New therapeutic agents such as proteins, peptides, and nucleic acid-based agents are being developed every year, making it vital to find a non-invasive route such as nasal or pulmonary for their administration. However, a major concern for some of these newly developed therapeutic agents is their poor absorption. Therefore, absorption enhancers have been investigated to address this major administration problem. This paper describes the basic concepts of transmucosal administration of drugs, and in particular the use of the pulmonary or nasal routes for administration of drugs with poor absorption. Strategies for the exploitation of absorption enhancers for the improvement of pulmonary or nasal administration are discussed, including use of surfactants, cyclodextrins, protease inhibitors, and tight junction modulators, as well as application of carriers such as liposomes and nanoparticles.

https://www.mdpi.com/1999-4923/11/3/113/pdf

Strategies to Enhance Drug Absorption via Nasal and Pulmonary Routes

In the last decade, biological drugs have rapidly proliferated and have now become an important therapeutic modality. This is because of their high potency, high specificity and desirable safety profile. The majority of biological drugs are peptide- and protein-based therapeutics with poor oral bioavailability. They are normally administered by parenteral injection (with a very few exceptions). Pulmonary delivery is an attractive non-invasive alternative route of administration for local and systemic delivery of biologics with immense potential to treat various diseases, including diabetes, cystic fibrosis, respiratory viral infection and asthma, etc. The massive surface area and extensive vascularisation in the lungs enable rapid absorption and fast onset of action. Despite the benefits of pulmonary delivery, development of inhalable biological drug is a challenging task. There are various anatomical, physiological and immunological barriers that affect the therapeutic efficacy of inhaled formulations. This review assesses the characteristics of biological drugs and the barriers to pulmonary drug delivery. The main challenges in the formulation and inhalation devices are discussed, together with the possible strategies that can be applied to address these challenges. Current clinical developments in inhaled biological drugs for both local and systemic applications are also discussed to provide an insight for further research.

https://www.mdpi.com/1999-4923/12/11/1025/pdf

Pulmonary Delivery of Biological Drugs.

Biologic products are large molecules such as proteins, peptides, nucleic acids, etc., which have already produced many new drugs for clinical use in the last decades. Due to the inherent challenges faced by biologics after oral administration (e.g., acidic stomach pH, digestive enzymes, and limited permeation through the gastrointestinal tract), several alternative routes of administration have been investigated to enable sufficient drug absorption into systemic circulation. This review describes the buccal, sublingual, pulmonary, and transdermal routes of administration for biologics with relevant details of the respective barriers. While all these routes avoid transit through the gastrointestinal tract, each has its own strengths and weaknesses that may be optimal for specific classes of compounds. Buccal and sublingual delivery enable rapid drug uptake through a relatively permeable barrier but are limited by small epithelial surface area, stratified epithelia, and the practical complexities of maintaining a drug delivery system in the mouth. Pulmonary delivery accesses the highly permeable and large surface area of the alveolar epithelium but must overcome the complexities of safe and effective delivery to the alveoli deep in the lung. Transdermal delivery offers convenient access to the body for extended-release delivery via the skin surface but requires the use of novel devices and formulations to overcome the skin’s formidable stratum corneum barrier. New technologies and strategies advanced to overcome these challenges are reviewed, and critical views in future developments of each route are given.

Challenges and Future Prospects for the Delivery of Biologics: Oral Mucosal, Pulmonary, and Transdermal Routes.

Identifying lipidic emulsomes for improved oxcarbazepine brain targeting: In vitro and rat in vivo studies

Inhalable dry powder prepared from folic acid-conjugated docetaxel liposomes alters pharmacodynamic and pharmacokinetic properties relevant to lung cancer chemotherapy.

Natural pulmonary surfactant (PS) and its artificial substitute phospholipid hexadecanol tyloxapol (PHT) are effective absorption enhancers on promoting recombinant human insulin (Rh-ins) absorption in vivo, but the in vitro efficacy and underlying mechanism remains unclear. In the current study, the permeation promoting effects of PS and PHT of insulin through Calu-3 monolayers in Transwell were evaluated. The viability of Calu-3 cells on conducting the permeation study was confirmed by TER and Electron Microscopy. Both PS and PHT significantly enhanced the permeation of Rh-ins and FD4 through calu-3 cells, with PS having a greater absorption enhancing effect than that of PHT. PS and PHT may interact directly with the tight junctions between cells and then result in intercellular permeation of peptide drugs. LDH release assay showed no significant acute toxicity of PS and PHT. The results indicated that these absorption enhancing agents may be useful as an absorption enhancer for pulmonary delivery of peptide and protein drugs.

Enhanced pulmonary absorption of recombinant human insulin by pulmonary surfactant and phospholipid hexadecanol tyloxapol through Calu-3 monolayers.

Flavanoids are important phytochemistry compositions in foods and traditional Chinese medicines (TCM) and are mainly oxidized by CYP1A family in vivo. Some methoxyflavones could also be metabolized through demethylation. Usually, flavanoids own one or more phenolic hydroxyl group in their molecular structures, which facilitate conjugation with glucuronic acid and sulphuric acid, forming metabolites with good water-solubility to excrete. Natural flavanoids mainly exist in glycoside, and after oral ,they would be easily metabolized to aglycone by hydratase in gut microflora and then absorbed into blood. Besides, many flavanoids have strong inhibitory actions on Cytochrome P450 enzymes, which are significant mechanisms in cancer precaution and tumor inhibition. In this paper, we reviewed lots of articles and summarized metabolism characteristics of flavanoids and metabolism interaction with Cytochrome P450 enzymes.

Research progress on drug metabolism of flavanoids

Objective To compare the pulmonary absorption characteristics of two insulin solutions-humalog (insulin lispro) and Novolin R (Biosynthetic Human insulin) with in vivo and in vitro methods. Methods Investigate the pharmacodynamics in Sprague Dawley (SD) rat model (in vivo studies) and permeability across Rana catesbeiana pulmonary membrane (in vitro studies) of Biosynthetic Human insulin (BHI) and insulin lispro (LI) at different doses. Results Both of the insulins could reduce blood glucose levels promptly after pulmonary administration. But LI showed a better tendency on hypoglycemic effect than BHI in the in vivo studies. In the in vitro studies, the apparent permeability coefficient (Papp) for BHI and LI were almost constant with increasing concentrations, which implied that insulin maybe passively diffuse through the Rana catesbeiana pulmonary membrane barrier. Interestingly, the Papp of LI was obviously higher than that of BHI, indicating that the permeability of LI across Rana catesbeiana pulmonary membrane was more effective than that of BHI. Conclusion These in vitro and in vivo results suggested that LI was easier to be absorbed in the lung than BHI and Rana catesbeiana pulmonary membrane had a potential ability, as a transport model, to predict in vivo pulmonary absorption of insulin.

Evaluation of insulin lispro and biosynthetic human insulin in pulmonary absorption: in vivo and in vitro studies.

The paper is aimed to investigate the effect of cyclosporine A (CyA) on the pharmacokinetics of ginkgolide B (GB) in rats, and to look for the mechanism of the changes in pharmacokinetic behaviors of GB. GB concentration in plasma, brain homogenate and urine samples of rats was determined by LC-MS. Effects of CyA on plasma levels, brain distributions as well as urinary excretions after intravenous administration of GB were evaluated. CyA co administrated intravenously at 10 mg kg(-1) or 20 mg kg(-1) significantly increased AUC(0-360 min) (P < 0.01) and decreased total CL of GB in rats. While co administrated CYP3A inhibitor itraconazole (ICZ) has no appreciable effect on the pharmacokinetic behavior of GB. CyA increased the brain uptake of GB in a dose-dependent manner. The brain distribution of GB was significantly increased at 5 min by different doses of CyA (P < 0.001), while at 20 and 60 min only high dose of CyA could significantly increase the levels of GB in the brain (P < 0.01 and P < 0.001). Different P-gp inhibitors CyA or verapamil (VER) or digoxin (DGX) decreased the urinary GB excretion, the urinary excretion of GB in 0-8 h were about 34.8% (P < 0.001), 59.4% (P < 0.001) and 79.7% (P < 0.05) of the control, separately. No appreciable effect of ICZ was observed on urinary excretion of GB. Coadministration of P-gp inhibitors CyA could significantly increase the plasma level, accelerate the brain distribution and decrease the urinary excretion of GB.

Effect of cyclosporine A on the pharmacokinetics of ginkgolide B in rats

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Enhanced pulmonary absorption of recombinant human insulin by pulmonary surfactant and phospholipid hexadecanol tyloxapol through Calu-3 monolayers.

Research progress on drug metabolism of flavanoids

Evaluation of insulin lispro and biosynthetic human insulin in pulmonary absorption: in vivo and in vitro studies.

Effect of cyclosporine A on the pharmacokinetics of ginkgolide B in rats