This special report gives an insight in the rationale of utilizing the nasal cavity for drug administration and the formulation as well as characterization of nasal preparations. As the nose is an ...easy-to-access, noninvasive and versatile location for absorption, this route of delivery will play an increasingly important role in future drug product development both for new and repurposed drugs. The nose can be utilized for local and systemic delivery including drug delivery to the central nervous system and the immune system. Typical formulation strategies and future developments are reviewed, which nowadays mostly comprise liquid formulations. Although they are straight forward to develop, a number of aspects from choice of solvent, osmolarity, pH, viscosity and more need to be considered, which determine formulation characteristics, not at least nasal deposition. Nasal powders offer higher stability and, along with more sophisticated nasal devices, may play a major role in the future.
Introduction: Nanoparticles are under discussion in drug delivery for more than 20 years now, but examples for nanoparticulate formulations in the treatment of respiratory diseases are rare and ...mostly limited to the administration of sub-micron drug particles (ultrafine particles). However, nanoparticles may also carry specific benefits for respiratory treatment. Are nanoparticles the next-generation drug carrier system to facilitate systemic delivery, sustained release and cancer treatment in the lungs?
Areas covered: This review will look into the promises and opportunities of the use of nanoparticles in the treatment of respiratory diseases. Important aspects to discuss are the fate of nanoparticles in the lung and mechanisms for reproducible delivery of nanoparticulate formulations to the lungs. Examples are given where nanoparticles may be advantageous over for traditional formulations and further aspects to explore are mentioned.
Expert opinion: The benefit of nanoparticulate systems for respiratory delivery adds to the portfolio of possible formulation strategies, depends on the intended functionality and needs more exploration. Advantages of such systems are only seen in special cases.
This opinion piece gives reasons for high dose DPI applications, points out challenges and shows opportunities and possible solutions for high dose DPI. This piece of work shall set the stage for ...more in-depth reviews of state of the art and research papers addressing the challenges of high dose DPI which shall be included in the special issue of IJP.
Vaccine delivery via mucosal surfaces is an interesting alternative to parenteral vaccine administration, as it avoids the use of a needle and syringe. Mucosal vaccine administration also targets the ...mucosal immune system, which is the largest lymphoid tissue in the human body. The mucosal immune response involves systemic, antigen-specific humoral and cellular immune response in addition to a local response which is characterised by a predominantly cytotoxic T cell response in combination with secreted IgA. This antibody facilitates pathogen recognition and deletion prior to entrance into the body. Hence, administration via the respiratory mucosa can be favoured for all pathogens which use the respiratory tract as entry to the body, such as influenza and for all diseases directly affecting the respiratory tract such as pneumonia. Additionally, the different mucosal tissues of the human body are interconnected via the so-called "common mucosal immune system", which allows induction of an antigen-specific immune response in distant mucosal sites. Finally, mucosal administration is also interesting in the area of therapeutic vaccination, in which a predominant cellular immune response is required, as this can efficiently be induced by this route of delivery. The review gives an introduction to respiratory vaccination, formulation approaches and application strategies.
MTT assay to evaluate and compare acute excipient toxicity on Calu-3 cells to facilitate a more rational choice of novel excipients in respiratory formulation development.
There are not many ...excipients already approved in drug products for the use in the respiratory tract. In this study, a rapid
in vitro screening procedure to assess and compare acute toxicity of soluble excipient substances on respiratory epithelial cells utilising the Calu-3 cell line is presented. The test substances are either dissolved in HBSS
+
HEPES buffer or are directly applied to the cellular surface. After 4
h incubation, the substances are removed and the cell viability is assessed using an MTT assay. The tested excipients include polysorbate 20 and 80, lactose and povidone 30 as well as glycerol and propylene glycol as examples of excipients already being used in formulations for application in the respiratory tract. These substances are sorted according to their toxic effect and new excipients not yet used in the respiratory tract like HPMC can be classified in this scheme. With this, besides information from systemic toxicity tests, a first valuation of the acute toxic effect of the substance on respiratory epithelial cells is gained. This can aid in the choice of new excipients being necessary for modern respiratory formulations comprising new active compounds as biomolecules or new delivery strategies such as sustained or prolonged delivery.
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The nasal physiology offers great potential for drug delivery but also poses specific challenges, among which the short residence time of applied drugs is one of the most striking. ...Formulating the drug as powder and using functional excipients are strategies to improve drug absorption. As nasal powders are still the minority on the market, there is a lack of data regarding their characterisation. This work aims at the characterisation of selected fillers (mannitol, microcrystalline cellulose) and mucoadhesives (pectin, chitosan glutamate, hydroxypropyl cellulose) with a set of methods that allows distinguishing their influences on dissolution and permeation of drugs, and on the viscoelasticity of the nasal fluid and thus the nasal residence time. Rheological studies revealed a potential of undissolved particles to prolong the residence time by increasing the elasticity of the nasal fluid. The assessment of drug dissolution showed a decreased dissolution rate in presence of insoluble or gelling excipients, which can be beneficial for drugs with low permeability, since embedded drugs are cleared slower than plain solutions. Drug permeation as important factor for the selection of excipients was evaluated with an RPMI 2650 cell model. Distinguishing the effects of excipients enables an effective selection of the most promising substances.
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Lung tuberculosis (TB) is the most deadly infectious disease worldwide although it is treatable. High doses of antibiotics are used for therapy over a period of at least 6 months. ...Since in many treated patients only subtherapeutic concentrations are reached in the infected tissue of the lung, about half a million cases of multi drug resistant tuberculosis (MDR TB) occur every year. In order to increase the concentration of the active pharmaceutical ingredient (API) at the site of the primary infection, inhalation of antibiotics seems to be promising. In this study, we show the capability of softpellets, engineered dry powder agglomerates, to deliver high doses to the lungs. For this, the antibiotic rifampicin was milled and processed into softpellets which were then dispersed utilising a novel high dose dry powder inhaler, the 8Shot from Hovione Technology. Aerodynamic assessment resulted in a fine particle dose of 21.35 mg with a device retention of < 15% after loading all eight chambers of the inhaler with 10 mg softpellet formulation. At the same time, we present a new process design to produce softpellets, namely vibro-pelletisation.
Nasal drug delivery is still primarily associated with locally-effective drugs, but next-generation products utilising the benefits of nasal administration-such as easy access to a relatively ...permeable mucosa, the presence of immunocompetent cells, and a direct route to the brain-are under investigation. Nasal powders offer the potential to improve the drugs' effects by providing higher resistance against the mucociliary clearance, and thus prolonging the contact time of the drug with its target site. However, suitable and easy-to-use in-vitro setups tailored to the characterisation of this effect are missing. In this study, a selection of excipients for powder formulations were used to evaluate the applicability of different methods which investigate the influence on the contact time. The combination of the assessment of rheological properties, dynamic vapour sorption, and adhesiveness on agar-mucin plates was found to be a valuable predictive tool. For the additional assessment of the sensations associated with the close contact of powders and the mucosa, a slug mucosal irritation assay was conducted and adapted to powders. These methods are regarded as being especially useful for comparative screenings in early formulation development.
In dry powder formulations for inhalation, coarse carrier particles are often used to improve handling, dosing and dispersion of the active pharmaceutical ingredient (API). Carrier particles, mostly ...alpha-lactose monohydrate crystals, always show a certain size distribution and are never exactly uniform in their geometry. This might be one factor of the rather high invivo variability in fine particle dose from dry powder inhalers. To address the inhomogeneity of carrier particles, additive manufacturing has come to mind. The parametric design of the perfect carrier geometry could further improve the efficiency of dry powder formulations. In this study, a numerical simulation setup using the discrete element method as well as an experimental approach with 3D printed particles were used to determine the loading capacity of a model API onto two different carrier geometries. The difference between the two geometries was reduced solely to their surface's topology to assess the impact of that. The results indicate differences in the loading capacity for the two geometries, depending on the loading process. This study highlights the importance of the carrier geometry for the efficiency of dry powder formulations and thus, strengthens the idea of artificially designed and printed carrier particles.
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Additive Manufacturing (AM) comprises a variety of techniques that enable fabrication of customised objects with specific attributes. The versatility of AM procedures and constant ...technological improvements allow for their application in the development of medicinal products and medical devices. This review provides an overview of AM applications related to respiratory sciences. For this purpose, both fields of research are briefly introduced and the potential benefits of integrating AM to respiratory sciences at different levels of pharmaceutical development are highlighted. Tailored manufacturing of microstructures as a particle design approach in respiratory drug delivery will be discussed. At the dosage form level, we exemplify AM as an important link in the iterative loop of data driven inhaler design, rapid prototyping and in vitro testing. This review also presents the application of bioprinting in the respiratory field for design of biorelevant in vitro cellular models, followed by an overview of AM-related processes in preventive and therapeutic care. Finally, this review discusses future prospects of AM as a component in a digital health environment.
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