Special Issue "New Approaches to Enhance Drug Solubility and Bioavailability"

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (28 September 2018).

Special Issue Editors

Prof. Dr. Jaehwi Lee
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Guest Editor
Chung-Ang University, College of Pharmacy, Seoul, South Korea
Interests: solubilization; bioavailability; particle technologies; lipid-based drug delivery; formulation design
Special Issues and Collections in MDPI journals
Prof. Min-Soo Kim
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Co-Guest Editor
College of Pharmacy, Pusan National University, Busan, Korea
Interests: solubilization; bioavailability; particle technologies; lipid-based drug delivery; formulation design; supercritical fluid technology; quality by design; process simulation; process analytical technology
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Solubility of drugs is a crucial determinant especially for good oral bioavailability. Thus, numerous solubilisation techniques have been developed such as complexation with cyclodextrins, use of lipids, cosolvents, and amphiphilic molecules as well as solid state modification of drug particles. However, these techniques are not regarded as being universal and thus, frequently limited to specific formulations. For example, micelles based on surfactants and amphiphilic polymers are able to solubilise poorly soluble drugs but they might not be intravenously injected due largely to concern of precipitation of the drug as a result of dilution effect. In addition, orally administered micelles suffer from extensive interaction with gastrointestinal environments such as pH, digestive enzymes and bile salts. For this reason, new approaches have been employed including combination of current solubilisation techniques and use newly developed materials in solubilizing poorly soluble drugs to enhance bioavailability.

This special issue is intended to introduce and highlight technological advances in solubilisation made for enhancing oral bioavailability. We welcome original and review articles concerning novel solubilisation techniques for better bioavailability.

Prof. Jaehwi Lee
Prof. Min-Soo Kim
Guest Editors

Manuscript Submission Information

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Keywords

  • solid dispersion
  • nanotechnology
  • lipid-based solubilisation
  • particle technology
  • solubilising formulations
  • polymeric solubilization
  • combined solubilization

Published Papers (11 papers)

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Research

Open AccessArticle
Enhancement of Aqueous Solubility and Dissolution of Celecoxib through Phosphatidylcholine-Based Dispersion Systems Solidified with Adsorbent Carriers
Pharmaceutics 2019, 11(1), 1; https://doi.org/10.3390/pharmaceutics11010001 - 20 Dec 2018
Cited by 12
Abstract
This study aimed to design phosphatidylcholine (PC)-based solid dispersion (SD) systems for enhancing the apparent aqueous solubility and dissolution of celecoxib (CLC), a selective cyclooxygenase-2 inhibitor with a highly hydrophobic property. Although PC-based dispersion formulations considerably increased solubilities of CLC, the lipidic texture [...] Read more.
This study aimed to design phosphatidylcholine (PC)-based solid dispersion (SD) systems for enhancing the apparent aqueous solubility and dissolution of celecoxib (CLC), a selective cyclooxygenase-2 inhibitor with a highly hydrophobic property. Although PC-based dispersion formulations considerably increased solubilities of CLC, the lipidic texture of PC was not appropriate as a solid dosage form for oral administration of CLC. To mask the lipidic texture of PC-based matrices, Neusilin® US2, an adsorbent material with a porous structure and large surface area widely used in the pharmaceutical industry, was employed and thereby fully powderized PC-based dispersion formulations could be fabricated. However, PC matrices containing CLC strongly adsorbed to the pores of Neusilin® US2 was not able to be rapidly released. To address this problem, different hydrophilic materials were examined to promote the release of the CLC-dispersed PC matrices from Neusilin® US2. Among tested hydrophilic materials, croscarmellose sodium was the most suitable to facilitate fast drug dissolution from Neusilin® US2 particles, showing significantly enhanced apparent aqueous solubility and dissolution behavior of CLC. Through differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared spectroscopy (FT-IR) analysis, a considerably reduced crystallinity of CLC dispersed in the PC-based dispersion formulations was demonstrated. The PC-based SD formulations developed in this study would be useful for improving the oral bioavailability of poorly soluble drugs such as CLC. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Choline-Amino Acid Ionic Liquids as Green Functional Excipients to Enhance Drug Solubility
Pharmaceutics 2018, 10(4), 288; https://doi.org/10.3390/pharmaceutics10040288 - 19 Dec 2018
Cited by 16
Abstract
The development of effective forms to incorporate poorly soluble drugs into delivery systems remains a problem. Thus, it is important to find alternatives such as finding excipients that increase drug solubility. Ionic liquids (ILs), particularly choline-based ILs, have been studied as solubility enhancers [...] Read more.
The development of effective forms to incorporate poorly soluble drugs into delivery systems remains a problem. Thus, it is important to find alternatives such as finding excipients that increase drug solubility. Ionic liquids (ILs), particularly choline-based ILs, have been studied as solubility enhancers in drug delivery systems. Nonetheless, to acknowledge this property as a functionality, it needs to be proven at non-toxic concentrations. Hence, herein two choline-amino acid ILs were studied as functional excipients by evaluating their influence on the solubility of the poorly water-soluble ferulic acid and rutin, while considering their safety. The solubility of the drugs was always higher in the presence of the ILs than in water. Ionic liquids did not affect the radical scavenging activity of the drugs or the cell viability. Moreover, stable oil-in-water (O/W) emulsions were prepared containing each drug and the ILs, allowing a significantly higher drug loading. Globally, our results suggest that choline-based ILs may act as green functional excipients, since at non-toxic concentrations they considerably improve drug solubility/loading, without influencing the antioxidant activity of the drugs, the cell viability, or the stability of the formulations. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Flurbiprofen-Loaded Solid SNEDDS Preconcentrate for the Enhanced Solubility, In-Vitro Dissolution and Bioavailability in Rats
Pharmaceutics 2018, 10(4), 247; https://doi.org/10.3390/pharmaceutics10040247 - 28 Nov 2018
Cited by 11
Abstract
The aim of this work was to prepare and optimize a solid self-nanoemulsifying drug delivery system pre-concentrate (SSP) containing water-insoluble flurbiprofen (FL) using a novel pseudo-ternary phase diagram. The pseudo-ternary phase diagram, composed of FL as the drug and dispersion core, Kollisolv MCT [...] Read more.
The aim of this work was to prepare and optimize a solid self-nanoemulsifying drug delivery system pre-concentrate (SSP) containing water-insoluble flurbiprofen (FL) using a novel pseudo-ternary phase diagram. The pseudo-ternary phase diagram, composed of FL as the drug and dispersion core, Kollisolv MCT 70 as the oil phase, and TPGS (tocopherol polyethylene glycol 1000 succinate) as the surfactant, was constructed for the determination of the SSP region. SSP was investigated in terms of particle size, physical state by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), in vitro dissolution and oral pharmacokinetics in rats. The determined SSP (FL/Kollisolv MCT 70/TPGS = 10/10/80, weight %) in the pseudo-ternary phase diagram had the melting point of 32.37 °C and uniform mean particle size of below 30 nm without any precipitation of FL in the dispersion. In the dissolution test, the SSP exhibited 95.70 ± 3.40% of release at 15 min, whereas the raw FL showed poor dissolution (i.e., 6.75 ± 1.30%) at that time point. In addition, the SSP showed the enhanced oral absorption (i.e., 1.93-fold increase in AUCinfinite) as compared to the suspension group of raw FL. Therefore, the developed SSP would be a promising drug delivery system with excellent solubilization, dissolution, and bioavailability for FL. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Solid Lipid Nanoparticles for Dibucaine Sustained Release
Pharmaceutics 2018, 10(4), 231; https://doi.org/10.3390/pharmaceutics10040231 - 14 Nov 2018
Cited by 8
Abstract
Dibucaine (DBC) is among the more potent long-acting local anesthetics (LA), and it is also one of the most toxic. Over the last decades, solid lipid nanoparticles (SLN) have been developed as promising carriers for drug delivery. In this study, SLN formulations were [...] Read more.
Dibucaine (DBC) is among the more potent long-acting local anesthetics (LA), and it is also one of the most toxic. Over the last decades, solid lipid nanoparticles (SLN) have been developed as promising carriers for drug delivery. In this study, SLN formulations were prepared with the aim of prolonging DBC release and reducing its toxicity. To this end, SLN composed of two different lipid matrices and prepared by two different hot-emulsion techniques (high-pressure procedure and sonication) were compared. The colloidal stability of the SLN formulations was tracked in terms of particle size (nm), polydispersity index (PDI), and zeta potential (mV) for 240 days at 4 °C; the DBC encapsulation efficiency was determined by the ultrafiltration/centrifugation method. The formulations were characterized by differential scanning calorimetry (DSC), electron paramagnetic resonance (EPR), and release kinetic experiments. Finally, the in vitro cytotoxicity against 3T3 fibroblast and HaCaT cells was determined, and the in vivo analgesic action was assessed using the tail flick test in rats. Both of the homogenization procedures were found suitable to produce particles in the 200 nm range, with good shelf stability (240 days) and high DBC encapsulation efficiency (~72–89%). DSC results disclosed structural information on the nanoparticles, such as the lower crystallinity of the lipid core vs. the bulk lipid. EPR measurements provided evidence of DBC partitioning in both SLNs. In vitro (cytotoxicity) and in vivo (tail flick) experiments revealed that the encapsulation of DBC into nanoparticles reduces its intrinsic cytotoxicity and prolongs the anesthetic effect, respectively. These results show that the SLNs produced are safe and have great potential to extend the applications of dibucaine by enhancing its bioavailability. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Experimental and Modeling Study of Drug Release from HPMC-Based Erodible Oral Thin Films
Pharmaceutics 2018, 10(4), 222; https://doi.org/10.3390/pharmaceutics10040222 - 09 Nov 2018
Cited by 10
Abstract
In this work hydroxypropyl methylcellulose (HPMC) fast-dissolving thin films for oral administration are investigated. Furosemide (Class IV of the Biopharmaceutical Classification System) has been used as a model drug for in vitro release tests using three different set-ups: the Franz cell, the millifluidic [...] Read more.
In this work hydroxypropyl methylcellulose (HPMC) fast-dissolving thin films for oral administration are investigated. Furosemide (Class IV of the Biopharmaceutical Classification System) has been used as a model drug for in vitro release tests using three different set-ups: the Franz cell, the millifluidic flow-through device, and the paddle type dissolution apparatus (USP II). In order to enable drug incorporation within HPMC films, a multifunctional excipient, hydroxypropyl- β -cyclodextrin (HP- β -CD) has been included in the formulation, and the influence of HP- β -CD on film swelling, erosion, and release properties has been investigated. Mathematical models capable of describing the swelling and release processes from HPMC erodible thin films in different apparatuses have been developed. In particular, we propose a new model for the description of drug transport and release in a Franz cell that accounts for the effect of the unavoidable imperfect mixing of the receptor chamber. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Development and Evaluation of a Water Soluble Fluorometholone Eye Drop Formulation Employing Polymeric Micelle
Pharmaceutics 2018, 10(4), 208; https://doi.org/10.3390/pharmaceutics10040208 - 28 Oct 2018
Cited by 11
Abstract
Low aqueous solubility of drug causes difficulties in preparation and inconvenience of administration. Polymeric micelles of fluorometholone (FML) using solid dispersion technique were prepared to develop an eye drop formulation with enhanced water solubility. Solid dispersions of FML were prepared at various FML:Soluplus [...] Read more.
Low aqueous solubility of drug causes difficulties in preparation and inconvenience of administration. Polymeric micelles of fluorometholone (FML) using solid dispersion technique were prepared to develop an eye drop formulation with enhanced water solubility. Solid dispersions of FML were prepared at various FML:Soluplus® w/w ratios using solvent evaporation method. A physical mixture was also prepared. Physicochemical characterization was performed with various methods. Ex vivo porcine corneal permeation of polymeric micelle, physical mixture, and commercial product were compared. FML solid dispersion (1:15) showed the highest solubility, which was c.a. 169.6- and 15.3-fold higher than that of pure FML and physical mixture. Characterization showed that the crystalline form of FML changed to amorphous state and polymeric micelles were formed in round micelle. Flucon®, a commercial product of FML, showed significantly large particle size and high poly dispersity index. In contrast, FML polymeric micelle showed submicron size with uniform size distribution. Ex vivo porcine corneal permeation study showed that permeation by polymeric micelles was significantly higher than that by the commercial product and physical mixture. In addition, confocal laser scanning microscopic analysis supported the enhanced porcine corneal tissue permeation property of polymeric micelle. In conclusion, polymeric micelle prepared with solid dispersion using Soluplus® can be a potential nanomedicine for ocular delivery of poorly water-soluble FML. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Molecular Disorder of Bicalutamide—Amorphous Solid Dispersions Obtained by Solvent Methods
Pharmaceutics 2018, 10(4), 194; https://doi.org/10.3390/pharmaceutics10040194 - 18 Oct 2018
Cited by 8
Abstract
The effect of solvent removal techniques on phase transition, physical stability and dissolution of bicalutamide from solid dispersions containing polyvinylpyrrolidone (PVP) as a carrier was investigated. A spray dryer and a rotavapor were applied to obtain binary systems containing either 50% or 66% [...] Read more.
The effect of solvent removal techniques on phase transition, physical stability and dissolution of bicalutamide from solid dispersions containing polyvinylpyrrolidone (PVP) as a carrier was investigated. A spray dryer and a rotavapor were applied to obtain binary systems containing either 50% or 66% of the drug. Applied techniques led to the formation of amorphous solid dispersions as confirmed by X-ray powder diffractometry and differential scanning calorimetry. Moreover, solid–solid transition from polymorphic form I to form II was observed for bicalutamide spray dried without a carrier. The presence of intermolecular interactions between the drug and polymer molecules, which provides the stabilization of molecularly disordered bicalutamide, was analyzed using infrared spectroscopy. Spectral changes within the region characteristic for amide vibrations suggested that the amide form of crystalline bicalutamide was replaced by a less stable imidic one, characteristic of an amorphous drug. Applied processes also resulted in changes of particle geometry and size as confirmed by scanning electron microscopy and laser diffraction measurements, however they did not affect the dissolution significantly as confirmed by intrinsic dissolution study. The enhancement of apparent solubility and dissolution were assigned mostly to the loss of molecular arrangement by drug molecules. Performed statistical analysis indicated that the presence of PVP reduces the mean dissolution time and improve the dissolution efficiency. Although the dissolution was equally affected by both applied methods of solid dispersion manufacturing, spray drying provides better control of particle size and morphology as well as a lower tendency for recrystallization of amorphous solid dispersions. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Enhanced Bioavailability of Tadalafil after Intranasal Administration in Beagle Dogs
Pharmaceutics 2018, 10(4), 187; https://doi.org/10.3390/pharmaceutics10040187 - 15 Oct 2018
Cited by 7
Abstract
Tadalafil is an oral selective phosphodiesterase type-5 inhibitor with demonstrated efficacy and safety that is used to treat erectile dysfunction. The purpose of this study is to compare the pharmacokinetic properties of tadalafil after conventional oral tablet administration and novel intranasal administration in [...] Read more.
Tadalafil is an oral selective phosphodiesterase type-5 inhibitor with demonstrated efficacy and safety that is used to treat erectile dysfunction. The purpose of this study is to compare the pharmacokinetic properties of tadalafil after conventional oral tablet administration and novel intranasal administration in beagle dogs. Fourteen 13-month-old male beagle dogs were randomly divided into two groups, and were given 5 mg tadalafil orally or intranasally in a parallel design. Blood samples were collected before and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 36 h after administration. The plasma concentration of tadalafil was determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The systemic exposure and absorption rate of tadalafil were significantly greater in the intranasal administration group than in the oral administration group. A one-compartment model with first-order absorption and elimination was sufficient to explain the pharmacokinetic characteristics observed after both oral and intranasal administration. This study indicates that the development of tadalafil nasal delivery systems is feasible and may lead to better results than the conventional oral route. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Effects of Formulation and Process Variables on Gastroretentive Floating Tablets with A High-Dose Soluble Drug and Experimental Design Approach
Pharmaceutics 2018, 10(3), 161; https://doi.org/10.3390/pharmaceutics10030161 - 17 Sep 2018
Cited by 13
Abstract
To develop sustained release gastro-retentive effervescent floating tablets (EFT), a quality-based experimental design approach was utilized during the composing of a hydrophilic matrix loaded with a high amount of a highly water-soluble model drug, metformin HCl. Effects of the amount of polyethylene oxide [...] Read more.
To develop sustained release gastro-retentive effervescent floating tablets (EFT), a quality-based experimental design approach was utilized during the composing of a hydrophilic matrix loaded with a high amount of a highly water-soluble model drug, metformin HCl. Effects of the amount of polyethylene oxide WSR 303 (PEO), sodium bicarbonate, and tablet compression force were used as independent variables. Various times required to release the drug, tablet tensile strength, floating lag time, tablet ejection force, and tablet porosity, were selected as the responses. Polymer screening showed that PEO had the highest gel strength among the various tested polymers. Sodium bicarbonate had the most significant effect on the release rate and floating lag time by retarding the rate from the hydrophilic matrices, whilst tablet compression force and PEO exerted the greatest influence on tablet properties (p < 0.0001). The design space was built in accordance with the drug release profiles, tensile strength, and floating lag time, following failure probability analysis using Monte Carlo simulations. The kinetic modeling revealed that the release mechanism was best described by the Korsmeyer-Peppas model. Overall, the current study provided a perspective on the systematic approach of gastro-retentive EFT, loaded with highly water-soluble drugs by applying quality by design concepts. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Dissolution Enhancement in Cocoa Extract, Combining Hydrophilic Polymers through Hot-Melt Extrusion
Pharmaceutics 2018, 10(3), 135; https://doi.org/10.3390/pharmaceutics10030135 - 21 Aug 2018
Cited by 5
Abstract
The aim of this study was to improve the physicochemical properties of cocoa extract (CE) using hot-melt extrusion (HME) for pharmaceutical proposes. A mixture design was applied using three distinct hydrophilic polymeric matrices (Soluplus, Plasdone S630, and Eudragit E). Systems obtained by HME [...] Read more.
The aim of this study was to improve the physicochemical properties of cocoa extract (CE) using hot-melt extrusion (HME) for pharmaceutical proposes. A mixture design was applied using three distinct hydrophilic polymeric matrices (Soluplus, Plasdone S630, and Eudragit E). Systems obtained by HME were evaluated using morphologic, chromatographic, thermic, spectroscopic, and diffractometric assays. The flow, wettability, and dissolution rate of HME powders were also assessed. Both CE and its marker theobromine proved to be stable under heating according to thermal analysis and Arrhenius plot under isothermal conditions. Physicochemical analysis confirmed the stability of CE HME preparations and provided evidence of drug–polymer interactions. Improvements in the functional characteristics of CE were observed after the extrusion process, particularly in dissolution and flow properties. In addition, the use of a mixture design allowed the identification of synergic effects by excipient combination. The optimized combination of polymers obtained considering four different aspects showed that a mixture of the Soluplus, Plasdone S630, and Eudragit E in equal proportions produced the best results (flowability index 88%; contact angle 47°; dispersibility 7.5%; and dissolution efficiency 87%), therefore making the pharmaceutical use of CE more feasible. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle
Development and Evaluation of Raloxifene-Hydrochloride-Loaded Supersaturatable SMEDDS Containing an Acidifier
Pharmaceutics 2018, 10(3), 78; https://doi.org/10.3390/pharmaceutics10030078 - 29 Jun 2018
Cited by 6
Abstract
Raloxifene hydrochloride (RLH) was formulated into a pH-modified supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) to increase drug solubility and dissolution rate. Optimal formulations of pH-modified S-SMEDDSs were developed by incorporating hydroxypropyl-cellulose-L as a precipitation inhibitor and phosphoric acid as a pH modifier (an [...] Read more.
Raloxifene hydrochloride (RLH) was formulated into a pH-modified supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) to increase drug solubility and dissolution rate. Optimal formulations of pH-modified S-SMEDDSs were developed by incorporating hydroxypropyl-cellulose-L as a precipitation inhibitor and phosphoric acid as a pH modifier (an acidifier). RLH was dissolved to greater extents by all pH-modified S-SMEDDSs compared with non-pH-modified S-SMEDDSs. In particular, phosphoric acid afforded greater drug dissolution than did the other acidifiers tested, perhaps because phosphoric acid better controlled the pH. More than 50% of the RLH was released from the pH-modified S-SMEDDS at pH 2.5 compared with only ~5% of the drug into aqueous buffer (pH 1.2 or 6.8) after dissolution of a conventional tablet. pH-modified S-SMEDDSs with a hydrophilic polymer and phosphoric acid improved the dissolution behavior of a drug exhibiting poor aqueous solubility. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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