Antimicrobial and diffusional correlation of N-alkyl betaines and N-alkyl-N,N-dimethylamine oxides from semisolids.

Previous studies have shown that two classes of amphoteric surfactants, N-alkyl betaines and N-alkyl-N,N-dimethylamine oxides, exhibit pronounced antimicrobial activity in combination and have potential for use in a semisolid formulation for topical or vaginal delivery. In this work, several potential delivery systems were prepared and evaluated for antimicrobial activity and diffusional properties. A novel antimicrobial test for semisolids was proposed that determined the contact time needed to kill microorganisms. The unformulated agents in solution exhibited the faster kill within 60 min, followed by the hydroxyethylcellulose gel formulation in 90 min, and the poloxamer gel and a cream that required several hours. Diffusion from the dosage form utilized a Slide-A-Lyzer diffusion cassette with a 10,000 MWCO membrane with (14)C-labeled active species added to the aforementioned antimicrobial formulations. Diffusion of the individual betaine and amine oxide derivatives were tracked over time to determine the diffusion rates and profiles of the components in each formulation and in solution. The betaine derivative diffused up to three times faster than the amine oxide derivative within the first 2 h, but the amount diffused was approximately equivalent at 24 h. The formulations delayed release in the same rank order as the contact time kill analysis: hydroxyethylcellulose gel > poloxamer gel > cream.

Cross-linked hemoglobin as a potential membrane for an artificial red blood cell.

A cross-linked hemoglobin membrane has been created with discerning permeability between dissolved hemoglobin and small molecules. Such a membrane could be used to enclose a sphere of hemoglobin solution thereby allowing the entire "cell" to transport oxygen. The hemoglobin membrane was cross-linked on a polycarbonate support; the mechanical support was necessary for diffusion experiments in this study and would not be used during any sphere preparation. A 30% methemoglobin solution in phosphate buffer was used to fill the pores of the 10 microm polycarbonate support, then cross-linked with a homobifunctional cross-linking agent. The cross-linked hemoglobin within the support was evaluated for hemoglobin and benzoic acid permeability in a side-by-side diffusion cell. Disuccinimidyl glutarate, disuccinimidyl suberate and disuccinimidyl tartrate were used as cross-linking agents. Disuccinimidyl glutarate, 4.65 mM, created a hemoglobin-impermeable membrane after cross-linking for 20 minutes, reducing the concentration to 0.46 mM required a cross-linking time to 60 minutes. Benzoic acid, representing a typical small molecule, was capable of diffusing through the disuccinimidyl glutarate cross-linked hemoglobin membrane at 87.2% of its diffusion through buffer.

A novel method for measuring gel strength of controlled release hydrogel tablets using a cone/plate rheometer.

A novel method for measuring gel strength of hydrogel controlled release (CR) tablets is presented. CR tablets containing hydroxypropyl methylcellulose (HPMC) were fixed to a glass plate, placed in a dissolution apparatus, and subjected to dissolution conditions corresponding to 50% drug release. Tablets were then removed from the dissolution apparatus without disturbing the swollen (gel) layer. Tablet gel strength (gamma) was determined by shearing the external gelled layer of the tablet by a cone/plate rheometer recording E, energy/volume, as a function of rotational speed of the cone, RPM. The RPM is increased to the point of "Shear Failure," RPMsf, i.e., until there is no further increase in E. Plots of E vs. RPM were fit to a bi-exponential equation, where epsilon is the zero RPM intercept of the plot. gamma is calculated from gamma = ERPMsf - epsilon. gamma is defined as the minimum energy input/unit volume needed to cause shear failure of the tablet gel layer. Mean gamma for tablets containing 50% theophylline and different ratios of HPMC to Fast Flo lactose were determined. Tablets containing 30%, 15%, and 8% HPMC K100MP have gamma means of 6600, 4700, and 1500 ergs/cm3, and percent relative standard deviations of 9, 13, 33%, respectively. Tablets made entirely of HPMC K100MP (no theophylline or lactose) have an gamma of 15,500 ergs/cm3. gamma values are significantly different (p < 0.0001) between the various formulations. gamma values also show a strong inverse correlation with the cumulative percent of drug released in vitro. Results obtained demonstrate the application of this novel method for measuring gel strength of different CR hydrogel tablets and using this strength to characterize drug diffusion in vitro.

The effect of formulation composition and dissolution parameters on the gel strength of controlled release hydrogel tablets.

The impact of hydrogel polymers and dissolution media on tablet gel strength, Gamma, of controlled release (CR) hydrogel tablets was investigated. CR tablets containing either hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or carbomer were formulated with theophylline and Fast Flo lactose, to produce tablets with a polymer content of 8, 15, and 30% w/w. Gamma was measured using a previously reported method. The drug dissolution profiles were similar, irrespective of polymer type or dissolution media (DI water, 0.1 N HCl, and pH 6.8 phosphate buffer), at the same % w/w level of polymer. Gamma, however, showed large and significant differences (p < or = 0.05) between tablets containing different polymers and between different dissolution media. Gamma values were HPMC KI00MP > HPC HXF > carbomer 971P (same % w/w) with absolute Gamma values at 30% w/w in DI water of 6600, 4600, and 1600 ergs/cm3, respectively. Gamma for HPMC based tablets was independent of changes in dissolution media, while the Gamma values for HPC tablets were 18% lower in acid and buffer than in DI water. Of the polymers tested, carbomer based tablets had the lowest Gamma values in all dissolution media and an unexpected 58% lower Gamma in buffer compared with DI water or acid. Gamma provides a quantitative measure of the effect of formulation and dissolution parameter changes on tablet gel layer strength, under in vitro stress conditions that may parallel in vivo tablet performance, but which cannot be deduced from a comparison of dissolution profiles or polymer viscosity.

Antimicrobial evaluation of N-alkyl betaines and N-alkyl-N, N-dimethylamine oxides with variations in chain length.

Alkyl betaines and alkyl dimethylamine oxides have been shown to have pronounced antimicrobial activity when used individually or in combination. Although several studies have been conducted with these compounds in combinations, only equimolar concentrations of the C(12)/C(12) and C(16)/C(14) chain lengths for the betaine and the amine oxide, respectively, have been investigated. This study investigates the antimicrobial activity of a wide range of chain lengths (C(8) to C(18)) for both the betaine and amine oxide and attempts to correlate their micelle-forming capabilities with their biological activity. A broth microdilution method was used to determine the MICs of these compounds singly and in various molar ratio combinations. Activity against both Staphylococcus aureus and Escherichia coli was investigated. Antimicrobial activity was found to increase with increasing chain length for both homologous series up to a point, exhibiting a cutoff effect at chain lengths of approximately 16 for betaine and 14 for amine oxide. Additionally, the C(18) oleyl derivative of both compounds exhibited activity in the same range as the peak alkyl compounds. Critical micelle concentrations were correlated with MICs, inferring that micellar activity may contribute to the cutoff effect in biological activity.

Drug release from film-coated chlorpheniramine maleate nonpareil beads: effect of water-soluble polymer, coating level, and soluble core material.

The purpose of this research was to use a new drug release model to study the effects of formulation parameters on drug release from a film-coated chlorpheniramine (CPM) nonpareil system. The film-coated CPM nonpareils were prepared by using a fluid bed apparatus. A hydroxylpropylmethylcellulose (HPMC) solution was blended with an aqueous ethylcellulose dispersion (Surelease) to adjust the permeability of the film. The apparent permeability of samples was obtained from dissolution data using a previously reported drug release equation. The apparent permeability was plotted versus the film coating level or the HPMC concentration in the film. When the natural logarithm of the apparent permeability versus coating level was graphed, a biphasic plot was observed in the group without HPMC in the film, showing the occurrence of a critical coating level. It was suggested that a mechanically formed porous film (due to an incomplete coating) could change to a nonporous film after the bead was completely coated. However, in the group that contained 12% HPMC in the film, the critical coating level was not observed. A porous film, formed by the leaching out of the water-soluble polymer, would not change to a nonporous film even after the bead is completely coated. Through a mathematical derivation, the decrease of apparent permeability versus coating level was related to the reduction of the total hole area. The apparent permeability was found to increase with the HPMC concentration. After a critical concentration was reached, the further addition of HPMC into the film caused a rapid increase in apparent permeability. The critical HPMC concentration was related to a minimum domain formation concentration (MDFC). A rapid increase of the drug release was observed when the dissolution profile of a sample made from a regular sugar nonpareil core (soluble) was compared with the sample made from a precoated nonpareil core (insoluble), which suggests that the drug release can be enhanced by the dissolution of the core. A minimum concentration of the HPMC was required to effectively modify permeability of the film. The critical coating level and critical concentration of HPMC can be determined from the apparent permeability plot using a previously published equation. The dissolution of a soluble core can greatly enhance the release of the drug from the nonpareil system.

The formation of a crosslinked carboxyhemoglobin membrane at an organic-aqueous interface.

A 30% carboxyhemoglobin solution was encapsulated with a membrane composed of crosslinked hemoglobin as a potential artificial red blood cell by adding a 25 microL droplet of 30% carboxyhemoglobin solution in phosphate buffer to a buffer-saturated toluene solution of a homobifunctional crosslinking agent. Disuccinimidyl glutarate, disuccinimidyl suberate, and terephthaldicarboxaldehyde proved successful in crosslinking hemoglobin at concentrations of 0.05%, 0.08%, and 4.3%, respectively (saturated levels in buffer-saturated toluene). Disuccinimidyl glutarate exhibited maximal crosslinking of 11.0% in approximately 30 minutes. Disuccinimidyl suberate and terephthaldicarboxaldehyde required at least 12 hours to form a viable sphere and crosslinked 39.4% and 37.8% of the hemoglobin in 18 hours. Membrane integrity was assessed by determining the permeability of uncrosslinked hemoglobin through the membrane as a function of time.

Charge-transfer complexes of iodine and nonionic surfactants: interpretation and use in the Winkler method.

Formation constants (Kc) and molar absorption coefficients (epsilon c) of complexes of iodine and various nonionic surfactants were determined, providing a basis for selection of a surfactant for use in a spectrophotometric modification of the Winkler method. The method of calculation of Kc and epsilon c was extended to include absorption by triiodide at the wavelength of maximum absorbance of the complex. Because the molar absorption coefficients of polyoxyethylene 10 oleyl ether (oleth 10) and polyoxyethylene 23 oleyl ether were significantly greater than those of other surfactants, they are superior candidates for use in the Winkler method. Formation constants could not be correlated with molecular characteristics of the surfactants such as alkyl chain or polyoxyethylene chain length, nor with physical characteristics of iodine-surfactant solutions such as reduction of iodine loss due to volatilization.

Effect of surfactant phase in perfluorocarbon emulsification efficiency.

The effect of preparation temperature on the emulsification efficiency of perfluoro-3-butyltetrahydrofuran (FC-75) was investigated. Polyoxyethylene (POE) oleyl ether surfactants were used as the emulsifier(s) in a range of HLB values of 7.5 to 9.5. The emulsions were prepared by paddle mixing as a method of low-shear emulsification. After centrifugation of the resulting O/W emulsions, the volume of FC-75 which separated was utilized as a measure of the emulsification efficiency. In general, emulsions prepared at temperatures where the surfactant was in a lamellar-to-isotropic surfactant solution transition, L alpha----L3, displayed a better emulsification efficiency than those prepared with other surfactant phases.

Bead coating. I. Change in release kinetics (and mechanism) due to coating levels.

Beads containing 50% acetaminophen (APAP) and 50% microcrystalline cellulose (Avicel PH 101) were prepared and then coated using an aqueous ethylcellulose based dispersion (Aquacoat) to evaluate the effect of the coating level on drug release. The APAP release was shown to be dependent on levels of the coating and a change in mechanism was suggested. Drug release from incompletely coated beads at low levels of coating can be described with the square root of time model, while drug release from beads with a high level of coating appears to be best described by zero-order release. At low coating levels, the drug release rate constant based on the square root relationship seems to be linear with the coating level. At high coating levels, drug release rate in terms of a zero-order model appears to be proportional to the reciprocal of the coating level.

Predicting coordinated lipid biosynthesis: application to the surfactant-accommodated epidermis.

Factorialized correlation analysis is proposed as a method for predicting the coordination of multiple enzyme pathways. The approach can be used potentially to find new relationships and to predict relationships that have been established in other tissues. However, careful tracer studies are needed to verify the cause-and-effect relationships between precursor and products. In this study, guinea pigs that were chronically treated with an anionic, a nonionic and a cationic surfactant passed through an irritation stage to a clinical state that appeared normal. The method was used to examine binary coordination of lipid biosynthesis in the epidermis by using a factorialized table of regression coefficients. Coordinated lipid relationships that have been reported in other tissues were predicted between sphingomyelin and cholesterol, as well as between phosphatidylcholine, phosphatidylserine and phosphatidylethanolamine. A new inverse relationship was found between triglycerides and both sphingomyelin and cholesterol, using this method. These data are discussed with respect to a membrane fluidization model for the accommodated state.

The pharmacodynamic response of the basal skin potential to quinidine gluconate.

The basal skin potential (BSP) was explored as an indirect means of continuously monitoring the cardiac response of quinidine gluconate. A method was developed to follow the BSP using a high impedance, recording polygraph and nonpolarizing calomel electrodes. Intravenous administration of quinidine gluconate caused time dependent changes in the BSP. Further studies showed that blood levels during the elimination phase and the QT interval of the electrocardiogram (ECG) over their entire time period were highly correlated with the BSP. Optimal correlation with the QT interval occurred when the BSP curve was shifted to earlier times by approximately 10 minutes, reflecting possible differences in the accessibility or mechanism of the respective pharmacologic compartments. Further application of the BSP for pharmacodynamic monitoring will require electrode refinements and an increased understanding of its mechanism of action.

Percutaneous absorption: a new physicochemical predictive model for maximum human in vivo penetration rates.

A diffusion model for stratum corneum-limited percutaneous absorption based on the interaction of the diffusate with the stratum corneum was derived. Two types of interactions were proposed, ion-dipole and lipid-lipid, based on current knowledge of the stratum corneum and on irreversible thermodynamic arguments. The resulting flux equations predict a linear dependence of flux on the dipole moment and ln X of the diffusates , where X is the mole fraction solubility. These flux equations were tested on 21 different diffusates whose human percutaneous absorption rates in vivo had been previously determined. A solubility method was used to classify the interaction pathway for each diffusate . Correlation of the maximum absorption rate for the lipid and polar pathways give correlation coefficients of 0.946 and 0.998, respectively. It is believed that these studies provide a starting point for the ultimate goal of percutaneous absorption research: to be able to bypass in vivo and in vitro studies and to predict absorption solely on the basis of the physicochemical properties of the diffusates .

Guinea pig ear as a new model for in vivo percutaneous absorption.

A new animal model for in vivo percutaneous absorption utilizing the hairless, relatively thick skin of the guinea pig ear is proposed. Topical absorption studies were carried out with [14C]hydrocortisone and [14C]testosterone. Systemic studies were also conducted to correct for incomplete urinary excretion. In addition, a single stratum corneum correction factor was developed from published data to enable the guinea pig ear skin to be directly compared with human forearm skin. A comparison of human percutaneous absorption with the corrected guinea pig ear absorption shows a high correlation for both hydrocortisone and testosterone. The effects of ambient changes in relative humidity are also discussed with respect to in vivo percutaneous absorption.

Influence of various anions on intestinal disappearance of hexamethonium chloride and pralidoxime chloride in rats.

The intestinal transfer of two poorly absorbed quaternary ammonium drugs, hexamethonium chloride (I) and pralidoxime chloride (II), in the presence of various organic and inorganic anions was investigated in the rat using a modified in situ gut technique. The results were in agreement with those of the conventional in situ loop and plasms drug level techniques. Of the anions investigated, cholate, desoxycholate, taurocholate, phoscholate, dehydrocholate, and hyodesoxycholate had the greatest effect on increasing the amount and rate of disappearance of I. Similarly, the amount and rate of disappearance of II were enhanced markedly in the presence of phoscholate and trichloroacetate. The effect of cholate and phoscholate was investigated in detail. The membrane permeability and histological studies indicated that these anions may compromise the structural integrity of the membrane tissue, thus enhancing drug transfer.

Separation of penicillin G potassium and its degradation products using high-pressure liquid chromatography.

A high-pressure liquid chromatographic technique was developed for the separation of penicillin G potassium and several of its decomposition products. The method utilized a buffered acetonitrile-phosphate mobile phase on a reversed-phase C18 column. Separation of penicillin G potassium and six degradation products was attained within 25 min.

A survey of the use and educational value of the hospital formularly manual.

The medical and nursing staffs of two affiliated hospitals were surveyed on their frequency and purpose of use of their hospital's formulary manual. A numerical rating of the perceived educational value of the manuals was also requested. Twenty-two per cent (141/650) of those surveyed completed their questionnaires. Ninety-six per cent of the respondents indicated use of the formulary manuals at least once a month; 62% used the manuals at least once a week. The frequency and character of use of various sections of the formulary manuals are presented. The perceived educational value of the manuals was rated 3 or greater on a scale of 1 (no value) to 5 (greatest value) by 80% of the respondents. The hospitals' formulary manuals are frequently referred to for various types of drug information. The professional staffs perceive the formulary manuals to be educationally valuable sources of drug information. Reasons for the low rate of response to the survey are presented. A plan of how to increase the response rate in a planned future survey is also presented.

Kinetics of absorption and elimination of pralidoxime chloride in dogs.

The kinetics of the absorption and elimination of pralidoxime chloride were investigated in the dog. Similar apparent elimination rate constants were obtained after intravenous, intramuscular, and oral administration. Although oral absorption occurred slowly, intramuscular absorption proceeded rapidly. With in situ techniques, it was found that no absorption occurred from the isolated stomach and duodenum but that absorption did take place from the jejunum and ileum.