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
Review Article

Systemic Delivery of Peptide Hormones Using Nasal Powders: Strategies and Future Perspectives

Author(s): Lisa Engio and Remigius U. Agu*

Volume 9, Issue 4, 2019

Page: [286 - 298] Pages: 13

DOI: 10.2174/2210303109666190617170026

Price: $65

Abstract

Background: Peptide Hormones (PH) are mainly administered as parenteral injections due to their peculiar physicochemical properties, and susceptibility to enzymatic degradation after oral administration. With invasive routes, however, patient safety, acceptability, and compliance become a concern, especially when a patient has a chronic condition that requires repeated injections. The delivery of peptide hormones via the nasal route has gained momentum over the last few decades as a noninvasive alternative to parenteral injections and commercially available nasal liquid products.

Objective: The aim of this paper was to review:

(1) The benefits and limitations of nasal powder products,

(2) Formulation strategies to enhance nasal delivery of peptide hormone drugs,

(3) Nasal powder devices, and

(4) Future perspectives of therapeutic nasal powders. The drugs examined specifically include calcitonin, desmopressin, ghrelin, glucagon, human growth hormone, insulin, octreotide, and oxytocin.

Methods: Nasal delivery of peptide hormones using powders was reviewed with the following databases: EBSCO, PUBMED, Web of Science, ClinicalTrials.gov, and EU Clinical Trials Register.

Results: Nasal powders are a promising drug delivery system that may be safer and more effective than traditional injections and presently marketed nasal liquids for peptide hormone drugs.

Conclusion: With sustained interest and growing body of supporting evidence, a range of nasal powders for systemic delivery of these drugs and delivery devices can be expected to enter the market in the future and offer more options to patients.

Keywords: Microparticles, nasal delivery devices, nasal drug delivery, peptide hormone, powder, systemic.

« Previous Next »
Graphical Abstract

[1]
Kumar, P.G.; Kiran, S. Strategies and prospects of nasal drug delivery systems. Int. J. Pharm. Sci. Res., 2012, 3, 648-658.
[2]
Ozsoy, Y.; Gungor, S.; Cevher, E. Nasal delivery of high molecular weight drugs. Molecules, 2009, 14(9), 3754-3779.
[http://dx.doi.org/10.3390/molecules14093754] [PMID: 19783956]
[3]
Tiozzo Fasiolo, L.; Manniello, M.D.; Tratta, E.; Buttini, F.; Rossi, A.; Sonvico, F.; Bortolotti, F.; Russo, P.; Colombo, G. Opportunity and challenges of nasal powders: Drug formulation and delivery. Eur. J. Pharm. Sci., 2018, 113, 2-17.
[http://dx.doi.org/10.1016/j.ejps.2017.09.027] [PMID: 28942007]
[4]
Illum, L. Nasal drug delivery: new developments and strategies. Drug Discov. Today, 2002, 7(23), 1184-1189.
[http://dx.doi.org/10.1016/S1359-6446(02)02529-1] [PMID: 12547019]
[5]
Illum, L. Nasal drug delivery - recent developments and future prospects. J. Control. Release, 2012, 161(2), 254-263.
[http://dx.doi.org/10.1016/j.jconrel.2012.01.024] [PMID: 22300620]
[6]
Salade, L.; Wauthoz, N.; Vermeersch, M.; Amighi, K.; Goole, J. Chitosan-coated liposome dry-powder formulations loaded with ghrelin for nose-to-brain delivery. Eur. J. Pharm. Biopharm., 2018, 129, 257-266.
[http://dx.doi.org/10.1016/j.ejpb.2018.06.011] [PMID: 29902517]
[7]
Teshima, D.; Yamauchi, A.; Makino, K.; Kataoka, Y.; Arita, Y.; Nawata, H.; Oishi, R. Nasal glucagon delivery using microcrystalline cellulose in healthy volunteers. Int. J. Pharm., 2002, 233(1-2), 61-66.
[http://dx.doi.org/10.1016/S0378-5173(01)00930-9] [PMID: 11897411]
[8]
Milewski, M.; Goodey, A.; Lee, D.; Rimmer, E.; Saklatvala, R.; Koyama, S.; Iwashima, M.; Haruta, S. Rapid Absorption of Dry-Powder Intranasal Oxytocin. Pharm. Res., 2016, 33(8), 1936-1944.
[http://dx.doi.org/10.1007/s11095-016-1929-x] [PMID: 27194003]
[9]
Vasa, D.M.; O’Donnell, L.A.; Wildfong, P.L.D. Influence of Dosage Form, Formulation, and Delivery Device on Olfac-tory Deposition and Clearance: Enhancement of Nose-to-CNS Uptake. J. Pharm. Innov., 2015, 10, 200-210.
[http://dx.doi.org/10.1007/s12247-015-9222-9]
[10]
Fransén, N.; Bredenberg, S.; Björk, E. Clinical study shows improved absorption of desmopressin with novel formulation. Pharm. Res., 2009, 26(7), 1618-1625.
[http://dx.doi.org/10.1007/s11095-009-9871-9] [PMID: 19296208]
[11]
Cho, W.; Kim, M.S.; Jung, M.S.; Park, J.; Cha, K.H.; Kim, J.S.; Park, H.J.; Alhalaweh, A.; Velaga, S.P.; Hwang, S.J. Design of salmon calcitonin particles for nasal delivery using spray-drying and novel supercritical fluid-assisted spray-drying processes. Int. J. Pharm., 2015, 478(1), 288-296.
[http://dx.doi.org/10.1016/j.ijpharm.2014.11.051] [PMID: 25445994]
[12]
Ishikawa, F.; Katsura, M.; Tamai, I.; Tsuji, A. Improved nasal bioavailability of elcatonin by insoluble powder formulation. Int. J. Pharm., 2001, 224(1-2), 105-114.
[http://dx.doi.org/10.1016/S0378-5173(01)00736-0] [PMID: 11472819]
[13]
Agerholm, C.; Bastholm, L.; Johansen, P.B.; Nielsen, M.H.; Elling, F. Epithelial transport and bioavailability of intranasally administered human growth hormone formulated with the absorption enhancers didecanoyl-L-α-phosphatidylcholine and α-cyclodextrin in rabbits. J. Pharm. Sci., 1994, 83(12), 1706-1711.
[http://dx.doi.org/10.1002/jps.2600831212] [PMID: 7891298]
[14]
Djupesland, P.G. Nasal drug delivery devices: characteristics and performance in a clinical perspective-a review. Drug Deliv. Transl. Res., 2013, 3(1), 42-62.
[http://dx.doi.org/10.1007/s13346-012-0108-9] [PMID: 23316447]
[15]
Pardeshi, C.V.; Vanjari, Y.H.; Kulkarni, A.D. Novel nasal devices for the efficient drug delivery: A systemic review. In-dian J. Novel Drug Deliv., 2015, 7, 1-9.
[16]
Berkenfeld, K.; Lamprecht, A.; McConville, J.T. Devices for dry powder drug delivery to the lung. AAPS PharmSciTech, 2015, 16(3), 479-490.
[http://dx.doi.org/10.1208/s12249-015-0317-x] [PMID: 25964142]
[17]
Pozzoli, M.; Rogueda, P.; Zhu, B.; Smith, T.; Young, P.M.; Traini, D.; Sonvico, F. Dry powder nasal drug delivery: challenges, opportunities and a study of the commercial Teijin Puvlizer Rhinocort device and formulation. Drug Dev. Ind. Pharm., 2016, 42(10), 1660-1668.
[http://dx.doi.org/10.3109/03639045.2016.1160110] [PMID: 26953090]
[18]
Tepper, S.J.; Cady, R.K.; Silberstein, S.; Messina, J.; Mahmoud, R.A.; Djupesland, P.G.; Shin, P.; Siffert, J. AVP-825 breath-powered intranasal delivery system containing 22 mg sumatriptan powder vs 100 mg oral sumatriptan in the acute treatment of migraines (The COMPASS study): a comparative randomized clinical trial across multiple attacks. Headache, 2015, 55(5), 621-635.
[http://dx.doi.org/10.1111/head.12583] [PMID: 25941016]
[19]
Meltzer, E.O.; Garadi, R.; Laforce, C.; Chadwick, S.J.; Berger, W.E.; Gross, G.; Edwards, M.R.; Crenshaw, K.; Wall, G.M. Comparative study of sensory attributes of two antihistamine nasal sprays: olopatadine 0.6% and azelastine 0.1%. Allergy Asthma Proc., 2008, 29(6), 659-668.
[http://dx.doi.org/10.2500/aap.2008.29.3181] [PMID: 19144261]
[20]
Djupesland, P.G.; Dočekal, P. Czech Migraine Investigators Group. Intranasal sumatriptan powder delivered by a novel breath-actuated bi-directional device for the acute treatment of migraine: A randomised, placebo-controlled study. Cephalalgia, 2010, 30(8), 933-942.
[http://dx.doi.org/10.1177/0333102409359314] [PMID: 20656704]
[21]
Luthringer, R.; Djupesland, P.G.; Sheldrake, C.D.; Flint, A.; Boeijinga, P.; Danjou, P.; Demazières, A.; Hewson, G. Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device. J. Pharm. Pharmacol., 2009, 61(9), 1219-1228.
[http://dx.doi.org/10.1211/jpp.61.09.0012] [PMID: 19703372]
[22]
ClinicalTrials.gov. A Study of Glucagon Nasal Powder in Participants With Type 1 Diabetes Mellitus.. https://clinicaltrials.gov/ct2/show/results/NCT03339453 (accessed Aug 3, 2018).
[23]
ClinicalTrials.gov. A Study of Nasal Glucagon (LY900018) in Japanese Participants With Diabetes Mellitus . https://clinicaltrials. gov/ct2/show/results/NCT03421379 (accessed Aug 3, 2018).
[24]
Calcitonin, E.M.A. http://www.ema.europa.eu/ema/index. jsp%3Fcurl=pages/medicines/human/referrals/Calcitonin/human_re ferral_000319.jsp%26mid=WC0b01ac0580024e99 (accessed Jul 20, 2018).
[25]
Health Canada. Synthetic Calcitonin (Salmon) Nasal Spray (NS) - Market Withdrawal of All Products, Effective October 1st, 2013 - For Health Professionals.. http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/34783a-eng.php (accessed July 20, 2018).
[26]
Lee, Y.H.; Kim, K.H.; Yoon, I.K.; Lee, K.E.; Chun, I.K.; Rhie, J.Y.; Gwak, H.S. Pharmacokinetic evaluation of formulated levodopa methyl ester nasal delivery systems. Eur. J. Drug Metab. Pharmacokinet., 2014, 39(4), 237-242.
[http://dx.doi.org/10.1007/s13318-013-0171-8] [PMID: 24363125]
[27]
Hussain, A.A. AL‐Bayatti, A. A.; Dakkuri, A.; Okochi, K.; Hussain, M. A. Testosterone 17β‐N,N‐Dimethylglycinate Hy-drochloride: A Prodrug with a Potential for Nasal Delivery of Testosterone. J. Pharm. Sci., 2002, 91, 785-789.
[http://dx.doi.org/10.1002/jps.10083] [PMID: 11920764]
[28]
Matsuyama, T.; Morita, T.; Horikiri, Y.; Yamahara, H.; Yoshino, H. Improved nasal absorption of salmon calcitonin by powdery formulation with N-acetyl-L-cysteine as a mucolytic agent. J. Control. Release, 2006, 115(2), 183-188.
[http://dx.doi.org/10.1016/j.jconrel.2006.08.004] [PMID: 16989920]
[29]
Matsuyama, T.; Morita, T.; Horikiri, Y.; Yamahara, H.; Yoshino, H. Influence of fillers in powder formulations containing N-acetyl-L-cysteine on nasal peptide absorption. J. Control. Release, 2007, 120(1-2), 88-94.
[http://dx.doi.org/10.1016/j.jconrel.2007.04.006] [PMID: 17512076]
[30]
Critchley, H.; Davis, S.S.; Farraj, N.F.; Illum, L. Nasal absorption of desmopressin in rats and sheep. Effect of a bioadhesive microsphere delivery system. J. Pharm. Pharmacol., 1994, 46(8), 651-656.
[http://dx.doi.org/10.1111/j.2042-7158.1994.tb03876.x] [PMID: 7815278]
[31]
Balducci, A.G.; Ferraro, L.; Bortolotti, F.; Nastruzzi, C.; Colombo, P.; Sonvico, F.; Russo, P.; Colombo, G. Antidiuretic effect of desmopressin chimera agglomerates by nasal administration in rats. Int. J. Pharm., 2013, 440(2), 154-160.
[http://dx.doi.org/10.1016/j.ijpharm.2012.09.049] [PMID: 23046665]
[32]
Sakr, F.M. Nasal administration of glucagon combined with dimethyl-B-cyclodextrin: Comparison of pharmacokinetics and pharmacodynamics of spray and powder formulations. Int. J. Pharm., 1996, 132, 189-194.
[http://dx.doi.org/10.1016/0378-5173(95)04385-3]
[33]
Reno, F.E.; Normand, P.; McInally, K.; Silo, S.; Stotland, P.; Triest, M.; Carballo, D.; Piché, C. A novel nasal powder formulation of glucagon: toxicology studies in animal models. BMC Pharmacol. Toxicol., 2015, 16, 29.
[http://dx.doi.org/10.1186/s40360-015-0026-9] [PMID: 26502880]
[34]
Sherr, J.L.; Ruedy, K.J.; Foster, N.C.; Piché, C.A.; Dulude, H.; Rickels, M.R.; Tamborlane, W.V.; Bethin, K.E.; DiMeglio, L.A.; Fox, L.A.; Wadwa, R.P.; Schatz, D.A.; Nathan, B.M.; Marcovina, S.M.; Rampakakis, E.; Meng, L.; Beck, R.W. T1D Exchange Intranasal Glucagon Investigators. Glucagon nasal powder: A promising alternative to intramuscular glucagon in youth with type 1 diabetes. Diabetes Care, 2016, 39(4), 555-562.
[http://dx.doi.org/10.2337/dc15-1606] [PMID: 26884472]
[35]
Illum, L.; Farraj, N.F.; Davis, S.S.; Johansen, B.R.; O’Hagan, D.T. Investigation of the nasal absorption of biosynthetic human growth hormone in sheep—use of a bioadhesive mi-crosphere delivery system. Int. J. Pharm., 1990, 63, 207-211.
[http://dx.doi.org/10.1016/0378-5173(90)90126-O]
[36]
Leitner, V.M.; Guggi, D.; Krauland, A.H.; Bernkop-Schnürch, A. Nasal delivery of human growth hormone: in vitro and in vivo evaluation of a thiomer/glutathione microparticulate delivery system. J. Control. Release, 2004, 100(1), 87-95.
[http://dx.doi.org/10.1016/j.jconrel.2004.08.001] [PMID: 15491813]
[37]
Cheng, Y.H.; Dyer, A.M.; Jabbal-Gill, I.; Hinchcliffe, M.; Nankervis, R.; Smith, A.; Watts, P. Intranasal delivery of recombinant human growth hormone (somatropin) in sheep using chitosan-based powder formulations. Eur. J. Pharm. Sci., 2005, 26(1), 9-15.
[http://dx.doi.org/10.1016/j.ejps.2005.03.014] [PMID: 15970435]
[38]
Jordan, F.; Shalet, S.M.; King, G. Proceedings of the Endocrine Society’s 95th Annual Meeting and Expo, San Francisco, CAJune 15-18, 2013
[39]
Jordan, F.; Shalet, S.; King, G. Proceedings of 9th Joint Meeting of Paediatric Endocrinology ESPE-PES-APEG-APPES-ASPAE-JSPE-SLEP, Milan, ItalySept 19-22, 20132013, , pp. FC16-213.
[40]
Lewis, A.L.; Jordan, F.; Illum, L. CriticalSorb™: enabling systemic delivery of macromolecules via the nasal route. Drug Deliv. Transl. Res., 2013, 3(1), 26-32.
[http://dx.doi.org/10.1007/s13346-012-0089-8] [PMID: 25787865]
[41]
Callens, C.; Remon, J.P. Evaluation of starch-maltodextrin-Carbopol 974 P mixtures for the nasal delivery of insulin in rabbits. J. Control. Release, 2000, 66(2-3), 215-220.
[http://dx.doi.org/10.1016/S0168-3659(99)00271-0] [PMID: 10742581]
[42]
Illum, L.; Fisher, A.N.; Jabbal-Gill, I.; Davis, S.S. Bioadhesive starch microspheres and absorption enhancing agents act synergistically to enhance the nasal absorption of polypeptides. Int. J. Pharm., 2001, 222(1), 109-119.
[http://dx.doi.org/10.1016/S0378-5173(01)00708-6] [PMID: 11404037]
[43]
Dyer, A.M.; Hinchcliffe, M.; Watts, P.; Castile, J.; Jabbal-Gill, I.; Nankervis, R.; Smith, A.; Illum, L. Nasal delivery of insulin using novel chitosan based formulations: a comparative study in two animal models between simple chitosan formulations and chitosan nanoparticles. Pharm. Res., 2002, 19(7), 998-1008.
[http://dx.doi.org/10.1023/A:1016418523014] [PMID: 12180553]
[44]
Callens, C.; Ceulemans, J.; Ludwig, A.; Foreman, P.; Remon, J.P. Rheological study on mucoadhesivity of some nasal powder formulations. Eur. J. Pharm. Biopharm., 2003, 55(3), 323-328.
[http://dx.doi.org/10.1016/S0939-6411(03)00024-9] [PMID: 12754007]
[45]
Haruta, S.; Hanafusa, T.; Fukase, H.; Miyajima, H.; Oki, T.; Haruta, S.; Hanafusa, T.; Fukase, H.; Miyajima, H.; Oki, T. An effective absorption behavior of insulin for diabetic treatment following intranasal delivery using porous spherical calcium carbonate in monkeys and healthy human volunteers. Diabetes Technol. Ther., 2003, 5(1), 1-9.
[http://dx.doi.org/10.1089/152091503763816409] [PMID: 12725701]
[46]
Varshosaz, J.; Sadrai, H.; Alinagari, R. Nasal delivery of insulin using chitosan microspheres. J. Microencapsul., 2004, 21(7), 761-774.
[http://dx.doi.org/10.1080/02652040400015403] [PMID: 15799226]
[47]
Krauland, A.H.; Leitner, V.M.; Grabovac, V.; Bernkop-Schnürch, A. In vivo evaluation of a nasal insulin delivery system based on thiolated chitosan. J. Pharm. Sci., 2006, 95(11), 2463-2472.
[http://dx.doi.org/10.1002/jps.20700] [PMID: 16886206]
[48]
Wang, J.; Tabata, Y.; Morimoto, K. Aminated gelatin microspheres as a nasal delivery system for peptide drugs: evaluation of in vitro release and in vivo insulin absorption in rats. J. Control. Release, 2006, 113(1), 31-37.
[http://dx.doi.org/10.1016/j.jconrel.2006.03.011] [PMID: 16707188]
[49]
Krauland, A.H.; Alonso, M.J. Chitosan/cyclodextrin nanoparticles as macromolecular drug delivery system. Int. J. Pharm., 2007, 340(1-2), 134-142.
[http://dx.doi.org/10.1016/j.ijpharm.2007.03.005] [PMID: 17459620]
[50]
Pringels, E.; Vervaet, C.; Verbeeck, R.; Foreman, P.; Remon, J.P. The addition of calcium ions to starch/Carbopol mixtures enhances the nasal bioavailability of insulin. Eur. J. Pharm. Biopharm., 2008, 68(2), 201-206.
[http://dx.doi.org/10.1016/j.ejpb.2007.05.008] [PMID: 17611089]
[51]
Jain, A.K.; Khar, R.K.; Ahmed, F.J.; Diwan, P.V. Effective insulin delivery using starch nanoparticles as a potential trans-nasal mucoadhesive carrier. Eur. J. Pharm. Biopharm., 2008, 69(2), 426-435.
[http://dx.doi.org/10.1016/j.ejpb.2007.12.001] [PMID: 18295464]
[52]
Bhumkar, D.R.; Joshi, H.M.; Sastry, M.; Pokharkar, V.B. Chitosan reduced gold nanoparticles as novel carriers for transmucosal delivery of insulin. Pharm. Res., 2007, 24(8), 1415-1426.
[http://dx.doi.org/10.1007/s11095-007-9257-9] [PMID: 17380266]
[53]
Wang, X.; Zheng, C.; Wu, Z.; Teng, D.; Zhang, X.; Wang, Z.; Li, C. Chitosan-NAC nanoparticles as a vehicle for nasal ab-sorption enhancement of insulin. J. Biomed. Mater. Res., 2009, 88B, 150-161.
[http://dx.doi.org/10.1002/jbm.b.31161]
[54]
Teijeiro-Osorio, D.; Remuñán-López, C.; Alonso, M.J. New generation of hybrid poly/oligosaccharide nanoparticles as carriers for the nasal delivery of macromolecules. Biomacromolecules, 2009, 10(2), 243-249.
[http://dx.doi.org/10.1021/bm800975j] [PMID: 19117404]
[55]
Harris, A.G.; Weeke, J.; Christensen, S.E.; Kaal, A.; Illum, P.; Orskov, H. Preliminary results with Sandostatin nasal powder in acromegalic patients. Metabolism, 1992, 41(9)(Suppl. 2), 72-75.
[http://dx.doi.org/10.1016/0026-0495(92)90035-9] [PMID: 1518437]
[56]
Invitti, C.; Fatti, L.; Camboni, M.G.; Porcu, L.; Danesi, L.; Delitala, G.; Cavagnini, F. Effect of chronic treatment with octreotide nasal powder on serum levels of growth hormone, insulin-like growth factor I, insulin-like growth factor binding proteins 1 and 3 in acromegalic patients. J. Endocrinol. Invest., 1996, 19(8), 548-555.
[http://dx.doi.org/10.1007/BF03349015] [PMID: 8905479]
[57]
Oechslein, C.R.; Fricker, G.; Kissel, T. Nasal delivery of octreotide: Absorption enhancement by particulate carrier systems. Int. J. Pharm., 1996, 139, 25-32.
[http://dx.doi.org/10.1016/0378-5173(96)04569-3]
[58]
Jain, A.K.; Thareja, S. In vitro and in vivo characterization of pharmaceutical nanocarriers used for drug delivery. Artif. Cells Nanomed. Biotechnol., 2019, 47(1), 524-539.
[http://dx.doi.org/10.1080/21691401.2018.1561457] [PMID: 30784319]
[59]
Ghadiri, M.; Vasheghani-Farahani, E.; Atyabi, F.; Kobarfard, F.; Mohamadyar-Toupkanlou, F.; Hosseinkhani, H. Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier. J. Biomed. Mater. Res. A, 2017, 105(10), 2851-2864.
[http://dx.doi.org/10.1002/jbm.a.36145] [PMID: 28639394]
[60]
Alibolandi, M.; Abnous, K.; Sadeghi, F.; Hosseinkhani, H.; Ramezani, M.; Hadizadeh, F. Folate receptor-targeted multimodal polymersomes for delivery of quantum dots and doxorubicin to breast adenocarcinoma: In vitro and in vivo evaluation. Int. J. Pharm., 2016, 500(1-2), 162-178.
[http://dx.doi.org/10.1016/j.ijpharm.2016.01.040] [PMID: 26802496]
[61]
Illum, L. Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems? J. Pharm. Sci., 2007, 96(3), 473-483.
[http://dx.doi.org/10.1002/jps.20718] [PMID: 17117404]
[62]
Desai, N. Challenges in development of nanoparticle-based therapeutics. AAPS J., 2012, 14(2), 282-295.
[http://dx.doi.org/10.1208/s12248-012-9339-4] [PMID: 22407288]
[63]
Samaridou, E.; Alonso, M.J. Nose-to-brain peptide delivery - The potential of nanotechnology. Bioorg. Med. Chem., 2018, 26(10), 2888-2905.
[http://dx.doi.org/10.1016/j.bmc.2017.11.001] [PMID: 29170026]
[64]
Agrawal, M.; Saraf, S.; Saraf, S.; Antimisiaris, S.G.; Chougule, M.B.; Shoyele, S.A.; Alexander, A. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J. Control. Release, 2018, 281, 139-177.
[http://dx.doi.org/10.1016/j.jconrel.2018.05.011] [PMID: 29772289]

Rights & Permissions Print Cite
Article Metrics
50
5
© 2024 Bentham Science Publishers | Privacy Policy