Physiological Parameters for Oral Delivery and in Vitro Testing

Abstract

Pharmaceutical solid oral dosage forms must undergo dissolution in the intestinal fluids of the gastrointestinal tract before they can be absorbed and reach the systemic circulation. Therefore, dissolution is a critical part of the drug-delivery process. The rate and extent of drug dissolution and absorption depend on the characteristics of the active ingredient as well as properties of the dosage form. Just as importantly, characteristics of the physiological environment such as buffer species, pH, bile salts, gastric emptying rate, intestinal motility, and hydrodynamics can significantly impact dissolution and absorption. While significant progress has been made since 1970 when the first compendial dissolution test was introduced (USP Apparatus 1), current dissolution testing does not take full advantage of the extensive physiologic information that is available. For quality control purposes, where the question is one of lot-to-lot consistency in performance, using nonphysiologic test conditions that match drug and dosage form properties with practical dissolution media and apparatus may be appropriate. However, where in vitro – in vivo correlations are desired, it is logical to consider and utilize knowledge of the in vivo condition. This publication critically reviews the literature that is relevant to oral human drug delivery. Physiologically relevant information must serve as a basis for the design of dissolution test methods and systems that are more representative of the human condition. As in vitro methods advance in their physiological relevance, better in vitro - in vivo correlations will be possible. This will, in turn, lead to in vitro systems that can be utilized to more effectively design dosage forms that have improved and more consistent oral bioperformance.

Drug release from matrix tablets: physiological parameters and the effect of food

“…Gastric fluid is a com-position of saliva, gastric secretions, dietary food and liquid and secretions from the liver [4]. The composition of the fluid in the upper small intestine, however, is made up of chime from the stomach, secretions from the liver, the pancreas and the wall of the small intestine.…”

“…This fluid composition is affected by fluid compartmentalisation, mixing patterns, permeation through the intestinal wall and the transit down the intestinal tract. Physiological characteristics such as pH, bile salts, gastric-emptying rates, buffer species, hydrodynamics, shear rates and intestinal motility can significantly impact dis-solution and absorption [4,13]. The methods for the aspiration of gastric or intestinal fluids and characterising them are vast and well documented in literature.…”

“…When a pH is such that a drug is in its ionic form, the drug behaves like a strong electrolyte and the drugs solubility becomes usually high as compared to its non-ionised form [4]. Drug products with pKa values especially in the physiological range thus have dissolution rates that are affected greatly by pH.…”

“…Echo-planar MRI was used in humans to monitor the changes in a viscous meals viscosity by Marciani et al [49] and they found significant reduction in the meals viscosity with time due to dilution by the gastric juice [49]. Viscosity is also affected by pH in addition to soluble meal content and concentration [4]. Test meals containing dietary fibres are administered that have viscosities ranging from 10 to > 10,000 cP [4,48,49] [4,50,51].…”

“…Drug dissolution and absorption rate are thus dependent on properties of the physiological environment and properties of the drug itself with parameters such as the dimension of the GI tract, volume and composition of fluid, the fluid hydrodynamics, properties of the intestinal membrane, drug dose and solubility, pKa, diffusion coefficient, permeability and particle size all playing a key role [4]. In an attempt to bridge the gap between the in vitro and in vivo dissolution and absorption, the Biopharmaceutics Classification System provides guidance for predicting in vivo performances of drug substances based on the drugs solubility, permeability and in-vitro results from testing [5].…”