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12 pages, 1285 KiB

Open AccessArticle

Efficacy of Combined Rifampicin Formulations Delivered by the Pulmonary Route to Treat Tuberculosis in the Guinea Pig Model

by Lucila Garcia-Contreras, Vasu Sethuraman, Masha Kazantseva and Anthony Hickey

Pharmaceutics 2021, 13(8), 1309; https://doi.org/10.3390/pharmaceutics13081309 - 21 Aug 2021

Cited by 6 | Viewed by 2983

Abstract

Liposomes, as vehicles alone or in combination with rifampicin (RIF) microparticles (RMs), were evaluated as vehicles to enhance the permeation of RIF into granulomas. RIF liposomes (RLs) were extruded through a 0.1 µm polypropylene membrane. RMs were prepared by the solvent evaporation method. [...] Read more.

Liposomes, as vehicles alone or in combination with rifampicin (RIF) microparticles (RMs), were evaluated as vehicles to enhance the permeation of RIF into granulomas. RIF liposomes (RLs) were extruded through a 0.1 µm polypropylene membrane. RMs were prepared by the solvent evaporation method. Four weeks after infection, guinea pigs (GPs) were assigned to groups treated with a combination of RM-RLs or RLs alone. RLs were nebulized after extrusion whereas RMs were suspended in saline and nebulized to GPs in a nose-only inhalation chamber. Necropsy was performed after the treatment; the lungs and spleen were resected for bacteriology. RLs had mean diameters of 137.1 ± 33.7 nm whereas RMs had a projected area diameter of 2.48 µm. The volume diameter of RMs was 64 ± 1 µm, indicating that RMs were aggregated. The treatment of TB-infected GPs with RLs significantly reduced their lung bacterial burden and wet spleen weight compared with those treated with blank liposomes. The treatment of TB-infected animals with RM-RLs also reduced their lung bacterial burden and wet spleen weight even though these reductions were not statistically different. Based on these results, the permeation of RIF into granulomas appears to be enhanced when encapsulated into liposomes delivered by the pulmonary route. Full article

(This article belongs to the Special Issue Methodology, Design and Regulatory Considerations for the Bioequivalence of Oral Inhaled Products)

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21 pages, 7014 KiB

Open AccessArticle

Optimization of the Transwell^® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

by Elham Amini, Abhinav Kurumaddali, Sharvari Bhagwat, Simon M. Berger and Günther Hochhaus

Pharmaceutics 2021, 13(8), 1109; https://doi.org/10.3390/pharmaceutics13081109 - 21 Jul 2021

Cited by 9 | Viewed by 3811

Abstract

The aim of this study was to further evaluate and optimize the Transwell^® system for assessing the dissolution behavior of orally inhaled drug products (OIDPs), using fluticasone propionate as a model drug. Sample preparation involved the collection of a relevant inhalable dose [...] Read more.

The aim of this study was to further evaluate and optimize the Transwell^® system for assessing the dissolution behavior of orally inhaled drug products (OIDPs), using fluticasone propionate as a model drug. Sample preparation involved the collection of a relevant inhalable dose fraction through an anatomical mouth/throat model, resulting in a more uniform presentation of drug particles during the subsequent dissolution test. The method differed from previously published procedures by (1) using a 0.4 µm polycarbonate (PC) membrane, (2) stirring the receptor compartment, and (3) placing the drug-containing side of the filter paper face downwards, towards the PC membrane. A model developed in silico, paired with the results of in vitro studies, suggested that a dissolution medium providing a solubility of about 5 µg/mL would be a good starting point for the method’s development, resulting in mean transfer times that were about 10 times longer than those of a solution. Furthermore, the model suggested that larger donor/receptor and sampling volumes (3, 3.3 and 2 mL, respectively) will significantly reduce the so-called “mass effect”. The outcomes of this study shed further light on the impact of experimental conditions on the complex interplay of dissolution and diffusion within a volume-limited system, under non-sink conditions. Full article

(This article belongs to the Special Issue Methodology, Design and Regulatory Considerations for the Bioequivalence of Oral Inhaled Products)

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10 pages, 378 KiB

Open AccessArticle

A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects

by Sawittree Sahakijpijarn, Moeezullah Beg, Stephanie M. Levine, Jay I. Peters and Robert O. Williams III

Pharmaceutics 2021, 13(5), 717; https://doi.org/10.3390/pharmaceutics13050717 - 13 May 2021

Cited by 7 | Viewed by 2909

Abstract

Due to the low and erratic bioavailability of oral tacrolimus (TAC), the long-term survival rate following lung transplantation remained low compared to other solid organs. TAC was reformulated and developed as inhaled formulations by thin film freezing (TFF). Previous studies reported that inhaled [...] Read more.

Due to the low and erratic bioavailability of oral tacrolimus (TAC), the long-term survival rate following lung transplantation remained low compared to other solid organs. TAC was reformulated and developed as inhaled formulations by thin film freezing (TFF). Previous studies reported that inhaled TAC combined with 50% w/w lactose (LAC) was safe and effective for the treatment of lung transplant rejection in rodent models. In this study, we aimed to investigate the safety and tolerability of TFF TAC-LAC in human subjects. The formulation can be delivered to the lung as colloidal dispersions after reconstitution and as a dry powder. Healthy subjects inhaled TAC-LAC colloidal dispersions at 3 mg TAC/dose via a vibrating mesh nebulizer in the first stage of this study and TAC-LAC dry powder at 3 mg TAC/dose via a single dose dry powder inhaler in the second stage. Our results demonstrated that oral inhalation of TAC-LAC colloidal dispersions and dry powder exhibited low systemic absorption. Additionally, they were well-tolerated with no changes in CBC, liver, kidney, and lung functions. Only mild adverse side effects (e.g., cough, throat irritation, distaste) were observed. In summary, pulmonary delivery of TFF TAC-LAC would be a safe and promising therapy for lung transplant recipients. Full article

(This article belongs to the Special Issue Methodology, Design and Regulatory Considerations for the Bioequivalence of Oral Inhaled Products)

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13 pages, 2391 KiB

Open AccessArticle

Assessment and Development of the Antifungal Agent Caspofungin for Aerosolized Pulmonary Delivery

by Iching G. Yu and David M. Ryckman

Pharmaceutics 2021, 13(4), 504; https://doi.org/10.3390/pharmaceutics13040504 - 7 Apr 2021

Cited by 4 | Viewed by 2840

Abstract

Invasive Pulmonary Aspergillosis (IPA) and Pneumocystis jiroveci Pneumonia (PCP) are serious fungal pulmonary diseases for immunocompromised patients. The brand name drug CANCIDAS^® (Caspofungin acetate for injection) is FDA approved to treat IPA, but is only 40% effective. Efficacious drug levels at the [...] Read more.

Invasive Pulmonary Aspergillosis (IPA) and Pneumocystis jiroveci Pneumonia (PCP) are serious fungal pulmonary diseases for immunocompromised patients. The brand name drug CANCIDAS^® (Caspofungin acetate for injection) is FDA approved to treat IPA, but is only 40% effective. Efficacious drug levels at the lung infection site are not achieved by systemic administration. Increasing the dose leads to toxicity. The objective, here, is to reformulate caspofungin for aerosolization to high drug concentration by lung targeted delivery and avoid systemic distribution. Described in this paper is a new, room temperature-stable formulation that meets these goals. The in vitro antifungal activity, solid state and reconstituted stability, and aerosol properties of the new formulation are presented. In addition, pharmacokinetic parameters and tissue distribution data are determined from nose-only inhalation studies in rats. Plasma and tissue samples were analyzed by High Performance Liquid Chromatography-tandem Mass Spectrometry (HPLC-MS-MS). Inhaled drug concentrations for caspofungin Active Pharmaceutical Ingredient (API), and the new formulation, were compared at the same dose. In the lungs, the parameters C_max and Area Under Curve (AUC) showed a 70%, and 60%, respective increase in drug deposition for the new formulation without significant systemic distribution. Moreover, the calculated pharmacodynamic indices suggest an improvement in efficacy. These findings warrant further animal toxicology studies and human clinical trials, with inhaled caspofungin, for treating IPA. Full article

(This article belongs to the Special Issue Methodology, Design and Regulatory Considerations for the Bioequivalence of Oral Inhaled Products)

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Review

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23 pages, 718 KiB

Open AccessReview

Dry Powder Inhalers in the Digitalization Era: Current Status and Future Perspectives

by Styliani Xiroudaki, Aurélie Schoubben, Stefano Giovagnoli and Dimitrios M. Rekkas

Pharmaceutics 2021, 13(9), 1455; https://doi.org/10.3390/pharmaceutics13091455 - 12 Sep 2021

Cited by 36 | Viewed by 6355

Abstract

During the last decades, the term “drug delivery systems” (DDSs) has almost fully replaced previously used terms, such as “dosage forms”, in an attempt to emphasize the importance of the drug carrier in ensuring the claimed safety and effectiveness of the product. However, [...] Read more.

During the last decades, the term “drug delivery systems” (DDSs) has almost fully replaced previously used terms, such as “dosage forms”, in an attempt to emphasize the importance of the drug carrier in ensuring the claimed safety and effectiveness of the product. However, particularly in the case of delivery devices, the term “system”, which by definition implies a profound knowledge of each single part and their interactions, is not always fully justified when using the DDS term. Within this context, dry powder inhalers (DPIs), as systems to deliver drugs via inhalation to the lungs, require a deep understanding of the complex formulation–device–patient interplay. As of now and despite the progress made in particle engineering and devices design, DPIs’ clinical performance is limited by variable patients’ breathing patterns. To circumvent this pitfall, next-generation DPIs should ideally adapt to the different respiratory capacity of individuals across age, health conditions, and other related factors. In this context, the recent wave of digitalization in the health care and industrial sectors may drive DPI technology towards addressing a personalized device–formulation–patient liaison. In this review, evolving technologies are explored and analyzed to outline the progress made as well as the gaps to fill to align novel DPIs technologies with the systems theory approach. Full article

(This article belongs to the Special Issue Methodology, Design and Regulatory Considerations for the Bioequivalence of Oral Inhaled Products)

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26 pages, 1957 KiB

Open AccessReview

A Quality by Design Framework for Capsule-Based Dry Powder Inhalers

by Li Ding, Ashlee D. Brunaugh, Sven Stegemann, Scott V. Jermain, Matthew J. Herpin, Justin Kalafat and Hugh D. C. Smyth

Pharmaceutics 2021, 13(8), 1213; https://doi.org/10.3390/pharmaceutics13081213 - 6 Aug 2021

Cited by 21 | Viewed by 7680

Abstract

Capsule-based dry powder inhalers (cDPIs) are widely utilized in the delivery of pharmaceutical powders to the lungs. In these systems, the fundamental nature of the interactions between the drug/formulation powder, the capsules, the inhaler device, and the patient must be fully elucidated in [...] Read more.

Capsule-based dry powder inhalers (cDPIs) are widely utilized in the delivery of pharmaceutical powders to the lungs. In these systems, the fundamental nature of the interactions between the drug/formulation powder, the capsules, the inhaler device, and the patient must be fully elucidated in order to develop robust manufacturing procedures and provide reproducible lung deposition of the drug payload. Though many commercially available DPIs utilize a capsule-based dose metering system, an in-depth analysis of the critical factors associated with the use of the capsule component has not yet been performed. This review is intended to provide information on critical factors to be considered for the application of a quality by design (QbD) approach for cDPI development. The quality target product profile (QTPP) defines the critical quality attributes (CQAs) which need to be understood to define the critical material attributes (CMA) and critical process parameters (CPP) for cDPI development as well as manufacturing and control. Full article

(This article belongs to the Special Issue Methodology, Design and Regulatory Considerations for the Bioequivalence of Oral Inhaled Products)

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24 pages, 1215 KiB

Open AccessReview

Inhalation Delivery for the Treatment and Prevention of COVID-19 Infection

by Basanth Babu Eedara, Wafaa Alabsi, David Encinas-Basurto, Robin Polt, Julie G. Ledford and Heidi M. Mansour

Pharmaceutics 2021, 13(7), 1077; https://doi.org/10.3390/pharmaceutics13071077 - 14 Jul 2021

Cited by 55 | Viewed by 11260

Abstract

Coronavirus disease-2019 (COVID-19) is caused by coronavirus-2 (SARS-CoV-2) and has produced a global pandemic. As of 22 June 2021, 178 million people have been affected worldwide, and 3.87 million people have died from COVID-19. According to the Centers for Disease Control and Prevention [...] Read more.

Coronavirus disease-2019 (COVID-19) is caused by coronavirus-2 (SARS-CoV-2) and has produced a global pandemic. As of 22 June 2021, 178 million people have been affected worldwide, and 3.87 million people have died from COVID-19. According to the Centers for Disease Control and Prevention (CDC) of the United States, COVID-19 virus is primarily transmitted between people through respiratory droplets and contact routes. Since the location of initial infection and disease progression is primarily through the lungs, the inhalation delivery of drugs directly to the lungs may be the most appropriate route of administration for treating COVID-19. This review article aims to present possible inhalation therapeutics and vaccines for the treatment of COVID-19 symptoms. This review covers the comparison between SARS-CoV-2 and other coronaviruses such as SARS-CoV/MERS, inhalation therapeutics for the treatment of COVID-19 symptoms, and vaccines for preventing infection, as well as the current clinical status of inhaled therapeutics and vaccines. Full article

(This article belongs to the Special Issue Methodology, Design and Regulatory Considerations for the Bioequivalence of Oral Inhaled Products)

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25 pages, 1202 KiB

Open AccessReview

Innovating on Inhaled Bioequivalence: A Critical Analysis of the Current Limitations, Potential Solutions and Stakeholders of the Process

by Jonattan Gallegos-Catalán, Zachary Warnken, Tania F. Bahamondez-Canas and Daniel Moraga-Espinoza

Pharmaceutics 2021, 13(7), 1051; https://doi.org/10.3390/pharmaceutics13071051 - 9 Jul 2021

Cited by 2 | Viewed by 5117

Abstract

Orally inhaled drug products (OIDPs) are an important group of medicines traditionally used to treat pulmonary diseases. Over the past decade, this trend has broadened, increasing their use in other conditions such as diabetes, expanding the interest in this administration route. Thus, the [...] Read more.

Orally inhaled drug products (OIDPs) are an important group of medicines traditionally used to treat pulmonary diseases. Over the past decade, this trend has broadened, increasing their use in other conditions such as diabetes, expanding the interest in this administration route. Thus, the bioequivalence of OIDPs is more important than ever, aiming to increase access to affordable, safe and effective medicines, which translates into better public health policies. However, regulatory agencies leading the bioequivalence process are still deciding the best approach for ensuring a proposed inhalable product is bioequivalent. This lack of agreement translates into less cost-effective strategies to determine bioequivalence, discouraging innovation in this field. The Next-Generation Impactor (NGI) is an example of the slow pace at which the inhalation field evolves. The NGI was officially implemented in 2003, being the last equipment innovation for OIDP characterization. Even though it was a breakthrough in the field, it did not solve other deficiencies of the BE process such as dissolution rate analysis on physiologically relevant conditions, being the last attempt of transferring technology into the field. This review aims to reveal the steps required for innovation in the regulations defining the bioequivalence of OIDPs, elucidating the pitfalls of implementing new technologies in the current standards. To do so, we collected the opinion of experts from the literature to explain these trends, showing, for the first time, the stakeholders of the OIDP market. This review analyzes the stakeholders involved in the development, improvement and implementation of methodologies that can help assess bioequivalence between OIDPs. Additionally, it presents a list of methods potentially useful to overcome some of the current limitations of the bioequivalence standard methodologies. Finally, we review one of the most revolutionary approaches, the inhaled Biopharmaceutical Classification System (IBCs), which can help establish priorities and order in both the innovation process and in regulations for OIDPs. Full article

(This article belongs to the Special Issue Methodology, Design and Regulatory Considerations for the Bioequivalence of Oral Inhaled Products)

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