Route-Specific Challenges in the Delivery of Poorly Water-Soluble Drugs

  • Chapter
  • First Online:
Formulating Poorly Water Soluble Drugs

Abstract

Poor aqueous solubility of new chemical entities presents various challenges in the development of effective drug delivery systems for various delivery routes. Poorly soluble drugs that are delivered orally may commonly result in low bioavailability and are often subject to considerable food effects. In addition, poorly soluble drugs intended for parenteral delivery may also have to be solubilized with large amounts of cosolvents and surfactants, oftentimes resulting in adverse physiological reactions. Other routes also offer unique opportunities for this class of drug molecules but also their own challenges. Ocular delivery of poorly soluble drugs is challenging due to the efficient absorption barriers and clearance mechanisms. Development of poorly soluble drugs administered mucosally through routes such as the nasal cavity, oral mucosa, and others may be restricted by the relatively small administered volume, the geometry of the administration site, and the excipients commonly used in these formulations. Successful formulation design of poorly soluble drugs’ intended alternative routes of administration may be hindered by the limited number of excipients generally recognized as safe for this route of delivery and the anatomical and physiological clearance mechanisms found in these tissues. In summary, this chapter reviews the specific challenges faced in the delivery of poorly water-soluble drugs via oral, parenteral, and mucosal administration.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free ship** worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  • Abdelbary AA, Al-mahallawi AM, Abdelrahim ME, Ali AM. Preparation, optimization, and in vitro simulated inhalation delivery of carvedilol nanoparticles loaded on a coarse carrier intended for pulmonary administration. Int J Nanomedicine. 2015;10:6339–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmed I, Patton TF. Importance of the noncorneal absorption route in topical ophthalmic drug delivery. IOVS. 1985;26(4):584–7.

    CAS  Google Scholar 

  • Akers MJ. Parenteral preparations, Remington: the science and practice of pharmacy. Baltimore, MD: Lippincott Williams & Wilkins; 2014.

    Google Scholar 

  • Alqawlaq S, Huzil JT, Ivanova MV, Foldvari M. Challenges in neuroprotective nanomedicine development: progress towards noninvasive gene therapy of glaucoma. Nanomedicine. 2012;7(7):1067–83.

    Article  CAS  PubMed  Google Scholar 

  • Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.

    Article  CAS  PubMed  Google Scholar 

  • Amin K, Dannenfelser RM. In vitro hemolysis: guidance for the pharmaceutical scientist. J Pharm Sci. 2006;95(6):1173–6.

    Article  CAS  PubMed  Google Scholar 

  • Anby MU, Williams HD, Feeney O, Edwards GA, Benameur H, Pouton CW, et al. Non-linear increases in Danazol exposure with dose in older vs. younger Beagle dogs: The potential role of differences in bile salt concentration, thermodynamic activity, and formulation digestion. Pharm Res. 2014;31(6):1536–52.

    Article  CAS  PubMed  Google Scholar 

  • Benet LZ. Predicting drug disposition via application of a biopharmaceutics drug disposition classification system. Basic Clin Pharmacol Toxicol. 2010;106(3):162–7.

    Article  CAS  PubMed  Google Scholar 

  • Benet L, et al. Predicting drug absorption and the effects of food on oral bioavailability. Bulletin Technique Gattefosse. 2006;99:9–16.

    Google Scholar 

  • Bhalla S. Parenteral drug delivery. In: Desai A, Lee M, editors. Gibaldi’s drug delivery systems in pharmaceutical care. Bethesda, MD: ASHP; 2007.

    Google Scholar 

  • Bittner B, Mountfield RJ. Intravenous administration of poorly soluble new drug entities in early drug discovery: the potential impact of formulation on pharmacokinetic parameters. Curr Opin Drug Discov Devel. 2002;5(1):59–71.

    CAS  PubMed  Google Scholar 

  • Blot F, Tavakoli R, Sellam S, Epardeau B, Faurisson F, Bernard N, et al. Nebulized cyclosporine for prevention of acute pulmonary allograft rejection in the rat: pharmacokinetic and histologic study. J Heart Lung Transplant. 1995;14(6 Pt 1):1162–72.

    CAS  PubMed  Google Scholar 

  • Boyd BJ, et al. Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems. Eur J Pharm Sci. 2019;137:104967.

    Article  CAS  PubMed  Google Scholar 

  • Bracq E, Lahiani-Skiba M, Guerbet M. Ethical observations on the choice of parenteral solvents. Drug Dev Ind Pharm. 2008;34(12):1306–10.

    Article  CAS  PubMed  Google Scholar 

  • Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007;59(7):645–66.

    Article  CAS  PubMed  Google Scholar 

  • Calvo P, Alonso MJ, Vila-Jato JL, Robinson JR. Improved ocular bioavailability of indomethacin by novel ocular drug carriers. J Pharm Pharmacol. 1996;48(11):1147–52.

    Article  CAS  PubMed  Google Scholar 

  • Carvalho TC, Peters JI, Williams RO. Influence of particle size on regional lung deposition – what evidence is there? Int J Pharm. 2011 Mar 15;406(1-2):1–10.

    Article  CAS  PubMed  Google Scholar 

  • Charman WN, Porter CJ, Mithani S, Dressman JB. Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. J Pharm Sci. 1997;86(3):269–82.

    Article  CAS  PubMed  Google Scholar 

  • Chaturvedi M, Kumar M, Pathak K. A review on mucoadhesive polymer used in nasal drug delivery system. J Adv Pharm Technol Res. 2011;2(4):215–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng YS, Holmes TD, Gao J, Guilmette RA, Li S, Surakitbanharn Y, et al. Characterization of nasal spray pumps and deposition pattern in a replica of the human nasal airway. J Aerosol Med. 2001;14(2):267–80.

    Article  CAS  PubMed  Google Scholar 

  • Chowhan M, Lang J, Missel P. Ophthalmic preparations. In: Allen Jr LV, Adejare A, Desselle SP, Felton LA, editors. Remington: the science and practice of pharmacy. 22nd ed. London; Philadelphia: Pharmaceutical Press; 2012.

    Google Scholar 

  • Clerico D, To W, Lanza D. Anatomy of the Human Nasal Passages. In: Handbook of Olfaction and Gustation [Internet]. New York: CRC Press; 2003. p. 1–16.

    Google Scholar 

  • Coon RA, Jones RA, Jenkins Jr LJ, Siegel J. Animal inhalation studies on ammonia, ethylene glycol, formaldehyde, dimethylamine, and ethanol. Toxicol Appl Pharmacol. 1970;16(3):646–655.

    Google Scholar 

  • Corcoran TE. Inhaled delivery of aerosolized cyclosporine. Adv Drug Deliv Rev. 2006;58(9–10):1119–27.

    Article  CAS  PubMed  Google Scholar 

  • Crowder TM, Rosati JA, Schroeter JD, Hickey AJ, Martonen TB. Fundamental effects of particle morphology on lung delivery: predictions of Stokes law and the particular relevance to dry powder inhaler formulation and development. Pharm Res. 2002;19(3):239–45.

    Article  CAS  PubMed  Google Scholar 

  • Custodio JM, Wu C-Y, Benet LZ. Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption. Adv Drug Deliv Rev. 2008;60(6):717–33.

    Article  CAS  PubMed  Google Scholar 

  • Dayal P, Shaik MS, Singh M. Evaluation of different parameters that affect droplet-size distribution from nasal sprays using the Malvern Spraytec®. J Pharm Sci. 2004;93(7):1725–42.

    Article  CAS  PubMed  Google Scholar 

  • Dhuria SV, Hanson LR, Frey WH. Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J Pharm Sci. 2010;99(4):1654–73.

    Article  CAS  PubMed  Google Scholar 

  • Ding S, Tien WL, Olejnik O. Nonirritating emulsions for sensitive tissue [Internet]. US5474979 A, 1995

    Google Scholar 

  • Djupesland PG. Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv Transl Res. 2013;3(1):42–62.

    Article  CAS  PubMed  Google Scholar 

  • Djupesland PG, Skretting A, Winderen M, Holand T. Breath actuated device improves delivery to target sites beyond the nasal valve. Laryngoscope. 2006;116(3):466–72.

    Article  PubMed  Google Scholar 

  • Donaldson K. Ultrafine particles. Occup Environ Med. 2001;58(3):211–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dowling RD, Zenati M, Burckart GJ, Yousem SA, Schaper M, Simmons RL, et al. Aerosolized cyclosporine as single-agent immunotherapy in canine lung allografts. Surgery. 1990;108(2):198–204.

    CAS  PubMed  Google Scholar 

  • Dressman JB, Vertzoni M, Goumas K, Reppas C. Estimating drug solubility in the gastrointestinal tract. Adv Drug Deliv Rev. 2007;59(7):591–602.

    Article  CAS  PubMed  Google Scholar 

  • Driscoll K. Effects of particle exposure and particle-elicited inflammatory cells on mutation in rat alveolar epithelial cells. Carcinogenesis. 1997;18(2):423–43.

    Article  CAS  PubMed  Google Scholar 

  • Drumond N, Couto AS, Costa A, Cabral-Marques H. Study of aerodynamic and release properties of inhaled particles containing cyclodextrins. J Incl Phenom Macrocycl Chem. 2014;80(1-2):25–30.

    Article  CAS  Google Scholar 

  • Dufour G, Bigazzi W, Wong N, Boschini F, de Tullio P, Piel G, et al. Interest of cyclodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide. Int J Pharm. 2015;495(2):869–78.

    Article  CAS  PubMed  Google Scholar 

  • Duret C, Wauthoz N, Sebti T, Vanderbist F, Amighi K. New inhalation-optimized itraconazole nanoparticle-based dry powders for the treatment of invasive pulmonary aspergillosis. Int J Nanomedicine. 2012;7:5475–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edwards A, Prausnitz MR. Fiber matrix model of sclera and corneal stroma for drug delivery to the eye. AIChE J. 1998;44(1):214–25.

    Article  CAS  Google Scholar 

  • Egger-Heigold B. The effect of excipients on pharmacokinetic parameters of parenteral drugs. PhD Thesis, University of Basel, Faculty of Science, 2005

    Google Scholar 

  • El-Gendy N, Selvam P, Soni P, Berkland C. Development of budesonide nanocluster dry powder aerosols: Processing. J Pharm Sci. 2012a;101(9):3425–33.

    Article  CAS  PubMed  Google Scholar 

  • El-Gendy N, Huang S, Selvam P, Soni P, Berkland C. Development of budesonide nanocluster dry powder aerosols: Formulation and stability. J Pharm Sci. 2012b;101(9):3445–55.

    Article  CAS  PubMed  Google Scholar 

  • Ellis AG, Crinis NA, Webster LK. Inhibition of etoposide elimination in the isolated perfused rat liver by Cremophor EL and Tween 80. Cancer Chemother Pharmacol. 1996;38(1):81–7.

    Article  CAS  PubMed  Google Scholar 

  • Engels FK, Mathot RA, Verweij J. Alternative drug formulations of docetaxel: a review. Anticancer Drugs. 2007;18(2):95–103.

    Article  CAS  PubMed  Google Scholar 

  • Evrard B, Bertholet P, Gueders M, Flament M-P, Piel G, Delattre L, et al. Cyclodextrins as a potential carrier in drug nebulization. J Control Release. 2004;96(3):403–10.

    Article  CAS  PubMed  Google Scholar 

  • FDA Guidance for Industry: Nonclinical studies for the safety evaluation of pharmaceutical excipients. Food and Drug Administration, 2005

    Google Scholar 

  • Filipović-Grčić, Hafner. Nasal powder drug delivery. In: Gad SC, editor. Pharmaceutical Manufacturing Handbook: Production and Processes. 1 edition. Hoboken, N.J: Wiley-Interscience, 2008. p. 668–699

    Google Scholar 

  • Fleisher D, Li C, Zhou Y, Pao LH, Karim A. Drug, meal and formulation interactions influencing drug absorption after oral administration clinical implications. Clin Pharmacokinet. 1999;36(3):233–54.

    Article  CAS  PubMed  Google Scholar 

  • Foo MY, Cheng Y-S, Su W-C, Donovan MD. The Influence of Spray Properties on Intranasal Deposition. J Aerosol Med. 2007;20(4):495–508.

    Article  CAS  PubMed  Google Scholar 

  • Foster JB, Lee WB. The tear film. In: Ocular surface disease: cornea, conjunctiva and tear film: Expert Consult – Online and Print, 1st edition. London: Saunders, 2013. p. 17–21

    Google Scholar 

  • Friedman NJ, Kaiser PK. Ocular anatomy, physiology, and embryology. In: Essentials of ophthalmology. Elsevier; 2007. p. 1–17.

    Google Scholar 

  • Gabor F, Fillafer C, Neutsch L, Ratzinger G, Wirth M. Improving oral delivery. In: Schaefer-Korting M, editor. Drug delivery. Berlin: Springer; 2010.

    Google Scholar 

  • Gavini E, Hegge AB, Rassu G, Sanna V, Testa C, Pirisino G, et al. Nasal administration of Carbamazepine using chitosan microspheres: In vitro/in vivo studies. Int J Pharm. 2006;307(1):9–15.

    Article  CAS  PubMed  Google Scholar 

  • Green M, et al. Abraxane®, a novel Cremophor®-free, albumin-bound particle form of paclitaxel for the treatment of advanced non-small-cell lung cancer. Ann Oncol. 2006;17(8):1263–8.

    Article  CAS  PubMed  Google Scholar 

  • Groneberg DA, Witt C, Wagner U, Chung KF, Fischer A. Fundamentals of pulmonary drug delivery. Respir Med. 2003;97(4):382–7.

    Article  CAS  PubMed  Google Scholar 

  • Gu C-H, Li H, Levons J, Lentz K, Gandhi RB, Raghavan K, et al. Predicting effect of food on extent of drug absorption based on physicochemical properties. Pharm Res. 2007;24(6):1118–30.

    Article  CAS  PubMed  Google Scholar 

  • Gupta A, Stein SW, Myrdal PB. Balancing ethanol cosolvent concentration with product performance in 134a-based pressurized metered dose inhalers. J Aerosol Med. 2003;16(2):167–74.

    Article  CAS  PubMed  Google Scholar 

  • Hardy JG, Lee SW, Wilson CG. Intranasal drug delivery by spray and drops. J Pharm Pharmacol. 1985;37(5):294–7.

    Article  CAS  PubMed  Google Scholar 

  • Heyder J, Gebhart J, Rudolf G, Schiller C, Stahlhofen W. Deposition of particles in the human respiratory tract in the size range 0.005–15 μm. J Aerosol Sci. 1986;17(5):811–25.

    Article  Google Scholar 

  • Hochman JH, Chiba M, Nishime J, Yamazaki M, Lin JH. Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4. J Pharmacol Exp Ther. 2000;292(1):310–8.

    CAS  PubMed  Google Scholar 

  • Hofmann AF, Mysels KJ. Bile salts as biological surfactants. Colloid Surface. 1987;30(1):145–73.

    Article  Google Scholar 

  • Illum L. Nasal drug delivery—possibilities, problems and solutions. J Control Release. 2003;87(1–3):187–98.

    Article  CAS  PubMed  Google Scholar 

  • Itin C, et al. Prolonged oral transmucosal delivery of highly lipophilic drug cannabidiol. Int J Pharm. 2020;581:119276.

    Article  CAS  PubMed  Google Scholar 

  • Jacobs C, Müller RH. Production and characterization of a budesonide nanosuspension for pulmonary administration. Pharm Res. 2002;19(2):189–94.

    Article  CAS  PubMed  Google Scholar 

  • Jain KK. Drug delivery systems – an overview. In: Jain KK, editor. Drug delivery systems. Totowa, NJ: Humana Press; 2008.

    Chapter  Google Scholar 

  • Jansook P, Stefánsson E, Thorsteinsdóttir M, Sigurdsson BB, Kristjánsdóttir SS, Bas JF, et al. Cyclodextrin solubilization of carbonic anhydrase inhibitor drugs: formulation of dorzolamide eye drop microparticle suspension. Eur J Pharm Biopharm. 2010;76(2):208–14.

    Article  CAS  PubMed  Google Scholar 

  • Jara MO, et al. Amorphous solid dispersions and the contribution of nanoparticles to in vitro dissolution and in vivo testing: niclosamide as a case study. Pharmaceutics. 2021;13(1):97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • **no J, Kamada N, Miyake M, Yamada K, Mukai T, Odomi M, et al. Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs. J Control Release. 2006;111(1–2):56–64.

    Article  CAS  PubMed  Google Scholar 

  • Johnson JLH, He Y, Yalkowsky SH. Prediction of precipitation-induced phlebitis: a statistical validation of an in vitro model. J Pharm Sci. 2003;92(8):1574–81.

    Article  CAS  PubMed  Google Scholar 

  • Kane FE, Burdan J, Cutino A, Green KE. IluvienTM: a new sustained delivery technology for posterior eye disease. Expert Opin Drug Deliv. 2008;5(9):1039–46.

    Article  CAS  PubMed  Google Scholar 

  • Kaur IP, Kakkar S. Nanotherapy for posterior eye diseases. J Control Release. 2014;193:100–12.

    Article  CAS  PubMed  Google Scholar 

  • Kim S-I. Aqueous-based pharmaceutical composition [Internet]. US7977045 B2, 2011

    Google Scholar 

  • Kim H, Robinson MR, Lizak MJ, Tansey G, Lutz RJ, Yuan P, et al. Controlled drug release from an ocular implant: an evaluation using dynamic three-dimensional magnetic resonance imaging. Invest Ophthalmol Vis Sci. 2004;45(8):2722–31.

    Article  PubMed  Google Scholar 

  • Kim JH, Jang SW, Han SD, Hwang HD, Choi H-G. Development of a novel ophthalmic ciclosporin A-loaded nanosuspension using top-down media milling methods. Pharmazie. 2011;66(7):491–5.

    CAS  PubMed  Google Scholar 

  • Kim J-E, Cho H-J, Kim D-D. Budesonide/cyclodextrin complex-loaded lyophilized microparticles for intranasal application. Drug Dev Ind Pharm. 2014;40(6):743–8.

    Article  CAS  PubMed  Google Scholar 

  • Klein CE, Chiu Y-L, Awni W, Zhu T, Heuser RS, Doan T, et al. The tablet formulation of lopinavir/ritonavir provides similar bioavailability to the soft-gelatin capsule formulation with less pharmacokinetic variability and diminished food effect. J Acquir Immune Defic Syndr. 2007;44(4):401–10.

    Article  CAS  PubMed  Google Scholar 

  • Knight B, Troutman M, Thakker DR. Deconvoluting the effects of P-glycoprotein on intestinal CYP3A: a major challenge. Curr Opin Pharmacol. 2006;6(5):528–32.

    Article  CAS  PubMed  Google Scholar 

  • Koziolek M, Schneider F, Grimm M, Modeβ C, Seekamp A, Roustom T, et al. Intragastric pH and pressure profiles after intake of the high-caloric, high-fat meal as used for food effect studies. J Control Release. 2015;220(Part A):71–8.

    Article  CAS  PubMed  Google Scholar 

  • Kristinsson J, Fridriksdóttir H, Thórisdóttir S, Sigurdardóttir A, Stefánsson E, Loftsson T. Dexamethasone-cyclodextrin-polymer co-complexes in aqueous eye drops. Aqueous humor pharmacokinetics in humans. Invest Ophthalmol Vis Sci. 1996;37(6):1199–203.

    CAS  PubMed  Google Scholar 

  • Krzyzaniak JF, Núñez Fa A, Raymond DM, Yalkowsky SH. Lysis of human red blood cells. 4. Comparison of in vitro and in vivo hemolysis data. J Pharm Sci. 1997;86(11):1215–7.

    Article  CAS  PubMed  Google Scholar 

  • Kublik H, Vidgren MT. Nasal delivery systems and their effect on deposition and absorption. Adv Drug Deliv Rev. 1998;29(1–2):157–77.

    Article  CAS  PubMed  Google Scholar 

  • Kumar M, Misra A, Mishra AK, Mishra P, Pathak K. Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting. J Drug Target. 2008;16(10):806–14.

    Article  CAS  PubMed  Google Scholar 

  • Labiris NR, Dolovich MB. Pulmonary drug delivery Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56(6):600–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lam JKW, et al. Transmucosal drug administration as an alternative route in palliative and end-of-life care during the COVID-19 pandemic. Adv Drug Deliv Rev. 2020;160:234–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee VHL, Yang JJ. Oral drug delivery. In: Hillery AM, Lloyd AW, Swarbrick J, editors. Drug delivery and targeting for pharmacists and pharmaceutical scientists. London: Taylor & Francis; 2001.

    Google Scholar 

  • Lee Y-C, Zocharski PD, Samas B. An intravenous formulation decision tree for discovery compound formulation development. Int J Pharm. 2003;253(1–2):111–9.

    Article  CAS  PubMed  Google Scholar 

  • Levine RR. Factors affecting gastrointestinal absorption of drugs. Am J Dig Dis. 1970;15(2):171–88.

    Article  CAS  PubMed  Google Scholar 

  • Li P, Zhao L. Develo** early formulations: practice and perspective. Int J Pharm. 2007;341(1–2):1–19.

    Article  CAS  PubMed  Google Scholar 

  • Li J, Wu L, Wu W, Wang B, Wang Z, **n H, et al. A potential carrier based on liquid crystal nanoparticles for ophthalmic delivery of pilocarpine nitrate. Int J Pharm. 2013;455(1–2):75–84.

    Article  CAS  PubMed  Google Scholar 

  • Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235–49.

    Article  CAS  PubMed  Google Scholar 

  • Liu B, Gordon WP, Richmond W, Groessl T, Tuntland T. Use of solubilizers in preclinical formulations: Effect of Cremophor EL on the pharmacokinetic properties on early discovery compounds. Eur J Pharm Sci. 2015;Forthcoming

    Google Scholar 

  • Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614–28.

    Article  CAS  PubMed  Google Scholar 

  • Loftsson T, Hreinsdóttir D, Stefánsson E. Cyclodextrin microparticles for drug delivery to the posterior segment of the eye: aqueous dexamethasone eye drops. J Pharm Pharmacol. 2007;59(5):629–35.

    Article  CAS  PubMed  Google Scholar 

  • Loftsson T, Sigurdsson HH, Konrádsdóttir F, Gísladóttir S, Jansook P, Stefánsson E. Topical drug delivery to the posterior segment of the eye: anatomical and physiological considerations. Pharmazie. 2008;63(3):171–9.

    CAS  PubMed  Google Scholar 

  • Loftsson T, Jansook P, Stefánsson E. Topical drug delivery to the eye: dorzolamide. Acta Ophthalmol. 2012;90(7):603–8.

    Article  CAS  PubMed  Google Scholar 

  • Martens TF, Vercauteren D, Forier K, Deschout H, Remaut K, Paesen R, et al. Measuring the intravitreal mobility of nanomedicines with single-particle tracking microscopy. Nanomedicine. 2013;8(12):1955–68.

    Article  CAS  PubMed  Google Scholar 

  • Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol. 2002;42(6):620–43.

    Article  CAS  PubMed  Google Scholar 

  • Marttin E, Verhoef JC, Merkus FW. Efficacy, safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein drugs. J Drug Target. 1998;6(1):17–36.

    Article  CAS  PubMed  Google Scholar 

  • Mathias N, Xu Y, Vig B, Kestur U, Saari A, Crison J, et al. Food effect in humans: predicting the risk through in vitro dissolution and in vivo pharmacokinetic models. AAPS J. 2015;17(4):988–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matilainen L, Toropainen T, Vihola H, Hirvonen J, Järvinen T, Jarho P, et al. In vitro toxicity and permeation of cyclodextrins in Calu-3 cells. J Control Release. 2008;126(1):10–6.

    Article  CAS  PubMed  Google Scholar 

  • McCallion ON, Taylor KM, Thomas M, Taylor AJ. Nebulization of fluids of different physicochemical properties with air-jet and ultrasonic nebulizers. Pharm Res. 1995;12(11):1682–8.

    Article  CAS  PubMed  Google Scholar 

  • McDonald C, Muzumdar PP. Prevention of precipitation of phenytoin in an infusion fluid by hydroxypropyl beta-cyclodextrin. J Clin Pharm Ther. 1998;23(3):235–9.

    Article  CAS  PubMed  Google Scholar 

  • Meyer CH, Michels S, Rodrigues EB, Hager A, Mennel S, Schmidt JC, et al. Incidence of rhegmatogenous retinal detachments after intravitreal antivascular endothelial factor injections. Acta Ophthalmol. 2011;89(1):70–5.

    Article  CAS  PubMed  Google Scholar 

  • Mitruka SN, Pham SM, Zeevi A, Li S, Cai J, Burckart GJ, et al. Aerosol cyclosporine prevents acute allograft rejection in experimental lung transplantation. J Thorac Cardiovasc Surg. 1998;115(1):28–37.

    Article  CAS  PubMed  Google Scholar 

  • Miyazaki S, Suzuki S, Kawasaki N, Endo K, Takahashi A, Attwood D. In situ gelling xyloglucan formulations for sustained release ocular delivery of pilocarpine hydrochloride. Int J Pharm. 2001;229(1–2):29–36.

    Article  CAS  PubMed  Google Scholar 

  • Mogalian E, Myrdal PB. Pharmaceutical solvents for pulmonary drug delivery. In: Augustijns P, Brewster M, editors. Solvent systems and their selection in pharmaceutics and Biopharmaceutics. New York: Springer; 2007.

    Google Scholar 

  • Mogalian E, Oliyai R, Stefanidis D, Zia V. Solid dispersion formulation of an antiviral compound [Internet]. US20140212487 A1, 2014

    Google Scholar 

  • Monschke M, Wagner KG. Amorphous solid dispersions of weak bases with pH-dependent soluble polymers to overcome limited bioavailability due to gastric pH variability – an in-vitro approach. Int J Pharm. 2019;564:162–70.

    Article  CAS  PubMed  Google Scholar 

  • Montharu J, Le Guellec S, Kittel B, Rabemampianina Y, Guillemain J, Gauthier F, et al. Evaluation of lung tolerance of ethanol, propylene glycol, and sorbitan monooleate as solvents in medical aerosols. J Aerosol Med Pulm Drug Deliv. 2010;23(1):41–6.

    Article  CAS  PubMed  Google Scholar 

  • Mottu F, Stelling M-J, Rüfenacht DA, Doelker E. Comparative hemolytic activity of undiluted organic water-miscible solvents for intravenous and intra-arterial injection. PDA J Pharm Sci Technol. 2001;55(1):16.

    CAS  PubMed  Google Scholar 

  • Mudra DR, Desino KE, Desai PV. In silico, in vitro and in situ models to assess interplay between CYP3A and P-gp. Curr Drug Metab. 2011;12(8):750–73.

    Article  CAS  PubMed  Google Scholar 

  • Nagai N, Yoshioka C, Mano Y, Tnabe W, Ito Y, Okamoto N, et al. A nanoparticle formulation of disulfiram prolongs corneal residence time of the drug and reduces intraocular pressure. Exp Eye Res. 2015;132:115–23.

    Article  CAS  PubMed  Google Scholar 

  • Narazaki R, Sanghvi R, Yalkowsky SH. Estimation of drug precipitation upon dilution of pH-controlled formulations. Mol Pharm. 2007;4(4):550–5.

    Article  CAS  PubMed  Google Scholar 

  • Naveh N, Muchtar S, Benita S. Pilocarpine incorporated into a submicron emulsion vehicle causes an unexpectedly prolonged ocular hypotensive effect in rabbits. J Ocul Pharmacol Ther. 1994;10(3):509–20.

    Article  CAS  Google Scholar 

  • Nernst W. Theorie der Reaktionsgeschwindigkeit in heterogenen Systemen. Zeitschrift f Physikalische Chemie. 1904;47:52–5.

    Article  CAS  Google Scholar 

  • Noakes T. Medical aerosol propellants. J Fluor Chem. 2002;118(1–2):35–45.

    Article  CAS  Google Scholar 

  • Noyes A, Whitney W. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19:930–4.

    Article  Google Scholar 

  • Oberdörster G. Pulmonary carcinogenicity of inhaled particles and the maximum tolerated dose. Environ Health Perspect. 1997;105(Suppl):1347–55.

    PubMed  PubMed Central  Google Scholar 

  • Ohira A, Hara K, Jóhannesson G, Tanito M, Ásgrímsdóttir GM, Lund SH, et al. Topical dexamethasone γ-cyclodextrin nanoparticle eye drops increase visual acuity and decrease macular thickness in diabetic macular oedema. Acta Ophthalmol. 2015;93(7):610–5.

    Article  CAS  PubMed  Google Scholar 

  • Ohnishi M, Sagitani H. The effect of nonionic surfactant structure on hemolysis. J Am Oil Chem Soc. 1993;70(7):679–84.

    Article  CAS  Google Scholar 

  • Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC, et al. The human intestinal cytochrome P450 “PIE” abstract. Methods. 2006;34(5):880–6.

    CAS  Google Scholar 

  • Panigone S, et al. Environmental impact of inhalers for respiratory diseases: decreasing the carbon footprint while preserving patient-tailored treatment. BMJ Open Respir Res. 2020;7(1):e000571.

    Article  PubMed  PubMed Central  Google Scholar 

  • Patel VF, et al. Advances in oral transmucosal drug delivery. J Control Release. 2011;153(2):106–16.

    Article  CAS  PubMed  Google Scholar 

  • Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov. 2007;6(1):67–74.

    Article  CAS  PubMed  Google Scholar 

  • Patton JS, Fishburn CS, Weers JG. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc. 2004;1(4):338–44.

    Article  CAS  PubMed  Google Scholar 

  • Perlman ME, Murdande SB, Gumkowski MJ, Shah TS, Rodricks CM, Thornton-Manning J, et al. Development of a self-emulsifying formulation that reduces the food effect for torcetrapib. Int J Pharm. 2008;351(1–2):15–22.

    Article  CAS  PubMed  Google Scholar 

  • Petursson G, Cole R, Hanna C. Treatment of glaucoma using minidrops of clonidine. Arch Ophthalmol. 1984;102(8):1180–1.

    Article  CAS  PubMed  Google Scholar 

  • Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392(1–2):1–19.

    Article  CAS  PubMed  Google Scholar 

  • Popov A. Mucus-penetrating particles and the role of ocular mucus as a barrier to micro-and nanosuspensions. J Ocul Pharmacol Ther. 2020;36(6):366–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pujara CP, Shao Z, Duncan MR, Mitra AK. Effects of formulation variables on nasal epithelial cell integrity: Biochemical evaluations. Int J Pharm. 1995;114(2):197–203.

    Article  CAS  Google Scholar 

  • Radi AE, Eissa S. Electrochemistry of cyclodextrin inclusion complexes of pharmaceutical compounds. Open Chem Biomed Meth J. 2010;3:74–85.

    Article  CAS  Google Scholar 

  • Reed KW, Yalkowsky SH. Lysis of human red blood cells in the presence of various cosolvents III. The relationship between hemolytic potential and structure. J Parenter Sci Technol. 1987;41(1):37–9.

    CAS  PubMed  Google Scholar 

  • Renwick LC, Donaldson K, Clouter A. Impairment of alveolar macrophage phagocytosis by ultrafine particles. Toxicol Appl Pharmacol. 2001;172(2):119–27.

    Article  CAS  PubMed  Google Scholar 

  • Renwick LC, Brown D, Clouter A, Donaldson K. Increased inflammation and altered macrophage chemotactic responses caused by two ultrafine particle types. Occup Environ Med. 2004;61(5):442–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saini D, Biris AS, Srirama PK, Mazumder MK. Particle size and charge distribution analysis of pharmaceutical aerosols generated by inhalers. Pharm Dev Technol. 2007;12(1):35–41.

    Article  CAS  PubMed  Google Scholar 

  • Sakurai E, Ozeki H, Kunou N, Ogura Y. Effect of Particle Size of Polymeric Nanospheres on Intravitreal Kinetics. Ophthalmic Res. 2001;33(1):31–6.

    Article  CAS  PubMed  Google Scholar 

  • Salem LB, Bosquillon C, Dailey LA, Delattre L, Martin GP, Evrard B, et al. Sparing methylation of beta-cyclodextrin mitigates cytotoxicity and permeability induction in respiratory epithelial cell layers in vitro. J Control Release. 2009;136(2):110–6.

    Article  CAS  PubMed  Google Scholar 

  • Sastry S, Nyshadham J, Fix J. Recent technological advances in oral drug delivery - a review. Pharmaceut Sci Tech Today. 2000;3(4):138–45.

    Article  CAS  Google Scholar 

  • Sauron R, Wilkins M, Jessent V, Dubois A, Maillot C, Weil A. Absence of a food effect with a 145 mg nanoparticle fenofibrate tablet formulation. Int J Clin Pharmacol Ther. 2006;44(2):64–70.

    Article  CAS  PubMed  Google Scholar 

  • Schütte JK, et al. Comparison of the therapeutic effectiveness of a dantrolene sodium solution and a novel nanocrystalline suspension of dantrolene sodium in malignant hyperthermia normal and susceptible pigs. Eur J Anaesthesiol (EJA). 2011;28(4):256–64.

    Article  CAS  Google Scholar 

  • Sebag J. Vitreous anatomy and pathology. In: Yanoff M, Duker JS, editors. Ophthalmology: Expert consult: Online and Print. 4th edition. Saunders, 2013. p. 687–9

    Google Scholar 

  • Shah SA, Dickens CJ, Ward DJ, Banaszek AA, George C, Horodnik W. Design of experiments to optimize an in vitro cast to predict human nasal drug deposition. J Aerosol Med Pulm Drug Deliv. 2014;27(1):21–9.

    Article  CAS  PubMed  Google Scholar 

  • Shalel S, Streichman S, Marmur A. The mechanism of hemolysis by surfactants: effect of solution composition. J Colloid Interface Sci. 2002;252(1):66–76.

    Article  CAS  PubMed  Google Scholar 

  • Sharif MS, Qahwaji R, Shahamatnia E, Alzubaidi R, Ipson S, Brahma A. An efficient intelligent analysis system for confocal corneal endothelium images. Comput Methods Programs Biomed. 2015;122(3):421–36.

    Article  CAS  PubMed  Google Scholar 

  • Shi Y, Porter W, Merdan T, Li LC. Recent advances in intravenous delivery of poorly water-soluble compounds. Expert Opin Drug Deliv. 2009;6(12):1261–82.

    Article  CAS  PubMed  Google Scholar 

  • Sigurdsson HH, Stefánsson E, Gudmundsdóttir E, Eysteinsson T, Thorsteinsdóttir M, Loftsson T. Cyclodextrin formulation of dorzolamide and its distribution in the eye after topical administration. J Control Release. 2005;102(1):255–62.

    Article  CAS  PubMed  Google Scholar 

  • Singla AK, Garg A, Aggarwal D (2002) Paclitaxel and its formulations. Int J Pharm 235(1–2):179–192

    Google Scholar 

  • Smith DA, Jones BC, Walker DK. Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics. Med Res Rev. 1996;16(3):243–66.

    Article  CAS  PubMed  Google Scholar 

  • Smyth HDC. The influence of formulation variables on the performance of alternative propellant-driven metered dose inhalers. Adv Drug Deliv Rev. 2003;55(7):807–28.

    Article  CAS  PubMed  Google Scholar 

  • Smyth HDC. Excipients for pulmonary formulations. In: Katdare A, Chaubal M, editors. Excipient development for pharmaceutical, biotechnology, and drug delivery systems. CRC Press; 2006. p. 225–44.

    Chapter  Google Scholar 

  • Sparreboom A, van Tellingen O, Nooijen WJ, Beijnen JH. Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle Cremophor EL. Cancer Res. 1996;56(9):2112–5.

    CAS  PubMed  Google Scholar 

  • Sparreboom A, van Zuylen L, Brouwer E, Loos WJ, de Bruijn P, Gelderblom H, et al. Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res. 1999;59(7):1454–7.

    CAS  PubMed  Google Scholar 

  • Stella VJ, He Q. Cyclodextrins. Toxicol Pathol. 2008;36(1):30–42.

    Article  CAS  PubMed  Google Scholar 

  • Stella V, Rao V, Zannou E, Zia V. Mechanisms of drug release from cyclodextrin complexes. Adv Drug Deliv Rev. 1999;36(1):3–16.

    Article  CAS  PubMed  Google Scholar 

  • Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res. 2004;21(2):201–30.

    Article  CAS  PubMed  Google Scholar 

  • Sugano K, Okazaki A, Sugimoto S, Tavornvipas S, Omura A, Mano T. Solubility and dissolution profile assessment in drug discovery. Drug Metab Pharmacokinet. 2007;22(4):225–54.

    Article  CAS  PubMed  Google Scholar 

  • Suman JD, Laube BL, Dalby R. Comparison of nasal deposition and clearance of aerosol generated by a nebulizer and an aqueous spray pump. Pharm Res. 1999;16(10):1648–52.

    Article  CAS  PubMed  Google Scholar 

  • Sunesen VH, Vedelsdal R, Kristensen HG, Christrup L, Müllertz A. Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug. Eur J Pharm Sci. 2005;24(4):297–303.

    Article  CAS  PubMed  Google Scholar 

  • Szebeni J, Muggia FM, Alving CR. Complement activation by Cremophor EL as a possible contributor to hypersensitivity to paclitaxel: an in vitro study. J Natl Cancer Inst. 1998;90(4):300–6.

    Article  CAS  PubMed  Google Scholar 

  • Tam JM, McConville JT, Williams RO, Johnston KP. Amorphous cyclosporin nanodispersions for enhanced pulmonary deposition and dissolution. J Pharm Sci. 2008;97(11):4915–33.

    Article  CAS  PubMed  Google Scholar 

  • Tamilvanan S, Benita S. The potential of lipid emulsion for ocular delivery of lipophilic drugs. Eur J Pharm Biopharm. 2004;58(2):357–68.

    Article  CAS  PubMed  Google Scholar 

  • Tamilvanan S, Kumar BA. Influence of acetazolamide loading on the (in vitro) performances of non-phospholipid-based cationic nanosized emulsion in comparison with phospholipid-based anionic and neutral-charged nanosized emulsions. Drug Dev Ind Pharm. 2011;37(9):1003–15.

    Article  CAS  PubMed  Google Scholar 

  • Tanaka Y, Goto T, Kataoka M, Sakuma S, Yamashita S. Impact of luminal fluid volume on the drug absorption after oral administration: analysis based on in vivo drug concentration–time profile in the gastrointestinal tract. J Pharm Sci. 2015;104(9):3120–7.

    Article  CAS  PubMed  Google Scholar 

  • Ten Tije AJ, Verweij J, Loos WJ, Sparreboom A. Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin Pharmacokinet. 2003;42(7):665–85.

    Article  CAS  PubMed  Google Scholar 

  • Tewes F, Brillault J, Couet W, Olivier J-C. Formulation of rifampicin-cyclodextrin complexes for lung nebulization. J Control Release. 2008;129(2):93–9.

    Article  CAS  PubMed  Google Scholar 

  • Thi THH, Azaroual N, Flament M-P. Characterization and in vitro evaluation of the formoterol/cyclodextrin complex for pulmonary administration by nebulization. Eur J Pharm Biopharm. 2009;72(1):214–8.

    Article  CAS  PubMed  Google Scholar 

  • Thomas C, Ahsan F. Nasal delivery of peptide and nonpeptide drugs. In: Gad SC, editor. Pharmaceutical manufacturing handbook: production and processes. 1st ed. Hoboken, N.J: Wiley-Interscience; 2008. p. 591–650.

    Chapter  Google Scholar 

  • Tolman JA, Williams RO. Advances in the pulmonary delivery of poorly water-soluble drugs: influence of solubilization on pharmacokinetic properties. Drug Dev Ind Pharm. 2009;36(1):1–30.

    Article  Google Scholar 

  • Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA. Trojan particles: large porous carriers of nanoparticles for drug delivery. Proc Natl Acad Sci U S A. 2002;99(19):12001–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuji A, Tamai I, Sasaki K. Intraocular penetration kinetics of prednisolone after subconjunctival injection in rabbits. Ophthalmic Res. 1988;20(1):31–43.

    Article  CAS  PubMed  Google Scholar 

  • Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev. 2006;58(11):1131–5.

    Article  CAS  PubMed  Google Scholar 

  • Van Santvliet L, Ludwig A. Determinants of eye drop size. Surv Ophthalmol. 2004;49(2):197–213.

    Article  PubMed  Google Scholar 

  • Van Zuylen L, Karlsson MO, Verweij J, Brouwer E, de Bruijn P, Nooter K, et al. Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles. Cancer Chemother Pharmacol. 2001;47(4):309–18.

    Article  CAS  PubMed  Google Scholar 

  • Vandervoort J, Ludwig A. Ocular drug delivery: nanomedicine applications. Nanomedicine. 2007;2(1):11–21.

    Article  CAS  PubMed  Google Scholar 

  • Verma P, Gupta RN, Jha AK, Pandey R. Development, in vitro and in vivo characterization of Eudragit RL 100 nanoparticles for improved ocular bioavailability of acetazolamide. Drug Deliv. 2013;20(7):269–76.

    Article  CAS  PubMed  Google Scholar 

  • Wang T, Noonberg S, Steigerwalt R, Lynch M, Kovelesky RA, Rodríguez CA, et al. Preclinical safety evaluation of inhaled cyclosporine in propylene glycol. J Aerosol Med. 2007;20(4):417–28.

    Article  PubMed  CAS  Google Scholar 

  • Wang S, Chen P, Zhang L, Yang C, Zhai G. Formulation and evaluation of microemulsion-based in situ ion-sensitive gelling systems for intranasal administration of curcumin. J Drug Target. 2012;20(10):831–40.

    Article  PubMed  CAS  Google Scholar 

  • Webster LK, Cosson EJ, Stokes KH, Millward MJ. Effect of the paclitaxel vehicle, Cremophor EL, on the pharmacokinetics of doxorubicin and doxorubicinol in mice. Br J Cancer. 1996;73(4):522–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weinreb RN, Khaw PT. Primary open-angle glaucoma. The Lancet. 2004;363(9422):1711–20.

    Article  Google Scholar 

  • Welling PG. Effects of food on drug absorption. Annu Rev Nutr. 1996;16:383–415.

    Article  CAS  PubMed  Google Scholar 

  • Wong J, Brugger A, Khare A, Chaubal M, Papadopoulos P, Rabinow B, et al. Suspensions for intravenous (IV) injection: a review of development, preclinical and clinical aspects. Adv Drug Deliv Rev. 2008;60(8):939–54.

    Article  CAS  PubMed  Google Scholar 

  • Woo JS, Song Y-K, Hong J-Y, Lim S-J, Kim C-K. Reduced food-effect and enhanced bioavailability of a self-microemulsifying formulation of itraconazole in healthy volunteers. Eur J Pharm Sci. 2008;33(2):159–65.

    Article  CAS  PubMed  Google Scholar 

  • Wu C-Y, Benet LZ. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22(1):11–23.

    Article  CAS  PubMed  Google Scholar 

  • Yalkowsky SH, Krzyzaniak JF, Ward GH. Formulation-related problems associated with intravenous drug delivery. J Pharm Sci. 1998;87(7):787–96.

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Tam J, Miller DA, Zhou J, McConville JT, Johnston KP, et al. High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers. Int J Pharm. 2008;361(1–2):177–88.

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Chow KT, Lang B, Wiederhold NP, Johnston KP, Williams RO. In vitro characterization and pharmacokinetics in mice following pulmonary delivery of itraconazole as cyclodextrin solubilized solution. Eur J Pharm Sci. 2010;39(5):336–47.

    Article  CAS  PubMed  Google Scholar 

  • Yasuji T, Kondo H, Sako K. The effect of food on the oral bioavailability of drugs: a review of current developments and pharmaceutical technologies for pharmacokinetic control. Ther Deliv. 2011;3(1):81–90.

    Article  CAS  Google Scholar 

  • Ying L, Tahara K, Takeuchi H. Drug delivery to the ocular posterior segment using lipid emulsion via eye drop administration: Effect of emulsion formulations and surface modification. Int J Pharm. 2013;453(2):329–35.

    Article  CAS  PubMed  Google Scholar 

  • Zaslavsky BY, Ossipov NN, Rogozhin SV. Action of surface-active substances of biological membranes III. Comparison of hemolytic activity of ionic and nonionic surfactants. Biochim Biophys Acta. 1978;510(1):151–9.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Zachary Warnken .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Warnken, Z., Smyth, H.D.C., Williams, R.O. (2022). Route-Specific Challenges in the Delivery of Poorly Water-Soluble Drugs. In: Williams III, R.O., Davis Jr., D.A., Miller, D.A. (eds) Formulating Poorly Water Soluble Drugs. AAPS Advances in the Pharmaceutical Sciences Series, vol 50. Springer, Cham. https://doi.org/10.1007/978-3-030-88719-3_1

Download citation

Publish with us

Policies and ethics

Navigation