| 1. |
- Boyd, Ben J., et al.
(författare)
-
Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems
- 2019
-
Ingår i: European Journal of Pharmaceutical Sciences. - : ELSEVIER. - 0928-0987 .- 1879-0720. ; 137
-
Tidskriftsartikel (refereegranskat)abstract
- Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds.
|
|
| 2. |
- Adler, Camille, et al.
(författare)
-
Flow-through cross-polarized imaging as a new tool to overcome the analytical sensitivity challenges of a low-dose crystalline compound in a lipid matrix
- 2015
-
Ingår i: Journal of Pharmaceutical and Biomedical Analysis. - : Elsevier BV. - 0731-7085 .- 1873-264X. ; 115, s. 20-30
-
Tidskriftsartikel (refereegranskat)abstract
- Assessing the physical state of a low-dose active compound in a solid lipid or polymer matrix is analytically challenging, especially if the matrix exhibits some crystallinity. The aim of this study was first to compare the ability of current methods to detect the presence of a crystalline model compound in lipid matrices. Subsequently, a new technique was introduced and evaluated because of sensitivity issues that were encountered with current methods. The new technique is a flow-through version of cross-polarized imaging in transmission mode. The tested lipid-based solid dispersions (SDs) consisted of beta-carotene (BC) as a model compound, and of Gelucire 50/13 or Geleol mono- and diglycerides as lipid matrices. The solid dispersions were analyzed by (hyper) differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and microscopic techniques including atomic force microscopy (AFM). DSC and XRPD could analyze crystalline BC at concentrations as low as 3% (w/w) in the formulations. However, with microscopic techniques crystalline particles were detected at significantly lower concentrations of even 0.5% (w/w) BC. A flow-through cross-polarized imaging technique was introduced that combines the advantage of analyzing a larger sample size with high sensitivity of microscopy. Crystals were detected easily in samples containing even less than 0.2% (w/w) BC. Moreover, the new tool enabled approximation of the kinetic BC solubility in the crystalline lipid matrices. As a conclusion, the flow-through cross-polarized imaging technique has the potential to become an indispensable tool for characterizing low-dose crystalline compounds in a lipid or polymer matrix of solid dispersions. (C) 2015 Elsevier B.V. All rights reserved.
|
|
| 3. |
- Adler, Camille, et al.
(författare)
-
Molecularly designed lipid microdomains for solid dispersions using a polymer/inorganic carrier matrix produced by hot-melt extrusion
- 2016
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 499:1-2, s. 90-100
-
Tidskriftsartikel (refereegranskat)abstract
- Amorphous solid dispersions have for many years been a focus in oral formulations, especially in combination with a hot-melt extrusion process. The present work targets a novel approach with a system based on a fatty acid, a polymer and an inorganic carrier. It was intended to adsorb the acidic lipid by specific molecular interactions onto the solid carrier to design disorder in the alkyl chains of the lipid. Such designed lipid microdomains (DLM) were created as a new microstructure to accommodate a compound in a solid dispersion. Vibrational spectroscopy, X-ray powder diffraction, atomic force microscopy as well as electron microscopic imaging were employed to study a system of stearic acid, hydroxypropylcellulose and aluminum magnesium silicate. beta-carotene was used as a poorly water-soluble model substance that is difficult to formulate with conventional solid dispersion formulations. The results indicated that the targeted molecular excipient interactions indeed led to DLMs for specific compositions. The different methods provided complementary aspects and important insights into the created microstructure. The novel delivery system appeared to be especially promising for the formulation of oral compounds that exhibit both high crystal energy and lipophilicity. (C) 2015 Elsevier B.V. All rights reserved.
|
|
| 4. |
- Adler, Camille, et al.
(författare)
-
Multifractal and mechanical analysis of amorphous solid dispersions
- 2017
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 523:1, s. 91-101
-
Tidskriftsartikel (refereegranskat)abstract
- The formulation of lipophilic and hydrophobic compounds is a challenge for the pharmaceutical industry and it requires the development of complex formulations. Our first aim was to investigate hot-melt extrudate microstructures by means of multifractal analysis using scanning electron microscopy imaging. Since the microstructure can affect solid dosage form performance such as mechanical properties, a second objective was to study the influence of the type of adsorbent and of the presence of an amorphous compound on extrudate hardness. β-Carotene (BC) was chosen as poorly water-soluble model compound. Formulations containing a polymer, a lipid and two different silica based inorganic carriers were produced by hot-melt extrusion. Based on scanning electron microscopy/energy dispersive X-ray spectroscopy, the obtained images were analyzed using multifractal formalism. The breaking force of the strands was assessed by a three point bending test. Multifractal analysis and three point bending results showed that the nature of interparticle interactions in the inorganic carrier as well as the presence of amorphous BC had an influence on the microstructure and thus on the mechanical performance. The use of multifractal analysis and the study of the mechanical properties were complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.
|
|
| 5. |
- Adler, Camille, et al.
(författare)
-
Multifractal Characterization of Pharmaceutical Hot-Melt Extrudates.
- 2017
-
Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 34:2, s. 321-332
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Multifractal geometry has become a powerful tool to describe complex structures in many fields. Our first aim was to combine imaging and multifractal analysis to better understand the microstructure of pharmaceutical extrudates. A second objective was to study erosion/dispersion behavior of the formulations because it would condition release of any drug.METHODS: Different formulations containing a lipid, a polymer and different silica based inorganic carriers were produced by hot-melt extrusion at various screw speeds. Multifractal analysis was based on scanning electron microscopy/energy dispersive X-Ray spectroscopy images. This microstructural analysis was complemented with dynamic optical imaging of formulation erosion/dispersion behavior.RESULTS: Multifractal analysis indicated that inorganic carrier type and concentration as well as the screw speed affected the microstructure of the extrudates. The aqueous erosion/dispersion study showed that only the type and concentration of inorganic carrier were important.CONCLUSIONS: The use of microstructural and dispersion analysis appeared to be complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.
|
|
| 6. |
- Gautschi, Nicolas, et al.
(författare)
-
Rapid determination of drug solubilization versus supersaturation in natural and digested lipids
- 2016
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier BV. - 0378-5173 .- 1873-3476. ; 513:1-2, s. 164-174
-
Tidskriftsartikel (refereegranskat)abstract
- Lipid-based formulations (LBFs) represent one of the successful formulation approaches that enable oral delivery of poorly water-soluble drugs. This work presents a simple equilibrium approach based on solubility in lipids and their corresponding digestion media to estimate a maximum drug supersaturation ratio (SRmax). This value of drug concentration normalized by the solubility in the aqueous digestion phase indicates the propensity for drug precipitation. A set of 16 structurally diverse drugs was first measured for their solubility in tricaprin and tricaprylin and results were compared to an empirical model based on molecular predictors. In the next step, digestion media were either prepared by in vitro lipolysis or by assembling a composition to mimic the endpoint of digestion. It was found that drug solubility in the pure lipids mainly was related to the melting point in that increased values resulted in reduced solubility. The solubility values measured in the lipolysis media correlated well with those obtained from assembled digestion media. Interestingly, the solubilization upon digestion was typically higher when using tricaprin than tricaprylin in spite of that the latter oil (as pure excipient) generally was a more potent solvent. This work suggests that a simplified digestion screen can be used to facilitate evaluation of formulations during early development. Estimation of SRmax provides an early risk assessment of drug precipitation for LBFs. The method is easily scaled down to the microtiter plate format and can be used for selecting candidate formulations that merit further evaluation in more complex and dynamic in vitro tests.
|
|
| 7. |
- Kuentz, Martin, et al.
(författare)
-
Synergistic Computational Modeling Approaches as Team Players in the Game of Solubility Predictions
- 2021
-
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier. - 0022-3549 .- 1520-6017. ; 110:1, s. 22-34
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Several approaches to predict and model drug solubility have been used in the drug discovery and development processes during the last decades. Each of these approaches have their own benefits and place, and are typically used as standalone approaches rather than in concert. The synergistic effects of these are often overlooked, partly due to the need of computational experts to perform the modeling and simulations as well as analyzing the data obtained. Here we provide our views on how these different approaches can be used to retrieve more information on drug solubility, ranging from multivariate data analysis over thermodynamic cycle modeling to molecular dynamics simulations. We are discussing aqueous solubility as well as solubility in more complex mixed solvents and media with colloidal structures present. We conclude that the field of computational pharmaceutics is in its early days but with a bright future ahead. However, education of computational formulators with broad knowledge of modeling and simulation approaches is imperative if computational pharmaceutics is to reach its full potential.
|
|
| 8. |
- Vinarov, Zahari, et al.
(författare)
-
Current challenges and future perspectives in oral absorption research : An opinion of the UNGAP network
- 2021
-
Ingår i: Advanced Drug Delivery Reviews. - : Elsevier. - 0169-409X .- 1872-8294. ; 171, s. 289-331
-
Forskningsöversikt (refereegranskat)abstract
- Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
|
|
