Dry powder inhalation: past,present and future

Introduction: Early dry powder inhalers (DPIs) were designed for low drug doses in asthma and COPD therapy. Nearly all concepts contained carrier-based formulations and lacked efficient dispersion principles. Therefore, particle engineering and powder processing are increasingly applied to achieve acceptable lung deposition with these poorly designed inhalers.

Areas covered: The consequences of the choices made for early DPI development with respect of efficacy, production costs and safety and the tremendous amount of energy put into understanding and controlling the dispersion performance of adhesive mixtures are discussed. Also newly developed particle manufacturing and powder formulation processes are presented as well as the challenges, objectives, and new tools available for future DPI design.

Expert opinion: Improved inhaler design is desired to make DPIs for future applications cost-effective and safe. With an increasing interest in high dose drug delivery, vaccination and systemic delivery via the lungs, innovative formulation technologies alone may not be sufficient. Safety is served by increasing patient adherence to the therapy, minimizing the use of unnecessary excipients and designing simple and self-intuitive inhalers, which give good feedback to the patient about the inhalation maneuver. For some applications, like vaccination and delivery of hygroscopic formulations, disposable inhalers may be preferred.     

Low density,good flowability cyclodextrin-raffinose binary carrier for dry powder inhaler: anti-hygroscopicity and aerosolization performance enhancement

Background: The hygroscopicity of raffinose carrier for dry powder inhaler (DPI) was the main obstacle for its further application. Hygroscopicity-induced agglomeration would cause deterioration of aerosolization performance of raffinose, undermining the delivery efficiency.

Methods: Cyclodextrin-raffinose binary carriers (CRBCs) were produced by spray-drying so as to surmount the above issue. Physicochemical attributes and formation mechanism of CRBCs were explored in detail. The flow property of CRBCs was examined by FT4 Powder Rheometer. Hygroscopicity of CRBCs was elucidated by dynamic vapor sorption study. Aerosolization performance was evaluated by in vitro deposition profile and in vivo pharmacokinetic profile of CRBC based DPI formulations.

Results: The optimal formulation of CRBC (R₄) was proven to possess anti-hygroscopicity and aerosolization performance enhancement properties. Concisely, the moisture uptake of R₄ was c.a. 5% which was far lower than spray-dried raffinose (R₀, c.a. 65%). R₄ exhibited a high fine particle fraction value of 70.56 ± 0.61% and it was 3.75-fold against R₀. The pulmonary and plasmatic bioavailability of R₄ were significantly higher than R₀ (p < 0.05).

Conclusion: CRBC with anti-hygroscopicity and aerosolization performance enhancement properties was a promising approach for pulmonary drug delivery, which could provide new possibilities to the application of hygroscopic carriers for DPI.     

In vitro evaluation of aerosol delivery of aztreonam lysine (AZLI): an adult mechanical ventilation model

Background: The delivery profile of Aztreonam lysine (AZLI) during mechanical ventilation (MV) is unknown. We evaluated the amount of AZLI drug delivered using an in vitro model of adult MV.

Methods: An adult lung model designed to mimic current clinical practice was used. Both nebulizers were placed before a Y-piece and 4 settings were tested: A) Aeroneb solo® [AS] with a t-piece; B) AS with the spacer; C) M-Neb® [MN] with a t-piece and D) MN with the spacer. Performance was evaluated in terms of: 1) Mass median aerodynamic diameter (MMAD); 2) Geometric standard deviation (GSD), 3) Fine particle dose (FPD), 4) Fine particle fraction (FPF), 5) Inhalable mass (IM), and 6) Recovery rate (RR).

Results: Both devices showed an adequate delivery of AZLI during MV, with MMAD between 2.4–2.5 µm and 87% of FPF. The FPD (38.8 and 31.7), IM (44.8 and 36.1) and RR (30 and 24) were similar for AS and MN respectively. Nebulizer aerosol delivery increased (50 and 70% respectively) for both nebulizers when using the spacer.

Conclusion: Both AS and MN showed a good aerosol delivery profile for AZLI during in vitro mechanical ventilation. Better aerosol delivery performance was obtained using the spacer.     

Microneedle-mediated delivery of viral vectored vaccines

Introduction: Microneedle array platforms are a promising technology for vaccine delivery, due to their ease of administration with no sharp waste generated, small size, possibility of targeted delivery to the specified skin depth and efficacious delivery of different vaccine formulations, including viral vectors.

Areas covered: Attributes and challenges of the most promising viral vector candidates that have advanced to the clinic and that have been leveraged for skin delivery by microneedles; The importance of understanding the immunobiology of antigen-presenting cells in the skin, in particular dendritic cells, in order to generate further improved skin vaccination strategies; recent studies where viral vectors expressing various antigens have been coupled with microneedle technology to examine their potential for improved vaccination.

Expert opinion: Simple, economic and efficacious vaccine delivery methods are needed to improve health outcomes and manage possible outbreaks of new emerging viruses. Understanding what innate/inflammatory signals are required to induce both immediate and long-term responses remains a major hurdle in the development of the effective vaccines. One approach to meet these needs is microneedle-mediated viral vector vaccination. In order for this technology to fulfil this potential the industry must invest significantly to further develop its design, production, biosafety, delivery and large-scale manufacturing.     

Future prospects for gene delivery systems

Introduction: Gene therapy is the challenging area of biotechnology. Despite its promise for critical diseases, it has serious safety and efficiency issues, particularly with regards to gene transfer systems.

Areas covered: We examined the current situation with gene transfer systems and addressed problems this technology. We then searched patent applications about in the area from the Patentscope online system, the international patent database. We analyzed the data obtained to get a general idea about gene delivery systems designed for future use and assessed approaches for more efficient, safer and valid delivery systems.

Expert opinion: When quality assurance terms are fulfilled, some of these issues (genetic changes, mutations) could be minimized during the production process. Modification of vectors for improving their efficiency and safety or development of alternative transfer systems could be the solutions for these problems. Gene transfer technologies are important for gene therapy and should demonstrate effective, target-specific and acceptable safety profiles. For this reason, searching for alternatives to current systems is a necessity.     

From nanoemulsions to self-nanoemulsions,with recent advances in self-nanoemulsifying drug delivery systems (SNEDDS)

Introduction: Lipid-based drug delivery systems (LBDDS) are the most promising technique to formulate the poorly water soluble drugs. Nanotechnology strongly influences the therapeutic performance of hydrophobic drugs and has become an essential approach in drug delivery research. Self-nanoemulsifying drug delivery systems (SNEDDS) are a vital strategy that combines benefits of LBDDS and nanotechnology. SNEDDS are now preferred to improve the formulation of drugs with poor aqueous solubility.

Areas covered: The review in its first part shortly describes the LBDDS, nanoemulsions and clarifies the ambiguity between nanoemulsions and microemulsions. In the second part, the review discusses SNEDDS and elaborates on the current developments and modifications in this area without discussing their associated preparation techniques and excipient properties.

Expert opinion: SNEDDS have exhibit the potential to increase the bioavailability of poorly water soluble drugs. The stability of SNEDDS is further increased by solidification. Controlled release and supersaturation can be achieved, and are associated with increased patient compliance and improved drug loads, respectively. Presence of biodegradable ingredients and ease of large-scale manufacturing combined with a lot of ‘drug-targeting opportunities’ give SNEDDS a clear distinction and prominence over other solubility enhancement techniques.     

Carriers for the targeted delivery of aerosolized macromolecules for pulmonary pathologies

Introduction: Macromolecules with unique effects and potency are increasingly being considered for application in lung pathologies. Numerous delivery strategies for these macromolecules through the lung have been investigated to improve the targeting and overall efficacy.

Areas covered: Targeting approaches from delivery devices, formulation strategies and specific targets are discussed.

Expert opinion: Although macromolecules are a heterogeneous group of molecules, a number of strategies have been investigated at the macro, micro, and nanoscopic scale for the delivery of macromolecules to specific sites and cells of lung tissues. Targeted approaches are already in use at the macroscopic scale through inhalation devices and formulations, but targeting strategies at the micro and nanoscopic scale are still in the laboratory stage. The combination of controlling lung deposition and targeting after deposition, through a combination of targeting strategies could be the future direction for the treatment of lung pathologies through the pulmonary route.     

Use of computational fluid dynamics deposition modeling in respiratory drug delivery

Introduction: Respiratory drug delivery is a surprisingly complex process with a number of physical and biological challenges. Computational fluid dynamics (CFD) is a scientific simulation technique that is capable of providing spatially and temporally resolved predictions of many aspects related to respiratory drug delivery from initial aerosol formation through respiratory cellular drug absorption.

Areas covered: This review article focuses on CFD-based deposition modeling applied to pharmaceutical aerosols. Areas covered include the development of new complete-airway CFD deposition models and the application of these models to develop a next-generation of respiratory drug delivery strategies.

Expert opinion: Complete-airway deposition modeling is a valuable research tool that can improve our understanding of pharmaceutical aerosol delivery and is already supporting medical hypotheses, such as the expected under-treatment of the small airways in asthma. These complete-airway models are also being used to advance next-generation aerosol delivery strategies, like controlled condensational growth. We envision future applications of CFD deposition modeling to reduce the need for human subject testing in developing new devices and formulations, to help establish bioequivalence for the accelerated approval of generic inhalers, and to provide valuable new insights related to drug dissolution and clearance leading to microdosimetry maps of drug absorption.     

DNA/RNA-based formulations for treatment of breast cancer

Introduction: To develop a successful formulation for the gene therapy of breast cancer, an effective therapeutic nucleic acid and a proper delivery system are essential. Increased understanding of breast cancer, and developments in biotechnology, material science and nanotechnology have provided a major impetus in the development of effective formulations for the gene therapy of breast cancer.

Areas covered: We discuss DNA/RNA-based formulations that can inhibit the growth of breast cancer cells and control the progress of breast cancer. Targets for the gene therapy of breast cancer, DNA/RNA-based therapeutics and delivery systems are summarized. And examples of successful DNA/RNA-based formulations for breast cancer gene therapy are reviewed.

Expert opinion: Several challenges remain in developing effective DNA/RNA-based formulations for treatment of breast cancer. Firstly, most of the currently utilized targets are not effective enough as monotherapy for breast cancer. Secondly, the requirements for co-delivery system make the preparation of formulation more complicated. Thirdly, nanoparticles with the modification of tumor-targeting ligands could be more unstable in circulation and normal tissues. Lastly, immune responses against the viral vectors are unfavorable for the gene therapy of breast cancer because of the damage to the host and the impaired therapeutic ability.     

The size and behavior of the human upper airway during inhalation of aerosols

Introduction: The mouth, the pharynx and the larynx are potential sites of aerosol deposition in the upper airway during inhalation of aerosolized drugs. The right angle bend of the lumen at the back of the mouth, the position of the tongue, the variable size and shape of the lumen in the pharynx and the larynx, and the breathing pattern could increase aerosol deposition in the upper airway and decrease lung deposition.

Areas covered: In this review, the anatomy of the upper airway from the oral cavity to the glottis and the impact of mandibular protrusion and incisal opening on the size of the upper airway are highlighted. In addition, the impact of inhalation maneuvers, inhaler mouthpiece geometries and a stepped mouthpiece on the size of the upper airway are discussed.

Expert opinion: The structure of the upper airway lumen does not have a fixed cross sectional area and is susceptible to both constriction and distension during inhalation. The size of the upper airway can be enlarged through mandibular protrusion and/or incisal opening which might decrease aerosol deposition in the upper airway and increase lung deposition.     

Solid lipid nanocarriers in drug delivery: characterization and design

Introduction: Solid lipid nanoparticles are promising drug carriers for systemic circulations as well as local applications. One of the major challenges for drug delivery is designing nanocarriers for efficient delivery of active substances to the target site and facilitating drug absorption.

Areas covered: In this article, the effects of excipients and particle preparation methods on the properties of solid lipid nanocarriers (SLNCs) and their impact on drug absorption and efficacies related to different administration routes are reviewed and discussed.

Expert opinion: SLNCs have special characteristics, making them attractive as drug delivery systems, for parenteral and oral delivery for systemic effects, or ocular, pulmonary and topical delivery to enhance local treatment efficacy and reducing systemic side effects. Both excipients and fabrication methods are crucial for the function and size of nanoparticles and should be considered simultaneously in designing particles to obtain the optimal drug absorption and efficacy, especially for local treatments. Despite the demonstrated advantages by the preclinical studies, further studies on improved understanding of the interactions of SLNCs with biological tissues of the target site is necessary for efficient designing functional nanoparticles for clinical applications.

Abbreviations: DG: diglycerides; FFA: free fatty acids; GMS: glyceryl monostearate; MG: monoglycerides; NLC: nanostructured lipid carriers; PL: phospholipids; SLM: solid lipid microparticles; SLN: solid lipid nanoparticles; SLNC: solid lipid nanocarriers; TG: triglycerides.     

Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders

Background: The in-situ gelation of thermosensitive nasal formulations with desirable spray characteristics at room temperature and ability to undergo a phase change to a semi-solid state with mucoadhesive behavior at physiological temperature has the potential to efficiently deliver therapeutics to brain. However, their application in nasal spray generation with favorable characteristics has not been investigated.

Methods: Thermosensitive chitosan (CS)-based formulations with different viscosities were prepared for intranasal delivery of ibuprofen using CS of various molecular weights. The formulation developed was optimized with regards to its physicochemical, rheological, biological properties and the generated aerosol characteristics.

Results: The formulations showed rapid gelation (4–7 min) at 30–35°C, which lies in the human nasal cavity temperature spectrum. The decrease in CS molecular weight to 110–150 kDa led to generation of optimum spray with lower Dv₅₀, wider spray area, and higher surface area coverage. This formulation also showed improved ibuprofen solubility that is approximately 100× higher than its intrinsic aqueous solubility, accelerated ibuprofen transport across human nasal epithelial cells and transient modulation of tight junctions.

Conclusions: A thermosensitive CS-based formulation has been successfully developed with suitable rheological properties, aerosol performance and biological properties that is beneficial for nose-to-brain drug delivery.     

Recent advance of nanoparticle-based topical drug delivery to the posterior segment of the eye

Introduction: Considering that the number of patients afflicted by posterior eye diseases is increasing, effective drug delivery is currently in high clinical demand. Topical administration has been identified as the preferred option, while sufferingfrom multiple barriers. The development of nanoparticle-based drug delivery system provides an option, which would enhance the drug permeability across the barriers and achieve the desired drug level in the targeted tissue.

Areas covered: This review highlights the barrier to the posterior segment of the eye via topical administration. The up-to-date development of lipid nanoparticles, liposomes, emulsions, spanlastics, micelles, polymeric nanoparticles, layered double hydroxides (LDH), dendrimers, cyclodextrins(CDs), and prodrugs are summarized. Moreover, nanocarriers currently in clinical trials for posterior segment diseases have been discussed.

Expert opinion: Topical nanoparticle-based drug delivery systems have demonstrated significant progress. An ideal formulation should prolong retention time on the surface, enhance drug permeability through the ocular tissues, and efficiently deliver drugs to the targeted site. To design the rational targeting nanoparticle-based drug delivery system, a better understanding of the distribution of transporters and receptors on the eye is required. Ultimately, there is an urgent need to develop targeting hybrid drug delivery systems with the combination of the advantages of several nanocarriers.     

Nanocrystal: a novel approach to overcome skin barriers for improved topical drug delivery

Introduction: Skin is an important route of drug delivery for the treatment of various dermatological conditions. The advent of nanotechnology is paving the roadmaps for topical drug delivery by providing sustained release as well as maintaining a localized effect, outweighing the toxicity concern.

Area covered: This review highlighted the morphology of skin, its barrier nature as well as drug penetration pathways after topical application of formulations. The existing methods to improve topical drug delivery, by infringing or permeating the skin barriers, are discussed. This context concretes the foundation to accentuate the need for the development of nanocrystal-based topical formulation. The mechanism of drug release, immediate as well as sustained release, after topical administration of drug nanocrystals is also elaborated. The special emphasis is given on the breakthrough achieved, in topical drug delivery using drug nanocrystals, so far in the plethora of literature, patents, and products, under clinical trial as well as in the market.

Expert opinion: The current research on nanocrystals for topical drug delivery is highlighting the breakthroughs achieved so far. The output of these research envisages that topical nanocrystals based formulations can be a novel strategy for the drugs which are facing solubility, bioavailability and toxicity concerns.     

Recent advances in oral delivery of biologics: nanomedicine and physical modes of delivery

Introduction: Research into oral delivery of biologics has a long and rich history but has not produced technologies used in the clinic. The area has evolved in terms of strategies to promote oral biologics delivery from early chemical absorption enhancers to nanomedicine to devices. Continued activity in this area is justifiable considering the remarkable proliferation of biologics.

Areas covered: The article discusses some physiological barriers to oral delivery of biologics, with a special focus on less characterized barriers such as the basement membrane. Recent progress in oral delivery of biologics via nanomedicine is subsequently covered. Finally, the emerging field of device-mediated gastrointestinal delivery of biotherapeutics is discussed.

Expert opinion: Oral delivery of biologics is considered a ‘panacea’ in drug delivery. Almost century-old approaches of utilizing chemical absorption enhancers have not produced clinically translated technologies. Nanomedicine for oral biologics delivery has demonstrated potential, but the field is relatively new, and technologies have not progressed to the clinic. Device-mediated oral biologics delivery (e.g. ultrasound or microneedles) is in its infancy. However, this space is likely to intensify owing to advances in electronics and materials, as well as the challenges and history related to clinical translation of alternative approaches.     

Microneedle arrays for vaccine delivery: the possibilities,challenges and use of nanoparticles as a combinatorial approach for enhanced vaccine immunogenicity

Introduction: Vaccination is one of the greatest breakthroughs of modern preventative medicine. Despite this, there remain problems surrounding delivery, efficacy and compliance. Thus, there is a pressing need to develop cost-effective vaccine delivery systems that could expand the use of vaccines, particularly within developing countries. Microneedle (MN) arrays, given their ease of use, painlessness and ability to target skin antigen presenting cells, provide an attractive platform for improved vaccine delivery and efficacy. Studies have demonstrated enhanced immunogenicity with the use of MN in comparison to conventional needle. More recently, dissolving MN have been used for efficient delivery of nanoparticles (NP), as a means to enhance antigen immunogenicity.

Areas covered: This review introduces the fields of MN technology and nanotechnology, highlighting the recent advances which have been made with these two technologies combined for enhanced vaccine delivery and efficacy. Some key questions that remain to be addressed for adoption of MN in a clinical setting are also evaluated.

Expert opinion: MN-mediated vaccine delivery holds potential for expanding access to vaccines, with individuals in developing countries likely to be the principal beneficiaries. The combinatorial approach of utilizing MN coupled with NP, provides opportunities to enhance the immunogenicity of vaccine antigens.     

Minimally invasive microneedles for ocular drug delivery

Introduction: Anterior and posterior segment eye diseases are highly challenging to treat, due to the barrier properties and relative inaccessibility of the ocular tissues. Topical eye drops and systemically delivered treatments result in low bioavailability. Alternatively, direct injection of medication into the ocular tissues is clinically employed to overcome the barrier properties, but injections cause significant tissue damage and are associated with a number of untoward side effects and poor patient compliance. Microneedles (MNs) has been recently introduced as a minimally invasive means for localizing drug formulation within the target ocular tissues with greater precision and accuracy than the hypodermic needles.

Areas covered: This review article seeks to provide an overview of a range of challenges that are often faced to achieve efficient ocular drug levels within targeted tissue(s) of the eye. It also describes the problems encountered using conventional hypodermic needle-based ocular injections for anterior and posterior segment drug delivery. It discusses research carried out in the field of MNs, to date.

Expert opinion: MNs can aid in localization of drug delivery systems within the selected ocular tissue. And, hold the potential to revolutionize the way drug formulations are administered to the eye. However, the current limitations and challenges of MNs application warrant further research in this field to enable its widespread clinical application.     

Oromucosal multilayer films for tailor-made,controlled drug delivery

Introduction: The oral mucosa has recently become increasingly important as an alternative administration route for tailor-made, controlled drug delivery. Oromucosal multilayer films, assigned to the monograph oromucosal preparations in the Ph.Eur. may be a promising dosage form to overcome the requirements related to this drug delivery site.

Areas covered: We provide an overview of multilayer films as drug delivery tools, and discuss manufacturing processes and characterization methods. We focus on the suitability of characterization methods for particular requirements of multilayer films. A classification was performed covering indication areas and APIs incorporated in multilayer film systems for oromucosal use in order to provide a summary of data published in this field.

Expert opinion: The shift in drug development to high molecular weight drugs will influence the field of pharmaceutical development and delivery technologies. For a high number of indication areas, such as hormonal disorders, cardiovascular diseases or local treatment of infections, the flexible layer design of oromucosal multilayer films provides a promising option for tailor-made, controlled delivery of APIs to or through defined surfaces in the oral cavity. However, there is a lack of discriminating or standardized testing methods to assess the quality of multilayer films in a reliable way.     

Emerging advances in P-glycoprotein inhibitory nanomaterials for drug delivery

Introduction: P-glycoprotein 1 (P-gp) pumps out many foreign/toxic substances out of the cells, including intracellular drugs, causing multidrug resistance (MDR) and chemotherapy failure. It remains quite a challenge to inhibit P-gp to combat MDR and improve cellular bioavailability since it requires efficient inhibitors along with adequate formulation strategy. Lately, nanocarriers are gaining much attention and form an attractive platform for delivering drugs into cells. Therefore, nanomaterials act as direct inhibitors of P-gp will be an attractive alternative to overcome MDR.

Area covered: This paper reviews the most recent advances on those nanomaterials that are currently in the developmental stage and has proven useful to treat P-gp involved MDR. Also, we emphasize those emerging multifunctional nanomaterials that can construct ‘smart’ carriers for both tumor targeting and P-gp inhibition. Furthermore, the mechanisms behind P-gp inhibition and the nanoformulation strategies for drug delivery are also discussed.

Expert opinion: In light of these updated reports, this review here seeks to suggest an alternative for the chemoresistant cases, and also bring about new thoughts on tackling P-gp concerned drug delivery issues. New advances in nanomaterials with P-gp inhibition are expected to broaden nanopharmaceutics and traditional chemotherapy applications in the coming years.     

Calcium silicate-based drug delivery systems

Introduction: Compared with other inorganic materials such as silica, metal oxides, noble metals and carbon, calcium silicate-based materials, especially nanostructured calcium silicate materials, have high biocompatibility, bioactivity and biodegradability, high specific surface area, nanoporous/hollow structure, high drug-loading capacity, pH-responsive drug release behavior and desirable drug release properties, and thus they are promising for the application in drug delivery. Calcium silicate-based drug delivery systems have a long drug-release time, which can significantly prolong the therapeutic effect of drugs. Another advantage of calcium silicate-based drug delivery systems is their pH-responsive drug release property, which can act as an ideal platform for targeted drug delivery.

Areas covered: In recent years, studies have been carried out on calcium silicate-based drug delivery systems, and important results and insights have been documented. This article is not intended to offer a comprehensive review on the research on calcium silicate-based drug delivery systems, but presents some examples reported in the literature, and includes new insights obtained by tracking the interactions between drug molecules and calcium silicate carriers on the molecular level using the synchrotron-based X-ray spectroscopy.

Expert opinion: Finally, our opinions on calcium silicate-based drug delivery systems are provided, and several research directions for the future studies are proposed.