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Pharmaceutics
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Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs
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Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (1 April 2023) | Viewed by 46007

Special Issue Editor

Dr. Rodolfo Pinal

E-Mail Website
Guest Editor
Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN 47906, USA
Interests: solubility; solubilization; amorphous; cocrystals; extrusion; polymers; excipients; films
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bioavailability is crucial for the successful development of pharmaceutical products, be it a novel drug or a new formulation of an existing drug. The interplay between drug solubility/solubilization and bioavailability is particularly interesting and relevant from both scientific and commercial standpoints, respectively. Bioavailability is the result of interweaving underlying physical and physiological phenomena. Accordingly, progress toward enhancing the bioavailability of poorly soluble drugs entails a multi-disciplinary approach, involving, among other things, physical characterization of solids, solution chemistry, pharmaceutical excipients, pharmaceutical processing, drug transporters and absorption enhancers. With the advent of patient-centric formulations, it is more important than ever to gather published sources detailing the latest advances toward a fundamental understanding of the bioavailability–solubility relationship from the various perspectives of sub-disciplines involved in this important pharmaceutical subject. This Special Issue of Pharmaceutics is brought to you with that aim.

Dr. Rodolfo Pinal
Guest Editor

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Keywords

  • absorption enhancers
  • additive manufacturing
  • amorphous
  • co-crystals
  • co-processed excipients
  • extrusion
  • lipid formulations
  • lipid nanoparticles
  • pharmaceutical material science
  • particle engineering
  • patient-centric
  • polymers
  • polymorphs
  • self-emulsifying delivery systems
  • solid dispersions
  • solubility
  • solubilization
  • spray-drying
  • supersaturation
  • transporters

Published Papers (19 papers)

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20 pages, 6140 KiB  
Article
Versatile Solid Modifications of Multicomponent Pharmaceutical Salts: Novel Metformin–Rhein Salts Based on Advantage Complementary Strategy Design
by Mingchao Yu, Meidai Liang, Qi An, Wenwen Wang, Baoxi Zhang, Shiying Yang, Jian Zhou, Xiuying Yang, Dezhi Yang, Li Zhang, Guanhua Du and Yang Lu
Pharmaceutics 2023, 15(4), 1196; https://doi.org/10.3390/pharmaceutics15041196 - 09 Apr 2023
Cited by 5 | Viewed by 1442
Abstract
This study aimed to develop an effective treatment for diabetes and diabetic complications, based on the advantage complementary strategy of drug–drug salt, by designing and synthesizing the multicomponent molecular salts containing metformin (MET) and rhein (RHE). Finally, the salts of MET–RHE (1:1), MET–RHE–H [...] Read more.
This study aimed to develop an effective treatment for diabetes and diabetic complications, based on the advantage complementary strategy of drug–drug salt, by designing and synthesizing the multicomponent molecular salts containing metformin (MET) and rhein (RHE). Finally, the salts of MET–RHE (1:1), MET–RHE–H2O (1:1:1), MET–RHE–ethanol–H2O (1:1:1:1), and MET–RHE–acetonitrile (2:2:1) were obtained, indicating the polymorphism of salts formed by MET and RHE. The structures were analyzed by the combination of characterization experiments and theoretical calculation, and the formation mechanism of polymorphism was discussed. The obtained results of in vitro evaluation showed that MET–RHE had a similar hygroscopicity with metformin hydrochloride (MET·HCl), and the solubility of the component of RHE increased by approximately 93 times, which laid a foundation for improving the bioavailability of MET and RHE in vivo. The evaluation of hypoglycemic activity in mice (C57BL/6N) indicated that MET–RHE exhibited better hypoglycemic activity than the parent drugs and the physical mixtures of MET and RHE. The above findings demonstrate that this study achieved the complementary advantages of MET and RHE through the multicomponent pharmaceutical salification technique, and provides new possibilities for the treatment of diabetic complications. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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15 pages, 1384 KiB  
Article
Preparation of Apixaban Solid Dispersion for the Enhancement of Apixaban Solubility and Permeability
by Juseung Lee, Jong-Ju Lee, Seungyeol Lee, Linh Dinh, Hangyu Oh, Sharif Md Abuzar, Jun-Hyun Ahn and Sung-Joo Hwang
Pharmaceutics 2023, 15(3), 907; https://doi.org/10.3390/pharmaceutics15030907 - 10 Mar 2023
Cited by 3 | Viewed by 2488
Abstract
(1) Background: Solid dispersion (SD) can help increase the bioavailability of poorly water-soluble drugs. Meanwhile, apixaban (APX)—a new anticoagulation drug—has low water solubility (0.028 mg/mL) and low intestinal permeability (0.9 × 10−6 cm/s across Caco-2 colonic cells), thus resulting in a low [...] Read more.
(1) Background: Solid dispersion (SD) can help increase the bioavailability of poorly water-soluble drugs. Meanwhile, apixaban (APX)—a new anticoagulation drug—has low water solubility (0.028 mg/mL) and low intestinal permeability (0.9 × 10−6 cm/s across Caco-2 colonic cells), thus resulting in a low oral bioavailability of <50%; (2) Methods: To solve the drawbacks of conventional APX products, a novel SD of APX in Soluplus® was prepared, characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR) spectroscopy techniques and evaluated for its solubility, intestinal permeability and pharmacokinetic performance. (3) Results: The crystallinity of the prepared APX SD was confirmed. The saturation solubility and apparent permeability coefficient increased 5.9 and 2.54 times compared to that of raw APX, respectively. After oral administration to the rats, the bioavailability of APX SD was improved by 2.31-fold compared to that of APX suspension (4) Conclusions: The present study introduced a new APX SD that potentially exhibits better solubility and permeability, thus increasing APX’s bioavailability. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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16 pages, 4218 KiB  
Article
Multi-Compartmental Dissolution Method, an Efficient Tool for the Development of Enhanced Bioavailability Formulations Containing Poorly Soluble Acidic Drugs
by Miklós Tamás Katona, Lili Nagy-Katona, Réka Szabó, Enikő Borbás, Péter Tonka-Nagy and Krisztina Takács-Novák
Pharmaceutics 2023, 15(3), 753; https://doi.org/10.3390/pharmaceutics15030753 - 24 Feb 2023
Cited by 1 | Viewed by 2092
Abstract
The purpose of this study was to investigate the applicability of the Gastrointestinal Simulator (GIS), a multi-compartmental dissolution model, to predict the in vivo performance of Biopharmaceutics Classification System (BCS) Class IIa compounds. As the bioavailability enhancement of poorly soluble drugs requires a [...] Read more.
The purpose of this study was to investigate the applicability of the Gastrointestinal Simulator (GIS), a multi-compartmental dissolution model, to predict the in vivo performance of Biopharmaceutics Classification System (BCS) Class IIa compounds. As the bioavailability enhancement of poorly soluble drugs requires a thorough understanding of the desired formulation, the appropriate in vitro modelling of the absorption mechanism is essential. Four immediate release ibuprofen 200 mg formulations were tested in the GIS using fasted biorelevant media. In addition to the free acid form, ibuprofen was present as sodium and lysine salts in tablets and as a solution in soft-gelatin capsules. In the case of rapid-dissolving formulations, the dissolution results indicated supersaturation in the gastric compartment, which affected the resulting concentrations in the duodenum and the jejunum as well. In addition, a Level A in vitro–in vivo correlation (IVIVC) model was established using published in vivo data, and then the plasma concentration profiles of each formulation were simulated. The predicted pharmacokinetic parameters were consistent with the statistical output of the published clinical study. In conclusion, the GIS method was found to be superior compared to the traditional USP method. In the future, the method can be useful for formulation technologists to find the optimal technique to enhance the bioavailability of poorly soluble acidic drugs. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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16 pages, 2580 KiB  
Article
Physicochemical Properties and Transdermal Absorption of a Flurbiprofen and Lidocaine Complex in the Non-Crystalline Form
by Qihui Xu, Takayuki Furuishi, Kaori Fukuzawa and Etsuo Yonemochi
Pharmaceutics 2023, 15(2), 318; https://doi.org/10.3390/pharmaceutics15020318 - 18 Jan 2023
Cited by 4 | Viewed by 2007
Abstract
Amorphous drug formulations exploiting drug–drug interactions have been extensively studied. This study aims to develop a transdermal system containing an amorphous complex of the nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen (FLU) and lidocaine (LDC) for alleviating chronic pain. The high-viscosity complex between FLU and [...] Read more.
Amorphous drug formulations exploiting drug–drug interactions have been extensively studied. This study aims to develop a transdermal system containing an amorphous complex of the nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen (FLU) and lidocaine (LDC) for alleviating chronic pain. The high-viscosity complex between FLU and LDC (Complex) was obtained by heating in ethanol. For the complex, attenuated total reflection-Fourier transform infrared spectroscopy showed a shift in the carboxy-group-derived peak of FLU, and differential scanning calorimetry indicated the endothermic peaks associated with the melting of FLU and LDC disappeared. 13C dipolar decoupling and 15N cross-polarization magic-angle spinning nuclear magnetic resonance measurement suggested the interaction between the carboxyl group of FLU and the secondary amine of LDC. The interaction between the aromatic rings of FLU and LDC contributed to the molecular complex formation. The solubility of FLU from the complex was about 100 times greater than FLU alone. The skin permeation flux of FLU from the complex through the hairless mouse skin was 3.8 times higher than FLU alone in hypromellose gel. Thus, adding LDC to the formulation can be an effective method for enhancing the skin permeation of NSAIDs, which can prove useful for treating chronic pain and inflammatory diseases. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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18 pages, 3602 KiB  
Article
Optimizing the Preparation of Silk Fibroin Nanoparticles and Their Loading with Polyphenols: Towards a More Efficient Anti-Inflammatory Effect on Macrophages
by Antonio José Ruiz-Alcaraz, María Ángeles Núñez-Sánchez, María Alejandra Asensio Ruiz, María Antonia Martínez-Sánchez, Alba Oliva-Bolarín, Teresa Martínez Martínez, José Julián Pérez Cuadrado, Bruno Ramos-Molina and Antonio Abel Lozano-Pérez
Pharmaceutics 2023, 15(1), 263; https://doi.org/10.3390/pharmaceutics15010263 - 12 Jan 2023
Cited by 3 | Viewed by 2096
Abstract
Silk fibroin nanoparticles (SFN) have become a promising tool in drug delivery systems due to their physicochemical characteristics. SFN have shown their outstanding properties as an active vehicle for polyphenols, enhancing their antioxidant and anti-inflammatory effects on macrophages; therefore, it becomes necessary to [...] Read more.
Silk fibroin nanoparticles (SFN) have become a promising tool in drug delivery systems due to their physicochemical characteristics. SFN have shown their outstanding properties as an active vehicle for polyphenols, enhancing their antioxidant and anti-inflammatory effects on macrophages; therefore, it becomes necessary to have an easy, reproducible and scalable production method. In order to improve the production of nanoparticles, we performed direct precipitation of non-dialyzed silk fibroin solutions and evaluated the reproducibility of the method using dynamic light scattering. We also studied the loading efficiency of three different natural polyphenols using propylene glycol as a solvent. The loaded nanoparticles were fully characterized and used to treat human macrophage cells to assess the anti-inflammatory activity of these nanoparticles. The measured hydrodynamic characteristics of the SFN and the overall yield of the process showed that the new preparation method is highly reproducible and repeatable. Thus, we not only present a new scalable method to prepare silk nanoparticles but also how to improve the loading of natural polyphenolic compounds to the SFN, as well as the important anti-inflammatory effects of these loaded nanoparticles in a cell model of human macrophage cells. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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14 pages, 2970 KiB  
Article
Lactone Stabilized by Crosslinked Cyclodextrin Metal-Organic Frameworks to Improve Local Bioavailability of Topotecan in Lung Cancer
by Ting Xiong, Tao Guo, Yaping He, Zeying Cao, Huipeng Xu, Wenting Wu, Li Wu, Weifeng Zhu and Jiwen Zhang
Pharmaceutics 2023, 15(1), 142; https://doi.org/10.3390/pharmaceutics15010142 - 31 Dec 2022
Cited by 3 | Viewed by 1507
Abstract
The protection of unstable anticancer molecules and their delivery to lesions are challenging issues in cancer treatment. Topotecan (TPT), a classic cytotoxic drug, is widely used for treating refractory lung cancer. However, the therapeutic effects of TPT are jeopardized by its active lactone [...] Read more.
The protection of unstable anticancer molecules and their delivery to lesions are challenging issues in cancer treatment. Topotecan (TPT), a classic cytotoxic drug, is widely used for treating refractory lung cancer. However, the therapeutic effects of TPT are jeopardized by its active lactone form that is intrinsically hydrolyzed in physiological fluids, resulting in low bioavailability. Herein, the TPT-loaded crosslinked cyclodextrin metal-organic framework (TPT@CL-MOF) was engineered to improve the local bioavailability of TPT for the treatment of lung cancer. CL-MOF exhibited the efficient loading (12.3 wt%) of TPT with sustained release characteristics. In particular the formulation offered excellent protection in vitro against hydrolysis and increased the half-life of TPT from approximately 0.93 h to 22.05 h, which can be attributed to the host–guest interaction between cyclodextrin and TPT, as confirmed by molecular docking. The TPT@CL-MOF could effectively kill the cancer cells and inhibit the migration and invasion of B16F10 cells in vitro. Moreover, TPT@CL-MOF was efficiently distributed in the lungs after intravenous administration. In an in vivo study using a B16F10 pulmonary metastatic tumor model, TPT@CL-MOF significantly reduced the number and size of metastatic lung nodules at a reduced low dose by five times, and no noticeable side effects were observed. Therefore, this study provides a possible alternative therapy for the treatment of lung cancer with the camptothecin family drugs or other unstable therapeutically significant molecules. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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19 pages, 4247 KiB  
Article
Solubility Characteristics of Acetaminophen and Phenacetin in Binary Mixtures of Aqueous Organic Solvents: Experimental and Deep Machine Learning Screening of Green Dissolution Media
by Piotr Cysewski, Tomasz Jeliński, Maciej Przybyłek, Wiktor Nowak and Michał Olczak
Pharmaceutics 2022, 14(12), 2828; https://doi.org/10.3390/pharmaceutics14122828 - 16 Dec 2022
Cited by 7 | Viewed by 2338
Abstract
The solubility of active pharmaceutical ingredients is a mandatory physicochemical characteristic in pharmaceutical practice. However, the number of potential solvents and their mixtures prevents direct measurements of all possible combinations for finding environmentally friendly, operational and cost-effective solubilizers. That is why support from [...] Read more.
The solubility of active pharmaceutical ingredients is a mandatory physicochemical characteristic in pharmaceutical practice. However, the number of potential solvents and their mixtures prevents direct measurements of all possible combinations for finding environmentally friendly, operational and cost-effective solubilizers. That is why support from theoretical screening seems to be valuable. Here, a collection of acetaminophen and phenacetin solubility data in neat and binary solvent mixtures was used for the development of a nonlinear deep machine learning model using new intuitive molecular descriptors derived from COSMO-RS computations. The literature dataset was augmented with results of new measurements in aqueous binary mixtures of 4-formylmorpholine, DMSO and DMF. The solubility values back-computed with the developed ensemble of neural networks are in perfect agreement with the experimental data, which enables the extensive screening of many combinations of solvents not studied experimentally within the applicability domain of the trained model. The final predictions were presented not only in the form of the set of optimal hyperparameters but also in a more intuitive way by the set of parameters of the Jouyban–Acree equation often used in the co-solvency domain. This new and effective approach is easily extendible to other systems, enabling the fast and reliable selection of candidates for new solvents and directing the experimental solubility screening of active pharmaceutical ingredients. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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20 pages, 1731 KiB  
Article
Assessing the Solubility of Baricitinib and Drug Uptake in Different Tissues Using Absorption and Fluorescence Spectroscopies
by Roya Mohammadi-Meyabadi, Negar Beirampour, Núria Garrós, Helen Lissette Alvarado, David Limón, Marcelle Silva-Abreu, Ana Cristina Calpena and Mireia Mallandrich
Pharmaceutics 2022, 14(12), 2714; https://doi.org/10.3390/pharmaceutics14122714 - 04 Dec 2022
Cited by 5 | Viewed by 5292
Abstract
The low water solubility of baricitinib (BCT) limits the development of new formulations for the topical delivery of the drug. The aims of this study were to assess the solubility of BCT in different solvents, including Transcutol, a biocompatible permeation enhancer that is [...] Read more.
The low water solubility of baricitinib (BCT) limits the development of new formulations for the topical delivery of the drug. The aims of this study were to assess the solubility of BCT in different solvents, including Transcutol, a biocompatible permeation enhancer that is miscible in water, to evaluate the drug uptake in human skin and porcine tissues (sclera, cornea, oral, sublingual, and vaginal), and to subsequently extract the drug from the tissues so as to determine the drug recovery using in vitro techniques. Analytical methods were developed and validated for the quantification of BCT in Transcutol using absorption and fluorescence spectroscopies, which are complementary to each other and permit the detection of the drug across a broad range of concentrations. Results show that Transcutol permits an increased drug solubility, and that BCT is able to penetrate the tissues studied. The solutions of BCT in Transcutol were stable for at least one week. Hence, Transcutol may be a suitable solvent for further development of topical formulations. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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16 pages, 3055 KiB  
Article
SEDEX—Self-Emulsifying Delivery Via Hot Melt Extrusion: A Continuous Pilot-Scale Feasibility Study
by Ožbej Zupančič, Aygün Doğan, Josip Matić, Varun Kushwah, Carolina Alva, Martin Spoerk and Amrit Paudel
Pharmaceutics 2022, 14(12), 2617; https://doi.org/10.3390/pharmaceutics14122617 - 27 Nov 2022
Cited by 1 | Viewed by 1813
Abstract
The aim of this study was to develop a continuous pilot-scale solidification and characterization of self-emulsifying drug delivery systems (SEDDSs) via hot melt extrusion (HME) using Soluplus® and Kollidon® VA-64. First, an oil-binding capacity study was performed to estimate the maximal [...] Read more.
The aim of this study was to develop a continuous pilot-scale solidification and characterization of self-emulsifying drug delivery systems (SEDDSs) via hot melt extrusion (HME) using Soluplus® and Kollidon® VA-64. First, an oil-binding capacity study was performed to estimate the maximal amount of SEDDSs that the polymers could bind. Then, HME was conducted using a Coperion 18 mm ZSK18 pilot plant-scale extruder with split-feeding of polymer and SEDDS in 10, 20, and 30% w/w SEDDSs was conducted. The prepared extrudates were characterized depending on appearance, differential scanning calorimetry, wide-angle X-ray scattering, emulsification time, droplet size, polydispersity index, and cloud point. The oil-binding studies showed that the polymers were able to bind up to 50% w/w of liquid SEDDSs. The polymers were processed via HME in a temperature range between 110 and 160 °C, where a plasticizing effect of the SEDDSs was observed. The extrudates were found to be stable in the amorphous state and self-emulsified in demineralized water at 37 °C with mean droplet sizes between 50 and 300 nm. A cloud point and phase inversion were evident in the Soluplus® samples. In conclusion, processing SEDDSs with HME could be considered a promising alternative to the established solidification techniques as well as classic amorphous solid dispersions for drug delivery. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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15 pages, 4915 KiB  
Article
Formulation Characterization and Pharmacokinetic Evaluation of Amorphous Solid Dispersions of Dasatinib
by Sathish Dharani, Eman M. Mohamed, Tahir Khuroo, Ziyaur Rahman and Mansoor A. Khan
Pharmaceutics 2022, 14(11), 2450; https://doi.org/10.3390/pharmaceutics14112450 - 13 Nov 2022
Cited by 5 | Viewed by 1615
Abstract
The aim of this study was to improve the physicochemical properties and oral bioavailability of dasatinib (DST) by the amorphous solid dispersion (ASD) approach using cellulose acetate butyrate (CAB) as a carrier. Various formulations of ASD (DST:CAB 1:1 to 1:5) were prepared by [...] Read more.
The aim of this study was to improve the physicochemical properties and oral bioavailability of dasatinib (DST) by the amorphous solid dispersion (ASD) approach using cellulose acetate butyrate (CAB) as a carrier. Various formulations of ASD (DST:CAB 1:1 to 1:5) were prepared by the solvent evaporation method. ASDs were characterized for physicochemical attributes, stability and pharmacokinetics. Scanning electron microscopy, Fourier transformed infrared, X-ray powder diffraction, and differential scanning calorimetry confirmed the transformation of the crystalline drug into amorphous phase. ASD formation resulted in a 3.7–4.9 fold increase in dissolution compared to DST or physical mixture. The ASDs formulation exhibited relative stability against transformation from the unstable amorphous phase to a stable crystalline phase that was indicated by spectral and X-ray powder diffraction data, and insignificant (p > 0.05) decrease in dissolution. Tmax, Cmax and AUC0-∞ of ASD were 4.3-fold faster and 2.0 and 1.5 fold higher than the corresponding physical mixture. In conclusion, the ASD of DST significantly improved dissolution and oral bioavailability which may be translated into a reduction in dose and adverse events. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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13 pages, 3647 KiB  
Article
Lipid/Clay-Based Solid Dispersion Formulation for Improving the Oral Bioavailability of Curcumin
by Jae Geun Song, Hye-Mi Noh, Sang Hoon Lee and Hyo-Kyung Han
Pharmaceutics 2022, 14(11), 2269; https://doi.org/10.3390/pharmaceutics14112269 - 24 Oct 2022
Cited by 6 | Viewed by 1593
Abstract
This study was conducted to develop a lipid/clay-based solid dispersion (LSD) formulation to enhance the dissolution and oral bioavailability of poorly soluble curcumin. Krill oil and aminoclay were used as a lipid and a stabilizer, respectively, and LSD formulations of curcumin were prepared [...] Read more.
This study was conducted to develop a lipid/clay-based solid dispersion (LSD) formulation to enhance the dissolution and oral bioavailability of poorly soluble curcumin. Krill oil and aminoclay were used as a lipid and a stabilizer, respectively, and LSD formulations of curcumin were prepared by an antisolvent precipitation method combined with freeze-drying process. Based on the dissolution profiles, the optimal composition of LSD was determined at the weight ratio of curcumin: krill oil: aminoclay of 1:5:5 in the presence of 0.5% of D-α-tocopherol polyethylene glycol succinate. The structural and morphological characteristics of the LSD formulation were determined using X-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy. Crystalline curcumin was changed to an amorphous form in the LSD formulation. At the pH of acidic to neutral, the LSD formulation showed almost complete drug dissolution (>90%) within 1 h, while pure curcumin exhibited minimal dissolution of less than 10%. Furthermore, the LSD formulation had significantly improved oral absorption of curcumin in rats, where Cmax and AUC of curcumin were 13- and 23-fold higher for the LSD formulation than for the pure drug. Taken together, these findings suggest that the krill oil-based solid dispersion formulation of curcumin effectively improves the dissolution and oral bioavailability of curcumin. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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21 pages, 5692 KiB  
Article
High-Shear Wet Granulation of SMEDDS Based on Mesoporous Carriers for Improved Carvedilol Solubility
by Mila Kovačević, Ilija German Ilić, Katarina Bolko Seljak and Alenka Zvonar Pobirk
Pharmaceutics 2022, 14(10), 2077; https://doi.org/10.3390/pharmaceutics14102077 - 29 Sep 2022
Cited by 4 | Viewed by 2068
Abstract
Mesoporous carriers are a convenient choice for the solidification of self-microemulsifying drug delivery systems (SMEDDS) designed to improve the solubility of poorly water-soluble drugs. They are known for high liquid load capacity and the ability to maintain characteristics of dry, free-flowing powders. Therefore, [...] Read more.
Mesoporous carriers are a convenient choice for the solidification of self-microemulsifying drug delivery systems (SMEDDS) designed to improve the solubility of poorly water-soluble drugs. They are known for high liquid load capacity and the ability to maintain characteristics of dry, free-flowing powders. Therefore, five different mesoporous carriers were used for the preparation of carvedilol-loaded SMEDDS granules by wet granulation methods—in paten (manually) and using a high-shear (HS) granulator. Granules with the highest SMEDDS content (63% and 66% of total granules mass, respectively) and suitable flow properties were obtained by Syloid® 244FP and Neusilin® US2. SMEDDS loaded granules produced by HS granulation showed superior flow characteristics compared to those obtained manually. All SMEDDS granules exhibited fast in vitro release, with 93% of carvedilol releasing from Syloid® 244FP-based granules in 5 min. Upon compaction into self-microemulsifying tablets, suitable tablet hardness and very fast disintegration time were achieved, thus producing orodispersible tablets. The compaction slightly slowed down the carvedilol release rate; nevertheless, upon 1 h (at pH 1.2) or 4 h (at pH 6.8) of in vitro dissolution testing, the amount of released drug was comparable with granules, confirming the suitability of orodispersible tablets for the production of the SMEDDS loaded single unit oral dosage form. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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18 pages, 23918 KiB  
Article
SmartFilm Tablets for Improved Oral Delivery of Poorly Soluble Drugs
by Ayat Abdelkader, Eduard Preis and Cornelia M. Keck
Pharmaceutics 2022, 14(9), 1918; https://doi.org/10.3390/pharmaceutics14091918 - 10 Sep 2022
Cited by 4 | Viewed by 2012
Abstract
(1) Background: Numerous oral drugs exhibit limited bioavailability due to their poor solubility and poor intestinal permeability. The smartFilm technology is an innovative approach that improves the drug aqueous solubility via incorporating the drug in an amorphous state into a cellulose-based matrix, i.e., [...] Read more.
(1) Background: Numerous oral drugs exhibit limited bioavailability due to their poor solubility and poor intestinal permeability. The smartFilm technology is an innovative approach that improves the drug aqueous solubility via incorporating the drug in an amorphous state into a cellulose-based matrix, i.e., paper. smartFilms can be transformed into a free-flowing physical form (i.e., paper granules) that can be compressed into tablets with optimum physico-chemical and pharmaceutical properties. The aim of this study was to investigate if smartFilm tablets are suitable for improved oral delivery of poorly water-soluble drugs. (2) Methods: Curcumin is a poorly soluble drug with low intestinal permeability and was used for the production of curcumin-loaded smartFilms. The curcumin-loaded smartFilms were transferred into smartFilm granules which were then compressed into curcumin-loaded smartFilm tablets. The tablets were characterized regarding their physico-chemical and pharmaceutical properties, and the intestinal permeability of curcumin was determined with the ex vivo porcine intestinal model. The ex vivo intestinal permeability of curcumin from the smartFilm tablets was compared to a physical mixture of curcumin and paper and to a classical and to an innovative commercial product, respectively. (3) Results: The produced curcumin-loaded smartFilm tablets fulfilled the European Pharmacopoeia requirements, incorporated curcumin in amorphous state within the cellulose matrix and exhibited an enhanced dissolution rate. The ex vivo intestinal permeation data were shown to correlate to the in vitro dissolution data. The ex vivo intestinal permeation of curcumin from the smartFilm tablets was about two-fold higher when compared to the physical mixture and the classical commercial product. No differences in the ex vivo bioavailability were found between the smartFilm tablets and the innovative commercial product. (4) Conclusions: smartFilm tablets are a cost-effective and industrially feasible formulation approach for the formulation of poorly water-soluble drugs, i.e., BCS class II and IV drugs. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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12 pages, 2619 KiB  
Article
Preparation and Characterization of Pazopanib Hydrochloride-Loaded Four-Component Self-Nanoemulsifying Drug Delivery Systems Preconcentrate for Enhanced Solubility and Dissolution
by Seung Ah Choi, Eun Ji Park, Jun Hak Lee, Kyoung Ah Min, Sung Tae Kim, Dong-Jin Jang, Han-Joo Maeng, Sung Giu Jin and Kwan Hyung Cho
Pharmaceutics 2022, 14(9), 1875; https://doi.org/10.3390/pharmaceutics14091875 - 05 Sep 2022
Cited by 9 | Viewed by 2200
Abstract
The aim of this study was to develop a four-component self-nanoemulsifying drug delivery system (FCS) to enhance the solubility and dissolution of pazopanib hydrochloride (PZH). In the solubility test, PZH showed a highly pH-dependent solubility (pH 1.2 > water >> pH 4.0 and [...] Read more.
The aim of this study was to develop a four-component self-nanoemulsifying drug delivery system (FCS) to enhance the solubility and dissolution of pazopanib hydrochloride (PZH). In the solubility test, PZH showed a highly pH-dependent solubility (pH 1.2 > water >> pH 4.0 and pH 6.8) and was solubilized at 70 °C in the order Kollisolv PG (5.38%, w/w) > Kolliphor RH40 (0.49%) > Capmul MCM C10 (0.21%) and Capmul MCM C8 (0.19%), selected as the solubilizer, the surfactant, and the oils, respectively. In the characterization of the three-component SNEDDS (TCS) containing Kolliphor RH40/Capmul MCM C10, the particle size of dispersion was very small (<50 nm) and the PZH loading was 0.5% at the weight ratio of 9/1. In the characterization of FCS containing additional Kollisolv PG to TCS, PZH loading was increased to 5.30% without any PZH precipitation, which was 10-fold higher compared to the TCS. The optimized FCS prepared with the selected formulation (Kolliphor RH40/Capmul MCM C10/Kollisolv PG) showed a consistently complete and high dissolution rate (>95% at 120 min) at four different pHs with 1% polysorbate 80, whereas the raw PZH and Kollisolv PG solution showed a pH-dependent poor dissolution rate (about 40% at 120 min), specifically at pH 6.8 with 1% polysorbate 80. In conclusion, PZH-loaded FCS in this work demonstrated enhanced solubility and a consistent dissolution rate regardless of medium pH. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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16 pages, 2644 KiB  
Article
Prostatic Therapeutic Efficacy of LENILUTS®, a Novel Formulation with Multi-Active Principles
by Erik Tedesco, Federico Benetti, Simone Castelli and Andrea Fratter
Pharmaceutics 2022, 14(9), 1866; https://doi.org/10.3390/pharmaceutics14091866 - 05 Sep 2022
Viewed by 1730
Abstract
Lower Urinary Tract Symptoms (LUTs) in men are usually associated to benign prostatic hyperplasia (BPH), a non-malignant prostate enlargement. Unfortunately, BPH etiology is still unclear. Recent works highlighted a relevant inflammation role in BPH onset and development. Consequently, to complement the 5-α reductase [...] Read more.
Lower Urinary Tract Symptoms (LUTs) in men are usually associated to benign prostatic hyperplasia (BPH), a non-malignant prostate enlargement. Unfortunately, BPH etiology is still unclear. Recent works highlighted a relevant inflammation role in BPH onset and development. Consequently, to complement the 5-α reductase (and α-adrenergic receptor agonists-based therapy, an anti-inflammatory therapy should be devised. To reduce potential adverse effects of multi-drug treatment, plant extract-based therapies are becoming increasingly common. Serenoa repens, the main phytotherapic treatment for BPH, is not sufficient to front the multi-faceted etiology of BPH. In response to this, a novel, multiple phytotherapic agents-based formulation, LENILUTS®, was developed. In the present work, we compared, using an in vitro approach, the prostatic safety and efficacy of LENILUTS® with a commercial formulation, based only on Serenoa repens, and a 5αR inhibitor, Dutasteride. Furthermore, preliminary in vitro experiments to investigate the active principles, bioaccessibility and bioavailability of LENILUTS® were performed. Our results showed a better prostatic safety and therapeutic efficacy of LENILUTS® compared to the commercial formulation and Dutasteride, with increased anti-inflammatory, and pro-apoptotic activity, and a stronger inhibitory effect on the release of the key enzyme 5αR and Prostatic-Specific Antigen (PSA). The limited bioaccessibility and bioavailability of the active principles of LENILUTS® were highlighted. Considering the results obtained, the LENILUTS® formulation is more promising for BPH and LUTs therapy compared to formulations based on Serenoa repens only, but further efforts should be made to improve the bioaccessibility and bioavailability of the active principles. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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21 pages, 8932 KiB  
Article
Modifying the Stability and Surface Characteristic of Anthocyanin Compounds Incorporated in the Nanoliposome by Chitosan Biopolymer
by Mina Homayoonfal, Mohammad Mousavi, Hossein Kiani, Gholamreza Askari, Stephane Desobry and Elmira Arab-Tehrany
Pharmaceutics 2022, 14(8), 1622; https://doi.org/10.3390/pharmaceutics14081622 - 03 Aug 2022
Cited by 5 | Viewed by 1622
Abstract
In this study, a novel approach was investigated to improve the stability of anthocyanin compounds (AC) by encapsulating them in nanoliposomes resulting from rapeseed lecithin alongside chitosan coating. The results indicate that the particle size, electrophoretic mobility, encapsulation efficiency, and membrane fluidity of [...] Read more.
In this study, a novel approach was investigated to improve the stability of anthocyanin compounds (AC) by encapsulating them in nanoliposomes resulting from rapeseed lecithin alongside chitosan coating. The results indicate that the particle size, electrophoretic mobility, encapsulation efficiency, and membrane fluidity of nanoliposomes containing anthocyanin compounds were 132.41 nm, −3.26 µm·cm/V·S, 42.57%, and 3.41, respectively, which changed into 188.95 nm, +4.80 µm·cm/V·S, 61.15%, and 2.39 after coating with chitosan, respectively. The results also suggest improved physical and chemical stability of nanoliposomes after coating with chitosan. TEM images demonstrate the produced particles were spherical and had a nanoscale, where the existence of a chitosan layer around the nanoparticles was visible. Shear rheological tests illustrate that the flow behavior of nanoliposomes was altered from Newtonian to shear thinning following chitosan incorporation. Further, chitosan diminished the surface area of the hysteresis loop (thixotropic behavior). The oscillatory rheological tests also show the presence of chitosan led to the improved mechanical stability of nanoliposomes. The results of the present study demonstrate that chitosan coating remarkably improved encapsulation efficiency, as well as the physical and mechanical stability of nanoliposomes. Thus, coating AC-nanoliposomes with chitosan is a promising approach for effective loading of AC and enhancing their stability to apply in the pharmaceutic and food industries. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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Review

Jump to: Research

18 pages, 1477 KiB  
Review
Microenvironmental pH Modification in Buccal/Sublingual Dosage Forms for Systemic Drug Delivery
by Shaolong He and Huiling Mu
Pharmaceutics 2023, 15(2), 637; https://doi.org/10.3390/pharmaceutics15020637 - 14 Feb 2023
Cited by 4 | Viewed by 2462
Abstract
Many drug candidates are poorly water-soluble. Microenvironmental pH (pHM) modification in buccal/sublingual dosage forms has attracted increasing interest as a promising pharmaceutical strategy to enhance the oral mucosal absorption of drugs with pH-dependent solubility. Optimizing drug absorption at the oral mucosa [...] Read more.
Many drug candidates are poorly water-soluble. Microenvironmental pH (pHM) modification in buccal/sublingual dosage forms has attracted increasing interest as a promising pharmaceutical strategy to enhance the oral mucosal absorption of drugs with pH-dependent solubility. Optimizing drug absorption at the oral mucosa using pHM modification is considered to be a compromise between drug solubility and drug lipophilicity (Log D)/permeation. To create a desired pHM around formulations during the dissolution process, a suitable amount of pH modifiers should be added in the formulations, and the appropriate methods of pHM measurement are required. Despite pHM modification having been demonstrated to be effective in enhancing the oral mucosal absorption of drugs, some potential risks, such as oral mucosal irritation and teeth erosion caused by the pH modifiers, should not been neglected during the formulation design process. This review aims to provide a short introduction to the pHM modification concept in buccal/sublingual dosage forms, the properties of saliva related to pHM modification, as well as suitable drug candidates and pH modifiers for pHM modifying buccal/sublingual formulations. Additionally, the methods of pHM measurement, pHM modification methods and the corresponding challenges are summarized in the present review. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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14 pages, 2229 KiB  
Review
A New Challenge for the Old Excipient Calcium Carbonate: To Improve the Dissolution Rate of Poorly Soluble Drugs
by Valeria Ambrogi
Pharmaceutics 2023, 15(1), 300; https://doi.org/10.3390/pharmaceutics15010300 - 16 Jan 2023
Cited by 2 | Viewed by 3131
Abstract
Calcium carbonate is an excipient traditionally used in solid dosage forms with several functions such as a diluent, a quick dissolution agent, a buffer and an opacifier. Recently, many other challenges have arisen for calcium carbonate and, among them, the possibility of using [...] Read more.
Calcium carbonate is an excipient traditionally used in solid dosage forms with several functions such as a diluent, a quick dissolution agent, a buffer and an opacifier. Recently, many other challenges have arisen for calcium carbonate and, among them, the possibility of using it as an excipient for improving the dissolution rate of poorly soluble drugs. As a consequence of their poor solubility in biological fluids, many active ingredients suffer from low and erratic bioavailability when administered by the oral route and thus, many formulation strategies and excipients have been proposed to overcome this problem. Among them, calcium carbonate has been proposed as an excipient for improving dissolution rates. Calcium carbonate has many interesting characteristics, in fact it dissolves quickly in gastric fluid, is inexpensive and is safe. It exists in different polymorphic forms and in porous morphology and recently a porous functionalized calcium carbonate has been proposed as a new excipient. This review is the first overview on the use of calcium carbonate as an excipient for improving drug dissolution rates. The drug loading procedure, the physical characterization of the drug/CaCO3 samples and their dissolution profiles will be described. Moreover, the possible mechanisms of dissolution improvement, such as the presence of the drug in amorphous or polymorphic forms, in small crystals, and the effects of CaCO3 dissolution in acidic medium will be discussed. Different polymorphic forms of calcium carbonate and the presence of porosity and functionalization will be analyzed as well and their effects on dissolution rates will be discussed. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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34 pages, 3441 KiB  
Review
Ionotropic Gelation and Chemical Crosslinking as Methods for Fabrication of Modified-Release Gellan Gum-Based Drug Delivery Systems
by Piotr Gadziński, Anna Froelich, Barbara Jadach, Monika Wojtyłko, Adam Tatarek, Antoni Białek, Julia Krysztofiak, Michał Gackowski, Filip Otto and Tomasz Osmałek
Pharmaceutics 2023, 15(1), 108; https://doi.org/10.3390/pharmaceutics15010108 - 28 Dec 2022
Cited by 21 | Viewed by 4675
Abstract
Hydrogels have a tridimensional structure. They have the ability to absorb a significant amount of water or other natural or simulated fluids that cause their swelling albeit without losing their structure. Their properties can be exploited for encapsulation and modified targeted drug release. [...] Read more.
Hydrogels have a tridimensional structure. They have the ability to absorb a significant amount of water or other natural or simulated fluids that cause their swelling albeit without losing their structure. Their properties can be exploited for encapsulation and modified targeted drug release. Among the numerous natural polymers suitable for obtaining hydrogels, gellan gum is one gaining much interest. It is a gelling agent with many unique features, and furthermore, it is non-toxic, biocompatible, and biodegradable. Its ability to react with oppositely charged molecules results in the forming of structured physical materials (films, beads, hydrogels, nanoparticles). The properties of obtained hydrogels can be modified by chemical crosslinking, which improves the three-dimensional structure of the gellan hydrogel. In the current review, an overview of gellan gum hydrogels and their properties will be presented as well as the mechanisms of ionotropic gelation or chemical crosslinking. Methods of producing gellan hydrogels and their possible applications related to improved release, bioavailability, and therapeutic activity were described. Full article
(This article belongs to the Special Issue Strategies for Enhancing the Bioavailability of Poorly Soluble Drugs)
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