Recent Progress in Formulation Approaches for Improving the Solubility and Bioavailability of Poorly Soluble Drugs

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 26278

Special Issue Editors

Faculty of Pharmacy, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece
Interests: crystal polymorphism; cocrystals; amorphous solid dispersions; nanocrystals; computational simulation of the solid state; artificial neural networks
Special Issues, Collections and Topics in MDPI journals
Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia
Interests: poorly soluble drugs; solid dispersions; amorphous formulation; nanocrystals; experimental design; 3D printing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The rise in the number of poorly soluble drugs over last several years has forced the pharmaceutical industry towards the development of formulation approaches for improving the solubility and bioavailability of these drugs. Although several decades have passed since the introduction of solid dispersion technology and other conventional formulation approaches (e.g., complexation with cyclodextrins; the use of salts, cosolvents, surfactants, and prodrugs), there is still a huge number of potential drugs with proved pharmacological activity that do not reach market due to undesired physicochemical and biopharmaceutical properties. Several problems hinder the market appearance of these formulations, such as inherent limitations of preparation techniques (the use of organic solvents or elevated temperatures), poor flowability and compressibility behavior of the obtained product, stability issues due to drug recrystallization from amorphous form or polymorphic transitions, as well as high formulation bulk caused by the high weight percentage of excipient required to ensure formulation stability. Several market withdrawals in the past few years caused by drug recrystallization and consequently changes in drug dissolution could probably have been avoided if more efforts were invested in understanding the physicochemical characteristics of drug–excipient systems by both analytical and molecular modelling techniques. Significant progress has been made during the last several years in this area, including the development of novel preparation techniques such as KinetiSol® dispersion, supercritical fluid processing, cryogenic processing, electrospinning, etc.; the application of formulation approaches which enable higher drug loading (e.g., nanocrystals or co-amorphous systems); as well as the use of advanced methods for physicochemical characterization. The introduction of molecular modelling and simulation tools and thermodynamic modelling in formulation development made possible the simulation of interactions between drugs and other formulation components on the molecular level and the elucidation of system physicochemical properties and potential stability issues. This should facilitate the achievement of the ultimate goal of developing formulations without stability concerns, which is a prerequisite to enter the market.

Therefore, both original and review papers focused on novel findings in formulation approaches for improving solubility and bioavailability of poorly soluble drugs—particularly solid dispersions, co-amorphous systems, and nanocrystals—are welcome in this Special issue. Submitted papers should address aspects of process optimization, elucidation of mechanisms responsible for drug amorphization and stabilization of the amorphous form, the application of molecular modelling and simulation tools in formulation development, downstream formulation processing into dosage forms suitable for the market, and the evaluation of bioavailability improvement through in vivo animal studies or in silico PBPK modelling.  

Prof. Dr. Kyriakos Kachrimanis
Dr. Djordje Medarevic
Guest Editors

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Keywords

  • solid dispersions
  • co-amorphous systems
  • nanocrystals
  • poorly soluble drugs
  • amorphous state
  • molecular modeling and simulation
  • thermodynamic modelling

Published Papers (12 papers)

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Research

17 pages, 2643 KiB  
Article
Formation of a Stable Co-Amorphous System for a Brick Dust Molecule by Utilizing Sodium Taurocholate with High Glass Transition Temperature
by Shohei Aikawa, Hironori Tanaka, Hiroshi Ueda, Masato Maruyama and Kazutaka Higaki
Pharmaceutics 2023, 15(1), 84; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics15010084 - 27 Dec 2022
Cited by 3 | Viewed by 1658
Abstract
Brick dust molecules are usually poorly soluble in water and lipoidal components, making it difficult to formulate them in dosage forms that provide efficient pharmacological effects. A co-amorphous system is an effective strategy to resolve these issues. However, their glass transition temperatures ( [...] Read more.
Brick dust molecules are usually poorly soluble in water and lipoidal components, making it difficult to formulate them in dosage forms that provide efficient pharmacological effects. A co-amorphous system is an effective strategy to resolve these issues. However, their glass transition temperatures (Tg) are relatively lower than those of polymeric amorphous solid dispersions, suggesting the instability of the co-amorphous system. This study aimed to formulate a stable co-amorphous system for brick dust molecules by utilizing sodium taurocholate (NaTC) with a higher Tg. A novel neuropeptide Y5 receptor antagonist (AntiY5R) and NaTC with Tg of 155 °C were used as the brick dust model and coformer, respectively. Ball milling formed a co-amorphous system for AntiY5R and NaTC (AntiY5R-NaTC) at various molar ratios. Deviation from the theoretical Tg value and peak shifts in Fourier-transform infrared spectroscopy indicated intermolecular interactions between AntiY5R and NaTC. AntiY5R-NaTC at equal molar ratios resulting in an 8.5-fold increase in AntiY5R solubility over its crystalline form. The co-amorphous system remained amorphous for 1 month at 25 °C and 40 °C. These results suggest that the co-amorphous system formed by utilizing NaTC as a coformer could stably maintain the amorphous state and enhance the solubility of brick dust molecules. Full article
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26 pages, 9028 KiB  
Article
Solvent Free Twin Screw Processed Silybin Nanophytophospholipid: In Silico, In Vitro and In Vivo Insights
by Gasper Fernandes, Sai Lalitha Alekhya Pusuluri, Ajinkya Nitin Nikam, Sumit Birangal, Gautham G. Shenoy and Srinivas Mutalik
Pharmaceutics 2022, 14(12), 2729; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14122729 - 06 Dec 2022
Cited by 4 | Viewed by 1321
Abstract
Silybin (SIL) is a polyphenolic phytoconstituent that is commonly used to treat liver disorders. It is difficult to fabricate an orally delivered SIL product due to its low oral bioavailability (0.95%). Therefore, the current research focusses on the development of a novel composition [...] Read more.
Silybin (SIL) is a polyphenolic phytoconstituent that is commonly used to treat liver disorders. It is difficult to fabricate an orally delivered SIL product due to its low oral bioavailability (0.95%). Therefore, the current research focusses on the development of a novel composition of a phospholipid complex, termed as nanophytophospholipid, of SIL by employing a unique, solvent-free Twin Screw Process (TSP), with the goal of augmenting the solubility and bioavailability of SIL. The optimised SIL-nanophytophospholipid (H6-SNP) was subjected to physicochemical interactions by spectrometry, thermal, X-ray and electron microscopy. The mechanism of drug and phospholipid interaction was confirmed by molecular docking and dynamics studies. Saturation solubility, in vitro dissolution, ex vivo permeation and preclinical pharmacokinetic studies were also conducted. H6-SNP showed good complexation efficiency, with a high practical yield (80%). The low particle size (334.7 ± 3.0 nm) and positively charged zeta potential (30.21 ± 0.3 mV) indicated the immediate dispersive nature of H6-SNP into nanometric dimensions, with good physical stability. Further high solubility and high drug release from the H6-SNP was also observed. The superiority of the H6-SNP was demonstrated in the ex vivo and preclinical pharmacokinetic studies, displaying enhanced apparent permeability (2.45-fold) and enhanced bioavailability (1.28-fold). Overall, these findings indicate that not only can phospholipid complexes be formed using solvent-free TSP, but also that nanophytophospholipids can be formed by using a specific quantity of lipid, drug, surfactant, superdisintegrant and diluent. This amalgamation of technology and unique composition can improve the oral bioavailability of poorly soluble and permeable phytoconstituents or drugs. Full article
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21 pages, 9085 KiB  
Article
Synthesis and Evaluation of Poly(3-hydroxypropyl Ethylene-imine) and Its Blends with Chitosan Forming Novel Elastic Films for Delivery of Haloperidol
by Sitthiphong Soradech, Pattarawadee Kengkwasingh, Adrian C. Williams and Vitaliy V. Khutoryanskiy
Pharmaceutics 2022, 14(12), 2671; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14122671 - 30 Nov 2022
Cited by 2 | Viewed by 1770
Abstract
This study aimed to develop novel elastic films based on chitosan and poly(3-hydroxypropyl ethyleneimine) or P3HPEI for the rapid delivery of haloperidol. P3HPEI was synthesized using a nucleophilic substitution reaction of linear polyethyleneimine (L-PEI) with 3-bromo-1-propanol. 1H-NMR and FTIR spectroscopies confirmed the [...] Read more.
This study aimed to develop novel elastic films based on chitosan and poly(3-hydroxypropyl ethyleneimine) or P3HPEI for the rapid delivery of haloperidol. P3HPEI was synthesized using a nucleophilic substitution reaction of linear polyethyleneimine (L-PEI) with 3-bromo-1-propanol. 1H-NMR and FTIR spectroscopies confirmed the successful conversion of L-PEI to P3HPEI, and the physicochemical properties and cytotoxicity of P3HPEI were investigated. P3HPEI had good solubility in water and was significantly less toxic than the parent L-PEI. It had a low glass transition temperature (Tg = −38.6 °C). Consequently, this new polymer was blended with chitosan to improve mechanical properties, and these materials were used for the rapid delivery of haloperidol. Films were prepared by casting from aqueous solutions and then evaporating the solvent. The miscibility of polymers, mechanical properties of blend films, and drug release profiles from these formulations were investigated. The blends of chitosan and P3HPEI were miscible in the solid state and the inclusion of P3HPEI improved the mechanical properties of the films, producing more elastic materials. A 35:65 (%w/w) blend of chitosan–P3HPEI provided the optimum glass transition temperature for transmucosal drug delivery and so was selected for further investigation with haloperidol, which was chosen as a model hydrophobic drug. Microscopic and X-ray diffractogram (XRD) data indicated that the solubility of the drug in the films was ~1.5%. The inclusion of the hydrophilic polymer P3HPEI allowed rapid drug release within ~30 min, after which films disintegrated, demonstrating that the formulations are suitable for application to mucosal surfaces, such as in buccal drug delivery. Higher release with increasing drug loading allows flexible dosing. Blending P3HPEI with chitosan thus allows the selection of desirable physicochemical and mechanical properties of the films for delivery of haloperidol as a poorly water-soluble drug. Full article
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16 pages, 4528 KiB  
Article
Co-Delivery of Paclitaxel Prodrug, Gemcitabine and Porphine by Micelles for Pancreatic Cancer Treatment via Chemo-Photodynamic Combination Therapy
by Qiwei Wu, Xiaodong Ma, Wenhui Zhou, Rong Yu, Jessica M. Rosenholm, Weizhong Tian, Lirong Zhang, Dongqing Wang and Hongbo Zhang
Pharmaceutics 2022, 14(11), 2280; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14112280 - 25 Oct 2022
Cited by 4 | Viewed by 1649
Abstract
Pancreatic carcinoma is an aggressive subtype of cancer with poor prognosis, known for its refractory nature. To address this challenge, we have established a stable nanoplatform that combines chemotherapy with photodynamic therapy (PDT) to achieve better curative efficacy. First, we designed and synthesized [...] Read more.
Pancreatic carcinoma is an aggressive subtype of cancer with poor prognosis, known for its refractory nature. To address this challenge, we have established a stable nanoplatform that combines chemotherapy with photodynamic therapy (PDT) to achieve better curative efficacy. First, we designed and synthesized a disulfide-bonded paclitaxel (PTX)-based prodrug, which was further mixed with gemcitabine (GEM) and photosensitizer THPP in an optimized ratio. Subsequently, the mixture was added dropwise into amphiphilic polymer DSPE-PEG water solution to form micelles composed of DSPE-PEG nanoparticles (TPG NPs). The TPG NPs were around 135 nm, and showed great ability of DTT stimulated release of PTX and GEM. Moreover, the TPG NPs can be efficiently uptaken by pancreatic cancer PANC-1 cells and effectively kill them, especially when combined with 650 nm laser irradiation. Finally, the TPG NPs have shown enhanced long-term circulation ability and also exhibited efficient anti-tumor activity in combination with 650 nm laser irradiation in a pancreatic cancer mouse model. In summary, the designed TPG NPs possesses great potential for co-delivery of paclitaxel prodrug, GEM and THPP, which enables combined chemo-photodynamic therapy for cancer treatment. In addition, the stimulated release of PTX prodrug and GEM also allows for better targeting of tumor cells and the increased therapeutic effect against cancer cells. Overall, the TPG NPs can serve as a good candidate for pancreatic cancer treatment. Full article
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18 pages, 3884 KiB  
Article
Dissolution Kinetics of Meloxicam Formulations Co-Milled with Sodium Lauryl Sulfate
by Jan Patera, Pavla Němečková and Petr Zámostný
Pharmaceutics 2022, 14(10), 2173; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14102173 - 12 Oct 2022
Cited by 1 | Viewed by 1578
Abstract
Meloxicam (MLX) is a poorly soluble drug exhibiting strong hydrophobicity. This combination of properties makes dissolution enhancement by particle size reduction ineffective; therefore, combined formulation approaches are required. Various approaches were investigated in this study, including milling, solid dispersions, and self-emulsified lipid formulations. [...] Read more.
Meloxicam (MLX) is a poorly soluble drug exhibiting strong hydrophobicity. This combination of properties makes dissolution enhancement by particle size reduction ineffective; therefore, combined formulation approaches are required. Various approaches were investigated in this study, including milling, solid dispersions, and self-emulsified lipid formulations. Whereas milling studies of MLX and its co-milling with various polymers have been reported in recent literature, this study is focused on investigating the dissolution kinetics of particulate formulations obtained by co-milling MLX with sodium lauryl sulfate (SLS) in a planetary ball mill with 5–25 wt.% SLS content. The effects of milling time and milling ball size were also investigated. No significant reduction in drug crystallinity was observed under the investigated milling conditions according to XRD data. For the dissolution study, we used an open-loop USP4 dissolution apparatus, and recorded dissolution profiles were fitted according to the Weibull model. The Weibull parameters and a novel criterion—surface utilization factor—were used to evaluate and discuss the drug release from the perspective of drug particle surface changes throughout the dissolution process. The most effective co-milling results were achieved using smaller balls (2 mm), with a co-milling time of up to 15 min SLS content of up to 15 wt.% to increase the dissolution rate by approximately 100 times relative to the physical mixture reference. The results suggest that for hydrophobic drugs, particle performance during dissolution is very sensitive to surface properties and not only to particle size. Co-milling with SLS prepares the surface for faster drug release than that achieved with direct mixing. Full article
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17 pages, 5490 KiB  
Article
Estimating the Dissolution of Anticancer Drugs in Supercritical Carbon Dioxide with a Stacked Machine Learning Model
by Maryam Najmi, Mohamed Arselene Ayari, Hamidreza Sadeghsalehi, Behzad Vaferi, Amith Khandakar, Muhammad E. H. Chowdhury, Tawsifur Rahman and Zanko Hassan Jawhar
Pharmaceutics 2022, 14(8), 1632; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14081632 - 05 Aug 2022
Cited by 9 | Viewed by 1940
Abstract
Synthesizing micro-/nano-sized pharmaceutical compounds with an appropriate size distribution is a method often followed to enhance drug delivery and reduce side effects. Supercritical CO2 (carbon dioxide) is a well-known solvent utilized in the pharmaceutical synthesis process. Reliable knowledge of a drug’s solubility [...] Read more.
Synthesizing micro-/nano-sized pharmaceutical compounds with an appropriate size distribution is a method often followed to enhance drug delivery and reduce side effects. Supercritical CO2 (carbon dioxide) is a well-known solvent utilized in the pharmaceutical synthesis process. Reliable knowledge of a drug’s solubility in supercritical CO2 is necessary for feasible study, modeling, design, optimization, and control of such a process. Therefore, the current study constructs a stacked/ensemble model by combining three up-to-date machine learning tools (i.e., extra tree, gradient boosting, and random forest) to predict the solubility of twelve anticancer drugs in supercritical CO2. An experimental databank comprising 311 phase equilibrium samples was gathered from the literature and applied to design the proposed stacked model. This model estimates the solubility of anticancer drugs in supercritical CO2 as a function of solute and solvent properties and operating conditions. Several statistical indices, including average absolute relative deviation (AARD = 8.62%), mean absolute error (MAE = 2.86 × 10−6), relative absolute error (RAE = 2.42%), mean squared error (MSE = 1.26 × 10−10), and regression coefficient (R2 = 0.99809) were used to validate the performance of the constructed model. The statistical, sensitivity, and trend analyses confirmed that the suggested stacked model demonstrates excellent performance for correlating and predicting the solubility of anticancer drugs in supercritical CO2. Full article
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12 pages, 3359 KiB  
Article
Enhanced Oral Bioavailability of MT-102, a New Anti-inflammatory Agent, via a Ternary Solid Dispersion Formulation
by Rajiv Bajracharya, Jae Geun Song, Sang Hoon Lee, Seong Hoon Jeong and Hyo-Kyung Han
Pharmaceutics 2022, 14(7), 1510; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14071510 - 21 Jul 2022
Cited by 6 | Viewed by 1622
Abstract
This study aimed to develop a solid dispersion (SD) of MT-102, a new anti-inflammatory agent, to improve its oral bioavailability. The ternary SD formulations of MT-102 (a poorly soluble extract of Isatis indigotica and Juglans mandshurica) were prepared using a solvent evaporation [...] Read more.
This study aimed to develop a solid dispersion (SD) of MT-102, a new anti-inflammatory agent, to improve its oral bioavailability. The ternary SD formulations of MT-102 (a poorly soluble extract of Isatis indigotica and Juglans mandshurica) were prepared using a solvent evaporation method with various drug/excipient ratios. Following that, the effectiveness of various SDs as an oral formulation of MT-102 was investigated using indirubin as a marker component. By forming SDs with hydrophilic polymers, the aqueous solubility of indirubin was significantly increased. SD-F4, containing drug, poloxamer 407 (P407), and povidone K30 (PVP K30) at a 1:2:2 weight ratio, exhibited the optimal dissolution profiles in the acidic to neutral pH range. Compared to pure MT-102 and a physical mixture, SD-F4 increased indirubin’s dissolution from MT-102 by approximately 9.86-fold and 2.21-fold, respectively. Additionally, SD-F4 caused the sticky extract to solidify, resulting in improved flowability and handling. As a result, compared to pure MT-102, the oral administration of SD-F4 significantly improved the systemic exposure of MT-102 in rats. Overall, the ternary SD formulation of MT-102 with a blended mixture of P407 and PVP K30 appeared to be effective at improving the dissolution and oral absorption of MT-102. Full article
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16 pages, 3421 KiB  
Article
Spray Dried Levodopa-Doped Powder Potentially for Intranasal Delivery
by Xuan Liu, Shen Yan, Mengyuan Li, Shengyu Zhang, Gang Guo, Quanyi Yin, Zhenbo Tong, Xiao Dong Chen and Winston Duo Wu
Pharmaceutics 2022, 14(7), 1384; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14071384 - 30 Jun 2022
Cited by 2 | Viewed by 2040
Abstract
This work was aimed to develop levodopa (L-dopa) nasal powder to achieve controllable drug release and high nasal deposition efficiency. A series of uniform microparticles, composed of amorphous L-dopa and excipients of hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), or hydroxypropyl-β-cyclodextrin (CD), were fabricated [...] Read more.
This work was aimed to develop levodopa (L-dopa) nasal powder to achieve controllable drug release and high nasal deposition efficiency. A series of uniform microparticles, composed of amorphous L-dopa and excipients of hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), or hydroxypropyl-β-cyclodextrin (CD), were fabricated by a self-designed micro-fluidic spray dryer. The effects of excipient type and drug/excipient mass ratio on the particle size, morphology, density, and crystal property, as well as the in vitro performance of drug release, mucoadhesion, and nasal deposition, were investigated. Increased amounts of added excipient, regardless of its type, could accelerate the L-dopa release to different extent. The addition of CD showed the most obvious effect, i.e., ~83% of L-dopa released in 60 min for SD-L1CD2, compared to 37% for raw L-dopa. HPMC could more apparently improve the particle mucoadhesion than PVP and CD, with respective adhesive forces of ~269, 111, and 26 nN for SD-L1H2, -L1P2, and -L1CD2. Nevertheless, the deposition fractions in the olfactory region for such samples were almost the same (~14%), probably ascribable to their quite similar particle aerodynamic diameter (~30 μm). This work demonstrates a feasible methodology for the development of nasal powder. Full article
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19 pages, 5326 KiB  
Article
Three-Dimensional Printing of a Container Tablet: A New Paradigm for Multi-Drug-Containing Bioactive Self-Nanoemulsifying Drug-Delivery Systems (Bio-SNEDDSs)
by Vineet R. Kulkarni, Mohsin Kazi, Ahmad Abdul-Wahhab Shahba, Aakib Radhanpuri and Mohammed Maniruzzaman
Pharmaceutics 2022, 14(5), 1082; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14051082 - 18 May 2022
Cited by 8 | Viewed by 2702
Abstract
This research demonstrates the use of fused deposition modeling (FDM) 3D printing to control the delivery of multiple drugs containing bioactive self-nano emulsifying drug-delivery systems (SNEDDSs). Around two-thirds of the new chemical entities being introduced in the market are associated with some inherent [...] Read more.
This research demonstrates the use of fused deposition modeling (FDM) 3D printing to control the delivery of multiple drugs containing bioactive self-nano emulsifying drug-delivery systems (SNEDDSs). Around two-thirds of the new chemical entities being introduced in the market are associated with some inherent issues, such as poor solubility and high lipophilicity. SNEDDSs provide for an innovative and easy way to develop a delivery platform for such drugs. Combining this platform with FDM 3D printing would further aid in developing new strategies for delivering poorly soluble drugs and personalized drug-delivery systems with added therapeutic benefits. This study evaluates the performance of a 3D-printed container system containing curcumin (CUR)- and lansoprazole (LNS)-loaded SNEDDS. The SNEDDS showed 50% antioxidant activity (IC50) at concentrations of around 330.1 µg/mL and 393.3 µg/mL in the DPPH and ABTS radical scavenging assay, respectively. These SNEDDSs were loaded with no degradation and leakage from the 3D-printed container. We were able to delay the release of the SNEDDS from the hollow prints while controlling the print wall thickness to achieve lag phases of 30 min and 60 min before the release from the 0.4 mm and 1 mm wall thicknesses, respectively. Combining these two innovative drug-delivery strategies demonstrates a novel option for tackling the problems associated with multi-drug delivery and delivery of drugs susceptible to degradation in, i.e., gastric pH for targeting disease conditions throughout the gastrointestinal tract (GIT). It is also envisaged that such delivery systems reported herein can be an ideal solution to deliver many challenging molecules, such as biologics, orally or near the target site in the future, thus opening a new paradigm for multi-drug-delivery systems. Full article
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15 pages, 6291 KiB  
Article
Acetic Acid as Processing Aid Dramatically Improves Organic Solvent Solubility of Weakly Basic Drugs for Spray Dried Dispersion Manufacture
by Molly S. Adam, Warren K. Miller, Amanda M. Pluntze, Aaron M. Stewart, Jonathan L. Cape, Michael E. Grass and Michael M. Morgen
Pharmaceutics 2022, 14(3), 555; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14030555 - 02 Mar 2022
Cited by 2 | Viewed by 2895 | Correction
Abstract
Many active pharmaceutical ingredients (APIs) in the pharmaceutical pipeline require bioavailability enhancing formulations due to very low aqueous solubility. Although spray dried dispersions (SDDs) have demonstrated broad utility in enhancing the bioavailability of such APIs by trapping them in a high-energy amorphous form, [...] Read more.
Many active pharmaceutical ingredients (APIs) in the pharmaceutical pipeline require bioavailability enhancing formulations due to very low aqueous solubility. Although spray dried dispersions (SDDs) have demonstrated broad utility in enhancing the bioavailability of such APIs by trapping them in a high-energy amorphous form, many new chemical entities (NCEs) are poorly soluble not just in water, but in preferred organic spray drying solvents, e.g., methanol (MeOH) and acetone. Spraying poorly solvent soluble APIs from dilute solutions leads to low process throughput and small particles that challenge downstream processing. For APIs with basic pKa values, spray solvent solubility can be dramatically increased by using an acid to ionize the API. Specifically, we show that acetic acid can increase API solubility in MeOH:H2O by 10-fold for a weakly basic drug, gefitinib (GEF, pKa 7.2), by ionizing GEF to form the transient acetate salt. The acetic acid is removed during drying, resulting in a SDD of the original GEF free base having performance similar to SDDs sprayed from solvents without acetic acid. The increase in solvent solubility enables large scale manufacturing for these challenging APIs by significantly increasing the throughput and reducing the amount of solvent required. Full article
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14 pages, 2412 KiB  
Article
Formulation Approaches for Improving the Dissolution Behavior and Bioavailability of Tolvaptan Using SMEDDS
by Jong-Hwa Lee and Gye-Won Lee
Pharmaceutics 2022, 14(2), 415; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14020415 - 14 Feb 2022
Cited by 5 | Viewed by 2858
Abstract
Tolvaptan, a selective vasopressin receptor antagonist, is a Class IV agent of Biopharmaceutical Classification System (BCS). To improve bioavailability after oral administration, the new tolvaptan-loaded self-microemulsifying drug delivery system (SMEDDS) was further optimized using a “design of the experiment (DoE)” including components of [...] Read more.
Tolvaptan, a selective vasopressin receptor antagonist, is a Class IV agent of Biopharmaceutical Classification System (BCS). To improve bioavailability after oral administration, the new tolvaptan-loaded self-microemulsifying drug delivery system (SMEDDS) was further optimized using a “design of the experiment (DoE)” including components of D-optional mixture design. Based on a solubility study of tolvaptan in various oils, surfactants, and cosurfactants, Capryol® 90, Tween 20, and Transcutol® HP [or polyethylene glycol 200 (PEG 200)] were finally selected for optimization of tolvaptan-loaded SMEDDS formulations. The fitting models of, and poly-nominal equations for, all response variables were acceptable, as revealed by analysis of variance (ANOVA, R2 > 0.900, p < 0.0001). The optimized formulations A-1 (Capryol® 90/Tween 20/Transcutol® HP = 10%/70%/20% w/w) and B-1 (Capryol® 90/Tween 20/PEG 200 = 10%/70%/20% w/w) with desirabilities of 0.905 and 1.000, respectively, showed low droplet size and the dissolution rate exceeded 95% at 15 and 60 min. The tolvaptan-loaded SMEDDS remained stable for 3 months under accelerated conditions, thus with no change in any of content, color, particle size, or dissolution rate. In a rat pharmacokinetic study, the bioavailability of formulations A-1 (16.6%) and B-1 (11.5%) were 23–33-fold higher than that of raw tolvaptan powder (0.5%). Thus, the use of “quality by design (QbD)” during development of tolvaptan-loaded SMEDDS improved the dissolution rate and oral drug bioavailability. Full article
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21 pages, 3852 KiB  
Article
Resveratrol Encapsulation and Release from Pristine and Functionalized Mesoporous Silica Carriers
by Simona Ioniţă, Daniel Lincu, Raul-Augustin Mitran, Laila Ziko, Nada K. Sedky, Mihaela Deaconu, Ana-Maria Brezoiu, Cristian Matei and Daniela Berger
Pharmaceutics 2022, 14(1), 203; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14010203 - 16 Jan 2022
Cited by 14 | Viewed by 2789
Abstract
Resveratrol, a naturally occurring polyphenol, has attracted significant attention due to its antioxidant, cardioprotective and anticancer potential. However, its low aqueous solubility limits resveratrol bioavailability and use. In this work, different mesoporous silica matrices were used to encapsulate the polyphenol and to increase [...] Read more.
Resveratrol, a naturally occurring polyphenol, has attracted significant attention due to its antioxidant, cardioprotective and anticancer potential. However, its low aqueous solubility limits resveratrol bioavailability and use. In this work, different mesoporous silica matrices were used to encapsulate the polyphenol and to increase its dissolution rate. Pristine MCM-41, MCM-48, SBA-15, SBA-16, FDU-12 and MCF silica were obtained. The influence of SBA-15 functionalized with aminopropyl, isocyanate, phenyl, mercaptopropyl, and propionic acid moieties on resveratrol loading and release profiles was also assessed. The cytotoxic effects were evaluated for mesoporous carriers and resveratrol-loaded samples against human lung cancer (A549), breast cancer (MDA-MB-231) and human skin fibroblast (HSF) cell lines. The effect on apoptosis and cell cycle were assayed for selected resveratrol-loaded carriers. The polyphenol molecules are encapsulated only inside the mesopores, mostly in amorphous state. All materials containing either pristine or functionalized silica carriers increased polyphenol dissolution rate. The influence of the physico-chemical properties of the mesoporous carriers and resveratrol–loaded supports on the kinetic parameters was identified. Resv@SBA-15-SH and Resv@SBA-15-NCO samples exhibited the highest anticancer effect against A549 cells (IC50 values were 26.06 and 36.5 µg/mL, respectively) and against MDA-MB-231 (IC50 values were 35.56 and 19.30 µg/mL, respectively), which highlights their potential use against cancer. Full article
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