A Novel Rheological Method to Assess Drug-Polymer Interactions Regarding Miscibility and Crystallization of Drug in Amorphous Solid Dispersions for Oral Drug Delivery.

Solid dispersions provide a key technology to formulate poorly water-soluble drugs, and a main task of early development is appropriate selection of polymer. This study investigates the use of a novel rheology-based approach to evaluate miscibility and interactions of drugs with polymers regarding amorphous solid drug dispersions for oral administration. Tacrolimus was used as model drug and hydroxypropyl cellulose, ethylcellulose, Soluplus, polyethyleneglycol 6000, Poloxamer-188 (Koliphor-188), and Eudragit S100 were used as excipients.

Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches - a PEARRL review.

Objectives: This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug.

Key Findings: Crystal lattice energy and the octanol-water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract.

Application of the solubility parameter concept to assist with oral delivery of poorly water-soluble drugs - a PEARRL review.

Objectives: Solubility parameters have been used for decades in various scientific fields including pharmaceutics. It is, however, still a field of active research both on a conceptual and experimental level. This work addresses the need to review solubility parameter applications in pharmaceutics of poorly water-soluble drugs.

Extrapolation of Valacyclovir Posology to Children Based on Pharmacokinetic Modeling.

Background: Valacyclovir is a prodrug of acyclovir. Although acyclovir is approved for children in Europe, valacyclovir is not approved, despite being used off-label. The aim of the study was to extrapolate the approved dosages of acyclovir, to valacyclovir dosages, in children using Monte Carlo simulations based on the population pharmacokinetic (PopPK) models of valacyclovir and acyclovir.

Extrapolation of enalapril efficacy from adults to children using pharmacokinetic/pharmacodynamic modelling.

Objectives: To extrapolate enalapril efficacy to children 0-6 years old, a pharmacokinetic/pharmacodynamic (PKPD) model was built using literature data, with blood pressure as the PD endpoint.

Methods: A PK model of enalapril was developed from literature paediatric data up to 16 years old. A PD model of enalapril was fitted to adult literature response vs time data with various doses.

Recent advances in oral pulsatile drug delivery.

Pulsatile drug delivery aims to release drugs on a programmed pattern i.e.: at appropriate time and/or at appropriate site of action.

In vitro methods can forecast the effects of intragastric residence on dosage form performance.

Intragastric conditions can affect the performance of solid dosage forms. For two cases, the ability of in vitro methods to forecast these effects was investigated: first, the ability of cholestyramine to sequester bile salts in the fed small intestine and, second, disintegration times of hard gelatin capsules. After incubating cholestyramine for 90 min in milk gradually digested with pepsin, the binding of taurocholates from fed state simulating intestinal fluid onto the resin became non-specific and the affinity constant was reduced from 220 l/mole (without prior incubation) to 60 l/mole.

Predictive models for oral drug absorption: from in silico methods to integrated dynamical models.

Poor oral absorption is one of the most common reasons for a drug to be terminated during development. Oral drug absorption is a complex process affected by many competing factors related to the compound, the formulation and the gastrointestinal physiology. Throughout drug development, in silico, computational and mathematical models play important roles in the support of drug development and decision making in absorption-related issues.

Estimation of intragastric solubility of drugs: in what medium?

Purpose: To measure the solubility of four drugs in human gastric aspirates, canine gastric aspirates (CGF) and simulated gastric fluids in order to propose a medium for estimating intragastric drug solubility relevant to a bioavailability study in the fasted state.

Materials And Methods: Intragastric environment after administration of water to healthy fasted adults and to healthy fasted dogs (this study) was initially characterized. Solubilities were then measured with the shake-flask method in gastric fluid aspirated after the administration of water to healthy fasted adults and to healthy fasted dogs, in various simulated gastric fluids, i.

Canine intestinal contents vs. simulated media for the assessment of solubility of two weak bases in the human small intestinal contents.

Purpose: This study was conducted to assess the relative usefulness of canine intestinal contents and simulated media in the prediction of solubility of two weak bases (dipyridamole and ketoconazole) in fasted and fed human intestinal aspirates that were collected under conditions simulating those in bioavailability/bioequivalence studies.

Methods: After administration of 250 mL of water or 500 mL of Ensure plus [both containing 10 mg/mL polyethylene glycol (PEG) 4000 as nonabsorbable marker], intestinal aspirates were collected from the fourth part of the duodenum of 12 healthy adults and from the mid-jejunum of four Labradors. Pooled samples were analyzed for PEG, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, bile salts, phospholipids, and neutral lipids.

Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies.

Purpose: This study was conducted to compare the luminal composition of the upper gastrointestinal tract in the fasted and fed states in humans, with a view toward designing in vitro studies to explain/predict food effects on dosage form performance.

Methods: Twenty healthy human subjects received 250 mL water or 500 mL Ensure plus (a complete nutrient drink) through a nasogastric tube and samples were aspirated from the gastric antrum or duodenum for a period up to 3.5 h, depending on location/fluid combination.

The delayed dissolution of paracetamol products in the canine fed stomach can be predicted in vitro but it does not affect the onset of plasma levels.

Although it is generally believed that paracetamol can be used as a marker of gastric emptying, there have been reports in the literature that show delayed dissolution of immediate release paracetamol tablets using standard in vitro setups and food-simulating media, delayed disintegration of paracetamol products in the fed stomach, and no correlation of paracetamol absorption with gastric emptying in the fed state. In this study, we confirmed that dissolution of Panodil and Apotel tablets is delayed in food-simulating media regardless of the in vitro hydrodynamics and on a formulation dependent manner. Further, we assessed the usefulness of in vitro dissolution data in the prediction of delayed disintegration time in the fed stomach and we examined the importance of delayed gastric disintegration on the onset of plasma levels using the canine model.