Clay and non-clay minerals in the pharmaceutical industry: Part I. Excipients and medical applications

Pica, the purposive consumption of nonfood substances, is a millennia-old nutritional enigma. Its worldwide ubiquity, prevalence among pregnant women and children, and association with both positive and negative health outcomes, especially micronutrient deficiencies, underscore the importance of understanding this behavior. Multiple proposed etiologies of pica are reviewed, including cultural expectations, psychological stress, hunger, dyspepsia, micronutrient deficiencies (Fe, Zn, and Ca), and protection against toxins and pathogens. Currently available data, although limited, best support the protection hypothesis as a cause of most types of pica, although some evidence suggests that pagophagy (ice consumption) may occur during iron deficiency. It is possible that the binding capacity of pica substances explains the association with micronutrient deficiencies; earth, starch, etc. may render micronutrients in ingesta unavailable for absorption. Increased research efforts are warranted and must be hypothesis driven, interdisciplinary, and permit the testing of multiple causal inferences.

Pica in Pregnancy: New Ideas About an Old Condition

Antacids are commonly used drugs which are considered inert and free of pharmacological effect by many patients and physicians. When administered with other drugs, antacids can alter absorption or excretion of these agents, at times reducing their plasma level and effect and in other cases causing toxicity. Although many antacid-drug interaction studies have been performed in animals or in vitro and others show only minor effects in man, several clinically important interactions and their mechanisms have been verified in man. Antacids which reduce drug dissolution or bind drugs in the gastrointestinal tract have been shown to inhibit absorption and reduce efficacy of tetracyclines, digoxin, phenytoin and certain psychotherapeutic agents. Aluminium hydroxide gel delays gastric emptying, delaying isoniazid absorption and lowering blood levels. By elevating urine pH, antacids cause accelerated excretion of acidic drugs like salicylate and per contra may cause retention of basic drugs like quinidine or amphetamine. While the efficacy of many drugs may not be affected by antacids, the absorption or excretion of other drugs which have not yet been studied are undoubtedly altered by antacid administration. It is therefore advisable, where possible, to administer other drugs at least a half to 1 hour before antacid ingestion to ensure consistent absorption and effect. Long-term antacid ingestion should be avoided when other drugs are taken, unless antacid use is clinically indicated and is of proven benefit.

Antacid Therapy and Drug Kinetics

The mechanisms of reduction in absorption of levofloxacin (LVFX) by coadministration of aluminum hydroxide were studied. The partition coefficient of LVFX (0.1 mM) between chloroform and phosphate buffer (pH 5.0) was reduced by 60 to 70% with the addition of metal ions such as Cu2+, Al3+, and Fe2+ (0.8 mM), which indicated the formation of LVFX-metal ion chelates. However, there was no significant difference in absorption from rat intestine between the synthetic LVFX-Al3+ (1:1) chelate (6.75 mM) and LVFX (6.75 mM) in an in situ recirculation experiment. On the other hand, Al(NO3)3 (1.5 mM) significantly inhibited the absorption of LVFX (1.5 mM) by 20% of the control in the in situ ligated loop experiment, in which partial precipitation of aluminum hydroxide was observed in the dosing solution. Data for adsorption of LVFX and ofloxacin (OFLX) from aqueous solution by aluminum hydroxide were shown to fit Langmuir plots, and the adsorptive capacities (rmax) and the K values were 7.0 mg/g and 1.77 x 10(4) M-1 for LVFX and 7.4 mg/g and 1.42 x 10(4) M-1 for OFLX, respectively. The rate of adsorption of several quinolones (50 microM) onto aluminum hydroxide (2.5 mg/ml) followed the order norfloxacin (NFLX) (72.0%) > enoxacin (ENX) (61.0%) > OFLX (47.2%) approximately LVFX (48.1%). The elution rate of adsorbed quinolones with water followed the rank order LVFX (17.9%) approximately OFLX (20.9%) approximately ENX (18.3%) > NFLX (11.9%). These results strongly suggest that adsorption of quinolones by aluminum hydroxide reprecipitated in the small intestine would play an important role in the reduced bioavailability of quinolones after coadministration with aluminum-containing antacids.

Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide.

The objective of this study was to develop an effective omeprazole buccal adhesive tablet with excellent bioadhesive force and good drug stability in human saliva. The omeprazole buccal adhesive tablets were prepared with various bioadhesive polymers, alkali materials, and croscarmellose sodium. Their physicochemical properties, such as bioadhesive force and drug stability in human saliva, were investigated. The release and bioavailability of omeprazole delivered by the buccal adhesive tablets were studied. As bioadhesive additives for the omeprazole tablet, a mixture of sodium alginate and hydroxypropylmethylcellulose (HPMC) was selected. The omeprazole tablets prepared with bioadhesive polymers alone had bioadhesive forces suitable for a buccal adhesive tablet, but the stability of omeprazole in human saliva was not satisfactory. Among alkali materials, only magnesium oxide could be an alkali stabilizer for omeprazole buccal adhesive tablets due to its strong waterproofing effect. Croscarmellose sodium ...

Physicochemical characterization and evaluation of buccal adhesive tablets containing omeprazole.

The adsorption of oxytetracycline hydrochloride, tetracycline hydrochloride, doxycycline hyclate, triacetyloleandomycin, chloramphenicol, ampicillin, and cloxacillin sodium was studied on various antacids namely, magnesium trisilicate, magnesium oxide, calcium carbonate, bismuth oxycarbonate, aluminium hydroxide, and kaolin. The adsorption of the various antibiotics by milk was also tested as milk is frequently used as an antacid. Charcoal was included in the present study as a model adsorbent having a large hydrophobic surface. The adsorption of the various antibiotics on the different antacids and other adsorbents in most cases obeyed the Freundlich adsorption isotherm. Magnesium trisilicate and magnesium oxide showed the highest adsorptive capacity, relative to other antacids used, for most antibiotics. Calcium carbonate and aluminium hydroxide and intermediate power while kaolin and bismuth oxycarbonate had the least adsorptive power. Charcoal exhibited a marked adsorption for all antibiotics tested. Tetracyclines were found to be more highly adsorbed than other antibiotics studied. Triacetyloleandomycin and chloramphenicol had intermediate values. Ampicillin was only adsorbed to a slight extent while cloxacillin was not adsorbed on the antacids used. The extent of adsorption was correlated to the structure of both the adsorbent and adsorbate, the pH of the adsorbent suspension, and to the polarity of the antibiotic in such pH. The reversibility of the adsorption process was studied in different media and at pH values similar to those of the gastrointestinal tract. The extent of elution was found to be inversely proportional to the adsorptive capacity of the different adsorbents. In general, 0.0143 n NaHCO3 solution was found to possess higher eluting properties than 0.01 n HCl. An exception to this pattern was observed with tetracyclines adsorbed on aluminium hydroxide where the elution with acid resulted in a higher degree of desorption. Careful in vitro and in vivo testing of drug availability is advisable prior to the concomitant administration of antibiotics with antacids or other adsorbents.

The in vitro adsorption of some antibiotics on antacids.

Effect of solubilizers on the stability of tetracycline.

The adsorption of sodium salicylate, salicylamide, acetylsalicylic acid, paracetamol, mefenamic acid, flufenamic acid, phenylbutazone, oxyphenbutazone, phenazone, aminophenazone, indometacin and methiazinic acid on some antacids was studied. The antacids used were magnesium trisilicate, magnesium oxide, aluminium hydroxide, bismuth oxycarbonate, calcium carbonate and kaolin. Magnesium oxide, followed by aluminium hydroxide and bismuth oxycarbonate showed a fairly high adsorptive capacity for salicylates, mefenamic acid, flufenamic acid, methiazinic acid, indometacin and to a lesser extent for phenylbutazone and oxyphenbutazone. On the other hand, magnesium trisilicate exhibited a tendency to adsorb phenazone, aminophenazone, indometacin and methiazinic acid. Kaolin was found to be a good adsorbent for anthranilic acid derivatives, indometacin and methiazinic acid. Calcium carbonate showed a weak adsorptive capacity for all drugs tested. The adsorption of phenylbutazone and salicylates on magnesium oxide, aluminium hydroxide and/or bismuth oxycarbonate obeyed the Freundlich adsorption isotherm. Elution study showed that salicylates and anthranilic acid derivatives were tenaciously held by magnesium oxide while magnesium trisilicate showed an intermediate retention power for phenazone and aminophenazone. Sodium hydrogen carbonate solution gave, in general, a higher eluting power than hydrochloric acid solution. A marked reduction in the apparent partition coefficients of all drugs tested was observed in the presence of magnesium trisilicate or aluminium hydroxide. Careful in vitro and in vivo testing of drug availability is advisable prior to the concomitant administration of antirheumatics with antacids or other adsorbents.

The in-vitro adsorption of some antirheumatics on antacids.

Oral absorption of tetracycline hydrochloride by human subjects was compared with its absorption when coadministered with magnesium trisilicate, citric acid or magnesium trisilicate-citric acid mixture. Evaluation of the absorption rate was done by means of urinary excretion measurements. The concomitant administration of magnesium trisilicate with tetracycline hydrochloride resulted in a dramatic reduction of the excretion rate of the drug. Ingestion of citric acid with tetracycline showed no significant effect on its absorption. Citric acid administration simultaneously with tetracycline hydrocloride-magnesium trisilicate combination failed to improve the absorption of tetracycline in the presence of magnesium trisilicate contrarily to preveious in vitro results. Conclusions were made that in vitro experiments are not always successful in the prediction of in vivo findings.

Effect of magnesium trisilicate and citric acid on the biovailability of tetracycline in man.

The effect of various additives on the adsorption of tetracycline hydrochloride on magnesium trisilicate or milk was investigated. Adsorption-elution, dialysis and sedimentation volume measurements were used in the present investigation. Citric acid was found to exert the highest adsorption suppressing effect of the antibiotic on both antacids. The nonionic surfactants, polyoxyethylene-23-lauryl ether (Brij 35) and polysorbate 80, had an intermediate action, while polyethylene glycol 6000 (PEG-6000), polyvinylpyrrolidone (PVP), sodium carboxymethylcellulose (CMC) and urea had only a slight effect. On the other hand, the effect of sodium benzoate and sodium salicylate varied with concentration. Results of the elution study showed that the efficiency of the additives, as eluting agents, was more or less parallel with their influence on adsorption. The presence of citrate or Brij 35, having the highest adsorption-suppressing effect, was found to have a negligible effect on the chemical stability or microbiological activity of tetracycline. Conclusions were made that the incorporation of some of these additives may possibly reduce tetracycline-antacids interactions and consequently improve the antibiotic availability when co-administered with antacids.

V F Naggar

Papers

The in vitro adsorption of some antibiotics on antacids.

Effect of solubilizers on the stability of tetracycline.

The in-vitro adsorption of some antirheumatics on antacids.

Effect of magnesium trisilicate and citric acid on the biovailability of tetracycline in man.

The effect of some additives on the adsorption of tetracycline hydrochloride on magnesium trisilicate and milk.