Опубликовать статью

Информационное партнерство

Инфоресурсы

Контакты

«

Vol. 25, Art. 5 (pp. 71-101)    |    2024       

»

The use of perfluorocarbons in the treatment of severe bronchopulmonary pathology. Part III: targeted delivery of medicines. (Analytical review)

Barinov V.A.,1 Bonitenko E.U.,1,2 Gladchuk A.S.,1 Belyakova N.A.1

1Federal State Budgetary Institution «Scientific and Clinical Center of Toxicology named after academician S.N. Golikov of the Federal Medical and Biological Agency
192019, Sankt-Peterburg, str. Behtereva, 1
E-mail: vladbar.57@yandex.ru
2Federal State Budgetary Science Institution «Scentific institute of occupational medicine named after academician N.F. Izmerova»
105275, Moskva, pr. Budennogo, 31

Brief summary

In the treatment of severe bronchopulmonary pathology, systemic administration of drugs is often associated with numerous difficulties associated with their degradation under the action of serum and hepatic enzymes and rapid renal clearance, as well as pulmonary blood flow disorders limiting passive diffusion of the drug from the blood into the lung parenchyma. These difficulties can be overcome by the use of local administration of drugs by inhalation or instillation into the respiratory way. It is believed that intrapulmonary administration of drugs may allow achieving higher concentrations in the affected areas compared to other routes of administration. At the same time, targeted delivery reduces systemic absorption, which protects non-target organs from drug side effects and allows the maximum dose of the drug to be delivered as intended. In this regard, it is critically important to select the optimal carrier for the drug, which would meet homogeneous distribution of the drug over the entire surface of the respiratory tract. From this point of view, the use of perfluorocarbon (PFC) liquids, due to a number of their unique physical and chemical properties, as carriers for targeted delivery of drugs to the lungs is promising. However, despite the fact that perfluorocarbons are promising agents for the administration of drugs directly into the lungs, the poor solubility of most of them in PFC liquids is a major obstacle to their use as a means of delivery. Thus, finding ways to disperse or solubilize drug molecules in perfluorocarbons is one of the main challenges that need to be solved in order to use the latter as a means of drug delivery to the lungs. The aim of the study is to identify promising approaches to the creation of drug emulsions and suspension in PFC liquids, which can be used for targeted delivery directly to the affected areas of light tissue to increase their therapeutic efficacy. Materials and methods. Russian and foreign scientific publications identified as a result of a search in scientific electronic libraries were used as materials. The main method of research was the generalization of available literature data on the methods of using PFC liquids as carriers for endotracheal administration of drugs. Outcomes. There are three main approaches in the literature that can be used for targeted delivery of drugs to the lungs using perfluorocarbons. The first and simplest is to dissolve the drug in PFC liquids and inject the resulting solution into the lungs. This method can be used when working with a number of fluorinated drugs, which are highly soluble in perfluorocarbons, unlike most other drugs. The second approach is related to the creation of suspensions, including solid pharmaceutical substances that are insoluble in perfluorocarbons. Such suspensions have been shown to have sufficiently high stability and good therapeutic efficacy. In order to increase the stability of suspensions, micronized forms and hollow porous microparticles containing drugs were developed, which have an affinity for perfluorocarbons. The latter have shown their high efficiency in various models of experimental pathology in both adult and newborn laboratory animals. Along with the technology for the production of hollow porous microparticles of drugs, solubilizing agents can also be used to increase the solubility of solid forms in perfluorocarbons. A third approach is to create inverse emulsions of the water-in-PFC liquid type, which allow for a more uniform and reproducible distribution of drugs compared to suspensions. It should also be noted that the creation of water-to-PFC liquid emulsions is a significantly less expensive and labor-intensive process. However, such emulsions, despite their homogeneous distribution in the lung tissues, have low stability, which significantly complicates the control of the dose of the injected drug. Emulsifiers, primarily surfactants, are used to stabilize aqueous droplets in order to create submicron emulsions of the water-in-PFC liquid type with a narrow range of particle distribution. The efficacy of this approach has been demonstrated on drugs of various pharmacological groups, such as antibiotics, vasoactive bronchodilators, mucolytics, glucocorticoids, as well as antituberculous, cholinergic and antitumor drugs. Conclusion. The question of the use of PFC liquids for targeted drug delivery remains not only open, but is also filled with new content. This is due to the fact that the main method of injecting drugs directly into the affected areas was their instillation into the lungs during (for newborns and premature infants) or after (for older children and adults) bronchoalveolar lavage. This approach allows not only targeted administration of drugs, but also to create optimal conditions for the implementation of their pharmacological action. It is also possible to formulate preliminary requirements for drug emulsions in PFCs depending on the pharmacological group of drugs used. At the same time, the main indicator is the stability of the drug emulsion in PFCs, according to which they can be divided into two main groups: unstable and stable. The main task of unstable emulsions is to ensure the injection of drugs directly into the target (affected) area of the lung until they are demulsified. At the same time, the main requirement for unstable drug emulsions is the simplicity of their preparation and, accordingly, their use. In turn, the use of stable drug emulsions is justified if it is necessary not only to deliver the drug to the affected areas of the lungs, but also to maintain high concentrations of the active ingredient in them for a long time. The analysis of the literature indicates that at present all the necessary approaches have been developed for the creation of both unstable and stable emulsions of drugs with different physicochemical properties from various pharmacological groups in PFC liquids for their targeted delivery to the target areas of the lungs during or after therapeutic bronchoalveolar lavage.


Key words

targeted delivery, perfluorocarbons, perfluorodecalin, perflubron, drugs, endotracheal administration, suspensions, emulsions, liquid ventilation, partial liquid ventilation

Reference list

1.Bennett W.D., Brown J.S., Zeman K.L. et al. Targeting delivery of aerosols to different lung regions. J. Aerosol. Med. 2002; 15(2): 179-188. doi: 10.1089/089426802320282301.


2. Rocha G. Inhaled Pharmacotherapy for Neonates: A Narrative Review. Turk Arch Pediatr 2022; 57: 5-17 DOI: 10.5152/TurkArchPediatr.2021.21125


3. Bonitenko E.U., Belyakova N.A., Barinov V.A. i dr. Primenenie perftoryglerodov pri lechenii tyajeloi bronholegochnoi patologii. Chast I: klassifikaciya metodov (analiticheskii obzor). Medlain.ry (Medline.ru). 2023; 24: 1368-1397.


4. Wolfson M.R., Shaffer T.H. Liquid ventilation: an adjunct for respiratory management. Paediatr Anaesth. 2004; 14(1): 15-23. doi: 10.1046/j.1460-9592.2003.01206.x


5. Wolfson M.R., Shaffer T.H. Pulmonary applications of perfluorochemical liquids: ventilation and beyond. Paediatr. Respir. Rev. 2005; 6(2): 117-127. doi: 10.1016/j.prrv.2005.03.010.


6. Lehmler H.J. Perfluorocarbon compounds as vehicles for pulmonary drug delivery. Expert. Opin. Drug Deliv. 2007; 4(3): 247-262. doi: 10.1517/17425247.4.3.247.


7. Alapati D., Shaffer T.H. Administration of drugs/gene products to the respiratory system: A historical perspective of the use of inert liquids. Front. Physiol. 2022; 13: 871893. doi: 10.3389/fphys.2022.871893.


8. Tremper K.K., Zaccari J., Cullen B.F., Hufstedler S.M. Liquid-gas partition coefficients of halothane and isoflurane in perfluorodecalin, fluosol-DA, and blood/fluosol-DA mixtures. Anesth. Analg. 1984; 63(7): 690-692.


9. Kimless-Garber D.B., Wolfson M.R., Carlsson C., Shaffer T.H. Halothane administration during liquid ventilation. Respir. Med. 1997; 91(5): 255-262. doi: 10.1016/s0954-6111(97)90028-7.


10. Schubert K.V., Kaler EW. Microemulsifying fluorinated oils with mixtures of fluorinated and hydrogenated surfactants. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 1994; 84(1): 97-106. doi: 10.1016/0927-7757(93)02704-I.


11. Hsu C.H., Jay M., Bummer P.M., Lehmler H.J. Chemical stability of esters of nicotinic acid intended for pulmonary administration by liquid ventilation. Pharm Res. 2003; 20(6): 918-925. doi: 10.1023/a:1023899505837.


12. Gurujeyalakshmi G., Wang Y., Giri S.N. Suppression of bleomycin-induced nitric oxide production in mice by taurine and niacin. Nitric Oxide. 2000; 4(4): 399-411. doi: 10.1006/niox.2000.0297


13. Venkatesan N., Chandrakasan G. In vivo administration of taurine and niacin modulate cyclophosphamide-induced lung injury. Eur. J. Pharmacol. 1994; 292(1): 75-80. doi: 10.1016/0926-6917(94)90028-0.


14. Lehmler H.J., Xu L., Vyas S.M. et al. Synthesis, physicochemical properties and in vitro cytotoxicity of nicotinic acid ester prodrugs intended for pulmonary delivery using perfluorooctyl bromide as vehicle. Int. J. Pharm. 2008; 353(1-2): 35-44. doi: 10.1016/j.ijpharm.2007.11.011


15. Shaffer T.H., Wolfson M.R., Greenspan J.S. et al. Perfluorochemical liquid as a respiratory medium. Artif. Cells Blood Substit. Immobil. Biotechnol. 1994; 22(2): 315-326. doi: 10.3109/10731199409117423.


16. Wolfson M.R., Greenspan J.S., Shaffer T.H. Pulmonary administration of vasoactive substances by perfluorochemical ventilation. Pediatrics. 1996; 97(4): 449-455.


17. Brunelli L., Hamilton E., Davis J.M. et al. Perfluorochemical liquids enhance delivery of superoxide dismutase to the lungs of juvenile rabbits. Pediatr. Res. 2006; 60(1): 65-70. doi: 10.1203/01.pdr.0000219392.73509.70.


18. Wolfson M.R., Enkhbaatar P., Fukuda S. et al. Perfluorochemical-facilitated plasminogen activator delivery to the airways: A novel treatment for inhalational smoke-induced acute lung injury. Clin. Transl. Med. 2020; 10(1): 258-274. doi: 10.1002/ctm2.26.


19. Dellamary L.A., Tarara T.E., Smith D.J. et al. Hollow porous particles in metered dose inhalers. Pharm. Res. 2000; 17(2): 168-174. doi: 10.1023/a:1007513213292.


20. Weers J.G. Dispersible powders for inhalation applications. Innov. Pharm. Tech. 2000, 1(7): 111-116.


21. Smith D.J., Gambone L.M., Tarara T. et al.Liquid dose pulmonary instillation of gentamicin PulmoSpheres formulations: tissue distribution and pharmacokinetics in rabbits. Pharm. Res. 2001; 18(11): 1556-1561. doi: 10.1023/a:1013078330485.


22. Dickson E.W., Heard S.O., Tarara T.E. et al. Liquid ventilation with perflubron in the treatment of rats with pneumococcal pneumonia. Crit. Care Med. 2002; 30(2): 393-395. doi: 10.1097/00003246-200202000-00021.


23. Dickson E.W., Doern G.V., Trevino L. et al. Prevention of descending pneumonia in rats with perflubron-delivered tobramycin. Acad. Emerg. Med. 2003; 10(10): 1019-1023. doi: 10.1111/j.1553-2712.2003.tb00567.x.


24. Cullen A.B., Cox C.A., Hipp S.J. et al. Intra-tracheal delivery strategy of gentamicin with partial liquid ventilation. Respir. Med. 1999; 93: 770-778. doi: 10.1016/s0954-6111(99)90261-5.


25. Cox C.A., Cullen A.B., Wolfson M.R., Shaffer T.H. Intratracheal administration of perfluorochemical-gentamicin suspension: A comparison to intravenous administration in normal and injured lungs. Pediatr. Pulmonol. 2001; 32: 142-151. doi: 10.1002/ppul.1100.


26. Weers J.G., Tarara T.E. The PulmoSphere? platform for pulmonary drug delivery. Ther Deliv. 2014; 5(3): 277-295. doi: 10.4155/tde.14.3.


27. Weers J.G., Miller D.P., Tarara T.E. Spray-dried PulmoSphere? formulations for inhalation comprising crystalline drug particles. AAPS PharmSciTech. 2019; 20(3): 103. doi: 10.1208/s12249-018-1280-0


28. Williams T.D., Jay M., Lehmler H.J. et al. Solubility enhancement of phenol and phenol derivatives in perfluorooctyl bromide. J. Pharm. Sci. 1998; 87(12): 1585-1589. doi: 10.1021/js980156l


29. Jung R., Pendland S.L., Martin S.J. Combined bactericidal activity of perfluorooctyl bromide and aminoglycosides against Pseudomonas aeruginosa. J. Antimicrob. Chemother. 2002; 50(6): 939-944. doi: 10.1093/jac/dkf226


30. Zelinka M.A., Wolfson M.R., Calligaro I. et al. A comparison of intratracheal and intravenous administration of gentamicin during liquid ventilation. Eur. J. Pediatr. 1997; 156(5): 401-404. doi: 10.1007/s004310050625.


31. Fox W.W., Weis C.M., Cox C. et al. Pulmonary administration of gentamicin during liquid ventilation in a newborn lamb lung injury model. Pediatrics. 1997; 100(5): E5. doi: 10.1542/peds.100.5.e5.


32. Jeng M.J., Lee Y.S., Soong W.J. Effects of perfluorochemicals for intrapulmonary vancomycin administration and partial liquid ventilation in an animal model of meconium-injured lungs. Acta Paediatr. Taiwan. 2007; 48(6): 309-316.


33. Nakazawa K., Uchida T., Matsuzawa Y. et al. Treatment of pulmonary hypertension and hypoxia due to oleic acid induced lung injury with intratracheal prostaglandin E1 during partial liquid ventilation // Anesthesiology. 1998; 89(3): 686-692. doi: 10.1097/00000542-199809000-00019.


34. Nakazawa K., Yokoyama K., Matsuzawa Y. et al. Pulmonary administration of prostacyclin (PGI2) during partial liquid ventilation in an oleic acid-induced lung injury: inhalation of aerosol or intratracheal instillation? Intensive Care Med. 2001; 27(1): 243-250. doi: 10.1007/s001340000756.


35. Mrozek J.D., Smith K.M., Simonton S.C. et al. Perfluorocarbon priming and surfactant: physiologic and pathologic effects. Crit. Care Med. 1999; 27(9): 1916-1922. doi: 10.1097/00003246-199909000-00033.


36. Wolfson M.R., Kechner N.E., Roache R.F. et al. Perfluorochemical rescue after surfactant treatment: effect of perflubron dose and ventilatory frequency. J. Appl. Physiol. 1998; 84(2): 624-640. doi: 10.1152/jappl.1998.84.2.624


37. Hartog A., Vazquez de Anda G.F., Gommers D. et al. Comparison of exogenous surfactant therapy, mechanical ventilation with high end-expiratory pressure and partial liquid ventilation in a model of acute lung injury. Br. J. Anaesth. 1999; 82(1): 81-86. doi: 10.1093/bja/82.1.81.


38. Bendel-Stenzel E.M., Smith K.M., Simonton S.C. et al. Surfactant and partial liquid ventilation via conventional and high-frequency techniques in an animal model of respiratory distress syndrome. Pediatr. Crit. Care Med. 2000; 1(1): 72-78. doi: 10.1097/00130478-200007000-00014


39. Chappell S.E., Wolfson M.R., Shaffer T.H. A comparison of surfactant delivery with conventional mechanical ventilation and partial liquid ventilation in meconium aspiration injury. Respir. Med. 2001; 95(7): 612-617. doi: 10.1053/rmed.2001.1114.


40. Wolf S., Lohbrunner H., Busch T. et al. Small dose of exogenous surfactant combined with partial liquid ventilation in experimental acute lung injury: effects on gas exchange, haemodynamics, lung mechanics, and lung pathology. Br. J. Anaesth. 2001; 87(4): 593-601. doi: 10.1093/bja/87.4.593


41. Jeng M.J., Kou Y.R., Sheu C.C., Hwang B. Effects of exogenous surfactant supplementation and partial liquid ventilation on acute lung injury induced by wood smoke inhalation in newborn piglets. Crit. Care Med. 2003; 31(4): 1166-1174. doi: 10.1097/01.CCM.0000059312.90697.32


42. Burkhardt W., Kraft S., Ochs M. et al. Persurf, a new method to improve surfactant delivery: a study in surfactant depleted rats. PLoS One. 2012; 7(10) :e47923. doi: 10.1371/journal.pone.0047923.


43. Weiss D.J., Strandjord T.P., Jackson J.C. et al. Perfluorochemical liquid-enhanced adenoviral vector distribution and expression in lungs of spontaneously breathing rodents. Exp. Lung Res. 1999; 25(4): 317-333. doi: 10.1080/019021499270222.


44. Weiss D.J., Strandjord T.P., Liggitt D., Clark J.G. Perflubron enhances adenovirus-mediated gene expression in lungs of transgenic mice with chronic alveolar filling. Hum. Gene Ther. 1999; 10(14): 2287-2293. doi: 10.1089/10430349950016933.


45. Weiss D.J., Bonneau L., Allen J.M. et al. Perfluorochemical liquid enhances adeno-associated virus-mediated transgene expression in lungs. Mol. Ther. 2000; 2(6): 624-630. doi: 10.1006/mthe.2000.0207.


46. Weiss D.J., Beckett T., Bonneau L. et al. Transient increase in lung epithelial tight junction permeability: an additional mechanism for enhancement of lung transgene expression by perfluorochemical liquids. Mol. Ther. 2003; 8(6): 927-935. doi: 10.1016/j.ymthe.2003.09.003.


47. Kazzaz J.A., Strayer M.S., Wu J. et al. Perfluorochemical liquid-adenovirus suspensions enhance gene delivery to the distal lung. Pulm. Med. 2011; 2011: 918036. doi: 10.1155/2011/918036.


48. Weiss D.J., Bonneau L., Liggitt D. Use of perfluorochemical liquid allows earlier detection of gene expression and use of less vector in normal lung and enhances gene expression in acutely injured lung. Mol. Ther. 2001; 3(5 Pt 1): 734-745 doi: 10.1006/mthe.2001.0321.


49. Lisby D.A., Ballard P.L., Fox W.W. et al. Enhanced distribution of adenovirus-mediated gene transfer to lung parenchyma by perfluorochemical liquid. Hum. Gene Ther. 1997; 8(8): 919-928. doi: 10.1089/hum.1997.8.8-919.


50. Weiss D.J., Baskin G.B., Shean M.K. et al. Use of perfluorochemical liquid to enhance adenoviral-mediated gene expression in lungs of spontaneously breathing non-human primates: feasibility and initial studies. Pediatr. Pulmonol. Suppl. 2000; 20: 235-236.


51. Krafft M.P., Riess J.G. Highly fluorinated amphiphiles and colloidal systems, and their applications in the biomedical field. A contribution. Biochimie. 1998; 80(5-6): 489-514. doi: 10.1016/s0300-9084(00)80016-4


52. Krafft M.P. Fluorocarbons and fluorinated amphiphiles in drug delivery and biomedical research. Adv. Drug Deliv. Rev. 2001; 47(2-3): 209-228. doi: 10.1016/s0169-409x(01)00107-7.


53. Riess J.G. Fluorous micro- and nanophases with a biomedical perspective. Tetrahedron, 2002; 58: 4113-4131.


54. Franz A.R., Röhlke W., Franke R.P. et al. Pulmonary administration of perfluorodecaline-gentamicin and perfluorodecaline-vancomycin emulsions. Am. J. Respir. Crit. Care Med. 2001; 164(9): 1595-1600. doi: 10.1164/ajrccm.164.9.2104088.


55. Sadtler V.M., Jeanneaux F., Krafft M.P. et al. Perfluoroalkylated amphiphiles with a morpholinophosphate or a dimorpholinophosphate polar head group. New J. Chem. 1998; 6: 609-613 doi: 10.1039/A708757H


56. Courrier H.M., Krafft M.P., Butz N. et al. Evaluation of cytotoxicity of new semi-fluorinated amphiphiles derived from dimorpholinophosphate. Biomaterials. 2003; 24(4): 689-696. doi: 10.1016/s0142-9612(02)00407-6.


57. Holtze C., Rowat A.C., Agresti J.J. et al. Biocompatible surfactants for water-in-fluorocarbon emulsions. Lab. Chip. 2008; 8(10): 1632-1639. doi: 10.1039/b806706f.


58. Debbabi K., Guittard F., Eastoe J. et al. Reverse water-in-fluorocarbon microemulsions stabilized by new polyhydroxylated nonionic fluorinated surfactants. Langmuir. 2009; 25(16): 8919-8926. doi: 10.1021/la803579b.


59. Sadtler V.M., Krafft M.P., Riess J.G. Achieving stable, reverse water-in-fluorocarbon emulsions. Angew. Chem. Int. Ed. Engl. 1996; 35: 1976-1978.


60. Ferguson S.K., Pak D.I., Hopkins J.L. et al. Pre-clinical assessment of a water-in-fluorocarbon emulsion for the treatment of pulmonary vascular diseases. Drug Deliv. 2019; 26(1): 147-157. doi: 10.1080/10717544.2019.1568621.


61. Butz N., Porté C., Courrier H. et al. Reverse water-in-fluorocarbon emulsions for use in pressurized metered-dose inhalers containing hydrofluoroalkane propellants. Int. J. Pharm. 2002; 238(1-2): 257-269. doi: 10.1016/s0378-5173(02)00086-8.


62. Courrier H.M., Pons F., Lessinger J.M., Frossard N. et al. In vivo evaluation of a reverse water-in-fluorocarbon emulsion stabilized with a semifluorinated amphiphile as a drug delivery system through the pulmonary route. Int. J. Pharm. 2004; 282(1-2): 131-140. doi: 10.1016/j.ijpharm.2004.06.011.


63. Orizondo R.A., Babcock C.I., Fabiilli M.L. et al. Characterization of a reverse-phase perfluorocarbon emulsion for the pulmonary delivery of tobramycin. J. Aerosol. Med. Pulm. Drug Deliv. 2014; 27(5): 392-399. doi: 10.1089/jamp.2013.1058.


64. Orizondo R.A., Fabiilli M.L., Morales M.A., Cook K.E. Effects of emulsion composition on pulmonary tobramycin delivery during antibacterial perfluorocarbon ventilation. J. Aerosol. Med. Pulm. Drug Deliv. 2016; 29(3): 251-259. doi: 10.1089/jamp.2015.1235.


65. Orizondo R.A., Nelson D.L., Fabiilli M.L., Cook K.E. Effects of fluorosurfactant structure and concentration on drug availability and biocompatibility in water-in-perfluorocarbon emulsions for pulmonary drug delivery. Colloid Polym. Sci. 2017; 295(12): 2413-2422.


66. Nelson D.L., Zhao Y., Fabiilli M.L., Cook K.E. In vitro evaluation of lysophosphatidic acid delivery via reverse perfluorocarbon emulsions to enhance alveolar epithelial repair. Colloids Surf B Biointerfaces. 2018; 169: 411-417. doi: 10.1016/j.colsurfb.2018.05.037


67. Galvin I.M., Steel A., Pinto R. et al. Partial liquid ventilation for preventing death and morbidity in adults with acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst. Rev. 2013. CD003707. doi: 10.1002/14651858.CD003707.pub3.


68. Kaushal A., McDonnell C.G., Davies M.W. Partial liquid ventilation for the prevention of mortality and morbidity in paediatric acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst. Rev. 2013: CD003845. doi: 10.1002/14651858.CD003845.pub3.


69. Bonitenko E.U., Barinov V.A., Belyakova N.A., Byrov A.A. Primenenie perftoryglerodov pri lechenii tyajeloi bronholegochnoi patologii. chast II: chastichnaya jidkostnaya ventilyaciya legkih (analiticheskii obzor). Medlain.ry (Medline.ru). 2023; 24: 1494-1552.