Permeability and retention studies of (-)epicatechin gel formulations in human cadaver skin.

(-)Epicatechin (EC) is a major antioxidant component of grape seed extract which has become increasingly popular in topical skin preparations. This study assessed the following: (1) the permeability through cellulose membranes of EC in three different gel formulations (Carbopol 940, Klucel, and Ultrez 10); (2) the effect of three different antioxidants (butylated hydroxytoluene (BHT), alpha-tocopherol (VE), and ascorbic acid (AA)) on the stability and penetration properties of EC; and (3) the permeability and retention of EC in Ultrez 10 gels, supplemented with BHT or VE, on human cadaver skin. Permeability studies through cellulose membranes showed that different gelling agents do not significantly affect the permeability of EC (n = 7/gel; p > 0.05). BHT and VE have antioxidant properties superior to AA (p < 0.05) and preserve 100% of the initial content of EC for 28 days. Permeation studies on cadaver human skin, following application of two anhydrous gel formulations (0.5% EC in Ultrez 10 containing BHT or VE), showed that EC was not detectable in the receiving solution. However, the EC amount in viable skin increased with time, indicating that EC penetrated and was retained in the upper part of the skin for approximately 1% and 3% of the dose for the formulations containing BHT and VE, respectively.

Controlled release from an electrorheological fluid dosage form: experimental results for a prototype system.

A new controlled-release technology that is based on electrorheological fluids (ERF) is described, and a model system is investigated. Humidified starch (duration of humidification is 30-35 minutes) was used as a filler material (approximately 20% w/w) in olive oil to make the ER system, and benzocaine (BZN) was used as the model drug. The average particle size of starch in the olive oil was approximately 200 nm. 1N HCl was used as the receiver medium and BZN was assayed by UV spectroscopy at 226 nm. A series of studies was done at five temperatures (25 degrees, 30 degrees, 35 degrees, 40 degrees, and 45 degrees C) and two external electric fields (E-fields) that were generated by applying potential drops across the diffusion apparatus of 0 V and 290 V. Control studies of BZN release from olive oil without filler showed little or no increase in release rates resulting from application of E-fields. In addition, while reversing the polarity for BZN in olive oil caused differences in release rates, these differences were too small to explain the results obtained for the ER systems. It was found that release of BZN increased significantly with the application of the electric field (approximately 53% increase at 25 degrees C). A plot of the log of the release rate vs 1/T was linear for the 0 V data but deviated from linearity for the 290 V data. The increase in release rates due to the E-field became smaller as the temperature was increased. The results are consistent with (but are not sufficient to prove) the hypothesis that the increased release rate is due to a small amount of ordering of the cornstarch filler particles in response to the applied E-field, which results in a reduction in the tortuosity of the system.

In vitro release and diffusion studies of promethazine hydrochloride from polymeric dermatological bases using cellulose membrane and hairless mouse skin.

The study was designed to investigate the feasibility of developing a transdermal drug dosage form of promethazine hydrochloride (PMH). The in vitro release and diffusion characteristics of PMH from various dermatological polymeric bases were studied using cellulose membrane and hairless mouse skin as the diffusion barriers. These included polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), cross-linked microcrystalline cellulose, and carboxyl methyl cellulose sodium (Avicel CL-611), and a modified hydrophilic ointment USP. In addition, the effects of several additive ingredients known to enhance the drug release from topical formulations were evaluated. The general rank order for the drug release from these formulations using cellulose membrane was observed to be PEG > HMPC > Avicel CL-611 > hydrophilic ointment base. The inclusion of the additives had little or no effect on the drug diffusion from these bases, except for the hydrophilic ointment formulation containing 15% ethanol, which provided a significant increase in the drug release. However, when these formulations were studied for drug diffusion through the hairless mouse skin, the Avicel CL-611 base containing 15% ethanol exhibited the optimum drug release. The data also revealed that this formulation gave the highest steady-state flux, diffusion, and permeability coefficient values and correlated well with the amount of drug release.

Ketoprofen suppository dosage forms: in vitro release and in vivo absorption studies in rabbits.

In vitro release of ketoprofen from suppository bases and in vivo absorption in rabbits were studied. Suppositories containing 50 mg of ketoprofen were prepared using theobroma oil, esterified (c10-c18) fatty acids, and polyethylene glycol 1000 bases. The displacement values of the drug were determined and found to be of the order of theobroma oil > esterified (c10-c18) fatty acids and polyethylene glycol 1000 bases. The suppository hardness data revealed that the theobroma oil base produced relatively brittle suppositories. Using the USP dissolution method, the release of ketoprofen was observed to be greatest from polyethylene glycol 1000 suppositories. With the dialysis technique, the maximum release of drug was obtained from theobroma oil suppository containing polysorbate 40 at a 6% level. Selected suppository formulations were evaluated for rectal absorption studies in rabbits. The in vivo data showed that the optimum drug absorption took place from the polyethylene glycol 1000 base and theobroma oil formulation containing 6% polysorbate 40.

Evaluation of the effect of different fatty acids on the percutaneous absorption of metaproterenol sulfate.

The in vitro permeation rates of metaproterenol sulfate (MPS) across hairless mouse skin and TESTSKIN living skin equivalent were very low unless skin permeation enhancers were included in the vehicle. An optimum balance should be established between the chain length of the fatty acid and its molar ratio to MPS in order to enhance its penetration through the skin. Thus, the best flux values were shown by capric acid: MPS, 3:1 molar ratio, and lauric acid:MPS, 1:1 and 2:1 molar ratio, while myristic acid:MPS, 1:1 molar ratio, was the optimum under the experimental conditions used. The mechanism of the enhancing effect was examined by measuring 1H NMR spectra and the apparent partition coefficient of MPS, lauric acid, and the mixture. The apparent partition coefficient of MPS between n-octanol and water was higher for the mixture with lauric acid than for MPS alone. A 1:1 molar ratio formulation of MPS and lauric acid was selected for the in vivo permeation study. The data indicated that lauric acid increased the diffusivity of MPS in the skin by forming a complex and by affecting its partition coefficient between the skin and the delivery system.

Design and evaluation of transdermal chlorpheniramine maleate drug delivery system.

The study was to develop a transdermal therapeutic system for chlorpheniramine maleate (CPM). The diffusion characteristics of CPM were determined using Franz diffusion cells, from gelled ethanol-water solutions of CPM (5, 10, and 20%). TESTSKIN Living Skin Equivalent (LSE) was used to study the enhancement effect of ethanol-water solutions. The 0.6 volume fraction of ethanol gave the highest diffusion rate of CPM (Jss = 1.591 mg/cm2h). The diffusion and partition coefficient data revealed that changes in ethanol volume fraction of the vehicle and ethylene vinyl acetate (EVA) membrane characteristics directly affect CPM partitioning and diffusion across EVA membranes and EVA-pressure sensitive adhesive (PSA) laminates. The data also suggest a possible interaction of CPM with the PSA. The steady state fluxes attained with 20% CPM gel is 34 micrograms/cm2h, which is enough to keep the drug within its therapeutic plasma levels.

Comparative in vitro diffusion studies for atenolol transdermal delivery system.

The purpose of this study was to screen atenolol as a candidate for transdermal drug delivery, and to study the release of atenolol from various gels. The percent atenolol release over time profiles indicates that for all the gelling agents used the amount of atenolol released is decreased by increasing the polymer concentration in the gel. The amount of atenolol released was found to be higher from Klucel gels, compared to Methocel and Carbopol gels, with Carbopol gels giving the least release. In studying the effect of atenolol concentration in the gel, it was observed that the amount of atenolol released was increased by increasing the drug concentration in the donor up to a limit corresponding to an atenolol concentration of approximately 2%. This seems to resemble the saturation solubility of atenolol into the gels. Hairless mouse skin and TESTSKIN LSE were used as in vitro skin models.

In vitro release of testosterone from suppository bases and in vivo absorption studies in human males.

Diffusion rates of testosterone from various suppository bases with and without surfactants were determined. In a limited study, selected suppository formulations were evaluated for efficiency of rectal absorption of testosterone in three male volunteers ranging in age from 25 to 30 years. Significant reductions in the ratios of urinary metabolites to free testosterone were observed with polyethylene glycol 1000, esterified (C10-C18) fatty acids, and theobroma oil-based samples.

Assessment of triethanolamine salicylate release from the dermatological bases and the commercial products.

Recently, triethanolamine salicylate (TEAS) is frequently being incorporated in several over-the-counter topical analgesic pharmaceutical products. Since the clinical efficacy of such dosage form depends upon the release of the active ingredient at the site of application, the present study was undertaken to study the in vitro release of the (TEAS) from commonly used ointment bases and two most popular commercial products in the U.S. market. Also, the effects of various penetration enhancers, such as, ethanol, propylene glycol, polyethylene glycol-400, dimethyl-sulfoxide (DMSO), polysorbate-80 and urea were evaluated. In general, the drug release from the experimental formulations was higher than the commercial products studied. The inclusion of the penetration enhancing ingredients increased the drug release from some of the formulations evaluated. The hydrophilic emulsion base with 10% ethanol exhibited the best in vitro drug release. The apparent viscosity profiles of the formulations showed no definite relationship with the amounts of drug release. However, significant differences in the (TEAS) release from the experimental formulations were observed.

In vitro release studies of methyl salicylate from the ointment bases and the commercial dermatological products.

Methyl salicylate, a lipophilic liquid is one of the most commonly used analgesic, counterirritant and rubifacient ingredients in the commercially marketed over-the-counter dermatological products. And, since the effectiveness of the topically applied product depends on the release of the drug from such a dosage form, the present study was proposed to investigate the in vitro release of methyl salicylate from the typical ointment bases and several commercial products. Also, the effects of various additive ingredients on the drug release from these bases were evaluated. In general, the selected ointment bases gave superior in vitro drug release profiles compared to all commercial products included in this study. The addition of ethanol at 10% level in these ointment bases significantly enhanced the drug release from the selected formulations.

Determination of the optimum solvent system for extraction of minoxidil from a tablet dosage form.

Several pharmaceutical solvent systems commonly employed by the pharmacist during the extemporaneous dispensing of minoxidil topical solution using Loniten tablets were evaluated. These included ethanol, propylene glycol, water and a commercially available liquid, Vehicle/N. A total of twenty-five (10 mg) Loniten tablets were pulverized in a wedgewood mortar for five minutes. The tablet powder was then dissolved in the experimental solvent system and stirred thoroughly for ten minutes. The liquid dispersion was filtered using the vacuum filter method and the powder residue was then washed twice to obtain a fixed volume of the filtrate. The concentration of minoxidil in each solvent system was determined spectrophotometrically at the wavelength range of 280 to 282 nm depending upon the solvent. The amount of minoxidil extracted in each sample was calculated using the previously constructed standard curve in the respective solvent system. From the data obtained, it was concluded that Vehicle/N is the optimum solvent for such use, and the drug recovery was about 99%. Whereas, the mixture of methanol/propylene glycol/water at a volume ratio of 6:2:2 was observed to be the second best with a drug recovery of 97%. The addition of sodium lauryl sulfate had no effect in enhancing the solubility of drug when used in a solvent with poor recovery profile of drug. Also, the presence of excipients of the tablet dosage form did not interfere with the extraction process of minoxidil.

Medicament release from suppository bases I: Physicochemical characteristics and bioavailability of indomethacin in rabbits.

This investigation was designed to determine the in vitro release of indomethacin from suppository bases and the in vivo bioavailability in rabbits. Suppositories containing 25 mg of indomethacin were made by the fusion method with theobroma oil, esterified fatty acids (C10-C18), and polyethylene glycol 1000. To produce an exact dosage form, a formula for the determination of the displacement value was derived, and it was found that theobroma oil greater than esterified fatty acids (C10-C18) greater than polyethylene glycol 1000. The suppository hardness was determined by using appropriate apparatus and it was found that the esterified fatty acids (C10-C18) allowed the formation of more brittle suppositories. The release rates were determined with the USP dissolution apparatus, with or without cellophane membrane, and it was found that polyethylene glycol 1000 greater than esterified fatty acids (C10-C18) greater than theobroma oil. The bioavailability of indomethacin after rectal administration was greater with polyethylene glycol base. Significant correlation was obtained during the first 45 min between the in vitro release (dialyzing tubing) and the in vivo bioavailability.

High-pressure liquid chromatographic determination of ibuprofen in plasma.

A sensitive, simple, and rapid method for the quantitation of ibuprofen in plasma, using 1-(p-fluorobenzoyl)-5-methoxy-2-methylindole acetic acid as the internal standard, was developed. The method is based on reversed-phase high-pressure liquid chromatography with a mobile phase containing acetonitrile--0.1 M acetic acid (55:45 v/v). The chromatographic elution time was 8.5 min, and ibuprofen quantities as low as 0.1 microgram/ml can be assayed. The suitability of the method is demonstrated.

Comparative bioavailability of three commercial acetaminophen tablets.

Four different acetaminophen products (three tablets and one liquid) were evaluated for their in vitro properties and in vivo comparative bioavailability. The in vivo properties included assay, hardness, thickness, friability, weight variation, content uniformity, disintegration, and dissolution. A statistically significant variation was observed in friability, disintegration, and dissolution. The dissolution rates were determined in 0.1 N HCl under sink conditions, and the T50% value for Brand A was 50 min while the values for Brands B and C were 1 min. The in vivo evaluation was completed in four subjects with a urinary excretion experiment using a crossover design. The calculated elimination half-lives were 4.12, 2.77, 3.14. amd 2 h for Brands A, B, and C and the standard, respectively. The relative bioavailabilities (with respect to solution) were 82, 87, and 92% for Brands A, B, and C, respectively. The mean amount excreted with Brand A was less than the reference at all time points, although it was not significant. Comparison of the in vitro and in vivo data for the three tablets indicated that the rate and amount of acetaminophen excreted may be related to the dissolution rate.

Quantitative determination of acetaminophen in plasma.

A simple method is described for the rapid quantitative analysis of acetaminophen in plasma. The acetaminophen and its conjugates present in the plasma following drug administration are hydrolyzed with 4 N HCl to p-aminophenol. This compound is coupled with 5% vanillin reagent to form a stable yellow color whose concentration is determined spectrophotometrically at 395 nm. Application of this method to a study of three dogs treated with 650 mg of acetaminophen is described.