for breakfast, lunch and dinner, respectively. These increases in pH occurred approximately one hour after each meal for all treatments. Following the AM dose of PN 400 on Day 9, the pH increase occurred approximately one hour earlier than the food induced increase in pH (see also FIG. 2). After the AM dose of EC E20+naproxen, the pH increase occurred at least 30 minutes later than PN 400.
The overall pH profiles on Day 9 showed an esomeprazole dose-related effect on intragastric pH beyond the influence of food intake. The effect on intragastric pH profiles was similar between PN 400/E30 and PN 400/E20, with each of these treatments reflecting a slower return of gastric contents to lower pH levels after food intake than either the PN400/E10 or EC E20+naproxen treatments.
Results on Day 9 for the ITT population were similar to those from the PP population. The initial Day 9 pH measurements from all treatments showed the mean intragastric pH after an overnight fast was between 2.0 and 3.0, which was higher than the initial pH (between 1.0 and 2.0) on Day 1 (FIG. 2).
As shown in Table 4, the primary PD response of this study, i.e., percent time intragastric pH>4.0 on Day 9, increased with esomeprazole dose in the PN 400 treatments. However, a greater increase in the primary PD response was observed when esomeprazole dose increased from 10 to 20 mg in PN 400, i.e., from 40.9 to 76.5%. There was only a small increase in intragastric pH>4.0, from 71.4 to 76.5%, as the esomeprazole dose increased from 20 to 30 mg in PN 400.
Secondary Pharmacodynamic Endpoint: Percent Time Intragastric pH>4.0 on Day 1
Results from Day 1 are set forth in Table 5. The LS mean percent time intragastric pH>4.0 ranged from approximately 13% with PN 400/E10 to approximately 28% with PN 400/E30.







TABLE 5







Percent of Time with Intragastric pH Greater


than 4.0 - Day 1 - Per-Protocol Population









Treatment















D



A
B
C
EC E20 +



PN 400/E30
PN 400/E20
PN 400/E10
Naproxen


% Time pH > 4.0
N = 25
N = 25
N = 24
N = 25





Mean (SD)
27.79 (22.63)
 20.50 (16.61)
 12.81 (11.11)
21.34 (13.63)


Median
19.96
15.26
9.09
16.82


% CV
81  
81  
87   
64  


Range
1.77-89.61
4.35-74.40
 3.00-53.75
3.16-58.20


LS Mean (SE)
27.90 (3.31) 
20.58 (3.31)
12.66 (3.35) 
21.51 (3.31) 



A vs. D
B vs. D
C vs. D



LS Mean Difference (SE)
6.39 (3.18)
−0.92 (3.18)
−8.85 (3.22) 
—


95% Confidence Interval
0.04-12.75
−7.28-5.43 
−15.28-−2.42
—









Mean pH data over 24 hours on Day 1 is presented in FIG. 2. The pH profiles on Day 1 showed that following an overnight fast, the mean baseline intragastric pH was low, between 1.0 and 2.0, prior to any treatment. There were three pH increases above pH 4.0 throughout the day that were associated with food intake at 1, 6 and 11 hours. The increase in intragastric pH occurred at approximately one hour after each meal for all treatments. There was only a minimal effect of any of the study treatments on intragastric pH, beyond the effect of food, throughout the first 24 hours on the first day of treatment.
Other Pharmacodynamic Findings
Analysis of percent time of pH>3.0 and >5.0 on Day 9 resulted in a similar pattern statistically as that of the primary endpoint of percent time pH>4 on Day 9 for PP population, with PN 400/E30 and PN 400/E20 showing a greater acid-reducing capacity than EC E20+naproxen, which had a greater capacity than PN 400/E10, based on LS mean differences and 95% CIs. Analysis results of percent time of pH>3.0 and >5.0 on Day 1 were similar as results for the primary endpoint of % time pH>4 on Day 1 based on the PP population. ITT population results were similar to those of the PP population.
As PN 400 is dosed BID, the individual time intervals corresponding to this dosing regimen, i.e., 0-10 hours and 10-24 hours, were analyzed for percent time intragastric pH>4.0 on Day 9. The results indicated that for the 0-10 hours period, PN 400/E30 treatment resulted in a greater percent time with intragastric pH>4.0 (84%) than treatment with EC E20+naproxen (71%). While PN 400/E20 also had a high percent time intragastric pH>4.0 (79%), the results were not statistically significantly different from the EC E20+naproxen treatment. With BID dosing, both PN400/E30 and PN400/E20 had greater percent time intragastric pH>4.0 (71% and 66%, respectively) compared to treatment with EC E20+naproxen (47%) for the 10-24 hour treatment interval. The PN400/E10 treatment had a lower percent time intragastric pH>4.0 compared to treatment with EC E20+naproxen for both the 0-10 hours (52%) and the 10-24 hours (33%) treatment interval.
Pharmacokinetic Endpoints
On Day 1, PK data analysis was performed for esomeprazole and naproxen plasma profiles obtained from 28 subjects completing PN 400/E30, PN 400/E20 and EC E20+naproxen; and 27 subjects completing PN 400/E10.
On Day 9, PK data analysis was performed for esomeprazole or naproxen plasma profiles from 28 subjects completing PN 400/E30 and EC E20+naproxen, and 27 subjects completing PN 400/E20 and PN 400/E10.
PK parameters for esomeprazole were determined following the three different PN 400 treatments and PK parameters for naproxen were determined following each of the 4 treatments including peak plasma concentration (Cmax) on Days 1 and 9; time to peak plasma concentration (tmax) on Days 1 and 9; area under the plasma concentration vs time curve from time zero to the last time point with measurable drug concentration (AUC0-t) on Days 1 and 9; and the terminal half-life (t1⁄2), if possible, following both the AM and PM doses on Days 1 and 9. In addition, the AUC from time zero (time of dosing) to 10 hours post-AM dose (AUC0-10,am) and AUC from time zero (time of dosing) to 14 hours post-PM dose (AUC0-14,pm) and a total daily AUC (AUC0-24) were determined on Days 1 and 9. PK parameters for esomeprazole following EC E20+naproxen included Cmax, tmax, AUC0-t, t1⁄2, and AUC0-24 following the AM dose on both Days 1 and 9.
Statistical analysis was performed using Analysis of Variance (ANOVA) to determine the point estimate and 90% CI of the Day 9 to Day 1 ratios for the following parameters for both naproxen and esomeprazole Cmax,am, Cmax,pm, AUC0-10, am, AUC0-14, pm, and AUC0-24.
Plasma esomeprazole and naproxen concentration vs. time data are listed by treatment, study day and subject. The concentration data were summarized by treatment and study day at each nominal (or scheduled) sampling time using descriptive statistics including mean, SD, % CV, median, minimum and maximum. Plasma concentrations below the LLOQ (i.e., 1 ng/mL for esomeprazole, and 0.10 μg/mL for naproxen) were treated as a zero value for calculating descriptive statistics. The mean/median value at a time point with one or more below the LLOQ (BQL) values was reported unless the mean/median value was below the LLOQ of the assay, in which case the value was reported as BQL. Individual subject plasma concentration vs time curves were plotted against the actual sampling time, and the mean/median plasma concentration vs. time curves were plotted against nominal sampling time by treatment.
The plasma concentration vs. time data of each analyte were subjected to non-compartmental analysis using WinNonlin version 4.1 (Pharsight Corporation, Mountain View, Calif.). The actual blood sampling time for each sample was used for PK data analysis. For analyte concentrations resulting from BID doses, i.e., esomeprazole in Treatments A, B, and C or naproxen in all 4 treatments, PK analysis was performed separately for the plasma profiles obtained after the AM and PM doses. Thus, the actual post-dose sampling times for concentration vs. time profiles after the PM dose were calculated based on the elapsed time from the actual dosing time of the PM dose.
For PK analysis, plasma concentrations below the LLOQ (BQL value) in individual profiles of each analyte were handled as follows. If the value occurred in a profile during the absorptive phase of the profile, i.e., before the maximum concentration in a profile was observed, it was assigned a value of zero concentration. A single BQL value occurring between two measurable analyte concentrations, not in the absorptive phase of a profile, was generally omitted. If two or more BQL values occurred in succession, post peak time (or during the elimination phase), the profile was determined to have terminated at the last time point with measurable analyte concentration of the profile.
PK parameters calculated for esomeprazole (following each of the three PN 400 treatments) and for naproxen (following each of the 4 treatments) on Days 1 and 9 included the following: Maximum observed plasma concentration following the AM dose (Cmax,am) and following the PM dose (Cmax,pm); Time to peak plasma concentration following the AM dose (tmax,am) and following the PM dose (tmax,pm); Time to the first measurable plasma concentration following the AM dose (tlag,am) and following the PM dose (tlag,pm); Area under the plasma concentration vs. time curve (AUC) from time zero to the last time point with measurable drug concentration (tlast) following the AM dose (AUC0-t,am) and following the PM dose (AUC0-t,pm), calculated using the linear-up and log-down trapezoidal method in WinNonlin; Apparent first-order elimination rate constant (λz,am and λz,pm), determined, if data permit, by the slope of the apparent terminal log-linear phase of the plasma drug concentration vs. time curve using at least 3 time points; Apparent plasma half-life (t1⁄2), if data permit, determined as 0.693/λz following the AM and PM doses, i.e., t1⁄2,am and t1⁄2, pm, respectively; AUC from time zero (time of AM dosing) to 10 hours after the AM dose (AUC0-10,am), if necessary, with extrapolation using λz,am estimate from tlast to 10 hrs post the AM dose; AUC from time zero (time of PM dosing) to 14 hours after the PM dose (AUC0-14,pm), if necessary, with extrapolation using λz,pm estimate from tlast to 14 hrs post PM dose; and Total daily AUC (AUC0-24) from time zero (time of AM dosing) to 24 hours after the AM dose, which is determined as AUC0-10,am+AUC0-14,pm.
The PK parameters calculated for esomeprazole following Treatment D after the AM dose on Days 1 and 9 included Cmax, tmax, AUC0-t, t1⁄2 and AUC0-24. The same methods as described above were applied.
Descriptive statistics, including mean, SD, % CV, median, minimum and maximum, were calculated for all PK parameters of naproxen and esomeprazole by treatment and study day. Geometric mean and associated 95% confidence interval (CI) were also calculated for all PK parameters, except tmax.
Statistical analysis was performed using ANOVA to determine the point estimate and associated 90% CI of the Day 9 to Day 1 ratios for the following parameters: Cmax,am, Cmax,pm, AUC0-10,am, AUC0-14,pm, and AUC0-24 for esomeprazole data in each of the three PN 400 treatments, and for naproxen data in each of the 4 treatments. For esomeprazole data from Treatment D, the Day 9 to Day 1 ratios for Cmax and AUC0-24 were determined. Natural log-transformed Cmax and AUC values were used for the analyses, thus geometric least-squares mean ratios for each parameter were determined.
Dose proportionality in the Cmax,am, Cmax,pm, AUC0-10,am, AUC0-14,pm, and AUC0-24 of esomeprazole from the three PN400 treatments was analyzed on Days 1 and 9 separately, using the power model as follows:

y=a*(dose)b 

ln(y)=ln(a)+b*ln(dose)

where y is the PK parameter value and ln=natural log. The power model included ln(dose) and period as fixed effects and subject as a random effect.

Esomeprazole
Table 6 summarizes the results from the PK analysis that was performed for esomeprazole plasma concentration vs. time data for the 28 subjects who completed PN 400/E30 and EC E20+naproxen treatments and 27 subjects who completed PN 400/E10 treatment on Days 1 and 9; and 28, and 27 subjects who completed PN 400/E20 treatment on Day 1 and Day 9, respectively.







TABLE 6







Summary of Esomeprazole Pharmacokinetic Results

















AUC0-10, am or





Day/Dose
Cmax
tmax
AUC0-14, pm
AUC0-24
t1⁄2


Treatment
Time
(ng/mL)
(hr)
(hr*ng/mL)
(hr*ng/mL)
(hr)





A
1
487
0.50
591

   0.892


PN 400/E30
AM
 (82)
(0.33-1.50)
(108)

(35)



1
187
1.50
388
978
   1.11



PM
(132)
(0.33-4.00)
(137)
(115)
(62)



9
1584 
0.50
2779 

   1.26



AM
 (39)
(0.17-1.50)
 (45)

(25)



9
810
1.00
2066 
4911 
   1.46



PM
 (59)
(0.33-8.00)
 (53)
 (42)
(34)


B
1
292
0.50
350

   0.846


PN 400/E20
AM
 (77)
(0.20-1.50)
(113)

(42)



1
  96.6
1.49
206
556
   0.994



PM
(104)
(0.33-3.00)
(141)
(119)
(55)



9
715
0.50
1216 

   1.12



AM
 (52)
(0.17-1.50)
 (69)

(33)



9
428
0.75
919
2134 
   1.31



PM
 (73)
(0.33-3.00)
 (84)
 (74)
(42)


C
1
138
0.33
148

   0.810


PN 400/E10
AM
 (71)
(0.17-3.10)
(111)

(48)



1
  35.3
1.50
  85.7
237
   0.878



PM
 (84)
(0.33-3.00)
(179)
(133)
(50)



9
278
0.33
368

   0.860



AM
 (57)
(0.17-1.00)
 (89)

(41)



9
  97.6
1.00
223
602
   1.09



PM
(136)
(0.33-2.00)
(134)
(103)
(47)


D
1
282
1.50
520
580
   1.09


EC E20 +
AM
 (66)
(1.00-16.0)
 (64)
 (67)
(44)


naproxen
9
435
1.50
1046 
1212 
   1.27



AM
 (48)
(1.00-14.0)
 (54)
 (47)
(36)





Values are mean (% CV) for all parameters, except for tmax, which are median (range).






Following oral administration of PN 400 on Day 1, esomeprazole concentrations were measurable at 10 minutes after the AM dose, and at 20-30 minutes after the PM dose. Plasma esomeprazole concentrations after the PM dose were lower than those after the AM dose on both days. Cmax and AUCs of esomeprazole increased nearly dose proportionally after the AM dose on Day 1, but more than dose proportionally after the PM dose on Day 1 and both the AM and PM doses on Day 9. Esomeprazole concentrations were much higher on Day 9 than on Day 1 for each PN 400 treatment. The geometric least-squares mean AUC0-24 ratios, Day 9 to Day 1, were 7.13, 4.10, and 2.26 for treatment with PN 400/E30, PN 400/E20, and PN 400/E10, respectively.
Following EC E20+naproxen treatment, the first measurable esomeprazole concentration was at 0.5 to 1.5 hrs post dose. To evaluate the effect of esomeprazole in the PN400/E20 treatment group with the EC E20 in the EC E20+naproxen treatment group, the PK parameters from PN400/E20 and EC E20+naproxen treatment groups were compared. On Day 1, esomeprazole Cmax,am mean values were approximately equal for the PN400/E20 and EC E20+naproxen treatments (292 and 282 ng/ml, respectively). The AUC0-10 mean values on Day 1 from the PN400/E20 treatment were approximately two-thirds that of the EC E20+naproxen treatment (350 vs. 520 hr·ng/ml, respectively). By Day 9, however, the esomeprazole AUC0-10 for the PN400/E20 treatment group was greater than the EC E20+naproxen treatment group (1216 vs 1046 hr·ng/ml, respectively) and Cmax,am from the PN400/E20 treatment group was almost double that of the EC E20+naproxen treatment group (715 vs 435 ng/ml, respectively).
Mean and median plasma esomeprazole concentration vs time profiles following all four treatments were plotted and the mean plots are presented in FIGS. 3 and 4. These figures demonstrate that esomeprazole concentrations following AM or PM doses on Day 1 or Day 9 increased with the esomeprazole dose in the PN 400 treatments. Furthermore, on both Days 1 and 9, esomeprazole concentrations after the AM dose were higher than those after the PM dose for each PN 400 treatment. Following EC E20+naproxen treatment, the mean profiles demonstrate a delayed absorption peak on both Days 1 and 9 as compared to PN 400. In addition, peak esomeprazole concentrations following EC E20+naproxen treatment were lower than those following PN 400/E20, especially on Day 9 (about 50% lower).
The pharmacokinetic parameters of esomeprazole following the AM and PM doses on Day 1 and Day 9 of each treatment group are summarized in Tables 7 to 10 below.







TABLE 7







Summary of Esomeprazole Pharmacokinetic Parameters by


Study Day and Dose Time for Treatment A (PN 400/E30)





















AUC0-10, am or





Dose
Statis-
Cmax
tmax
AUC0-t
AUC0-14, pm
AUC0-24
t1⁄2


Day
Time
tics
(ng/ml)
(hr)
(hr*ng/mL)
(hr*ng/mL)
(hr*ng/ml)
(hr)


















1
AM
Mean
487

588
591

0.892



n = 28
% CV
82

109
108

35




Median
325
0.50
352
354

0.810




Min
52.1
0.33
59.4
61.0

0.520




Max
1400
1.50
3087
3087

1.96


1
PM
Mean
187

385
388
978
1.11



n = 28
% CV
132

138
137
115
62




Median
114
1.50
204
207
579
0.861




Min
21.1
0.33
37.4
40.3
101
0.593




Max
1290
4.00
2315
2315
5402
3.89


9
AM
Mean
1584

2778
2779

1.26



n = 28
% CV
39

46
45

25




Median
1560
0.50
2586
2586

1.18




Min
384
0.17
874
879

0.83




Max
3520
1.50
5841
5841

1.80


9
PM
Mean
810

1990
2066
4911
1.46a



n = 28
% CV
59

57
53
42
34




Median
749
1.00
2090
2159
5488
1.38




Min
13.7
0.33
21.7
342
1519
0.75




Max
1970
8.00
4956
4956
9770
2.91





an = 27













TABLE 8







Summary of Esomeprazole Pharmacokinetic Parameters by


Study Day and Dose Time for Treatment B (PN 400/E20)





















AUC0-10, am or





Dose
Statis-
Cmax
tmax
AUC0-t
AUC0-14, pm
AUC0-24
t1⁄2


Day
Time
Tics
(ng/mL)
hr)
(hr*ng/mL)
(hr*ng/mL)
(hr*ng/mL)
(hr)


















1
AM
Mean
292

348
350

0.846



n = 28
% CV
77

114
113

42




Median
209
0.50
245
248

0.696




Min
47.1
0.20
57.0
58.1

0.434




Max
916
1.50
1971
1971

1.90


1
PM
Mean
96.6

203
206
556
0.994



n = 28
% CV
104

144
141
119
55




Median
71.7
1.49
106
108
362
0.844




Min
16.0
0.33
24.3
28.6
86.7
0.410




Max
439
3.00
1459
1459
3429
2.82


9
AM
Mean
715

1215
1216

1.12



n = 27
% CV
52

70
69

33




Median
700
0.50
947
948

1.03




Min
112
0.17
186
188

0.485




Max
1300
1.50
2931
2931

1.82


9
PM
Mean
428

914
919
2134
1.31



n = 27
% CV
73

85
84
74
42




Median
373
0.75
603
642
1727
1.32




Min
30.5
0.33
59.3
63.5
288
0.686




Max
1300
3.00
2931
2931
5737
3.10
















TABLE 9







Summary of Esomeprazole Pharmacokinetic Parameters by


Study Day and Dose Time for Treatment C (PN 400/E10)





















AUC0-10, am or





Dose
Statis-
Cmax
tmax
AUC0-t
AUC0-14, pm
AUC0-24
t1⁄2


Day
Time
Tics
(ng/mL)
(hr)
(hr*ng/mL)
(hr*ng/mL)
(hr*ng/mL)
(hr)


















1
AM
Mean
138

143
148

0.810



n = 27
% CV
71

115
111

48




Median
123
0.33
84.8
105

0.703




Min
24.4
0.17
35.0
  36.1

0.454




Max
370
3.10
882
882

2.21


1
PM
Mean
35.3

80.6
  85.7b
 237b
0.878a



n = 27
% CV
84

188
179
133
50




Median
32.1
1.50
41.8
  48.7
155
0.734




Min
4.2
0.33
8.40
   9.80
  45.9
0.593




Max
141
3.00
818
818
1700 
2.67


9
AM
Mean
278

366
368

0.860



n = 27
% CV
57

90
 89

41




Median
242
0.33
223
224

0.653




Min
33.0
0.17
41.0
  42.6

0.526




Max
594
1.00
1284
1284 

1.85


9
PM
Mean
97.6

215
 223b
 602b
1.09b



n = 27
% CV
136

137
134
103
47




Median
42.2
1.00
69.9
  76.9
306
0.944




Min
11.0
0.33
17.3
  18.8
  63.7
0.370




Max
554
2.00
1076
1080 
2186 
2.79





an = 25;


bn = 26













TABLE 10







Summary of Esomeprazole Pharmacokinetic Parameters by Study


Day and Dose Time for Treatment D (EC E20 + Naproxen)
















Dose
Statis-
Cmax
tmax
AUC0-t
AUC0-10, am
AUC0-24
t1⁄2


Day
Time
Tics
(ng/mL)
(hr)
(hr*ng/mL)
(hr*ng/mL)
(hr*ng/mL)
(hr)


















1
AM
Mean
282

567
 540b
 580b
1.09b



n = 28
% CV
66

68
 60
 67
44




Median
231
1.50
466
471
471
0.931




Min
1.1
1.00
143
143
144
0.633




Max
678
16.0
1777
1359 
1777 
2.56


9
AM
Mean
435

1136
1046 
1212b 
1.27a



n = 28
% CV
48

52
 54
 47
36




Median
453
1.50
1056
859
1123 
1.16




Min
98.0
1.00
292
289
429
0.755




Max
939
14.0
2279
2217 
2279 
2.46





an = 25;


bn = 26






Naproxen
Table 11 summarizes the results from the PK analysis that was performed for naproxen plasma concentration vs. time data for the 28 subjects who completed PN 400/E30 and EC E20+naproxen treatments and 27 subjects who completed the PN 400/E10 treatment on Days 1 and 9; and 28, and 27 subjects who completed PN 400/E20 treatment on Day 1 and Day 9, respectively.







TABLE 11







Naproxen Pharmacokinetic Parameters














Day/


AUC0-10, am or





Dose
Cmax
tmax
AUC0-14, pm
AUC0-24
t1⁄2


Treatment
Time
(μg/mL)
(hr)
(hr*μg/mL)
(hr*μg/mL)
(hr)





A
1
  48.1
4.00
259

   8.52


PN 400/E30
AM
(53)
(2.00-10.0)
 (56)

(25)



1
  68.9
14.0 
471
730 
  12.1



PM
(28)
(0.50-14.0)
 (30)
(32)
(30)



9
  80.9
3.00
603

   9.17



AM
(23)
(0.00-8.00)
 (21)

(21)



9
  76.2
10.4 
648
1251 
  12.3



PM
(23)
(0.00-14.0)
 (20)
(16)
(27)


B
1
  44.4
4.00
231

   8.75


PN 400/E20
AM
(68)
(2.00-10.0)
 (70)

(33)



1
  71.5
14.0 
450
680 
  11.8



PM
(26)
(0.00-14.0)
 (33)
(36)
(28)



9
  86.2
3.00
607

   9.42



AM
(22)
(0.00-8.05)
 (19)

(23)



9
  76.8
10.0 
678
1275 
  11.3



PM
(18)
(0.00-14.0)
 (16)
(15)
(28)


C
1
  57.0
4.00
310

   9.24


PN 400/E10
AM
(31)
(2.00-10.0)
 (35)

(42)



1
  68.6
10.0 
508
819 
  12.7



PM
(26)
(0.00-14.0)
 (29)
(21)
(23)



9
  87.1
2.50
637

   9.91



AM
(21)
(0.00-8.00)
 (17)

(26)



9
  78.6
14.0 
672
1309 
  10.5



PM
(17)
(1.50-14.0)
 (19)
(15)
(23)


D
1
  65.5
1.50
409

   8.85


EC E20 +
AM
(25)
(0.75-6.00)
 (16)

(22)


naproxen
1
  81.5
1.50
685
1094 
  15.4



PM
(14)
(0.50-2.50)
 (10)
(12)
(31)



9
  90.0
1.50
617

   9.32



AM
(19)
(0.50-4.00)
 (12)

(23)



9
  86.5
1.50
769
1387 
  14.4



PM
(13)
(0.75-4.00)
 (10)
(10)
(17)





Values are mean (% CV) for all parameters, except for tmax, which are median (range).






Following oral administration of PN 400 on Day 1, the first measurable naproxen concentrations occurred at about 2 hrs post AM dose. Plasma exposure to naproxen was comparable among the three PN 400 treatments. Following repeated doses of PN 400, the Day 9 to Day 1 naproxen concentration ratio was consistent with the expected accumulation based on the half-life estimates of naproxen. The variability in naproxen AUC between AM and PM doses was less on Day 9 than on Day 1, reflecting that naproxen levels are approximately at steady state with repeat dosing. Cmax values were somewhat more variable between the AM and PM doses on Day 1 compared to Day 9, with mean AM levels being lower than mean PM levels for all treatments on Day 1 and mean AM levels slightly higher than mean PM levels for all treatments on Day 9.
Following the first (AM) dose of Treatment D on Day 1, plasma naproxen concentrations were measurable in all subjects at the first sampling time, i.e., 10 minutes post-dose and then up to 24 hours post AM dose (or 14 hours post PM dose), demonstrating typical performance of non-enteric coated naproxen.
Mean and median plasma naproxen concentration vs time profiles following all 4 treatments are presented in FIGS. 5 and 6.
The PK parameters of naproxen following administration of the AM and PM doses on Day 1 and Day 9 of each treatment are summarized in Tables 12 to 15 below.







TABLE 12







Summary of Naproxen Pharmacokinetic Parameters by Study


Day and Dose Time for Treatment A (PN 400/E30)





















AUC0-10, am or





Dose
Statis-
Cmax
tmax
AUC0-t
AUC0-14, pm
AUC0-24
t1⁄2


Day
Time
Tics
(μg/mL)
(hr)
(hr*μg/mL)
(hr*μg/mL)
(hr*μg/mL)
(hr)


















1
AM
Mean
48.1

259
259

8.52a



n = 28
% CV
53

56
56

25




Median
53.2
4.00
339
339

7.86




Min
0.0
2.00
0.0
0.0

6.07




Max
82.5
10.0
428
428

13.8


1
PM
Mean
68.9

471
471
730
12.1b



n = 28
% CV
28

30
30
32
30




Median
68.5
14.0
464
464
780
10.8




Min
31.9
0.50
190
190
190
7.16




Max
114
14.0
716
716
1092
19.2


9
AM
Mean
80.9

603
603

9.17c



n = 28
% CV
23

21
21

21




Median
80.0
3.00
568
568

9.31




Min
44.5
0.00
345
345

5.32




Max
139
8.00
944
944

13.2


9
PM
Mean
76.2

648
648
1251
12.3d



n = 28
% CV
23

20
20
16
27




Median
69.7
10.4
635
635
1269
12.0




Min
53.9
0.00
384
384
729
6.56




Max
127
14.0
932
932
1744
22.1





an = 17;


bn = 21;


cn = 26;


dn = 24.













TABLE 13







Summary of Naproxen Pharmacokinetic Parameters by Study


Day and Dose Time for Treatment B (PN 400/E20)





















AUC0-10, am or





Dose
Statis-
Cmax
tmax
AUC0-t
AUC0-14, pm
AUC0-24
t1⁄2


Day
Time
Tics
(μg/mL)
(hr)
(hr*μg/mL)
(hr*μg/mL)
(hr*μg/mL)
(hr)


















1
AM
Mean
44.4

231
231

8.75a



n = 28
% CV
68

70
70

33




Median
50.1
4.00
291
291

7.72




Min
0.00
2.00
0.00
0.0

6.07




Max
94.4
10.0
490
490

15.1


1
PM
Mean
71.5

450
450
680
11.8b



n = 28
% CV
26

33
33
36
28




Median
69.4
14.0
443
443
756
10.9




Min
45.1
0.00
159
157
157
6.70




Max
110
14.0
831
831
977
18.7


9
AM
Mean
86.2

607
607

9.42b



n = 27
% CV
22

19
19

23




Median
85.1
3.00
577
577

8.65




Min
53.5
0.00
378
378

5.48




Max
137
8.05
856
856

13.9


9
PM
Mean
76.8

668
678
1275
11.3c



n = 27
% CV
18

16
16
15
28




Median
73.0
10.0
661
661
1306
10.9




Min
51.2
0.00
458
458
939
7.97




Max
116
14.0
847
847
1659
19.2





an = 15,


bn = 22,


cn = 20













TABLE 14







Summary of Naproxen Pharmacokinetic Parameters by Study


Day and Dose Time for Treatment C (PN 400/E10)





















AUC0-10, am or





Dose
Statis-
Cmax
tmax
AUC0-t
AUC0-14, pm
AUC0-2
t1⁄2


Day
Time
Tics
(μg/mL)
(hr)
(hr*μg/mL)
(hr*μg/mL)
(hr*μg/mL)
(hr)


















1
AM
Mean
57.0

310
310

9.24a



n = 97
% CV
31

35
35

42




Median
60.3
4.00
339
339

7.88




Min
6.90
2.00
50.5
50.5

3.36




Max
88.2
10.0
488
488

21.8


1
PM
Mean
68.6

508
508
819
12.7b



n = 27
zzz5 CV
26

29
29
21
23




Median
70.0
10.0
512
512
805
12.5




Min
30.0
0.00
271
271
454
6.93




Max
97.2
14.0
791
791
1225
20.2


9
AM
Mean
87.1

637
637

9.91c



n = 27
% CV
21

17
17

26




Median
83.9
2.50
654
654

9.29




Min
45.0
0.00
332
332

6.88




Max
120
8.00
787
787

16.1


9
PM
Mean
78.6

672
672
1309
10.5b



n = 27
% CV
17

19
19
15
23




Median
73.5
14.0
687
687
1328
9.98




Min
62.4
1.50
349
349
681
7.17




Max
109
14.0
953
953
1647
16.1





an = 22;


bn = 25;


cn = 23.













TABLE 15







Summary of Naproxen Pharmacokinetic Parameters by Study


Day and Dose Time for Treatment D (EC E20 + Naproxen)





















AUC0-10, am or





Dose
Statis-
Cmax
tmax
AUC0-t
AUC0-14, pm
AUC0-24
t1⁄2


Day
Time
tics
(μg/mL)
(hr)
(hr*μg/mL)
(hr*μg/mL)
(hr*μg/mL)
(hr)


















1
AM
Mean
65.5

409
409

8.85a



n = 28
% CV
25

16
16

22




Median
67.0
1.50
411
411

8.44




Min
39.9
0.75
293
293

6.17




Max
113
6.00
562
562

14.1


1
PM
Mean
81.5

685
685
1094
15.4



n = 28
% CV
14

10
10
12
31




Median
80.8
1.50
662
662
1068
14.7




Min
58.2
0.50
592
592
909
9.04




Max
107
2.50
855
855
1398
32.8


9
AM
Mean
90.0

617
617

9.32



n = 28
% CV
19

12
12

23




Median
87.0
1.50
619
619

9.39




Min
59.4
0.50
493
493

5.77




Max
126
4.00
793
793

15.4


9
PM
Mean
86.5

769
769
1387
14.4



n = 28
% CV
13

10
10
10
17




Median
89.6
1.50
760
760
1371
14.7




Min
67.3
0.75
619
619
1130
10.5




Max
123
4.00
930
930
1723
21.1





an = 27.






Drug Concentrations or Pharmacokinetics in Relation to Pharmacodynamic Measurements
As shown in FIG. 7, the relationship between the mean total plasma exposure to esomeprazole, i.e., AUC0-24 on Day 9 (representing steady-state exposure), and the mean percent time with intragastric pH>4.0 on Day 9 (the primary PD endpoint) can be described by a typical pharmacological maximal response (Emax) model defined below:

Effect=(Emax*AUC0-24)/(EC50+AUC0-24),

where

    
    
        Effect=Mean percent time intragastric pH>4.0 on Day 9 (assuming zero time intragastric pH>4.0 when esomeprazole AUC0-24 equals zero)
        Emax=Maximal Effect
        EC50=Plasma mean AUC0-24 required to produce 50% of the Maximal Effect
    
    


The Emax was estimated to be 90.4% of time with intragastric pH>4.0 over the daily interval at steady state. The AUC0-24 value required to achieve half (or 50%) of the maximal response was estimated to be 713 hr*ng/mL. Following PN 400/E20, the PD response had achieved about 80% of the maximal response, which was only slightly less than that (85% of Emax) achieved by PN 400/E30.
Repeat doses of PN 400/E30 and PN 400/E20 resulted in faster onset of increased intragastric pH (at about 1 hour post dose) than EC E20+naproxen, which was at about 1.5 hours post-dose (FIG. 1).
As shown in the FIG. 8A, the release of naproxen from PN 400 occurred 1.5 to 2 hours post AM dose. Before naproxen was absorbed to peak concentrations following PN 400 treatment, intragastric pH had already achieved high levels, well above pH 4.0 (FIG. 8A). In fact, with the BID regimen of PN 400/E20, given 1 hour before a meal, the intragastric pH was maintained at above 4.0 for greater than 70% of time over a 24-hour period, which would encompass any rise in plasma naproxen concentrations throughout the day.
In contrast, EC E20+naproxen produced peak naproxen concentrations that preceded the increase in intragastric pH (FIG. 8B). In fact, peak naproxen concentrations occurred 1 to 2 hours post dose, which coincided with the time period when intragastric pH was lowest (FIG. 8B).

## Claims

1. A method for delivering a pharmaceutical composition to a patient in need thereof, comprising:
orally administering to the patient an AM unit dose form and, 10 hours (±20%) later, a PM unit dose form, wherein:
the AM and PM unit dose forms each comprises:
i) naproxen, or a pharmaceutically acceptable salt thereof, in an amount to provide 500 mg of naproxen, and
ii) esomeprazole, or a pharmaceutically acceptable salt thereof, in an amount to provide 20 mg of esomeprazole;
said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said AM and PM unit dose forms at a pH of 0 or greater,
the AM and PM unit dose forms target:
i) a pharmacokinetic (pk) profile for naproxen where:
a) for the AM dose of naproxen, the mean Cmax is 86.2 μg/mL (±20%) and the median Tmax is 3.0 hours (±20%); and
b) for the PM dose of naproxen, the mean Cmax is 76.8 μg/mL (±20%) and the median Tmax is 10 hours (±20%); and

ii) a pharmacokinetic (pk) profile for esomeprazole where:
a) for the AM dose of esomeprazole, the mean area under the plasma concentration-time curve from when the AM dose is administered to 10 hours (±20%) after the AM dose is administered (AUC0-10,am) is 1216 hr*ng/mL (±20%),
b) for the PM dose of esomeprazole, the mean area under the plasma concentration-time curve from when the PM dose is administered to 14 hours (±20%) after the PM dose is administered (AUC0-14,pm) is 919 hr*ng/mL (±20%), and
c) the total mean area under the plasma concentration-time curve for esomeprazole from when the AM dose is administered to 24 hours (±20%) after the AM dose is administered (AUC0-24) is 2000 hr*ng/mL (±20%); and

the AM and PM unit dose forms further target a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period after reaching steady state that is at least about 60%.

2. The method according to claim 1, wherein the mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period is at least about 71%.

3. The method according to claim 1, wherein said unit dose form is administered for a period of at least about 6 days.

4. The method according to claim 2, wherein said unit dose form is administered for a period of at least about 9 days.

5. The method according to claim 1, wherein said AM and PM unit dose forms are each a multilayer tablet comprising at least one core and at least a first layer and a second layer, wherein:
i) said core comprises naproxen, or pharmaceutically acceptable salt thereof;
ii) said first layer is a coating that at least begins to release the naproxen, or pharmaceutically acceptable salt thereof, when the pH of the surrounding medium is about 3.5 or greater; and
iii) said second layer comprises esomeprazole or a pharmaceutically acceptable salt thereof, wherein said esomeprazole or pharmaceutically acceptable salt thereof is released at a pH of from about 0 or greater.

6. The method according to claim 5, wherein said esomeprazole is released at a pH of from about 0 to about 2.

7. The method according to claim 5, wherein said multi-layer tablet is substantially free of sodium bicarbonate.