Advances in pulmonary drug delivery by Philip Chi Lip Kwok, Hak-Kim Chan

By Philip Chi Lip Kwok, Hak-Kim Chan

The respiration tract has been used to carry biologically energetic chemical compounds into the human physique for hundreds of years. notwithstanding, the lungs are complicated of their anatomy and body structure, which poses demanding situations to drug supply. Inhaled formulations are quite often extra refined than these for oral and parenteral management. Pulmonary drug improvement is for this reason a hugely really expert sector due to its many distinctive concerns and demanding situations. fast development is being made and gives novel ideas to latest remedy difficulties. Advances in Pulmonary Drug Delivery highlights the most recent advancements during this field.

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Formulation of siRNA into aerosols for inhalation 2. siRNA-containing particles reach the lower respiratory tract 3. Intact siRNA reaches the target cells and enters through endocytosis Lysosomes 4. siRNA escapes from endosomes, avoids degradation, and releases from the delivery agent RISC Endosomes siRNA 5. 1 Schematic illustrates steps involved in the delivery of siRNA into the lungs� (Reproduced from Lam, J�K�-W� et al�, Adv. Drug Deliv.

Intact siRNA reaches the target cells and enters through endocytosis Lysosomes 4. siRNA escapes from endosomes, avoids degradation, and releases from the delivery agent RISC Endosomes siRNA 5. 1 Schematic illustrates steps involved in the delivery of siRNA into the lungs� (Reproduced from Lam, J�K�-W� et al�, Adv. Drug Deliv.

5 Increasing polyethylene glycol molecular weight increases glucose lowering action time following inhalation of 2K–5K PEGylated insulins in anesthetized dogs� (Response to sc NPH insulin in humans is shown in the dotted line�) insulin was well tolerated at inhaled doses that would support clinical investigation, whereas higher-molecular-weight PEG insulins produced some mild inflammation, which made them unsuitable for clinical development� FUTURE DIRECTIONS Although inhaled proteins and peptides have shown limited success thus far, there are a number of opportunities for future success� Appropriate situations must be assessed to determine if there is an unmet medical need that can be addressed with inhaled therapies� It seems only a matter of time before some inhaled antibodies are developed to treat some forms of local respiratory disease� Of course, the correct receptors and time action need to be addressed, and so this is not a simple endeavor� Other proteins or peptides may also be good candidates to treat local respiratory disease, such as dealing with protease–antiprotease imbalances� Modified proteins or peptides have been developed to improve pharmacokinetics for systemic delivery� In my personal opinion, pegylation provides the most promising approach for increasing systemic half-lives� It has been demonstrated that by using PEGs in the molecular weight range of 2–5 kDa, lung disappearance half-lives of the order of 7–12 h can be achieved [62], which is excellent for many therapies since it allows optimal once or twice a day dosing� PEGs greater than 5K tended to show a longlived component in the lung and are unlikely to be compatible with once a day dosing� Further use of inhaled proteins and peptides has definite promise� There should be careful consideration of dealing with clear unmet clinical needs and validated target selection� In addition, cost needs to be considered� Advances in protein manufacture to reduce cost will help� High-efficiency delivery systems are needed with careful consideration of aerosol properties for reproducible delivery to the lung with high deposition efficiency in the alveolar region� Excellent vibrating mesh devices for liquid delivery such as those by Aerogen and Pari should be considered� Engineered dry powder formulations advances such as those by Novartis (PulmoSphere), Civitas (ARCUS), and Pulmatrix (iSPERSE) can also aid inhaled protein development� Inhaled Proteins and Peptides 19 SUMMARY • The development of Pulmozyme and Exubera has shown that both local and systemic use of inhaled proteins can be safe and efficacious� • There are a number of opportunities for future success including inhaled antibodies, approaches to address protease–antiprotease imbalances contributing to lung disease, and PEGylated proteins and peptides to improve pharmacokinetics� • Future therapies should concentrate on unmet medical needs and validated targets� • High-efficiency delivery systems are needed with careful consideration of aerosol properties for reproducible delivery to the lung with high deposition efficiency in the alveolar region� • Cost needs to be considered� Advances in protein manufacture and biosimilars to reduce cost will help� REFERENCES 1� Depreter F, Picher C, Amighi K� Inhaled proteins: Challenges and perspectives� International Journal of Pharmaceutics 447: 251–280 (2013)� 2� Kane C, O’Neil K, Conk M, Picha K� Inhalation delivery of protein therapeutics� Inflammation & Allergy—Drug Targets 12(2): 81–87 (2013)� 3� Patton JS, Byron PR� Inhaling medicines: Delivering drugs to the body through the lungs� Nature Reviews—Drug Discovery 6: 67–74 (2007)� 4� Wolff RK� Safety of inhaled proteins for therapeutic use� Journal of Aerosol Medicine 11(4): 197–219 (1998)� http://online�liebertpub�com/doi/abs/10�1089/ jam�1998�11�197� 5� McElroy MC, Kirton C, Gliddon D, Wolff RK� Inhaled biopharmaceutical drug development: Non-clinical considerations and case studies� Inhalation Toxicology 5(4): 219–232 (2013)� 6� Siekmeier R, Scheuch S� Systemic treatment by inhalation of macromolecules— Principles, problems and examples� Journal of Physiology and Pharmacology 59(Suppl� 6): 53–79 (2008)� 7� Ponce R, Abad L, Amaravadi L, Gelzleichter T, Gore E, Green J et al� Immunogenicity of biologically-derived therapeutics: Assessment and interpretation of nonclinical safety studies� Regulatory Toxicology and Pharmacology 54: 164–182 (2009)� 8� ICH S6 (R1)� Preclinical safety evaluation of biotechnology-derived pharmaceuticals (2011)� http://www�ich�org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/ S6_R1/Step4/S6_R1_Guideline�pdf� Accessed Jan, 2016� 9� Cavagnaro J� The principles of the ICH S6 and the case-by-case approach� In Preclinical Safety Evaluation of Biopharmaceuticals: A Science-Based Approach to Facilitating Clinical Trials, Cavagnaro J, ed� John Wiley & Sons, Hoboken, NJ, pp� 45–65 (2008)� 10� Clarke J, Hurst C, Martin P, Vahle J, Ponce R, Mounho B, Heidel S, Andrews L, Reynolds T, Cavagnaro J� Duration of chronic toxicity studies for biotechnologyderived pharmaceuticals: Is 6 months still appropriate?

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