Comparison of adsorbed films of a polyvinylpyrrolidone copolymer with spread monolayers.

The adsorption of a polyvinylpyrrolidone-polyvinyl acetate graft copolymer from solution was studied by surface pressure measurement. Adsorption from the dilute solutions was slow, limited, in part, by diffusion of polymer molecules to the surface. When absorbed monolayers were compressed on a surface balance, the resulting surface pressure values paralled those of a spread monolayer, strongly suggesting that the structures of adsorbed and spread monolayers are the same.

Membrane-solvent-solute interaction in a model permeation system.

In this study, methyl- and propylparaben flux from various alcohol donors through polydimethylsiloxane membranes was investigated. Flux from saturated alcohol vehicles was markedly increased relative to water and glycol systems. The uptake of neat alcohol, a measure of solvent membrane interaction, gave a good rank order correlation to the flux data for a particular paraben. The major influence of the alcohols was an increase in membrane solubility of paraben, with a smaller effect on the diffusion coefficient. High paraben donor solubility indirectly reduced the solvent-membrane interaction leading to attenuated flux. Paraben membrane solubility was influenced by the amount of alcohol sorbed from saturated systems and the affinity of the paraben for the alcohol. This conforms to the concept of imbibed alcohol molecules being organized into clusters. The alteration in barrier properties of the membrane was found to require the presence of sorbed alcohol and was reversible upon removal of the solvent.

Flocculation of suspensions containing nonionic surfactants by sorbitol.

Aqueous suspensions of sulfamerazine, salicylamide, and butamben, containing either polysorbate 20 or polysorbate 80 as a wetting agent, were deflocculated. The presence of relatively high concentrations of sorbitol in the suspensions resulted in flocculation due to dehydration of surfactant polyoxyethylene groups (reflected by the cloud point). The critical flocculation concentration of sorbitol was reduced by raising the storage temperature, lowering the surfactant concentration, switching from polysorbate 80 to polysorbate 20, or adding sodium sulfate to the suspension formulation. Both the cloud point and the sorbitol critical flocculation concentration depended on the particular drug that was suspended. Methylparaben lowered the cloud point, suggesting that the choice of preservative could influence the suspension characteristics in certain cases. The various dehydrating influences were additive. By assuming that interparticle repulsion becomes negligible at the cloud point, it was possible to use cloud point curves to estimate the critical flocculation concentration of sorbitol.

Viscosity of xanthan gum solutions at low shear rates.

The viscosity of xanthan gum solutions in the low shear region was investigated with the aid of a Couette instrument. All solutions were highly pseudoplastic . Solutions containing 0.3-0.5% of the gum exhibited a highly ordered phase at very low shear. Viscosity, the degree of pseudoplasticity , and the value of the transition from soft gel to pseudoplastic behavior were directly related to gum concentration. The effect of the addition of a salt on viscosity depended on the xanthan gum concentration. The viscosity of a 0.3% xanthan gum solution was practically unaffected by the salts. Higher gum concentrations exhibited a viscosity increase when salt was present. Concentrations less than 0.3% exhibited a viscosity decrease in the presence of a salt. All viscosity effects seemed to reach limiting values at approximately 10(-3) to 3.3 X 10(-3) N salt. No major differences were observed between sodium chloride, calcium chloride, and sodium citrate in their influence on xanthan gum viscosity.

Surfactant solutions as test liquids for measurement of critical surface tension.

Contact angles of various liquids and surfactant solutions on polytef and paraffin were measured. Critical surface tension values were obtained by extrapolation of plots of cosine of the contact angles versus corresponding surface tension values. Contact angles measured using polyoxyethylene octylphenols produced linear Zisman plots and yielded critical surface tensions that agreed with accepted values. This liquid series provides a reasonable approach to the measurement of critical surface tension for solid drugs that are soluble in organic liquids but relatively insoluble in water.

Critical surface tensions of pharmaceutical solids.

Advancing contact angles measured on compacts of several drugs by the sessile drop method and also by penetration through a column of drug granules were used to find the critical surface tension of the drugs. After liquid was delivered at a very slow rate, the contact angle of sessile drops decreased with time, but use of a consistent method of timing always led to the same value for critical surface tension. Results from penetration studies and work on compacts were in agreement, provided that the surfaces of the compacts were smooth and highly reflective. Critical surface tension of the six drugs, three analgesics and three sulfonamides, ranged from 31 to 33 dynes/cm. The critical surface tension of mixtures of phenacetin and microcrystalline cellulose was not a linear function of the relative surface fractions of the two materials. If the surface contained 25% or more of phenacetin, the critical surface tension barely differed from that of pure phenacetin.

Flocculation effect of xanthan gum in pharmaceutical suspensions.

The particulate structure in suspensions of magnesium carbonate, aluminum hydroxide, calcium carbonate, and zinc oxide was assessed by sedimentation volume studies, measurement of particle size by an electronic particle sizer, and visualization by microscopy. The results of the particle-size measruement did not always agree with results from the other techniques. magnesium carbonate, aluminum hydroxide, and zinc oxide were flocculated in water. The addition of xanthan gum increased flocculation of magnesium carbonate and aluminum hydroxide and apparently caused partial deflocculation of zinc oxide suspensions. Calcium carbonate suspensions were deflocculated in water, and xanthan gum did not significantly change the properties. Studies with sodium chloride showed that flocculation cannot be attributed to changes in double-layer repulsion. Flocculation in the suspensions studied appeared to be consistent with a bridging mechanism.

Effect of formulation factors on penetration of hydrocortisone through mouse skin.

The effect of formulation factors on the steady-state flux of hydrocortisone through mouse skin was evaluated. The flux of hydrocortisone from solutions containing propylene glycol as a cosolvent varied inversely with the propylene glycol concentration. Solutions containing 2-propanol gave flux values higher than those obtained from propylene glycol solutions and independent of the 2-propanol concentration. Addition of polysorbate 80 to 2-propanol-water solutions produced an increase in flux at low surfactant concentrations that reached an apparent limiting value at higher concentrations. The penetration flux was the same from solutions and gels. The role of vehicle-skin interactions in penetration is emphasized.

Interaction of xanthan gum with suspended solids.

Xanthan gum was adsorbed significantly by magnesium carbonate, aluminum hydroxide, zinc oxide, and calcium carbonate, giving Langmuir-type isotherms. Saturation adsorption was higher from 0.9% NaCl than from water due to reduced mutual repulsion of polymer segments in the presence of the salt. Adsorption resulted from electrostatic attraction between positively charged particles and the negatively charged polymer. zeta-Potential measurements correlated with the adsorption data but were not predictive of the flocculation state. The result indicate that flocculation of magnesium carbonate and aluminum hydroxide by xanthan gum is consistent with a bridging mechanism.

A model for alcohol-enhanced permeation through polydimethylsiloxane membranes.

In this study the influence of paraben concentration on flux from solution in 1-propanol through polydimethylsiloxane membranes was investigated. Alcohol was sorbed by the polymer membrane leading to changes in membrane dimensions and increased membrane capacity to contain paraben (partition coefficient). Diffusion coefficients were not significantly influenced by alcohol sorption. Flux was increased 5-30 fold over nonimbibed donors such as water and polyols. An increase in paraben concentration reduced alcohol activity, its uptake by the membrane, and consequently the partition coefficient of paraben. As a result, flux increased with paraben concentration, reached a peak, and then declined. Maximal membrane concentration involves a trade-off between alcohol-membrane interaction (solvent activity) and paraben concentration, and occurred at paraben concentrations in the range of 1.3 to 1.4 mmol/g. At equimolar concentrations, flux was highest for methylparaben and declined as the series was ascended. Differences in flux between parabens at a specified molar concentration were due only to differences in diffusivity.

Correlation of water and lidocaine flux enhancement by cationic surfactants in vitro.

The penetration of radiolabeled water and lidocaine through human epidermis was studied simultaneously using a flow-through apparatus under infinite-dose conditions. The donors were suspensions of lidocaine in propylene glycol:water mixtures containing cationic surfactants of varying alkyl chain length from three classes: alkyl dimethylbenzyl ammonium halides, alkyl trimethyl ammonium halides, and alkyl pyridinium halides. Each skin sample served as its own control; each was subjected to sequential treatments of control formulation with no surfactant, test formulation, and then a repeat control. Higher surfactant concentration resulted in greater enhancement ratios for both permeants. Peak surfactant enhancement effects were seen at alkyl chain lengths of 12 or 14 carbons. Strong correlation was noted between the enhancement ratios of water and lidocaine. Water permeation can serve as a predictor of the effects of surface-active compounds on the permeation of drugs. The data suggest that water and lidocaine utilize the same pathway through the horny layer.

Evaluation of penetration enhancement of lidocaine by nonionic surfactants through hairless mouse skin in vitro.

The effect of two nonionic surfactants (polyoxyethylene sorbitan monoesters) on percutaneous absorption of lidocaine in the presence of various concentrations of propylene glycol is reported. Comparisons were made in vitro using excised hairless mouse skin as the barrier membrane. Under infinite dose conditions, steady-state flux was enhanced by surfactants at high propylene glycol concentrations. The same trend was observed following application of a thin layer of formulation to the skin (finite-dose conditions). However, penetration behavior was complex due to: (a) changes in vehicle composition following application, (b) temperature changes resulting from evaporation or moisture uptake, and (c) depletion of lidocaine as a result of penetration with compositions that lost water by evaporation. Two peaks in the flux versus time curve were observed. Surfactant monomer concentration in the vehicles was increased in the presence of propylene glycol.

Molecular arrangement in monolayers containing cholesterol and dipalmitoyl lecithin.

The molecular arrangement of dipalmitoyl lecithin and cholesterol in mixed monolayers was investigated with the aid of a physical model. The two lipids are miscible at the surface, but there is no indication of a specific interaction. In equimolar mixed monolayers at 25 and 37 degrees, the lipids are in tail contact. Lecithin molecules are able to remain hydrated in the mixed monolayers at high values of surface pressure.

Interaction of hydrocortisone with model membranes containing phospholipid and cholesterol.

Pure and mixed monolayers of lecithin and cholesterol were spread on substrates of dissolved hydrocortisone at 25 and 37 degrees. The presence of hydrocortisone increased the surface pressure of dipalmitoyl and egg lecithin films that were in head contact. The increase in surface pressure was dependent on steroid concentration. There were no significant interactions with coherent cholesterol monolayers. Penetration of hydrocortisone was decreased by the addition of cholesterol to the monolayer system. These model membrane systems indicate that hydrocortisone interacts with the hydrated polar head group of the phospholipid and not with films whose molecules are in hydrocarbon tail contact.

Flocculation of sulfamerazine suspensions by a cationic polymer.

Flocculation by a cationic polymer of sulfamerazine suspensions containing a wetting agent was evaluated. Suspensions with sufficient surfactant concentrations to ensure complete wetting were deflocculated. When the anionic surfactant, dioctyl sodium sulfosuccinate, was used as a wetting agent, the suspensions were flocculated over a limited polymer concentration range. Flocculation was attributed to simultaneous interaction of a polymer molecule with more than one particle. At higher polymer concentrations, the particles were covered completely with polymer, leading to repulsion between the particles and deflocculation of the suspensions. The polymer concentration required for flocculation provided evidence for interaction between the anionic surfactant and the cationic polymer. Suspensions containing a nonionic surfactant also were flocculated using various polymer concentrations. When a surfactant mixture was employed in the suspensions, the peak sedimentation volume of flocculated systems and the concentration of polymer at the peak depended on the surfactant mixture composition.

Noninvasive assessment of anesthetic activity of topical lidocaine formulations.

The effectiveness of a series of lidocaine formulations in producing anesthesia after topical application was evaluated in human volunteers. The formulations, five suspensions in 20% propylene glycol and one cream, were applied to the forearms for 3 h with occlusion with Hilltop chambers. Testing for anesthesia was performed electrometrically. All lidocaine-containing formulations produced significantly greater anesthesia than the blanks. The formulation containing tetradecyltrimethylammonium bromide produced greater anesthesia than that containing octadecyltrimethylammonium chloride. Changing the pH of the formulation from 7.9 to 10.0 had no significant effect. Other formulations (sodium lauryl sulfate and the cream) were no more effective than the plain formulation without surfactants. The rank order for the suspension formulations was the same as for steady-state permeation in in vitro experiments. However, application of the cream formulation produced greater effect in vivo than was anticipated from in vitro flux values.

The quality of skin care products and their ingredients.

Several ingredients used in skin products have been criticized as being excessively harsh, allergenic, or otherwise unsuitable for use, especially in the elderly population. Preservatives, in particular, have been condemned, leading to a proliferation of "preservative-free" products. Other descriptive/promotional phrases with negative connotations are "fragrance-free" and "emulsifier-free." Inferences regarding these designations might suggest that preservatives, fragrances, emulsifiers, and a number of other ingredients serve no important function, are superfluous in terms of product quality, and, therefore, should be left out of all skin products. While this is obviously not the case, neither is the obverse. Ingredients used in skin care products should be carefully chosen to support or maintain the overall effectiveness and utility of the product, and the concentration of such ingredients should be given careful consideration. After briefly reviewing skin structure and changes that occur during aging, this article examines the concept of product quality. Major nondrug ingredient categories will be addressed, including the reasons for using such ingredients in skin care products, the products in which they are required, the limitations and choices available within each category, and guidelines for product selection.

Kinetics of permeation and metabolism of alpha-tocopherol and alpha-tocopheryl acetate in micro-Yucatan pig sin.

The objective of this research was to investigate the permeation and metabolism of alpha-tocopheryl acetate (alpha-TAc) and alpha-tocopherol (alpha-T) from solution and emulsion formulations and to delineate the kinetics of such metabolism. Simple formulations containing alpha-TAc and alpha-T were applied to fresh, viable micro-Yucatan skin dermatomed to a thickness of 250-300 microns, as a finite dose in a flow-through diffusion system. The experiments were stopped at time intervals of 2, 6, 12, and 24 hours. At the end of each time interval, the amounts removed by washing, retained in the stratum corneum (SC), and penetrated into the viable skin and receptor were determined by a validated HPLC method. Receptor concentrations were below the limit of detection. alpha-TAc underwent metabolism in pig skin to the active antioxidant alpha-T. The metabolite appeared as early as two hours after application. The extent of metabolism was highest at 6-12 hours after application. No metabolism was detected in the stratum corneum. Delivery of alpha-T from isopropyl myristate (IPM) solution was more efficient than utilization of alpha-TAc from the same solution. Approximately 1.5% of alpha-T yielded the same viable skin concentration as 5% alpha-TAc. Topical application of alpha-tocopherol or its prodrug acetate was capable of enhancing the overall antioxidant capacity of pig skin. The hydrolytic pathway of alpha-TAc leading to the active antioxidant alpha-T could possibly be saturable.

Effect of formulation on the delivery and metabolism of alpha-tocopheryl acetate.

The effect of delivery system on the permeation and metabolism of alpha-tocopheryl acetate (alpha-TAc) was studied in micro-Yucatan pig skin, which closely resembles human skin. Various alpha-tocopheryl acetate formulations, including a simple isopropyl myristate (IPM) solution, an o/w emulsion, microemulsions, which differed in their oily phase content, and alcoholic and hydroalcoholic gels were made. A suitable HPLC method was developed and validated to separate and quantify alpha-TAc and alpha-tocopherol (alpha-T). Dulbecco's modified phosphate-buffered saline with 3% bovine serum albumin (DMPBS-BSA 3%) served as the receptor media to ensure tissue viability and to maintain skin conditions. Finite doses (5 microl) of the formulations were applied to viable pig skin using a statistically approved randomized complete block design. Data were analyzed using Tukey's studentized range test, and interday variability was estimated using an F-test. About 70% of the active was recovered from the wash, representing the amount adhering to the surface of the skin. alpha-TAc underwent metabolism in pig skin to the active antioxidant, alpha-T. The identity of the HPLC peaks were confirmed by spiking studies using known standards. The extent of metabolism was found to be formulation-dependent. No alpha-T was, however, detected in the stratum corneum. A higher extent of metabolism was obtained for the IPM solution, a microemulsion containing IPM as the oily phase, and the hydroalcoholic gel, when calculated based on the percent of total alpha-TAc permeated in the viable skin. Metabolism occurred in pig skin to the extent of 15-20% in terms of the total amount of alpha-TAc permeated in the viable skin and stratum corneum. Thus the topical delivery and metabolism of alpha-TAc were found to be dependent on formulation.

Deposition of salicylic acid into hamster sebaceous.

In an earlier paper, we identified vehicles that are miscible with sebum, using differential scanning calorimetry (DSC). In this paper, the potential of these vehicles to deliver salicylic acid (SA) into the sebum-filled follicles of hamster ears is examined. The main objective of this study is to correlate the melting transitions of a model sebum with the follicular delivery of SA, using two different types of vehicles (fatty and polar). Generally, the fatty vehicles show higher deposition than the polar vehicles. Follicular delivery of salicylic acid correlates well with its solubility in the respective vehicles. This extent of deposition also shows a relationship with the effect of the vehicle on thermal behavior of the model sebum. The nature of the relationship depends on the vehicle (polar or fatty) tested. We conclude that DSC could be used to identify appropriate vehicles for drugs whose follicular delivery depends on solubility. The results also suggest that delivery into the sebaceous glands occurs by two different mechanisms, depending upon the polarity of the vehicle and the physicochemical properties of the drug. The results of these experiments are further extended to investigate follicular delivery of SA from two different types of oil-in-water emulsion formulations. From these studies we conclude that either increasing the volume of the oil phase or changing the emulsion to a water-in-oil emulsion would increase follicular deposition. Our research highlights the role of sebum, its compatibility with drug molecules, and vehicle selection in the transport of drugs into the follicles. The overall results of these experiments provide a reasonable understanding of the mechanisms underlying the transport of drugs to, and subsequently through, the sebaceous follicle.