Pharmaceutics

15 pages, 1979 KiB

Open AccessArticle

Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development

by Milica Markovic, Moran Zur, Noa Fine-Shamir, Ester Haimov, Isabel González-Álvarez and Arik Dahan

Pharmaceutics 2020, 12(3), 295; https://doi.org/10.3390/pharmaceutics12030295 - 24 Mar 2020

Cited by 16 | Viewed by 5055

Abstract

The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug [...] Read more.

The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high P_eff marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol’s solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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15 pages, 2844 KiB

Open AccessArticle

An Assessment of Mesoporous Silica Nanoparticle Architectures as Antigen Carriers

by Xinyue Huang and Helen E Townley

Pharmaceutics 2020, 12(3), 294; https://doi.org/10.3390/pharmaceutics12030294 - 24 Mar 2020

Cited by 7 | Viewed by 3083

Abstract

Mesoporous silica nanoparticles (MSNPs) have the potential to be used as antigen carriers due to their high surface areas and highly ordered pore network. We investigated the adsorption and desorption of diphtheria toxoid as a proof-of-concept. Two series of nanoparticles were prepared—(i) small [...] Read more.

Mesoporous silica nanoparticles (MSNPs) have the potential to be used as antigen carriers due to their high surface areas and highly ordered pore network. We investigated the adsorption and desorption of diphtheria toxoid as a proof-of-concept. Two series of nanoparticles were prepared—(i) small pores (SP) (<10 nm) and (ii) large pores (LP) (>10 nm). SBA-15 was included as a comparison since this is commercially available and has been used in a large number of studies. External diameters of the particles ranged from 138 to 1509 nm, surface area from 632 to 1110 m²/g and pore size from 2.59 to 16.48 nm. Antigen loading was assessed at a number of different ratios of silica-to-antigen and at 4 °C, 20 °C and 37 °C. Our data showed that protein adsorption by the SP series was in general consistently lower than that shown by the large pore series. Unloading was then examined at 4 °C, 20 °C and 37 °C and a pH 1.2, 4.5, 6.8 and 7.4. There was a trend amongst the LP particles towards the smallest pores showing the lowest release of antigen. The stability of the MSNP: antigen complex was tested at two different storage temperatures, and storage in solution or after lyophilization. After 6 months there was negligible release from any of the particles under any of the storage conditions. The particles were also shown not to cause hemolysis. Full article

(This article belongs to the Special Issue Silica Nanoparticles for Delivery of Therapeutics and Imaging Agents)

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10 pages, 2183 KiB

Open AccessArticle

Alendronic Acid as Ionic Liquid: New Perspective on Osteosarcoma

by Sónia Teixeira, Miguel M. Santos, Maria H. Fernandes, João Costa-Rodrigues and Luís C. Branco

Pharmaceutics 2020, 12(3), 293; https://doi.org/10.3390/pharmaceutics12030293 - 24 Mar 2020

Cited by 20 | Viewed by 4432

Abstract

Herein the quantitative synthesis of eight new mono- and dianionic Organic Salts and Ionic Liquids (OSILs) from alendronic acid (ALN) is reported by following two distinct sustainable and straightforward methodologies, according to the type of cation. The prepared ALN-OSILs were characterized by spectroscopic [...] Read more.

Herein the quantitative synthesis of eight new mono- and dianionic Organic Salts and Ionic Liquids (OSILs) from alendronic acid (ALN) is reported by following two distinct sustainable and straightforward methodologies, according to the type of cation. The prepared ALN-OSILs were characterized by spectroscopic techniques and their solubility in water and biological fluids was determined. An evaluation of the toxicity towards human healthy cells and also human breast, lung and bone (osteosarcoma) cell lines was performed. Globally, it was observed that the monoanionic OSILs showed lower toxicity than the corresponding dianionic structures to all cell types. The highest cytotoxic effect was observed in OSILs containing a [C₂OHMIM] cation, in particular [C₂OHMIM][ALN]. The latter showed an improvement in IC₅₀ values of ca. three orders of magnitude for the lung and bone cancer cell lines as well as fibroblasts in comparison with ALN. The development of OSILs with high cytotoxicity effect towards the tested cancer cell types, and containing an anti-resorbing molecule such as ALN may represent a promising strategy for the development of new pharmacological tools to be used in those pathological conditions. Full article

(This article belongs to the Special Issue Ionic Liquids and Deep Eutectic Solvents for Application in Pharmaceutics)

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11 pages, 2028 KiB

Open AccessArticle

Safe Practice of Y-Site Drug Administration: The Case of Colistin and Parenteral Nutrition

by Maciej Stawny, Aleksandra Gostyńska, Malwina Nadolna and Anna Jelińska

Pharmaceutics 2020, 12(3), 292; https://doi.org/10.3390/pharmaceutics12030292 - 24 Mar 2020

Cited by 14 | Viewed by 3785

Abstract

A serious problem in everyday clinical practice is the co-administration of drugs using the same infusion line. Potential complications of co-administration of incompatible drugs include precipitation in the infusion line or central venous catheter leading to its occlusion. Administration of precipitate and large [...] Read more.

A serious problem in everyday clinical practice is the co-administration of drugs using the same infusion line. Potential complications of co-administration of incompatible drugs include precipitation in the infusion line or central venous catheter leading to its occlusion. Administration of precipitate and large lipid droplets into the venous system may lead to the embolization of capillaries and local or systemic inflammatory reactions, with the consequences of venous thrombosis, chronic venous insufficiency, and even pulmonary embolism. The co-administration of drugs must always be confirmed and clearly defined. The study aimed to determine the interaction between colistin (COL) in the dose used during intermittent hemodialysis and five different ready-to-use PN admixtures (PN) (Kabiven, Smofkabiven, Olimel N9E, Nutriflex Lipid Special, and Nutriflex Omega Special). COL-PN compatibilities were tested by comparing physicochemical properties (pH, zeta potential, lipid emulsion particle size) of COL and PN at three time points: immediately after sample preparation, after ten minutes, and after four hours. No changes in the visual inspection were observed. Both PN without COL and COL-PN samples remained white, homogeneous oil-in-water emulsions with no signs of phase separation, precipitation, or color change. There were no significant changes in pH, and the mean droplet diameter remained below the acceptance limit of 500 nm. The zeta potential and osmolality of COL-PN samples ranged from −21.4 to −7.22 mV and from 567 to 1304 mOsm/kg, respectively. The COL does not influence the physical stability of studied PN admixtures. The co-infusion of COL with Kabiven, Nutriflex Lipid Special, Olimel N9E, Nutriflex Omega Special, and Smofkabiven is possible in the dose used during intermittent hemodialysis. Full article

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9 pages, 1118 KiB

Open AccessArticle

Optimal Connection for Tiotropium SMI Delivery through Mechanical Ventilation: An In Vitro Study

by Tien-Pei Fang, Yu-Ju Chen, Tsung-Ming Yang, Szu-Hu Wang, Ming-Szu Hung, Shu-Hua Chiu, Hsin-Hsien Li, James B. Fink and Hui-Ling Lin

Pharmaceutics 2020, 12(3), 291; https://doi.org/10.3390/pharmaceutics12030291 - 24 Mar 2020

Cited by 5 | Viewed by 6020

Abstract

We aimed to quantify Soft Mist Inhalers (SMI) delivery to spontaneous breathing model and compare with different adapters via endotracheal tube during mechanical ventilation or by manual resuscitation. A tiotropium SMI was used with a commercial in-line adapter and a T-adapter placed between [...] Read more.

We aimed to quantify Soft Mist Inhalers (SMI) delivery to spontaneous breathing model and compare with different adapters via endotracheal tube during mechanical ventilation or by manual resuscitation. A tiotropium SMI was used with a commercial in-line adapter and a T-adapter placed between the Y-adapter and the inspiratory limb of the ventilator circuit during mechanical ventilation. The SMI was actuated at the beginning of inspiration and expiration. In separate experiments, a manual resuscitator with T-adapter was attached to endotracheal tube, collecting filter, and a passive test lung. Drug was eluted from collecting filters with salt-based solvent and analyzed using high-performance liquid chromatography. Results showed the percent of SMI label dose inhaled was 3-fold higher with the commercial in-line adapter with actuation during expiration than when synchronized with inspiration. SMI with T-adapter delivery via ventilator was similar to inhalation (1.20%) or exhalation (1.02%), and both had lower delivery dose than with manual resuscitator (2.80%; p = 0.01). The inhaled dose via endotracheal tube was much lower than inhaled dose with spontaneous breathing (22.08%). In conclusion, the inhaled dose with the commercial adapter was higher with SMI actuated during expiration, but still far less than reported spontaneous inhaled dose. Full article

(This article belongs to the Special Issue Drug Delivery through Pulmonary)

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25 pages, 4871 KiB

Open AccessReview

Nanogel: A Versatile Nano-Delivery System for Biomedical Applications

by Yanlong Yin, Ben Hu, Xiao Yuan, Li Cai, Huile Gao and Qian Yang

Pharmaceutics 2020, 12(3), 290; https://doi.org/10.3390/pharmaceutics12030290 - 23 Mar 2020

Cited by 169 | Viewed by 11822

Abstract

Nanogel-based nanoplatforms have become a tremendously promising system of drug delivery. Nanogels constructed by chemical crosslinking or physical self-assembly exhibit the ability to encapsulate hydrophilic or hydrophobic therapeutics, including but not limited to small-molecule compounds and proteins, DNA/RNA sequences, and even ultrasmall nanoparticles, [...] Read more.

Nanogel-based nanoplatforms have become a tremendously promising system of drug delivery. Nanogels constructed by chemical crosslinking or physical self-assembly exhibit the ability to encapsulate hydrophilic or hydrophobic therapeutics, including but not limited to small-molecule compounds and proteins, DNA/RNA sequences, and even ultrasmall nanoparticles, within their 3D polymer network. The nanosized nature of the carriers endows them with a specific surface area and inner space, increasing the stability of loaded drugs and prolonging their circulation time. Reactions or the cleavage of chemical bonds in the structure of drug-loaded nanogels have been shown to trigger the controlled or sustained drug release. Through the design of specific chemical structures and different methods of production, nanogels can realize diverse responsiveness (temperature-sensitive, pH-sensitive and redox-sensitive), and enable the stimuli-responsive release of drugs in the microenvironments of various diseases. To improve therapeutic outcomes and increase the precision of therapy, nanogels can be modified by specific ligands to achieve active targeting and enhance the drug accumulation in disease sites. Moreover, the biomembrane-camouflaged nanogels exhibit additional intelligent targeted delivery features. Consequently, the targeted delivery of therapeutic agents, as well as the combinational therapy strategy, result in the improved efficacy of disease treatments, though the introduction of a multifunctional nanogel-based drug delivery system. Full article

(This article belongs to the Special Issue New Formulations for Cancer Therapy)

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22 pages, 4257 KiB

Open AccessArticle

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

by Debora Zanolla, Dritan Hasa, Mihails Arhangelskis, Gabriela Schneider-Rauber, Michele R. Chierotti, Jennifer Keiser, Dario Voinovich, William Jones and Beatrice Perissutti

Pharmaceutics 2020, 12(3), 289; https://doi.org/10.3390/pharmaceutics12030289 - 23 Mar 2020

Cited by 23 | Viewed by 5225

Abstract

Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and [...] Read more.

Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list of multicomponent forms of PZQ a relevant example of a racemic hemihydrate (PZQ-HH), obtainable from commercial PZQ (polymorphic Form A) through mechanochemistry. Noteworthy, the formation of the new hemihydrate strongly depends on the initial polymorphic form of PZQ and on the experimental conditions used. The new PZQ-HH has been fully characterized by means of HPLC, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (SEM), Powder X-Ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), FT-IR, polarimetry, solid-state NMR (SS-NMR), solubility and intrinsic dissolution rate (IDR), and in vitro tests on Schistosoma mansoni adults. The crystal structure was solved from the powder X-ray diffraction pattern and validated by periodic-DFT calculations. The new bioactive hemihydrate was physically stable for three months and showed peculiar biopharmaceutical features including enhanced solubility and a double intrinsic dissolution rate in water in comparison to the commercially available PZQ Form A. Full article

(This article belongs to the Special Issue Drug Polymorphism and Dosage Form Design)

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26 pages, 2431 KiB

Open AccessReview

Nanostructured Lipid Carriers for Delivery of Chemotherapeutics: A Review

by Mohamed Haider, Shifaa M. Abdin, Leena Kamal and Gorka Orive

Pharmaceutics 2020, 12(3), 288; https://doi.org/10.3390/pharmaceutics12030288 - 23 Mar 2020

Cited by 294 | Viewed by 15367

Abstract

The efficacy of current standard chemotherapy is suboptimal due to the poor solubility and short half-lives of chemotherapeutic agents, as well as their high toxicity and lack of specificity which may result in severe side effects, noncompliance and patient inconvenience. The application of [...] Read more.

The efficacy of current standard chemotherapy is suboptimal due to the poor solubility and short half-lives of chemotherapeutic agents, as well as their high toxicity and lack of specificity which may result in severe side effects, noncompliance and patient inconvenience. The application of nanotechnology has revolutionized the pharmaceutical industry and attracted increasing attention as a significant means for optimizing the delivery of chemotherapeutic agents and enhancing their efficiency and safety profiles. Nanostructured lipid carriers (NLCs) are lipid-based formulations that have been broadly studied as drug delivery systems. They have a solid matrix at room temperature and are considered superior to many other traditional lipid-based nanocarriers such as nanoemulsions, liposomes and solid lipid nanoparticles (SLNs) due to their enhanced physical stability, improved drug loading capacity, and biocompatibility. This review focuses on the latest advances in the use of NLCs as drug delivery systems and their preparation and characterization techniques with special emphasis on their applications as delivery systems for chemotherapeutic agents and different strategies for their use in tumor targeting. Full article

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12 pages, 883 KiB

Open AccessReview

Quality by Design: Development of the Quality Target Product Profile (QTPP) for Semisolid Topical Products

by Sarika Namjoshi, Maryam Dabbaghi, Michael S. Roberts, Jeffrey E. Grice and Yousuf Mohammed

Pharmaceutics 2020, 12(3), 287; https://doi.org/10.3390/pharmaceutics12030287 - 23 Mar 2020

Cited by 77 | Viewed by 19335

Abstract

In recent years, the “quality by design” (QbD) approach has been used for developing pharmaceutical formulations. This is particularly important for complex dosage forms such as topical semisolid products. The first step for developing a product using this efficient approach is defining the [...] Read more.

In recent years, the “quality by design” (QbD) approach has been used for developing pharmaceutical formulations. This is particularly important for complex dosage forms such as topical semisolid products. The first step for developing a product using this efficient approach is defining the quality target product profile (QTPP), a list of quality attributes (QAs) that are required to be present in the final product. These quality attributes are affected by the ingredients used as well as manufacturing procedure parameters. Hence, critical material attributes (CMAs) and critical process parameters (CPPs) need to be specified. Possible failure modes of a topical semisolid product can be determined based on the physiochemical properties of ingredients and manufacturing procedures. In this review, we have defined and specified QTPP, QAs, CMAs and CPPs that are required for developing a topical semisolid product based on the QbD approach. Full article

(This article belongs to the Special Issue Quality by Design (QbD) for Topical Dermatological and Transdermal Product Development)

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15 pages, 1597 KiB

Open AccessArticle

Development and Evaluation of a Reconstitutable Dry Suspension Containing Isoniazid for Flexible Pediatric Dosing

by Oluwatoyin A. Adeleke, Rose K. Hayeshi and Hajierah Davids

Pharmaceutics 2020, 12(3), 286; https://doi.org/10.3390/pharmaceutics12030286 - 23 Mar 2020

Cited by 8 | Viewed by 4928

Abstract

Tuberculosis (TB) is a major cause of childhood death. Despite the startling statistics, it is neglected globally as evidenced by treatment and clinical care schemes, mostly extrapolated from studies in adults. The objective of this study was to formulate and evaluate a reconstitutable [...] Read more.

Tuberculosis (TB) is a major cause of childhood death. Despite the startling statistics, it is neglected globally as evidenced by treatment and clinical care schemes, mostly extrapolated from studies in adults. The objective of this study was to formulate and evaluate a reconstitutable dry suspension (RDS) containing isoniazid, a first-line anti-tubercular agent used in the treatment and prevention of TB infection in both children and adults. The RDS formulation was prepared by direct dispersion emulsification of an aqueous-lipid particulate interphase coupled with lyophilization and dry milling. The RDS appeared as a cream-white free-flowing powder with a semi-crystalline and microparticulate nature. Isoniazid release was characterized with an initial burst up to 5 minutes followed by a cumulative release of 67.88% ± 1.88% (pH 1.2), 60.18% ± 3.33% (pH 6.8), and 49.36% ± 2.83% (pH 7.4) over 2 h. An extended release at pH 7.4 and 100% drug liberation was achieved within 300 min. The generated release profile best fitted the zero order kinetics (R² = 0.976). RDS was re-dispersible and remained stable in the dried and reconstituted states over 4 months and 11 days respectively, under common storage conditions. Full article

(This article belongs to the Special Issue Pharmaceutical Particulates and Membranes for Delivery of Drugs and Bioactive Molecules)

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16 pages, 3203 KiB

Open AccessArticle

Pectin-Tannic Acid Nano-Complexes Promote the Delivery and Bioactivity of Drugs in Pancreatic Cancer Cells

by Sumeet S. Chauhan, Advait B. Shetty, Elham Hatami, Pallabita Chowdhury and Murali M. Yallapu

Pharmaceutics 2020, 12(3), 285; https://doi.org/10.3390/pharmaceutics12030285 - 22 Mar 2020

Cited by 39 | Viewed by 5763

Abstract

Pancreatic cancer (PanCa) is a lethal disease. Conventional chemotherapies for PanCa offer severe systemic toxicities. Thus, the development of a successful nanomedicine-based therapeutic regimen with augmented therapeutic efficacy is highly sought. Naturally occurring pectin and modified pectin-based drug delivery systems exhibit remarkable self-targeting [...] Read more.

Pancreatic cancer (PanCa) is a lethal disease. Conventional chemotherapies for PanCa offer severe systemic toxicities. Thus, the development of a successful nanomedicine-based therapeutic regimen with augmented therapeutic efficacy is highly sought. Naturally occurring pectin and modified pectin-based drug delivery systems exhibit remarkable self-targeting ability via galactose residues to various cancer cells. Herein, we developed and used an innovative approach of highly stable nanocomplexes based on modified pectin and tannic acid (MPT-NCs). The nanocomplex formation was enabled by strong intermolecular interactions between pectin and tannic acid under very mild conditions. These nanocomplexes were characterized by particle size and morphology (DLS, TEM, and SEM), FT-IR spectroscopy, and zeta potential measurements. Additionally, MPT-NCs were capable of encapsulating anticancer drugs (5-fluorouracil, gemcitabine, and irinotecan) through tannic acid binding. The in vitro bioactivity of these drug MPT-NCs were evaluated in pancreatic cancer adenocarcinoma (PDAC) cell lines (HPAF-II and PANC-1). A dose-dependent internalization of nanocomplexes was evident from microscopy and flow cytometry analysis. Both proliferation and colony formation assays indicated the anticancer potential of pectin drug nanocomplexes against PDAC cells compared to that of free drug treatments. Together, the pectin-based nanocomplexes could be a reliable and efficient drug delivery strategy for cancer therapy. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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17 pages, 4134 KiB

Open AccessArticle

A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice

by Júlia Companys-Alemany, Andreea L. Turcu, Aina Bellver-Sanchis, Maria I Loza, José M. Brea, Anna M Canudas, Rosana Leiva, Santiago Vázquez, Mercè Pallàs and Christian Griñán-Ferré

Pharmaceutics 2020, 12(3), 284; https://doi.org/10.3390/pharmaceutics12030284 - 22 Mar 2020

Cited by 45 | Viewed by 6624

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo efficacy of the RL-208, a new NMDA receptor blocker described recently, with favourable [...] Read more.

Alzheimer’s disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo efficacy of the RL-208, a new NMDA receptor blocker described recently, with favourable pharmacokinetic properties was evaluated in Senescence accelerated mice prone 8 (SAMP8), a mice model of late-onset AD (LOAD). Oral administration of RL-208 improved cognitive performance assessed by using the three chamber test (TCT), novel object recognition test (NORT), and object location test (OLT). Consistent with behavioural results, RL-208 treated-mice groups significantly changed NMDAR2B phosphorylation state levels but not NMDAR2A. Calpain-1 and Caspase-3 activity was reduced, whereas B-cell lymphoma-2 (BCL-2) levels increased, indicating reduced apoptosis in RL-208 treated SAMP8. Superoxide Dismutase 1 (SOD1) and Glutathione Peroxidase 1 (GPX1), as well as a reduction of hydrogen peroxide (H₂O₂), was also determined in RL-208 mice. RL-208 treatment induced an increase in mature brain-derived neurotrophic factor (mBDNF), prevented Tropomyosin-related kinase B full-length (TrkB-FL) cleavage, increased protein levels of Synaptophysin (SYN) and Postsynaptic density protein 95 (PSD95). In whole, these results point out to an improvement in synaptic plasticity. Remarkably, RL-208 also decreased the protein levels of Cyclin-Dependent Kinase 5 (CDK5), as well as p25/p35 ratio, indicating a reduction in kinase activity of CDK5/p25 complex. Consequently, lower levels of hyperphosphorylated Tau (p-Tau) were found. In sum, these results demonstrate the neuroprotectant role of RL-208 through NMDAR blockade. Full article

(This article belongs to the Section Drug Targeting and Design)

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19 pages, 4813 KiB

Open AccessArticle

Impact of Particle and Equipment Properties on Residence Time Distribution of Pharmaceutical Excipients in Rotary Tablet Presses

by Daniel Puckhaber, Sebastian Eichler, Arno Kwade and Jan Henrik Finke

Pharmaceutics 2020, 12(3), 283; https://doi.org/10.3390/pharmaceutics12030283 - 21 Mar 2020

Cited by 14 | Viewed by 4897

Abstract

Paddle feeders are devices commonly used in rotary tablet presses to facilitate constant and efficient die filling. Adversely, the shear stress applied by the rotating paddles is known to affect the bulk properties of the processed powder dependent on the residence time. This [...] Read more.

Paddle feeders are devices commonly used in rotary tablet presses to facilitate constant and efficient die filling. Adversely, the shear stress applied by the rotating paddles is known to affect the bulk properties of the processed powder dependent on the residence time. This study focuses on the residence time distribution (RTD) of two commonly applied excipients (microcrystalline cellulose, MCC; dicalcium phosphate, DCP), which exhibit different flow properties inside rotary tablet presses. To realistically depict the powder flow inside rotary tablet presses, custom-made tracer powder was developed. The applied method was proven to be appropriate as the tracer and bulk powder showed comparable properties. The RTDs of both materials were examined in two differently scaled rotary tablet presses and the influence of process parameters was determined. To analyze RTDs independent of the mass flow, the normalized variance was used to quantify intermixing. Substantial differences between both materials and tablet presses were found. Broader RTDs were measured for the poorer flowing MCC as well as for the production scale press. The obtained results can be used to improve the general understanding of powder flow inside rotary tablet presses and amplify scale-up and continuous production process development. Full article

(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)

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24 pages, 3791 KiB

Open AccessArticle

Topical Delivery of Meloxicam using Liposome and Microemulsion Formulation Approaches

by Julia Zhang, Anna Froelich and Bozena Michniak-Kohn

Pharmaceutics 2020, 12(3), 282; https://doi.org/10.3390/pharmaceutics12030282 - 21 Mar 2020

Cited by 37 | Viewed by 6237

Abstract

The aim of this study is to develop, characterize and compare conventional liposome, deformable liposome (transfersome) and microemulsion formulations as potential topical delivery systems for meloxicam. Liposomes were characterized in terms of vesicle size, zeta potential and entrapment efficiency. For microemulsions, particle size, [...] Read more.

The aim of this study is to develop, characterize and compare conventional liposome, deformable liposome (transfersome) and microemulsion formulations as potential topical delivery systems for meloxicam. Liposomes were characterized in terms of vesicle size, zeta potential and entrapment efficiency. For microemulsions, particle size, electrical conductivity and viscosity studies were performed to assess the structure of the investigated systems. An ex vivo skin permeation study has been conducted to compare these formulations. The dermal and transdermal delivery of meloxicam using these formulations can be a promising alternative to conventional oral delivery of non-steroidal anti-inflammatory drugs (NSAIDs) with enhanced local and systemic onset of action and reduced side effects. Full article

(This article belongs to the Special Issue Nanosystems as Drug Delivery Carrier: From Nature to the Medication)

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13 pages, 2464 KiB

Open AccessArticle

Synthesis and Characterization of Polyfumarateurethane Nanoparticles for Sustained Release of Bupivacaine

by Soo-Yong Park, Jiin Kang, Ji-Young Yoon and Ildoo Chung

Pharmaceutics 2020, 12(3), 281; https://doi.org/10.3390/pharmaceutics12030281 - 21 Mar 2020

Cited by 4 | Viewed by 3411

Abstract

Biodegradable polyfumarateurethane (PFU) for use as a bupivacaine delivery vehicle, synthesized using di-(2-hydroxypropyl fumarate) (DHPF), polyethylene glycol (PEG) and 1,6-hexamethylene diisocyanate (HMDI), was designed to be degradable through the hydrolysis and enzymatic degradation of the ester bonds in its polymer backbone. Using a [...] Read more.

Biodegradable polyfumarateurethane (PFU) for use as a bupivacaine delivery vehicle, synthesized using di-(2-hydroxypropyl fumarate) (DHPF), polyethylene glycol (PEG) and 1,6-hexamethylene diisocyanate (HMDI), was designed to be degradable through the hydrolysis and enzymatic degradation of the ester bonds in its polymer backbone. Using a water-in-oil-in-water double emulsion techniques, nanoparticles encapsulating water or fluorescein isothiocyanate (FITC) were fabricated to avoid the immune system owing to the presence of PEG on their surface. The morphologies of these nanoparticles were characterized by DLS, TEM, FE-SEM, and fluorescent microscopies. The present study explored the encapsulation, loading efficiency and in vitro drug release of bupivacaine encapsulated with biodegradable PFU nanoparticles for the treatment of local anesthesia. Various concentrations of bupivacaine were encapsulated into nanoparticles and their encapsulation efficiencies and drug loading were investigated. Encapsulation efficiency was highest when 2.5% bupivacaine was encapsulated. Drug release behavior from the bupivacaine-loaded PFU nanoparticles followed a sustained release profile. Full article

(This article belongs to the Special Issue Encapsulation Techniques Applied to Pharmaceutics)

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13 pages, 1750 KiB

Open AccessArticle

Enhanced Chondrogenic Differentiation Activities in Human Bone Marrow Aspirates via sox9 Overexpression Mediated by pNaSS-Grafted PCL Film-Guided rAAV Gene Transfer

by Jagadeesh K. Venkatesan, Weikun Meng, Ana Rey-Rico, Gertrud Schmitt, Susanne Speicher-Mentges, Céline Falentin-Daudré, Amélie Leroux, Henning Madry, Véronique Migonney and Magali Cucchiarini

Pharmaceutics 2020, 12(3), 280; https://doi.org/10.3390/pharmaceutics12030280 - 21 Mar 2020

Cited by 18 | Viewed by 3195

Abstract

Background: The delivery of therapeutic genes in sites of articular cartilage lesions using non-invasive, scaffold-guided gene therapy procedures is a promising approach to stimulate cartilage repair while protecting the cargos from detrimental immune responses, particularly when targeting chondroreparative bone marrow-derived mesenchymal stromal cells [...] Read more.

Background: The delivery of therapeutic genes in sites of articular cartilage lesions using non-invasive, scaffold-guided gene therapy procedures is a promising approach to stimulate cartilage repair while protecting the cargos from detrimental immune responses, particularly when targeting chondroreparative bone marrow-derived mesenchymal stromal cells in a natural microenvironment like marrow aspirates. Methods: Here, we evaluated the benefits of providing a sequence for the cartilage-specific sex-determining region Y-type high-mobility group box 9 (SOX9) transcription factor to human marrow aspirates via recombinant adeno-associated virus (rAAV) vectors delivered by poly(ε-caprolactone) (PCL) films functionalized via grafting with poly(sodium styrene sulfonate) (pNaSS) to enhance the marrow chondrogenic potential over time. Results: Effective sox9 overexpression was observed in aspirates treated with pNaSS-grafted or ungrafted PCL films coated with the candidate rAAV-FLAG-hsox9 (FLAG-tagged rAAV vector carrying a human sox9 gene sequence) vector for at least 21 days relative to other conditions (pNaSS-grafted and ungrafted PCL films without vector coating). Overexpression of sox9 via rAAV sox9/pNaSS-grafted or ungrafted PCL films led to increased biological and chondrogenic differentiation activities (matrix deposition) in the aspirates while containing premature osteogenesis and hypertrophy without impacting cell proliferation, with more potent effects noted when using pNaSS-grafted films. Conclusions: These findings show the benefits of targeting patients’ bone marrow via PCL film-guided therapeutic rAAV (sox9) delivery as an off-the-shelf system for future strategies to enhance cartilage repair in translational applications. Full article

(This article belongs to the Special Issue Scaffold-Mediated Gene Delivery)

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19 pages, 2026 KiB

Open AccessArticle

The Comparison of Two Challenging Low Dose APIs in a Continuous Direct Compression Process

by Tuomas Ervasti, Hannes Niinikoski, Eero Mäki-Lohiluoma, Heidi Leppinen, Jarkko Ketolainen, Ossi Korhonen and Satu Lakio

Pharmaceutics 2020, 12(3), 279; https://doi.org/10.3390/pharmaceutics12030279 - 20 Mar 2020

Cited by 18 | Viewed by 5171

Abstract

Segregation is a common problem in batch-based direct compression (BDC) processes, especially with low-dose tablet products, as is the preparation of a homogenous mixture. The scope of the current work was to explore if a continuous direct compression (CDC) process could serve as [...] Read more.

Segregation is a common problem in batch-based direct compression (BDC) processes, especially with low-dose tablet products, as is the preparation of a homogenous mixture. The scope of the current work was to explore if a continuous direct compression (CDC) process could serve as a solution for these challenges. Furthermore, the principle of a platform formulation was demonstrated for low dose tablets. The combination of filler excipients and the API in the formulation used was suitable for direct compression, but also prone to induce segregation in BDC process. The CDC process was found to be very promising; it was shown that tablets with the desired quality parameters could be manufactured successfully with both of the APIs studied. Powder analysis indicated that the APIs display some fundamental differences in their physical properties, which was also reflected in powder mixture properties and, hence, eventually in processing. However, process parameters, especially mixer impeller speed, were not found to have any significant influence on end product quality. The study suggests that a CDC process can be a viable solution to resolve the challenges described. Moreover, manufacturing by using a universal platform formulation seems to be a feasible way for producing low-dose tablets. Full article

(This article belongs to the Special Issue Continuous Pharmaceutical Manufacturing)

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15 pages, 2188 KiB

Open AccessArticle

Design of a Gene Panel to Expose the Versatile Role of Hepatic Stellate Cells in Human Liver Fibrosis

by Fransien van Dijk, Christa M. Hazelhoff, Eduard Post, Gerian G. H. Prins, Krista Rombouts, Klaas Poelstra, Peter Olinga and Leonie Beljaars

Pharmaceutics 2020, 12(3), 278; https://doi.org/10.3390/pharmaceutics12030278 - 20 Mar 2020

Cited by 6 | Viewed by 3861

Abstract

The pivotal cell involved in the pathogenesis of liver fibrosis, i.e., the activated hepatic stellate cell (HSC), has a wide range of activities during the initiation, progression and even regression of the disease. These HSC-related activities encompass cellular activation, matrix synthesis and degradation, [...] Read more.

The pivotal cell involved in the pathogenesis of liver fibrosis, i.e., the activated hepatic stellate cell (HSC), has a wide range of activities during the initiation, progression and even regression of the disease. These HSC-related activities encompass cellular activation, matrix synthesis and degradation, proliferation, contraction, chemotaxis and inflammatory signaling. When determining the in vitro and in vivo effectivity of novel antifibrotic therapies, the readout is currently mainly based on gene and protein levels of α-smooth muscle actin (α-SMA) and the fibrillar collagens (type I and III). We advocate for a more comprehensive approach in addition to these markers when screening potential antifibrotic drugs that interfere with HSCs. Therefore, we aimed to develop a gene panel for human in vitro and ex vivo drug screening models, addressing each of the HSC-activities with at least one gene, comprising, in total, 16 genes. We determined the gene expression in various human stellate cells, ranging from primary cells to cell lines with an HSC-origin, and human liver slices and stimulated them with two key profibrotic factors, i.e., transforming growth factor β (TGFβ) or platelet-derived growth factor BB (PDGF-BB). We demonstrated that freshly isolated HSCs showed the strongest and highest variety of responses to these profibrotic stimuli, in particular following PDGF-BB stimulation, while cell lines were limited in their responses. Moreover, we verified these gene expression profiles in human precision-cut liver slices and showed similarities with the TGFβ- and PDGF-BB-related fibrotic responses, as observed in the primary HSCs. With this study, we encourage researchers to get off the beaten track when testing antifibrotic compounds by including more HSC-related markers in their future work. This way, potential compounds will be screened more extensively, which might increase the likelihood of developing effective antifibrotic drugs. Full article

(This article belongs to the Special Issue Antifibrotic Drugs)

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20 pages, 1523 KiB

Open AccessReview

piggyBac-Based Non-Viral In Vivo Gene Delivery Useful for Production of Genetically Modified Animals and Organs

by Masahiro Sato, Emi Inada, Issei Saitoh, Satoshi Watanabe and Shingo Nakamura

Pharmaceutics 2020, 12(3), 277; https://doi.org/10.3390/pharmaceutics12030277 - 19 Mar 2020

Cited by 17 | Viewed by 6790

Abstract

In vivo gene delivery involves direct injection of nucleic acids (NAs) into tissues, organs, or tail-veins. It has been recognized as a useful tool for evaluating the function of a gene of interest (GOI), creating models for human disease and basic research targeting [...] Read more.

In vivo gene delivery involves direct injection of nucleic acids (NAs) into tissues, organs, or tail-veins. It has been recognized as a useful tool for evaluating the function of a gene of interest (GOI), creating models for human disease and basic research targeting gene therapy. Cargo frequently used for gene delivery are largely divided into viral and non-viral vectors. Viral vectors have strong infectious activity and do not require the use of instruments or reagents helpful for gene delivery but bear immunological and tumorigenic problems. In contrast, non-viral vectors strictly require instruments (i.e., electroporator) or reagents (i.e., liposomes) for enhanced uptake of NAs by cells and are often accompanied by weak transfection activity, with less immunological and tumorigenic problems. Chromosomal integration of GOI-bearing transgenes would be ideal for achieving long-term expression of GOI. piggyBac (PB), one of three transposons (PB, Sleeping Beauty (SB), and Tol2) found thus far, has been used for efficient transfection of GOI in various mammalian cells in vitro and in vivo. In this review, we outline recent achievements of PB-based production of genetically modified animals and organs and will provide some experimental concepts using this system. Full article

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

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44 pages, 1302 KiB

Open AccessReview

Erythrocytes as Carriers: From Drug Delivery to Biosensors

by Larisa Koleva, Elizaveta Bovt, Fazoil Ataullakhanov and Elena Sinauridze

Pharmaceutics 2020, 12(3), 276; https://doi.org/10.3390/pharmaceutics12030276 - 18 Mar 2020

Cited by 73 | Viewed by 14197

Abstract

Drug delivery using natural biological carriers, especially erythrocytes, is a rapidly developing field. Such erythrocytes can act as carriers that prolong the drug’s action due to its gradual release from the carrier; as bioreactors with encapsulated enzymes performing the necessary reactions, while remaining [...] Read more.

Drug delivery using natural biological carriers, especially erythrocytes, is a rapidly developing field. Such erythrocytes can act as carriers that prolong the drug’s action due to its gradual release from the carrier; as bioreactors with encapsulated enzymes performing the necessary reactions, while remaining inaccessible to the immune system and plasma proteases; or as a tool for targeted drug delivery to target organs, primarily to cells of the reticuloendothelial system, liver and spleen. To date, erythrocytes have been studied as carriers for a wide range of drugs, such as enzymes, antibiotics, anti-inflammatory, antiviral drugs, etc., and for diagnostic purposes (e.g., magnetic resonance imaging). The review focuses only on drugs loaded inside erythrocytes, defines the main lines of research for erythrocytes with bioactive substances, as well as the advantages and limitations of their application. Particular attention is paid to in vivo studies, opening-up the potential for the clinical use of drugs encapsulated into erythrocytes. Full article

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

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12 pages, 2157 KiB

Open AccessArticle

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

by Nathan A. Rohner, Dung Nguyen and Horst A. von Recum

Pharmaceutics 2020, 12(3), 275; https://doi.org/10.3390/pharmaceutics12030275 - 17 Mar 2020

Cited by 7 | Viewed by 2653

Abstract

For many chronic fibrotic conditions, there is a need for local, sustained antifibrotic drug delivery. A recent trend in the pharmaceutical industry is the repurposing of approved drugs. This paper investigates drugs that are classically used for anthelmintic activity (pyrvinium pamoate (PYR)), inhibition [...] Read more.

For many chronic fibrotic conditions, there is a need for local, sustained antifibrotic drug delivery. A recent trend in the pharmaceutical industry is the repurposing of approved drugs. This paper investigates drugs that are classically used for anthelmintic activity (pyrvinium pamoate (PYR)), inhibition of adrenal steroidgenesis (metyrapone (MTP)), bactericidal effect (rifampicin (RIF), and treating iron/aluminum toxicity (deferoxamine mesylate (DFOA)), but are also under investigation for their potential positive effect in wound healing. In this role, they have not previously been tested in a localized delivery system suitable for obtaining the release for the weeks-to-months timecourse needed for wound resolution. Herein, two cyclodextrin-based polymer systems, disks and microparticles, are demonstrated to provide the long-term release of all four tested non-conventional wound-healing drugs for up to 30 days. Higher drug affinity binding, as determined from PyRx binding simulations and surface plasmon resonance in vitro, corresponded with extended release amounts, while drug molecular weight and solubility correlated with the improved drug loading efficiency of cyclodextrin polymers. These results, combined, demonstrate that leveraging affinity interactions, in combination with drug choice, can extend the sustained release of drugs with an alternative, complimentary action to resolve wound-healing and reduce fibrotic processes. Full article

(This article belongs to the Special Issue Antifibrotic Drugs)

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14 pages, 10249 KiB

Open AccessArticle

Crosslinked Hyaluronan Electrospun Nanofibers for Ferulic Acid Ocular Delivery

by Maria Aurora Grimaudo, Angel Concheiro and Carmen Alvarez-Lorenzo

Pharmaceutics 2020, 12(3), 274; https://doi.org/10.3390/pharmaceutics12030274 - 17 Mar 2020

Cited by 50 | Viewed by 4253

Abstract

Electrospun nanofibers are gaining interest as ocular drug delivery platforms that may adapt to the eye surface and provide sustained release. The aim of this work was to design an innovative ophthalmic insert composed of hyaluronan (HA) nanofibers for the dual delivery of [...] Read more.

Electrospun nanofibers are gaining interest as ocular drug delivery platforms that may adapt to the eye surface and provide sustained release. The aim of this work was to design an innovative ophthalmic insert composed of hyaluronan (HA) nanofibers for the dual delivery of an antioxidant (ferulic acid, FA) and an antimicrobial peptide (ε-polylysine, ε-PL). Polyvinylpyrrolidone (PVP) was added to facilitate the electrospinning process. Fibers with diameters of approx. 100 nm were obtained with PVP 5%-HA 0.8% w/v and PVP 10%-HA 0.5% w/v mixtures in ethanol:water 4:6 v/v. An increase in PVP concentration to 20% w/v in both presence and absence of HA rendered fibers of approx. 1 µm. PVP 5%-HA 0.8% w/v fibers were loaded with 83.3 ± 14.0 µg FA per mg. After nanofibers crosslinking with ε-PL, blank and FA-loaded inserts showed a mean thickness of 270 ± 21 µm and 273 ± 41 µm, respectively. Blank and FA-loaded inserts completely released ε-PL within 30 min under sink conditions, whereas FA-loaded inserts released the antioxidant within 20 min. Both blank and FA-loaded inserts were challenged against Pseudomonas aeruginosa and Staphylococcus aureus, demonstrating their efficacy against relevant microbial species. Full article

(This article belongs to the Special Issue Nano-Micro Encapsulation of Drugs)

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4 pages, 153 KiB

Open AccessEditorial

Reconciling Quality by Design and Transdermal Product Development

by Kenneth Miller II

Pharmaceutics 2020, 12(3), 273; https://doi.org/10.3390/pharmaceutics12030273 - 17 Mar 2020

Cited by 2 | Viewed by 2235

Abstract

Since my first exposure to the acronym ‘QbD’ more than ten years ago, I have been trying to understand exactly what QbD is and how I might incorporate its teachings into my twenty-odd years of experience developing transdermal systems. I feel I have [...] Read more.

Since my first exposure to the acronym ‘QbD’ more than ten years ago, I have been trying to understand exactly what QbD is and how I might incorporate its teachings into my twenty-odd years of experience developing transdermal systems. I feel I have made little progress since then. Eventually, I came to realize that while QbD has its merits, it is not a guide for (transdermal) product development, despite so often being described as such. Instead, I have come to consider QbD as a language useful for organizing and presenting the array of data supporting the approval of a new product, but it still leaves the experimental approach entirely up to the developer. What QbD does provide to the development community is a means of conveying product information through a consistent framework facilitating both internal and regulatory review. As a result, new ‘QbD’ product applications tend to be more uniform and complete than the applications that preceded the initiative. Full article

(This article belongs to the Special Issue Quality by Design (QbD) for Topical Dermatological and Transdermal Product Development)

24 pages, 3169 KiB

Open AccessArticle

On the Usefulness of Two Small-Scale In Vitro Setups in the Evaluation of Luminal Precipitation of Lipophilic Weak Bases in Early Formulation Development

by Patrick J. O’Dwyer, Georgios Imanidis, Karl J. Box and Christos Reppas

Pharmaceutics 2020, 12(3), 272; https://doi.org/10.3390/pharmaceutics12030272 - 16 Mar 2020

Cited by 23 | Viewed by 4483

Abstract

A small-scale biphasic dissolution setup and a small-scale dissolution-permeation (D-P) setup were evaluated for their usefulness in simulating the luminal precipitation of three lipophilic weak bases—dipyridamole, ketoconazole and itraconazole. The transition from the gastric to intestinal environment was incorporated into both experimental procedures. [...] Read more.

A small-scale biphasic dissolution setup and a small-scale dissolution-permeation (D-P) setup were evaluated for their usefulness in simulating the luminal precipitation of three lipophilic weak bases—dipyridamole, ketoconazole and itraconazole. The transition from the gastric to intestinal environment was incorporated into both experimental procedures. Emulsification during the biphasic dissolution experiments had a minimal impact on the data, when appropriate risk mitigation steps were incorporated. Precipitation parameters estimated from the in vitro data were inputted into the Simcyp^® physiologically based pharmacokinetic (PBPK) modelling software and simulated human plasma profiles were compared with previously published pharmacokinetic data. Average C_max and AUC values estimated using experimentally derived precipitation parameters from the biphasic experiments deviated from corresponding published actual values less than values estimated using the default simulator parameters for precipitation. The slow rate of transport through the biomimetic membrane in the D-P setup limited its usefulness in forecasting the rates of in vivo precipitation used in the modelling of average plasma profiles. Full article

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26 pages, 1409 KiB

Open AccessArticle

Predicting Pharmaceutical Particle Size Distributions Using Kernel Mean Embedding

by Daan Van Hauwermeiren, Michiel Stock, Thomas De Beer and Ingmar Nopens

Pharmaceutics 2020, 12(3), 271; https://doi.org/10.3390/pharmaceutics12030271 - 16 Mar 2020

Cited by 14 | Viewed by 4370

Abstract

In the pharmaceutical industry, the transition to continuous manufacturing of solid dosage forms is adopted by more and more companies. For these continuous processes, high-quality process models are needed. In pharmaceutical wet granulation, a unit operation in the ConsiGma

^{TM}

-25 continuous powder-to-tablet [...] Read more.

In the pharmaceutical industry, the transition to continuous manufacturing of solid dosage forms is adopted by more and more companies. For these continuous processes, high-quality process models are needed. In pharmaceutical wet granulation, a unit operation in the ConsiGma

^{TM}

-25 continuous powder-to-tablet system (GEA Pharma systems, Collette, Wommelgem, Belgium), the product under study presents itself as a collection of particles that differ in shape and size. The measurement of this collection results in a particle size distribution. However, the theoretical basis to describe the physical phenomena leading to changes in this particle size distribution is lacking. It is essential to understand how the particle size distribution changes as a function of the unit operation’s process settings, as it has a profound effect on the behavior of the fluid bed dryer. Therefore, we suggest a data-driven modeling framework that links the machine settings of the wet granulation unit operation and the output distribution of granules. We do this without making any assumptions on the nature of the distributions under study. A simulation of the granule size distribution could act as a soft sensor when in-line measurements are challenging to perform. The method of this work is a two-step procedure: first, the measured distributions are transformed into a high-dimensional feature space, where the relation between the machine settings and the distributions can be learnt. Second, the inverse transformation is performed, allowing an interpretation of the results in the original measurement space. Further, a comparison is made with previous work, which employs a more mechanistic framework for describing the granules. A reliable prediction of the granule size is vital in the assurance of quality in the production line, and is needed in the assessment of upstream (feeding) and downstream (drying, milling, and tableting) issues. Now that a validated data-driven framework for predicting pharmaceutical particle size distributions is available, it can be applied in settings such as model-based experimental design and, due to its fast computation, there is potential in real-time model predictive control. Full article

(This article belongs to the Special Issue Continuous Pharmaceutical Manufacturing)

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16 pages, 2439 KiB

Open AccessArticle

Preparation, Characterization, and In Vivo Pharmacokinetic Evaluation of Polyvinyl Alcohol and Polyvinyl Pyrrolidone Blended Hydrogels for Transdermal Delivery of Donepezil HCl

by Santosh Bashyal, Chang Yell Shin, Sang Min Hyun, Sun Woo Jang and Sangkil Lee

Pharmaceutics 2020, 12(3), 270; https://doi.org/10.3390/pharmaceutics12030270 - 16 Mar 2020

Cited by 25 | Viewed by 5692

Abstract

Transdermal delivery systems are emerging platforms for the delivery of donepezil hydrochloride (DH) for treating Alzheimer’s disease. The primary aim of this study was to develop polyvinyl alcohol and polyvinyl pyrrolidone blended hydrogels and to evaluate their feasibility for delivering DH via a [...] Read more.

Transdermal delivery systems are emerging platforms for the delivery of donepezil hydrochloride (DH) for treating Alzheimer’s disease. The primary aim of this study was to develop polyvinyl alcohol and polyvinyl pyrrolidone blended hydrogels and to evaluate their feasibility for delivering DH via a transdermal route. Physicochemical properties, such as gel fraction (%), swelling ratio (%), weight loss (%), mechanical strength, elongation at break, and Young’s modulus of the prepared hydrogels were evaluated. Furthermore, in vitro skin permeation and in vivo pharmacokinetic studies were performed. With an increased concentration of propylene glycol (PG), the gel fraction (%), maximum strength, and elongation at break decreased. However, the swelling ratio (%) and weight loss (%) of hydrogels increased with increased PG content. The 26% PG-hydrogel was superior, with an enhancement ratio of 12.9 (*** p < 0.001). In addition, the 11% PG-hydrogel and 1% PG-hydrogel exhibited an enhancement ratio 6.30-fold (*** p < 0.001) and 2.85-fold (* p < 0.05) higher than that exhibited by control, respectively, indicating a promising effect of PG on skin permeation. In addition, in vivo pharmacokinetic studies on hairless rats assessed the expediency for transdermal delivery of DH. The transdermal delivery of optimized hydrogel-patches with two different doses of DH revealed that the maximum plasma concentration and area under the curve were dose dependent, and the time to reach the maximum concentration was 8 h. Thus, optimized hydrogels have the potential to enhance the transdermal delivery of DH and could be a novel clinical approach. Full article

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

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39 pages, 2422 KiB

Open AccessReview

Drug Delivery to the Posterior Segment of the Eye: Biopharmaceutic and Pharmacokinetic Considerations

by Rubén Varela-Fernández, Victoria Díaz-Tomé, Andrea Luaces-Rodríguez, Andrea Conde-Penedo, Xurxo García-Otero, Asteria Luzardo-Álvarez, Anxo Fernández-Ferreiro and Francisco J. Otero-Espinar

Pharmaceutics 2020, 12(3), 269; https://doi.org/10.3390/pharmaceutics12030269 - 16 Mar 2020

Cited by 218 | Viewed by 13786

Abstract

The treatment of the posterior-segment ocular diseases, such as age-related eye diseases (AMD) or diabetic retinopathy (DR), present a challenge for ophthalmologists due to the complex anatomy and physiology of the eye. This specialized organ is composed of various static and dynamic barriers [...] Read more.

The treatment of the posterior-segment ocular diseases, such as age-related eye diseases (AMD) or diabetic retinopathy (DR), present a challenge for ophthalmologists due to the complex anatomy and physiology of the eye. This specialized organ is composed of various static and dynamic barriers that restrict drug delivery into the target site of action. Despite numerous efforts, effective intraocular drug delivery remains unresolved and, therefore, it is highly desirable to improve the current treatments of diseases affecting the posterior cavity. This review article gives an overview of pharmacokinetic and biopharmaceutics aspects for the most commonly-used ocular administration routes (intravitreal, topical, systemic, and periocular), including information of the absorption, distribution, and elimination, as well as the benefits and limitations of each one. This article also encompasses different conventional and novel drug delivery systems designed and developed to improve drug pharmacokinetics intended for the posterior ocular segment treatment. Full article

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

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16 pages, 3821 KiB

Open AccessArticle

Comparative Pharmacokinetics and Pharmacodynamics of a Novel Sodium-Glucose Cotransporter 2 Inhibitor, DWP16001, with Dapagliflozin and Ipragliflozin

by Min-Koo Choi, So Jeong Nam, Hye-Young Ji, Mi Jie Park, Ji-Soo Choi and Im-Sook Song

Pharmaceutics 2020, 12(3), 268; https://doi.org/10.3390/pharmaceutics12030268 - 15 Mar 2020

Cited by 34 | Viewed by 5729

Abstract

Since sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced blood glucose level by inhibiting renal tubular glucose reabsorption mediated by SGLT2, we aimed to investigate the pharmacokinetics and kidney distribution of DWP16001, a novel SGLT2 inhibitor, and to compare these properties with those of dapagliflozin [...] Read more.

Since sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced blood glucose level by inhibiting renal tubular glucose reabsorption mediated by SGLT2, we aimed to investigate the pharmacokinetics and kidney distribution of DWP16001, a novel SGLT2 inhibitor, and to compare these properties with those of dapagliflozin and ipragliflozin, representative SGLT2 inhibitors. The plasma exposure of DWP16001 was comparable with that of ipragliflozin but higher than that of dapagliflozin. DWP16001 showed the highest kidney distribution among three SGLT2 inhibitors when expressed as an area under curve (AUC) ratio of kidney to plasma (85.0 ± 16.1 for DWP16001, 64.6 ± 31.8 for dapagliflozin and 38.4 ± 5.3 for ipragliflozin). The organic anion transporter-mediated kidney uptake of DWP16001 could be partly attributed to the highest kidney uptake. Additionally, DWP16001 had the lowest half-maximal inhibitory concentration (IC₅₀) to SGLT2, a target transporter (0.8 ± 0.3 nM for DWP16001, 1.6 ± 0.3 nM for dapagliflozin, and 8.9 ± 1.7 nM for ipragliflozin). The inhibition mode of DWP16001 on SGLT2 was reversible and competitive, but the recovery of the SGLT2 inhibition after the removal of SGLT2 inhibitors in CHO cells overexpressing SGLT2 was retained with DWP16001, which is not the case with dapagliflozin and ipragliflozin. In conclusion, selective and competitive SGLT2 inhibition of DWP16001 could potentiate the efficacy of DWP16001 in coordination with the higher kidney distribution and retained SGLT2 inhibition of DWP16001 relative to dapagliflozin and ipragliflozin. Full article

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

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17 pages, 2261 KiB

Open AccessArticle

Characteristic of K3 (CpG-ODN) as a Transcutaneous Vaccine Formulation Adjuvant

by Sayami Ito, Sachiko Hirobe, Takuto Kawakita, Mio Saito, Ying-Shu Quan, Fumio Kamiyama, Ken J. Ishii, Mizuho Nagao, Takao Fujisawa, Masashi Tachibana and Naoki Okada

Pharmaceutics 2020, 12(3), 267; https://doi.org/10.3390/pharmaceutics12030267 - 15 Mar 2020

Cited by 13 | Viewed by 5023

Abstract

Transcutaneous immunization (TCI) is easy to use, minimally invasive, and has excellent efficacy in vaccines against infections. We focused on toll-like receptor (TLR) ligands as applicable adjuvants for transcutaneous formulations and characterized immune responses. TCI was performed using poke-and-patch methods, in which puncture [...] Read more.

Transcutaneous immunization (TCI) is easy to use, minimally invasive, and has excellent efficacy in vaccines against infections. We focused on toll-like receptor (TLR) ligands as applicable adjuvants for transcutaneous formulations and characterized immune responses. TCI was performed using poke-and-patch methods, in which puncture holes are formed with a polyglycolic acid microneedle on the back skin of mice. Various TLR ligands were applied to the puncture holes and covered with an ovalbumin-loaded hydrophilic gel patch. During the screening process, K3 (CpG-oligonucleotide) successfully produced more antigen-specific antibodies than other TLR ligands and induced T helper (Th) 1-type polarization. Transcutaneously administered K3 was detected in draining lymph nodes and was found to promote B cell activation and differentiation, suggesting a direct transcutaneous adjuvant activity on B cells. Furthermore, a human safety test of K3-loaded self-dissolving microneedles (sdMN) was performed. Although a local skin reaction was observed at the sdMN application site, there was no systemic side reaction. In summary, we report a K3-induced Th1-type immune response that is a promising adjuvant for transcutaneous vaccine formulations using MN and show that K3-loaded sdMN can be safely applied to human skin. Full article

(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)

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9 pages, 223 KiB

Open AccessEditorial

3D Printing of Pharmaceuticals and Drug Delivery Devices

by Essyrose Mathew, Giulia Pitzanti, Eneko Larrañeta and Dimitrios A. Lamprou

Pharmaceutics 2020, 12(3), 266; https://doi.org/10.3390/pharmaceutics12030266 - 15 Mar 2020

Cited by 108 | Viewed by 12769

Abstract

The process of 3D printing (3DP) was patented in 1986; however, the research in the field of 3DP did not become popular until the last decade. There has been an increasing research into the areas of 3DP for medical applications for fabricating prosthetics, [...] Read more.

The process of 3D printing (3DP) was patented in 1986; however, the research in the field of 3DP did not become popular until the last decade. There has been an increasing research into the areas of 3DP for medical applications for fabricating prosthetics, bioprinting and pharmaceutics. This novel method allows the manufacture of dosage forms on demand, with modifications in the geometry and size resulting in changes to the release and dosage behaviour of the product. 3DP will allow wider adoption of personalised medicine due to the diversity and simplicity to change the design and dosage of the products, allowing the devices to be designed specific to the individual with the ability to alternate the drugs added to the product. Personalisation also has the potential to decrease the common side effects associated with generic dosage forms. This Special Issue Editorial outlines the current innovative research surrounding the topic of 3DP, focusing on bioprinting and various types of 3DP on applications for drug delivery as well advantages and future directions in this field of research. Full article

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

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