Gamma irradiated micro system for long-term parenteral contraception: An alternative to synthetic polymers.

An injectable system of levonorgestrel (LNG) was developed using biodegradable polymer of natural origin. The parenteral system was optimized for particle size and higher drug loading. The microparticulate system was characterised by scanning electron microscopy, encapsulation efficiency, moisture content, IR, DSC, XRD, residual solvent content, sterility testing, test of abnormal toxicity and test for pyrogens. The microparticles were sterilised by gamma irradiation (2.5Mrad). The system was injected intramuscularly in rabbits and the blood levels of LNG were determined using radioimmunoassay technique. An optimized drug to polymer ratio of 0.3-1.0 (w/w ratio) gave improved drug loading of about 52%. In vivo studies in rabbits showed that the drug was released in a sustained manner for a period of 1 month. The AUC(0-t) was found to be 9363.6+/-2340pg/mLday(-1) with MRT calculated to be about 16 days and Kel of 0.01day(-1). LNG levels were maintained between 200 and 400pg/mL. In vivo release exhibited an initial burst effect which was not observed in the in vitro dissolution. This promising "Progestin-only" long-term contraceptive with improved user compliance is an alternative to the synthetic expensive polymeric carriers.

International validation of novel pyrogen tests based on human monocytoid cells.

It is a requirement that parenteral medicines be tested for pyrogens (fever causing agents) using one of two animal-based tests: the rabbit pyrogen test and the bacterial endotoxin test. Understanding the human fever reaction has led to novel non-animal alternative tests based on in vitro activation of human monocytoid cells in response to pyrogens. Using 13 prototypic drugs, clean or contaminated with pyrogens, we have validated blindly six novel pyrogen tests in ten laboratories. Compared with the rabbit test, the new tests have a lower limit of detection and are more accurate as well as cost and time efficient. In contrast to the bacterial endotoxin test, all tests are able to detect Gram-positive pyrogens. The validation process showed that at least four of the tests meet quality criteria for pyrogen detection. These validated in vitro pyrogen tests overcome several shortcomings of animal-based pyrogen tests. Our data suggest that animal testing could be completely replaced by these evidence-based pyrogen tests and highlight their potential to further improve drug safety.

Atropine availability as an antidote for nerve agent casualties: validated rapid reformulation of high-concentration atropine from bulk powder.

STUDY OBJECTIVE: Atropine is the preferred antidote for immediate management of toxicity associated with nerve agents or other cholinergic syndromes. A large-scale exposure to a nerve agent or organophosphate insecticide might result in many victims presenting for care within a short period of time. This situation would require the prompt availability of a large amount of atropine to provide treatment. Antidote stocks at many hospitals are inadequate to meet this demand. Atropine that is commercially available comes supplied at concentrations of either 0.4 mg/mL or 1 mg/mL, thereby requiring intravenous administration because of the volume necessary to administer the commonly recommended initial dose of 2 to 6 mg. Moderately ill victims may not require an intravenous line for other care, and in the setting of overwhelmed resources, intramuscular administration is faster and easier to perform. METHODS: To facilitate the delivery of larger atropine doses, we developed a method of fortifying existing injectable atropine with bulk pharmaceutical-grade atropine powder to a concentration of 2 mg/mL, thereby increasing the amount available and facilitating its intramuscular administration. An independent analysis of the resulting formulation was undertaken to assess its potency, absence of pyrogens, and stability. RESULTS: The amount of atropine initially present varied by less than +/-5%, within the range allowed by the US Pharmacopeia for the original product. The product was pyrogen free and maintained its potency at refrigeration temperature for at least 8 weeks after preparation and at room temperature for 4 weeks. Once all materials were available, the compounding of this preparation required about 1 hour to complete. CONCLUSION: Existing atropine stocks can be readily augmented by fortification with powdered atropine accurately and inexpensively. Common pharmaceutical guidelines recommend refrigeration for compounded products such as this if not completely used within 28 days.

Current practices in endotoxin and pyrogen testing in biotechnology. The Quality Assurance/Quality Control Task Group. Parenteral Drug Association.

This article presents the results of a nationwide survey of the biotechnology industry regarding endotoxin and pyrogen testing and control. It identifies procedures and methods being used by biotechnology companies, and firms working with biotechnology products, in the testing for and detection of endotoxin and other pyrogenic substances. The review attempts to identify areas of commonality and standardization within the industry and includes topics for discussion at the end of the survey results.

Technical requirements for rapid high-efficiency therapies.

Significant reductions in treatment time are possible with rapid high-efficiency hemodialysis and hemodiafiltration, provided the therapies are implemented so as to maintain adequacy of solute and fluid removal without compromising patient comfort. The key technical elements necessary for such implementation include high blood flow rates, higher efficiency dialyzers/diafilters, ultrafiltration control systems, and bicarbonate as the buffer source. In addition, hemodiafiltration requires schemes to ensure sterility and nonpyrogenicity of the infusion fluid and appropriate balancing of the rates of ultrafiltration and reinfusion. In general, rapid high-efficiency therapies are technically more complex than standard therapy, and rapid hemodiafiltration appears to be more complex than rapid hemodialysis. The technology required for rapid hemodialysis currently exists, but it needs to be fine-tuned and integrated for routine application.

Nitroglycerin injection manufactured by a hospital pharmacy.

A method used by a hospital pharmacy department for manufacturing and testing a ready-to-administer i.v. nitroglycerin injection is described, and costs for this extemporaneously prepared injection are compared with costs for commercially available nitroglycerin products for i.v. use. A powder adsorbate containing one part nitroglycerin and nine parts lactose was used to prepare nitroglycerin injection in two strengths: 0.04 mg/mL (250-mL quantities) in 0.9% sodium chloride injection and 0.4 mg/mL (400-mL quantities) in 5% dextrose injection. Each batch was tested for sterility, for presence of pyrogens (endotoxin testing), and for nitroglycerin concentration (spectrophotometric assay). In one year, a total of 1217 bottles of nitroglycerin injection were prepared. This required 75 hours; preparation from commercial i.v. nitroglycerin products would have required approximately 200 hours (including admixture preparation). First-year costs for extemporaneous preparation (excluding costs of i.v. solutions and containers) were approximately $2200, far less than drug costs alone for the commercial i.v. nitroglycerin products. Nitroglycerin injection of high quality and confirmed potency was prepared extemporaneously in a hospital pharmacy department. Costs for this method were substantially less than those for use of commercial i.v. nitroglycerin products.

Los pirógenos y la albúmina / Pyrogens and albumin

Los pirógenos han sido y son en la actualidad uno de los principales problemas que presentan en la Industría Farmacéutica al nivel mundial y por eso varios han sido los intentos por estandarizar un método para su análisis y numerosos los esfuerzos por eliminarlos de las soluciones contaminadas. Pero sólo el método que emplea al conejo es el que se acepta internacionalmente como oficial. Con respecto a la eliminación del pirógeno podemos decir que resulta más conveniente evitarlo que suprimirlo. Los productos de origen biológico son de los que mayor complicación presentan a la hora de su análisis y en donde menos se ha profundizado. Este trabajo tiene por objetivo dar a conocer los aspectos fundamentales estudiados hasta el presente sobre los pirógenos e introducir el aspecto del mismo en la albúmina como tema que cobra en nuestro país gran actualidad

Assessment of the interferon-like activity in preparations of leukocyte pyrogen.

Preparations of crude leukocytes from rabbit peritoneal exudates contain interferon-like activity which may be separated from pyrogen activity both by Sephadex chromatography and by purification of the pyrogen. This indicates that, despite some similarities, leukocyte pyrogen is not an interferon.

Pharmaceutical assessment of amygdalin (Laetrile) products.

The National Cancer Institute (NCI) recently acquired a large supply of formulated products of amygdalin manufactured by Cyto Pharma of Mexico, for possible use in a clinical trial in the US. Tablets for oral administration and ampules of the injectable produce were obtained. Both forms were extensively analyzed and evaluated by several analytic and pharmaceutical laboratories under contract with the NCI. Analytic test procedures were developed to determine the chemical integrity and quantitative composition of the formulated products. Routine physical and biologic tests were also performed to evaluate the manufacturing quality of both dosage forms. The results indicate that both the oral and injectable forms of amygdalin were substandard by US criteria for manufactured pharmaceutical products. All samples were determined to be chemically subpotent, mislabeled, and of poor manufacturing quality. More than 20 samples of the ampules were found by visual inspection to contain microbial contamination. Other samples were found to be pyrogenic. Based on the results of the testing performed, both tablet and ampule forms of amygdalin manufactured by Cyto Pharma of Mexico are considered unfit for use in man.