Skip to main content
SpringerLink
Log in

Formulation and Characterization of Polysaccharide Microparticles for Pulmonary Delivery of Sodium Cromoglycate

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

ABSTRACT

Sodium cromoglycate (SC) is an antiasthmatic and antiallergenic drug commonly used for chronic inhalation therapy; however, many daily intakes are required due to the fast drug clearance from airways. For these reasons, SC polymeric particles for inhalatory administration with adequate aerosolization and mucoadhesive properties were designed to prolong the drug residence time in the site of action. Sodium carboxymethylcellulose (CMCNa), sodium hyaluronate, and sodium alginate were selected to co-process SC by spray drying. The influence of these polysaccharides on the spray drying process and powder quality was evaluated (among others, morphology, size, moisture content, hygroscopicity, flowability, densities, liquid sorption, and stability). In vitro aerosolization, drug release, and mucoadhesion performance were also studied. Particularly, a novel method to comparatively evaluate the interaction between formulations and mucin solution (mucoadhesion test) was proposed as a rapid methodology to measure adhesion properties of inhalable particles, being the results as indicative of clearance probability. Among all the studied formulations, the powder based on SC and CMCNa exhibited the best mucoadhesion and aerosolization performance, the highest process yield and adequate moisture content, hygroscopicity, and stability. SC-CMCNa formulation arose as a promising inhalatory system to reduce the daily intakes and to increase the patient compliance.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

REFERENCES

  1. Mullane K. The increasing challenge of discovering asthma drugs. Biochem Pharmacol. 2011;82:586–99. doi:10.1016/j.bcp.2011.06.033.

    Article  CAS  PubMed  Google Scholar 

  2. Kraneveld AD, Sagar S, Garssen J, Folkerts G. Biochim Biophys Acta (BBA) - Mol Basis Dis. 2012;1822:93–9. doi:10.1016/j.bbadis.2011.06.013.

    Article  CAS  Google Scholar 

  3. Fernández Tena A, Clarà PC. Deposition of inhaled particles in the lungs. Arch Bronconeumol. 2012;48:240–6. doi:10.1016/j.arbres.2012.02.003.

    Article  PubMed  Google Scholar 

  4. Rahimpour Y, Kouhsoltani M, Hamishehkar H. Alternative carriers in dry powder inhaler formulations. Drug Discov Today. 2014;19:618–26. doi:10.1016/j.drudis.2016.05.009.

    Article  PubMed  Google Scholar 

  5. Gradon L, Sosnowski TR. Formation of particles for dry powder inhalers. Adv Powder Technol. 2014;25:43–55. doi:10.1016/j.apt.2013.09.012.

    Article  CAS  Google Scholar 

  6. Hoppentocht M, Hagedoorn P, Frijlink HW, de Boer AH. Technological and practical challenges of dry powder inhalers and formulations. Adv Drug Deliv Rev. 2014;75:18–31. doi:10.1016/j.addr.2014.04.004.

    Article  CAS  PubMed  Google Scholar 

  7. El-Sherbiny IM, Smyth HDC. Biodegradable nano-micro carrier systems for sustained pulmonary drug delivery: (I) self-assembled nanoparticles encapsulated in respirable/swellable semi-IPN microspheres. Int J Pharm. 2010;395:132–41. doi:10.1016/j.ijpharm.2010.05.032.

    Article  CAS  PubMed  Google Scholar 

  8. Healy AM, Amaro MI, Paluch KJ, Tajber L. Dry powders for oral inhalation free of lactose carrier particles. Adv Drug Deliv Rev. 2014;75:32–52. doi:10.1016/j.addr.2014.04.005.

    Article  CAS  PubMed  Google Scholar 

  9. Hickey AJ. Controlled delivery of inhaled therapeutic agents. J Control Release. 2014;190:182–8. doi:10.1016/j.jconrel.2014.05.058.

    Article  CAS  PubMed  Google Scholar 

  10. Holgate ST. Trials and tribulations in identifying new biologic treatments for asthma. Trends Immunol. 2012;33:238–46. doi:10.1016/j.it.2012.02.003.

    Article  CAS  PubMed  Google Scholar 

  11. Laube BL, Edwards AM, Dalby RN, Creticos PS, Norman PS. The efficacy of slow versus faster inhalation of cromolyn sodium in protecting against allergen challenge in patients with asthma. J Allergy Clin Immunol. 1998;101:475–83. doi:10.1016/S0091-6749(98)70376-8.

    Article  CAS  PubMed  Google Scholar 

  12. Chew NYK, Bagster DF, Chan HK. Effect of particle size, air flow and inhaler device on the aerosolisation of disodium cromoglycate powders. Int J Pharm. 2000;206:75–83. doi:10.1002/jps.20426.

    Article  CAS  PubMed  Google Scholar 

  13. Lindström M, Svensson JO, Meurling L, Svartengren K, Anderson M, Svartengren M. A simple pharmacokinetic method to evaluate the pulmonary dose in clinical practice—analyses of inhaled sodium cromoglycate. Respir Med. 2004;98:9–16. doi:10.1016/j.rmed.2003.08.010.

    Article  PubMed  Google Scholar 

  14. Liang Z, Ni R, Zhou J, Mao S. Recent advances in controlled pulmonary drug delivery. Drug Discov Today. 2014;1–10. doi:10.1016/j.drudis.2014.09.020.

  15. Sosnik A, das Neves J, Sarmento B. Mucoadhesive polymers in the design of nano-drug delivery systems for administration by non-parenteral routes: a review. Prog Polym Sci. 2014;39:2030–75. doi:10.1016/j.progpolymsci.2014.07.010.

    Article  CAS  Google Scholar 

  16. Sivadas N, O’Rourke D, Tobin A, Buckley V, Ramtoola Z, Kelly JG, et al. A comparative study of a range of polymeric microspheres as potential carriers for the inhalation of proteins. Int J Pharm. 2008;358:159–67. doi:10.1016/j.ijpharm.2008.03.024.

    Article  CAS  PubMed  Google Scholar 

  17. Razavi Rohani SS, Abnous K, Tafaghodi M. Preparation and characterization of spray-dried powders intended for pulmonary delivery of insulin with regard to the selection of excipients. Int J Pharm. 2014;465:464–78. doi:10.1016/j.ijpharm.2014.02.030.

    Article  CAS  PubMed  Google Scholar 

  18. Surendrakumar K, Martyn GP, Hodgers ECM, Jansen M, Blair JA. Sustained release of insulin from sodium hyaluronate based dry powder formulations after pulmonary delivery to beagle dogs. J Control Release. 2003;91:385–94. doi:10.1016/S0168-3659(03)00263-3.

    Article  CAS  PubMed  Google Scholar 

  19. Xu E-Y, Guo J, Xu Y, Li H-Y, Seville PC. Influence of excipients on spray-dried powders for inhalation. Powder Technol. 2014;256:217–23. doi:10.1016/j.powtec.2014.02.033.

    Article  CAS  Google Scholar 

  20. Smyth HDC, Hickey AJ. Controlled pulmonary drug delivery. New York: Springer; 2011.

    Book  Google Scholar 

  21. Ceschan NE, Bucalá V, Ramírez-Rigo MV. Polymeric microparticles containing indomethacin for inhalatory administration. Powder Technol. 2015;285:51–61. doi:10.1016/j.powtec.2015.02.001.

    Article  CAS  Google Scholar 

  22. Nolan LM, Li J, Tajber L, Corrigan OI, Healy AM. Particle engineering of materials for oral inhalation by dry powder inhalers. II-Sodium cromoglicate. Int J Pharm. 2011;405:36–46. doi:10.1016/j.ijpharm.2010.11.040.

    Article  CAS  PubMed  Google Scholar 

  23. Vidgrén MT, Vidgrén PA, Paronen TP. Comparison of physical and inhalation properties of spray-dried and mechanically micronized disodium cromoglicate. Int J Pharm. 1987;35:139–44.

    Article  Google Scholar 

  24. Vidgren P, Vidgren M, Arppe J, Hakuli T, Laine E, Paronen P. In vitro evaluation of spray-dried mucoadhesive microspheres for nasal administration. Drug Dev Ind Pharm. 1992;18:581–97.

    Article  CAS  Google Scholar 

  25. Lencina MMS. Síntesis y Caracterización de hidrogeles de alginato y N-isopropilacrilamida para aplicaciones biomedicas. Ph D Thesis Universidad Nacional del Sur, Argentina, Bahía Blanca; 2013.

  26. Salama R, Hoe S, Chan HK, Traini D, Young PM. Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 1: influence of polymer concentration on physical and in vitro characteristics. Eur J Pharm Biopharm. 2008;69:486–95. doi:10.1016/j.ejpb.2007.12.019.

    Article  CAS  PubMed  Google Scholar 

  27. Najafabadi AR, Gilani K, Barghi M, Rafiee-Tehrani M. The effect of vehicle on physical properties and aerosolisation behaviour of disodium cromoglycate microparticles spray dried alone or with l-leucine. Int J Pharm. 2004;285:97–108. doi:10.1016/j.ijpharm.2004.07.027.

    Article  CAS  PubMed  Google Scholar 

  28. Rowe RC, Sheskey PJ, Quinn ME. Handbook of pharmaceutical excipients. 6th ed. London: Pharmaceutical Press; 2009.

    Google Scholar 

  29. Silva DA, Feitosa JPA, Maciel JS, Paula HCB, de Paula RCM. Characterization of crosslinked cashew gum derivatives. Carbohydr Polym. 2006;66:16–26. doi:10.1016/j.carbpol.2006.02.021.

    Article  CAS  Google Scholar 

  30. Soares JP, Santos JE, Chierice GO, Cavalheiro ETG. Thermal behavior of alginic acid and its sodium salt. Ecletica Quim. 2004;29:53–6.

    Article  Google Scholar 

  31. Standard practice for maintaining constant relative humidity by means of aqueous glycerin solutions. In: ASTM International, editor. Norm D5032-97; 2003.

  32. United States Pharmacopeia and National Formulary, USP 30–NF 25, The United States Pharmacopeial Convention Inc., Rockville USA, Mack Printing; 2007.

  33. Ceschan NE, Bucalá V, Ramírez-Rigo MV. New alginic acid-atenolol microparticles for inhalatory drug targeting. Mater Sci Eng C. 2014;41:255–66. doi:10.1016/j.msec.2014.04.040.

    Article  CAS  Google Scholar 

  34. Palazzo F, Giovagnoli S, Schoubben A, Blasi P, Rossi C, Ricci M. Development of a spray-drying method for the formulation of respirable microparticles containing ofloxacin-palladium complex. Int J Pharm. 2013;440:273–82. doi:10.1016/j.ijpharm.2012.05.045.

    Article  CAS  PubMed  Google Scholar 

  35. Marple VA, Roberts DL, Romay FJ, Miller NC, Truman KG, Van Oort M, et al. Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing). Part I: design. J Aerosol Med. 2003;16:283–99. doi:10.1089/089426803769017659.

    Article  PubMed  Google Scholar 

  36. Mitchell J, Newman S, ChanIn HK. In vitro and in vivo aspects of cascade impactor tests and inhaler performance: a review. AAPS PharmSciTech. 2007;8:E1–12. doi:10.1208/pt0804110.

    Article  Google Scholar 

  37. Nahar K, Gupta N, Gauvin R, Absar S, Patel B, Gupta V, et al. In vitro, in vivo and ex vivo models for studying particle deposition and drug absorption of inhaled pharmaceuticals. Eur J Pharm Sci. 2013; 805–0818. doi:10.1016/j.ejps.2013.06.004

  38. Rissler J, Asking L, Dreyer JK. Methodology to study impactor particle reentrainment and a proposed stage coating for the NGI. J Aerosol Med Pulm Drug Deliv. 2009;22:309–16. doi:10.1089/jamp.2008.0735.

    Article  CAS  PubMed  Google Scholar 

  39. Mitchell JP. Practices of coating collection surfaces of cascade impactors: a survey of members of the European Pharmaceutical Aerosol Group (EPAG). Drug Delivery to the Lungs, The Aerosol Society, London, UK; 2003. p. 75–78.

  40. Donovan MJ, Smyth HDC. Influence of size and surface roughness of large lactose carrier particles in dry powder inhaler formulations. Int J Pharm. 2010;402:1–9. doi:10.1016/j.ijpharm.2010.08.045.

    Article  CAS  PubMed  Google Scholar 

  41. Woertz C, Preis M, Breitkreutz J, Kleinebudde P. Assessment of test methods evaluating mucoadhesive polymers and dosage forms: an overview. Eur J Pharm Biopharm. 2013;85:843–53. doi:10.1016/j.ejpb.2013.06.023.

    Article  CAS  PubMed  Google Scholar 

  42. Hassan EE, Gallo JM. A simple rheological method for the in vitro assessment of mucin-polymer bioadhesive bond strength. Pharm Res. 1990;7:491–5. doi:10.1023/A:1015812615635.

    Article  CAS  PubMed  Google Scholar 

  43. Rossi S, Bonferoni MC, Lippoli G, Bertoni M, Ferrari F, Caramella C, et al. Influence of mucin type on polymer-mucin rheological interactions. Biomaterials. 1995;16:1073–9. doi:10.1016/0142-9612(95)98903-R.

    Article  CAS  PubMed  Google Scholar 

  44. Tamburic S, Duncan QM, Craig DQM. A comparison of different in vitro methods for measuring mucoadhesive performance. Eur J Pharm Biopharm. 1997;44:159–67. doi:10.1016/S0939-6411(97)00073-8.

    Article  CAS  Google Scholar 

  45. Hagesaether E, Sande SA. In vitro measurements of mucoadhesive properties of six types of pectin. Drug Dev. 2007;33:417–25. doi:10.1080/03639040600920630.

    CAS  Google Scholar 

  46. Ivarsson D, Wahlgren M. Comparison of in vitro methods of measuring mucoadhesion: ellipsometry, tensile strength and rheological measurements. Colloids Surf B: Biointerfaces. 2012;92:353–9. doi:10.1016/j.colsurfb.2011.12.020.

    Article  CAS  PubMed  Google Scholar 

  47. Bredenberg S, Nyström C. In-vitro evaluation of bioadhesion in particulate systems and possible improvement using interactive mixtures. J Pharm Pharmacol. 2003;55:169–77. doi:10.1211/002235702423.

    Article  CAS  PubMed  Google Scholar 

  48. Texture analysis instruments. http://www.tectra.hu/pdf-docs/Lloyd-TAPlus.pdf. Accessed 10 Oct 2015

  49. Mishra M, Mishra B. Mucoadhesive microparticles as potential carriers in inhalation delivery of doxycycline hyclate: a comparative study. Acta Pharm Sin B. 2012;2:518–26. doi:10.1016/j.apsb.2012.05.001.

    Article  CAS  Google Scholar 

  50. May S, Jensen B, Weiler C, Wolkenhauer M, Schneide M, Lehr C-M. Dissolution testing of powders for inhalation: influence of particle deposition and modeling of dissolution profiles. Pharm Res. 2014;31:3211–24. doi:10.1007/s11095-012-0744-2.

    Article  CAS  PubMed  Google Scholar 

  51. Salama R, Traini D, Chan H-K, Young PM. Preparation and characterisation of controlled release co-spray dried drug–polymer microparticles for inhalation 2: evaluation of in vitro release profiling methodologies for controlled release respiratory aerosols. Eur J Pharm Biopharm. 2008;70:145–52. doi:10.1016/j.ejpb.2008.04.009.

    Article  CAS  PubMed  Google Scholar 

  52. Negrin Villavivencia JA. Asma bronquial. Aspectos básicos para un tratamiento integral según la etapa clínica, Editorial Ciencia Médicas, La Habana; 2004.

  53. Escudero JJ, Ferrero C, Jiménez-Castellanos MR. Compaction properties, drug release kinetics and fronts movement studies from matrices combining mixtures of swellable and inert polymers. II. Effect of HPMC with different degrees of methoxy/hydroxypropyl substitution. Int J Pharm. 2010;387:56–64. doi:10.1016/j.ijpharm.2009.12.001.

    Article  CAS  PubMed  Google Scholar 

  54. Nogami H, Nagai T, Fukuoka E, Sonobe T. Disintegration of the aspirin tablets containing potato starch and microcrystalline cellulose in various concentrations. Chem Pharm Bull. 1969;17:1450–5.

    Article  CAS  PubMed  Google Scholar 

  55. Vergnaud JM. Liquid transport controlled release processes in polymeric materials: applications to oral dosage forms. Int J Pharm. 1993;90:89–94. doi:10.1016/0378-5173(93)90145-6.

    Article  CAS  Google Scholar 

  56. Sinha Roy D, Rohera BD. Comparative evaluation of rate of hydration and matrix erosion of HEC and HPC and study of drug release from their matrices. Eur J Pharm Sci. 2002;16:193–9. doi:10.1016/S0928-0987(02)00103-3.

    Article  CAS  PubMed  Google Scholar 

  57. Shrestha AK, Howes T, Adhikari BP, Bhandari B. Water sorption and glass transition properties of spray dried lactose hydrolyzed skim milk powder. Food Sci Technol-LEB. 2007;40:1593–600. doi:10.1016/j.lwt.2006.11.003.

    Article  CAS  Google Scholar 

  58. best@buchi, 59 (2010). https://partnernet.buchi.com/uploads/media/59_Laboratory_Scale_Spray_Drying_of_inhalable_drugs.pdf (accessed 02 Oct 2014).

  59. Rabbani NR, Seville PC. The influence of formulation components on the aerosolisation properties of spray-dried powders. J Control Release. 2005;110:130–40. doi:10.1016/j.jconrel.2005.09.004.

    Article  CAS  PubMed  Google Scholar 

  60. Chew NYK, Shekunov BY, Tong HHY, Chow AHL, Savage C, Wu J, et al. Effect of amino acids on the dispersion of disodium cromoglycate powders. J Pharm Sci. 2005;94:2289–300. doi:10.1002/jps.20426.

    Article  CAS  PubMed  Google Scholar 

  61. Gallo L, Llabot JM, Allemandi D, Bucalá V, Piña J. Influence of spray-drying operating conditions on Rhamnus purshiana (Cáscara sagrada) extract powder physical properties. Powder Technol. 2011;208:205–14. doi:10.1016/j.powtec.2010.12.021.

    Article  CAS  Google Scholar 

  62. Gilani K, Najafabadi AR, Barghi M, Rafiee-Tehrani M. The effect of water to ethanol feed ratio on physical properties and aerosolization behavior of spray dried cromolyn sodium particles. J Pharm Sci. 2005;94:1048–59. doi:10.1002/jps.20315.

    Article  CAS  PubMed  Google Scholar 

  63. Hu J, Dong Y, Pastorin G, Kiong WN, Tan RBH. Spherical agglomerates of pure drug nanoparticles for improved pulmonary delivery in dry powder inhalers. J Nanopart Res. 2013;1560:3–12. doi:10.1007/s11051-013-1560-2.

    Google Scholar 

  64. Torres Suárez AI, Gil Alegre ME. Globalización de los requisitos para la comercialización de medicamentos: importancia de la humedad ambiental en el diseño de los estudios de estabilidad. An R Acad Nac Farm. 2005;71:111–26.

    Google Scholar 

  65. Barron MK, Young TJ, Johnston KP, Williams RO. Investigation of processing parameters of spray freezing into liquid to prepare polyethylene glycol polymeric particles for drug delivery. AAPS PharmSciTech. 2003;4:1–13.

    Article  PubMed Central  Google Scholar 

  66. Vidgren M, Kärkkäinen A, Karjalainen P, Nuutinen J, Paronen P. In vitro and in vivo deposition of drug particles inhaled from pressurized aerosol and dry powder inhaler. Drug Dev Ind Pharm. 1988;14:15–7. doi:10.3109/03639048809152038. 2649–2665.

    Article  Google Scholar 

  67. Bettelheim FA. An x-ray diffraction investigation of sodium hyaluronate. J Phys Chem. 1959;63:2069–71. doi:10.1021/j150582a028.

    Article  CAS  Google Scholar 

  68. Gallo L, Piña J, Bucalá V, Allemandi D, Ramírez-Rigo MV. Development of a modified-release hydrophilic matrix system of a plant extract based on co-spray-dried powders. Powder Technol. 2013;241:252–62. doi:10.1016/j.powtec.2013.03.011.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

FONCyT (PICT-2013-1765), CONICET (PIP 112-2011-0100336112), and UNS (PGI 24/B209) grants support this study. Loreana Gallo thanks CONICET for her posdoctoral fellowship. The authors thank Dr. Marcelo Villar for his collaboration in the thermograms analysis and Lic. Fernanda Cabrera for her technical assistance.

Author information

Authors and Affiliations

  1. Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, San Juan 670, (8000), Bahía Blanca, Argentina

    Loreana Gallo & María Verónica Ramírez-Rigo

  2. Department of Chemical Engineering-PLAPIQUI, Universidad Nacional del Sur-CONICET, Camino La Carrindanga Km. 7, (8000), Bahía Blanca, Argentina

    Loreana Gallo, Verónica Bucalá & María Verónica Ramírez-Rigo

Authors
  1. Loreana Gallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Verónica Bucalá
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. María Verónica Ramírez-Rigo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to María Verónica Ramírez-Rigo.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 211 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gallo, L., Bucalá, V. & Ramírez-Rigo, M.V. Formulation and Characterization of Polysaccharide Microparticles for Pulmonary Delivery of Sodium Cromoglycate. AAPS PharmSciTech 18, 1634–1645 (2017). https://doi.org/10.1208/s12249-016-0633-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-016-0633-9

KEY WORDS

Search

Navigation