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15 pages, 3761 KiB

Open AccessArticle

Evaluation of Pharmacobezoar Formation from Suspensions of Spray-Dried Amorphous Solid Dispersions: An MRI Study in Rats

by Hannes Gierke, Susan Mouchantat, Sabine Berg, Michael Grimm, Stefan Hadlich, Marie-Luise Kromrey, Thomas Nolte, Teresa Pfrommer, Vincent Rönnpagel, Adrian Rump, Kerstin Schaefer, Ann-Cathrin Willmann and Werner Weitschies

Pharmaceutics 2023, 15(3), 887; https://doi.org/10.3390/pharmaceutics15030887 - 09 Mar 2023

Viewed by 1252

Abstract

Spray-dried amorphous solid dispersions of new chemical entities and pH-dependent soluble polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were found to form solid agglomerates in the gastrointestinal tract of rodents after oral administration. These agglomerates, referring to descriptions of intra-gastrointestinal aggregated oral dosage forms [...] Read more.

Spray-dried amorphous solid dispersions of new chemical entities and pH-dependent soluble polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were found to form solid agglomerates in the gastrointestinal tract of rodents after oral administration. These agglomerates, referring to descriptions of intra-gastrointestinal aggregated oral dosage forms termed pharmacobezoars, represent a potential risk for animal welfare. Previously, we introduced an in vitro model to assess the agglomeration potential of amorphous solid dispersions from suspensions and how it can be reduced. In this work, we investigated if the in vitro effective approach of viscosity enhancement of the vehicle used to prepare suspensions of amorphous solid dispersions could reduce the pharmacobezoar formation potential following repeated daily oral dosing to rats as well. The dose level of 2400 mg/kg/day used in the main study was determined in a dose finding study carried out in advance. In the dose finding study, MRI investigations were carried out at short time intervals to gain insights into the process of pharmacobezoar formation. Whereas MRI investigations underlined the importance of the forestomach for the formation of pharmacobezoars, viscosity enhancement of the vehicle reduced the incidence of pharmacobezoars, delayed the onset of pharmacobezoar formation and reduced the overall mass of pharmacobezoars found at necropsy. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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12 pages, 1612 KiB

Open AccessArticle

HS 3D-SeboSkin Model Enables the Preclinical Exploration of Therapeutic Candidates for Hidradenitis Suppurativa/Acne Inversa

by Christos C. Zouboulis, Xiaoxiao Hou, Henriette von Waldthausen, Konstantin C. Zouboulis and Amir M. Hossini

Pharmaceutics 2023, 15(2), 619; https://doi.org/10.3390/pharmaceutics15020619 - 12 Feb 2023

Cited by 1 | Viewed by 2002

Abstract

Despite the rapid development in hidradenitis suppurativa (HS) research, the immediate introduction of potent therapeutic compounds in clinical trials and the lack of definitive outcome measures have led to the discontinuation of potential therapeutic compound studies. HS is a solely human disease, and [...] Read more.

Despite the rapid development in hidradenitis suppurativa (HS) research, the immediate introduction of potent therapeutic compounds in clinical trials and the lack of definitive outcome measures have led to the discontinuation of potential therapeutic compound studies. HS is a solely human disease, and therefore, the search for preclinical human models has been given priority. The 3D-SeboSkin model, a co-culture of human skin explants with human SZ95 sebocytes as a feeder layer, has been shown to prevent the rapid degeneration of human skin in culture and has been validated for HS preclinical studies. In this work, the HS 3D-SeboSkin model has been employed to characterize cellular and molecular effects of the EMA- and FDA-approved biologic adalimumab. Adalimumab, a tumor necrosis factor-α inhibitor, was shown to target inflammatory cells present in HS lesions, inducing a prominent anti-inflammatory response and contributing to tissue regeneration through a wound healing mechanism. Adalimumab inhibited the lesional tissue expression of TNF-α, IL-3, IL-15, and MCP-3 and downregulated the secretion of IL-1α, IL-5, RANTES, MCP-2, TNF-α, TNF-β, TGF-β, and IFN-γ. In contrast, IL-6 was stimulated. The compound failed to modify abnormal epithelial cell differentiation present in the HS lesions. Patients with Hurley stage II lesions exhibited stronger expression of autophagy proteins in perilesional than in lesional skin. Adalimumab modified the levels of the pro-apoptotic proteins LC3A, LC3B, and p62 in an individual, patient-dependent manner. Finally, adalimumab did not modify the NFκB signal proteins in SZ95 sebocytes and NHK-19 keratinocytes, used to study this specific pathway. The administration of the validated HS 3D-SeboSkin model in ex vivo studies prior to clinical trials could elucidate the individual pathogenetic targets of therapeutic candidates and, therefore, increase the success rates of clinical studies, minimizing HS drug development costs. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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24 pages, 26882 KiB

Open AccessArticle

In situ Formation of Polymer Microparticles in Bacterial Nanocellulose Using Alternative and Sustainable Solvents to Incorporate Lipophilic Drugs

by Tom Bellmann, Jana Thamm, Uwe Beekmann, Dana Kralisch and Dagmar Fischer

Pharmaceutics 2023, 15(2), 559; https://doi.org/10.3390/pharmaceutics15020559 - 07 Feb 2023

Cited by 3 | Viewed by 1987

Abstract

Bacterial nanocellulose has been widely investigated in drug delivery, but the incorporation of lipophilic drugs and controlling release kinetics still remain a challenge. The inclusion of polymer particles to encapsulate drugs could address both problems but is reported sparely. In the present study, [...] Read more.

Bacterial nanocellulose has been widely investigated in drug delivery, but the incorporation of lipophilic drugs and controlling release kinetics still remain a challenge. The inclusion of polymer particles to encapsulate drugs could address both problems but is reported sparely. In the present study, a formulation approach based on in situ precipitation of poly(lactic-co-glycolic acid) within bacterial nanocellulose was developed using and comparing the conventional solvent N-methyl-2-pyrrolidone and the alternative solvents poly(ethylene glycol), Cyrene^TM and ethyl lactate. Using the best-performing solvents N-methyl-2-pyrrolidone and ethyl lactate, their fast diffusion during phase inversion led to the formation of homogenously distributed polymer microparticles with average diameters between 2.0 and 6.6 µm within the cellulose matrix. Despite polymer inclusion, the water absorption value of the material still remained at ~50% of the original value and the material was able to release 32 g/100 cm² of the bound water. Mechanical characteristics were not impaired compared to the native material. The process was suitable for encapsulating the highly lipophilic drugs cannabidiol and 3-O-acetyl-11-keto-β-boswellic acid and enabled their sustained release with zero order kinetics over up to 10 days. Conclusively, controlled drug release for highly lipophilic compounds within bacterial nanocellulose could be achieved using sustainable solvents for preparation. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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21 pages, 3905 KiB

Open AccessArticle

Development and Characterization of Novel In-Situ-Forming Oleogels

by Anne Dümichen, Henrike Lucas, Marie-Luise Trutschel and Karsten Mäder

Pharmaceutics 2023, 15(1), 254; https://doi.org/10.3390/pharmaceutics15010254 - 11 Jan 2023

Cited by 2 | Viewed by 1915

Abstract

PLGA-based in situ forming implants (ISFI) often require a high amount of potentially toxic solvents such as N methyl-Pyrrolidone (NMP). The aim of the present study was to develop lipid in-situ-forming oleogels (ISFOs) as alternative delivery systems. 12-Hydroxystearic acid (12-HSA) was selected as [...] Read more.

PLGA-based in situ forming implants (ISFI) often require a high amount of potentially toxic solvents such as N methyl-Pyrrolidone (NMP). The aim of the present study was to develop lipid in-situ-forming oleogels (ISFOs) as alternative delivery systems. 12-Hydroxystearic acid (12-HSA) was selected as the oleogelling agent and three different oleoformulations were investigated: (a) 12-HSA, peanut oil (PO), NMP; (b) 12-HSA, medium-chain triglycerides (MCT), ethanol; (c) 12-HSA, isopropyl myristate (IPM), ethanol. The effects of the 12-HSA concentration, preparation method, and composition on the mechanical stability were examined using a texture analysis and oscillating rheology. The texture analysis was used to obtain information on the compression strength. The amplitude sweeps were analyzed to provide information on the gel strength and the risk of brittle fractures. The frequency sweeps allowed insights into the long-term stability and risk of syneresis. The syringeability of the ISFOs was tested, along with their acute and long-term cytotoxicity in vitro. The developed ISFOs have the following advantages: (1) the avoidance of highly acidic degradation products; (2) low amounts of organic solvents required; (3) low toxicity; (4) low injection forces, even with small needle sizes. Therefore, ISFOs are promising alternatives to the existing polymer/NMP-based ISFIs. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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16 pages, 2000 KiB

Open AccessArticle

Green Manufacturing for Herbal Remedies with Advanced Pharmaceutical Technology

by Martin Tegtmeier, Larissa Knierim, Axel Schmidt and Jochen Strube

Pharmaceutics 2023, 15(1), 188; https://doi.org/10.3390/pharmaceutics15010188 - 05 Jan 2023

Cited by 2 | Viewed by 3131

Abstract

Herbal remedies are in most cases still manufactured with traditional equipment installations and processes. Innovative chemical process engineering methods such as modeling and process intensification with green technology could contribute to the economic and ecologic future of those botanicals. The integration of modern [...] Read more.

Herbal remedies are in most cases still manufactured with traditional equipment installations and processes. Innovative chemical process engineering methods such as modeling and process intensification with green technology could contribute to the economic and ecologic future of those botanicals. The integration of modern unit operations such as water-based pressurized hot water extraction and inline measurement devices for process analytical technology approaches in traditional extraction processes is exemplified. The regulatory concept is based on the quality-by-design demand for autonomous feed-based recipe operation with the aid of digital twins within advanced process control. This may include real-time release testing to the automatic cleaning of validation issues. Digitalization and Industry 4.0 methods, including machine learning and artificial intelligence, are capable of keeping natural product extraction manufacturing and can contribute significantly to the future of human health. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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14 pages, 2951 KiB

Open AccessArticle

Solubility Enhanced Formulation Approaches to Overcome Oral Delivery Obstacles of PROTACs

by Florian Pöstges, Kevin Kayser, Jan Appelhaus, Marius Monschke, Michael Gütschow, Christian Steinebach and Karl G. Wagner

Pharmaceutics 2023, 15(1), 156; https://doi.org/10.3390/pharmaceutics15010156 - 03 Jan 2023

Cited by 8 | Viewed by 4146

Abstract

PROteolysis TArgeting Chimaeras (PROTACs) offer new opportunities in modern medicine by targeting proteins that are undruggable to classic inhibitors. However, due to their hydrophobic structure, PROTACs typically suffer from low solubility, and oral bioavailability remains challenging. At the same time, due to their [...] Read more.

PROteolysis TArgeting Chimaeras (PROTACs) offer new opportunities in modern medicine by targeting proteins that are undruggable to classic inhibitors. However, due to their hydrophobic structure, PROTACs typically suffer from low solubility, and oral bioavailability remains challenging. At the same time, due to their investigative state, the drug supply is meager, leading to limited possibilities in terms of formulation development. Therefore, we investigated the solubility enhancement employing mini-scale formulations of amorphous solid dispersions (ASDs) and liquisolid formulations of the prototypic PROTAC ARCC-4. Based on preliminary supersaturation testing, HPMCAS (L Grade) and Eudragit^® L 100-55 (EL 100-55) were demonstrated to be suitable polymers for supersaturation stabilization of ARCC-4. These two polymers were selected for preparing ASDs via vacuum compression molding (VCM), using drug loads of 10 and 20%, respectively. The ASDs were subsequently characterized with respect to their solid state via differential scanning calorimetry (DSC). Non-sink dissolution testing revealed that the physical mixtures (PMs) did not improve dissolution. At the same time, all ASDs enabled pronounced supersaturation of ARCC-4 without precipitation for the entire dissolution period. In contrast, liquisolid formulations failed in increasing ARCC-4 solubility. Hence, we demonstrated that ASD formation is a promising principle to overcome the low solubility of PROTACs. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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13 pages, 1063 KiB

Open AccessArticle

Pharmacokinetics and Pharmacodynamics (PK/PD) of Corallopyronin A against Methicillin-Resistant Staphylococcus aureus

by Katharina Rox, Tim Becker, Andrea Schiefer, Miriam Grosse, Alexandra Ehrens, Rolf Jansen, Tilman Aden, Stefan Kehraus, Gabriele M. König, Anna K. Krome, Marc P. Hübner, Karl G. Wagner, Marc Stadler, Kenneth Pfarr and Achim Hoerauf

Pharmaceutics 2023, 15(1), 131; https://doi.org/10.3390/pharmaceutics15010131 - 30 Dec 2022

Cited by 2 | Viewed by 1775

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is a World Health Organization’s high priority pathogen organism, with an estimated > 100,000 deaths worldwide in 2019. Thus, there is an unmet medical need for novel and resistance-breaking anti-infectives. The natural product Co-rallopyronin A (CorA), currently in preclinical [...] Read more.

Methicillin-resistant Staphylococcus aureus (MRSA) is a World Health Organization’s high priority pathogen organism, with an estimated > 100,000 deaths worldwide in 2019. Thus, there is an unmet medical need for novel and resistance-breaking anti-infectives. The natural product Co-rallopyronin A (CorA), currently in preclinical development for filariasis, is efficacious against MRSA in vitro. In this study, we evaluated the pharmacokinetics of CorA after dosing in mice. Furthermore, we determined compound concentrations in target compartments, such as lung, kidney and thigh tissue, using LC-MS/MS. Based on the pharmacokinetic results, we evaluated the pharmacodynamic profile of CorA using the standard neutropenic thigh and lung infection models. We demonstrate that CorA is effective in both standard pharmacodynamic models. In addition to reaching effective levels in the lung and muscle, CorA was detected at high levels in the thigh bone. The data presented herein encourage the further exploration of the additional CorA indications treatment of MRSA- and methicillin-sensitive S. aureus- (MSSA) related infections. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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14 pages, 3094 KiB

Open AccessArticle

An In Vitro Model to Investigate the Potential of Solid Dispersions to Form Pharmacobezoars

by Hannes Gierke, Kerstin Schaefer, Lukas Gerlich, Ann-Cathrin Willmann, Verena Bialetzki, Georg Boeck, Teresa Pfrommer, Thomas Nolte and Werner Weitschies

Pharmaceutics 2022, 14(12), 2608; https://doi.org/10.3390/pharmaceutics14122608 - 26 Nov 2022

Cited by 1 | Viewed by 1110

Abstract

The formation of pharmacobezoars from suspensions of spray-dried amorphous solid dispersions (SD-ASDs) of new chemical entities (NCEs) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) represents a non-compound related adverse effect in preclinical oral toxicity studies in rodents. Whereas the contribution of the insolubility of [...] Read more.

The formation of pharmacobezoars from suspensions of spray-dried amorphous solid dispersions (SD-ASDs) of new chemical entities (NCEs) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) represents a non-compound related adverse effect in preclinical oral toxicity studies in rodents. Whereas the contribution of the insolubility of the carrier polymer to this process taking place in the acidic environment of the rodent stomach is conclusive, unawareness of the extent of in vivo pharmacobezoar formation is adverse. In order to evaluate the risk of pharmacobezoar formation before in vivo administration, we subsequently introduce an in vitro model to assess the agglomeration potential of solid dispersions. To verify that the pharmacobezoar formation potential can be assessed based on the observed agglomeration potential, we conducted a sequence of experiments with two HPMC-AS-based SD-ASD formulations. In vitro, we found their different in vivo pharmacobezoar formation potential reflected by a significantly increased agglomerated mass of formulation 1 per day compared to formulation 2. In order to find an approach to reduce the agglomeration potential of solid dispersion from suspensions, we further applied the model to investigate the impact of the viscosity of the vehicle used to prepare suspensions on agglomerate formation. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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11 pages, 2233 KiB

Open AccessArticle

Leveraging Dissolution by Autoinjector Designs

by Christoph Spangardt, Christoph Keßler, Ramona Dobrzewski, Antonia Tepler, Simon Hanio, Bernd Klaubert and Lorenz Meinel

Pharmaceutics 2022, 14(11), 2544; https://doi.org/10.3390/pharmaceutics14112544 - 21 Nov 2022

Viewed by 1221

Abstract

Chemical warfare or terrorism attacks with organophosphates may place intoxicated subjects under immediate life-threatening and psychologically demanding conditions. Antidotes, such as the oxime HI-6, which must be formulated as a powder for reconstitution reflecting the molecule’s light sensitivity and instability in aqueous solutions, [...] Read more.

Chemical warfare or terrorism attacks with organophosphates may place intoxicated subjects under immediate life-threatening and psychologically demanding conditions. Antidotes, such as the oxime HI-6, which must be formulated as a powder for reconstitution reflecting the molecule’s light sensitivity and instability in aqueous solutions, dramatically improve recovery—but only if used soon after exposure. Muscle tremors, anxiety, and loss of consciousness after exposure jeopardize proper administration, translating into demanding specifications for the dissolution of HI-6. Reflecting the patients’ catastrophic situation and anticipated desire to react immediately to chemical weapon exposure, the dissolution should be completed within ten seconds. We are developing multi-dose and single-dose autoinjectors to reliably meet these dissolution requirements. The temporal and spatial course of dissolution within the various autoinjector designs was profiled colorimetrically. Based on these colorimetric insights with model dyes, we developed experimental setups integrating online conductometry to push experiments toward the relevant molecule, HI-6. The resulting blueprints for autoinjector designs integrated small-scale rotor systems, boosting dissolution across a wide range of viscosities, and meeting the required dissolution specifications driven by the use of these drug products in extreme situations. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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17 pages, 4085 KiB

Open AccessArticle

Processing of Lipid Nanodispersions into Solid Powders by Spray Drying

by Denise Steiner, Leonie V. Schumann and Heike Bunjes

Pharmaceutics 2022, 14(11), 2464; https://doi.org/10.3390/pharmaceutics14112464 - 15 Nov 2022

Cited by 1 | Viewed by 1539

Abstract

Spray drying is a promising technology for drying lipid nanodispersions. These formulations can serve as carrier systems for poorly water-soluble active pharmaceutical ingredients (APIs) that are loaded into the lipid matrix to improve their bioavailability. Once the API-loaded nanocarriers have been further processed [...] Read more.

Spray drying is a promising technology for drying lipid nanodispersions. These formulations can serve as carrier systems for poorly water-soluble active pharmaceutical ingredients (APIs) that are loaded into the lipid matrix to improve their bioavailability. Once the API-loaded nanocarriers have been further processed into solid dosage forms, they could be administered orally, which is usually preferred by patients. Various solid lipids as well as oils were used in this study to prepare lipid nanodispersions, and it was shown that their nanoparticulate properties could be maintained when lactose in combination with SDS was used as matrix material in the spray-drying process. In addition, for lipid nanoemulsions loaded with fenofibrate, a good redispersibility with particle sizes below 300 nm at a lipid content of 26.8 wt.% in the powders was observed. More detailed investigations on the influence of the drying temperature yielded good results when the inlet temperature of the drying air was set at 110 °C or above, enabling the lactose to form an amorphous matrix around the embedded lipid particles. A tristearin suspension was developed as a probe to measure the temperature exposure of the lipid particles during the drying process. The results with this approach indicate that the actual temperature the particles were exposed to during the drying process could be higher than the outlet temperature. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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19 pages, 4387 KiB

Open AccessArticle

A Novel Two-Chamber Setup for Containment Investigations with Special Focus on the Dustiness of Pharmaceutical Powders Depending on the Airflow

by Steffen Wirth, Martin Schöler, Jonas Brügmann and Claudia S. Leopold

Pharmaceutics 2022, 14(11), 2387; https://doi.org/10.3390/pharmaceutics14112387 - 05 Nov 2022

Viewed by 1421

Abstract

In the present study, it was shown that a newly developed two-chamber setup (TCS) for containment investigations consisting of an emission and a detection chamber may serve to predict the dustiness of HPAPIs in a sealed system at different flow conditions. These flow [...] Read more.

In the present study, it was shown that a newly developed two-chamber setup (TCS) for containment investigations consisting of an emission and a detection chamber may serve to predict the dustiness of HPAPIs in a sealed system at different flow conditions. These flow conditions include the plain diffusive transport and the diffusive transport with the oppositely directed convective flow of airborne particles of the safe surrogate substance acetaminophen (ACAM). A linear correlation was found between an atomized amount of up to 400 mg of ACAM and the resulting dust emissions. The dust emission was reduced significantly by an oppositely directed convective flow. The results from the examinations, using either atomized ACAM or smoke for the determination of the evacuation time of the detection chamber, indicated that both methods are comparable. Furthermore, computational fluid dynamics (CFD) simulations were performed to determine the evacuation time. A time period of 9 min was sufficient for a reproducible evacuation and a reliable detection of most airborne ACAM particles within the detection chamber. CFD simulations were also carried out to simulate the air velocity resulting from various pressure differences and to visualize the flow of the airborne particles within the detection chamber. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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19 pages, 5170 KiB

Open AccessArticle

Understanding the Multidimensional Effects of Polymorphism, Particle Size and Processing for D-Mannitol Powders

by Lena Mareczek, Carolin Riehl, Meike Harms and Stephan Reichl

Pharmaceutics 2022, 14(10), 2128; https://doi.org/10.3390/pharmaceutics14102128 - 07 Oct 2022

Cited by 2 | Viewed by 2738

Abstract

The relevance of the polymorphic form, particle size, and processing of mannitol for the mechanical properties of solid oral dosage forms was examined. Thus, particle and powder properties of spray granulated β D-mannitol, β D-mannitol, and δ D-mannitol were assessed in this study [...] Read more.

The relevance of the polymorphic form, particle size, and processing of mannitol for the mechanical properties of solid oral dosage forms was examined. Thus, particle and powder properties of spray granulated β D-mannitol, β D-mannitol, and δ D-mannitol were assessed in this study with regards to their manufacturability. D-mannitol is a commonly used excipient in pharmaceutical formulations, especially in oral solid dosage forms, and can be crystallized as three polymorphic forms, of which β is the thermodynamically most stable form and δ is a kinetically stabilized polymorph. A systematic analysis of the powders as starting materials and their respective roller compacted granules is presented to elucidate the multidimensional effects of powder and granules characteristics such as polymorphic form, particle size, and preprocessing on the resulting tablets’ mechanical properties. In direct compression and after roller compaction, δ polymorph displayed superior tableting properties over β mannitol, but was outperformed by spray granulated β mannitol. This could be primarily correlated to the higher specific surface area, leading to higher bonding area and more interparticle bonds within the tablet. Hence, it was shown that surface characteristics and preprocessing can prevail over the impact of polymorphism on manufacturability for oral solid dosage forms. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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12 pages, 3135 KiB

Open AccessArticle

Development of a Hot-Melt-Extrusion-Based Spinning Process to Produce Pharmaceutical Fibers and Yarns

by Christoph Rosenbaum, Linus Großmann, Ellen Neumann, Petra Jungfleisch, Emre Türeli and Werner Weitschies

Pharmaceutics 2022, 14(6), 1229; https://doi.org/10.3390/pharmaceutics14061229 - 10 Jun 2022

Cited by 3 | Viewed by 2093

Abstract

Fibers and yarns are part of everyday life. So far, fibers that are also used pharmaceutically have mainly been produced by electrospinning. The common use of spinning oils and the excipients they contain, in connection with production by melt extrusion, poses a regulatory [...] Read more.

Fibers and yarns are part of everyday life. So far, fibers that are also used pharmaceutically have mainly been produced by electrospinning. The common use of spinning oils and the excipients they contain, in connection with production by melt extrusion, poses a regulatory challenge for pharmaceutically usable fibers. In this publication, a newly developed small-scale direct-spinning melt extrusion system is described, and the pharmaceutically useful polyvinyl filaments produced with it are characterized. The major parts of the system were newly developed or extensively modified and manufactured cost-effectively within a short time using rapid prototyping (3D printing) from various materials. For example, a stainless-steel spinneret was developed in a splice design for a table-top melt extrusion system that can be used in the pharmaceutical industry. The direct processing of the extruded fibers was made possible by a spinning system developed called Spinning-Rosi, which operates continuously and directly in the extrusion process and eliminates the need for spinning oils. In order to prevent instabilities in the product, further modifications were also made to the process, such as a the moisture encapsulation of the melt extrusion line at certain points, which resulted in a bubble-free extrudate with high tensile strength, even in a melt extrusion line without built-in venting. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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16 pages, 3476 KiB

Open AccessArticle

Increasing the Batch Size of a QESD Crystallization by Using a MSMPR Crystallizer

by Jerome Hansen and Peter Kleinebudde

Pharmaceutics 2022, 14(6), 1227; https://doi.org/10.3390/pharmaceutics14061227 - 09 Jun 2022

Cited by 4 | Viewed by 1588

Abstract

Quasi-emulsion solvent diffusion (QESD) crystallizations can improve the micromeritic properties of drugs and excipients. A solution is dispersed in a miscible antisolvent as a transient emulsion. Using this technique, substances that normally crystallize in the form of e.g., needles, agglomerate into spherical, hollow [...] Read more.

Quasi-emulsion solvent diffusion (QESD) crystallizations can improve the micromeritic properties of drugs and excipients. A solution is dispersed in a miscible antisolvent as a transient emulsion. Using this technique, substances that normally crystallize in the form of e.g., needles, agglomerate into spherical, hollow particles. A disadvantage of QESD crystallizations is that the particle size of the agglomerates decreases with an increased solvent fraction of the mother liquor. Therefore, in batch production, many consecutive runs have to be performed, which is a time- and material-intensive process. The aim of this study was to convert a previously used lab-scale batch crystallizer into a mixed-suspension, mixed-product removal (MSMPR) crystallizer, since the batch size could be simply increased by increasing the run time of the system. The mean residence time (MRT) and solvent fraction in the system was predicted and verified using actual measurement curves. The experiments showed that >50 g QESD metformin hydrochloride could be crystallized in a single run, without observing a large shift in the particle size, while maintaining good flowability. Observations regarding the effect of the MRT on the particle size distribution could be verified for the production on a larger scale than previously described. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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16 pages, 6181 KiB

Open AccessArticle

Influence of Oil Polarity and Cosurfactants on the Foamability of Mono- and Diacylphosphatidylcholine Stabilized Emulsions

by Manuel Bunk and Rolf Daniels

Pharmaceutics 2022, 14(6), 1212; https://doi.org/10.3390/pharmaceutics14061212 - 07 Jun 2022

Viewed by 1456

Abstract

Foam formulations are safe and effective therapy options for the treatment of chronic skin conditions that require the application of a topical formulation to delicate skin areas, such as scalp psoriasis or seborrheic dermatitis. This study focused on the development of foamable emulsions [...] Read more.

Foam formulations are safe and effective therapy options for the treatment of chronic skin conditions that require the application of a topical formulation to delicate skin areas, such as scalp psoriasis or seborrheic dermatitis. This study focused on the development of foamable emulsions based on aqueous phospholipid blends. The effects of cosurfactants (nonionic Lauryglucoside (LG); zwitterionic Lauramidopropyl betaine (LAPB)), as well as of oil phases of different polarities, namely paraffin oil (PO), medium-chain triglycerides (MCT) and castor oil (CO), were investigated. The foaming experiments showed that both the type of cosurfactant, as well as the type of oil phase, affects the quality of the resulting foam. Emulsions that were based on a combination of hydrogenated lysophosphatidylcholine (hLPC) and a non-hydrogenated phospholipid, as well as LG as a cosurfactant and MCT as an oil phase, yielded the most satisfactory results. Furthermore, profile analysis tensiometry (PAT), polarization microscopy and laser diffraction analysis were used to characterize the developed formulations. These experiments suggest that the employed phospholipids predominantly stabilize the emulsions, while the cosurfactants are mainly responsible for the formation and stabilization of the foams. However, it appears that both sets of excipients are needed in order to acquire stable emulsions with satisfactory foaming properties. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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14 pages, 3207 KiB

Open AccessArticle

An Advanced Bioreactor Simulating Dynamic Physiological Conditions in the Human Ascending Colon: MimiCol³

by Regine Beeck, Annemarie Dols, Felix Schneider, Dariah-Sohreh Seradj, Julius Krause, Philipp Schick and Werner Weitschies

Pharmaceutics 2022, 14(5), 1049; https://doi.org/10.3390/pharmaceutics14051049 - 13 May 2022

Cited by 2 | Viewed by 1845

Abstract

In recent years, the colon has become a hot topic in biopharmaceutical research as several in vitro models of the human colon have been presented. A major focus is on the characterization of the microbiota and its capabilities. The aim of the present [...] Read more.

In recent years, the colon has become a hot topic in biopharmaceutical research as several in vitro models of the human colon have been presented. A major focus is on the characterization of the microbiota and its capabilities. The aim of the present study was to further develop the MimiCol, preserving its properties and accelerating data acquisition. Emphasis was placed on the simplicity of its design and easy scalability. To prove the viability of the concept, degradation of sulfasalazine was investigated, and the bacterial composition during the experiment was assessed by 16S rRNA sequencing. The transfer of the experimental conditions to the new model was successful. Commercially available components were implemented in the setup. The model MimiCol³ represented the colon ascendens satisfactorily in its properties regarding volume, pH value, and redox potential. 16S rRNA sequencing led to further insights into the bacterial composition in the vessels. Degradation of sulfasalazine was in good agreement with in vivo data. The new model of the colon ascendens MimiCol³ enabled us to collect more reliable data, as three experiments were conducted simultaneously under the same conditions. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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12 pages, 3013 KiB

Open AccessArticle

Proof-of-Concept for Adjusted Surface Energies and Modified Fines as a Novel Concept in Particle Engineering for DPI Formulations

by Nicholas Bungert, Mirjam Kobler and Regina Scherließ

Pharmaceutics 2022, 14(5), 951; https://doi.org/10.3390/pharmaceutics14050951 - 28 Apr 2022

Cited by 2 | Viewed by 2064

Abstract

Currently marketed dry powder inhaler (DPI) medicine lacks drug delivery performance due to insufficient powder dispersion. In carrier-based blends, incomplete drug detachment is typically attributed to excessive adhesion forces between carrier and drug particles. Adding force control agents (FCA) is known to increase [...] Read more.

Currently marketed dry powder inhaler (DPI) medicine lacks drug delivery performance due to insufficient powder dispersion. In carrier-based blends, incomplete drug detachment is typically attributed to excessive adhesion forces between carrier and drug particles. Adding force control agents (FCA) is known to increase drug detachment. Several researchers accounted this effect to a decrease in carrier surface energy (SE). In turn, an increase in SE should impede drug detachment. In this proof-of-concept study, we investigated the influence of the SE of the carrier material in binary blends by intentionally inverting the FCA approach. We increased SEs by dry particle coating utilising high-shear mixing, which resulted in decreased respirable fractions of the respective blends. Thus, we confirmed the SE of the carrier influences drug delivery and should be considered in formulation approaches. Complementing engineering techniques on the carrier level, we evaluated a method to modify the SE of extrinsic fines in ternary powder blends for inhalation. By the co-milling of fine lactose and an additive, we tailored the SE and hence the adhesiveness of additional fine excipients. Thus, the extent and the strength of drug–fines agglomerates may be controllable. For ternary DPI formulations, this work highlights the potential benefits of matching the SE of both fines and drugs. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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17 pages, 3266 KiB

Open AccessEditor’s ChoiceArticle

Cucumber-Derived Exosome-like Vesicles and PlantCrystals for Improved Dermal Drug Delivery

by Abraham M. Abraham, Sabrina Wiemann, Ghazala Ambreen, Jenny Zhou, Konrad Engelhardt, Jana Brüßler, Udo Bakowsky, Shu-Ming Li, Robert Mandic, Gabriella Pocsfalvi and Cornelia M. Keck

Pharmaceutics 2022, 14(3), 476; https://doi.org/10.3390/pharmaceutics14030476 - 22 Feb 2022

Cited by 23 | Viewed by 3919

Abstract

(1) Background: Extracellular vesicles (EVs) are considered to be efficient nanocarriers for improved drug delivery and can be derived from mammalian or plant cells. Cucumber-derived EVs are not yet described in the literature. Therefore, the aim of this study was to produce and [...] Read more.

(1) Background: Extracellular vesicles (EVs) are considered to be efficient nanocarriers for improved drug delivery and can be derived from mammalian or plant cells. Cucumber-derived EVs are not yet described in the literature. Therefore, the aim of this study was to produce and characterize cucumber-derived EVs and to investigate their suitability to improve the dermal penetration efficacy of a lipophilic active ingredient (AI) surrogate. (2) Methods: The EVs were obtained by classical EVs isolation methods and by high pressure homogenization (HPH). They were characterized regarding their physico-chemical and biopharmaceutical properties. (3) Results: Utilization of classical isolation and purification methods for EVs resulted in cucumber-derived EVs. Their dermal penetration efficacy for the AI surrogate was 2-fold higher when compared to a classical formulation and enabled a pronounced transdermal penetration into the viable dermis. HPH resulted in submicron sized particles composed of a mixture of disrupted plant cells. A successful isolation of pure EVs from this mixture was not possible with classical EVs isolation methods. The presence of EVs was, therefore, proven indirectly. For this, the lipophilic drug surrogate was admixed to the cucumber juice either prior to or after HPH. Admixing of the drug surrogate to the cucumber prior to the HPH resulted in a 1.5-fold increase in the dermal penetration efficacy, whereas the addition of the AI surrogate to the cucumber after HPH was not able to improve the penetration efficacy. (4) Conclusions: Results, therefore, indicate that HPH causes the formation of EVs in which AI can be incorporated. The formation of plant EVs by HPH was also indicated by zeta potential analysis. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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Review

Jump to: Research

41 pages, 7915 KiB

Open AccessReview

Opportunities and Challenges of Switchable Materials for Pharmaceutical Use

by Deniz Ceylan Tuncaboylu and Christian Wischke

Pharmaceutics 2022, 14(11), 2331; https://doi.org/10.3390/pharmaceutics14112331 - 28 Oct 2022

Cited by 6 | Viewed by 1875

Abstract

Switchable polymeric materials, which can respond to triggering signals through changes in their properties, have become a major research focus for parenteral controlled delivery systems. They may enable externally induced drug release or delivery that is adaptive to in vivo stimuli. Despite the [...] Read more.

Switchable polymeric materials, which can respond to triggering signals through changes in their properties, have become a major research focus for parenteral controlled delivery systems. They may enable externally induced drug release or delivery that is adaptive to in vivo stimuli. Despite the promise of new functionalities using switchable materials, several of these concepts may need to face challenges associated with clinical use. Accordingly, this review provides an overview of various types of switchable polymers responsive to different types of stimuli and addresses opportunities and challenges that may arise from their application in biomedicine. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Germany)

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