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Current (regular) preparation of cefaclor (CCL) require the 3-time-a-day administration. S6472 (sustained release preparation) which can be used with the twice-a-day administration in the morning and the evening is capsule and granule preparations consisting of 40% of nonenteric and 60% of enteric coated granules of CCL. Phase I clinical studies of S6472 were conducted in 12 nonfasted healthy adult male volunteers with cross over method using a single dose of 375 mg in capsule and granule forms of S6472, and 250 mg in capsule form of regular CCL as a control drug. The volunteers received the 3 preparations at 1-week interval. The summary of the results from the above studies is as follows: Grouping of the volunteers. The 12 volunteers were divided into 3 groups (each group consists of 4 volunteers) and there were no significant differences between each group regarding background factors of the volunteers. Tolerance. None of the volunteers who received the 3 preparations at 1-week interval complained of subjective abnormalities. No abnormalities which are considered to be due to S6472 and regular CCL were found in the clinical laboratory tests carried out before the administration and 1 week after the completion of the studies. Plasma level. There were no significant differences between capsule and granule forms of S6472 regarding Cmax and AUC, and it was confirmed that bioavailability of both preparations was the same. It was also confirmed that plasma levels of the 2 preparations of S6472 were maintained for longer period of time than those of regular CCL. Urinary excretion. Mean urine levels of the 2 preparations of S6472 every 2 hours after the administration were confirmed to be maintained for longer period of time than those of regular CCL. There were no significant differences between the 2 preparations of S6472 regarding urinary recovery rate. However, the significant differences between the 2 preparations of S6472 and regular CCL were observed. Urinary recovery rate of the 2 preparations of S6472 was 87 approximately 88% of that of regular CCL.

In order to see absorption and excretion of S6472 (sustained release preparations of cefaclor (CCL], 3 studies regarding, 1) influence of meals (single dose of 375 mg in capsule form), 2) dose response (single dose of 375 mg vs. 750 mg in granule form) and 3) continuous administration (twice-a-day administration of 750 mg in granule form for 8 days) were conducted in 15 healthy adult male volunteers using capsule and granule forms of S6472. The following is the summary of the results from the above studies: Tolerance. In the above 3 studies, none of the 15 volunteers complained of subjective abnormalities. In the clinical laboratory tests performed before the administration of S6472 and at the next day of the completion of the studies, the values from the laboratory tests were within normal range. Influence of meals. The average time for peak plasma level of CCL and decrease in the plasma level following the administration of S6472 were the fastest in the fasted volunteers, followed by the volunteers with light meals and usual meals. From this, it was confirmed that plasma levels of CCL were maintained for longer period of time in the non-fasted volunteers than in the fasted volunteers. In the volunteers who had light and usual meals, the peak plasma levels, AUC of the plasma levels and urinary recovery rate were almost the same. Influence by amount of meals was scarcely observed. Dose response. Mean serum levels and their AUC in the volunteers receiving 750 mg of S6472 were approximately twice as much as those in the volunteers receiving 375 mg of S6472, and dose response between the 2 doses was confirmed. Continuous administration. Mean serum levels and their AUC at the first dose and the 15th dose (final dose) were almost the same. In the continuous administration of S6472 for 8 days (15 doses), no accumulation of CCL in the body was observed.

Fundamental and clinical studies on S6472, a new prolonged acting preparation of cefaclor, were performed and the following results were obtained. Serum level and urinary excretion. 750 mg of S6472, 500 mg of cefaclor (CCL) and 500 mg of cephalexin (CEX) were orally administered in 6 healthy adult volunteers by the cross over method to measure serum level and urinary excretion. The serum level-time curve of S6472 showed 2 peaks at 1 and 6 hours after administration. The peak serum level of S6472 was 4.2 micrograms/ml and 2.9 micrograms/ml, respectively, 1 and 6 hours after administration. The peak serum level of CCL and CEX was 5.8 micrograms/ml and 12.1 micrograms/ml, respectively, 2 hours after administration. The urine level-time curve of S6472 also showed 2 peaks at 0-2 and 4-6 hours after administration and the peak urine level was 1,320 micrograms/ml and 994 micrograms/ml, respectively, 0-2 and 4-6 hours after administration. The peak urine level of CCL was 1,337 micrograms/ml, 0-2 hours after administration and that of CEX was 2,079 micrograms/ml, 2-4 hours. The mean urinary excretion of S6472, CCL and CEX was 56%, 69% and 94% of dose at 12 hours after administration. Clinical evaluation. S6472 was tried in 200 cases of various urinary tract infections. For one group of 85 cases with acute uncomplicated cystitis, clinical effects were evaluated as excellent in 40 cases, moderate in 42 cases and poor in 3 cases, and the overall clinical effectiveness rate was 96.5%. For another group of 68 cases with complicated urinary tract infection, clinical effects were evaluated as excellent in 9 cases, moderate in 27 cases and poor in 32 cases, and the overall clinical effectiveness rate was 52.9%. Side effects. Side effects were observed in 7 cases with diarrhea, epigastralgia, stomatitis, eruption and facial swelling. Administration of S6472 was discontinued in 2 cases, but in 7 cases all symptoms were transient.

This study was conducted to develop a prolonged action preparation of cefaclor (CCL) which can offer, with the twice-a-day administration, as much effectiveness as its conventional preparation (Kefral capsule) with the 3 times-a-day administration. Absorption site of CCL in gastrointestinal tract, preparation form (enteric coated granules) which slowly release CCL, dissolution property of the form, and mixed ratio of the form and rapid release form (nonenteric coated granules) were studied and complex granules consisting of 40% of nonenteric coated granules and 60% of enteric coated granules which dissolve at pH 6 were chosen as a prolonged action preparation of CCL. Bactericidal activity of the prolonged action preparation (S6472) was confirmed to be the same as that of the conventional preparation by comparative viable cell count study in which concentrations of CCL simulated to plasma concentrations following the administration of S6472 at the dosage of 375 mg b.i.d. and the conventional preparation at the dosage of 250 mg t.i.d. were used. From the above, S6472 is considered to be a prolonged action preparation of CCL which serve our purpose. Since S6472 can be given with the twice-a-day administration, its daytime administration is not necessary. Therefore, S6472 is considered to be much useful preparation for the patients.

A 500 mg dose of cefaclor (CCL) was administered orally before surgery to each of patients with respiratory diseases and in fasting. Average concentrations of CCL in sera were 4.04 micrograms/ml at 1.5 hours, 3.03 micrograms/ml at 2 hours, 1.68 microgram/ml at 3 hours and 0.45 microgram/ml at 5 hours after administration. Average concentrations in lung tissues during operation were 0.120 microgram/g at 3 hours, 0.272 microgram/g at 4 hours and 0.297 microgram/g at 5 hours after administration. Ratios of concentrations of CCL in lung tissues to that in sera were from 7.1 to 66.0 percent. The CCL was considered to be a useful antibiotic for the treatment of patients with respiratory diseases.

Fundamental and clinical studies on S 6472 were carried out and following results were obtained. Serum concentrations after single oral administration showed 2 peaks at 1 or 2 hours and 5 or 6 hours in the cases with normal meal. Namely this drug has much more maintenance of serum concentration than normal cefaclor. In maintenance of serum concentrations after the administration, there were no obviously difference between normal and heavy meal. S 6472 was administered twice a day to 7 patients with various infections (bronchopneumonia 2 cases, acute bronchitis 1 case, purulent tonsillitis 4 cases) and clinical responses were all effective results. Pathogenic bacteria of S. aureus, S. pneumoniae, S. pyogenes and H. influenzae were completely eliminated in all cases. No significant side effects were observed. On the above results, this administration method of S 6472 twice a day was considered to be good response against mild or moderate bacterial infections in children.

A study in which 375 mg of S6472 was orally given to 3 healthy adult volunteers before a meal, after a light meal, and after a usual meal in the cross-over method revealed the highest levels, both in serum and urine, in cases treated before a meal. In cases administered after a light or square meal, the serum level was less, but approximately 2 micrograms/ml over 6 hours after administration. No difference was seen in the AUC. The effective rate of S6472 when given at 750 approximately 1,500 mg/day was 74.6% in 62 patients with skin or soft tissue infectious diseases. Neither subjective or objective adverse reactions were seen in any case. Clinical laboratory testing revealed 1 case each of anemia and increased BUN, for which S6472 was not responsible.

Serum and/or urine levels of cefaclor (CCL) were studied in 4 patients during the therapy with CCL. In patients with severely impaired renal function, moderately higher serum and urine levels of CCL persisted, serum half-lives of CCL were moderately prolonged and urinary excretion of CCL slightly decreased. Although dosage modification of CCL is necessary in patients with renal dysfunction, multiple doses of 250 mg every 8 hours may be safe and effective even in patients with impaired renal function.