Biopharmaceutical Classification System Class 2 compounds

Fig. 15.5. The biopharmaceutics classification system (BCS). Drug-like molecules are grouped into four BCS classes based on their solubility and permeability. A drug is regarded as a highly soluble compound if the maximum dose given orally is soluble in 250 mL fluid in the...

The example of amprenavir, an HIV-1 protease inhibitor, shows that intestinal metabolism can also be used as a strategy to enhance the bioavailability of compounds. In the biopharmaceutics classification system (BCS), amprenavir can be categorized as a class II compound it is poorly soluble but highly permeable [51]. Fosamprenavir, the water-soluble phosphate salt of amprenavir, on the other hand, shows poor transepithelial transport. However, after oral administration of fosamprenavir, this compound is metabolized into amprenavir in the intestinal lumen and in the enterocytes mainly by alkaline phosphatases, resulting in an increased intestinal absorption [51, 174],... 

The publication of the U.S. FDA Guidelines allowing the waiver of bioequivalence study for compounds classified as Class I based on the Biopharmaceutics Classification System... 

Following oral administration, dissolution of the drug molecule in the intestinal milieu is a prerequisite for the absorption process. According to the Biopharmaceutical Classification System (BCS) [2], poor water-soluble compounds (i.e., aqueous solubility less than 100 pg/ mL) are class 2 or class 4 compounds. For class 2 compounds, the absorption level is dictated by the dissolution properties of the molecule in the gastrointestinal (GI) fluids. BCS class 4 compounds, which are characterized by both low solubility and poor intestinal wall permeability, are generally poor drug candidates (unless the dose is very low). 

The Biopharmaceutics Classification System (BCS)3 defines four classes of compounds based upon solubility and permeability. Particle size and size distribution... 

With the advent of new biotechnological techniques endogenous compounds like insulin, buserelin or octreotide have become available at affordable prices. All of these substances still have to undergo needle application. Until today the development of alternative delivery systems for the nasal, buccal, peroral, rectal and pulmonary routes for the administration of those class III drugs according to the biopharmaceutics classification system (BCS) (Amidon et al. 1995) could not keep pace with this development of endogenous compounds or is not economic enough for the health care payers (e.g. insulin application via the pulmonary route). 

Figure 1. Biopharmaceutical Classification System and Development Classification System. Class I compounds are defined as soluble and permeable through the gastrointestinal tract, Class II as poorly soluble but permeable through the GI tract, Class III as soluble but poorly permeable and Class IV as both poorly soluble and permeable. The further classification of Class II and III (simple and complex) is intended to provide additional data on the develop-ability of the drug candidate.

The biopharmaceutical classification system (BCS) was first introduced in 1995 to facilitate the drug development, and it is based on two independent variables that influence bioavailability, viz., aqueous solubility and intestinal permeability (Amidon et al. 1995 FDA 2000). Compounds that belong to BCS class II or IV are of primary interests from a formulation perspective and, therefore, solubility enhancement using formulation intervention is the key driver for improving the bioavailability of poorly soluble drugs. From a conceptual perspective, the dissolution rate can be expressed by the following equation (Noyes and Whitney 1897) ... 

Solid dispersion is defined as one type of method to produce an amorphous compound by incorporating a hydrophobic drug into a hydrophilic carrier (Chiou and Riegelman 1971). It is one of the most studied methods to solubilize and to enhance dissolution rate of biopharmaceutical classification system (BCS) class 2 compounds. For instance, a solid dispersion of ritonavir (Law et al. 2001), ER-3421 (a dual 5-lipoxygenase/cyclooxygenase inhibitor Kushida et al. 2002), was found to have a much higher dissolution rate than the crystalline counterpart and resulted in higher area under curve (AUC) and Cmax in the in vivo study. 

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