Sponsor's consideration of product development strategies

To evaluate the food effect of Ibuprofen CR Tablets 600 mg (IBUCR), and its bioavailability comparison versus 3 doses of the reference arms including Advil® Ibuprofen Tablets 200 mg (IBUAdv) and Motrin® IB Ibuprofen Tablets 200 mg (IBUMot) in normal healthy volunteers.

This randomized, open label, four-way crossover phase I study is to evaluate the food effect of Ibuprofen CR Tablets 600 mg (IBUCR), and its bioavailability comparison versus 3 doses of the reference arms including Advil® Ibuprofen Tablets 200 mg (IBUAdv) and Motrin® IB Ibuprofen Tablets 200 mg (IBUMot) in normal healthy volunteers.

This study will enroll at least 26 evaluable subjects. The duration for test and reference treatments is 24 to 32 hours with a washout period of at least 5 days after the last dose administration of study drugs. The total study will take at least 28 days.

Subjects who meet all eligible requirements for participating in the study will receive all following interventions according to one of the 4 random sequences by Williams design.

1. One tablet of IBUCR 600 mg under fasting condition
2. One tablet of IBUCR 600 mg under fed condition
3. IBUAdv with a 4-hour dosing interval for 3 tablets (3×200 mg, q4h) under fasting condition
4. IBUMot with a 4-hour doing interval for 3 tablets (3×200 mg, q4h) under fasting condition

The blood sampling schedule are described as follows:

-For subjects receiving IBUCR (fed and fasted): Before dose administration (blank) and at 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 12h, 18h, 24h, 28h, 32h post-dose (A total of 17 samples per subject)

-For subjects receiving IBUAdv/IBUMot (fasted): Before dose administration (blank) and at 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 12h, 16h, 20h, 24h post-dose (A total of 25 samples per subject)

Inclusion Criteria:

1. Subjects are 20 years of age or older.

2. Subjects whose body mass index (BMI) at screening is within a range of ≧18.5 kg/m2 and <25.0 kg/m2.

   BMI = Body Weight (kg) / [Height (m)]2 And body weight is not less than 50 kg and 45 kg for males and females, respectively.

3. Subject's medical history shows no contraindication to the test medications (hypersensitivity to ibuprofen or any component of test and reference products).

4. Subjects who are judged to be in good health by the investigator based upon the results of physical examinations (PEs), chest X-ray (within 180 days prior to the first dose of the study) and routine laboratory tests.

5. The female subject shows negative pregnancy test results within 30 days prior to the first dose of the study.

6. The Subject did not take any of the following medications in the specified durations:

   • Any medication within 14 days prior to the first dose of the study
   • Any enzyme inducer or inhibitor within 30 days prior to the first dose of the study

7. Subject understood and has signed the written informed consent form.

Exclusion Criteria:

1. Subjects with any properly diagnosed disease within 30 days prior to the first dose of the study.
2. Subjects with a clinically significant hematological, endocrine, cardiovascular, hepatic, renal, gastrointestinal, and/or pulmonary disorder; subjects with any predisposing condition that might interfere with the absorption, distribution, metabolism and excretion of drugs; subjects who has had any previous gastrointestinal surgery, except appendectomy if performed >90 days prior to the first dose of the study
3. Subjects who require treatment with any medications, either prescription or non-prescription (excluding vitamins and food supplements), within 30 days prior to the first dose of the study
4. Subjects who have received any known hepatic or renal clearance-altering agents (e.g., erythromycin, cimetidine, barbiturates, phenothiazine, clarithromycin, trolearndomycin, ketoconazole, miconazole, fluconazole, itraconazole) for a period of up to 30 days prior to the first dose of the study
5. The subject had participated in investigational drug trials and took any investigational drug within 60 days prior to the first dose of the study.
6. The subject had blood donation more than 250 and 500 mL within 60 and 90 days, respectively prior to the first dose of the study.
7. The subject had a history of drug abuse or alcohol abuse.
8. Subjects cannot stop smoking and caffeine-intakes for 48 hours prior to the first dose of the study and during the entire study period.
9. Subjects who are pregnant or lactating
10. For enrollment of female subjects with child-bearing potential, the subject must be practicing sexual abstinence or be using and willing to continue to use a medically acceptable form of birth control for at least 30 days prior to screening (that period will extend to 3 months for oral contraceptive use) and for at least 30 days after the last dose of study drug. For a subject to be considered not to be of child-bearing potential, she must have been amenorrheic for at least 2 years, or must have had a hysterectomy, a bilateral tubal ligation, and/or a bilateral oophorectomy (as determined by the medical history). The male partner of a female study subject with childbearing potential must use a condom and ensure that his partner uses a suitable method of contraception as outlined above.
11. Subjects who are inappropriate to participate in this study, as judged by the medical investigator or sub-investigator
12. Subjects with any contraindication to the use of test medications
13. Subjects who are carriers of hepatitis B virus, hepatitis C virus, or are syphilis (STS) positive, or human immunodeficiency virus (HIV) positive