Pharmaceutics

13 pages, 3102 KiB

Open AccessArticle

Doxorubicin-Conjugated PAMAM Dendrimers for pH-Responsive Drug Release and Folic Acid-Targeted Cancer Therapy

by Mengen Zhang, Jingyi Zhu, Yun Zheng, Rui Guo, Shige Wang, Serge Mignani, Anne-Marie Caminade, Jean-Pierre Majoral and Xiangyang Shi

Pharmaceutics 2018, 10(3), 162; https://doi.org/10.3390/pharmaceutics10030162 - 19 Sep 2018

Cited by 73 | Viewed by 7271

Abstract

We present here the development of multifunctional doxorubicin (DOX)-conjugated poly(amidoamine) (PAMAM) dendrimers as a unique platform for pH-responsive drug release and targeted chemotherapy of cancer cells. In this work, we covalently conjugated DOX onto the periphery of partially acetylated and folic acid (FA)-modified [...] Read more.

We present here the development of multifunctional doxorubicin (DOX)-conjugated poly(amidoamine) (PAMAM) dendrimers as a unique platform for pH-responsive drug release and targeted chemotherapy of cancer cells. In this work, we covalently conjugated DOX onto the periphery of partially acetylated and folic acid (FA)-modified generation 5 (G5) PAMAM dendrimers through a pH-sensitive cis-aconityl linkage to form the G5.NHAc-FA-DOX conjugates. The formed dendrimer conjugates were well characterized using different methods. We show that DOX release from the G5.NHAc-FA-DOX conjugates follows an acid-triggered manner with a higher release rate under an acidic pH condition (pH = 5 or 6, close to the acidic pH of tumor microenvironment) than under a physiological pH condition. Both in vitro cytotoxicity evaluation and cell morphological observation demonstrate that the therapeutic activity of dendrimer-DOX conjugates against cancer cells is absolutely related to the DOX drug released. More importantly, the FA conjugation onto the dendrimers allowed a specific targeting to cancer cells overexpressing FA receptors (FAR), and allowed targeted inhibition of cancer cells. The developed G5.NHAc-FA-DOX conjugates may be used as a promising nanodevice for targeted cancer chemotherapy. Full article

(This article belongs to the Special Issue Dendrimers in Nanomedical Applications: Update and Future Directions)

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25 pages, 1487 KiB

Open AccessArticle

Effects of Formulation and Process Variables on Gastroretentive Floating Tablets with A High-Dose Soluble Drug and Experimental Design Approach

by Prakash Thapa and Seong Hoon Jeong

Pharmaceutics 2018, 10(3), 161; https://doi.org/10.3390/pharmaceutics10030161 - 17 Sep 2018

Cited by 36 | Viewed by 5973

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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18 pages, 3187 KiB

Open AccessArticle

Permeability Behavior of Nanocrystalline Solid Dispersion of Dipyridamole Generated Using NanoCrySP Technology

by Ashish Girdhar, Poonam Singh Thakur, Sneha Sheokand and Arvind K. Bansal

Pharmaceutics 2018, 10(3), 160; https://doi.org/10.3390/pharmaceutics10030160 - 17 Sep 2018

Cited by 12 | Viewed by 4533

Abstract

Nanocrystals research has been an area of significant interest lately, providing oral bioavailability benefits to solubility- and/or dissolution rate-limited drugs. Drug nanocrystals are generated using top-down or bottom-up technologies. Combination technologies (Nanoedge, Nanopure XP and SmartCrystal) have been recently developed to generate nanocrystals [...] Read more.

Nanocrystals research has been an area of significant interest lately, providing oral bioavailability benefits to solubility- and/or dissolution rate-limited drugs. Drug nanocrystals are generated using top-down or bottom-up technologies. Combination technologies (Nanoedge, Nanopure XP and SmartCrystal) have been recently developed to generate nanocrystals of improved properties. Our lab has also contributed in this field by providing a ‘novel’ platform technology, NanoCrySP, for the generation of nanocrystals. NanoCrySP-generated nanocrystals have improved the oral bioavailability of various molecules. In this study, we aim to assess the permeability behavior of nanocrystals generated by NanoCrySP. Three samples of Dipyridamole (DPM) drug were used in this study: (1) DPM (micron-sized powder), (2) nanocrystals of DPM (NS), generated by media milling (as control) and, (3) nanocrystalline solid dispersion containing DPM (NSD) in the matrix of mannitol (MAN), generated using NanoCrySP technology. In vitro (Caco-2 cell lines) and ex vivo (everted gut sac) studies were conducted in this work. Cellular permeability (P_app) from apical-to-basolateral side in Caco-2 cell monolayer was found to be in the order NS > NSD > DPM, which was the same as their apparent solubility values. Higher P_app from a basolateral-to-apical side suggested a significant contribution of the P-gp efflux transport for DPM, while NS exhibited much higher inhibition of the efflux mechanism than NSD. Both NS and NSD showed higher permeation from the jejunum region in the ex vivo everted gut sac study. Interestingly, P_app of NSD was similar to NS in ex vivo everted gut sac model, however, NSD showed higher mucoadhesion than NS and DPM in this study. Full article

(This article belongs to the Special Issue Feature Papers for 10th Anniversary of Pharmaceutics)

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26 pages, 1418 KiB

Open AccessReview

Mucosal Applications of Poloxamer 407-Based Hydrogels: An Overview

by Elena Giuliano, Donatella Paolino, Massimo Fresta and Donato Cosco

Pharmaceutics 2018, 10(3), 159; https://doi.org/10.3390/pharmaceutics10030159 - 12 Sep 2018

Cited by 196 | Viewed by 12238

Abstract

Poloxamer 407, also known by the trademark Pluronic^® F127, is a water-soluble, non-ionic triblock copolymer that is made up of a hydrophobic residue of polyoxypropylene (POP) between the two hydrophilic units of polyoxyethylene (POE). Poloxamer 407-based hydrogels exhibit an interesting reversible thermal [...] Read more.

Poloxamer 407, also known by the trademark Pluronic^® F127, is a water-soluble, non-ionic triblock copolymer that is made up of a hydrophobic residue of polyoxypropylene (POP) between the two hydrophilic units of polyoxyethylene (POE). Poloxamer 407-based hydrogels exhibit an interesting reversible thermal characteristic. That is, they are liquid at room temperature, but they assume a gel form when administered at body temperature, which makes them attractive candidates as pharmaceutical drug carriers. These systems have been widely investigated in the development of mucoadhesive formulations because they do not irritate the mucosal membranes. Based on these mucoadhesive properties, a simple administration into a specific compartment should maintain the required drug concentration in situ for a prolonged period of time, decreasing the necessary dosages and side effects. Their main limitations are their modest mechanical strength and, notwithstanding their bioadhesive properties, their tendency to succumb to rapid elimination in physiological media. Various technological approaches have been investigated in the attempt to modulate these properties. This review focuses on the application of poloxamer 407-based hydrogels for mucosal drug delivery with particular attention being paid to the latest published works. Full article

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22 pages, 6295 KiB

Open AccessArticle

Preparation, Characterization, and In Vivo Evaluation of an Oral Multiple Nanoemulsive System for Co-Delivery of Pemetrexed and Quercetin

by Rudra Pangeni, Vijay Kumar Panthi, In-Soo Yoon and Jin Woo Park

Pharmaceutics 2018, 10(3), 158; https://doi.org/10.3390/pharmaceutics10030158 - 12 Sep 2018

Cited by 30 | Viewed by 4993

Abstract

Co-administration of conventional and natural chemotherapeutics offers synergistic anticancer efficacy while minimizing adverse effects. In this study, an oral co-delivery system for pemetrexed (PMX) and quercetin (QCN) was designed based on water-in-oil-in-water nanoemulsion (NE), which is highly absorbable because it enhances the intestinal [...] Read more.

Co-administration of conventional and natural chemotherapeutics offers synergistic anticancer efficacy while minimizing adverse effects. In this study, an oral co-delivery system for pemetrexed (PMX) and quercetin (QCN) was designed based on water-in-oil-in-water nanoemulsion (NE), which is highly absorbable because it enhances the intestinal membrane permeability of PMX and aqueous solubility of QCN. To create this system, an ion-pairing complex of PMX with N^α-deoxycholyl-l-lysyl-methylester (DCK) was formed and further incorporated with QCN into the NE, yielding PMX/DCK-QCN-NE. The results revealed synergistic inhibitory effects on human lung carcinoma (A549) cell proliferation and migration after combined treatment with PMX/DCK and QCN. The intestinal membrane permeability and cellular uptake of PMX/DCK and QCN from the NE were significantly improved via facilitated transport of PMX by the interaction of DCK with bile acid transporters, as well as NE formulation-mediated alterations in the membrane structure and fluidity, which resulted in 4.51- and 23.9-fold greater oral bioavailability of PMX and QCN, respectively, than each free drug. Tumor growth in A549 cell-bearing mice was also maximally suppressed by 62.7% after daily oral administration of PMX/DCK-QCN-NE compared with controls. Thus, PMX/DCK-QCN-NE is a promising oral nanocarrier of PMX and QCN for synergistic anticancer efficacy and long-term chemotherapy. Full article

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22 pages, 919 KiB

Open AccessReview

Developments in Taste-Masking Techniques for Traditional Chinese Medicines

by Xiao Zheng, Fei Wu, Yanlong Hong, Lan Shen, Xiao Lin and Yi Feng

Pharmaceutics 2018, 10(3), 157; https://doi.org/10.3390/pharmaceutics10030157 - 12 Sep 2018

Cited by 42 | Viewed by 7941

Abstract

A variety of pharmacologically active substances, including chemotherapeutic drugs and the substances from traditional Chinese medicine (TCM), always exhibit potent bioactivities after oral administration. However, their unpleasant taste (such as bitterness) and/or odor always decrease patient compliance and thus compromise their curative efficacies [...] Read more.

A variety of pharmacologically active substances, including chemotherapeutic drugs and the substances from traditional Chinese medicine (TCM), always exhibit potent bioactivities after oral administration. However, their unpleasant taste (such as bitterness) and/or odor always decrease patient compliance and thus compromise their curative efficacies in clinical application. Therefore, the developments of taste-masking techniques are of great significance in improving their organoleptic properties. However, though a variety of taste-masking techniques have been successfully used to mask the unpalatable taste of chemotherapeutic drugs, their suitability for TCM substances is relatively limited. This is mainly due to the fact that the bitter ingredients existing in multicomponent TCM systems (i.e., effective fractions, single Chinese herbs, and compound preparations) are always unclear, and thus, there is lack of tailor-made taste-masking techniques to be utilized to conceal their unpleasant taste. The relevant studies are also relatively limited. As a whole, three types of taste-masking techniques are generally applied to TCM, including (i) functional masking via sweeteners, bitter blockers, and taste modifiers; (ii) physical masking via polymer film-coating or lipid barrier systems; and (iii) biochemical masking via intermolecular interaction, β-cyclodextrin inclusion, or ion-exchange resins. This review fully summarizes the results reported in this field with the purpose of providing an informative reference for relevant readers. Full article

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15 pages, 2339 KiB

Open AccessArticle

Effect on Nail Structure and Transungual Permeability of the Ethanol and Poloxamer Ratio from Cyclodextrin-Soluble Polypseudorotaxanes Based Nail Lacquer

by Elena Cutrín-Gómez, Soledad Anguiano-Igea, M. Begoña Delgado-Charro, José Luis Gómez-Amoza and Francisco J. Otero-Espinar

Pharmaceutics 2018, 10(3), 156; https://doi.org/10.3390/pharmaceutics10030156 - 11 Sep 2018

Cited by 16 | Viewed by 4657

Abstract

Aqueous-based nail lacquers have shown potential in promoting the diffusion of drugs into the nail. In our laboratory, we have recently developed a transungual delivery system based on an aqueous dispersion of cyclodextrin-poloxamer soluble polypseudorotaxanes, supramolecular host−guest assemblies that improves the drug permeation [...] Read more.

Aqueous-based nail lacquers have shown potential in promoting the diffusion of drugs into the nail. In our laboratory, we have recently developed a transungual delivery system based on an aqueous dispersion of cyclodextrin-poloxamer soluble polypseudorotaxanes, supramolecular host−guest assemblies that improves the drug permeation into the nail. However, the high-water content and the rheological and adhesive properties of this lacquer negatively affect properties that play a fundamental role in the patients’ acceptance such as stickiness, nail film formation or drying rate, properties. In this work, we have optimized the composition of these lacquers to improve these properties whilst maintaining good drug permeation profiles. Incorporating ethanol into the vehicle and reducing the proportion of Poloxamer 407 (PL), provided a good strategy. The use of hydro-ethanolic mixtures (>50% ethanol) and the reduction of the poloxamer concentration significantly improved the lacquer drying speed by reducing the stickiness and promoting film formation on the nail surface. Additionally, in a surprising way, the use of hydro-ethanolic vehicles further enhanced the permeation of ciclopirox olamine and clobetasol propionate, used for the treatment of onychomycosis and nail psoriasis respectively, into the nail and hooves. Full article

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13 pages, 6383 KiB

Open AccessArticle

Amorphous Nanoparticulate Formulation of Sirolimus and Its Tablets

by Yudong Shen, Xingya Li and Yuan Le

Pharmaceutics 2018, 10(3), 155; https://doi.org/10.3390/pharmaceutics10030155 - 11 Sep 2018

Cited by 16 | Viewed by 5288

Abstract

Nanocrystallization and amorphization have proven to be two effective strategies to improve the bioavailability of water-insoluble drugs. The purpose of our work was to develop a nano-formulated tablet of sirolimus (SRL) for enhanced dissolution. Amorphous SRL nanocomposites were prepared using anti-solvent precipitation via [...] Read more.

Nanocrystallization and amorphization have proven to be two effective strategies to improve the bioavailability of water-insoluble drugs. The purpose of our work was to develop a nano-formulated tablet of sirolimus (SRL) for enhanced dissolution. Amorphous SRL nanocomposites were prepared using anti-solvent precipitation via a high-gravity rotating packed bed. Various factors that affect particle size and size distribution, such as excipients, rotating speed, antisolvent/solvent flow rate, were investigated. Structure, stability and in vitro dissolution of the as-prepared SRL were evaluated. Furthermore, the nanoparticulated SRL tablet formula was screened to control drug release. Importantly, SRL tablets exhibit different dissolution profile by adjusting HPMC (hydroxypropyl methyl cellulose) content, which makes them more suitable for various formulation developments. Full article

(This article belongs to the Special Issue Novel Formulation Strategies for Enhancing Dissolution and/or Oral Bioavailability)

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13 pages, 1626 KiB

Open AccessFeature PaperArticle

Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice

by Hua Wang, Lifeng Xiao, Jianguo Tao, Venkat Srinivasan, Brendan F. Boyce, Frank H. Ebetino, Babatunde O. Oyajobi, Robert K. Boeckman, Jr. and Lianping Xing

Pharmaceutics 2018, 10(3), 154; https://doi.org/10.3390/pharmaceutics10030154 - 10 Sep 2018

Cited by 29 | Viewed by 5114

Abstract

Multiple myeloma (MM) is the most common cancer affecting the bone and bone marrow and remains incurable for most patients; novel therapies are therefore needed. Bortezomib (Btz) is an FDA-approved drug for the treatment of patients with MM. However, its severe side effects [...] Read more.

Multiple myeloma (MM) is the most common cancer affecting the bone and bone marrow and remains incurable for most patients; novel therapies are therefore needed. Bortezomib (Btz) is an FDA-approved drug for the treatment of patients with MM. However, its severe side effects require a dose reduction or the potential discontinuation of treatment. To overcome this limitation, we conjugated Btz to a bisphosphonate (BP) residue lacking anti-osteoclastic activity using a novel chemical linker and generated a new bone-targeted Btz-based (BP-Btz) proteasome inhibitor. We demonstrated that BP-Btz, but not Btz, bound to bone slices and inhibited the growth of MM cells in vitro. In a mouse model of MM, BP-Btz more effectively reduced tumor burden and bone loss with less systemic side effects than Btz. Thus, BP-Btz may represent a novel therapeutic approach to treat patients with MM. Full article

(This article belongs to the Special Issue Bone Targeted Drug Delivery)

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11 pages, 3281 KiB

Open AccessArticle

Iontophoretic Transdermal Delivery of Human Growth Hormone (hGH) and the Combination Effect of a New Type Microneedle, Tappy Tok Tok^®

by Gyubin Noh, Taekwang Keum, Jo-Eun Seo, Santosh Bashyal, Nyeon-Sik Eum, Min Jung Kweon, Sooyeun Lee, Dong Hwan Sohn and Sangkil Lee

Pharmaceutics 2018, 10(3), 153; https://doi.org/10.3390/pharmaceutics10030153 - 07 Sep 2018

Cited by 22 | Viewed by 5796

Abstract

Transdermal drug administration presents several advantages and it is therefore favorable as an alternative drug delivery route. However, transdermal delivery of biopharmaceutical drugs is made difficult by the skin barrier. Microneedle application and iontophoresis are strategies which can be used to overcome this [...] Read more.

Transdermal drug administration presents several advantages and it is therefore favorable as an alternative drug delivery route. However, transdermal delivery of biopharmaceutical drugs is made difficult by the skin barrier. Microneedle application and iontophoresis are strategies which can be used to overcome this barrier. Therefore, recombinant human growth hormone (rhGH) was used as a model macromolecular drug and was transdermally delivered using microneedle application and iontophoresis. Methylene blue staining, stereomicroscopy and scanning electron microscope (SEM) imaging were used to characterize the microchannels produced. To optimize the iontophoresis protocol, the effects of molecular charge and current density on transdermal delivery were evaluated in an in vitro permeation study using excised rat skin tissues. Using the optimized iontophoresis protocol, the combination effects of iontophoretic delivery via microchannels were evaluated in three different experimental designs. The flux obtained with anodal iontophoresis in citrate buffer was approximately 10-fold higher that that with cathodal iontophoresis in phosphate buffered saline (PBS). Flux also increased with current density in anodal iontophoresis. The combination of iontophoresis and microneedle application produced higher flux than single application. These results suggest that anodal iontophoresis with higher current density enhances the permeation of macromolecules through microchannels created by microneedles. In conclusion, the combination of iontophoresis and microneedles is a potential strategy for the enhancement of transdermal delivery of macromolecular drugs. Full article

(This article belongs to the Special Issue Iontophoresis for Drug Delivery and Non-Invasive Sampling Applications)

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15 pages, 1231 KiB

Open AccessArticle

Pharmacokinetics and Anti-Gastric Ulceration Activity of Oral Administration of Aceclofenac and Esomeprazole in Rats

by Tae Hwan Kim, Subindra Kazi Thapa, Da Young Lee, Seung Eun Chung, Jun Young Lim, Hyeon Myeong Jeong, Chang Ho Song, Youn-Woong Choi, Sang-Min Cho, Kyu-Yeol Nam, Won-Ho Kang, Soyoung Shin and Beom Soo Shin

Pharmaceutics 2018, 10(3), 152; https://doi.org/10.3390/pharmaceutics10030152 - 06 Sep 2018

Cited by 8 | Viewed by 5443

Abstract

This study examined the effects of esomeprazole on aceclofenac pharmacokinetics and gastrointestinal complications in rats. Aceclofenac alone, or in combination with esomeprazole, was orally administered to male Sprague-Dawley rats. Plasma concentrations of aceclofenac, its major metabolite diclofenac, and esomeprazole were simultaneously determined by [...] Read more.

This study examined the effects of esomeprazole on aceclofenac pharmacokinetics and gastrointestinal complications in rats. Aceclofenac alone, or in combination with esomeprazole, was orally administered to male Sprague-Dawley rats. Plasma concentrations of aceclofenac, its major metabolite diclofenac, and esomeprazole were simultaneously determined by a novel liquid chromatography-tandem mass spectrometry method. Gastrointestinal damage was determined by measuring ulcer area and ulcer lesion index of the stomach. Oral administration of aceclofenac induced significant gastric ulceration, which was inhibited by esomeprazole administration. Following concurrent administration of aceclofenac and esomeprazole, overall pharmacokinetic profiles of aceclofenac and metabolic conversion to diclofenac were unaffected by esomeprazole. Aceclofenac metabolism and pharmacokinetics were not subject to significant food effects, whereas bioavailability of esomeprazole decreased in fed compared to fasting conditions. In contrast, the pharmacokinetics of aceclofenac and esomeprazole were significantly altered by different dosing vehicles. These results suggest that co-administration of esomeprazole with aceclofenac may reduce aceclofenac-induced gastrointestinal complications without significant pharmacokinetic interactions. The optimal combination and clinical significance of the benefits of the combination of aceclofenac and esomeprazole need to be further evaluated. Full article

(This article belongs to the Special Issue Drug Metabolism, Pharmacokinetics and Bioanalysis)

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22 pages, 21305 KiB

Open AccessArticle

Development of Dual Drug Loaded Nanosized Liposomal Formulation by A Reengineered Ethanolic Injection Method and Its Pre-Clinical Pharmacokinetic Studies

by Muhammad Sarfraz, Attia Afzal, Tan Yang, Yongkang Gai, Shahid Masood Raza, Muhammad Waseem Khan, Yao Cheng, Xiang Ma and Guangya Xiang

Pharmaceutics 2018, 10(3), 151; https://doi.org/10.3390/pharmaceutics10030151 - 06 Sep 2018

Cited by 48 | Viewed by 5992

Abstract

Oleanolic acid (OA), which is a natural pentacyclic terpenoid, has been identified for hepato-protective, nephron-protective and cardio-tonic properties. In contrast, doxorubicin (DOX) is a famous anti-cancer drug but its efficacy is a question mark because of its known cardio-toxicity. We developed a combined [...] Read more.

Oleanolic acid (OA), which is a natural pentacyclic terpenoid, has been identified for hepato-protective, nephron-protective and cardio-tonic properties. In contrast, doxorubicin (DOX) is a famous anti-cancer drug but its efficacy is a question mark because of its known cardio-toxicity. We developed a combined nanoliposomal formulation of DOX with OA, as adjuvant, to overwhelm toxic effects of DOX without compromising anticancer activity. The entrapment efficiency and the particle size were brought in limit by the reengineered ethanolic injection method (REIM), without further extrusion. The developed formulations were stable over the study period of two months. A modified HPLC method was employed for the analysis of OA (drug retention time, Tr = 12 ± 1 min). The recovery of OA against spiked plasma samples was more than 90%. MTT assay showed anti-apoptotic synergism against HepG2 cells at non-fixed ratio (combination index, CI < 1). A sustained in vivo drug release of experimental drugs was depicted over 24 h. Histopathological examination and laboratory findings indicated no visible sign of toxicity in the treated mice group against combined delivery. Hence, this combined nanoliposomal formulation was tagged as a safer therapy for the DOX based cancer treatments. Full article

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20 pages, 1440 KiB

Open AccessReview

Thermo-Sensitive Vesicles in Controlled Drug Delivery for Chemotherapy

by Elisabetta Mazzotta, Lorena Tavano and Rita Muzzalupo

Pharmaceutics 2018, 10(3), 150; https://doi.org/10.3390/pharmaceutics10030150 - 05 Sep 2018

Cited by 46 | Viewed by 5210

Abstract

Thermo-sensitive vesicles are a promising tool for triggering the release of drugs to solid tumours when used in combination with mild hyperthermia. Responsivity to temperature makes them intelligent nanodevices able to provide a site-specific chemotherapy. Following a brief introduction concerning hyperthermia and its [...] Read more.

Thermo-sensitive vesicles are a promising tool for triggering the release of drugs to solid tumours when used in combination with mild hyperthermia. Responsivity to temperature makes them intelligent nanodevices able to provide a site-specific chemotherapy. Following a brief introduction concerning hyperthermia and its advantageous combination with vesicular systems, recent investigations on thermo-sensitive vesicles useful for controlled drug delivery in cancer treatment are reported in this review. In particular, the influence of bilayer composition on the in vitro and in vivo behaviour of thermo-sensitive formulations currently under investigation have been extensively explored. Full article

(This article belongs to the Special Issue Non-Ionic Surfactant Vesicles for Drug Delivery)

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14 pages, 1856 KiB

Open AccessArticle

Co-Amorphous Screening for the Solubility Enhancement of Poorly Water-Soluble Mirabegron and Investigation of Their Intermolecular Interactions and Dissolution Behaviors

by Ji-Hun An, Changjin Lim, Alice Nguvoko Kiyonga, In Hwa Chung, In Kyu Lee, Kilwoong Mo, Minho Park, Wonno Youn, Won Rak Choi, Young-Ger Suh and Kiwon Jung

Pharmaceutics 2018, 10(3), 149; https://doi.org/10.3390/pharmaceutics10030149 - 05 Sep 2018

Cited by 20 | Viewed by 4412

Abstract

In the present study, the screening of Mirabegron (MBR) co-amorphous was performed to produce water-soluble and thermodynamically stable MBR co-amorphous with the purpose of overcoming the water solubility problem of MBR. MBR is Biopharmaceutics Classification System (BCS) class II drug used for the [...] Read more.

In the present study, the screening of Mirabegron (MBR) co-amorphous was performed to produce water-soluble and thermodynamically stable MBR co-amorphous with the purpose of overcoming the water solubility problem of MBR. MBR is Biopharmaceutics Classification System (BCS) class II drug used for the treatment of an overreactive bladder. The co-amorphous screening was carried out by means of the vacuum evaporation crystallization technique in methanol solvent using three water-soluble carboxylic acids, characterized by a pKa difference greater than 3 with MBR such as fumaric acid (FA), l-pyroglutamic acid (PG), and citric acid (CA). Powder X-ray diffraction (PXRD) results suggested that all solid materials produced at MBR-FA (1 equivalent (eq.)/1 equivalent (eq.)), MBR-PG (1 eq./1 eq.), and MBR-CA (1 eq./1 eq.) conditions were amorphous state solid materials. Furthermore, by means of solution-state nuclear magnetic resonance (NMR) (¹H, ¹³C, and 2D) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy, we could assess that MBR and carboxylic acid molecules were linked via ionic interactions to produce MBR co-amorphous. Besides, solid-state cross polarization (CP)/magic angle spinning (MAS) ¹³C-NMR analysis was conducted for additional assessment of MBR co-amorphous. Afterwards, dissolution tests of MBR co-amorphouses, MBR crystalline solid, and MBR amorphous were carried out for 12 h to evaluate and to compare their solubilities, dissolution rates, and phase transformation phenomenon. Here, the results suggested that MBR co-amorphouses displayed more than 57-fold higher aqueous solubility compared to MBR crystalline solid, and PXRD monitoring result suggested that MBR co-amorphouses were able to maintain their amorphous state for more than 12 h. The same results revealed that MBR amorphous exhibited increased solubility of approximatively 6.7-fold higher compared to MBR crystalline solid. However, the PXRD monitoring result suggested that MBR amorphous undergo rapid phase transformation to crystalline form in just 35 min and that within an hour all MBR amorphous are completely converted to crystalline solid. Accordingly, the increase in MBR co-amorphous’ solubility was attributed to the presence of ionic interactions in MBR co-amorphous molecules. Moreover, from the differential scanning calorimetry (DSC) monitoring results, we predicted that the high glass transition temperature (T_g) of MBR co-amorphous compared to MBR amorphous was the main factor influencing the phase stability of MBR co-amorphous. Full article

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10 pages, 1351 KiB

Open AccessArticle

Franz Diffusion Cell Approach for Pre-Formulation Characterisation of Ketoprofen Semi-Solid Dosage Forms

by Constain H. Salamanca, Alvaro Barrera-Ocampo, Juan C. Lasso, Nathalia Camacho and Cristhian J. Yarce

Pharmaceutics 2018, 10(3), 148; https://doi.org/10.3390/pharmaceutics10030148 - 05 Sep 2018

Cited by 108 | Viewed by 36277

Abstract

This study aimed to evaluate and compare, using the methodology of Franz diffusion cells, the ketoprofen (KTP) releasing profiles of two formulations: A gel and a conventional suspension. The second aim was to show that this methodology might be easily applied for the [...] Read more.

This study aimed to evaluate and compare, using the methodology of Franz diffusion cells, the ketoprofen (KTP) releasing profiles of two formulations: A gel and a conventional suspension. The second aim was to show that this methodology might be easily applied for the development of semi-solid prototypes and claim proof in pre-formulation stages. Drug release analysis was carried out under physiological conditions (pH: 5.6 to 7.4; ionic strength 0.15 M; at 37 °C) for 24 h. Three independent vertical Franz cells were used with a nominal volume of the acceptor compartment of 125 mL and a diffusion area of 2.5 cm². Additionally, two different membranes were evaluated: A generic type (regenerated cellulose) and a transdermal simulation type (Strat-M^®). The KTP permeation profiles demonstrated that depending on the membrane type and the vehicle used, the permeation is strongly affected. High permeation efficiencies were obtained for the gel formulation, and the opposite effect was observed for the suspension formulation. Moreover, the permeation studies using Strat-M membranes represent a reproducible methodology, which is easy to implement for pre-formulation stage or performance evaluation of semi-solid pharmaceutical products for topical or transdermal administration. Full article

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13 pages, 3222 KiB

Open AccessArticle

Oral Bioavailability and Lymphatic Transport of Pueraria Flavone-Loaded Self-Emulsifying Drug-Delivery Systems Containing Sodium Taurocholate in Rats

by Jin Qiao, Danyang Ji, Shilin Sun, Guangyuan Zhang, Xin Liu, Bingxue Sun and Qingxiang Guan

Pharmaceutics 2018, 10(3), 147; https://doi.org/10.3390/pharmaceutics10030147 - 05 Sep 2018

Cited by 27 | Viewed by 4376

Abstract

We developed self-microemulsifying drug-delivery systems (SMEDDS), including bile salts, to improve the oral bioavailability of pueraria flavones (PFs). The physical properties of the SMEDDS using Cremophor RH 40, and bile salts as mixed surfactants at weight ratios of 10:0–0:10 were determined. The particle [...] Read more.

We developed self-microemulsifying drug-delivery systems (SMEDDS), including bile salts, to improve the oral bioavailability of pueraria flavones (PFs). The physical properties of the SMEDDS using Cremophor RH 40, and bile salts as mixed surfactants at weight ratios of 10:0–0:10 were determined. The particle sizes of PFs-SMEDDS_NR containing sodium taurocholate (NaTC) and Cremophor RH 40, and PFs-SMEDDS_R containing Cremophor RH 40 were measured upon dilution with deionized water and other aqueous media. Dilution volume presented no remarkable effects on particle size, whereas dilution media slightly influenced particle size. PFs-SMEDDS_NR and PFs-SMEDDS_R provided similar release rates in pH-1.2 hydrochloride solution. However, the release rate of PFs-SMEDDS_NR was faster than that of PFs-SMEDDS_R in pH-6.8 phosphate buffer containing 20 mM NaTC and 500 U/mL porcine pancreas lipase. The pharmacokinetics and bioavailability were measured in rats. The oral bioavailability of PFs-SMEDDS_NR was 2.57- and 2.28-fold that of a suspension of PFs (PFs-suspension) before and after the blockade of the lymphatic transport route by cycloheximide, respectively. These results suggested PFs-SMEDDS_NR could significantly improve the oral relative absorption of PFs via the lymphatic uptake pathway. SMEDDS containing NaTC may provide an effective approach for enhancing the oral bioavailability of PFs. Full article

(This article belongs to the Special Issue Novel Formulation Strategies for Enhancing Dissolution and/or Oral Bioavailability)

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19 pages, 4347 KiB

Open AccessArticle

Folate and Borneol Modified Bifunctional Nanoparticles for Enhanced Oral Absorption

by Yifan Yang, Yunzhi Yin, Jun Zhang, Tiantian Zuo, Xiao Liang, Jing Li and Qi Shen

Pharmaceutics 2018, 10(3), 146; https://doi.org/10.3390/pharmaceutics10030146 - 04 Sep 2018

Cited by 14 | Viewed by 3965

Abstract

Oral delivery is considered the preferred route of administration due to its convenience and favorable compliance. Here, docetaxel (DTX) loaded polylactic-co-glycolic acid (PLGA) nanoparticles, coated with polyethyleneimine–folic acid (PEI-FA) and polyethyleneimine–borneol (PEI-BO), were designed to enhance oral absorption (FA/BO-PLGA-NPs). The FA/BO-PLGA-NPs were spherical [...] Read more.

Oral delivery is considered the preferred route of administration due to its convenience and favorable compliance. Here, docetaxel (DTX) loaded polylactic-co-glycolic acid (PLGA) nanoparticles, coated with polyethyleneimine–folic acid (PEI-FA) and polyethyleneimine–borneol (PEI-BO), were designed to enhance oral absorption (FA/BO-PLGA-NPs). The FA/BO-PLGA-NPs were spherical and smooth with an average size of (137.0 ± 2.1) nm. Encapsulation efficiency (EE%) and drug loading (DL%) were (80.3 ± 1.8)% and (2.3 ± 0.3)%, respectively. In vitro release studies showed that approximately 62.1% of DTX was released from FA/BO-PLGA-NPs in media at pH 7.4. The reverted gut sac method showed that the absorption of FA/BO-PLGA-NPs in the intestines was approximately 6.0 times that of DTX. Moreover, cellular uptake suggested that the obtained FA/BO-PLGA-NPs could be efficiently internalized into Caco-2 cells via FA-mediated active targeting and BO-mediated P-glycoprotein (P-gp) inhibition. Pharmacokinetics study demonstrated that after oral administration of DTX at a dose of 10 mg/kg in FA/BO-PLGA-NPs, the bioavailability of FA/BO-PLGA-NPs was enhanced by approximately 6.8-fold compared with that of DTX suspension. FA/BO-PLGA-NPs caused no obvious irritation to the intestines. Overall, the FA/BO-PLGA-NP formulation remarkably improved the oral bioavailability of DTX and exhibited a promising perspective in oral drug delivery. Full article

(This article belongs to the Special Issue Novel Formulation Strategies for Enhancing Dissolution and/or Oral Bioavailability)

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23 pages, 2911 KiB

Open AccessReview

Magnetogels: Prospects and Main Challenges in Biomedical Applications

by Sérgio R. S. Veloso, Paula M. T. Ferreira, J. A. Martins, Paulo J. G. Coutinho and Elisabete M. S. Castanheira

Pharmaceutics 2018, 10(3), 145; https://doi.org/10.3390/pharmaceutics10030145 - 04 Sep 2018

Cited by 28 | Viewed by 5740

Abstract

Drug delivery nanosystems have been thriving in recent years as a promising application in therapeutics, seeking to solve the lack of specificity of conventional chemotherapy targeting and add further features such as enhanced magnetic resonance imaging, biosensing and hyperthermia. The combination of magnetic [...] Read more.

Drug delivery nanosystems have been thriving in recent years as a promising application in therapeutics, seeking to solve the lack of specificity of conventional chemotherapy targeting and add further features such as enhanced magnetic resonance imaging, biosensing and hyperthermia. The combination of magnetic nanoparticles and hydrogels introduces a new generation of nanosystems, the magnetogels, which combine the advantages of both nanomaterials, apart from showing interesting properties unobtainable when both systems are separated. The presence of magnetic nanoparticles allows the control and targeting of the nanosystem to a specific location by an externally applied magnetic field gradient. Moreover, the application of an alternating magnetic field (AMF) not only allows therapy through hyperthermia, but also enhances drug delivery and chemotherapeutic desired effects, which combined with the hydrogel specificity, confer a high therapeutic efficiency. Therefore, the present review summarizes the magnetogels properties and critically discusses their current and recent biomedical applications, apart from an outlook on future goals and perspectives. Full article

(This article belongs to the Special Issue Nanotheranostics and Cancer: Where Are We Now?)

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16 pages, 3269 KiB

Open AccessArticle

DOX-Vit D, a Novel Doxorubicin Delivery Approach, Inhibits Human Osteosarcoma Cell Proliferation by Inducing Apoptosis While Inhibiting Akt and mTOR Signaling Pathways

by Zaid H. Maayah, Ti Zhang, Marcus Laird Forrest, Samaa Alrushaid, Michael R. Doschak, Neal M. Davies and Ayman O. S. El-Kadi

Pharmaceutics 2018, 10(3), 144; https://doi.org/10.3390/pharmaceutics10030144 - 04 Sep 2018

Cited by 14 | Viewed by 4471

Abstract

Doxorubicin (DOX) is a very potent and effective anticancer agent. However, the effectiveness of DOX in osteosarcoma is usually limited by the acquired drug resistance. Recently, Vitamin D (Vit-D) was shown to suppress the growth of many human cancer cells. Taken together, we [...] Read more.

Doxorubicin (DOX) is a very potent and effective anticancer agent. However, the effectiveness of DOX in osteosarcoma is usually limited by the acquired drug resistance. Recently, Vitamin D (Vit-D) was shown to suppress the growth of many human cancer cells. Taken together, we synthesized DOX-Vit D by conjugating Vit-D to DOX in order to increase the delivery of DOX into cancer cells and mitigate the chemoresistance associated with DOX. For this purpose, MG63 cells were treated with 10 µM DOX or DOX-Vit D for 24 h. Thereafter, MTT, real-time PCR and western blot analysis were used to determine cell proliferation, genes and proteins expression, respectively. Our results showed that DOX-Vit D, but not DOX, significantly elicited an apoptotic signal in MG63 cells as evidenced by induction of death receptor, Caspase-3 and BCLxs genes. Mechanistically, the DOX-Vit D-induced apoptogens were credited to the activation of p-JNK and p-p38 signaling pathway and the inhibition of proliferative proteins, p-Akt and p-mTOR. Our findings propose that DOX-Vit D suppressed the growth of MG63 cells by inducing apoptosis while inhibiting cell survival and proliferative signaling pathways. DOX-Vit D may serve as a novel drug delivery approach to potentiate the delivery of DOX into cancer cells. Full article

(This article belongs to the Special Issue Drug Delivery Technology Development in Canada)

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14 pages, 1791 KiB

Open AccessArticle

Simultaneous Determination of Chlorogenic Acid Isomers and Metabolites in Rat Plasma Using LC-MS/MS and Its Application to A Pharmacokinetic Study Following Oral Administration of Stauntonia Hexaphylla Leaf Extract (YRA-1909) to Rats

by Won-Gu Choi, Ju-Hyun Kim, Dong Kyun Kim, Yongnam Lee, Ji Seok Yoo, Dae Hee Shin and Hye Suk Lee

Pharmaceutics 2018, 10(3), 143; https://doi.org/10.3390/pharmaceutics10030143 - 02 Sep 2018

Cited by 17 | Viewed by 5211

Abstract

Stauntonia hexaphylla leaf extract (YRA-1909), which is widely used for the antirheumatic properties, has been under phase 2 clinical trials in patients with rheumatoid arthritis since April 2017. Liquid chromatography-tandem mass spectrometric method while using liquid–liquid extraction with ethyl acetate was validated for [...] Read more.

Stauntonia hexaphylla leaf extract (YRA-1909), which is widely used for the antirheumatic properties, has been under phase 2 clinical trials in patients with rheumatoid arthritis since April 2017. Liquid chromatography-tandem mass spectrometric method while using liquid–liquid extraction with ethyl acetate was validated for the simultaneous determination of the major active components of YRA-1909, including chlorogenic acid (CGA), neochlorogenic acid (NCGA), cryptochlorogenic acid (CCGA), and their metabolites (i.e., caffeic acid (CA), caffeic acid 3-O-glucuronide (CA-3-G), caffeic acid 4-O-glucuronide (CA-4-G), and ferulic acid (FA)) in rat plasma and applied to a pharmacokinetic study of YRA-1909 in rats. Seven analytes were separated on Halo C18 while using gradient elution of formic acid and methanol, and then quantified in selected reaction monitoring mode whle using negative electrospray ionization. Following oral administration of YRA-1909 at doses of 25, 50, and 100 mg/kg to male Sprague-Dawley rats, CGA, NCGA, and CCGA were rapidly absorbed and metabolized to CA, CA-3-G, and CA-4-G. The area under the plasma concentration-time curve (AUC_last) of CGA, NCGA, CCGA, and three metabolites linearly increased as the YRA-1909 dose increased. Other pharmacokinetic parameters were comparable among three doses studied. AUC_last values for CA, CA-3-G, and CA-4-G exceeded those for CGA, NCGA, and CCGA. Full article

(This article belongs to the Special Issue Drug Metabolism, Pharmacokinetics and Bioanalysis)

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13 pages, 3006 KiB

Open AccessArticle

Processing Impact on Performance of Solid Dispersions

by Dan Zhang, Yung-Chi Lee, Zaher Shabani, Celeste Frankenfeld Lamm, Wei Zhu, Yongjun Li and Allen Templeton

Pharmaceutics 2018, 10(3), 142; https://doi.org/10.3390/pharmaceutics10030142 - 30 Aug 2018

Cited by 25 | Viewed by 4381

Abstract

The development of a weakly basic compound is often challenging due to changes in pH that the drug experiences throughout the gastrointestinal tract. As the drug transitions from the low pH of the stomach to the higher pH of the small intestine, drug [...] Read more.

The development of a weakly basic compound is often challenging due to changes in pH that the drug experiences throughout the gastrointestinal tract. As the drug transitions from the low pH of the stomach to the higher pH of the small intestine, drug solubility decreases. A stomach with a higher pH, caused by food or achlorhydric conditions brought about by certain medications, decreases even the initial solubility. This decreased drug solubility is reflected in lower in vivo exposures. In many cases, a solubility-enabling approach is needed to counteract the effect of gastrointestinal pH changes. Solid dispersions of amorphous drug in a polymer matrix have been demonstrated to be an effective tool to enhance bioavailability, with the potential to mitigate the food and achlorhydric effects frequently observed with conventional formulations. Because solid dispersions are in a metastable state, they are particularly sensitive to processing routes that may control particle attributes, stability, drug release profile, and bioperformance. A better understanding of the impacts of processing routes on the solid dispersion properties will not only enhance our ability to control the product properties, but also lower development risks. In this study, a weakly basic compound with greatly reduced solubility in higher pHs was incorporated into a solid dispersion via both spray drying and hot melt extrusion. The properties of the solid dispersion via these two processing routes were compared, and the impact on dissolution behavior and in vivo performance of the dispersions was investigated. Full article

(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)

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13 pages, 1475 KiB

Open AccessArticle

Characterization of CYPs and UGTs Involved in Human Liver Microsomal Metabolism of Osthenol

by Pil Joung Cho, Sanjita Paudel, Doohyun Lee, Yun Ji Jin, GeunHyung Jo, Tae Cheon Jeong, Sangkyu Lee and Taeho Lee

Pharmaceutics 2018, 10(3), 141; https://doi.org/10.3390/pharmaceutics10030141 - 30 Aug 2018

Cited by 7 | Viewed by 4403

Abstract

Osthenol is a prenylated coumarin isolated from the root of Angelica koreana and Angelica dahurica, and is an O-demethylated metabolite of osthole in vivo. Its various pharmacological effects have been reported previously. The metabolic pathway of osthenol was partially confirmed in [...] Read more.

Osthenol is a prenylated coumarin isolated from the root of Angelica koreana and Angelica dahurica, and is an O-demethylated metabolite of osthole in vivo. Its various pharmacological effects have been reported previously. The metabolic pathway of osthenol was partially confirmed in rat osthole studies, and 11 metabolic products were identified in rat urine. However, the metabolic pathway of osthenol in human liver microsomes (HLM) has not been reported. In this study, we elucidated the structure of generated metabolites using a high-resolution quadrupole-orbitrap mass spectrometer (HR-MS/MS) and characterized the major human cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) isozymes involved in osthenol metabolism in human liver microsomes (HLMs). We identified seven metabolites (M1-M7) in HLMs after incubation in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and uridine 5′-diphosphoglucuronic acid (UDPGA). As a result, we demonstrated that osthenol is metabolized to five mono-hydroxyl metabolites (M1-M5) by CYP2D6, 1A2, and 3A4, respectively, a 7-O-glucuronide conjugate (M6) by UGT1A9, and a hydroxyl-glucuronide (M7) from M5 by UGT1A3 in HLMs. We also found that glucuronidation is the dominant metabolic pathway of osthenol in HLMs. Full article

(This article belongs to the Special Issue Drug Metabolism, Pharmacokinetics and Bioanalysis)

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14 pages, 2452 KiB

Open AccessArticle

Development and Evaluation of a Reconstitutable Dry Suspension to Improve the Dissolution and Oral Absorption of Poorly Water-Soluble Celecoxib

by Hye-In Kim, Sang Yeob Park, Seok Ju Park, Jewon Lee, Kwan Hyung Cho, Jun-Pil Jee, Hee-Cheol Kim, Han-Joo Maeng and Dong-Jin Jang

Pharmaceutics 2018, 10(3), 140; https://doi.org/10.3390/pharmaceutics10030140 - 29 Aug 2018

Cited by 16 | Viewed by 5856

Abstract

This study aims at developing and evaluating reconstitutable dry suspension (RDS) improved for dissolution rate, oral absorption, and convenience of use of poorly water-soluble celecoxib (CXB). Micro-sized CXB particle was used to manufacture nanosuspension by using bead milling and then RDS was made [...] Read more.

This study aims at developing and evaluating reconstitutable dry suspension (RDS) improved for dissolution rate, oral absorption, and convenience of use of poorly water-soluble celecoxib (CXB). Micro-sized CXB particle was used to manufacture nanosuspension by using bead milling and then RDS was made by spray-drying the nanosuspension with effective resuspension agent, dextrin. The redispersibility, morphology, particle size, crystallinity, stability, dissolution, and pharmacokinetic profile of the RDS were evaluated. RDS was effectively reconstituted into nanoparticles in 775.8 ± 11.6 nm. It was confirmed that CXB particles are reduced into needle-shape ones in size after the bead-milling process, and the description of CXB was the same in the reconstituted suspension. Through the CXB crystallinity study using differential scanning calorimetry (DSC) and XRD analysis, it was identified that CXB has the CXB active pharmaceutical ingredient (API)’s original crystallinity after the bead milling and spray-drying process. In vitro dissolution of RDS was higher than that of CXB powder (93% versus 28% dissolution at 30 min). Furthermore, RDS formulation resulted in 5.7 and 6.3-fold higher area under the curve (AUC_∞) and peak concentration (C_max) of CXB compared to after oral administration of CXB powder in rats. Collectively, our results suggest that the RDS may be a potential oral dosage formulation for CXB to improve its bioavailability and patient compliance. Full article

(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)

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23 pages, 3825 KiB

Open AccessReview

Lyophilization of Liposomal Formulations: Still Necessary, Still Challenging

by Silvia Franzé, Francesca Selmin, Elena Samaritani, Paola Minghetti and Francesco Cilurzo

Pharmaceutics 2018, 10(3), 139; https://doi.org/10.3390/pharmaceutics10030139 - 28 Aug 2018

Cited by 146 | Viewed by 10651

Abstract

Nowadays, the freeze-drying of liposome dispersions is still necessary to provide a solid dosage form intended for different routes of administration (i.e., parenteral, oral, nasal and/or pulmonary). However, after decades of studies the optimization of process conditions remains still challenging since the freezing [...] Read more.

Nowadays, the freeze-drying of liposome dispersions is still necessary to provide a solid dosage form intended for different routes of administration (i.e., parenteral, oral, nasal and/or pulmonary). However, after decades of studies the optimization of process conditions remains still challenging since the freezing and the dehydration destabilize the vesicle organization with the concomitant drug leakage. Starting from the thermal properties of phospholipids, this work reviews the main formulation and process parameters which can guarantee a product with suitable characteristics and increase the efficiency of the manufacturing process. In particular, an overview of the cryo- and/or lyo-protective mechanisms of several excipients and the possible use of co-solvent mixtures is provided. Attention is also focused on the imaging methods recently proposed to characterize the appearance of freeze-dried products and liposome dispersions upon reconstitution. The combination of such data would allow a better knowledge of the factors causing inter-vials variability in the attempt to improve the quality of the final medicinal product. Full article

(This article belongs to the Special Issue Micro and Nano Encapsulation Techniques)

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14 pages, 2811 KiB

Open AccessArticle

Stabilization of the CD81 Large Extracellular Loop with De Novo Disulfide Bonds Improves Its Amenability for Peptide Grafting

by Stefan Vogt, Gerhard Stadlmayr, Katharina Stadlbauer, Flávio Sádio, Peter Andorfer, Johannes Grillari, Florian Rüker and Gordana Wozniak-Knopp

Pharmaceutics 2018, 10(3), 138; https://doi.org/10.3390/pharmaceutics10030138 - 27 Aug 2018

Cited by 8 | Viewed by 4021

Abstract

Tetraspan proteins are significantly enriched in the membranes of exosomal vesicles (EVs) and their extracellular domains are attractive targets for engineering towards specific antigen recognition units. To enhance the tolerance of a tetraspanin fold to modification, we achieved significant thermal stabilization of the [...] Read more.

Tetraspan proteins are significantly enriched in the membranes of exosomal vesicles (EVs) and their extracellular domains are attractive targets for engineering towards specific antigen recognition units. To enhance the tolerance of a tetraspanin fold to modification, we achieved significant thermal stabilization of the human CD81 large extracellular loop (hCD81 LEL) via de novo disulfide bonds. The best mutants were shown to exhibit a positive shift in the melting temperature (T_m) of up to 25 °C. The combination of two most potent disulfide bonds connecting different strands of the protein resulted in a mutant with a T_m of 109 °C, 43 °C over the T_m of the wild-type hCD81 LEL. A peptide sequence binding to the human transferrin receptor (hTfr) was engrafted into the D-segment of the hCD81 LEL, resulting in a mutant that still exhibited a compact fold. Grafting of the same peptide sequence between helices A and B resulted in a molecule with an aberrant profile in size exclusion chromatography (SEC), which could be improved by a de novo cysteine bond connecting both helices. Both peptide-grafted proteins showed an enhanced internalization into the cell line SK-BR3, which strongly overexpresses hTfr. In summary, the tetraspan LEL fold could be stabilized to enhance its amenability for engineering into a more versatile protein scaffold. Full article

(This article belongs to the Special Issue Protein Therapeutics)

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14 pages, 1803 KiB

Open AccessArticle

Effect of 5-Oxo-2-Pyrrolidinecarboxylic Acid (PCA) as a New Topically Applied Agent for Dry Eye Syndrome Treatment

by Silvia Tampucci, Daniela Monti, Susi Burgalassi, Eleonora Terreni, Erica Zucchetti, Filippo Baldacci and Patrizia Chetoni

Pharmaceutics 2018, 10(3), 137; https://doi.org/10.3390/pharmaceutics10030137 - 25 Aug 2018

Cited by 10 | Viewed by 3942

Abstract

The aim of the study was the evaluation of the suitability of 5-oxo-2-pyrrolidinecarboxylic acid (PCA), also in combination with hyaluronic acid (HA), as artificial tears for treatment of dry eye syndrome (DES). Different aqueous formulations containing 0.10% w/w of PCA were used to [...] Read more.

The aim of the study was the evaluation of the suitability of 5-oxo-2-pyrrolidinecarboxylic acid (PCA), also in combination with hyaluronic acid (HA), as artificial tears for treatment of dry eye syndrome (DES). Different aqueous formulations containing 0.10% w/w of PCA were used to determine: (i) ex vivo permeation profile of PCA in isolated rabbit corneas; (ii) in vivo residence time of PCA in the precorneal area of rabbits; and (iii) in vivo ability of PCA to counteract the reduction of tear production in an experimental model of DES induced in rabbits. The pharmacokinetic profile of PCA in tear fluid was characterized by high concentrations immediately after application, followed by a rapid decrease, with half-life values of 17.16 and 22.27 min for solutions containing PCA alone and in combination with HA, respectively, when 100 µL of solutions were instilled. The addition of HA almost doubled the PCA bioavailability minimizing the ex vivo apparent corneal permeability of PCA. A positive Shirmer Test Score (STS) was observed for PCA compared to contralateral eyes at all days of treatment for PCA/HA formulation. PCA provides protection from desiccation probably for its osmoprotective activity and high water–binding capability, and this behaviour was enhanced by HA. Full article

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17 pages, 1887 KiB

Open AccessFeature PaperReview

Stimuli Responsive Polymeric Systems for Cancer Therapy

by Ali Alsuraifi, Anthony Curtis, Dimitrios A. Lamprou and Clare Hoskins

Pharmaceutics 2018, 10(3), 136; https://doi.org/10.3390/pharmaceutics10030136 - 22 Aug 2018

Cited by 48 | Viewed by 5322

Abstract

Nanoscale polymers systems have dominated the revolution of drug delivery advancement. Their potential in the fight against cancer is unrivalled with other technologies. Their functionality increase, targeting ability and stimuli responsive nature have led to a major boom in research focus. This review [...] Read more.

Nanoscale polymers systems have dominated the revolution of drug delivery advancement. Their potential in the fight against cancer is unrivalled with other technologies. Their functionality increase, targeting ability and stimuli responsive nature have led to a major boom in research focus. This review article concentrates on the use of these smart polymers in cancer therapy. Nanotechnologies have shown potential as drug carriers leading to increased drug efficacy and penetration. Multifunctional smart carriers which can release their payload upon an external or internal trigger such as pH or temperature are proving to be major frontrunners in the development of effective strategies to overcome this disease with minimal patient side effects. Full article

(This article belongs to the Special Issue Micro and Nano Encapsulation Techniques)

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14 pages, 11093 KiB

Open AccessArticle

Dissolution Enhancement in Cocoa Extract, Combining Hydrophilic Polymers through Hot-Melt Extrusion

by Ludmila A. G. Pinho, Saulo G. Souza, Ricardo N. Marreto, Livia L. Sa-Barreto, Tais Gratieri, Guilherme M. Gelfuso and Marcilio Cunha-Filho

Pharmaceutics 2018, 10(3), 135; https://doi.org/10.3390/pharmaceutics10030135 - 21 Aug 2018

Cited by 11 | Viewed by 3676

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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29 pages, 333 KiB

Open AccessReview

Nanocrystals of Poorly Soluble Drugs: Drug Bioavailability and Physicochemical Stability

by Maria Rosa Gigliobianco, Cristina Casadidio, Roberta Censi and Piera Di Martino

Pharmaceutics 2018, 10(3), 134; https://doi.org/10.3390/pharmaceutics10030134 - 21 Aug 2018

Cited by 185 | Viewed by 11740

Abstract

Many approaches have been developed over time to overcome the bioavailability limitations of poorly soluble drugs. With the advances in nanotechnology in recent decades, science and industry have been approaching this issue through the formulation of drugs as nanocrystals, which consist of “pure [...] Read more.

Many approaches have been developed over time to overcome the bioavailability limitations of poorly soluble drugs. With the advances in nanotechnology in recent decades, science and industry have been approaching this issue through the formulation of drugs as nanocrystals, which consist of “pure drugs and a minimum of surface active agents required for stabilization”. They are defined as “carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range, typically between 10–800 nm”. The primary importance of these nanoparticles was the reduction of particle size to nanoscale dimensions, with an increase in the particle surface area in contact with the dissolution medium, and thus in bioavailability. This approach has been proven successful, as demonstrated by the number of such drug products on the market. Nonetheless, despite the definition that indicates nanocrystals as a “carrier-free” system, surface active agents are necessary to prevent colloidal particles aggregation and thus improve stability. In addition, in more recent years, nanocrystal properties and technologies have attracted the interest of researchers as a means to obtain colloidal particles with modified biological properties, and thus their interest is now also addressed to modify the drug delivery and targeting. The present work provides an overview of the achievements in improving the bioavailability of poorly soluble drugs according to their administration route, describes the methods developed to overcome physicochemical and stability-related problems, and in particular reviews different stabilizers and surface agents that are able to modify the drug delivery and targeting. Full article

(This article belongs to the Special Issue Dissolution Enhancement of Poorly Soluble Drugs)

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17 pages, 2729 KiB

Open AccessArticle

Pharmacokinetics and Brain Distribution of the Active Components of DA-9805, Saikosaponin A, Paeonol and Imperatorin in Rats

by Mi Hye Kwon, Jin Seok Jeong, Jayoung Ryu, Young Woong Cho and Hee Eun Kang

Pharmaceutics 2018, 10(3), 133; https://doi.org/10.3390/pharmaceutics10030133 - 20 Aug 2018

Cited by 10 | Viewed by 4696

Abstract

DA-9805 is a botanical anti-Parkinson’s drug candidate formulated from ethanol extracts of the root of Bupleurum falcatum, the root cortex of Paeonia suffruticosa, and the root of Angelica dahurica. The pharmacokinetics (PKs) and brain distribution of active/representative ingredients of DA-9805, [...] Read more.

DA-9805 is a botanical anti-Parkinson’s drug candidate formulated from ethanol extracts of the root of Bupleurum falcatum, the root cortex of Paeonia suffruticosa, and the root of Angelica dahurica. The pharmacokinetics (PKs) and brain distribution of active/representative ingredients of DA-9805, Saikosaponin a (SSa; 1.1–4.6 mg/kg), Paeonol (PA; 14.8–59.2 mg/kg), and Imperatorin (IMP; 1.4–11.5 mg/kg) were evaluated following the intravenous or oral administration of each pure component and the equivalent dose of DA-9805 in rats. All three components had greater dose-normalized areas under the plasma concentration-time curve (AUC) and slower clearance with higher doses, following intravenous administration. By contrast, dose-proportional AUC values of SSa, PA, and IMP were observed following the oral administration of each pure component (with the exception of IMP at the highest dose) or DA-9805. Compared to oral administration of each pure compound, DA-9805 administration showed an increase in the AUC of SSa (by 96.1–163%) and PA (by 155–164%), possibly due to inhibition of their metabolism by IMP or other component(s) in DA-9805. A delay in the absorption of PA and IMP was observed when they were administered as DA-9805. All three components of DA-9805 showed greater binding values in brain homogenates than in plasma, possibly explaining why the brain-to-plasma ratios were greater than unity following multiple oral administrations of DA-9805. By contrast, their levels in cerebrospinal fluid were negligible. Our results further our understanding of the comprehensive PK characteristics of SSa, PA, and IMP in rats and the comparative PKs between each pure component and DA-9805. Full article

(This article belongs to the Special Issue Drug Metabolism, Pharmacokinetics and Bioanalysis)

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