Pharmaceutics

13 pages, 1928 KiB

Open AccessArticle

Stability Study of Isoniazid and Rifampicin Oral Solutions Using Hydroxypropyl-Β-Cyclodextrin to Treat Tuberculosis in Paediatrics

by Ana Santoveña-Estévez, Javier Suárez-González, Amor R. Cáceres-Pérez, Zuleima Ruiz-Noda, Sara Machado-Rodríguez, Magdalena Echezarreta, Mabel Soriano and José B. Fariña

Pharmaceutics 2020, 12(2), 195; https://doi.org/10.3390/pharmaceutics12020195 - 24 Feb 2020

Cited by 13 | Viewed by 4962

Abstract

(1) Background: First-line antituberculosis treatment in paediatrics entails the administration of Isoniazid, Pyrazinamide, and Rifampicin. This study examines the possibility of developing a combined dose liquid formulation for oral use that would facilitate dose adjustment and adherence to treatment for younger children. (2) [...] Read more.

(1) Background: First-line antituberculosis treatment in paediatrics entails the administration of Isoniazid, Pyrazinamide, and Rifampicin. This study examines the possibility of developing a combined dose liquid formulation for oral use that would facilitate dose adjustment and adherence to treatment for younger children. (2) Methods: The active pharmaceutical ingredients stability under in vitro paediatric digestive pH conditions have been checked. The samples were studied as individual or fixed combined paediatric dosages to determine the pH of maximum stability. The use of hydroxypropyl-β-cyclodextrin to improve Rifampicin solubility and the use of ascorbic acid to increase the stability of the formulation have been studied. (3) Results: Maximum stability of combined doses was determined at pH 7.4, and maximum complexation at pH 8.0. Taking this into account, formulations presented the minimum dose of two active pharmaceutical ingredients dissolved. The addition of ascorbic acid at 0.1% w/v enables the detection of a higher remaining quantity of both drugs after three days of storage at 5 °C. (4) Conclusions: a formulation which combines the minimum paediatric dosages dissolved recommended by WHO for Isoniazid and Rifampicin has been developed. Future assays are needed to prolong the stability of the formulation with the aim of incorporating Pyrazinamide to the solution. Full article

(This article belongs to the Special Issue Paediatric Drug Delivery)

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15 pages, 629 KiB

Open AccessReview

Chimeric Antigen Receptor-T-Cell Therapy for B-Cell Hematological Malignancies: An Update of the Pivotal Clinical Trial Data

by Gils Roex, Tom Feys, Yves Beguin, Tessa Kerre, Xavier Poiré, Philippe Lewalle, Peter Vandenberghe, Dominique Bron and Sébastien Anguille

Pharmaceutics 2020, 12(2), 194; https://doi.org/10.3390/pharmaceutics12020194 - 24 Feb 2020

Cited by 45 | Viewed by 11042

Abstract

Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell [...] Read more.

Chimeric antigen receptor (CAR)-T-cell therapy is an innovative form of adoptive cell therapy that has revolutionized the treatment of certain hematological malignancies, including B-cell non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (ALL). The treatment is currently also being studied in other B-cell neoplasms, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). CD19 and B-cell maturation antigen (BCMA) have been the most popular target antigens for CAR-T-cell immunotherapy of these malignancies. This review will discuss the efficacy and toxicity data from the pivotal clinical studies of CD19- and BCMA-targeted CAR-T-cell therapies in relapsed/refractory B-cell malignancies (NHL, ALL, CLL) and MM, respectively. Full article

(This article belongs to the Special Issue Cell-Based Drug-Delivery Platforms)

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20 pages, 8103 KiB

Open AccessArticle

Effect of Oxaliplatin-Loaded Poly (d,l-Lactide-co-Glycolic Acid) (PLGA) Nanoparticles Combined with Retinoic Acid and Cholesterol on Apoptosis, Drug Resistance, and Metastasis Factors of Colorectal Cancer

by Ana Luiza C. de S. L. Oliveira, Raimundo Fernandes de Araújo Júnior, Thaís Gomes de Carvalho, Alan B. Chan, Timo Schomann, Filippo Tamburini, Lioe-Fee de Geus-Oei and Luis J. Cruz

Pharmaceutics 2020, 12(2), 193; https://doi.org/10.3390/pharmaceutics12020193 - 23 Feb 2020

Cited by 27 | Viewed by 5583

Abstract

Apoptosis signaling pathways, drug resistance, and metastasis are important targets to develop new cancer treatments. We developed cholesterol-coated Poly(d,l-Lactide-co-Glycolic Acid) (PLGA) nanoparticles for effective encapsulation and delivery of retinoic acid and oxaliplatin to analyze their antitumor activity [...] Read more.

Apoptosis signaling pathways, drug resistance, and metastasis are important targets to develop new cancer treatments. We developed cholesterol-coated Poly(d,l-Lactide-co-Glycolic Acid) (PLGA) nanoparticles for effective encapsulation and delivery of retinoic acid and oxaliplatin to analyze their antitumor activity in colorectal cancer. The cell viability and proliferation of tumoral cells lines (CT-26 and SW-480) decreased when compared to control in vitro after treatment with the nanoparticles. In addition, apoptosis of CT-26 cells increased. Importantly, cytoprotection of nontumor cells was detected. Expression of pro-apoptotic proteins was upregulated, while anti-apoptotic proteins were downregulated either in vitro or in vivo. In addition, drug resistance and metastasis factors were downregulated in vivo. Human colorectal tumors that highly expressed BCL-2 and Ki-67 had a greater tendency towards death within 60 months. Our results show that loading oxaliplatin combined with retinoic acid and cholesterol in a nanoparticle formulation enables determination of optimal antitumor activity and subsequent treatment efficacy. Full article

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38 pages, 1663 KiB

Open AccessReview

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System

by Ana P. Spencer, Marília Torrado, Beatriz Custódio, Sara C. Silva-Reis, Sofia D. Santos, Victoria Leiro and Ana P. Pêgo

Pharmaceutics 2020, 12(2), 192; https://doi.org/10.3390/pharmaceutics12020192 - 23 Feb 2020

Cited by 19 | Viewed by 5630

Abstract

Central nervous system (CNS) disorders encompass a vast spectrum of pathological conditions and represent a growing concern worldwide. Despite the high social and clinical interest in trying to solve these pathologies, there are many challenges to bridge in order to achieve an effective [...] Read more.

Central nervous system (CNS) disorders encompass a vast spectrum of pathological conditions and represent a growing concern worldwide. Despite the high social and clinical interest in trying to solve these pathologies, there are many challenges to bridge in order to achieve an effective therapy. One of the main obstacles to advancements in this field that has hampered many of the therapeutic strategies proposed to date is the presence of the CNS barriers that restrict the access to the brain. However, adequate brain biodistribution and neuronal cells specific accumulation in the targeted site also represent major hurdles to the attainment of a successful CNS treatment. Over the last few years, nanotechnology has taken a step forward towards the development of therapeutics in neurologic diseases and different approaches have been developed to surpass these obstacles. The versatility of the designed nanocarriers in terms of physical and chemical properties, and the possibility to functionalize them with specific moieties, have resulted in improved neurotargeted delivery profiles. With the concomitant progress in biology research, many of these strategies have been inspired by nature and have taken advantage of physiological processes to achieve brain delivery. Here, the different nanosystems and targeting moieties used to achieve a neuronal delivery reported in the open literature are comprehensively reviewed and critically discussed, with emphasis on the most recent bioinspired advances in the field. Finally, we express our view on the paramount challenges in targeted neuronal delivery that need to be overcome for these promising therapeutics to move from the bench to the bedside. Full article

(This article belongs to the Special Issue Bioinspired Design in Drug Delivery)

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19 pages, 3922 KiB

Open AccessArticle

Co-Encapsulation of Mitoxantrone and β-Elemene in Solid Lipid Nanoparticles to Overcome Multidrug Resistance in Leukemia

by Kambere Amerigos Daddy J.C., Minglei Chen, Faisal Raza, Yanyu Xiao, Zhigui Su and Qineng Ping

Pharmaceutics 2020, 12(2), 191; https://doi.org/10.3390/pharmaceutics12020191 - 23 Feb 2020

Cited by 27 | Viewed by 4635

Abstract

Multidrug resistance (MDR) due to P-glycoprotein (P-gp) overexpression is a major obstacle to successful leukemia chemotherapy. The combination of anticancer chemotherapy with a chemosensitizer of P-gp inhibitor is promising to overcome MDR, generate synergistic effects, and maximize the treatment effect. Herein, we co-encapsulated [...] Read more.

Multidrug resistance (MDR) due to P-glycoprotein (P-gp) overexpression is a major obstacle to successful leukemia chemotherapy. The combination of anticancer chemotherapy with a chemosensitizer of P-gp inhibitor is promising to overcome MDR, generate synergistic effects, and maximize the treatment effect. Herein, we co-encapsulated a chemotherapeutic drug of mitoxantrone (MTO) and a P-gp inhibitor of β-elemene (βE) in solid lipid nanoparticles (MTO/βE-SLNs) for reversing MDR in leukemia. The MTO/βE-SLNs with about 120 nm particle size possessed good colloidal stability and sustained release behavior. For the cellular uptake study, doxorubicin (DOX) was used as a fluorescence probe to construct SLNs. The results revealed that MTO/βE-SLNs could be effectively internalized by both K562/DOX and K562 cells through the pathway of caveolate-mediated endocytosis. Under the optimized combination ratio of MTO and βE, the in vitro cytotoxicity study indicated that MTO/βE-SLNs showed a better antitumor efficacy in both K562/DOX and K562 cells than other MTO formulations. The enhanced cytotoxicity of MTO/βE-SLNs was due to the increased cellular uptake and blockage of intracellular ATP production and P-gp efflux by βE. More importantly, the in vivo studies revealed that MTO/βE-SLNs could significantly prolong the circulation time and increase plasma half-life of both MTO and βE, accumulate into tumor and exhibit a much higher anti-leukemia effect with MDR than other MTO formulations. These findings suggest MTO/βE-SLNs as a potential combined therapeutic strategy for overcoming MDR in leukemia. Full article

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15 pages, 2195 KiB

Open AccessArticle

A Comparative Study of the Effect of Different Stabilizers on the Critical Quality Attributes of Self-Assembling Nano Co-Crystals

by Bwalya A. Witika, Vincent J. Smith and Roderick B. Walker

Pharmaceutics 2020, 12(2), 182; https://doi.org/10.3390/pharmaceutics12020182 - 23 Feb 2020

Cited by 17 | Viewed by 5452

Abstract

Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used orally to manage HIV/AIDS infection. A pseudo one-solvent bottom-up approach was used to develop and produce nano co-crystals of 3TC and AZT. Equimolar amounts of 3TC dissolved in de-ionized water and AZT in methanol [...] Read more.

Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used orally to manage HIV/AIDS infection. A pseudo one-solvent bottom-up approach was used to develop and produce nano co-crystals of 3TC and AZT. Equimolar amounts of 3TC dissolved in de-ionized water and AZT in methanol were rapidly injected into a pre-cooled vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer. The particle size, polydispersity index and Zeta potential were elucidated. Further characterization was undertaken using powder X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and energy dispersive X-ray spectroscopy scanning electron microscopy. Different surfactants were assessed for their ability to stabilize the nano co-crystals and for their ability to produce nano co-crystals with specific and desirable critical quality attributes (CQA) including particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < −30 mV. All surfactants produced co-crystals in the nanometer range. The PDI and PS are concentration-dependent for all nano co-crystals manufactured while only ZP was within specification when sodium dodecyl sulfate was used in the process. Full article

(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)

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55 pages, 1839 KiB

Open AccessReview

Does the Polypill Improve Patient Adherence Compared to Its Individual Formulations? A Systematic Review

by Ana Baumgartner, Katarina Drame, Stijn Geutjens and Marja Airaksinen

Pharmaceutics 2020, 12(2), 190; https://doi.org/10.3390/pharmaceutics12020190 - 22 Feb 2020

Cited by 50 | Viewed by 5592

Abstract

Many patients, especially those with a high pill burden and multiple chronic illnesses, are less adherent to medication. In medication treatments utilizing polypills, this problem might be diminished since multiple drugs are fused into one formulation and, therefore, the therapy regimen is simplified. [...] Read more.

Many patients, especially those with a high pill burden and multiple chronic illnesses, are less adherent to medication. In medication treatments utilizing polypills, this problem might be diminished since multiple drugs are fused into one formulation and, therefore, the therapy regimen is simplified. This systematic review summarized evidence to assess the effect of polypills on medication adherence. The following databases were searched for articles published between 1 January 2000, and 14 May 2019: PubMed, Web of Science, Cochrane Library, and Scopus. Medication adherence was the only outcome assessed, regardless of the method of measuring it. Sixty-seven original peer-reviewed articles were selected. Adherence to polypill regimens was significantly higher in 56 articles (84%) compared to multiple pill regimens. This finding was also supported by the results of 13 out of 17 selected previously published systematic reviews and meta-analyses dealing with this topic. Adherence can be improved through the formulation of polypills, which is probably why the interest in researching them is growing. There are many polypills on the market, but the adherence studies so far focused mainly on a small range of medical conditions. Full article

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16 pages, 2240 KiB

Open AccessArticle

Sphingomyelin-Based Nanosystems (SNs) for the Development of Anticancer miRNA Therapeutics

by Surasa Nagachinta, Belen Lopez Bouzo, Abi Judit Vazquez-Rios, Rafael Lopez and Maria de la Fuente

Pharmaceutics 2020, 12(2), 189; https://doi.org/10.3390/pharmaceutics12020189 - 22 Feb 2020

Cited by 31 | Viewed by 4242

Abstract

Gene replacement therapy with oncosuppressor microRNAs (miRNAs) is a promising alternative to interfere with cancer progression. However, miRNAs are highly inefficient in a biological environment, hampering a successful translation to clinics. Nanotechnology can tackle this drawback by providing delivery systems able to efficiently [...] Read more.

Gene replacement therapy with oncosuppressor microRNAs (miRNAs) is a promising alternative to interfere with cancer progression. However, miRNAs are highly inefficient in a biological environment, hampering a successful translation to clinics. Nanotechnology can tackle this drawback by providing delivery systems able to efficiently deliver them to cancer cells. Thus, the objective of this work was to develop biocompatible nanosystems based on sphingomyelin (SM) for the intracellular delivery of miRNAs to colorectal cancer cells. We pursued two different approaches to select the most appropriate composition for miRNA delivery. On the one hand, we prepared sphingomyelin-based nanosystems (SNs) that incorporate the cationic lipid stearylamine (ST) to support the association of miRNA by the establishment of electrostatic interactions (SNs–ST). On the other hand, the cationic surfactant (DOTAP) was used to preform lipidic complexes with miRNA (Lpx), which were further encapsulated into SNs (SNs-Lpx). Restitution of miRNA145 levels after transfection with SNs-Lpx was related to the strongest anticancer effect in terms of tumor proliferation, colony forming, and migration capacity assays. Altogether, our results suggest that SNs have the potential for miRNA delivery to develop innovative anticancer therapies. Full article

(This article belongs to the Special Issue Non-Viral Gene Delivery Systems)

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15 pages, 3428 KiB

Open AccessArticle

A Proof-of-Concept Study on the Therapeutic Potential of Au Nanoparticles Radiolabeled with the Alpha-Emitter Actinium-225

by Evangelia-Alexandra Salvanou, Dimitris Stellas, Charalampos Tsoukalas, Barbara Mavroidi, Maria Paravatou-Petsotas, Nikolaos Kalogeropoulos, Stavros Xanthopoulos, Franck Denat, Gautier Laurent, Rana Bazzi, Stephane Roux and Penelope Bouziotis

Pharmaceutics 2020, 12(2), 188; https://doi.org/10.3390/pharmaceutics12020188 - 21 Feb 2020

Cited by 48 | Viewed by 4882

Abstract

Actinium-225 (²²⁵Ac) is receiving increased attention for its application in targeted radionuclide therapy, due to the short range of its emitted alpha particles in conjunction with their high linear energy transfer, which lead to the eradication of tumor cells while sparing [...] Read more.

Actinium-225 (²²⁵Ac) is receiving increased attention for its application in targeted radionuclide therapy, due to the short range of its emitted alpha particles in conjunction with their high linear energy transfer, which lead to the eradication of tumor cells while sparing neighboring healthy tissue. The objective of our study was the evaluation of a gold nanoparticle radiolabeled with ²²⁵Ac as an injectable radiopharmaceutical form of brachytherapy for local radiation treatment of cancer. Au@TADOTAGA was radiolabeled with ²²⁵Ac at pH 5.6 (30 min at 70 °C), and in vitro stability was evaluated. In vitro cytotoxicity was assessed in U-87 MG cancer cells, and in vivo biodistribution was performed by intravenous and intratumoral administration of [²²⁵Ac]²²⁵Ac-Au@TADOTAGA in U-87 MG tumor-bearing mice. A preliminary study to assess therapeutic efficacy of the intratumorally-injected radio-nanomedicine was performed over a period of 22 days, while the necrotic effect on tumors was evaluated by a histopathology study. We have shown that [²²⁵Ac]²²⁵Ac-Au@TADOTAGA resulted in the retardation of tumor growth after its intratumoral injection in U87MG tumor-bearing mice, even though very low activities were injected per mouse. This gold nanoparticle radiopharmaceutical could be applied as an unconventional brachytherapy in injectable form for local radiation treatment of cancer. Full article

(This article belongs to the Special Issue Targeted Radionuclide Tumor Therapy)

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9 pages, 2289 KiB

Open AccessCommunication

Formulating a Stable Mannitol Infusion while Maintaining Hyperosmolarity

by Oisín Kavanagh, Fiona Hogan, Caoimhe Murphy, Denise Croker and Gavin Walker

Pharmaceutics 2020, 12(2), 187; https://doi.org/10.3390/pharmaceutics12020187 - 21 Feb 2020

Cited by 4 | Viewed by 8568

Abstract

Mannitol infusion is commonly used in the treatment of intracranial hypertension following traumatic brain injury. It has long been known to have stability issues, specifically, mannitol recrystallises from solutions greater than 10% w/v in ambient conditions. This can happen at any [...] Read more.

Mannitol infusion is commonly used in the treatment of intracranial hypertension following traumatic brain injury. It has long been known to have stability issues, specifically, mannitol recrystallises from solutions greater than 10% w/v in ambient conditions. This can happen at any time, whether on the pharmacy shelf or during a medical procedure. This study describes the stability limits of 20% w/v mannitol infusion (the most common strength used clinically) and proposes a number of safer, stable and tuneable hyperosmotic formulations of mannitol in combination with clinically acceptable osmotic agents (NaCl, sorbitol and glycerol). Full article

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15 pages, 2194 KiB

Open AccessArticle

MiR-219a-5p Enriched Extracellular Vesicles Induce OPC Differentiation and EAE Improvement More Efficiently Than Liposomes and Polymeric Nanoparticles

by Iñaki Osorio-Querejeta, Susana Carregal-Romero, Ana Ayerdi-Izquierdo, Imre Mäger, Leslie A. Nash, Matthew Wood, Ander Egimendia, M. Betanzos, Ainhoa Alberro, Leire Iparraguirre, Laura Moles, Irantzu Llarena, Marco Möller, Felipe Goñi-de-Cerio, Goran Bijelic, Pedro Ramos-Cabrer, Maider Muñoz-Culla and David Otaegui

Pharmaceutics 2020, 12(2), 186; https://doi.org/10.3390/pharmaceutics12020186 - 21 Feb 2020

Cited by 60 | Viewed by 5020

Abstract

Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs [...] Read more.

Remyelination is a key aspect in multiple sclerosis pathology and a special effort is being made to promote it. However, there is still no available treatment to regenerate myelin and several strategies are being scrutinized. Myelination is naturally performed by oligodendrocytes and microRNAs have been postulated as a promising tool to induce oligodendrocyte precursor cell differentiation and therefore remyelination. Herein, DSPC liposomes and PLGA nanoparticles were studied for miR-219a-5p encapsulation, release and remyelination promotion. In parallel, they were compared with biologically engineered extracellular vesicles overexpressing miR-219a-5p. Interestingly, extracellular vesicles showed the highest oligodendrocyte precursor cell differentiation levels and were more effective than liposomes and polymeric nanoparticles crossing the blood–brain barrier. Finally, extracellular vesicles were able to improve EAE animal model clinical evolution. Our results indicate that the use of extracellular vesicles as miR-219a-5p delivery system can be a feasible and promising strategy to induce remyelination in multiple sclerosis patients. Full article

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20 pages, 2751 KiB

Open AccessArticle

Intracellular Delivery of Anti-SMC2 Antibodies against Cancer Stem Cells

by Sara Montero, Joaquin Seras-Franzoso, Fernanda Andrade, Francesc Martinez-Trucharte, Mireia Vilar-Hernández, Manuel Quesada, Helena Xandri, Diego Arango, Ibane Abasolo, Diana Rafael and Simo Schwartz, Jr.

Pharmaceutics 2020, 12(2), 185; https://doi.org/10.3390/pharmaceutics12020185 - 21 Feb 2020

Cited by 16 | Viewed by 3867

Abstract

Structural maintenance of chromosomes protein 2 (SMC2) is a central component of the condensin complex involved in DNA supercoiling, an essential process for embryonic stem cell survival. SMC2 over-expression has been related with tumorigenesis and cancer malignancy and its inhibition is regarded as [...] Read more.

Structural maintenance of chromosomes protein 2 (SMC2) is a central component of the condensin complex involved in DNA supercoiling, an essential process for embryonic stem cell survival. SMC2 over-expression has been related with tumorigenesis and cancer malignancy and its inhibition is regarded as a potential therapeutic strategy even though no drugs are currently available. Here, we propose to inhibit SMC2 by intracellular delivery of specific antibodies against the SMC2 protein. This strategy aims to reduce cancer malignancy by targeting cancer stem cells (CSC), the tumoral subpopulation responsible of tumor recurrence and metastasis. In order to prevent degradation and improve cellular internalization, anti-SMC2 antibodies (Ab-SMC2) were delivered by polymeric micelles (PM) based on Pluronic^® F127 amphiphilic polymers. Importantly, scaffolding the Ab-SMC2 onto nanoparticles allowed its cellular internalization and highly increased its efficacy in terms of cytotoxicity and inhibition of tumorsphere formation in MDA-MB-231 and HCT116 breast and colon cancer cell lines, respectively. Moreover, in the case of the HCT116 cell line G1, cell-cycle arrest was also observed. In contrast, no effects from free Ab-SMC2 were detected in any case. Further, combination therapy of anti-SMC2 micelles with paclitaxel (PTX) and 5-Fluorouracil (5-FU) was also explored. For this, PTX and 5-FU were respectively loaded into an anti-SMC2 decorated PM. The efficacy of both encapsulated drugs was higher than their free forms in both the HCT116 and MDA-MB-231 cell lines. Remarkably, micelles loaded with Ab-SMC2 and PTX showed the highest efficacy in terms of inhibition of tumorsphere formation in HCT116 cells. Accordingly, our data clearly suggest an effective intracellular release of antibodies targeting SMC2 in these cell models and, further, strong cytotoxicity against CSC, alone and in combined treatments with Standard-of-Care drugs. Full article

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10 pages, 3908 KiB

Open AccessArticle

Oleogels with Birch Bark Dry Extract: Extract Saving Formulations through Gelation Enhancing Additives

by Kashif Ahmad Ghaffar and Rolf Daniels

Pharmaceutics 2020, 12(2), 184; https://doi.org/10.3390/pharmaceutics12020184 - 21 Feb 2020

Cited by 9 | Viewed by 3543

Abstract

Triterpenes from the outer bark of birch have many beneficial biological and pharmacological activities. In particular, its wound healing efficacy is of paramount importance. Apart from that, particles of a birch bark dry extract aggregate into a three dimensional network when they are [...] Read more.

Triterpenes from the outer bark of birch have many beneficial biological and pharmacological activities. In particular, its wound healing efficacy is of paramount importance. Apart from that, particles of a birch bark dry extract aggregate into a three dimensional network when they are dispersed in lipids yielding a semi-solid oleogel. However, gel formation requires high amounts of the extract, which then acts at once as the active ingredient and the gelling agent. Infrared spectra of the respective mixtures proved that hydrogen bonds play a crucial role in the formation of the gel network. Dicarboxylic acids had almost no effect on gel strength. Monoalcohols increased the firmness of the oleogel with a decreasing effect from methanol > ethanol > butanol > octanol. All tested terminal diols increased the gel strength whereas vicinal diols affected the gel strength negatively. The effect was highly dependent on their concentration. The different effects of the diols are linked to their structure and polarity. The most pronounced enhancement of gelation was found for 1,6-hexanediol, which reduced the amount of triterpene extract (TE), which is necessary for the formation of an oleogel by a factor of 10. Full article

(This article belongs to the Special Issue Semisolid Dosage)

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23 pages, 1915 KiB

Open AccessReview

Non-Viral in Vitro Gene Delivery: It is Now Time to Set the Bar!

by Nina Bono, Federica Ponti, Diego Mantovani and Gabriele Candiani

Pharmaceutics 2020, 12(2), 183; https://doi.org/10.3390/pharmaceutics12020183 - 21 Feb 2020

Cited by 113 | Viewed by 9274

Abstract

Transfection by means of non-viral gene delivery vectors is the cornerstone of modern gene delivery. Despite the resources poured into the development of ever more effective transfectants, improvement is still slow and limited. Of note, the performance of any gene delivery vector in [...] Read more.

Transfection by means of non-viral gene delivery vectors is the cornerstone of modern gene delivery. Despite the resources poured into the development of ever more effective transfectants, improvement is still slow and limited. Of note, the performance of any gene delivery vector in vitro is strictly dependent on several experimental conditions specific to each laboratory. The lack of standard tests has thus largely contributed to the flood of inconsistent data underpinning the reproducibility crisis. A way researchers seek to address this issue is by gauging the effectiveness of newly synthesized gene delivery vectors with respect to benchmarks of seemingly well-known behavior. However, the performance of such reference molecules is also affected by the testing conditions. This survey points to non-standardized transfection settings and limited information on variables deemed relevant in this context as the major cause of such misalignments. This review provides a catalog of conditions optimized for the gold standard and internal reference, 25 kDa polyethyleneimine, that can be profitably replicated across studies for the sake of comparison. Overall, we wish to pave the way for the implementation of standardized protocols in order to make the evaluation of the effectiveness of transfectants as unbiased as possible. Full article

(This article belongs to the Special Issue Gene Delivery Vectors and Physical Methods: Present and Future Trends)

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21 pages, 9470 KiB

Open AccessArticle

Model-Based Optimisation and Control Strategy for the Primary Drying Phase of a Lyophilisation Process

by Brecht Vanbillemont, Niels Nicolaï, Laurens Leys and Thomas De Beer

Pharmaceutics 2020, 12(2), 181; https://doi.org/10.3390/pharmaceutics12020181 - 20 Feb 2020

Cited by 17 | Viewed by 4993

Abstract

The standard operation of a batch freeze-dryer is protocol driven. All freeze-drying phases (i.e., freezing, primary and secondary drying) are programmed sequentially at fixed time points and within each phase critical process parameters (CPPs) are typically kept constant or linearly interpolated between two [...] Read more.

The standard operation of a batch freeze-dryer is protocol driven. All freeze-drying phases (i.e., freezing, primary and secondary drying) are programmed sequentially at fixed time points and within each phase critical process parameters (CPPs) are typically kept constant or linearly interpolated between two setpoints. This way of operating batch freeze-dryers is shown to be time consuming and inefficient. A model-based optimisation and real-time control strategy that includes model output uncertainty could help in accelerating the primary drying phase while controlling the risk of failure of the critical quality attributes (CQAs). In each iteration of the real-time control strategy, a design space is computed to select an optimal set of CPPs. The aim of the control strategy is to avoid product structure loss, which occurs when the sublimation interface temperature (

T_{i}

) exceeds the the collapse temperature (

T_{c}

) common during unexpected disturbances, while preventing the choked flow conditions leading to a loss of pressure control. The proposed methodology was experimentally verified when the chamber pressure and shelf fluid system were intentionally subjected to moderate process disturbances. Moreover, the end of the primary drying phase was predicted using both uncertainty analysis and a comparative pressure measurement technique. Both the prediction of

T_{i}

and end of primary drying were in agreement with the experimental data. Hence, it was confirmed that the proposed real-time control strategy is capable of mitigating the effect of moderate disturbances during batch freeze-drying. Full article

(This article belongs to the Special Issue Pharmaceutical Freeze Drying and Spray Drying)

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12 pages, 15637 KiB

Open AccessArticle

Large Volume Direct Injection Ultra-High Performance Liquid Chromatography–Tandem Mass Spectrometry-Based Comparative Pharmacokinetic Study between Single and Combinatory Uses of Carthamus tinctorius Extract and Notoginseng Total Saponins

by Jinfeng Chen, Xiaoyu Guo, Yingyuan Lu, Mengling Shi, Haidong Mu, Yi Qian, Jinlong Wang, Mengqiu Lu, Mingbo Zhao, Pengfei Tu, Yuelin Song and Yong Jiang

Pharmaceutics 2020, 12(2), 180; https://doi.org/10.3390/pharmaceutics12020180 - 20 Feb 2020

Cited by 8 | Viewed by 2881

Abstract

The combination of Carthamus tinctorius extract (CTE) and notoginseng total saponins (NGTS), namely, CNP, presents a synergistic effect on myocardial ischemia protection. Herein, comparative pharmacokinetic studies between CNP and CTE/NGTS were conducted to clarify their synergistic mechanisms. A large volume direct injection ultra-high [...] Read more.

The combination of Carthamus tinctorius extract (CTE) and notoginseng total saponins (NGTS), namely, CNP, presents a synergistic effect on myocardial ischemia protection. Herein, comparative pharmacokinetic studies between CNP and CTE/NGTS were conducted to clarify their synergistic mechanisms. A large volume direct injection ultra-high performance liquid chromatography–tandem mass spectrometry (LVDI-UHPLC-MS/MS) platform was developed for sensitively assaying the multi-component pharmacokinetic and in vitro cocktail assay of cytochrome p450 (CYP450) before and after compatibility of CTE and NGTS. The pharmacokinetic profiles of six predominantly efficacious components of CNP, including hydroxysafflor yellow A (HSYA); ginsenosides Rg₁ (GRg₁), Re (GRe), Rb₁ (GRb₁), and Rd (GRd); and notoginsenoside R₁ (NGR₁), were obtained, and the results disclosed that CNP could increase the exposure levels of HSYA, GRg₁, GRe, GRb₁, and NGR₁ at varying degrees. The in vitro cocktail assay demonstrated that CNP exhibited more potent inhibition on CYP1A2 than CTE and NGTS, and GRg₁, GRb₁, GRd, quercetin, kaempferol, and 6-hydroxykaempferol were found to be the major inhibitory compounds. The developed pharmacokinetic interaction-based strategy provides a viable orientation for the compatibility investigation of herb medicines. Full article

(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics)

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19 pages, 9790 KiB

Open AccessArticle

Halloysite- and Montmorillonite-Loaded Scaffolds as Enhancers of Chronic Wound Healing

by Giuseppina Sandri, Angela Faccendini, Marysol Longo, Marco Ruggeri, Silvia Rossi, Maria Cristina Bonferoni, Dalila Miele, Adriele Prina-Mello, Carola Aguzzi, Cesar Viseras and Franca Ferrari

Pharmaceutics 2020, 12(2), 179; https://doi.org/10.3390/pharmaceutics12020179 - 20 Feb 2020

Cited by 38 | Viewed by 3867

Abstract

The increase in life expectancy and the increasing prevalence of diabetic disease and venous insufficiency lead to the increase of chronic wounds. The prevalence of ulcers ranges from 1% in the adult population to 3–5% in the over 65 years population, with 3–5.5% [...] Read more.

The increase in life expectancy and the increasing prevalence of diabetic disease and venous insufficiency lead to the increase of chronic wounds. The prevalence of ulcers ranges from 1% in the adult population to 3–5% in the over 65 years population, with 3–5.5% of the total healthcare expenditure, as recently estimated. The aim of this work was the design and the development of electrospun scaffolds, entirely based on biopolymers, loaded with montmorillonite (MMT) or halloysite (HNT) and intended for skin reparation and regeneration, as a 3D substrate mimicking the dermal ECM. The scaffolds were manufactured by means of electrospinning and were characterized for their chemico-physical and preclinical properties. The scaffolds proved to possess the capability to enhance fibroblast cells attachment and proliferation with negligible proinflammatory activity. The capability to facilitate the cell adhesion is probably due to their unique 3D structure which are assisting cell homing and would facilitate wound healing in vivo. Full article

(This article belongs to the Special Issue Clay-Based Pharmaceutical Formulations and Drug Delivery Systems)

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3 pages, 162 KiB

Open AccessEditorial

Drug Delivery of siRNA Therapeutics

by Gaetano Lamberti and Anna Angela Barba

Pharmaceutics 2020, 12(2), 178; https://doi.org/10.3390/pharmaceutics12020178 - 20 Feb 2020

Cited by 9 | Viewed by 3617

Abstract

Small interfering RNA (siRNA) is a class of nucleic acid-based drugs (NABDs) able to block gene expression by interaction with mRNA before its translation [...] Full article

(This article belongs to the Special Issue Drug Delivery of siRNA Therapeutics)

11 pages, 1144 KiB

Open AccessArticle

Theory of Structural and Secondary Relaxation in Amorphous Drugs under Compression

by Anh D. Phan and Katsunori Wakabayashi

Pharmaceutics 2020, 12(2), 177; https://doi.org/10.3390/pharmaceutics12020177 - 19 Feb 2020

Cited by 11 | Viewed by 3461

Abstract

Compression effects on alpha and beta relaxation process of amorphous drugs are theoretically investigated by developing the elastically collective nonlinear Langevin equation theory. We describe the structural relaxation as a coupling between local and nonlocal activated process. Meanwhile, the secondary beta process is [...] Read more.

Compression effects on alpha and beta relaxation process of amorphous drugs are theoretically investigated by developing the elastically collective nonlinear Langevin equation theory. We describe the structural relaxation as a coupling between local and nonlocal activated process. Meanwhile, the secondary beta process is mainly governed by the nearest-neighbor interactions of a molecule. This assumption implies the beta relaxation acts as a precursor of the alpha relaxation. When external pressure is applied, a small displacement of a molecule is additionally exerted by a pressure-induced mechanical work in the dynamic free energy, which quantifies interactions between a molecule with its nearest neighbors. The local dynamics has more restriction and it induces stronger effects of collective motions on single-molecule dynamics. Thus, the alpha and beta relaxation times are significantly slowed down with increasing compression. We apply this approach to determine the temperature and pressure dependence of the alpha and beta relaxation time for curcumin, glibenclamide, and indomethacin, and compare numerical results with prior experimental studies. Both qualitative and quantitative agreement between theoretical calculations and experiments validate our assumptions and reveal their limitations. Our approach would pave the way for the development of the drug formulation process. Full article

(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)

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13 pages, 987 KiB

Open AccessArticle

RETRACTED: Drug Flux across RPE Cell Models: The Hunt for an Appropriate Outer Blood–Retinal Barrier Model for Use in Early Drug Discovery

by Laura Hellinen, Heidi Hongisto, Eva Ramsay, Kai Kaarniranta, Kati-Sisko Vellonen, Heli Skottman and Marika Ruponen

Pharmaceutics 2020, 12(2), 176; https://doi.org/10.3390/pharmaceutics12020176 - 19 Feb 2020

Cited by 8 | Viewed by 3531 | Retraction

Abstract

The retinal pigment epithelial (RPE) cell monolayer forms the outer blood–retinal barrier and has a crucial role in ocular pharmacokinetics. Although several RPE cell models are available, there have been no systematic comparisons of their barrier properties with respect to drug permeability. We [...] Read more.

The retinal pigment epithelial (RPE) cell monolayer forms the outer blood–retinal barrier and has a crucial role in ocular pharmacokinetics. Although several RPE cell models are available, there have been no systematic comparisons of their barrier properties with respect to drug permeability. We compared the barrier properties of several RPE secondary cell lines (ARPE19, ARPE19mel, and LEPI) and both primary (hfRPE) and stem-cell derived RPE (hESC-RPE) cells by investigating the permeability of nine drugs (aztreonam, ciprofloxacin, dexamethasone, fluconazole, ganciclovir, ketorolac, methotrexate, voriconazole, and quinidine) across cell monolayers. ARPE19, ARPE19mel, and hfRPE cells displayed a narrow P_app value range, with relatively high permeation rates (5.2–26 × 10⁻⁶ cm/s. In contrast, hESC-RPE and LEPI cells efficiently restricted the drug flux, and displayed even lower P_app values than those reported for bovine RPE-choroid, with the range of 0.4–32 cm⁻⁶/s (hESC-RPE cells) and 0.4–29 × 10⁻⁶ cm/s, (LEPI cells). Therefore, ARPE19, ARPE19mel, and hfRPE cells failed to form a tight barrier, whereas hESC-RPE and LEPI cells restricted the drug flux to a similar extent as bovine RPE-choroid. Therefore, LEPI and hESC-RPE cells are valuable tools in ocular drug discovery. Full article

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10 pages, 2249 KiB

Open AccessArticle

A Mixed Micellar Formulation for the Transdermal Delivery of an Indirubin Analog

by Seol Hwa Seo, Eunhwan Kim, Yechan Joo, Juseung Lee, Kyung Taek Oh, Sung-Joo Hwang and Kang-Yell Choi

Pharmaceutics 2020, 12(2), 175; https://doi.org/10.3390/pharmaceutics12020175 - 19 Feb 2020

Cited by 17 | Viewed by 3849

Abstract

Indirubin is an active component of Dang Gui Long Hui Wan, which has been used in traditional Chinese medicine to treat inflammatory diseases as well as for the prevention and treatment of human cancer, such as chronic myeloid leukemia. The therapeutic effects of [...] Read more.

Indirubin is an active component of Dang Gui Long Hui Wan, which has been used in traditional Chinese medicine to treat inflammatory diseases as well as for the prevention and treatment of human cancer, such as chronic myeloid leukemia. The therapeutic effects of indirubin analogs have been underestimated due to its poor water solubility and low bioavailability. To improve the solubility and bioavailability of indirubin analogs, we prepared a mixed micellar formulation with Kolliphor® EL and Tween 80 as surfactants, and PEG 400 as a co-surfactant, followed by complexation with (2-hydroxyproply)-β-cyclodextrin at appropriate ratios. Overall, improving the solubility and skin penetration of indirubin analogs can increase clinical efficacy and provide maximum flux through the skin. Full article

(This article belongs to the Special Issue Transdermal Drug Delivery Systems)

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15 pages, 1323 KiB

Open AccessArticle

Controlled Release of Highly Hydrophilic Drugs from Novel Poly(Magnesium Acrylate) Matrix Tablets

by Rebeca Simancas-Herbada, Ana Fernández-Carballido, Juan Aparicio-Blanco, Karla Slowing, Jorge Rubio-Retama, Enrique López-Cabarcos and Ana-Isabel Torres-Suárez

Pharmaceutics 2020, 12(2), 174; https://doi.org/10.3390/pharmaceutics12020174 - 19 Feb 2020

Cited by 12 | Viewed by 4196

Abstract

The potential of a new poly(magnesium acrylate) hydrogel (PAMgA) as a pharmaceutical excipient for the elaboration of matrix tablets for the extended release of highly hydrophilic drugs was evaluated. The polymer was synthetized with two different crosslinking degrees that were characterized by FTIR [...] Read more.

The potential of a new poly(magnesium acrylate) hydrogel (PAMgA) as a pharmaceutical excipient for the elaboration of matrix tablets for the extended release of highly hydrophilic drugs was evaluated. The polymer was synthetized with two different crosslinking degrees that were characterized by FTIR and DSC. Their acute oral toxicity was determined in a mouse model, showing no toxicity at doses up to 10 g/kg. Matrix tablets were prepared using metformin hydrochloride as a model drug and the mechanisms involved in drug release (swelling and/or erosion) were investigated using biorrelevant media. This new hydrogel effectively controlled the release of small and highly hydrophilic molecules as metformin, when formulated in matrix tablets for oral administration. The rate of metformin release from PAMgA matrices was mainly controlled by its diffusion through the gel layer (Fickian diffusion). The swelling capacity and the erosion of the matrix tablets influenced the metformin release rate, that was slower at pH 6.8, where polymer swelling is more intensive, than in gastric medium, where matrix erosion is slightly more rapid. The crosslinking degree of the polymer significantly influenced its swelling capacity in acid pH, where swelling is moderate, but not in intestinal fluid, where swelling is more intense. Full article

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11 pages, 1287 KiB

Open AccessArticle

Usefulness of Artificial Membrane, Strat-M^®, in the Assessment of Drug Permeation from Complex Vehicles in Finite Dose Conditions

by Florencio Jr Arce, Narumi Asano, Gerard Lee See, Shoko Itakura, Hiroaki Todo and Kenji Sugibayashi

Pharmaceutics 2020, 12(2), 173; https://doi.org/10.3390/pharmaceutics12020173 - 19 Feb 2020

Cited by 43 | Viewed by 5197

Abstract

The ban on the use of animals in testing cosmetic products has led to the development of animal-free in vitro methods. Strat-M^® is an artificial membrane engineered to mimic human skin and is recommended as a replacement for skin. However, its usefulness [...] Read more.

The ban on the use of animals in testing cosmetic products has led to the development of animal-free in vitro methods. Strat-M^® is an artificial membrane engineered to mimic human skin and is recommended as a replacement for skin. However, its usefulness in the assessment of the permeation of cosmetics in in-use conditions remains unverified. No data have been published on its comparative performance with the membrane of choice, porcine skin. The comparative permeability characteristics of Strat-M^® and porcine skin were investigated using Franz diffusion cells. Caffeine (CF) and rhododendrol (RD) in complex vehicles with varying concentrations of polyols were applied as finite and infinite doses. Good rank orders of permeation from finite dose experiments were observed for RD. High correlations were observed in RD permeation between Strat-M^® and porcine skin under finite and infinite dose conditions, whereas only finite dose conditions for CF were associated with good correlations. Permeation from formulations with high polyol content and residual formulations was enhanced due to the disruption of the integrity of the Strat-M^® barrier. The usefulness of Strat-M^® in the assessment of dermal permeation may be limited to finite dose conditions and not applicable to infinite dose conditions or formulations applied in layers. Full article

(This article belongs to the Special Issue Transdermal Drug Delivery Systems)

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14 pages, 4741 KiB

Open AccessArticle

3D Printed Tablets (Printlets) with Braille and Moon Patterns for Visually Impaired Patients

by Atheer Awad, Aliya Yao, Sarah J. Trenfield, Alvaro Goyanes, Simon Gaisford and Abdul W. Basit

Pharmaceutics 2020, 12(2), 172; https://doi.org/10.3390/pharmaceutics12020172 - 19 Feb 2020

Cited by 122 | Viewed by 11720

Abstract

Visual impairment and blindness affects 285 million people worldwide, resulting in a high public health burden. This study reports, for the first time, the use of three-dimensional (3D) printing to create orally disintegrating printlets (ODPs) suited for patients with visual impairment. Printlets were [...] Read more.

Visual impairment and blindness affects 285 million people worldwide, resulting in a high public health burden. This study reports, for the first time, the use of three-dimensional (3D) printing to create orally disintegrating printlets (ODPs) suited for patients with visual impairment. Printlets were designed with Braille and Moon patterns on their surface, enabling patients to identify medications when taken out of their original packaging. Printlets with different shapes were fabricated to offer additional information, such as the medication indication or its dosing regimen. Despite the presence of the patterns, the printlets retained their original mechanical properties and dissolution characteristics, wherein all the printlets disintegrated within ~5 s, avoiding the need for water and facilitating self-administration of medications. Moreover, the readability of the printlets was verified by a blind person. Overall, this novel and practical approach should reduce medication errors and improve medication adherence in patients with visual impairment. Full article

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34 pages, 2816 KiB

Open AccessReview

Nanomaterials Designed for Antiviral Drug Delivery Transport across Biological Barriers

by Florina-Daniela Cojocaru, Doru Botezat, Ioannis Gardikiotis, Cristina-Mariana Uritu, Gianina Dodi, Laura Trandafir, Ciprian Rezus, Elena Rezus, Bogdan-Ionel Tamba and Cosmin-Teodor Mihai

Pharmaceutics 2020, 12(2), 171; https://doi.org/10.3390/pharmaceutics12020171 - 18 Feb 2020

Cited by 154 | Viewed by 15427

Abstract

Viral infections are a major global health problem, representing a significant cause of mortality with an unfavorable continuously amplified socio-economic impact. The increased drug resistance and constant viral replication have been the trigger for important studies regarding the use of nanotechnology in antiviral [...] Read more.

Viral infections are a major global health problem, representing a significant cause of mortality with an unfavorable continuously amplified socio-economic impact. The increased drug resistance and constant viral replication have been the trigger for important studies regarding the use of nanotechnology in antiviral therapies. Nanomaterials offer unique physico-chemical properties that have linked benefits for drug delivery as ideal tools for viral treatment. Currently, different types of nanomaterials namely nanoparticles, liposomes, nanospheres, nanogels, nanosuspensions and nanoemulsions were studied either in vitro or in vivo for drug delivery of antiviral agents with prospects to be translated in clinical practice. This review highlights the drug delivery nanosystems incorporating the major antiviral classes and their transport across specific barriers at cellular and intracellular level. Important reflections on nanomedicines currently approved or undergoing investigations for the treatment of viral infections are also discussed. Finally, the authors present an overview on the requirements for the design of antiviral nanotherapeutics. Full article

(This article belongs to the Special Issue Drug Delivery across Biological Barriers)

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17 pages, 17756 KiB

Open AccessArticle

pH-Sensitive Mixed Micelles Assembled from PDEAEMA-PPEGMA and PCL-PPEGMA for Doxorubicin Delivery: Experimental and DPD Simulations Study

by Chufen Yang, Wenyao Liu, Jiayu Xiao, Cong Yuan, Yaoxi Chen, Jianwei Guo, Hangbo Yue, Dongyu Zhu, Wenjing Lin, Shengqiu Tang and Xiaoying Dong

Pharmaceutics 2020, 12(2), 170; https://doi.org/10.3390/pharmaceutics12020170 - 18 Feb 2020

Cited by 21 | Viewed by 4240

Abstract

To decrease critical micelle concentration (CMC), improve stability, and keep high drug-loading capacity, three pH-sensitive mixed micelles applied for anticancer drug controlled delivery were prepared by the mixture of polymers poly (N,N-diethylaminoethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (PDEAEMA-PPEGMA) and [...] Read more.

To decrease critical micelle concentration (CMC), improve stability, and keep high drug-loading capacity, three pH-sensitive mixed micelles applied for anticancer drug controlled delivery were prepared by the mixture of polymers poly (N,N-diethylaminoethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (PDEAEMA-PPEGMA) and polycaprolactone-b-poly (poly(ethylene glycol) methyl ether methacrylate) (PCL-PPEGMA), which were synthesized and confirmed by ¹H NMR and gel permeation chromatographic (GPC). The critical micelle concentration (CMC) values of the prepared mixed micelles were low, and the micellar sizes and zeta potentials of the blank mixed micelles demonstrated good pH-responsive behavior. Combined experimental techniques with dissipative particle dynamics (DPD) simulation, the particle sizes, zeta potentials, drug loading content (LC), encapsulation efficiency (EE), aggregation morphologies, and doxorubicin (DOX) distribution of the mixed micelles were investigated, and the high DOX-loading capacity of the mixed micelles was found. Both in vitro DOX release profiles and DPD simulations of the DOX dynamics release process exhibited less leakage and good stability in neutral conditions and accelerated drug release behavior with a little initial burst in slightly acidic conditions. Cytotoxicity tests showed that the polymer PDEAEMA-PPEGMA and the blank mixed micelles had good biocompatibility, and DOX-loaded mixed micelles revealed certain cytotoxicity. These results suggest that the drug-loaded mixed micelles that consisted of the two polymers PDEAEMA-PPEGMA and PCL-PPEGMA can be new types of pH-responsive well-controlled release anticancer drug delivery mixed micelles. Full article

(This article belongs to the Special Issue Advanced Polymeric-Based Nanocarriers for Drug Delivery and Theranosis)

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12 pages, 3547 KiB

Open AccessArticle

Zein/MCM-41 Nanocomposite Film Incorporated with Cinnamon Essential Oil Loaded by Modified Supercritical CO₂ Impregnation for Long-Term Antibacterial Packaging

by Xiaojing Liu, Jingfu Jia, Shulei Duan, Xue Zhou, Anya Xiang, Ziling Lian and Fahuan Ge

Pharmaceutics 2020, 12(2), 169; https://doi.org/10.3390/pharmaceutics12020169 - 18 Feb 2020

Cited by 27 | Viewed by 3648

Abstract

Antimicrobial medicine and food packages based on bio-based film containing essential oils have attracted great attention worldwide. However, the controlled release of essential oils from these film nanocomposites is still a big challenge. In this study, a long-term antibacterial film nanocomposite composed of [...] Read more.

Antimicrobial medicine and food packages based on bio-based film containing essential oils have attracted great attention worldwide. However, the controlled release of essential oils from these film nanocomposites is still a big challenge. In this study, a long-term antibacterial film nanocomposite composed of zein film and cinnamon essential oil (CEO) loaded MCM-41 silica nanoparticles was prepared. The CEO was loaded into MCM-41 particles via modified supercritical impregnation efficiently with a high drug load (>40 wt%). The morphologies of the prepared nanoparticles and film nanocomposite were characterized by a scanning electron microscope. The release behaviors of CEO under different temperatures, high humidity, continuous illumination and in phosphate buffer solution (PBS) solution were investigated. The results showed that the film nanocomposite had an outstanding release-control effect. The addition of MCM-41 nanoparticles also improved the mechanical properties of zein films. The antibacterial effect of CEO was significantly prolonged by the film nanocomposite; indicating the CEO film nanocomposite fabricated via modified supercritical CO₂ impregnation was a potential long-term antibacterial medicine or food package material. Full article

(This article belongs to the Special Issue Functional Polymers as Innovative Tools in the Delivery of Antimicrobial Agents)

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13 pages, 2338 KiB

Open AccessArticle

Impact of Mucin on Drug Diffusion: Development of a Straightforward In Vitro Method for the Determination of Drug Diffusivity in the Presence of Mucin

by Margherita Falavigna, Paul C. Stein, Gøril Eide Flaten and Massimiliano Pio di Cagno

Pharmaceutics 2020, 12(2), 168; https://doi.org/10.3390/pharmaceutics12020168 - 17 Feb 2020

Cited by 35 | Viewed by 6108

Abstract

Mucosal drug delivery accounts for various administration routes (i.e., oral, vaginal, ocular, pulmonary, etc.) and offers a vast surface for the permeation of drugs. However, the mucus layer which shields and lubricates all mucosal tissues can compromise drugs from reaching the epithelial site, [...] Read more.

Mucosal drug delivery accounts for various administration routes (i.e., oral, vaginal, ocular, pulmonary, etc.) and offers a vast surface for the permeation of drugs. However, the mucus layer which shields and lubricates all mucosal tissues can compromise drugs from reaching the epithelial site, thus affecting their absorption and therapeutic effect. Therefore, the effect of the mucus layer on drug absorption has to be evaluated early in the drug-development phase, prior to in vivo studies. For this reason, we developed a simple, cost-effective and reproducible method employing UV-visible localized spectroscopy for the assessment of the interaction between mucin and drugs with different physicochemical characteristics. The mucin–drug interaction was investigated by measuring the drug relative diffusivity (D_rel) in the presence of mucin, and the method was validated by fitting experimental and mathematical data. In vitro permeability studies were also performed using the mucus-covered artificial permeation barrier (mucus–PVPA, Phospholipid Vesicle-based Permeation Assay) for comparison. The obtained results showed that the diffusion of drugs was hampered by the presence of mucin, especially at higher concentrations. This novel method proved to be suitable for the investigation on the extent of mucin–drug interaction and can be successfully used to assess the impact that the mucus layer has on drug absorption. Full article

(This article belongs to the Special Issue Mucoadhesive and Mucosal Drug Delivery Systems)

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18 pages, 2097 KiB

Open AccessArticle

Transport Mechanisms of Polymannuronic Acid and Polyguluronic Acid Across Caco-2 Cell Monolayers

by Yu Wang, Xu Bai, Bo Hu, Maochen Xing, Qi Cao, Aiguo Ji and Shuliang Song

Pharmaceutics 2020, 12(2), 167; https://doi.org/10.3390/pharmaceutics12020167 - 17 Feb 2020

Cited by 17 | Viewed by 3695

Abstract

Detailed knowledge of the intestinal transport of polymannuronic acid (PM) and polyguluronic acid (PG) is critical for understanding their biological activities. To investigate the transport in the gastrointestinal tract, PM and PG were chemically modified with tyramine and conjugated with fluorescein isothiocyanate (FITC) [...] Read more.

Detailed knowledge of the intestinal transport of polymannuronic acid (PM) and polyguluronic acid (PG) is critical for understanding their biological activities. To investigate the transport in the gastrointestinal tract, PM and PG were chemically modified with tyramine and conjugated with fluorescein isothiocyanate (FITC) to synthesize FITC-PM (F-PM) and FITC-PG (F-PG) successfully. The transport mechanisms of F-PM and F-PG across the intestinal epithelial cell monolayers (Caco-2 cell monolayers) were then investigated. The results demonstrated that the transport of F-PM and F-PG into epithelial cells was time- and energy-dependent, which was mediated by the macropinocytosis pathway and the clathrin- and caveolae (or lipid raft)-mediated endocytic pathway. The transport process of F-PM and F-PG in Caco-2 cells depended on the acidification of endosomes and involved lysosomes. Tubulin mediated the transport of F-PM, but not of F-PG. Moreover, the absorption enhancer chitosan (CS) promoted the transport of F-PM and F-PG, increasing the apparent permeability coefficient (Papp) by 1.9-fold and 2.6-fold, respectively, by reversibly opening the tight junction (TJ). In summary, this study provided a comprehensive understanding of the transport of PM and PG in the small intestinal epithelial cells, which will provide a theoretical basis for the development of PM and PG with good intestinal absorption. Full article

(This article belongs to the Special Issue Intestinal Drug Absorption)

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17 pages, 5573 KiB

Open AccessArticle

A 3D Bioprinted Pseudo-Bone Drug Delivery Scaffold for Bone Tissue Engineering

by Pariksha Jolene Kondiah, Pierre P. D. Kondiah, Yahya E. Choonara, Thashree Marimuthu and Viness Pillay

Pharmaceutics 2020, 12(2), 166; https://doi.org/10.3390/pharmaceutics12020166 - 17 Feb 2020

Cited by 52 | Viewed by 6438

Abstract

A 3D bioprinted pseudo-bone drug delivery scaffold was fabricated to display matrix strength, matrix resilience, as well as porous morphology of healthy human bone. Computer-aided design (CAD) software was employed for developing the 3D bioprinted scaffold. Further optimization of the scaffold was undertaken [...] Read more.

A 3D bioprinted pseudo-bone drug delivery scaffold was fabricated to display matrix strength, matrix resilience, as well as porous morphology of healthy human bone. Computer-aided design (CAD) software was employed for developing the 3D bioprinted scaffold. Further optimization of the scaffold was undertaken using MATLAB^® software and artificial neural networks (ANN). Polymers employed for formulating the 3D scaffold comprised of polypropylene fumarate (PPF), free radical polymerized polyethylene glycol- polycaprolactone (PEG-PCL-PEG), and pluronic (PF127). Simvastatin was incorporated into the 3D bioprinted scaffolds to further promote bone healing and repair properties. The 3D bioprinted scaffold was characterized for its chemical, morphological, mechanical, and in vitro release kinetics for evaluation of its behavior for application as an implantable scaffold at the site of bone fracture. The ANN-optimized 3D bioprinted scaffold displayed significant properties as a controlled release platform, demonstrating drug release over 20 days. The 3D bioprinted scaffold further displayed formation as a pseudo-bone matrix, using a human clavicle bone model, induced with a butterfly fracture. The strength of the pseudo-bone matrix, evaluated for its matrix hardness (MH) and matrix resilience (MR), was evaluated to be as strong as original bone, having a 99% MH and 98% MR property, to healthy human clavicle bones. Full article

(This article belongs to the Special Issue 3D Printing of Pharmaceuticals and Drug Delivery Devices)

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