Pharmaceutical availability

Food and Drug Administration, HHS, International Conference on Harmonisation Guidance on S8 Immunotoxicity Studies for Human Pharmaceuticals availability. Notice, Fed. Regist., 71, 19193,2006. 

S2B Guidance on Genotoxicity A Standard Battery for Genotoxicity Testing of Pharmaceuticals Availability Notice Nov 97... 

S6A Guidance on Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals Availability Nov 97... 

US EPA [Online], Pharmaceuticals, available http //www.epa.gov/epawaste/hazard/wastetypes/universal/pharm. 

U.S. Code of Federal Regulations (CFR), Title 21, Part 211, Current good manufacturing practice for finished pharmaceuticals, available http //www.accessdata.fda.gov/scripts/ cdrh/cfdocs/cfcfr/CRFSearch.cfm CFRPart=211, accessed Dec. 5, 2006. 

International Conference on Harmonisation Draft Guideline on Vali- dation of Analytical Procedures for Pharmaceuticals Availability, Fed. Reg., 59 9750 (1994). 

Purified captan. Antimicrobial and preservative for cosmetics and topical pharmaceuticals. Available as a white powder. 

Establishing pharmaceutical availability of the active moiety both in vitro and in vivo in humans and, if required, also in animals. 

Information on pharmaceuticals available on the Russian market that is more or less complete can be found in the commercially published Vidal reference books and The Register of Pharmaceutical Products in Russia (both annual editions) and New Pharmaceuticals, edited by M. D. Mashkovsky. 

Dissolution rate shall be included as a requirement for batch relecise to ensure batch to batch quality/pharmaceutical availability/bioequivalence, for all products containing one or more active ingredients where such a requirement forms part of the final product specification. Application may be made for proposed intervals of dissolution rate testing as criteria for batch release if adequate statistically processed validation data are available and submitted. This applies only to standard production lot sizes that have been validated. The proposed frequency of dissolution testing must be based on the validation results and the following factors ... 

Due to possible differences, especially in pharmaceutical availability, the fact that drug preparations have chemical equivalence — equal contents of active agent — in no way guarantees biological equivalence45-48 66> 67). This nonequivalence is manifested in differences in the biological availability profile. 

Pharmaceutical Research and Manufacturers of America. Backgrounders and Facts Marketing and Promotion of Pharmaceuticals, Available at http //www.phrma.org/ publications/documents/backgrounders//2000-10-23.184. phtml (accessed January 8, 2001). 

Benzyl alcohol is a preservative that may be present in multidose vials of bacteriostatic sodium chloride and bacteriostatic water for injection and pharmaceuticals available in multidose vials for parenteral use. An association between the presence of benzyl alcohol in solutions used for flushing intravascular catheters and to reconstitute medications and a gasping syndrome and deaths in neonates was first reported in the early 1980s.The neonates also displayed clinical findings such as an elevated anion gap, metabolic acidosis, CNS depression, seizures, respiratory failure, renal and hepatic failures, cardiovascular collapse, and death. Those at highest risk were premature infants who weighted less... 

ICH Guidance M3 (Rl) (2000). Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals. Available at www.ich.org (accessed July 1 2007). 

Discovering new drugs has never been a simple matter. From ancient times to the beginning of the last century, treatment for illness or disease was based mainly on folklore and traditional curative methods derived from plants and other natural sources. The isolation and chemical characterization of the principal components of some of these traditional medicines, mainly alkaloids and the like, spawned the development of the modem pharmaceutical industry and the production of drugs in mass quantities. Within the last century, however, the changes the industry has undergone have been profound. As the companion chapters of this volume describe, the emphasis has changed from isolation of active constituents to creation of new, potent chemical entities. This evolution from folklore to science is responsible for the thousands of pharmaceuticals available worldwide at present (1). 

Examples in which increased "pharmaceutical availability" is important include glucocorticoids [such as dexamethasone (lO)or methyl-... 

European Medicines Agency. 2011. ICH guideline S6 (Rl)—PrecUnical safety evaluation of biotechnology—Derived pharmaceuticals. Available from http // www.ema.europa.eu/docs/en GB/document library/Scientific guide-line/2009/09/WC500002828.pdf. Accessed Jime 2011. 

Food and Drug Administration. 2010. ICH guidelines S9—Guidance for industry S9 non-clinical evaluation for anticancer pharmaceuticals. Available from http //www. fda.gov/downloads/Drugs/.../Guidances/ucm085389.pdf. Accessed November 10,2013 (ICH Topic S9 March 2010). 

International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human use (2000) S7A—Safety Pharmacological Studies for Human Pharmaceuticals. Available at http //www.ich.org/products/ guidelines/safety/article/safety-guidelines.html (accessed on October 16, 2015). 

The choice of a diluent may influence the absorption of an active substance, which was seen in the l%Os in Australia. The diluent of phenytoin sodium capsules was changed from calcium sulfate dihydrate to lactose, which strongly enhanced the bioavailabdity of phenytoin sodium. Plasma levels of phenytoin increased up to fourfold, which led to an increased reporting of adverse events [8,9]. This case drew worldwide attention and resulted in an increased awareness of the importance of pharmaceutical availability and bioavailability of active substances in the development of solid oral dosage forms. 

Reduced pharmaceutical availability colloidal silicon dioxide has a large surface area, which may facilitate adsorption to the active substance. This may reduce the pharmaceutical availability of the active substance. 

The most important incompatibility in capsules is the adsorption of active substances to excipients and vice versa. Sparingly water-soluble active substances may adsorb to non-water soluble excipients such as microcrystalline cellulose (diluent). On the other hand, the very fine glidant, colloidal anhydrous silica, can adsorb onto active substance particles. Especially for low dosed active substances, relatively large fractions may adsorb or be adsorbed. Such adsorption may delay the dissolution of the active substance, resulting in a delayed or incomplete release of the substance. This may lead to a reduced pharmaceutical availability and ultimately a lower therapeutic activity. Substances known to adsorb to microcrystalline cellulose are ethinylestradiol and dexamethasone [24]. 

Active substances that are dissolved in water are, if they remain in solution, immediately available for absorption after taking on an empty stomach. If they precipitate in the acidic environment of the empty stomach the precipitation will often be so fine that it easily passes the closed pylorus and re-dissolves, after which rapid absorption is still possible. The pharmaceutical availability (actually the dissolution rate of the solid substance) of suspensions for oral use depends on many factors including solubility in vivo, the crystal modification and the particle size and the viscosity of the suspension. In practice it occurs that an active substance (such as phenobarbital) may be formulated as a suspension in water or as a solution in a lipophilic solvent such as acetem (see Sect. 23.3.6). Beware that changing from a suspension into a solution may cause a great increase in absorption rate and thus cause a change in pharmacodynamics. 

Often, the active substance is released from its administration form in a dissolved state. If this is not the case, the active substance must first dissolve in aqueous environment after it has been released. Only in the dissolved state, can an active substance pass biological membranes separating the site of administration from the systemic circulation (the blood circulation) via which transport to the site of action occurs. The fraction of the administered active substance that dissolves in the aqueous fluid adjacent to the biological membranes and thereby becomes available for passing them is called the pharmaceutical availability. The fraction of the total amount of the administered active substance that ultimately reaches the systemic circulation in an unchanged form is called bioavailability. By definition, an intravenously injected medicine will have a bioavailability of 1.0 (or 100 %). When a medicine is administered via a different route, its bioavailability will be reduced, due to, for example, incomplete dissolution or losses during the transport of dissolved active substance to the systemic circulation. 

The bioavailability of an active substance is defined as the fraction of the active substance that reaches the systemic circulation intact. It equals the pharmaceutical availability in vivo, minus the loss of the active substance during the absorption into the systemic circulation, due to incomplete membrane passage or loss caused by metabolism of the active substance during the absorption process. 

Release of the active substance from the dosage form facilitated by disintegration or dissolution or both (= pharmaceutical availability)... 

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