OF THE DISINTEGRATION TIME AND ABSORPTION OF PIVAMPICILLIN CAPSULES AND TABLETS

Transcription

1 Br. J. clin. Pharmac. (1979), 8, A GASTROSCOPIC AND PHARMACOLOGICAL STUDY OF TH DISINTGRATION TIM AND ABSORPTION OF PIVAMPICILLIN CAPSULS AND TABLTS H. HY, P. MATZN & J. THORUP ANDRSN ndocrinological, Radiological and Gastroenterological Departments, University of Copenhagen, 2650 Hvidovre, Denmark. DIDRIKSN & B. NILSN Leo Pharmaceutical Products, 2750 Ballerup, Denmark 1 An in vitro investigation showed that pivampicillin tablets disintegrated more rapidly than pivampicillin capsules. This result was demonstrated and confirmed by gastroscopy in a cross-over study in healthy volunteers. 2 There were no differences in serum levels of ampicillin obtained with the two preparations, but compared with non-gastroscoped volunteers, there was delay of h in the appearance of peak serum ampicillin concentrations after gastroscopy. 3 Half of the volunteers receiving pivampicillin capsules developed hyperaemia, interstitial bleeding or erosions of the gastric mucous membrane. No such reactions were seen after pivampicillin tablets. 4 In one volunteer, a pivampicillin capsule was trapped in a not previously noticed hiatus hernia and local changes and pain occurred. Introduction Pivampicillin is one of a variety of esters that have been synthesized in order to improve the oral absorption of ampicillin. Oral administration of pivampicillin results in a rapid and complete absorption of ampicillin, with peak levels approximately three times those obtained after an equimolar dose of ampicillin (Roholt, Nielsen & Kristensen, 1974). Pivampicillin was originally formulated in capsules containing the easily soluble pivampicillin hydrochloride, whereas today mainly pivampicillin tablets containing the much less soluble pivampicillin base are used. The absorption is the same after pivampicillin hydrochloride and pivampicillin base, presumably due to a rapid conversion in the stomach of the pivampicillin base to the hydrochloride. Previous studies have shown a low incidence of upper gastrointestinal side effects of about 4% (Hey, Medalen, Moelstad & Stokholm, 1977) when using pivampicillin tablets. With pivampicillin capsules upper gastrointestinal side effects are recorded in 12% of the patients (Danoe & From Hansen, 1973) and 10% (Brumfitt, Franklin, Hayek & Pursell, 1973). It is assumed that when pivampicillin tablets disintegrate the contents are spread rapidly over a /79/ $1.00 large area of the stomach, whilst the capsules settle down on the mucous membrane of the stomach and release their contents over a limited area with the subsequent risk of local irritation. The purpose of the present study was to investigate this hypothesis more closely. Methods 1. In vitro The disintegration time in water of 18 tablets and 18 capsules was measured using the method described in the USP XIX (1975). The solubility in citrate phosphate buffer (ph 2.5) of 24 tablets and 24 capsules was measured according to the USP XIX (1975). The pivampicillin was measured spectrophotometrically using a Beckmann spectrophotometer, Model In vivo Six healthy male volunteers aged from 20 to 32 years (mean 24 years) underwent gastroscopy after $ Macmillan Journals Ltd 1979

2 238 H. HY, P. MATZN, J. THORUP ANDRSN,. DIDRIKSN & B. NILSN receiving either a pivampicillin tablet or capsule. Any volunteer with a previous history of gastric disease or sensitivity to penicillin was excluded. Acetylsalicylic acid or antirheumatic drugs were not allowed for up to 1 week prior to the study and no other medication, alcohol or beer was permitted during the preceding 24 h. The volunteers were fasted for 6 h before the investigation. A cannula was inserted into the right anticubital vein for taking blood samples, and another in the left hand for injecting diazepam. Diazepam (10-15mg) was injected immediately before gastroscopy. The study was performed as a randomized cross-over trial. On the first day, the volunteers were given either one pivampicillin capsule (containing 350mg pivampicillin hydrochloride) or one pivampicillin tablet (containing 350mg pivampicillin base). On the second test day, tablets were substituted for capsules and vice versa. For the study Pondocilling capsules and tablets, made available by Leo Pharmaceutical Products, Ballerup, were used. Both preparations were given with 20 ml water, and the volunteer stood whilst swallowing the capsule or tablet. The pharynx was then anesthetized with a lignocaine spray before the volunteer lay down. Gastroscopy was performed 2 min after ingestion of the pivampicillin, using an Olympus GF-B2 fibre gastroscope. The volunteer was placed on his left side and the gastroscope inserted. The position of the volunteer was changed to give the best possible view of the location of the drug in the stomach and pictures were taken with an Olympus ndoscope camera, SC The rapidity and manner in which the pivampicillin preparations disintegrated were carefully assessed. In particular, notice was taken of any changes of the mucous membrane of the stomach, such as hyperaemia, interstitial haemorrhage or erosions. Photographs were taken at 3-min intervals for up to 35 min after ingestion for documentation of the endoscopical findings. After disintegration of the drug, defined as the moment when it had completely dispersed, the gastroscope was removed. 3. xamination of serum Blood samples were taken for measuring ampicillin levels at 0, 15, 30, 40, 50, 60, 90 and 120 min after ingestion of the drug. Pivampicillin is rapidly and completely hydrolyzed into ampicillin after absorption. The antibiotic activity in serum is expressed as anhydrous ampicillin. The activity was assayed by an agar cup-plate technique with Sarcina lutea ATCC 9341 as the test organism and a standard preparation of ampicillin as a reference compound. It soon became apparent that peak levels were occurring later than normally seen, and further blood B 200 U, Time after ingestion (min) Figure 1 Dissolution of pivampicillin from tablets (0) and capsules (0) in vitro (mean and range). samples were taken 150 min after ingestion. Furthermore, one of the volunteers was given one pivampicillin tablet without gastroscopy in order to compare serum levels. thics All the volunteers were informed of the purpose and the procedure of the trial and that they could not expect any diagnostic nor therapeutic advantage in joining it. The slight risks connected with lignocaine and diazepam anesthesia, pivampicillin ingestion and gastroscopy were pointed out. thical approvement was obtained before the start of the study. In this way the procedure of the investigation is in the accordance with the Helsinki declaration 2. Results 1. In vitro A significantly faster disintegration time for pivampicillin tablets (mean 9.5min) compared with pivampicillin capsules (mean 10.9 min) was demonstrated (P< 0.05). The dissolution rate in citrate phosphate buffer was also higher for the pivampicillin tablets than for the capsules (Figure 1). When calculating T80,, i.e. the time at which 80% of the drug had dissolved, the mean value for the tablets was found to be 7.5 min and for the capsules 9.3 mm (P<0.01).

3 DISINTGRATION TIM AND ABSORPTION OF PIVAMPICILLIN 239 3min 3min 6 min 9min 12 min 15min 18min 21 min 21 min Figure 2 The disintegration of capsules. ndoscopic findings at various times after pivampicillin ingestion. Many areas of hyperaemia, fresh interstitial bleeding or erosions are seen in the gastric mucosa. 16

4 240 H. HY, P. MATZN, J. THORUP ANDRSN,. DIDRIKSN & B. NILSN 3 min 3 min 6 min 6min 9 min 12 min Figure 3 The disintegration of tablets. ndoscopic findings at various times after pivampicillin ingestion. During the disintegration of the tablets, the gastric mucosa appeared normal. The tablets are seen spread over a large area of the stomach. Figure 4 2's1 rn'iir 24 i-rim The disintegration of capsules. The capsule is seen lying in a hiatus hernia, surrounded by erosions.

5 DISINTGRATION TIM AND ABSORPTION OF PIVAMPICILLIN 241._) a) cn I~ I L Time after ingestion (min) Figure 5 Ampicillin serum levels (mean and range) in six healthy volunteers during and after gastroscopy. 0 tablet, 0 capsule. ci I I 11 A I14 1 ci Time after ingesiton (min) Figure 6 Ampicillin serum levels in one person with (0) and without (0) gastroscopy. 2. In vivo Gastroscopy showed a significant difference in the disintegration of the capsules and tablets. When the tablets disintegrated, their contents rapidly spread over a large area of the mucous membrane, whereas disintegration of the capsules took place more slowly, and the contents remained in a more limited area. The contents of the capsule were released either through pores in the gelatin case or by the case breaking. The mean disintegration time for the pivampicillin tablets was 14min (range 9-20min), and for the capsules 21 min (range min), (P=0.03). Half of the volunteers receiving the capsules showed hyperaemia, interstitial bleeding or erosions of the gastric mucosa, whereas the mucous membrane appeared normal after the ingestion of pivampicillin tablets (Figure 2 and 3). In one volunteer we observed a pivampicillin capsule trapped in a hiatus hernia (Figure 4). 3. Serum level measurements Ampicillin serum levels are shown in Figure 5. A delay in appearance of the peak serum concentration occurred. Normally this is reached about 1 h after ingestion in normal fasting volunteers (Figure 6) but in this study, the peak levels occurred h after administration of the drug. The differences observed in the disintegration times of the two drugs did not seem to influence the absorption and serum levels. The influence of gastroscopy on serum concentrations is shown in Figure 6. After gastroscopy, peak serum levels were delayed. 17 Without gastroscopy, serum concentrations were similar to the results found in patients confined to bed (Hultberg & Backelin, 1972). Discussion In order to achieve the ideal dosage form for the oral administration of a drug, the bioavailability and the side effects of the drug are of the greatest importance. In both the in vitro and in vivo experiments in the present study, it appears that even though the absorption of ampicillin is similar, there is a statistically significant difference in the disintegration rates of pivampicillin tablets and capsules in the stomach. We have shown that the tablets disintegrated quickly and distributed their contents over a large area of the mucous membrane. The capsules settled down in the membranous folds and released their contents over a limited area. After ingestion of the capsules, half of the volunteers showed visible changes in the mucous membrane, such as hyperaemia, interstitial bleeding or erosions, whereas no changes were seen after tablets. Peak serum levels appeared later in these recumbent volunteers (within h) than in fasting persons not lying down (within 1 h). This may be due to various reasons. The insertion of the gastroscope in the stomach and insufflation of air may prevent complete contact between the drug and the mucous membrane. Premedication with diazepam may reduce intestinal motility although this is uncertain. In the volunteer in whom the absorption of pivampicillin was compared with and without

6 242 H. HY, P. MATZN, J. THORUP ANDRSN,. DIDRIKSN & B. NILSN gastroscopy, a higher and earlier peak serum level of ampicillin occurred without gastroscopy, similar to that seen in patients confined to bed. In a study carried out with "S labelled pivampicillin, (Swahn, 1976), it was demonstrated that up to 30% of the drug was absorbed in the stomach. It appears that this absorption is inhibited by gastroscopy. The positioning of the patient when taking oral drugs can be very important. Before gastroscopy, the volunteer was placed on his left side. As a consequence of this, the drugs were frequently seen to be lying in the fundus of the stomach. Praetorius & Faber (1950) showed that for the most rapid absorption, tablets should be taken with an ample volume of liquid and with the person in an upright position before lying down on his right side in order to increase the passage of the drug to the intestine. In one volunteer, a capsule was trapped in a not previously observed hiatus hernia and local changes and pain were observed. Similar cases with both pivampicillin capsules (Carlborg, 1976) and other preparations (Pemberton, 1970; McCall, 1975; vans & Roberts, 1976) have been described. References BRUMFITT, W., FRANKLIN, I., HAYK, L. & PURSLL, RITA (1973). Treatment of urinary tract infection with pivampicillin. Scand. J. infect. Dis., 5, CARLBORG, B. (1976). Complications when drugs accidentally dissolve in the oesophagus and the airways. Lakartidningen, 73, DANO, P. & FROM HANSN, P. (1973). Antibiotic treatment with pivampicillin chloride in respiratory and urinary tract infections. Chemotherapy, 18, VANS, K.T. & ROBRTS, G.M. (1976). Where do all the tablets go? Lancet, ii, HY, H., MDALN, T.J., MOLSTAD, P.M. & STOKHOLM, K. (1977). A clinical evaluation of the tolerance to pivampicillin tablets. Infection, 5, HULTBRG, R. & BACKLIN, BIRGIT (1972). Studies on the absorption of pivampicillin and ampicillin. Scand. J. infect. Dis., 4, McCALL, A.J. (1975). Slow-K ulceration of oesophagus with aneurysmal left atrium. Br. med. J., 3, PMBRTON, J. (1970). Oesophageal obstruction and ulceration caused by oral potassium therapy. Br. Heart J., 32, PRATORIUS,. & FABR, J.H. (1950). On the disintegration of tablets and their passage through the oesophagus and stomach with reference to the absorption of analgesics and sleeping drugs. Ugeskr. Laeg., 112, ROHOLT, K., NILSN, B. & KRISTNSN, DL (1974). Clinical pharmacology of pivampicillin. Antimicrob. Agents Chemother., 6, SWAHN, A. (1976). Gastrointestinal absorption and metabolism of two 35S-labelled ampicillin esters. ur. J. clin. Pharmac., 9,