Pharmaceutics

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20 pages, 4895 KiB

Open AccessArticle

Different BCS Class II Drug-Gelucire Solid Dispersions Prepared by Spray Congealing: Evaluation of Solid State Properties and In Vitro Performances

by Serena Bertoni, Beatrice Albertini and Nadia Passerini

Pharmaceutics 2020, 12(6), 548; https://doi.org/10.3390/pharmaceutics12060548 - 12 Jun 2020

Cited by 20 | Viewed by 4642

Abstract

Delivery of poorly water soluble active pharmaceutical ingredients (APIs) by semi-crystalline solid dispersions prepared by spray congealing in form of microparticles (MPs) is an emerging method to increase their oral bioavailability. In this study, solid dispersions based on hydrophilic Gelucires^® (Gelucire^® [...] Read more.

Delivery of poorly water soluble active pharmaceutical ingredients (APIs) by semi-crystalline solid dispersions prepared by spray congealing in form of microparticles (MPs) is an emerging method to increase their oral bioavailability. In this study, solid dispersions based on hydrophilic Gelucires^® (Gelucire^® 50/13 and Gelucire^® 48/16 in different ratio) of three BCS class II model compounds (carbamazepine, CBZ, tolbutamide, TBM, and cinnarizine, CIN) having different physicochemical properties (logP, pKa, Tm) were produced by spray congealing process. The obtained MPs were investigated in terms of morphology, particles size, drug content, solid state properties, drug-carrier interactions, solubility, and dissolution performances. The solid-state characterization showed that the properties of the incorporated drug had a profound influence on the structure of the obtained solid dispersion: CBZ recrystallized in a different polymorphic form, TBM crystallinity was significantly reduced as a result of specific interactions with the carrier, while smaller crystals were observed in case of CIN. The in vitro tests suggested that the drug solubility was mainly influenced by carrier composition, while the drug dissolution behavior was affected by the API solid state in the MPs after the spray congealing process. Among the tested APIs, TBM-Gelucire dispersions showed the highest enhancement in drug dissolution as a result of the reduced drug crystallinity. Full article

(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)

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17 pages, 5044 KiB

Open AccessArticle

Qualification of Non-Halogenated Organic Solvents Applied to Microsphere Manufacturing Process

by Hyunjin Shim and Hongkee Sah

Pharmaceutics 2020, 12(5), 425; https://doi.org/10.3390/pharmaceutics12050425 - 6 May 2020

Cited by 6 | Viewed by 3377

Abstract

As a non-halogenated dispersed solvent, ethyl acetate has been most commonly used for the manufacturing of poly-d,l-lactide-co-glycolide (PLGA) microspheres. However, ethyl acetate-based microencapsulation processes face several limitations. This study was aimed at proposing ethyl formate as an alternative. Evaluated [...] Read more.

As a non-halogenated dispersed solvent, ethyl acetate has been most commonly used for the manufacturing of poly-d,l-lactide-co-glycolide (PLGA) microspheres. However, ethyl acetate-based microencapsulation processes face several limitations. This study was aimed at proposing ethyl formate as an alternative. Evaluated in this study was the solvent qualification of ethyl formate and ethyl acetate for microencapsulation of a hydrophobic drug into PLGA microspheres. An oil-in-water emulsion solvent extraction technique was developed to load progesterone into PLGA microspheres. Briefly, right after emulsion droplets were temporarily stabilized, they were subject to primary solvent extraction. Appearing semisolid, embryonic microspheres were completely hardened through subsequent secondary solvent extraction. Changes in process parameters of the preparative technique made it possible to manipulate the properties of emulsion droplets, progesterone behavior, and microsphere quality. Despite the two solvents showing comparable Hansen solubility parameter distances toward PLGA, ethyl formate surpassed ethyl acetate in relation to volatility and water miscibility. These features served as advantages in the microsphere manufacturing process, helping produce PLGA microspheres with better quality in terms of drug crystallization, drug encapsulation efficiency, microsphere size homogeneity, and residual solvent content. The present ethyl formate-based preparative technique could be an attractive method of choice for the production of drug-loaded PLGA microspheres. Full article

(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)

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13 pages, 1403 KiB

Open AccessArticle

Investigating the Effect of Encapsulation Processing Parameters on the Viability of Therapeutic Viruses in Electrospraying

by Tayo Sanders II, Anita Milicic and Eleanor Stride

Pharmaceutics 2020, 12(4), 388; https://doi.org/10.3390/pharmaceutics12040388 - 24 Apr 2020

Cited by 2 | Viewed by 3311

Abstract

The ability of viruses to introduce genetic material into cells can be usefully exploited in a variety of therapies and also vaccination. Encapsulating viruses to limit inactivation by the immune system before reaching the desired target and allowing for controlled release is a [...] Read more.

The ability of viruses to introduce genetic material into cells can be usefully exploited in a variety of therapies and also vaccination. Encapsulating viruses to limit inactivation by the immune system before reaching the desired target and allowing for controlled release is a promising strategy of delivery. Conventional encapsulation methods, however, can significantly reduce infectivity. The aim of this study was to investigate electrospraying as an alternative encapsulation technique. Two commonly used therapeutic viruses, adenovirus (Ad) and modified vaccinia Ankara (MVA), were selected. First, solutions containing the viruses were electrosprayed in a single needle configuration at increasing voltages to examine the impact of the electric field. Second, the effect of exposing the viruses to pure organic solvents was investigated and compared to that occurring during coaxial electrospraying. Infectivity was determined by measuring the luminescence produced from lysed A549 cells after incubation with treated virus. Neither Ad nor MVA exhibited any significant loss in infectivity when electrosprayed within the range of electrospraying parameters relevant for encapsulation. A significant decrease in infectivity was only observed when MVA was electrosprayed at the highest voltage, 24 kV, and when MVA and Ad were exposed to selected pure organic solvents. Thus, it was concluded that electrospraying would be a viable method for virus encapsulation. Full article

(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)

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16 pages, 3595 KiB

Open AccessArticle

A Portable Device for the Generation of Drug-Loaded Three-Compartmental Fibers Containing Metronidazole and Iodine for Topical Application

by Francis Brako, Chaojie Luo, Rupy Kaur Matharu, Lena Ciric, Anthony Harker, Mohan Edirisinghe and Duncan Q. M. Craig

Pharmaceutics 2020, 12(4), 373; https://doi.org/10.3390/pharmaceutics12040373 - 18 Apr 2020

Cited by 9 | Viewed by 3860

Abstract

The use of combination therapies for the treatment of a range of conditions is now well established, with the component drugs usually being delivered either as distinct medicaments or combination products that contain physical mixes of the two active ingredients. There is, however, [...] Read more.

The use of combination therapies for the treatment of a range of conditions is now well established, with the component drugs usually being delivered either as distinct medicaments or combination products that contain physical mixes of the two active ingredients. There is, however, a compelling argument for the development of compartmentalised systems whereby the release, stability and incorporation environment of the different drugs may be tailored. Here we outline the development of polymeric fine fiber systems whereby two drugs used for the treatment of wounds may be separately incorporated. Fibers were delivered using a newly developed handheld electrospinning device that allows treatment at the site of need. Crucially, the delivery system is portable and may be used for the administration of drug-loaded fibers directly into the wound in situ, thereby potentially allowing domiciliary or site-of-trauma administration. The three-layered fiber developed in this study has polyethylene glycol as the outermost layer, serving as a structural support for the inner layers. The inner layers comprised iodine complexed with polyvinylpyrrolidone (PVP) and metronidazole dispersed in polycaprolactone (PCL) as a slow release core. The systems were characterized in terms of structure and architecture using scanning electron microscopy, transmission electron microscopy, attenuated total reflection Fourier transform infrared spectroscopy and diffractometry. As antibacterial creams are still used for managing infected wounds, the performance of our trilayered fiber was studied in comparison with creams containing similar active drugs. Drug release was measured by UV analysis, while antimicrobial efficiency was measured using agar diffusion and suspension methods. It was found that the trilayered systems, averaging 3.16 µm in diameter, released more drug over the study period and were confirmed by the microbacterial studies to be more effective against P. aeruginosa, a bacterium commonly implicated in infected wounds. Overall, the portable system has been shown to be capable of not only incorporating the two drugs in distinct layers but also of delivering adequate amounts of drugs for a more effective antibacterial activity. The portability of the device and its ability to generate distinct layers of multiple active ingredients make it promising for further development for wound healing applications in terms of both practical applicability and antimicrobial efficacy. Full article

(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)

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20 pages, 7430 KiB

Open AccessArticle

Quality by Design Micro-Engineering Optimisation of NSAID-Loaded Electrospun Fibrous Patches

by Kazem Nazari, Prina Mehta, Muhammad Sohail Arshad, Shahabuddin Ahmed, Eleftherios G. Andriotis, Neenu Singh, Omar Qutachi, Ming-Wei Chang, Dimitrios G. Fatouros and Zeeshan Ahmad

Pharmaceutics 2020, 12(1), 2; https://doi.org/10.3390/pharmaceutics12010002 - 18 Dec 2019

Cited by 7 | Viewed by 3674

Abstract

The purpose of this study was to apply the Quality by Design (QbD) approach to the electrospinning of fibres loaded with the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin (INDO) and diclofenac sodium (DICLO). A Quality Target Product Profile (QTPP) was made, and risk assessments [...] Read more.

The purpose of this study was to apply the Quality by Design (QbD) approach to the electrospinning of fibres loaded with the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin (INDO) and diclofenac sodium (DICLO). A Quality Target Product Profile (QTPP) was made, and risk assessments (preliminary hazard analysis) were conducted to identify the impact of material attributes and process parameters on the critical quality attributes (CQAs) of the fibres. A full factorial design of experiments (DoE) of 20 runs was built, which was used to carry out experiments. The following factors were assessed: Drugs, voltage, flow rate, and the distance between the processing needle and collector. Release studies exhibited INDO fibres had greater total release of active drug compared to DICLO fibres. Voltage and distance were found to be the most significant factors of the experiment. Multivariate statistical analytical software helped to build six feasible design spaces and two flexible, universal design spaces for both drugs, at distances of 5 cm and 12.5 cm, along with a flexible control strategy. The current findings and their analysis confirm that QbD is a viable and invaluable tool to enhance product and process understanding of electrospinning for the assurance of high-quality fibres. Full article

(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)

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15 pages, 1580 KiB

Open AccessArticle

Macrophage Targeting pH Responsive Polymersomes for Glucocorticoid Therapy

by Virgínia M. Gouveia, Loris Rizzello, Claudia Nunes, Alessandro Poma, Lorena Ruiz-Perez, António Oliveira, Salette Reis and Giuseppe Battaglia

Pharmaceutics 2019, 11(11), 614; https://doi.org/10.3390/pharmaceutics11110614 - 15 Nov 2019

Cited by 21 | Viewed by 7331

Abstract

Glucocorticoid (GC) drugs are the cornerstone therapy used in the treatment of inflammatory diseases. Here, we report pH responsive poly(2-methacryloyloxyethyl phosphorylcholine)–poly(2-(diisopropylamino)ethyl methacrylate) (PMPC–PDPA) polymersomes as a suitable nanoscopic carrier to precisely and controllably deliver GCs within inflamed target cells. The in vitro cellular [...] Read more.

Glucocorticoid (GC) drugs are the cornerstone therapy used in the treatment of inflammatory diseases. Here, we report pH responsive poly(2-methacryloyloxyethyl phosphorylcholine)–poly(2-(diisopropylamino)ethyl methacrylate) (PMPC–PDPA) polymersomes as a suitable nanoscopic carrier to precisely and controllably deliver GCs within inflamed target cells. The in vitro cellular studies revealed that polymersomes ensure the stability, selectivity and bioavailability of the loaded drug within macrophages. At molecular level, we tested key inflammation-related markers, such as the nuclear factor-κB, tumour necrosis factor-α, interleukin-1β, and interleukin-6. With this, we demonstrated that pH responsive polymersomes are able to enhance the anti-inflammatory effect of loaded GC drug. Overall, we prove the potential of PMPC–PDPA polymersomes to efficiently promote the inflammation shutdown, while reducing the well-known therapeutic limitations in GC-based therapy. Full article

(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)

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17 pages, 2666 KiB

Open AccessArticle

Design and Development of Liquid Drug Reservoirs for Microneedle Delivery of Poorly Soluble Drug Molecules

by Mary-Carmel Kearney, Peter E. McKenna, Helen L. Quinn, Aaron J. Courtenay, Eneko Larrañeta and Ryan F. Donnelly

Pharmaceutics 2019, 11(11), 605; https://doi.org/10.3390/pharmaceutics11110605 - 13 Nov 2019

Cited by 37 | Viewed by 5878

Abstract

The poor aqueous solubility of existing and emerging drugs is a major issue faced by the pharmaceutical industry. Water-miscible organic solvents, termed co-solvents, can be used to enhance the solubility of poorly soluble substances. Typically, drugs with poor aqueous solubility and Log P [...] Read more.

The poor aqueous solubility of existing and emerging drugs is a major issue faced by the pharmaceutical industry. Water-miscible organic solvents, termed co-solvents, can be used to enhance the solubility of poorly soluble substances. Typically, drugs with poor aqueous solubility and Log P > 3 are not amenable to delivery across the skin. This study investigated the use of co-solvents as reservoirs to be used in combination with hydrogel-forming microneedles to enhance the transdermal delivery of hydrophobic compounds, namely Nile red, olanzapine and atorvastatin. A custom-made Franz cell apparatus was fabricated to test the suitability of a liquid drug reservoir in combination with polymeric microneedles. A co-solvency approach to reservoir formulation proved effective, with 83.30% ± 9.38% of Nile red dye, dissolved in 1 mL poly(ethylene glycol) (PEG 400), permeating neonatal porcine skin over 24 h. PEG 400 and propylene glycol were found to be suitable reservoir media for olanzapine and atorvastatin, with approximately 50% of each drug delivered after 24 h. This work provides crucial proof-of-concept evidence that the manipulation of microneedle reservoir properties is an effective method to facilitate microneedle-mediated delivery of hydrophobic compounds. Full article

(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)

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Review

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58 pages, 4735 KiB

Open AccessReview

Unraveling Particle Formation: From Single Droplet Drying to Spray Drying and Electrospraying

by Eline Boel, Robin Koekoekx, Sien Dedroog, Iurii Babkin, Maria Rosaria Vetrano, Christian Clasen and Guy Van den Mooter

Pharmaceutics 2020, 12(7), 625; https://doi.org/10.3390/pharmaceutics12070625 - 4 Jul 2020

Cited by 95 | Viewed by 9382

Abstract

Spray drying and electrospraying are well-established drying processes that already have proven their value in the pharmaceutical field. However, there is currently still a lack of knowledge on the fundamentals of the particle formation process, thereby hampering fast and cost-effective particle engineering. To [...] Read more.

Spray drying and electrospraying are well-established drying processes that already have proven their value in the pharmaceutical field. However, there is currently still a lack of knowledge on the fundamentals of the particle formation process, thereby hampering fast and cost-effective particle engineering. To get a better understanding of how functional particles are formed with respect to process and formulation parameters, it is indispensable to offer a comprehensive overview of critical aspects of the droplet drying and particle formation process. This review therefore closely relates single droplet drying to pharmaceutical applications. Although excellent reviews exist of the different aspects, there is, to the best of our knowledge, no single review that describes all steps that one should consider when trying to engineer a certain type of particle morphology. The findings presented in this article have strengthened the predictive value of single droplet drying for pharmaceutical drying applications like spray drying and electrospraying. Continuous follow-up of the particle formation process in single droplet drying experiments hence allows optimization of manufacturing processes and particle engineering approaches and acceleration of process development. Full article

(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)

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