Georgios Imanidis

Luminal Lipid Phases after Administration of a Triglyceride Solution of Danazol in the Fed State and Their Contribution to the Flux of Danazol Across Caco-2 Cell Monolayers

The first aim of this study was to characterize the luminal contents and their micellar phase after the administration of a heterogeneous liquid meal to healthy adults. The second aim was to evaluate the impact of micellar lipids and coarse lipid particles on danazol flux through intestinal monolayers. A third aim was to compare the micellar composition in the upper small intestine with the composition of fed state simulating intestinal fluid (FeSSIF-V2), a medium that has been proposed for investigating dissolution of poorly soluble drugs in the fed state. Danazol (150 mg), predissolved in the olive oil portion of the meal, was administered via the gastric port of a two-lumen tube to the antrum of eight adults. Aspirates from the ligament of Treitz [collected up to 4 h postdosing (~15 mL every 30 min)] were characterized physicochemically. Comparison of these characteristics with FeSSIF-V2 indicates that FeSSIF-V2 is an appropriate medium for evaluating drug solubilization in the luminal micellar phase in the fed state. Individual aspirates and their corresponding micellar phases were also diluted with aqueous transport medium and subjected to Caco-2 cell permeation experiments. Permeability coefficients for danazol in the diluted aspirates were smaller than those for the diluted micellar phases, which in turn were similar to those for aqueous transport medium. The high danazol concentrations overcompensated the reduced permeability coefficient values in the diluted aspirates in terms of total drug flux. We conclude that drug dissolved in the coarse lipid particles formed after administration of a triglyceride solution can directly contribute to the flux of lipophilic drugs across the intestinal mucosa.

Advancing in-vitro drug precipitation testing: new process monitoring tools and a kinetic nucleation and growth model

Objectivesu2002 Poorly soluble weak bases often precipitate during intestinal passage, potentially leading to incomplete drug absorption. The underlying in‐vivo and in‐vitro drug precipitation mechanisms are not well understood. Thus, new analytical tools and a kinetic nucleation and growth model were introduced to in‐vitro drug precipitation testing in biorelevant media.

Biorelevant media for transport experiments in the Caco-2 model to evaluate drug absorption in the fasted and the fed state and their usefulness.

In this work we developed and characterized transport media that simulate the composition of micellar phase of intestinal fluids in the fasted and, especially, in the fed state and are appropriate for evaluating intestinal drug permeability characteristics using the Caco-2 model (FaSSIF-TM(Caco) and FeSSIF-TM(Caco), respectively). Media composition was based on FaSSIF-V2 and FeSSIF-V2 and recently reported data on total lipid concentrations in the micellar phase of contents of the upper small intestine in the fasted and the fed state and was adapted for cell culture compatibility. Permeation data were evaluated by compartmental kinetic modeling. Permeability coefficients, P, of hydrophilic drugs were not affected by media composition. In contrast, P values of a series of lipophilic compounds measured with FaSSIF-TM(Caco) and FeSSIF-TM(Caco), and reflecting transport by diffusion were smaller than those obtained with a purely aqueous reference transport medium, aq-TM(Caco), following the rank order aq-TM(Caco)>FaSSIF-TM(Caco)>FeSSIF-TM(Caco). The decline of permeability values was stronger as lipophilicity of the compounds increased. Compared with values estimated using aq-TM(Caco), permeability was reduced, depending on the compound, by more than 20- to 100-fold when measured with FeSSIF-TM(Caco) whereas compound ranking in regard to the permeability characteristics was also affected. The impact of reduced P value on flux through the mucosa, hence on drug absorption, in combination with the drug amount loaded on colloidal particles needs to be taken into consideration in PBPK modeling especially when the food effect is evaluated.

Different modes of dynamic image analysis in monitoring of pharmaceutical dry milling process

This article focuses on the process analytical technology (PAT) of pharmaceutical dry milling. The first objective is to compare different modes of dynamic image analysis namely, on-line, in-line and at-line for monitoring powder milling. The second objective is to introduce time evolving size and shape analysis (TESSA). Thus, a conical mill was equipped with a dynamic image analysis system which consisted of a xenon flash light and charge-coupled device (CCD) camera. Different pharmaceutical excipients and granulates were chosen as models. The results from the on-line, in-line and the at-line measurement modes showed similar size distributions for the various materials studied, however differences were observed that were mainly attributed to sampling and dispersion. A high correlation of 0.975 (p<0.001) was observed between on-line d(50) and at-line d(50) when compared to 0.917 (p<0.001) between in-line d(50) and at-line d(50). The concept of TESSA was found to be useful in detecting changes in milling conditions including the successful detection of a damaged screen when intentionally introduced in the milling process. This monitoring approach of particle size and shape has potential to reduce product variability, facilitates process development, and ultimately helps in establishing quality by design concept for the manufacture of solid dosage forms.

Biopharmaceutical Modeling of Drug Supersaturation During Lipid-Based Formulation Digestion Considering an Absorption Sink

PurposeIn vitro lipolysis is widely utilized for predicting in vivo performance of oral lipid-based formulations (LBFs). However, evaluation of LBFs in the absence of an absorption sink may have limited in vivo relevance. This study aimed at employing biopharmaceutical modeling to simulate LBF digestion and drug supersaturation in a continuous absorptive environment.MethodsThree fenofibrate-loaded LBFs were characterized in vitro (dispersion and lipolysis) and drug precipitation was monitored using in-line Raman spectroscopy. In vitro data were combined with pharmacokinetic data derived from an in vivo study in pigs to simulate intestinal LBF transit. This biopharmaceutical model allowed calculation of lipolysis-triggered drug supersaturation while drug and lipolysis products are absorbed from the intestine.ResultsThe biopharmaceutical model predicted that, in a continuous absorption environment, fenofibrate supersaturation was considerably lower compared to in vitro lipolysis (non-sink). Hence, the extensive drug precipitation observed in vitro was predicted to be unlikely in vivo. The absorption of lipolysis products increased drug supersaturation, but drug precipitation was unlikely for highly permeable drugs.ConclusionsBiopharmaceutical modeling is a valuable approach for predicting LBFs performance in vivo. In the absence of in vitro tools simulating absorptive conditions, modeling strategies should be further considered.

A Systematic Dilution Study of Self-Microemulsifying Drug Delivery Systems in Artificial Intestinal Fluid Using Dynamic Laser Light Backscattering

Self-microemulsifying drug delivery systems provide a key technology to formulate poorly soluble drugs. The development of candidate formulations is commonly based on a screening of in vitro dilution characteristics. Because in vitro dilution is conducted in many different ways, the comparability of data is often limited and the involved factors are not properly understood. This article aims to systematically study the impact of formulation factors, temperature, dilution medium, and its amount in view of the phase behavior and particle size. Three types of self-microemulsifying delivery vehicles were formulated and diluted in artificial intestinal fluid and water. Different testing conditions were studied in the framework of statistical designs. The main response parameter was the colloidal particle size, which was measured using dynamic laser light backscattering. The tested formulations resulted in swollen micelles at a high dilution of 1:100 up to 1:1,000. At a lower dilution of 1:10, the particle size was increased depending on the system. Interactions of the dilution level with other parameters were found significant. Based on the obtained results, it seems reasonable to screen such systems first at a higher dilution in water at room temperature to facilitate experimentation. The selected systems may then, in a second step, be further studied at a different lower dilution in water or in artificial intestinal fluid at 37°C. We found that the Cremophor formulations were particularly robust with respect to producing constant small particles at different dilution levels. More research is needed to explore the biopharmaceutical relevance of these in vitro findings.

In Vitro and Ex Vivo Investigation of the Impact of Luminal Lipid Phases on Passive Permeability of Lipophilic Small Molecules Using PAMPA

ABSTRACTPurposeEvaluate the impact of luminal micellar phase on passive permeability of five lipophilic (1.9u2009≤u2009clogPu2009u2009≤u20099.0) small molecules using biorelevant media and evaluate the impact of luminal coarse lipid particles on danazol permeability after oral administration of a triglyceride solution to fed adults using PAMPA.MethodsPermeability of carbamazepine, furosemide, danazol, and Compound A was evaluated using Prisma™ HT, FaSSIF-V2, and FeSSIF-V2 in the donor compartment. Compound B could not be tested using Prisma™ HT, due to negligible solubility. Individual intestinal aspirates collected after administration of danazol solution in the olive oil portion of a meal and corresponding micellar phases were subjected to PAMPA. Commercially available Acceptor Sink Buffer was used in all cases.ResultsUnlike with furosemide (under constant pH) and Compound B, permeability of carbamazepine, danazol, and Compound A steadily decreased in the presence of increasing micelle concentration of media. Danazol permeability from aspirates was reduced compared to that from micellar phases; fluxes were similar.ConclusionsUsing PAMPA, the impact of luminal micellar phase on passive permeability of lipophilic molecules varies with the molecule. After administration of a triglyceride solution of danazol, high danazol concentrations in coarse lipid particles balance in terms of drug flux the reduced permeability.n FigureEstimating Papp using PAMPA, intestinal fluids, and simulated intestinal fluids

In vitro digestion kinetics of excipients for lipid-based drug delivery and introduction of a relative lipolysis half life.

Background: Lipid-based drug delivery systems are widely used for enhancing the solubility of poorly water soluble drugs in the gastro-intestinal tract. Following oral intake, lipid systems undergo digestion in the stomach as well as the intestine. Lipolysis is here a complex process at the oil/water interface, influenced by numerous factors. Purpose: To study the digestibility of nine excipients often used in lipid-based drug delivery systems. In addition, we introduced a mathematical model to describe in vitro lipolysis kinetics. A relative lipolysis half life was defined using the reference excipient medium-chain triglycerides. Methods: Using pH-stat equipment, the NaOH consumption was determined in an in vitro lipolysis assay. Results: We identified two classes of excipients. Some additives were partially hydrolysed, whereas other excipients displayed complete lipolysis. For the latter class, a simplified mathematical model provided a good first approximation of initial lipolysis kinetics. Conclusions: Digestion characterization of excipients is important for the development of lipid-based delivery systems. The applied kinetic model and the concept of a relative lipolysis half life seemed to be promising tools for comparing in vitro lipolysis results.

Chewability testing in the development of a chewable tablet for hyperphosphatemia

Abstract The official Pharmacopeia does not include a test procedure for the in vitro estimation of the chewability of tablets and publications in the scientific literature on this subject are rare. The purpose of this study was to evaluate a number of different test procedures for assessing chewability, starting from standard breaking force and strength testing and progressing to develop new procedures that simulate the actual chewing action on tablets. A further goal was to apply these test procedures to characterize the chewability of the novel phosphate binder PA21 in comparison with a commercially available phosphate binder chewable tablet product based on lanthanum (Fosrenol®) and a chewable tablet product containing calcium (Calcimagon®) – the latter being used as a standard for its very good chewability. For this purpose, a number of development formulations (different batches of PA21) were tested. The radial or diametrical tablet breaking force offers a poor means of assessing chewability while the axial breaking force was concluded to better reflect the effect of chewing on the tablet. Measurement of tablet behavior upon repeated loading afforded the best simulation of the actual chewing action and was found to have a good discriminating power with respect to chewability of the tested tablets, especially when the tablet was moistened with artificial saliva. The developed tests are shown to be more suitable for evaluating chewing properties of tablets than currently used Pharmacopeial tests. Following ICHQ6, which calls for specification of hardness for chewable tablets, these test procedures enabled the optimal chewability features of PA21 tablets in development to be confirmed whilst still maintaining capabilities for robust production and transportation processes.

In silico prediction of the solubility advantage for amorphous drugs – Are there property-based rules for drug discovery and early pharmaceutical development?

Oral delivery of poorly water-soluble compounds is often a substantial challenge. Once a drug candidate is selected, it is desirable to predict, based on chemical structure, which formulation technology has the highest potential to enhance drug solubility and absorption. Due to the importance of amorphous drug formulations, this work aimed at calculating the solubility ratio of amorphous and crystalline drug using in silico methods only. Molecular modeling together with multivariate methods was employed and a particular aim was to find simple structure-based rules for the technology selection of amorphous drug formulations. As a result, calculated estimates for reference compounds were generally higher than experimentally obtained amorphous solubility ratios; however, the rank order of the values revealed a significant correlation (p=0.036). Subsequently, a set of 56 neutral poorly water-soluble compounds resulted in a good partial least square model with R² of 0.803. Most important for the amorphous solubility ratio was molecular weight, number of hydrogen bond acceptors, melting point, number of torsional bonds and polar surface area. By considering the Lipinsky rules, we proposed suitable ranges of these molecular predictors with respect to selecting promising amorphous drug formulations. Such structure-based guidance can help in early formulation development of challenging drug candidates, thereby leading to substantial cost savings. However, there is certainly more experimental research needed to finally assess how broadly the presented concepts can be applied.