Absorption different formulations

Polystyrene One of the high volume plastics, is relatively low in cost, easy to process, has sparkling clarity, and low water absorption. But basic form (crystal PS) is brittle, with low heat and chemical resistance, poor weather resistance. High impact polystyrene is made with butadiene modifiers provides significant improvements in impact strength and elongation over crystal polystyrene, accompanied by a loss of transparency and little other property improvement. PS is used in many different formulations. 

Different formulation principles, dosage forms, and DDSs are commonly evaluated in animal models, and attempts are made to predict human absorption on the basis of such studies.80 Human studies are also conducted in some cases to confirm predictions from animal models. Chiou et a 1.81,82 demonstrated that there is a highly significant correlation of absorption (r2 = 0.97) between humans and rats with a slope near unity. In comparison, the correlation of absorption between dog and human was poor (r2 = 0.512) as compared to that between rat and human (r2 = 0.97). Therefore, although dog has been commonly employed as an animal model for studying oral absorption in drug discovery and development, one may need to exercise caution in the interpretation of data obtained. 

Increasing the concentration increases the penetration, but not to the same degree. Solubility of the corticosteroid in the vehicle is an other determinant of absorption and efficacy. So different formulations of the same corticosteroid can end up in a different efficacy classification. Efficacy can be further augmented by using the corticosteroid under occlusion. Occlusion with plastic enhances penetration and also absorption. However, with increased absorption also the risk of systemic side-effects increases. Systemic absorption will suppress the pituitary-adrenal axis and may cause Cushing s syndrome and a plethora of other adverse events (see Chapter 24, Section Il.b). Even small amounts absorbed may already cause growth retardation in children. 

Two differential spectrophotometric methods were used by Chatterjee et al. for the simultaneous analysis of diloxanide furoate and metronidazole in pharmaceutical formulations [24]. The first method involved measurement of the absorbance of a methanolic solution of the two drugs at 259 and 311 nm. Since the absorbance of diloxanide furoate at 311 nm is zero, the concentration of metronidazole is directly measured, and a simple equation based on absorbance ratios is used to calculate the concentration of diloxanide furoate. The second method was a differential spectrophotometric determination based on pH-induced spectral changes, on changing from an acidic to an alkaline solution. A marked bathochromic shift was exhibited by metronidazole, while diloxanide furoate showed a slight hypsochromic shift. The wavelength of maximum absorption difference for diloxanide furoate was 267 nm, where metronidazole did not absorb. Similarly, diloxanide furoate did not interfere with metronidazole at when measured at 322 nm. 

Pharmacokinetics Absorption differs between formulations. Protein binding 50%-80%. Bound to serum albumin. Metabolized to salicylate glucuronides and salicyluric acid. Excreted in urine. 

Insulin has a half-life of only a few minutes when injected intravenously. It is therefore prepared in different formulations for subcutaneous injection, with different half-lives of absorption, giving different durations of action. The main formulations, with their approximate durations of action are given in Table 2. 

Another technique is to monitor drug or toxicant excretion rather than blood concentrations, especially when blood or plasma concentrations are very low. Using the same equations, the AUC is now replaced by chemical concentrations in urine, feces, and expired air. Some chemicals are primarily excreted by the kidney and urine data alone may be necessary. The rate and extent of absorption are clearly important for therapeutic and toxicological considerations. For example, different formulations of the same pesticide can change the absorption rate in skin or gastrointestinal tract, and not bioavailability, but can result in blood concentrations near the toxic dose. Also different formulations can result in similar absorption rates but different bioavailability. 

Blood concentration-time curves, illustrating how changes in the rate of absorption and extent of bioavailability can influence both the duration of action and the effectiveness of the same total dose of a drug administered in three different formulations. The dashed line indicates the target concentration (TC) of the drug in the blood. 

Schwarb, F., B. Gabard, G. lost, Th. Rufli, and C. Surber, Percutaneous absorption of salicylic acid in man following topical administration of different formulations. Dermatology, 1997, 195 129. 

The utility of this approach is shown in Figure 1.1 (b), in which the oral bioavailability of a drag from three different formulations is assessed by comparing their respective Cp vs T curves. Formulations A and B have similar AUCs, indicating that the drag is absorbed to a similar extent from both formulations however, formulation A has a faster rate of absorption, indicating that this formulation shows a rapid onset of therapeutic action. Formulation B has a slower onset of therapeutic action, but the therapeutic effect is sustained longer than that obtained with formulation A. Formulation C demonstrates both a slow rate and extent of absorption, in comparison to the other two formulations. 

Disposition in the Body. Slowly but almost completely absorbed after oral administration the rate of absorption is variable, being prolonged after large doses, and the bioavailability may vary considerably between different formulations. Aromatic hydroxylation is the major metabolic pathway and about 50 to 70% of a dose may be excreted as free or conjugated 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) in 24 hours the excretion of this metabolite is dose-dependent and decreases as the dose is increased. Phenytoin hydroxylation is capacity-limited, and is therefore readily inhibited by agents which compete for its metabolic pathways. Less than 5% of a dose is excreted as unchanged drug. Minor metabolites include 5-(3-hydroxyphenyl)-5-phenylhydantoin, 3,4-dihydro-3,4-dihydroxy-phenytoin, catechol, and 3-D-methylcatechol. Up to about 15% of a dose may be eliminated in the faeces. 

Volhner, U. Muller, B.W. Mesens, J. Willfert, B. Peters, T. In vitro skin pharmacokinetics of liarozole percutaneous absorption studies with different formulations of cylcodex-trin derivatives in rats. Int. J. Pharm. 1993, 99, 51-58. 

Factors affecting drug absorption include formulation, disease state, food effect, and drug-drug interaction. Formulations used for oral administration include solutions, suspensions, capsules, and uncoated and coated tablets. Depending on the formulation of a drug, the absorption characteristics may differ substantially. 

Nitrates can be administered by various routes. For example, glyceryl trinitrate is used not only as traditional sublingual tablets but also in the form of modified-release tablets, buccal tablets, aerosolized oral spray, intravenous injection, and topical ointment or skin patches for percutaneous absorption (23). These different formulations have been developed largely as a means of controlling the onset and duration of action of glyceryl trinitrate, since in conventional oral form its action is limited by marked hepatic first-pass metabolism. 

Antacids Indometacin ( other NSAIDs) Variable effects of different formulations aluminium-containing antacids reduce the rate and extent of absorption of indometacin sodium bicarbonate increases the rate and extent of absorption of indometacin No action required, unless a marked reduction in absorption results in a poor response to the NSAID, in which case dosages may need to be increased or the antacid withdrawn... 

The absorption of lithium by the gut has not been widely studied. The pharmacokinetic mechanisms have clinical significance, however, because of the use of differing formulations and treatment regimes, each with its own apparent advantage. Early studies indicated a passive mode of absorption (163). Two types of study have recently ex-... 

Finally, no laboratory test can mimic the complexity of the biological environment and the dynamic factors involved in dmg absorption in patients, but well-designed in vitro experiments can elucidate whether different formulations are comparable in terms of their key feamres. At best, in vitro tests are predictors of quality of performance in the patient at the least they can ensure consistency of response where, for example, chemical assays of dmg content in generic products may give identical results, release studies may show differences due to dmg-excipient interactions which may be of significance. 

A colorimetric method for microdetermination of sulfonamides based on diazotization of the drug with sodium nitrite and hydrochloric acid has been reported (59). The diazonium salt is then coupled with 8-hydroxyquinoline in alkaline medium and the absorbance of the developed color measured at its maximum wavelength. A similar method involves diazotization and coupling of the sulfonamide with indole in alkaline solution to form an intense yellow azo dye which exhibits maximum absorption at 449 nm. Beer s law is obeyed over the concentration range 1-32 /ig/ml with a relative standard deviation of less than 2% (60). The reaction of sulfonamides with chloramine-T in sulfuric acid gives a yellow product which is suitable for the determination of sulfonamides in different formulations. It has an accuracy similar to that of the Bratton and Marshall method (61). 

This approach is robust because it does not rely on any pharmacokinetic assumptions and allows the characterization of absorption processes among different drugs if IV data are available. For example, differences in the absorption profiles between fluticasone propionate and budesonide can easily be identified with this method, while differences in fmax were not able to readily provide this information. The mean residence time without availability of intravenous data should not be used to compare absorption profiles of different drug entities, because it is also determined by the systemic elimination of the drug. This approach is, however, suitable for evaluating the differences of different formulations of the same drug. 

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