Login Register Cart 0
Generic placeholder image

Drug Delivery Letters

Editor-in-Chief

ISSN (Print): 2210-3031
ISSN (Online): 2210-304X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Letter Article

Efficiency of a Lyophilizate for Dry Powder Inhalation System for Drug Delivery of Ghrelin in Monkeys

Author(s): Tomomi Akita*, Kahori Miyamoto and Chikamasa Yamashita*

Volume 14, Issue 1, 2024

Published on: 02 October, 2023

Page: [89 - 95] Pages: 7

DOI: 10.2174/0122103031265565230921103638

Price: $65

Open Access Journals Promotions 2
Abstract

Background: A lyophilizate for dry powder inhalation (LDPI) system is unique in that its formulation, a lyophilized cake, is aerosolized just upon inhalation by convection flow of air. An LDPI system may be advantageous, especially for biopharmaceutics, such as proteins and peptides, because formulations can be manufactured without high temperature and shear stress. It was already reported that formulations of peptides used in an LDPI system showed high aerosolization performance. However, it was not confirmed whether the LDPI system could deliver drugs efficiently enough for practical use.

Objective: In this study, we compared the drug delivery efficiency of an LDPI system with intravenous and subcutaneous injections.

Methods: We administered LDPI formulations containing ghrelin as model formulations to monkeys and measured pharmacokinetic profiles.

Results: As a result of pharmacokinetics testing in the monkeys, the bioavailability of an inhaled drug was 5-15%.

Conclusion: It is expected that the LDPI system can deliver drugs efficiently enough for practical use even in the systemic application of bio-pharmaceutics.

Keywords: Dry powder inhalation, bioavailability, transpulmonary drug delivery, ghrelin, monkey, pharmacokinetics.

« Previous
Graphical Abstract

[1]
Yamashita, C.; Ibaragi, S.; Fukunaga, Y.; Akagi, A. Composition, vessel, dry powder inhalation system, and related methods for transpulmonary administration. US Patent 7448379, 2008.
[2]
Miyamoto, K.; Taga, H.; Akita, T.; Yamashita, C. Simple method to measure the aerodynamic size distribution of porous particles generated on lyophilizate for dry powder inhalation. Pharmaceutics, 2020, 12(10), 976.
[http://dx.doi.org/10.3390/pharmaceutics12100976] [PMID: 33076510]
[3]
Yamashita, C.; Matsushita, H.; Ibaragi, S.; Akagi, A. nhalation device for transpulmonary administration. US Patent 7708014, 2010.
[4]
Yamashita, C.; Fukunaga, Y.; Akagi, A. Dry powder inhalation system for transpulmonary administration. US Patent 7735485, 2010.
[5]
Patton, J.S.; Byron, P.R. Inhaling medicines: Delivering drugs to the body through the lungs. Nat. Rev. Drug Discov., 2007, 6(1), 67-74.
[http://dx.doi.org/10.1038/nrd2153] [PMID: 17195033]
[6]
Sahane, S.; Nikhar, A.; Bhaskaran, S.; Mundhada, D. Dry powder inhaler: An advance technique for pulmonary drug delivery system. Int J Pharm Chem Sci., 2012, 1, 1376-1383.
[7]
ElKasabgy, N.A.; Adel, I.M.; Elmeligy, M.F. Respiratory tract: Structure and attractions for drug delivery using dry powder inhalers. AAPS PharmSciTech, 2020, 21(7), 238.
[http://dx.doi.org/10.1208/s12249-020-01757-2] [PMID: 32827062]
[8]
Ye, Y.; Ma, Y.; Zhu, J. The future of dry powder inhaled therapy: Promising or discouraging for systemic disorders? Int. J. Pharm., 2022, 614, 121457.
[http://dx.doi.org/10.1016/j.ijpharm.2022.121457] [PMID: 35026316]
[9]
Anderson, P.J. History of aerosol therapy: Liquid nebulization to MDIs to DPIs. Respir. Care, 2005, 50(9), 1139-1150.
[PMID: 16122398]
[10]
Lavorini, F.; Corrigan, C.J.; Barnes, P.J.; Dekhuijzen, P.R.N.; Levy, M.L.; Pedersen, S.; Roche, N.; Vincken, W.; Crompton, G.K. Retail sales of inhalation devices in European countries: So much for a global policy. Respir. Med., 2011, 105(7), 1099-1103.
[http://dx.doi.org/10.1016/j.rmed.2011.03.012] [PMID: 21489771]
[11]
Sorino, C.; Negri, S.; Spanevello, A.; Visca, D.; Scichilone, N. Inhalation therapy devices for the treatment of obstructive lung diseases: The history of inhalers towards the ideal inhaler. Eur. J. Intern. Med., 2020, 75, 15-18.
[http://dx.doi.org/10.1016/j.ejim.2020.02.023] [PMID: 32113944]
[12]
Owens, D.R. New horizons-alternative routes for insulin therapy. Nat. Rev. Drug Discov., 2002, 1(7), 529-540.
[http://dx.doi.org/10.1038/nrd836] [PMID: 12120259]
[13]
Pandaya, S.; Misra, A. Inhalable glucagon-like peptide 1 porous particles prepared by spray freeze drying technique. J. Aerosol Med. Pulm. Drug Deliv., 2016, 29, A16.
[14]
Bajracharya, R.; Song, J.G.; Back, S.Y.; Han, H.K. Recent advancements in non-invasive formulations for protein drug delivery. Comput. Struct. Biotechnol. J., 2019, 17, 1290-1308.
[http://dx.doi.org/10.1016/j.csbj.2019.09.004] [PMID: 31921395]
[15]
Johnson, K. Preparation of peptide and protein powders for inhalation. Adv. Drug Deliv. Rev., 1997, 26(1), 3-15.
[http://dx.doi.org/10.1016/S0169-409X(97)00506-1] [PMID: 10837528]
[16]
Pilcer, G.; Amighi, K. Formulation strategy and use of excipients in pulmonary drug delivery. Int. J. Pharm., 2010, 392(1-2), 1-19.
[http://dx.doi.org/10.1016/j.ijpharm.2010.03.017] [PMID: 20223286]
[17]
Depreter, F.; Pilcer, G.; Amighi, K. Inhaled proteins: Challenges and perspectives. Int. J. Pharm., 2013, 447(1-2), 251-280.
[http://dx.doi.org/10.1016/j.ijpharm.2013.02.031] [PMID: 23499756]
[18]
Schlocker, W.; Gschlieser, S.; Bernkopschnürch, A. Evaluation of the potential of air jet milling of solid protein-poly(acrylate) complexes for microparticle preparation. Eur. J. Pharm. Biopharm., 2006, 62(3), 260-266.
[http://dx.doi.org/10.1016/j.ejpb.2005.09.001] [PMID: 16246537]
[19]
Ito, T.; Yamazoe, E.; Tahara, K. Dry powder inhalers for proteins using cryo-milled electrospun polyvinyl alcohol nanofiber mats. Molecules, 2022, 27(16), 5158.
[http://dx.doi.org/10.3390/molecules27165158] [PMID: 36014394]
[20]
Bjelošević, M.; Zvonar Pobirk, A.; Planinšek, O.; Ahlin Grabnar, P. Excipients in freeze-dried biopharmaceuticals: Contributions toward formulation stability and lyophilisation cycle optimisation. Int. J. Pharm., 2020, 576, 119029.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119029] [PMID: 31953087]
[21]
Weers, J.G.; Miller, D.P. Formulation design of dry powders for inhalation. J. Pharm. Sci., 2015, 104(10), 3259-3288.
[http://dx.doi.org/10.1002/jps.24574] [PMID: 26296055]
[22]
Saha, T.; Sinha, S.; Harfoot, R.; Quiñones-Mateu, M.E.; Das, S.C. Manipulation of spray-drying conditions to develop an inhalable ivermectin dry powder. Pharmaceutics, 2022, 14(7), 1432.
[http://dx.doi.org/10.3390/pharmaceutics14071432] [PMID: 35890327]
[23]
Alhajj, N.; O’Reilly, N.J.; Cathcart, H. Quality by design-Spray drying of ciprofloxacin-quercetin fixed-dose combination intended for inhalation. Int. J. Pharm., 2023, 642, 123151.
[http://dx.doi.org/10.1016/j.ijpharm.2023.123151] [PMID: 37364778]
[24]
Myślińska, M.; Stocker, M.W.; Ferguson, S.; Healy, A.M. A comparison of spray-drying and co-precipitation for the generation of amorphous solid dispersions (ASDs) of hydrochlorothiazide and simvastatin. J. Pharm. Sci., 2023, 112(8), 2097-2114.
[http://dx.doi.org/10.1016/j.xphs.2023.02.012] [PMID: 36805392]
[25]
Parkins, D.A.; Lashmar, U.T. The formulation of biopharmaceutical products. Pharm. Sci. Technol. Today, 2000, 3(4), 129-137.
[http://dx.doi.org/10.1016/S1461-5347(00)00248-0] [PMID: 10754542]
[26]
Ohori, R.; Kiuchi, S.; Sugiyama, S.; Miyamoto, K.; Akita, T.; Yamashita, C. Efficient optimization of high-dose formulation of novel lyophilizates for dry powder inhalation by the combination of response surface methodology and time-of-flight measurement. Int. J. Pharm., 2020, 581, 119255.
[http://dx.doi.org/10.1016/j.ijpharm.2020.119255] [PMID: 32217154]
[27]
Miyamoto, K.; Ishibashi, Y.; Akita, T.; Yamashita, C. Systemic delivery of hghrelin derivative by lyophilizate for dry powder inhalation system in monkeys. Pharmaceutics, 2021, 13(2), 233.
[http://dx.doi.org/10.3390/pharmaceutics13020233] [PMID: 33562278]
[28]
Miyamoto, K.; Yanagisawa, M.; Taga, H.; Yamaji, H.; Akita, T.; Yamashita, C. Optimization of very low-dose formulation of Vitamin D3 with lyophilizate for dry powder inhalation system by simple method based on time-of-flight theory. Pharmaceutics, 2021, 13(5), 632.
[http://dx.doi.org/10.3390/pharmaceutics13050632] [PMID: 33946783]
[29]
Hotta, M.; Ohwada, R.; Akamizu, T.; Shibasaki, T.; Takano, K.; Kangawa, K. Ghrelin increases hunger and food intake in patients with restricting-type anorexia nervosa: A pilot study. Endocr. J., 2009, 56(9), 1119-1128.
[http://dx.doi.org/10.1507/endocrj.K09E-168] [PMID: 19755753]
[30]
Khatib, N.; Gaidhane, S.; Gaidhane, A.M.; Khatib, M.; Simkhada, P.; Gode, D.; Zahiruddin, Q.S. Ghrelin: Ghrelin as a regulatory Peptide in growth hormone secretion. J. Clin. Diagn. Res., 2014, 8(8), MC13-MC17.
[http://dx.doi.org/10.7860/JCDR/2014/9863.4767] [PMID: 25302229]
[31]
Mihalache, L.; Gherasim, A.; Niță, O.; Ungureanu, M.C.; Pădureanu, S.S.; Gavril, R.S.; Arhire, L.I. Effects of ghrelin in energy balance and body weight homeostasis. Hormones, 2016, 15(2), 186-196.
[http://dx.doi.org/10.14310/horm.2002.1672] [PMID: 27376422]
[32]
Smith, A.; Woodside, B.; Abizaid, A. Ghrelin and the control of energy balance in females. Front. Endocrinol., 2022, 13, 904754.
[http://dx.doi.org/10.3389/fendo.2022.904754] [PMID: 35909536]
[33]
Kojima, M.; Hosoda, H.; Date, Y.; Nakazato, M.; Matsuo, H.; Kangawa, K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 1999, 402(6762), 656-660.
[http://dx.doi.org/10.1038/45230] [PMID: 10604470]
[34]
Yuan, M.J.; Li, W.; Zhong, P. Research progress of ghrelin on cardiovascular disease. Biosci. Rep., 2021, 41(1), BSR20203387.
[http://dx.doi.org/10.1042/BSR20203387] [PMID: 33427286]
[35]
Sun, Y.; Wang, P.; Zheng, H.; Smith, R.G. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc. Natl. Acad. Sci. USA, 2004, 101(13), 4679-4684.
[http://dx.doi.org/10.1073/pnas.0305930101] [PMID: 15070777]
[36]
Hosoda, H. Effect of ghrelin on the cardiovascular system. Biology, 2022, 11(8), 1190.
[http://dx.doi.org/10.3390/biology11081190] [PMID: 36009817]
[37]
Kojima, M.; Kangawa, K. Ghrelin: Structure and function. Physiol. Rev., 2005, 85(2), 495-522.
[http://dx.doi.org/10.1152/physrev.00012.2004] [PMID: 15788704]
[38]
Moose, J.E.; Leets, K.A.; Mate, N.A.; Chisholm, J.D.; Hougland, J.L. An overview of ghrelin O-acyltransferase inhibitors: A literature and patent review for 2010-2019. Expert Opin. Ther. Pat., 2020, 30(8), 581-593.
[39]
Shiimura, Y.; Horita, S.; Hamamoto, A.; Asada, H.; Hirata, K.; Tanaka, M.; Mori, K.; Uemura, T.; Kobayashi, T.; Iwata, S.; Kojima, M. Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode. Nat. Commun., 2020, 11(1), 4160.
[http://dx.doi.org/10.1038/s41467-020-17554-1] [PMID: 32814772]
[40]
Date, Y.; Murakami, N.; Kojima, M.; Kuroiwa, T.; Matsukura, S.; Kangawa, K.; Nakazato, M. Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. Biochem. Biophys. Res. Commun., 2000, 275(2), 477-480.
[http://dx.doi.org/10.1006/bbrc.2000.3342] [PMID: 10964690]
[41]
Hosoda, H.; Kojima, M.; Kangawa, K. Ghrelin and the regulation of food intake and energy balance. Mol. Interv., 2002, 2(8), 494-503.
[http://dx.doi.org/10.1124/mi.2.8.494] [PMID: 14993401]
[42]
Nguyen, N.N.; Singh, R.G.; Petrov, M.S. Association between intrapancreatic fat deposition and the leptin/ghrelin ratio in the fasted and postprandial states. Ann. Nutr. Metab., 2022, 78(1), 14-20.
[http://dx.doi.org/10.1159/000520068] [PMID: 34710871]
[43]
Dimaraki, E.V.; Jaffe, C.A. Role of endogenous ghrelin in growth hormone secretion, appetite regulation and metabolism. Rev. Endocr. Metab. Disord., 2007, 7(4), 237-249.
[http://dx.doi.org/10.1007/s11154-006-9022-0] [PMID: 17195943]
[44]
Colldén, G.; Tschöp, M.; Müller, T. Therapeutic potential of targeting the ghrelin pathway. Int. J. Mol. Sci., 2017, 18(4), 798.
[http://dx.doi.org/10.3390/ijms18040798] [PMID: 28398233]
[45]
Cornejo, M.P.; Denis, R.G.P.; García Romero, G.; Fernández, G.; Reynaldo, M.; Luquet, S.; Perello, M. Ghrelin treatment induces rapid and delayed increments of food intake: A heuristic model to explain ghrelin’s orexigenic effects. Cell. Mol. Life Sci., 2021, 78(19-20), 6689-6708.
[http://dx.doi.org/10.1007/s00018-021-03937-0] [PMID: 34559253]
[46]
Nakazato, M.; Murakami, N.; Date, Y.; Kojima, M.; Matsuo, H.; Kangawa, K.; Matsukura, S. A role for ghrelin in the central regulation of feeding. Nature, 2001, 409(6817), 194-198.
[http://dx.doi.org/10.1038/35051587] [PMID: 11196643]
[47]
Schalla, M.; Stengel, A. The Role of Ghrelin in Anorexia Nervosa. Int. J. Mol. Sci., 2018, 19(7), 2117.
[http://dx.doi.org/10.3390/ijms19072117] [PMID: 30037011]
[48]
Yamada, C.; Iizuka, S.; Nahata, M.; Hattori, T.; Takeda, H. Vulnerability to psychological stress‐induced anorexia in female mice depends on blockade of ghrelin signal in nucleus tractus solitarius. Br. J. Pharmacol., 2020, 177(20), 4666-4682.
[http://dx.doi.org/10.1111/bph.15219] [PMID: 32754963]
[49]
Akamizu, T.; Takaya, K.; Irako, T.; Hosoda, H.; Teramukai, S.; Matsuyama, A.; Tada, H.; Miura, K.; Shimizu, A.; Fukushima, M.; Yokode, M.; Tanaka, K.; Kangawa, K. Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur. J. Endocrinol., 2004, 150(4), 447-455.
[http://dx.doi.org/10.1530/eje.0.1500447] [PMID: 15080773]
[50]
Strasser, F.; Lutz, T.A.; Maeder, M.T.; Thuerlimann, B.; Bueche, D.; Tschöp, M.; Kaufmann, K.; Holst, B.; Brändle, M.; von Moos, R.; Demmer, R.; Cerny, T. Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: A randomised, placebo-controlled, double-blind, double-crossover study. Br. J. Cancer, 2008, 98(2), 300-308.
[http://dx.doi.org/10.1038/sj.bjc.6604148] [PMID: 18182992]
[51]
Lundholm, K.; Gunnebo, L.; Körner, U.; Iresjö, B.M.; Engström, C.; Hyltander, A.; Smedh, U.; Bosaeus, I. Effects by daily long term provision of ghrelin to unselected weight-losing cancer patients. Cancer, 2010, 116(8), 2044-2052.
[http://dx.doi.org/10.1002/cncr.24917] [PMID: 20186829]
[52]
Miki, K.; Maekura, R.; Nagaya, N.; Nakazato, M.; Kimura, H.; Murakami, S.; Ohnishi, S.; Hiraga, T.; Miki, M.; Kitada, S.; Yoshimura, K.; Tateishi, Y.; Arimura, Y.; Matsumoto, N.; Yoshikawa, M.; Yamahara, K.; Kangawa, K. Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease: A multicenter, randomized, double-blind, placebo-controlled trial. PLoS One, 2012, 7(5), e35708.
[http://dx.doi.org/10.1371/journal.pone.0035708] [PMID: 22563468]
[53]
Levinson, B; Gertner, J Randomized study of the efficacy and safety of SUN11031 (synthetic human ghrelin) in cachexia associated with chronic obstructive pulmonary disease. e-SPEN Journal., 2012, 7(5), e171-e5.
[54]
Mansson, J.V.; Alves, F.D.; Biolo, A.; Souza, G.C. Use of ghrelin in cachexia syndrome: A systematic review of clinical trials. Nutr. Rev., 2016, 74(11), 659-669.
[http://dx.doi.org/10.1093/nutrit/nuw029] [PMID: 27753623]
[55]
Antosova, Z.; Mackova, M.; Kral, V.; Macek, T. Therapeutic application of peptides and proteins: Parenteral forever? Trends Biotechnol., 2009, 27(11), 628-635.
[http://dx.doi.org/10.1016/j.tibtech.2009.07.009] [PMID: 19766335]
[56]
Hay, PJ; Touyz, S; Claudino, AM; Lujic, S; Smith, CA; Madden, S Inpatient versus outpatient care, partial hospitalisation and waiting list for people with eating disorders. Cochrane Database of Systematic Reviews, 2019, 1(1), CD010827.
[http://dx.doi.org/10.1002/14651858.CD010827.pub2]
[57]
Miyamoto, K.; Akita, T.; Yamashita, C. Radiolabeling method for lyophilizate for dry powder inhalation formulations. Pharmaceutics, 2022, 14(4), 759.
[http://dx.doi.org/10.3390/pharmaceutics14040759] [PMID: 35456593]
[58]
Labiris, N.R.; Dolovich, M.B. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. Br. J. Clin. Pharmacol., 2003, 56(6), 588-599.
[http://dx.doi.org/10.1046/j.1365-2125.2003.01892.x] [PMID: 14616418]
[59]
Ke, W.R.; Chang, R.Y.K.; Kwok, P.C.L.; Tang, P.; Chen, L.; Chen, D.; Chan, H.K. Administration of dry powders during respiratory supports. Ann. Transl. Med., 2021, 9(7), 596.
[http://dx.doi.org/10.21037/atm-20-3946] [PMID: 33987294]
[60]
Groneberg, D.A.; Witt, C.; Wagner, U.; Chung, K.F.; Fischer, A. Fundamentals of pulmonary drug delivery. Respir. Med., 2003, 97(4), 382-387.
[http://dx.doi.org/10.1053/rmed.2002.1457] [PMID: 12693798]
[61]
Carvalho, T.C.; Peters, J.I.; Williams, R.O., III Influence of particle size on regional lung deposition-what evidence is there? Int. J. Pharm., 2011, 406(1-2), 1-10.
[http://dx.doi.org/10.1016/j.ijpharm.2010.12.040] [PMID: 21232585]
[62]
Sheth, P.; Stein, S.W.; Myrdal, P.B. Factors influencing aerodynamic particle size distribution of suspension pressurized metered dose inhalers. AAPS PharmSciTech, 2015, 16(1), 192-201.
[http://dx.doi.org/10.1208/s12249-014-0210-z] [PMID: 25273026]
[63]
Quarta, E.; Chiappi, M.; Adamiano, A.; Tampieri, A.; Wang, W.; Tetley, T.D.; Buttini, F.; Sonvico, F.; Catalucci, D.; Colombo, P.; Iafisco, M.; Degli Esposti, L. Inhalable microparticles embedding biocompatible magnetic iron-doped hydroxyapatite nanoparticles. J. Funct. Biomater., 2023, 14(4), 189.
[http://dx.doi.org/10.3390/jfb14040189] [PMID: 37103279]

Rights & Permissions Print Cite
Article Metrics
19
2
Wayfinder Image
Open Access Journals Promotions
© 2024 Bentham Science Publishers | Privacy Policy