Dissolution-limited absorption

From Eq. (12), the dependence of Fa on both An and Do is apparent. The relationship suggests that a lower fraction of dose will be absorbed at a higher dose. However, for compounds with low solubility and/or high dose, the concentration in the intestinal lumen may not be the same as the solubility, owing to slow dissolution. Dissolution-limited absorption is discussed in Section III.B. 

Class II drugs, i.e., low-solubility/high-permeability compounds, are expected to have a dissolution-limited absorption. Thus, for these types of drugs an IVIVC... 

If not in an ER product, a drug is likely to exhibit dissolution-limited absorption if it is poorly soluble in the GI lumen. Usually, identification of a compound with dissolution-limited GI absorption is based on D S ratio (4) when D S is about < 250 mL over the pH range of 1-7.5, the compound is usually considered to have less than ideal lumenal dissolution characteristics (3,5), with 250 mL being a conservative estimate of the total volume of fluids that will be in contact with the dose in the upper GI tract under fasting conditions. However, this approach has several weaknesses ... 

Sometimes, absorption can be described by sequential zero-order and Lrst-order absorption processes. Conceptually, if the Lrst-order rate constant is linked to the zero-order input, the model can be postulated as the consequence of dissolution-limited absorption (Garrigues et al., 1991 Holford et al., 1992). 

This study indicates that dissolution-limited absorption is a prerequisite for rVrVC using dissolution, but one should also realize that modihcation of the biorelevant media, in terms of composition, but also dissolution conditions, might result in development of a model that does provide for an IVIVC. 

Sometimes, two first-order absorption processes do not adequately describe the data and the absorption profiles are better described by a combination of first-order and zero-order processes (40, 56-59). Lag time may be added for each type of absorption, which then will determine whether the two processes are simultaneous or sequential. Moreover, if the first-order rate constant is finked to the zero-order input parameters, the model can be interpreted as the consequence of dissolution-limited absorption. The ordering of the processes (first-order absorption first, or zero-order absorption first) is usually empirical or data driven. Pathophysiology and/or physicochemical characteristics of the compound may help in deciding the order. 

Nanosizing and amorphous formulation approaches were examined with some success, providing approximately five- and nine-fold enhancements in exposure in dogs, respectively, compared to the formulation used in the clinical capsule [57], These data, along with the data from solution dosing, provided evidence that addressing dissolution-limited absorption had the potential to improve plasma exposure of BMS-488043 (9) following oral administration. 

Several different niacin formulations are available niacin immediate-release (IR), niacin sustained-release (SR), and niacin extended-release (ER).28,29 These formulations differ in terms of dissolution and absorption rates, metabolism, efficacy, and side effects. Limitations of niacin IR and SR are flushing and hepatotoxicity, respectively. These differences appear related to the dissolution and absorption rates of niacin formulations and its subsequent metabolism. Niacin IR is available by prescription (Niacor ) as well as a dietary supplement which is not regulated by the FDA.28 Currently, there are no FDA-approved niacin SR products, thus, all SR products are available only as dietary supplements. 

The intrinsic dissolution rate is the rate of mass transfer from the solid phase to the liquid phase. Information on the intrinsic dissolution rate is important in early drug product development. It has been suggested that drugs with intrinsic dissolution rates of less than 0.1 mg/(min cm2) will have dissolution rate-limited absorption, while drugs with intrinsic dissolution rates greater than 0.1 mg/ (min cm2) are unlikely to have dissolution rate problems. 

A special case in dissolution-limited bioavailability occurs when the assumption of sink condition in vivo fails that is, the drug concentration in the intestine is dose to the saturation solubility. Class IV compounds, according to BCS, are most prone to this situation due to the combination of low solubility and low permeability, although the same could also happen for class II compounds, depending primarily on the ratio between dose and solubility. Non-sink conditions in vivo lead to less than proportional increases of bioavailability for increased doses. This is illustrated in Fig. 21.8, where the fraction of drug absorbed has been simulated by use of an compartmental absorption and intestinal transit model [35] for different doses and for different permeabilities of a low-solubility, aprotic compound. 

Hydrodynamics in the upper GI tract contribute to in vivo dissolution. Our ability to forecast dissolution of poorly soluble drugs in vitro depends on our knowledge of and ability to control hydrodynamics as well as other factors influencing dissolution. Provided suitable conditions (apparatus, hydrodynamics, media) are chosen for the dissolution test, it seems possible to predict dissolution limitations to the oral absorption of drugs and to reflect variations in hydrodynamic conditions in the upper GI tract. The fluid volume available for dissolution in the gut lumen, the contact time of the dissolved compound with the absorptive sites, and particle size have been identified as the main hydrodynamic determinants for the absorption of poorly soluble drugs in vivo. The influence of these factors is usually more pronounced than that of the motility pattern or the GI flow rates per se. 

The physiologically based model developed by Willman et al. [53, 54], for the prediction of both rat and human Fibs, was shown to be predictive for the human situation if passively transported compounds were studied. In their study, they used a semiempirical formula for the prediction of human permeability trained with a set of 119 passively transported drugs that did not show solubility or dissolution rate-limited absorption. 

In many cases in drug development, the solubility of some leads is extremely low. Fast dissolution rate of many drug delivery systems, for example, particle size reduction, may not be translated into good Gl absorption. The oral absorption of these molecules is usually limited by solubility (VWIImann et al., 2004). In the case of solubility limited absorption, creating supersaturation in the Gl Luids for this type of insoluble drugs is very critical as supersaturation may provide great improvement of oral absorption (Tanno et al., 2004 Shanker, 2005). The techniques to create the so-called supersaturation in the Gl Luids may include microemulsions, emulsions, liposomes, complexations, polymeric micelles, and conventional micelles, which can be found in some chapters in the book. 

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