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Solid Dispersions for Bioavailability Enhancement

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (20 December 2023) | Viewed by 12614

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Special Issue Editor

Dr. Matthias Manne Knopp

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Guest Editor

Department of Pharmacy, Bioneer A/S, 2100 Copenhagen, Denmark
Interests: amorphous solid dispersions; bioavailability enhancement; enabling formulations; biorelevant in vitro models; in vitro–in vivo correlation; PK prediction

Special Issue Information

Dear Colleagues,

I am pleased to invite you to contribute to this Special Issue intended to highlight new advances in solid dispersions for bioavailability enhancement. Solid dispersions (SDs) have gained considerable attention in recent years as one of the most promising approaches to enhance the bioavailability of poorly soluble drugs. SDs can be prepared using various techniques, such as spray-drying and hot melt extrusion, by dispersing a poorly soluble drug in a polymeric matrix, which prevents drug crystallization and enhances both the solubility and the dissolution rate.

This Special Issue aims to provide a comprehensive overview of the recent advances in the field of SDs for bioavailability enhancement covering the development, characterization, and evaluation of SDs, as well as their applications in drug delivery. The collection of articles will hopefully contribute to advancements in the field, and ultimately, the development of more effective and safe medicines for patients.

The Special Issue serves as a platform for researchers to present their latest findings and insights in this rapidly growing field and welcomes original research articles and reviews that cover various aspects of SDs for bioavailability enhancement including (but not limited to) the following:

Development and optimization of SDs using various techniques;
Physical and chemical characterization of SDs;
Evaluation of the in vitro and in vivo performance of SDs;
Mechanistic understanding of the behavior of SDs;
Regulatory considerations and challenges in the development of SDs.

I look forward to receiving your contributions.

Dr. Matthias Manne Knopp
Guest Editor

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Keywords

solid dispersions
bioavailability enhancement
solubility enhancement
supersaturation
amorphous
drug–polymer interactions
physical stability
in vivo pharmacokinetics

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Published Papers (5 papers)

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Research

11 pages, 1269 KiB

Open AccessArticle

Effect of Drug Loading in Mesoporous Silica on Amorphous Stability and Performance

by Christoffer G. Bavnhøj, Matthias M. Knopp and Korbinian Löbmann

Pharmaceutics 2024, 16(2), 163; https://doi.org/10.3390/pharmaceutics16020163 - 24 Jan 2024

Cited by 5 | Viewed by 1528

Abstract

The encapsulation of drugs within mesoporous silica (MS) has for several years been a subject of research. Previous studies proposed that drug loadings up to the monomolecular loading capacity (MLC) are the optimal choice for maintaining the drug in an amorphous form, whereas filling the pores above the monolayer and up to the pore filling capacity (PFC) may introduce some physical instabilities. The aim of this study was to assess the effect of drug loading in MS-based amorphous formulations on the stability of the amorphous form of the drug as well as the dissolution. In particular, the following drug loadings were investigated: below MLC, at MLC, between MLC and PFC and at PFC. The drug-loaded MS formulations were analyzed directly after preparation and after 18 months of storage under accelerated conditions (40 °C in both dry and humid conditions). The MLC and PFC for the drug celecoxib (CEL) on the MS ParteckSLC500 (SLC) were determined at 33.5 wt.% and 48.4 wt.%, respectively. This study found that SLC can effectively preserve the amorphous form of the drug for 18 months, provided that the loading is below the PFC (<48.4 wt.%) and no humidity is present. On the other hand, drug loading at the PFC showed recrystallization even when stored under dry conditions. Under humid conditions, however, all samples, regardless of drug loading, showed recrystallization upon storage. In terms of dissolution, all freshly prepared formulations showed supersaturation. For drug loadings below PFC, a degree of supersaturation (DS) around 15 was measured before precipitation was observed. For drug loadings at PFC, the DS was found to be lower and only 6-times compared to the crystalline solubility. Lastly, for those samples that remained amorphous during storage for 18 months, the release profiles were found to be the same as the freshly loaded samples, with similar C_max, T_max and dissolution rate. Full article

(This article belongs to the Special Issue Solid Dispersions for Bioavailability Enhancement)

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15 pages, 4901 KiB

Open AccessArticle

Evaluation of a Three-Fluid Nozzle Spraying Process for Facilitating Spray Drying of Hydrophilic Polymers for the Creation of Amorphous Solid Dispersions

by Lena Karin Mueller, Laura Halstenberg, Nicole Di Gallo and Thomas Kipping

Pharmaceutics 2023, 15(11), 2542; https://doi.org/10.3390/pharmaceutics15112542 - 27 Oct 2023

Cited by 5 | Viewed by 2690

Abstract

Amorphous solid dispersions (ASDs) enable formulations to improve the solubility of poorly soluble active pharmaceutical ingredients (APIs). The amorphous state is reached through the disruption of the crystalline lattice of an API resulting in an increased apparent solubility with faster disintegration. Nevertheless, this form is characterized by a high-energy state which is prone to re-crystallization. To ensure a stable ASD, excipients, e.g., polymers that form a matrix in which an API is dispersed, are used. The applicable polymer range is usually linked to their solubility in the respective solvent, therefore limiting the use of hydrophilic polymers. In this work, we show the applicability of the hydrophilic polymer, polyvinyl alcohol (PVA), in spray-dried solid dispersions. Using a three-fluid nozzle approach, this polymer can be used to generate ASDs with a targeted dissolution profile that is characterized by a prominent spring and desired parachute effect showing both supersaturation and crystallization inhibition. For this purpose, the polymer was tested in formulations containing the weakly basic drug, ketoconazole, and the acidic drug, indomethacin, both classified as Biopharmaceutics Classification System (BSC) class II drugs, as well as the weakly basic drug ritonavir classified as BCS IV. Furthermore, ritonavir was used to show the enhanced drug-loading capacity of PVA derived from the advantageous viscosity profile that makes the polymer an interesting candidate for spray drying applications. Full article

(This article belongs to the Special Issue Solid Dispersions for Bioavailability Enhancement)

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14 pages, 4220 KiB

Open AccessArticle

Optimization and Production of Aceclofenac-Loaded Microfiber Solid Dispersion by Centrifugal Spinning

by Enikő Bitay, Attila Levente Gergely and Zoltán-István Szabó

Pharmaceutics 2023, 15(9), 2256; https://doi.org/10.3390/pharmaceutics15092256 - 31 Aug 2023

Cited by 6 | Viewed by 1716

Abstract

Aceclofenac-loaded polyvinylpyrrolidone fiber-based amorphous solid dispersion was produced successfully by centrifugal spinning. The solution concentration and rotational speed were optimized to produce the fiber-based drug carrier system, with a determined production rate of 12.7 g/h dry solid fibers. The obtained fibers were bead-free and smooth-surfaced with an average diameter of 7.5 ± 2.5 μm. Gas chromatographic determinations revealed that ethanol, as a residual solvent, was well below the regulatory limit of 0.5%. Differential scanning calorimetric investigation and infrared spectroscopic measurements were used to track the physicochemical changes that intervene during fiber formation in the solid state. The results revealed that the rapid evaporation of the solvent was accompanied by a probable crystalline to amorphous transition of the active substance during centrifugal spinning. In vitro dissolution studies revealed an instantaneous disintegration of the fibrous structure and a rapid release of the active substance, with the microfibrous webs greatly outperforming the crystalline active substance, especially in the early time-points. This implies that centrifugal spinning offers a viable scale-up production process to prepare drug-loaded fiber-based solid dispersions. Full article

(This article belongs to the Special Issue Solid Dispersions for Bioavailability Enhancement)

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19 pages, 5750 KiB

Open AccessArticle

Factors That Influence Sustained Release from Hot-Melt Extrudates

by Yaser Mansuroglu and Jennifer Dressman

Pharmaceutics 2023, 15(7), 1996; https://doi.org/10.3390/pharmaceutics15071996 - 20 Jul 2023

Cited by 4 | Viewed by 2782

Abstract

Hot-melt extrusion is a well-established tool in the pharmaceutical industry, mostly implemented to increase the solubility of poorly soluble drugs. A less frequent application of this technique is to obtain formulations with extended release. This study investigated the influence of polymer choice, drug loading, milling and hydrodynamics on the release of a model drug, flurbiprofen, from sustained-release hot-melt extrudates with Eudragit polymers. The choice of polymer and degree of particle size reduction of the extrudate by milling were the two key influences on the release profile: the percentage release after 12 h varied from 6% (2 mm threads) to 84% (particle size <125 µm) for Eudragit RL extrudates vs. 4.5 to 62% for the corresponding Eudragit RS extrudates. By contrast, the release profile was largely independent of drug loading and robust to hydrodynamics in the dissolution vessel. Thus, hot-melt extrusion offers the ability to tailor the release of the API to the therapeutic indication through a combination of particle size and polymer choice while providing robustness over a wide range of hydrodynamic conditions. Full article

(This article belongs to the Special Issue Solid Dispersions for Bioavailability Enhancement)

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17 pages, 3935 KiB

Open AccessArticle

Influence of Polyvinylpyrrolidone Molecular Weight and Concentration on the Precipitation Inhibition of Supersaturated Solutions of Poorly Soluble Drugs

by Afnan Bany Odeh, Boushra El-Sayed, Matthias Manne Knopp, Thomas Rades and Lasse Ingerslev Blaabjerg

Pharmaceutics 2023, 15(6), 1601; https://doi.org/10.3390/pharmaceutics15061601 - 26 May 2023

Cited by 7 | Viewed by 3198

Abstract

Supersaturating drug delivery systems such as solid dispersions of a drug in a polymer are frequently used in pharmaceutical development to enable oral delivery of poorly soluble drugs. In this study, the influence of the concentration and molecular weight of polyvinylpyrrolidone (PVP) on the precipitation inhibition of the poorly soluble drugs albendazole, ketoconazole and tadalafil is investigated to expand the understanding of the mechanism of PVP as a polymeric precipitation inhibitor. A three-level full-factorial design was used to delineate the influence of polymer concentration and viscosity of the dissolution medium on precipitation inhibition. Solutions of PVP K15, K30, K60 or K120 at concentrations of 0.1, 0.5 and 1% (w/v), as well as isoviscous solutions of PVP of increasing molecular weight, were prepared. Supersaturation of the three model drugs was induced by the use of a solvent-shift method. Precipitation of the three model drugs from supersaturated solutions in the absence and presence of polymer was investigated by the use of a solvent-shift method. Time–concentration profiles of the respective drugs in the absence and presence of polymer pre-dissolved in the dissolution medium were obtained by the use of a μDISS Profiler™ to determine the onset of nucleation and the precipitation rate. Multiple linear regression was used to evaluate the hypothesis that precipitation inhibition is influenced by the PVP concentration (i.e., the number of repeat units of the polymer) and the medium viscosity of the polymer for the three model drugs. This study showed that an increased concentration of PVP (i.e., an increased concentration of the PVP repeat units, independent of the molecular weight of the polymer) in solution increased the onset of nucleation and decreased the precipitation rate of the respective drugs during supersaturation, which can be explained by an increase in molecular interactions between the drug and polymer with increasing concentrations of polymer. In contrast, the medium viscosity had no significant influence on the onset of the nucleation and precipitation rate of the drugs, which can be explained by solution viscosity having a negligible effect on the rate of drug diffusion from bulk solution to the crystal nuclei. In conclusion, the precipitation inhibition of the respective drugs is influenced by the concentration of PVP, i.e., by molecular interactions between the drug and polymer. In contrast, the molecular mobility of the drug in solution, i.e., the medium viscosity, has no influence on the precipitation inhibition of the drugs. Full article

(This article belongs to the Special Issue Solid Dispersions for Bioavailability Enhancement)

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