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Solubilization and Controlled Release of Poorly Water-Soluble Drugs

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 52819

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Special Issue Editors

Prof. Dr. Beom-Jin Lee

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Guest Editor

College of Pharmacy, Ajou University, Suwon 16499, Korea
Interests: controlled bioavailability of poorly soluble and poorly absorbable drugs; solubilization, formulation, and development of patient-centric dosage forms; advanced nano-based delivery systems using fattigation (fatty acid conjugation) and click chemistry
Special Issues, Collections and Topics in MDPI journals

Dr. Phuong Ha-Lien Tran

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School of Medicine and Institute for Mental and Physical Health and Clinical Translation (iMPACT), Deakin University, Australia
Interests: bioavailability; solubilization technology; controlled delivery systems; targeted nano-delivery systems; extracellular vesicles; theranostics

Special Issue Information

Dear Colleagues,

In the last decade, emerging trends in combinatorial chemistry and drug design have rendered newly developed drug molecules with higher lipophilicity, larger molecular weight, and poor water solubility. These properties are associated with a variety of rate limiting dissolution, slow absorption, and low bioavailability that may lead to the failures of developing many promising agents, including lead compounds, in vital therapeutic areas. At first, the optimization of physicochemical properties of such poorly water-soluble molecules for enhanced solubility, dissolution, and ultimately enhanced bioavailability is the most important prerequisite for pharmaceutical researchers to develop drug products. A variety of approaches have been used to overcome the poor water solubility and enhance the dissolution rate of drugs, such as solid dispersion, salt formation, supercritical fluid technology, prodrugs, co-crystal formation, cyclodextrin complexes, lipid-based formulations, and nanosized drug delivery systems, etc. Secondly, to achieve an appropriate delivery system of poorly water soluble drugs that can modulate the drug release at desired rates, times and/ or locations for an effective medication, state-of-art technologies of engineering the surface of delivery systems as well as a modification of the payload are taken into consideration. Of note, once these delivery systems are formulated to satisfy enhanced solubility and controlled release, they offer several patient-centered advantages, such as reduced high total doses, reduced dosing frequency, and gastrointestinal side effects, and improved patient acceptance and compliance. In addition, the most up-to-date studies have showcased promising natural delivery systems of poor water molecules with versatile and multifunctional activities as the next generation of theranostic (therapeutic and diagnostic) applications in medicine.

This Special Issue aims to highlight the latest progress and research of pharmaceutical and biopharmaceutical technologies to address and solve the problems of poorly water-soluble drugs, as well as present innovative delivery systems of these drugs and formulation of various routes of administration via solubilization and controlled release. The Special Issue also covers studies that could help shed light on how the new delivery systems worked out to present the most relevant contributions in developing effective medical applications of poorly water soluble drugs for patient centricity.

Prof. Dr. Beom-Jin Lee
Dr. Phuong Ha-Lien Tran
Guest Editors

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Keywords

solubilization technology
controlled release
poorly water soluble drug
drug delivery sytems
formulation of various routes of administration
pharmaceutical technology
surface engineering
biopharmaceutics
therapeutics/ Diagnostics
patient centricity and unmet medical needs

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Published Papers (13 papers)

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28 pages, 20225 KiB

Open AccessArticle

The Promising Role of Chitosan–Poloxamer 188 Nanocrystals in Improving Diosmin Dissolution and Therapeutic Efficacy against Ferrous Sulfate-Induced Hepatic Injury in Rats

by Neamet S. Lotfy, Thanaa M. Borg and Elham A. Mohamed

Pharmaceutics 2021, 13(12), 2087; https://doi.org/10.3390/pharmaceutics13122087 - 5 Dec 2021

Cited by 9 | Viewed by 2665

Abstract

Diosmin (DSN) exhibits poor water solubility and low bioavailability. Although nanocrystals (NCs) are successful for improving drug solubility, they may undergo crystal growth. Therefore, DSN NCs were prepared, employing sonoprecipitation utilizing different stabilizers. The optimum stabilizer was combined with chitosan (CS) as an electrostatic stabilizer. NCs based on 0.15% w/v poloxamer 188 (PLX188) as a steric stabilizer and 0.04% w/v CS were selected because they showed the smallest diameter (368.93 ± 0.47 nm) and the highest ζ-potential (+40.43 ± 0.15 mV). Mannitol (1% w/v) hindered NC enlargement on lyophilization. FT-IR negated the chemical interaction of NC components. DSC and XRD were performed to verify the crystalline state. DSN dissolution enhancement was attributed to the nanometric rod-shaped NCs, the high surface area, and the improved wettability. CS insolubility and its diffusion layer may explain controlled DSN release from CS-PLX188 NCs. CS-PLX188 NCs were more stable than PLX188 NCs, suggesting the significance of the combined electrostatic and steric stabilization strategies. The superiority of CS-PLX188 NCs was indicated by the significantly regulated biomarkers, pathological alterations, and inducible nitric oxide synthase (iNOS) expression of the hepatic tissue compared to DSN suspension and PLX188 NCs. Permeation, mucoadhesion, and cellular uptake enhancement by CS may explain this superiority. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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14 pages, 3680 KiB

Open AccessArticle

Antimicrobial Activities of Propolis in Poloxamer Based Topical Gels

by Seong-Hyeon An, Eunmi Ban, In-Young Chung, You-Hee Cho and Aeri Kim

Pharmaceutics 2021, 13(12), 2021; https://doi.org/10.3390/pharmaceutics13122021 - 26 Nov 2021

Cited by 15 | Viewed by 2823

Abstract

Propolis contains a group of compounds with various activities. However, their low solubility is a drawback for the development of pharmaceutical formulations. In this study, poloxamers as a solubilizer and gelling agent were evaluated to develop a topical antimicrobial formulation of propolis. The effects of poloxamer type and concentration on the propolis solubility, release rate, and antimicrobial activities were investigated. Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) were the representative bacteria and fungi, respectively. At 5%, poloxamer 407 (P407) and poloxamer 188 (P188) enhanced the propolis solubility by 2.86 and 2.06 folds, respectively; at 10%, they were 2.81 and 2.59 folds, respectively. The micelle size in the P188 formulation increased in the presence of propolis, whereas there was no change in the P407 formulation. Release rates of propolis decreased with the P188 concentration increase, which was attributed to viscosity increase. Both P188 and P407 formulations showed antimicrobial activity against S. aureus in a time-kill kinetics assay. However, only the P188 formulation reduced the cell’s numbers significantly against C. albicans, compared to the control. We speculate that P188 mixed micelles were more effective in releasing free active compounds to exhibit anti-microbial activity compared to the P407 micelles encapsulating the hydrophobic compounds in their cores. Propolis in P188 formulation is proposed as a potential topical antimicrobial agent based on its activity against both S. aureus and C. albicans. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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21 pages, 3126 KiB

Open AccessArticle

Supersaturation and Solubilization upon In Vitro Digestion of Fenofibrate Type I Lipid Formulations: Effect of Droplet Size, Surfactant Concentration and Lipid Type

by Vladimir Katev, Sonya Tsibranska-Gyoreva, Zahari Vinarov and Slavka Tcholakova

Pharmaceutics 2021, 13(8), 1287; https://doi.org/10.3390/pharmaceutics13081287 - 18 Aug 2021

Cited by 4 | Viewed by 2657

Abstract

Lipid-based formulations (LBF) enhance oral drug absorption by promoting drug solubilization and supersaturation. The aim of the study was to determine the effect of the lipid carrier type, drop size and surfactant concentration on the rate of fenofibrate release in a bicarbonate-based in vitro digestion model. The effect of the lipid carrier was studied by preparing type I LBF with drop size ≈ 2 µm, based on medium-chain triglycerides (MCT), sunflower oil (SFO), coconut oil (CNO) and cocoa butter (CB). The drop size and surfactant concentration effects were assessed by studying MCT and SFO-based formulations with a drop size between 400 nm and 14 µm and surfactant concentrations of 1 or 10%. A filtration through a 200 nm filter followed by HPLC analysis was used to determine the aqueous fenofibrate, whereas lipid digestion was followed by gas chromatography. Shorter-chain triglycerides were key in promoting a faster drug release. The fenofibrate release from long-chain triglyceride formulations (SFO, CNO and CB) was governed by solubilization and was enhanced at a smaller droplet size and higher surfactant concentration. In contrast, supersaturation was observed after the digestion of MCT emulsions. In this case, a smaller drop size and higher surfactant had negative effects: lower peak fenofibrate concentrations and a faster onset of precipitation were observed. The study provides new mechanistic insights on drug solubilization and supersaturation after LBF digestion, and may support the development of new in silico prediction models. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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21 pages, 5382 KiB

Open AccessArticle

Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches

by Yanqing Wang, Weijuan Huang, Nannan Wang, Defang Ouyang, Lifeng Xiao, Sirui Zhang, Xiaozheng Ou, Tingsha He, Rongmin Yu and Liyan Song

Pharmaceutics 2021, 13(8), 1236; https://doi.org/10.3390/pharmaceutics13081236 - 11 Aug 2021

Cited by 4 | Viewed by 2709

Abstract

Arteannuin B (AB) has been found to demonstrate obvious anti-tumor activity. However, AB is not available for clinical use due to its very low solubility and very short half-life. This study aimed to develop AB long sustained-release microspheres (ABMs) to improve the feasibility of clinical applications. Firstly, AB-polylactic-co-glycolic acid (PLGA) microspheres were prepared by a single emulsification method. In vitro characterization studies showed that ABMs had a low burst release and stable in vitro release for up to one week. The particle size of microspheres was 69.10 μm (D₅₀). The drug loading is 37.8%, and the encapsulation rate is 85%. Moreover, molecular dynamics modeling was firstly used to simulate the preparation process of microspheres, which clearly indicated the molecular image of microspheres and provided in-depth insights for understanding several key preparation parameters. Next, in vivo pharmacokinetics (PK) study was carried out to evaluate its sustained release effect in Sprague-Dawley (SD) rats. Subsequently, the methyl thiazolyl tetrazolium (MTT) method with human lung cancer cells (A549) was used to evaluate the in vitro efficacy of ABMs, which showed the IC₅₀ of ABMs (3.82 μM) to be lower than that of AB (16.03 μM) at day four. Finally, in vivo anti-tumor activity and basic toxicity studies were performed on BALB/c nude mice by subcutaneous injection once a week, four times in total. The relative tumor proliferation rate T/C of AMBs was lower than 40% and lasted for 21 days after administration. The organ index, organ staining, and tumor cell staining indicated the excellent safety of ABMs than Cis-platinum. In summary, the ABMs were successfully developed and evaluated with a low burst release and a stable release within a week. Molecular dynamics modeling was firstly applied to investigate the molecular mechanism of the microsphere preparation. Moreover, the ABMs possess excellent in vitro and in vivo anti-tumor activity and low toxicity, showing great potential for clinical applications. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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16 pages, 3089 KiB

Open AccessArticle

Biobased Ionic Liquids as Multitalented Materials in Lipidic Drug Implants

by Ana Júlio, Anaisa Sultane, Ana Silveira Viana, Joana Portugal Mota and Tânia Santos de Almeida

Pharmaceutics 2021, 13(8), 1163; https://doi.org/10.3390/pharmaceutics13081163 - 28 Jul 2021

Cited by 4 | Viewed by 2060

Abstract

Lipidic implants are valuable controlled delivery systems that present good biocompatibility and are useful for long-lasting therapies. However, these promising systems can present inflexible drug release profiles that limit their performance. Thus, finding new materials to overcome this drawback is crucial. Herein, lipidic implants containing caffeine and poorly soluble salicylic acid and rutin were developed. The inclusion of Gelucire^® 50/02, sucrose, and two biobased ionic liquids, [Cho][Phe] and [Cho][Glu], were evaluated as a mean to improve the performance of the systems. The formulation procedure, dye content distribution, drug content, drug release, water content, and lipidic erosion of the developed systems were assessed. AFM analysis of the implants containing ILs was also performed. The results demonstrated that neither Gelucire^® 50/02 nor sucrose were suitable tools to improve the drug release profile. In contrast, the ILs proved to be promising materials for multiple reasons; not only did they facilitate the formulation and incorporation of the studied drugs into the implants, but they also allowed a more suitable release profile, with [Cho][Glu] allowing a higher drug release due to its ability to increase surface wrinkling. Hence, this study showcases ILs as multitalented materials in lipid-based drug implants. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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10 pages, 2268 KiB

Open AccessArticle

High Solubilization and Controlled Release of Paclitaxel Using Thermosponge Nanoparticles for Effective Cancer Therapy

by Jin Sil Lee, Hyeryeon Oh, Daekyung Sung, Jin Hyung Lee and Won Il Choi

Pharmaceutics 2021, 13(8), 1150; https://doi.org/10.3390/pharmaceutics13081150 - 27 Jul 2021

Cited by 7 | Viewed by 2163

Abstract

Cancer, which is a leading cause of death, contributes significantly to reducing life expectancy worldwide. Even though paclitaxel (PTX) is known as one of the main anticancer drugs, it has several limitations, including low solubility in aqueous solutions, a limited dosage range, an insufficient release amount, and patient resistance. To overcome these limitations, we suggest the development of PTX-loaded thermosponge nanoparticles (PTX@TNP), which result in improved anticancer effects, via a simple nanoprecipitation method, which allows the preparation of PTX@TNPs with hydrophobic interactions without any chemical conjugation. Further, to improve the drug content and yield of the prepared complex, the co-organic solvent ratio was optimized. Thus, it was observed that the drug release rate increased as the drug capacity of PTX@TNPs increased. Furthermore, increasing PTX loading led to considerable anticancer activity against multidrug resistance (MDR)-related colorectal cancer cells (HCT 15), implying a synergistic anticancer effect. These results suggest that the solubilization of high drug amounts and the controlled release of poorly water-soluble PTX using TNPs could significantly improve its anticancer therapy, particularly in the treatment of MDR-p-glycoprotein-overexpressing cancers. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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16 pages, 2382 KiB

Open AccessArticle

Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease

by Tarek A. Ahmed, Khalid M. El-Say, Fathy I. Abd-Allah, Abdelsattar M. Omar, Moustafa E. El-Araby, Yosra A. Muhammad, Piyusha P. Pagare, Yan Zhang, Khadijah A. Mohmmad, Osheiza Abdulmalik and Martin K. Safo

Pharmaceutics 2021, 13(8), 1148; https://doi.org/10.3390/pharmaceutics13081148 - 27 Jul 2021

Cited by 5 | Viewed by 2319

Abstract

Background: Aromatic aldehydes, with their ability to increase the oxygen affinity of sickle hemoglobin, have become important therapeutic agents for sickle cell disease (SCD). One such compound, voxelotor, was recently approved for SCD treatment. Methyl 6-((2-formyl-3-hydroxyphenoxy)methyl) picolinate (PP10) is another promising aromatic aldehyde, recently reported by our group. Like voxelotor, PP10 exhibits O₂-dependent antisickling activity, but, unlike voxelotor, PP10 shows unique O₂-independent antisickling effect. PP10, however, has limited solubility. This study therefore aimed to develop oral and parenteral formulations to improve PP10 solubility and bioavailability. Methods: Oral drug tablets with 2-hydroxypropyl beta cyclodextrin (HP-β-CD), polyvinylpyrrolidone, or Eudragit L100-55 PP10-binary system, and an intravenous (IV) formulation with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or HP-β-CD, were developed. The pharmacokinetic behavior of the formulations was studied in Sprague-Dawley rats. PP10, a methylester, and its acid metabolite were also studied in vitro with sickle whole blood to determine their effect on Hb modification, Hb oxygen affinity, and sickle red blood cell inhibition. Results: Aqueous solubility of PP10 was enhanced ~5 times with the HP-β-CD binary system, while the TPGS aqueous micelle formulation was superior, with a drug concentration of 0.502 ± 0.01 mg/mL and a particle size of 26 ± 3 nm. The oral tablets showed relative and absolute bioavailabilities of 173.4% and 106.34%, respectively. The acid form of PP10 appeared to dominate in vivo, although both PP10 forms demonstrated pharmacologic effect. Conclusion: Oral and IV formulations of PP10 were successfully developed using HP-β-CD binary system and TPGS aqueous micelles, respectively, resulting in significantly improved solubility and bioavailability. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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14 pages, 4020 KiB

Open AccessArticle

Enhanced Bioavailability of AC1497, a Novel Anticancer Drug Candidate, via a Self-Nanoemulsifying Drug Delivery System

by Kshitis Chandra Baral, Jae-Geun Song, Sang Hoon Lee, Rajiv Bajracharya, Godesi Sreenivasulu, Minkyoung Kim, Kyeong Lee and Hyo-Kyung Han

Pharmaceutics 2021, 13(8), 1142; https://doi.org/10.3390/pharmaceutics13081142 - 27 Jul 2021

Cited by 18 | Viewed by 3833

Abstract

AC1497 is an effective dual inhibitor of malate dehydrogenase 1 and 2 targeting cancer metabolism. However, its poor aqueous solubility results in low bioavailability, limiting its clinical development. This study was conducted to develop an effective self-nanoemulsifying drug delivery system (SNEDDS) of AC1497 to improve its oral absorption. Based on the solubility of AC1497 in various oils, surfactants, and cosurfactants, Capryol 90, Kolliphor RH40, and Transcutol HP were selected as the components of SNEDDS. After testing various weight ratios of Capryol 90 (20–30%), Kolliphor RH40 (35–70%), and Transcutol HP (10–35%), SNEDDS-F4 containing 20% Capryol 90, 45% Kolliphor RH40, and 35% Transcutol HP was identified as an optimal SNEDDS with a narrow size distribution (17.8 ± 0.36 nm) and high encapsulation efficiency (93.6 ± 2.28%). Drug release from SNEDDS-F4 was rapid, with approximately 80% of AC1497 release in 10 min while the dissolution of the drug powder was minimal (<2%). Furthermore, SNEDDS-F4 significantly improved the oral absorption of AC1497 in rats. The maximum plasma concentration and area under the plasma concentration–time curve of AC1497 were, respectively 6.82- and 3.14-fold higher for SNEDDS-F4 than for the drug powder. In conclusion, SNEDDS-F4 with Capryol 90, Kolliphor RH40, and Transcutol HP (20:45:35, w/w) effectively improves the solubility and oral absorption of AC1497. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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21 pages, 5055 KiB

Open AccessArticle

Experimental and Theoretical Study on Theobromine Solubility Enhancement in Binary Aqueous Solutions and Ternary Designed Solvents

by Tomasz Jeliński, Dawid Stasiak, Tomasz Kosmalski and Piotr Cysewski

Pharmaceutics 2021, 13(8), 1118; https://doi.org/10.3390/pharmaceutics13081118 - 22 Jul 2021

Cited by 11 | Viewed by 3519

Abstract

The solubility of theobromine was studied both experimentally and theoretically. The solubility was determined spectrophotometrically at 25 °C in neat organic solvents, aqueous binary mixtures, Natural Deep Eutectic Solvents (NADES) and ternary NADES mixtures with water. It was found that addition of water in unimolar proportions with some organic solvents increases theobromine solubility compared to neat solvents. Additionally, using NADES results in a solubility increase of the studied compound not only in relation to water but also DMSO. The addition of water (0.2 molar fraction) to NADES is responsible for an even larger increase of solubility. The measured solubilities were interpreted in terms of three theoretical frameworks. The first one—belonging to the set of data reduction techniques—proved to be very efficient in quantitative back-computations of excess solubility of theobromine in all studied systems. The default approach utilizing the well-recognized COSMO-RS (Conductor-like Screening Model for Real Solvents) framework offered at most a qualitative solubility description. The extended search for possible contacts provided evidence for the existence of many intermolecular complexes that alter the electron density of the solute molecule, thus influencing solubility computations. Taking into account such intermolecular contacts by using the COSMO-RS-DARE (Conductor-like Screening Model for Realistic Solvation-Dimerization, Aggregation, and Reaction Extension) framework seriously increased the accuracy of solubility computations. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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18 pages, 4217 KiB

Open AccessArticle

Development and Optimization of Cinnamon Oil Nanoemulgel for Enhancement of Solubility and Evaluation of Antibacterial, Antifungal and Analgesic Effects against Oral Microbiota

by Khaled M. Hosny, Rasha A. Khallaf, Hani Z. Asfour, Waleed Y. Rizg, Nabil A. Alhakamy, Amal M. Sindi, Hala M. Alkhalidi, Walaa A. Abualsunun, Rana B. Bakhaidar, Alshaimaa M. Almehmady, Wesam H. Abdulaal, Muhammed A. Bakhrebah, Mohammed S. Alsuabeyl, Ahmed K. Kammoun, Adel F. Alghaith and Sultan Alshehri

Pharmaceutics 2021, 13(7), 1008; https://doi.org/10.3390/pharmaceutics13071008 - 2 Jul 2021

Cited by 21 | Viewed by 3866

Abstract

Oral health is a key contributor to a person’s overall health and well-being. Oral microbiota can pose a serious threat to oral health. Thus, the present study aimed to develop a cinnamon oil (CO)-loaded nanoemulsion gel (NEG1) to enhance the solubilization of oil within the oral cavity, which will enhance its antibacterial, antifungal, and analgesic actions against oral microbiota. For this purpose, the CO-loaded nanoemulsion (CO-NE) was optimized using I-optimal response surface design. A mixture of Pluracare L44 and PlurolOleique CC 497 was used as the surfactant and Capryol was used as the co-surfactant. The optimized CO-NE had a globule size of 92 ± 3 nm, stability index of 95% ± 2%, and a zone of inhibition of 23 ± 1.5 mm. This optimized CO-NE formulation was converted into NEG1 using 2.5% hydroxypropyl cellulose as the gelling agent. The rheological characterizations revealed that the NEG1 formulation exhibited pseudoplastic behavior. The in vitro release of eugenol (the marker molecule for CO) from NEG1 showed an enhanced release compared with that of pure CO. The ex vivo mucosal permeation was found to be highest for NEG1 compared to the aqueous dispersion of CO-NE and pure cinnamon oil. The latency reaction time during the hot-plate test in rats was highest (45 min) for the NEG1 sample at all-time points compared with those of the other tested formulations. The results showed that the CO-NEG formulation could be beneficial in enhancing the actions of CO against oral microbiota, as well as relieving pain and improving overall oral health. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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17 pages, 1740 KiB

Open AccessArticle

Investigating In Vitro and Ex Vivo Properties of Artemether/Lumefantrine Double-Fixed Dose Combination Lipid Matrix Tablets Prepared by Hot Fusion

by Christi A. Wilkins, Lissinda H. du Plessis and Joe M. Viljoen

Pharmaceutics 2021, 13(7), 922; https://doi.org/10.3390/pharmaceutics13070922 - 22 Jun 2021

Cited by 4 | Viewed by 2404

Abstract

Highly lipophilic antimalarial drugs, artemether and lumefantrine, whilst an effective fixed-dose combination treatment to lower the malarial disease burden, are therapeutically hindered by low aqueous solubility and varied bioavailability. This work investigates the plausibility of directly compressed lipid matrix tablets, their role as lipid-based formulations and their future standing as drug delivery systems. Lipid matrix tablets were manufactured from solid lipid dispersions in various lipid:drug ratios employing hot fusion—the melt mixing of highly lipophilic drugs with polymer(s). Sequential biorelevant dissolution media, multiple mathematical models and ex vivo analysis utilizing porcine tissue samples were employed to assess drug release kinetics and more accurately predict in vitro performance. Directly compressed stearic acid tablets in a 0.5:1 lipid:drug ratio were deemed optimal within investigated parameters. Biorelevant media was of immense value for artemether release analysis, with formulation SA0.5C1 (Stearic Acid:double fixed dose in a 0.5:1 ratio (i.e., Stearic acid 70 mg + Lumefantrine 120 mg + Artemether 20 mg); CombiLac^® as filler (q.s.); and 1% w/w magnesium stearate) yielding a higher percentage of artemether release (97.21%) than the commercially available product, Coartem^® (86.12%). However, dissolution media lacked the specificity to detect lumefantrine. Nonetheless, stearic acid lipid:drug ratios governed drug release mechanisms. This work demonstrates the successful utilization of lipids as pharmaceutical excipients, particularly in the formulation of lipid matrix tablets to augment the dissolution of highly lipophilic drugs, and could thus potentially improve current malarial treatment regimens. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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14 pages, 18262 KiB

Open AccessArticle

Role of Surfactant Micellization for Enhanced Dissolution of Poorly Water-Soluble Cilostazol Using Poloxamer 407-Based Solid Dispersion via the Anti-Solvent Method

by Gang Jin, Hai V. Ngo, Jing-Hao Cui, Jie Wang, Chulhun Park and Beom-Jin Lee

Pharmaceutics 2021, 13(5), 662; https://doi.org/10.3390/pharmaceutics13050662 - 5 May 2021

Cited by 16 | Viewed by 4238

Abstract

This study aimed to investigate the role of micellization of sodium lauryl sulfate (SLS) in poloxamer 407 (POX)-based solid dispersions (POX-based SDs) using the anti-solvent method in enhancing the dissolution rate of practically water-insoluble cilostazol (CLT). Herein, SLS was incorporated into CLT-loaded SDs, at a weight ratio of 50:50:10 of CLT, POX, and SLS by three different methods: anti-solvent, fusion (60 °C), and solvent (ethanol) evaporation. The SDs containing micellar SLS in the anti-solvent method were superior in the transformation of the crystalline form of the drug into a partial amorphous state. It was notable that there was an existence of a hydrophobic interaction between the surfactant and the hydrophobic regions of polymer chain via non-covalent bonding and the adsorption of micellar SLS to the POX-based SDs matrix. Moreover, SLS micellization via the anti-solvent method was effectively interleaved in SDs and adhered by the dissolved CLT, which precluded drug particles from aggregation and recrystallization, resulting in improved SD wettability (lower contact angle) and reduced particle size and dissolution rate. In contrast, SDs without micellar SLS prepared by the solvent method exerted drug recrystallization and an increase of particle size, resulting in decreased dissolution. Incorporation of surfactant below or above critical micellar concentration (CMC) in SDs using the anti-solvent method should be considered in advance. Dissolution results showed that the pre-added incorporation of micellar SLS into POX-based SDs using the anti-solvent method could provide a way of a solubilization mechanism to enhance the dissolution rate of poorly water-soluble drugs. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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30 pages, 3922 KiB

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Challenges of Dissolution Methods Development for Soft Gelatin Capsules

by Festo Damian, Mohammad Harati, Jeff Schwartzenhauer, Owen Van Cauwenberghe and Shawn D. Wettig

Pharmaceutics 2021, 13(2), 214; https://doi.org/10.3390/pharmaceutics13020214 - 4 Feb 2021

Cited by 26 | Viewed by 14729

Abstract

Recently, the development of soft gelatin capsules (SGCs) dosage forms has attracted a great deal of interest in the oral delivery of poorly water-soluble drugs. This is attributed to the increased number of poorly soluble drugs in the pipeline, and hence the challenges of finding innovative ways of developing bioavailable and stable dosage forms. Encapsulation of these drugs into SGCs is one of the approaches that is utilized to deliver the active ingredients to the systemic circulation to overcome certain formulation hurdles. Once formulated, encapsulated drugs in the form of SGCs require suitable in vitro dissolution test methods to ensure drug product quality and performance. This review focuses on challenges facing dissolution test method development for SGCs. A brief discussion of the physicochemical and formulation factors that affect the dissolution properties of SGCs will be highlighted. Likewise, the influence of cross-linking of gelatin on the dissolution properties of SGCs will also be discussed. Full article

(This article belongs to the Special Issue Solubilization and Controlled Release of Poorly Water-Soluble Drugs)

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