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The effect of the inclusion of several concentrations of surface-active agents in four different types of ointment bases on the percutaneous absorption of salicylic acid and sodium salicylate was determined. Hydrophilic ointment, petrolatum, hydrophilic petrolatum containing water, and polyethylene glycol ointment were modified either by varying the concentration of surface-active agent present in the U. S. P. XV formula, or by adding varying amounts of surface-active agents to those bases in which none was originally present. Sorbitan monostearate, polyoxyethylene 20 sorbitan monostearate, and polyoxyethylene 40 stearate were studied as representative of lipophilic and hydrophilic surface-active agents of the nonionic type. The results indicate a correlation between percutaneous absorption and the degree of interaction of the polyoxyethylene groups present in the hydrophilic surface-active agents with the salicylates.

Forty-eight substances and combinations were studied for their possible effectiveness as preservatives for solutions of nonionic surfactants of the sorbitan partial fatty acid ester and polyoxyethylene ester types. Results indicated that sorbic acid (0.2 per cent w/v); phenylmercuric borate (0.007 per cent w/v); phenylmercuric nitrate (0.01 per cent w/v); phenylmercuric acetate (0.007 per cent w/v); n -trichloromethylmercapto-4-cyclohexene-1,2-dicarboximide (Vancide® 89 RE, 0.04 per cent w/v); diethylene glycol monomethyl ether (methyl Carbitol, 3 per cent w/v); hexylene glycol (3 per cent w/v); and benzalkonium chloride (0.1 per cent w/v) are effective in preserving these solutions. The failure of various phenolic preservatives to preserve these surfactant solutions is attributed to complex formation between phenolic and polyether groups. Studies on various cosmetic formulations containing nonionic surfactants indicate that sorbic acid (0.2 per cent w/w) and combinations of sorbic acid and hexylene glycol are effective preservatives. These preservatives were also found effective in products containing sorbitol as well as nonionic surfactants.

An approach to the evaluation of the percutaneous absorption of drugs from ointment bases is described. Salicylic acid and sodium salicylate were selected as test drugs for incorporation into ointment bases representing each of four physical types of ointment vehicles. These ointments were applied to the intact shaved skin of the rabbit and confined by a specially designed bandage. Concentration of salicylate in the blood was determined at hourly intervals following application of the ointment. Salicylic acid was most effectively absorbed from hydrophilic ointment. The extent of absorption from the other ointments studied, in decreasing order, was: hydrophilic petrolatum containing water, petrolatum, and polyethylene glycol ointment. Sodium salicylate was also absorbed to the greatest extent from hydrophilic ointment, although the degree of absorption was considerably less than that observed with salicylic acid. On the basis of salicylate blood levels, no significant absorption of sodium salicylate occurred from ointments prepared with petrolatum, hydrophilic petrolatum containing water, or polyethylene glycol ointment.

Seven chemical substances or combinations of these substances presently employed as preservatives in ophthalmic solutions were studied to note their effectiveness as antibacterial agents against 13 different strains of Pseudomonas aeruginosa. New in vitro methods were devised. Among the latter were techniques to (a) differentiate between bacteriostatic and bactericidal activities and (b) determine the sterilizing time for each antibacterial agent. The methods presented here have several advantages over those previously employed and those now in use. An in vivo procedure was also employed in evaluating these chemical agents to note whether the findings were in agreement with the final results obtained in the in vitro studies. The following chemicals were examined: chlorobutanol, benzal-konium chloride, thimerosol, combinations of methyl and propylparaben, phenyl-mercuric nitrate, phenylethyl alcohol, and polymyxin B sulfate.

Ointment bases have been prepared utilizing Na, K, Ca, Mg, H, and Volclay bentonites as major constituents of these bases. Observations are reported on the relative swellin power of these bentonites, and the color intensity and pH of their bases. Anti-inkctive ointments were prepared utilizin these bases as carriers for the drugs, and studies of the bacteriological activity of tfese ointments are reported. These ointments show greater antibacterial activity than their respective U.S. P. and N. F. ointments. Sulfathiazole, phenol, and ammoniated mercury showed greater activity when incorporated into a H bentonite base than when these drugs were incorporated into the other bentonite bases.

It has been shown from the apparent first-order urinary excretion studies of D-(-)-mandelic acid and certain of its homologs, DL-tropic acid, D-(-)-4-hydroxy-4-phenylbutanoic acid, DL-phenyllactic acid, and D-(-)-benzyllactic acid, that the biological half-lives of the homologs are significantly shorter than that of D-(-)-mandelic acid in rats. Since these compounds, which differ from each other in their content of methylene groups around the carboxyl group, exhibit negligible metabolism and protein binding, low pKa values (3.3-4.7), and low lipid solubility at the physiological pH, and are primarily recovered in the urine in the intact form, they are utilized in these studies as model compounds to study the effect of hydrophobic group(s) on the rate of secretion. These compounds are shown to exert a mutual inhibitory effect on their renal tubular secretion, indicating a common “carrier” mechanism for their secretion. The utilization of these compounds indicated that the addition of methylene group(s) in the vicinity of the carboxyl group of the mandelic acid molecule increased its affinity for the carrier molecules of the renal tubular secretion system in rats.

From the pseudo-first-order urinary excretion studies of D-(-)mandelic acid and DL-tropic acid in rats, data regarding the apparent initial secretion rate versus dose (i.v.) are obtained for these compounds and treated according to the Michaelis-Menten kinetics. While the values of maximum apparent initial secretion rate (Vm) determined for these compounds are similar, the value of the dose of the substrate required to produce one-half of the maximum apparent initial secretion rate (Km) determined for D-(-)-mandelic acid is found to be about twice that determined for DL-tropic acid. Data have been obtained to demonstrate that these compounds competitively inhibit the renal tubular secretion of each other, thereby strongly indicating that these compounds share a common carrier transport system for their secretion. Data obtained in the present studies and those described earlier are utilized to distinguish a certain structural characteristic around the cationic site of the “carrier” molecules of the renal tubular secretion system in rats.

A method has been developed for the analytical determination of sorbitol-sucrose water systems. The sucrose content is determined by the Lane-Eynon Method, sorbitol not interfering. Sorbitol concentration is determined by a modified T.G.A. Method 47 using periodic acid oxidation, both invert sugar resulting from the procedure and sorbitol undergoing oxidation. The periodic acid consumption is corrected for the amount equivalent to the invert sugar and the sorbitol concentration is then calculated. The solubility behavior of sorbitol-sucrose-water systems at 25° is reported.

A study of the effect of pH on the inhibitory concentrations of sorbitol and a study of the effectiveness of various preservatives, suitable for internal use, in preventing the growth of organisms in sorbitol solutions have been carried out. From a practical viewpoint, although pH does have some influence on the inhibitory effect of solutions of sorbitol, it alone cannot insure against the growth of certain organisms. Fifteen preservatives and preservative combinations were studied for their effectiveness in sorbitol solutions. It was found that, of these, only a combination of methyl-paraben (0.12% w/v) and propylparaben (0.02% w/v), and sorbic acid (0.15% w/v) were generally effective in preserving aqueous sorbitol solutions. In the case of sorbic acid, an occasional failure to protect the solution was observed.

The stability of vitamin B 12 was studied in aqueous solutions of sorbitol, glycerin, dextrose, and sucrose. Solutions were kept at 25°, 45°, and 100° for periods up to one hundred and forty days. Vitamin B 12 content was determined spectrophotometrically using an absorption maximum of 361 mμ. It was found that vitamin B 12 is compatible with sorbitol and glycerin at 25° and 45°. Dextrose and sucrose solutions were found to cause the loss of vitamin B 12 in solution. Dextrose was more destructive to the vitamin than was sucrose.

A comparison of the inhibitory concentrations pf various sugars and polyols on the growth of various organisms has been made. Glycerin was found to have a lower inhibitory concentration than levulose and dextrose. Sorbitol and invert sugar inhibit the growth of organisms in a concentration lower than that required with sucrose. The inhibitory effect of each substance is believed to be largely one of osmotic pressure.

A method is described for the quantitative assay of aconite tincture. The principle employed involves the administration of intravenous injections of the tincture in mice. A comparison of LD 50 doses of Reference Standard Aconitine Solution with diluted tinctures is employed for the assay. The standard error of a series of assays was found to be less than two per cent.

Pseudo-first-order rate constants for the overall elimination of (−)-mandelic acid both in the absence (K) and in the presence (Kas) of sulfadiazine, sulfamethazine, or sulfamerazine were determined in three human subjects. Since the extent of metabolism of (−)-mandelic acid was not significantly altered in the presence of these sulfonamides, the ratio of the rate constants, K/Kas, has been calculated as a measure of the inhibitory effect of each sulfonamide on the urinary excretion of (−)-mandelic acid. For the dosage levels of the inhibitors employed, the range of such ratios found in all three subjects is 1.29—1.55 due to sulfadiazine, 1.33—1.62 due to sulfamethazine, and 1.33-1.76 due to sulfamerazine. Similar inhibitory effects were observed on the urinary excretion of sulfadiazine in the presence of (−)-mandelic acid in two subjects. Therefore, it is concluded that these compounds probably share the same renal tubular transport system(s) for their secretion in humans.

Solutions of drugs were sublingually administered to anesthetized animals whose esophagus had been ligated and trachea cannulated.This method was devised so that there would he no possibility of the drug being swallowed.As determined by the time for convulsions to appear in anesthetized rats or for death to occur in anesthetized mice, strychnine sulfate in alcohol, strychnine sulfate in water, and strychnine in alcohol were found to be well absorbed sublingually, and in that order, while strychnine suspended in water was not absorbed.The use of the base or the salt and the vehicle employed had a more important effect on sublingual absorption than on oral absorption.Aconitine in alcohol was more rapidly absorbed sublingually than aconitine hydrochloride in water although there was no difference in subcutaneous absorption.Alcoholic solutions of Pentothal® and pentobarbital as well as aqueous solutions of their sodium salts were absorbed sublingually as demonstrated by the increased sleeping time of anesthetized mice.Alcoholic solutions produced the greatest increase.The form of a drug and the vehicle used play an important role in sublingual absorption.

Glycerin and sorbitol were found to supplement each other in their inhibition of both molds and bacteria. It is believed that this inhibitory action is purely one of osmotic effect. Propylene glycol appears to have a specific inhibitory effect against bacteria and most molds; the addition of 10% w/v propylene glycol was found to inhibit the growth of these organisms. Thirty per cent w/v propylene glycol is required to inhibit Monilia albicans. Studies have indicated that the inhibition produced by the addition of propylene glycol to sorbitol solutions is not purely the result of osmotic effect, as is the case with glycerin, but probably one related to its chemical structure. It may, therefore, be concluded that propylene glycol has a significant and useful preservative activity in many preparations including those made with sorbitol.