Dry powder inhalers for pulmonary drug delivery

The pulmonary route is an interesting route for drug administration, both for effective local therapy (asthma, chronic obstructive pulmonary disease or cystic fibrosis) and for the systemic administration of drugs (e.g., peptides and proteins). Well-designed dry powder inhalers are highly efficient systems for pulmonary drug delivery. However, they are also complicated systems, the the performance of which relies on many aspects, including the design of the inhaler (e.g., resistance to air flow and the used de-agglomeration principle to generate the inhalation aerosol), the powder formulation and the air flow generated by the patient. The technical background of these aspects, and how they may be tuned in order to obtain desired performance profiles, is reviewed. In light of the technical background, new developments and possibilities for further improvements are discussed.     

Pulmonary delivery of dry powders to rats: tolerability limits of an intra-tracheal administration model

The inhaled route is increasingly developed to deliver locally acting or systemic therapies, and rodent models are used to assess tolerance before clinical studies. Endotracheal intubation of rats with a probe which generates powder aerosols enables controlled administration of drug directly into the respiratory tract. However, preliminary observations of intratracheal powder administration procedures have raised concerns with regard to pulmonary safety. The aim of the present work was to evaluate the safety of intra-tracheal administration of dry powder in a rat model. Sixty animals were administered various volumes of air alone, lactose or magnesium stearate through a Microsprayer(?) (Pencentury, USA). The mass of powder actually delivered to each animal was calculated. Rats were sacrificed immediately after administration, and the lungs, trachea and larynx were removed and examined for gross pathology. The mass of powder delivered varied, the full dose being rarely delivered. About one third of the administration procedures resulted in respiratory failure, and macroscopic pulmonary lesions were observed in about 55% of animals. Lung damages were observed with air alone, lactose and magnesium stearate. In conclusion, artifacts observed with this technique may limit the relevance of the model. These observations are particularly important in the context of regulatory toxicity studies.     

Novel alternative methods for the delivery of drugs for the treatment of asthma

Successful delivery of dry powder aerosols to the lung requires careful consideration of the powder production process, formulation and inhaler device. Newer production methods are emerging to prepare powders with desirable characteristics for inhalational administration. The conventional formulation approach of adding coarse lactose carriers to the drug to form binary powder systems to enhance powder flow and dispersion properties has been expanded to using finer carrier particles and hydrophobic materials, as well as ternary systems. Particle morphology and surface properties have also been explored to enhance powder performance. For the inhaler device, the new generation inhalers are designed to reduce or completely decouple the influence of air flow on the aerosol generation. Each of these determinants for powder aerosol delivery is reviewed with a strong focus on the patent literature that contains enormous information about the latest development in this field.     

Clinical perspectives on pulmonary systemic and macromolecular delivery

The large epithelial surface area, the high organ vascularization, the thin nature of the alveolar epithelium and the immense capacity for solute exchange are factors that led the lung to serve as an ideal administration route for the application of drugs for treatment of systemic disorders. However, the deposition behaviour of aerosol particles in the respiratory tract depends on a number of physical (e.g. properties of the particle), chemical (e.g. properties of the drug) and physiological (e.g. breathing pattern, pulmonary diseases) factors. If these are not considered, it will not be possible to deposit a reproducible and sufficient amount of drug in a predefined lung region by means of aerosol inhalation. The lack of consideration of such issues led to many problems in inhalation drug therapy for many years mainly because physiological background of aerosol inhalation was not fully understood. However, over the last 20 years, there has been considerable progress in aerosol research and in the understanding of the underlying mechanisms of particle inhalation and pulmonary particle deposition. As a consequence, an increasing number of studies have been performed for the lung administration of drugs using a variety of different inhalation techniques. This review describes the physical and in part some of the physiological requirements that need to be considered for the optimization of pulmonary drug delivery to target certain lung regions.     

Nasal route and drug delivery systems

Nasal drug administration has been used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. The nasal administration of drugs, including numerous compound, peptide and protein drugs, for systemic medication has been widely investigated in recent years. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in rapid systemic drug absorption. Several approaches are here discussed for increasing the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. The article highlights the importance and advantages of the drug delivery systems applied via the nasal route, which have bioadhesive properties. Bioadhesive, or more appropriately, mucoadhesive systems have been prepared for both oral and peroral administration in the past. The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. In this review we discuss the effects of microspheres and other bioadhesive drug delivery systems on nasal drug absorption. Drug delivery systems, such as microspheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and that swell easily when in contact with the nasal mucosa. These drug delivery systems have the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions. The mechanisms and effectiveness of these drug delivery systems are described in order to guide the development of specific and effective therapies for the future development of peptide preparations and other drugs that otherwise should be administered parenterally. As a consequence, bioavailability and residence time of the drugs that are administered via the nasal route can be increased by bioadhesive drug delivery systems. Although the majority of this work involving the use of microspheres, liposomes and gels is limited to the delivery of macromolecules (e.g., insulin and growth hormone), the general principles involved could be applied to other drug candidates. It must be emphasized that many drugs can be absorbed well if the contact time between formulation and the nasal mucosa is optimized.     

Dry powder inhalers in COPD,lung inflammation and pulmonary infections

Introduction: The number of pulmonary diseases that are effectively treated by aerosolized medicine continues to grow.

Areas covered: These diseases include chronic obstructive pulmonary disease (COPD), lung inflammatory diseases (e.g., asthma) and pulmonary infections. Dry powder inhalers (DPIs) exhibit many unique advantages that have contributed to the incredible growth in the number of DPI pharmaceutical products. To improve the performance, there are a relatively large number of DPI devices available for different inhalable powder formulations. The relationship between formulation and inhaler device features on performance of the drug–device combination product is critical. Aerosol medicine products are drug–device combination products. Device design and compatibility with the formulation are key drug–device combination product aspects in delivering drugs to the lungs as inhaled powders. In addition to discussing pulmonary diseases, this review discusses DPI devices, respirable powder formulation and their interactions in the context of currently marketed DPI products used in the treatment of COPD, asthma and pulmonary infections.

Expert opinion: There is a growing line of product options available for patients in choosing inhalers for treatment of respiratory diseases. Looking ahead, combining nanotechnology with optimized DPI formulation and enhancing device design presents a promising future for DPI development.     

Single-use disposable dry powder inhalers for pulmonary drug delivery

IMPORTANCE OF THE FIELD: The understanding of pulmonary drug delivery and thus its utilization for medical purposes has remarkably advanced over the last decades. It has been recognized that this route of administration offers many advantages and several drug delivery systems have been developed accordingly. Thereby, single-use disposable dry powder inhalers may be considered an economically and therapeutically valuable option for both local and systemic administration of drugs to treat a variety of different disease states. AREAS COVERED IN THIS REVIEW/WHAT THE READER WILL GAIN: This review highlights the required characteristics and potential applications of single-use disposable dry powder inhalers considering advantages as well as limitations of these drug delivery devices. Until now, such drug delivery systems have not become widely accepted. Several devices are available or under development and a few products have reached or completed the clinical phase, but none of them have received market authorization as yet. TAKE HOME MESSAGE: Recent advances in formulation and device design, however, can be considered encouraging and should eventually lead to a wider establishment of single-use disposable dry powder inhalers in pulmonary drug delivery.     

Micron-size drug particles: common and novel micronization techniques

Drug powders containing micron-size drug particles are used in several pharmaceutical dosage forms. Many drugs, especially newly developed substances, are poorly water soluble, which limits their oral bioavailability. The dissolution rate can be enhanced by using micronized drugs. Small drug particles are also required in administration forms, which require the drug in micron-size size due to geometric reasons in the organ to be targeted (e.g., drugs for pulmonary use). The common technique for the preparation of micron-size drugs is the mechanical comminution (e.g., by crushing, grinding, and milling) of previously formed larger particles. In spite of the widespread use of this technique, the milling process does not represent the ideal way for the production of small particles because drug substance properties and surface properties are altered in a mainly uncontrolled manner. Thus, techniques that prepare the drug directly in the required particle size are of interest. Because physicochemical drug powder properties are decisive for the manufacturing of a dosage form and for therapeutic success, the characterization of the particle surface and powder properties plays an important role. This article summarizes common and novel techniques for the production of a drug in small particle size. The properties of the resulting products that are obtained by different techniques are characterized and compared.     

Techniques for drug delivery to the airways, and the assessment of lung function in animal models.

A common approach to understanding the mechanisms underlying clinical asthma and in new drug development is to mimic the disease in animal models. When developing animal models of pulmonary diseases, such as asthma, the experimentally induced disease may be characterized in terms of pathophysiological changes induced (e.g., inflammation, smooth muscle contraction) or by the indices of lung function that are effected by such changes. Similarly, the effects of drugs can be assessed in terms of the reversal of disease- or mediator-induced changes in lung function. Small animals, such as the guinea pig and rat, are commonly used for the assessment of lung function in models of pulmonary diseases, such as asthma, and to evaluate the effects of drugs. A variety of techniques, differing in their level of sophistication, has been developed to measure parameters of lung function in small laboratory animals. Simple techniques involve the visual assessment of the response of a conscious animal to bronchoconstriction induced by an inhaled spasmogen or antigen. This technique is rapid but gives results that are difficult to interpret in physiological terms. Bronchospasm can be better assessed in anesthetized, mechanically ventilated animals by recording bronchial tone as changes in either 1) ventilation circuit pressure or 2) air overflow as the lungs are inflated. These techniques are widely used but because they require surgical intervention they are not suited to long-term or repeat studies. In addition, they give only a limited indication of the physiological changes that affect airway caliber. To improve the models available, researchers have subsequently developed techniques that use the same physiological principles as some of the tests applied to the assessment of lung function in humans. These techniques allow the measurement of parameters of respiratory mechanics, such as lung compliance and airway resistance, that determine the relationship between pulmonary pressure changes and air flow into and out of the lungs. Continued development has resulted in models that use nonsurgical plethysmographic techniques. These allow the long-term or repeated measurement of lung function in conscious animals under minimal restraint. In the treatment of asthma, inhalation is the preferred route of administration of a drug as it allows rapid drug delivery to the site of action. Systemic effects are reduced, and the therapeutic dose is minimized. Drugs are generally inhaled as either nebulized liquids or dry-powder formulations. Because drug inhalation requires patient cooperation, techniques have been modified to allow drug delivery to the airways of experimental animals.(ABSTRACT TRUNCATED AT 400 WORDS)     

In Vitro Considerations to Support Bioequivalence of Locally Acting Drugs in Dry Powder Inhalers for Lung Diseases

Dry powder inhalers (DPIs) are used to deliver locally acting drugs (e.g., bronchodilators and corticosteroids) for treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Demonstrating bioequivalence (BE) for DPI products is challenging, primarily due to an incomplete understanding of the relevance of drug concentrations in blood or plasma to equivalence in drug delivery to the local site(s) of action. Thus, BE of these drug/device combination products is established based on an aggregate weight of evidence, which utilizes in vitro studies to demonstrate equivalence of in vitro performance, pharmacokinetic or pharmacodynamic studies to demonstrate equivalence of systemic exposure, and pharmacodynamic and clinical endpoint studies to demonstrate equivalence in local action. This review discusses key aspects of in vitro studies in supporting the establishment of BE for generic locally acting DPI products. These aspects include comparability in device resistance and equivalence in in vitro testing for single inhalation (actuation) content and aerodynamic particle size distribution.     

Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) for pulmonary application: A review of the state of the art

Drug delivery by inhalation is a noninvasive means of administration that has following advantages for local treatment for airway diseases: reaching the epithelium directly, circumventing first pass metabolism and avoiding systemic toxicity. Moreover, from the physiological point of view, the lung provides advantages for systemic delivery of drugs including its large surface area, a thin alveolar epithelium and extensive vasculature which allow rapid and effective drug absorption. Therefore, pulmonary application is considered frequently for both, the local and the systemic delivery of drugs. Lipid nanoparticles – Solid Lipid Nanoparticles and Nanostructured Lipid Carriers – are nanosized carrier systems in which solid particles consisting of a lipid matrix are stabilized by surfactants in an aqueous phase. Advantages of lipid nanoparticles for the pulmonary application are the possibility of a deep lung deposition as they can be incorporated into respirables carriers due to their small size, prolonged release and low toxicity. This paper will give an overview of the existing literature about lipid nanoparticles for pulmonary application. Moreover, it will provide the reader with some background information for pulmonary drug delivery, i.e., anatomy and physiology of the respiratory system, formulation requirements, application forms, clearance from the lung, pharmacological benefits and nanotoxicity.     

Single-use disposable dry powder inhalers for pulmonary drug delivery

Importance of the field: The understanding of pulmonary drug delivery and thus its utilization for medical purposes has remarkably advanced over the last decades. It has been recognized that this route of administration offers many advantages and several drug delivery systems have been developed accordingly. Thereby, single-use disposable dry powder inhalers may be considered an economically and therapeutically valuable option for both local and systemic administration of drugs to treat a variety of different disease states.

Areas covered in this review/What the reader will gain: This review highlights the required characteristics and potential applications of single-use disposable dry powder inhalers considering advantages as well as limitations of these drug delivery devices. Until now, such drug delivery systems have not become widely accepted. Several devices are available or under development and a few products have reached or completed the clinical phase, but none of them have received market authorization as yet.

Take home message: Recent advances in formulation and device design, however, can be considered encouraging and should eventually lead to a wider establishment of single-use disposable dry powder inhalers in pulmonary drug delivery.     

Inhalation of nanoparticle-based drug for lung cancer treatment: Advantages and challenges

Ever since the success of developing inhalable insulin, drug delivery via pulmonary administration has become an attractive route to treat chronic diseases. Pulmonary delivery system for nanotechnology is a relatively new concept especially when applicable to lung cancer therapy. Nano-based systems such as liposome, polymeric nanoparticles or micelles are strategically designed to enhance the therapeutic index of anti-cancer drugs through improvement of their bioavailability, stability and residency at targeted lung regions. Along with these benefits, nano-based systems also provide additional diagnostic advantages during lung cancer treatment, including imaging, screening and drug tracking. Nevertheless, delivery of nano-based drugs via pulmonary administration for lung cancer therapy is still in its infancy and numerous challenges are expected. Pharmacology, immunology, toxicology and large-scale manufacturing (stability and activity of drugs) are some aspects in nanotechnology that should be taken into consideration for the development of inhalable nano-based chemotherapeutic drugs. This review will focus on the current inhalable nano-based drugs for lung cancer treatment.     

Formulation aspects and ex-vivo examination of buccal drug delivery systems

Application of buccal dosage forms has several advantages. Buccal route can be used for systemic delivery because the mucosa has a rich blood supply and it is relatively permeable. This route of drug delivery is of special advantages, including the bypass of first pass effect and the avoidance of presystemic elimination within the GIT. Buccal delivery systems enable the systemic delivery of peptides and proteins. In our previous study the physiological background of this application and the excipients of the possible formulations were reviewed. In the present work the formulation and ex vivo examination aspects of buccal drug delivery systems are summarized.     

Pharmaceutical Development and Technology (PDT) announcements

Abstract

The treatment of lung diseases including lung cancer and tuberculosis is one of the most challenging problems in clinical practice, because the conventional drug delivery systems cannot deliver drug effectively to the lung, which result in low therapeutic effect. Therefore, lung-targeted drug delivery systems (LTDDS) that can deliver drug to the lung in an effective way to increase drug concentration in lung tissue and reduce drug distribution in other organs and tissues become an ideal strategy to treat lung diseases. The LTDDS mainly include microparticles (microspheres and microencapsules), liposomes and nanoparticles via intravenous administration, and dry powder carriers and nebulized suspensions via pulmonary inhalation. As lungs possess the large absorptive surface area, the low thickness of the epithelial barrier and good blood supply, pulmonary inhalation has received great attention. Intravenous route is the commonly practiced method for administration of larger doses of drugs into the body. Numerous drugs can be delivered directly into general circulation by avoiding their first-pass metabolism and have potential to transport drugs to the lung via intravenous administration. This present article reviews the development, evaluation and application of LTDDS via intravenous administration for the treatment of lung diseases reported in the past decades.     

Polymer-drug conjugates: recent progress on administration routes

Introduction: Polymer-drug conjugates are an important part of polymer therapeutics. Recently, they have been used as an appealing platform for drug delivery. As a delivery vector, the route of administration performs a serious impact on the accessibility of drug molecules to their respective target site and therapeutic index. Furthermore, the physicochemical and biological properties of conjugates also correlate distinctly with the route of administration.

Areas covered: This article reviews the recent advances of polymer-drug conjugates as drug delivery systems through parenteral, enteral and topical routes. In particular, it mainly focuses on the classical and emerging routes such as injection, oral, transdermal, pulmonary and ocular routes using polymer-drug conjugates as delivery systems.

Expert opinion: Although polymer-conjugated drug delivery systems reported so far face severe shortcoming of being incomplete methodology and limited routes for administration (mostly concentrated in injection), some polymer carriers like poly(amidoamine) and hyaluronic acid still offer an appealing platform to deliver drug. Acquiring the particular characteristics of each polymer carrier, exploiting novel biodegradable polymer, expanding classical drug administration ways by emerging routes and developing a rational and systematic methodology to design administration routes will be the promising directions.     

RETRACTED: Pulmonary route of administration is instrumental in developing therapeutic interventions against respiratory diseases

Pulmonary route of drug delivery has drawn significant attention due to the limitations associated with conventional routes and available treatment options. Drugs administered through pulmonary route has been an important research area that focuses on to developing effective therapeutic interventions for asthma, chronic obstructive pulmonary disease, tuberculosis, lung cancer etc. The intravenous route has been a natural route of delivery of proteins and peptides but associated with several issues including high cost, needle-phobia, pain, sterility issues etc. These issues might be addressed by the pulmonary administration of macromolecules to achieving an effective delivery and efficacious therapeutic impact. Efforts have been made to develop novel drug delivery systems (NDDS) such as nanoparticles, microparticles, liposomes and their engineered versions, polymerosomes, micelles etc to achieving targeted and sustained delivery of drug(s) through pulmonary route. Further, novel approaches such as polymer-drug conjugates, mucoadhesive particles and mucus penetrating particles have attracted significant attention due to their unique features for an effective delivery of drugs. Also, use of semi flourinated alkanes is in use for improvising the pulmonary delivery of lipophilic drugs. Present review focuses on to unravel the mechanism of pulmonary absorption of drugs for major pulmonary diseases. It summarizes the development of interventional approaches using various particulate and vesicular drug delivery systems. In essence, the orchestrated attempt presents an inflammatory narrative on the advancements in the field of pulmonary drug delivery.     

A review of the technical aspects of drug nebulization

Nebulizers are widely used for the inhalation of drug solutions in a variety of respiratory diseases. The efficacy of nebulizer therapy is influenced by a great number of factors, including the design of the device and the characteristics of the drug solution. Incorrect cleaning, maintenance and disinfection procedures may change the nebulizer performance in time, whereas patient factors can influence the lung deposition of the generated aerosol. In this review the technical aspects of nebulization of drug solutions will be discussed. Two main parameters are generally used to evaluate the performance of nebulizers: the droplet size distribution of the aerosol and the drug output rate. The droplet size distribution and the drug output rate are basically determined by the design and user conditions of the nebulizer. A higher gas flow of the compressor in a jet nebulizer or a higher vibration frequency of the piezo electric crystal in an ultrasonic nebulizer, decreases the droplet size. The choice of the type of nebulizer for nebulization of a certain drug solution may initially be based on laboratory evaluation. The major part of the mass or volume distribution should preferably correspond with aerodynamic particle diameters in the range of 1 to 5 micrometer. The intended drug output must be realized within a reasonable nebulization time (less than 30 min). From the drug output only a minor fraction will be deposited in the lung. The relation between in vitro and in vivo deposition is only partly understood and to date it has not been possible to predict drug delivery only from in vitro studies on nebulizers. Therefore, studies in patients should be performed before a drug solution for nebulization can be recommended for clinical practice. The mechanical properties of nebulizers are likely to change during use. An average utilization time of nebulizers is not available. Therefore, the performance of nebulizers should be checked periodically. Patient compliance in nebulizer therapy is relatively low. This is partly due to the fact that, at present, drug solutions for nebulizers cannot be administered efficiently within a short period of time. More efficient systems should be developed. If possible, nebulizers should be substituted to more efficient systems, e.g. dry powder inhalers or metered dose inhalers.     

Molecular buckets: cyclodextrins for oral cancer therapy

The oral route is preferred by patients for drug administration due to its convenience, resulting in improved compliance. Unfortunately, for a number of drugs (e.g., anticancer drugs), this route of administration remains a challenge. Oral chemotherapy may be an attractive option and especially appropriate for chronic treatment of cancer. However, this route of administration is particularly complicated for the administration of anticancer drugs ascribed to Class IV of the Biopharmaceutical Classification System. This group of compounds is characterized by low aqueous solubility and low intestinal permeability. This review focuses on the use of cyclodextrins alone or in combination with bioadhesive nanoparticles for oral delivery of drugs. The state-of-the-art technology and challenges in this area is also discussed.     

Novolizer: how does it fit into inhalation therapy?

Inhalation therapy is the preferred route of administration of anti-asthmatic drugs to the lungs. However, the vast majority of patients cannot use their inhalers correctly, particularly pressurised metered dose inhalers (pMDIs). The actual proportion of patients who do not use their inhalers correctly may even be under-estimated as GPs tend to over-estimate correct inhalation technique. Dry powder inhalers (DPIs) have many advantages over pMDIs. Unlike pMDIs, they are environmentally-friendly, contain no propellant gases and, more importantly, they are breath-activated, so that the patient does not need to coordinate actuation of the inhaler with inspiration. Three key parameters for correct inhaler use should be considered when evaluating existing or future DPI devices and especially when choosing the appropriate device for the patient: (1) usability, (2) particle size distribution of the emitted drug and (3) intrinsic airflow resistance of the device. The Novolizer is a breath-activated, multidose, refillable DPI. It is easy to use correctly, has multiple feedback and control mechanisms which guide the patient through the correct inhalation manoeuvre. In addition, the Novolizer has an intelligent dose counter, which resets only after a correct inhalation and may help to monitor patient compliance. The Novolizer has a comparable or better lung deposition than the Turbuhaler at similar or higher peak inspiratory flow (PIF) rates. A flow trigger valve system ensures a clinically effective fine particle fraction (FPF) and sufficient drug delivery, which is important for a good lung deposition. The FPF produced through the Novolizer is also relatively independent of flow rate and the device shows better reproducibility of metering and delivery performance compared to the Turbuhaler. The low-to-medium airflow resistance means that the Novolizer is easy for patients to use correctly. Even children, patients with severe asthma and patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) have no problems to generate the trigger inspiratory flow rate required to activate the Novolizer. The Novolizer uses an advanced DPI technology and may improve patient compliance.