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Arsenic and cancer: the still unanswered question.

For some 2,500 years, arsenic was considered an important element of pharmacopeias and was praised for its medicinal qualities. However, an incidental link with cancer was suggested during the nineteenth century, and since that time a controversy has ensued with regard to the compound's tumorigenicity. Several epidemiological surveys, for example, have suggested that arsenic induces lung, liver, or skin cancer in humans. On the other hand, all experimental attempts to reproduce such neoplasms in laboratory animals have consistently failed, thereby denying support to the human data. Recently arsenic was reported to be mutagenic. However, because of the inconsistency of most mutagenesis findings at present, this also cannot be regarded as supporting evidence. Furthermore, a recent trend has been to consider arsenic as beneficial in cancer prevention and in maintaining the health of farm animals, and, perhaps, humans. A critical review of epidemiological and experimental data from the literature has been made in an attempt to present an objective picture of this controversial and sensitive question and to encourage further research, which may ultimately determine whether arsenic deserves its execrable reputation.

Administration, Oral↗

Extemporaneous compounding of pain and symptom control medications.

This paper introduces a new series in the Journal on extemporaneously compounded dosage forms for symptom control. Some advantages and limitations of compounded medications are described and issues that clinicians should consider are mentioned. Topics that will be discussed in future papers in this series are described. Changes of compounding-related chapters of the United States Pharmacopeia from advisory statements to enforceable standards are discussed. As an example of important formulation considerations, some physical-chemical characteristics and route of administration characteristics of opioid analgesics are discussed.

Administration, Oral↗

Adjusting dissolution specifications for the variability induced by storage conditions.

The United States Pharmacopeia requires that drug products meet established dissolution specifications throughout their shelf life. Whereas chemical stability for six months at accelerated storage conditions is generally regarded as providing a two-year expiry period, stress conditions are not considered predictive of dissolution stability at controlled room temperature. This paper presents an application of response surface methodology intended to incorporate the variability induced by storage temperature and relative humidity into robust product dissolution specifications. Contour plots, depicting one-sided tolerance limits of percent released, are presented as a function of crushing strength and dissolution time.

Compressive Strength↗

Comparison of dissolution profiles for albendazole tablets using USP apparatus 2 and 4.

The in vitro dissolution of albendazole from three different commercially available products (200 mg tablets) was studied using U.S. Pharmacopeia (USP) Apparatus 2 and USP Apparatus 4 in order to compare the release performance of the drug in two essentially different dissolution systems. For both cases, 0.1 N HCl was used as dissolution medium. Only the reference product and one of the generic products studied met the 80% USP 24 specification for albendazole dissolved at 30 min, using USP Apparatus 2. Although the reference product reached 80% of albendazole dissolved at 30 min when Apparatus 4 was used, the generic products' dissolution performance was markedly reduced in this system. Though dissolution rate was slower using Apparatus 4, the total quantity of albendazole dissolved from the reference product, represented by area under the dissolution profile, was practically the same regardless of the system used. Dissolution kinetics of albendazole was adequately described by Weibull's function for all the products. The dissolution time (t(d)) derived from data fitting to this function showed significant differences among the products studied. Data analysis based on analysis of variance (ANOVA) showed nonequivalence among the dissolution profiles of generic products compared with the reference product either with the dissolution vessel system or the flow-through cell, as well as nonequivalence among the dissolution profiles using both apparatuses with the same product. Though differences in the dissolution profiles for generic products against the reference product in both systems were found, USP Apparatus 4 showed higher discriminative capacity in differentiating the release characteristics of the products tested.

Albendazole↗

Acrylic matrix type nicotine transdermal patches: in vitro evaluations and batch-to-batch uniformity.

Nicotine transdermal patches (NTPs) were fabricated using an acrylic pressure sensitive adhesive emulsion to form a transparent matrix film. An automated thin layer chromatography (TLC) plate scraper was used to control the thickness of the cast nicotine matrix film. The in vitro release behavior and permeation of nicotine across abdominal human epidermis (HE) from the NTPs was studied using United States Pharmacopeia (USP) dissolution apparatus 5 (paddle over disk) and modified Franz-diffusion cell, respectively. The release of nicotine from the NTPs showed a good linear correlation with the square root of time (R2 > 0.99). This indicated a matrix diffusion controlled-release mechanism. The surface morphology of the matrix of the NTP was uniform and nonporous before and after release, indicating that the dried adhesive nicotine matrix was a homogeneous single-phase film. Neither the nicotine content in the range 4.70-8.41% w/w nor the film thicknesses of the NTPs affected the apparent diffusion coefficient of nicotine in the acrylic matrix. A good relationship between the amount of nicotine permeated across the HE and the square root of time was also observed with R2 > 0.98. This study also showed that the NTPs provided a good delivery system with more than 65% of the nicotine delivery being controlled by the device. Moreover, the release of nicotine from six production batches met the criteria of USP 24. This finding presented a good potential of this method for upscaling to industrial manufacturing.

Acrylic Resins↗

Gastroretentive delivery systems: hollow beads.

The objective of this study was to develop a floatable multiparticulate system with potential for intragastric sustained drug delivery. Cross-linked beads were made by using calcium and low methoxylated pectin (LMP), which is an anionic polysaccharide, and calcium, LMP, and sodium alginate. Beads were dried separately in an air convection type oven at 40 degrees C for 6 hours and in a freeze dryer to evaluate the changes in bead characteristics due to process variability. Riboflavin (B-2), tetracycline (TCN), and Methotrexate (MTX) were used as model drugs for encapsulation. Ionic and nonionic excipients were added to study their effects on the release profiles of the beads. The presence of noncross linking agents in low amounts (less than 2%) did not significantly interfere with release kinetics. For an amphoteric drug like TCN, which has pH dependent solubility, three different pHs (1.5, 5.0, and 8.0) of cross-linking media were used to evaluate the effects of pH on the drug entrapment capacity of the beads. As anticipated, highest entrapment was possible when cross-linking media pH coincided with least drug solubility. Evaluation of the drying process demonstrated that the freeze-dried beads remained buoyant over 12 hours in United States Pharmacopeia (USP) hydrochloride buffer at pH 1.5, whereas the air-dried beads remained submerged throughout the release study. Confocal laser microscopy revealed the presence of air-filled hollow spaces inside the freeze dried beads, which was responsible for the flotation property of the beads. However, the release kinetics from freeze dried beads was independent of hydrodynamic conditions. Calcium-pectinate-alginate beads released their contents at much faster rates than did calcium-pectinate beads (100% in 10 hours vs. 50% in 10 hours). It appears that the nature of cross-linking, drying method, drug solubility, and production approach are all important and provide the opportunity and potential for development of a gastroretentive drug delivery system.

Alginates↗

The influence of excipients on the stability of the moisture sensitive drugs aspirin and niacinamide: comparison of tablets containing lactose monohydrate with tablets containing anhydrous lactose.

The purpose of this study is to test the hypothesis that in tablet formulations, moisture-sensitive drugs formulated with lactose monohydrate have the same stability as formulations containing anhydrous lactose, and to characterize the kinetics of niacinamide degradation in the solid state. Aspirin and niacinamide decomposition were used as indicators of stability. Aspirin and niacinamide tablets containing either lactose monohydrate or anhydrous lactose were separately investigated at different temperatures and relative humidities; the stability tests were done at 25 degrees C--60% RH, 40 degrees C--80% RH, 60 degrees C--60% RH, 60 degrees C--80% RH, and 80 degrees C--80% RH. Official U.S. Pharmacopeia methods were used for the aspirin and niacinamide assays. Statistical analysis showed that tablets containing lactose monohydrate have the same stability as tablets containing anhydrous lactose, which means that even though water is present in the crystal structure, the bound water does not influence the reaction rate. In addition, niacinamide degradation in the solid-state can be described by a third order rate equation.

Aspirin↗

Optimization of methacrylic acid ester copolymers blends as controlled release coatings using response surface methodology.

The aim of this study was to statistically optimize the use of blends of methacrylic acid ester copolymers with different permeability properties as controlled-release coating systems for tablets to produce predictable predesigned release profiles. A full factorial design was used to study and optimize the use of methacrylic acid ester copolymers Eudragit RS 30D and Eudragit RL 30D as coating materials for controlled release. Directly compressed theophylline tablets were coated with aqueous dispersions containing different proportions of the two copolymers using a side-vented coating pan (Accela Cota). The effect of polymer loading level at 5, 7.5, and 10% weight gain and curing time at 50 degrees C for 12 and 24 hours were also evaluated. Coated tablets were tested for their drug release in water using a United States Pharmacopeia (USP) dissolution apparatus #2. The results showed that increasing the content of the lower permeability copolymer Eudragit RS 30D, increasing the polymer load, and increasing curing time at 50 degrees C resulted in slower drug release. A statistical model that describes and predicts the drug release properties of the coated tablets as a function of the copolymers ratio in the coating dispersion, polymer load, and curing time at 50 degrees C was developed. The most significant factor affecting drug release was found to be the ratio of the two copolymers in the coating dispersion followed by the curing time at 50 degrees C and the polymer loading level. Good correlations were observed between the model fitted values andthe experimental values. An optimized formula prepared by superimposing two-dimensional contour plots was prepared; its release profile was found to be in agreement with the prediction obtained from the model.

Delayed-Action Preparations↗

Powder functionality test: a methodology for rheological and mechanical characterization.

In most pharmaceutical formulations, the part of the excipients, in quantity and number, is larger than that of active principles, justifying particular attention to their characteristics to ensure quality, efficacy, and reproducibility of final forms. Whereas chemical specifications are described in Pharmacopeias, physical characteristics, up to now, have not been sufficiently considered. Nevertheless, there is a need for tests to objectively compare technological performances of products and justify composition of medicinal products. The powder functionality test described in this article is based on the analysis of the global behavior of materials under pressure. The powder compression is performed using an instrumented uniaxial press, Lloyd 6000R, and a compression cell of 1 cm3 in volume, allowing a complete and early characterization with a few grams of material. Indices characterizing packing, densification energies, energetic yields, and deformation mode of the particles are proposed from the analysis of compression cycles. Cohesion and energy of rupture are deduced from the diametral rupture cycles of the compacts. Application of this methodology to supplied celluloses has shown better flow properties of microcrystalline celluloses due to their higher bulk density and particle size. The energy fraction lost as frictions is very important and independent of the type of celluloses, whereas elastic energy is higher for powdered celluloses P100 and G250. Finally the efficacy to convert compaction energy into cohesion is higher for products with a small degree of polymerization, i.e., microcrystalline celluloses, except A301 and A302, which also are distinguished by their low porosity.

Algorithms↗

Pyrogenic reactions associated with single daily dosing of intravenous gentamicin.

OBJECTIVE: To identify risk factors associated with an unexpected outbreak of pyrogenic reactions (PR) following intravenous gentamicin. DESIGN: We conducted two cohort studies. PRs were defined as chills, rigors, or shaking within 3 hours after initiating the gentamicin infusion during the preepidemic (December 1, 1997-January 15, 1998) or epidemic (May 1-June 15, 1998) periods. We tested gentamicin vials for endotoxin using the limulus amebocyte lysate assay. SETTING: Inpatient services of a large community hospital in Los Angeles, California. RESULTS: During the epidemic period, 22 (15%) of 152 patients developed documented PRs following intravenous gentamicin. PRs were more likely among patients receiving single daily dosing (SDD) than multiple daily dosing gentamicin (20/73 [27%] vs. 2/79 [3%]; relative risk, 10.8; 95% confidence interval, 2.6 44.7). Laboratory analysis of gentamicin vials found endotoxin levels that were higher among Fujisawa-brand gentamicin (implicated brand) than gentamicin used after the outbreak terminated (non-implicated brand). Although endotoxin levels in the vials did not exceed US Pharmacopeia limits (1.7 endotoxin units/mg gentamicin), the use of SDD gentamicin may place patients at greater risk of receiving doses of endotoxin above the threshold for PRs in humans. CONCLUSIONS: Reassessment of the acceptable amounts of endotoxin in gentamicin and other parenteral products should be considered when dosing intervals used in clinical practice change.

Adolescent↗

Metering performance of several metered-dose inhalers with different spacers/holding chambers.

Metered-dose inhalers (MDI) are routinely used to administer inhaled antiasthma drugs. Actuation-inhalation coordination problems are overcome and systemic side effects are reduced by using spacers/holding chambers (SP/HCHs). Many of these devices do not allow the use of the manufacturer's actuator. The objectives of this study were (a) to investigate the effect of the interaction of eight MDI products with four different SP/HCHs on their metering performance (MP); and (b) to test the hypothesis whether the MP obtained with a SP/HCH and a given drug (MDI) can be extrapolated to other MDIs, even for members of its particular drug class. The procedure outlined in The United States Pharmacopeia-The National Formulary was used (determination of canister weight changes after actuation). The SP/HCH tested were Aerochamber, Inspirease, and ACE. The MDIs tested were salmeterol xinafoate; albuterol with chlorofluorocarbons and 1,1,1,2-tetrafluoroethane as propellants; cromolyn sodium; nedocromil sodium; flunisolide; beclomethasone dipropionate; and fluticasone propionate. Only flunisolide-Inspirease presented an unacceptable MP. Although within the acceptable limits, the MP varied significantly between the following MDI-SP/HCH combinations: Optihaler-fluticasone propionate and Optihaler-cromolyn sodium < to Aerochamber-fluticasone propionate and Aerochamber-cromolyn sodium (p = 0.0015 and p = 0.0007, respectively); and Inspirease-flunisolide and Optihaler-flunisolide < Aerochamber flunisolide (p = 0.003 and p = 0.005, respectively). MP did not significantly vary when albuterol with chlorofluorocarbons or 1,1,1,2-tetrafluoroethane as propellants, salmeterol xinafoate, beclomethasone dipropionate, and nedocromil sodium were attached to any of the SP/HCHs studied. Our results emphasize the capital importance of choosing the right combination of MDI and SP/HCH for aerosol delivery. The MP obtained with a drug and a SP/HCH cannot be expected to be similar for other MDIs, even for members of its drug class. These data also suggest the need for regulatory agencies to approve an MDI to be used only with the SP/HCHs tested.

Administration, Inhalation↗

1,536-well assay development and screening using whole cell displacement binding and laser scanning imaging.

A screen of a GPCR against Pharmacopeia's combinatorial libraries was performed using 1,536-well plates in a 1.5-microl assay volume with an LSI that was specially modified to enable detection at these volumes. The screen encompassed approximately 4 x 10(6) compounds. The assay uses a CHO cell line that expresses human CXCR1. The plate format chosen was the Corning 1536 low-profile wafer plate. The performance of the screen is evaluated, and the necessity to obtain cytotoxicity data from the same well is described.

Animals↗

Radioiodine dispensing and usage in a centralized hospital nuclear pharmacy.

131I sodium iodide is the radiopharmaceutical of choice for both diagnosis and therapy in patients with various thyroid abnormalities. The radioiodide capsule has been the preferred dosage form, primarily because it provides a more convenient and safer vehicle for radioiodine administration. However, encapsulated 131I costs approximately twice as much a liquid 131I and does not provide as much flexibility as 131I solution in dosage selection. Also, the bioavailability of the capsular radioiodide preparation is inferior to that of the aqueous dosage form. The patient must swallow multiple capsules when a large amount of 131I activity is used. Capsule form is not suitable for any patient who has difficulty swallowing a capsule, has a feeding tube, or requires intravenous injection of 131I solution. In addition, radioiodide capsules must be analyzed statistically to ensure that the dosage units meet the United States Pharmacopeia uniformity requirements. If liquid radioiodine is used, distilled water rather than tap water should be used for dose preparation. It also is recommended that an antioxidant (e.g., sodium thiosulfate, sodium bisulfite), disodium edetate, and a pH adjustment of 7.5-9.0 be used to reduce radioiodide volatility. Due to the acceleration of the oxidative reaction caused by heat and light, 131I should be stored in a dark, cool environment. To comply with the quality management program implemented by the US Nuclear Regulatory Commission on January 27, 1992, all of the required information (e.g., prescribed dosage, procedure date, and signature of the authorized user) for a valid written directive is preprinted to ensure that the written directive is completed entirely and appropriately. Before each administration of therapeutic 131I solution, the calculated dose is verified by the prescribing physician, and the measured dose of 131I is reconfirmed by a second nuclear medicine technologist. Each patient's identity is verified by two methods (i.e., patient's full name and birth date).

Biological Availability↗

Revised USP standards for product dating, packaging, and temperature monitoring.

Revisions in the standards of the United States Pharmacopeia (USP) related to product dating, packaging, and temperature monitoring are discussed. USP has revised product dating specifications as they relate to pharmacy practice. Pharmacists are required to affix beyond-use dates and not expiration dates to the prescription or repackaged vial. With respect to beyond-use dates for nonsterile products that are repackaged into unit dose or single-unit containers, the requirement has been changed from the previous period of six months from the date of repackaging or 25% of the time remaining until the expiration date, whichever is less, to one year. The type of packaging container, the material used in packaging, and the permeability of the container to moisture are important issues for pharmacists to consider. USP requires that the pharmacy facility where dispensing or repackaging occurs be maintained at controlled room temperature such that the calculated mean kinetic temperature does not exceed 25 degrees C. USP standards for product dating, packaging, and temperature monitoring have changed, and pharmacists must educate themselves about these revisions.

Drug Labeling↗

Blueprint for implementing USP chapter 797 for compounding sterile preparations.

PURPOSE: Guidelines for adopting and successfully implementing the requirements of the United States Pharmacopeia (USP) chapter 797 for compounding sterile preparations are presented. SUMMARY: The quality of a compounded sterile preparation (CSP) is directly related to the methods used to ensure that the CSP achieves the desired goal of purity, potency, and sterility. A properly designed, constructed, and maintained cleanroom contributes to the quality of CSPs. Design criteria of a sample clean-room are supplied, as are a summary and comparison of the liquid disinfectants that can be used to clean and sanitize the facility and maintain environmental controls. All activities associated with cleaning the cleanroom, including air and surface sampling, must be properly documented in logs, examples of which are provided. A robust employee-training program for properly teaching aseptic technique and a method to verify that personnel have successfully completed the program are integral to compliance with chapter 797 and thoroughly discussed herein. Emerging compounding and testing technology is also discussed. CONCLUSION: Although the task of compliance with the requirements of USP chapter 797 may appear overwhelming, complicated, expensive, and even unattainable, quality can be established via a methodical and organized approach. After the systems have been implemented, maintaining them requires vigilance and follow-up. Compliance with chapter 797 involves up-front and ongoing costs associated with establishing these systems, but the time, energy, and cost required to maintain them are far less than those of retrospective or manual systems of collecting, reviewing, and collating quality assurance data on a monthly basis.

Data Collection↗

Separation and quantitation of insulins and related substances in bulk insulin crystals and in injectables by reversed-phase high performance liquid chromatography and the effect of temperature on the separation.

The Food and Drug Administration performs potency assays of insulin products as part of the insulin certification program required by the Code of Federal Regulations. The official method specified in the United States Pharmacopeia (USP) is a bioassay measuring the depression of blood sugar concentrations in rabbits treated with the insulin under test and the official standard. The insulin products resulting from today's technology include highly purified isolates from bovine or porcine pancreas and insulin that is identical in structure to human insulin. A study of the effects of temperature on the separation of the components in insulin injectables led to the development of a reversed-phase high performance liquid chromatographic (HPLC) method that uses a sulfate buffer/acetonitrile mobile phase at 40 degrees C for the separation and quantitation of bovine, porcine, and human insulins and related substances. This HPLC method reduces analysis time to 1/60 of that required for the bioassay and yields more information about purity than the percent nitrogen determination that is one of the USP official procedures. The results of HPLC analyses were compared with those for the bioassay by means of a potency/area conversion factor computed on a species by species basis. Results for the bioassays and the HPLC determinations for 40 lots of bulk crystalline insulin were compared in this study; in general, the HPLC estimates fell within the 95% confidence interval for combined independent bioassays.

Animals↗

Application of fast LC to pharmaceutical analysis: dopamine.HCl.

A reversed-phase HPLC method for the determination of the dopamine hydrochloride content of pharmaceutical intravenous solutions is developed using short (3-cm) columns packed with 3-micron particles. Total analysis time for the stability indicating assay, which is capable of separating the analyte from all its common degradates and formulation matrix components, is 2 min. The assay is equivalent in performance (accuracy, precision, separation behavior, ruggedness) to a standard method recommended by the United States Pharmacopeia (USP). Common components of conventional HPLC systems are evaluated with respect to their utility for this application of fast LC.

Chromatography, Liquid↗

Rapid analysis of phentolamine by high-performance liquid chromatography.

A rapid liquid chromatographic method is validated for the quantitative analysis of phentolamine. Phentolamine exists in three forms for this investigation: as a mesylate salt, hydrochloride salt, and free base. In solution, phentolamine dissociates from its salt and is chromatographed as free phentolamine. This validation confirms the analysis of each form, which is simply based upon molar mass differences encountered in weighing. As such, both the United States Pharmacopeia hydrochloride and mesylate standards are used throughout this validation to demonstrate this equivalency. The validation demonstrates that this method may be used to quantitate phentolamine, regardless of its salt form.

Antihypertensive Agents↗