Swellable hydrogel microparticle-based pressurized metered dose inhaler (pMDI) formulations allow delivery of small respirable sized particles (1–5 microns), which swell upon the deposition in the deep lung and therefore can elude alveolar macrophage uptake via their larger geometric sizes. In addition, optimized surface chemistry may allow for sustained release of drug for multiple days.
Methods:
Drug-loaded PLGA nanoparticles encapsulated in PEG/chitosan (Cs) graft copolymer-based hydrogel microparticles were synthesized and characterized. Physical stability of dispersions within Hydrofluoroalkane propellant systems was assessed. The formulations were evaluated for aerosolization performance using a Next Generation Impactor.
Results:
Low density PEG/chitosan (Cs) graft copolymer-based hydrogel microparticles containing drug-loaded PLGA nanoparticles has an average diameter of 1–2 μm. These dispersions showed good compatibility with HFA227ea. Suspension stability was found to vary with the concentration of hydrogel particles. It was typically between 1 to 5 min and was found to be easily redispersible. Aerosolization studies showed fine particle fraction as high as 65% could be achieved.
Conclusions:
These swellable hydrogel-based microparticle pMDI formulations could be used as potential delivery vehicles for nanoparticle therapeutics.
Get full access to this article
View all access options for this article.
References
1.
PattonJS, ByronPR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov, 2007; 6:67–74.
EdwardsDA, HanesJ, CaponettiG, HrkachJ, Ben-JebriaA, EskewML, MintzesJ, DeaverD, LotanN, LangerR. Large porous particles for pulmonary drug delivery. Science, 1997; 276:1868–1872.
8.
YangY, BajajN, XuaP, OhndK, TsifanskyeMD, YeoY. Development of highly porous large PLGA microparticles for pulmonary drug delivery. Biomaterials, 2009; 30:1947–1953.
9.
KoushikK, DhandaD, CheruvuN, KompellaU. Pulmonary delivery of deslorelin: large-porous PLGA particles and HPβCD complexes. Pharm Res, 2004; 21:1119–1126.
10.
WuL, Al-HaydariM, da RochaSR. Novel propellant-driven inhalation formulations: engineering polar drug particles with surface-trapped hydrofluoroalkane-philes. Eur J Pharm Sci, 2008; 33:146–158.
11.
ShoyeleSA, CawthorneS. Particle engineering techniques for inhaled biopharmaceuticals. Adv Drug Deliv Rev, 2006; 58:1009–1029.
WuL, da RochaSRP. Biocompatible and biodegradable copolymer stabilizers for hydrofluoroalkane dispersions: a colloidal probe microscopy investigation. Langmuir, 2007; 23:12104–12110.
14.
SuhJ, ChoyKL, LaiSK, SukJS, TangBC, PrabhuS, HanesJ. PEGylation of nanoparticles improves their cytoplasmic transport. Int J Nanomed, 2007; 2:735–741.
15.
WangYY, LaiSK, SukJS, PaceA, ConeR, HanesJ. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that “slip” through the human mucus barrier. Angew Chem Int Ed Engl, 2008; 47:9726–9729.
16.
McGillS, CuylearCL, AdolphiNL, OsinskiM, SmythHDC. Magnetically responsive nanoparticles for drug delivery applications using low magnetic field strengths. Nanobioscience, 2009; 8:33–42.
17.
GrenhaA, SeijoB, Remuñán-LópezC. Microencapsulated chitosan nanoparticles for lung protein delivery. Eur J Pharm Sci, 2005; 25:427–437.
18.
DickinsonPA, HowellsSW, KellawayIW. Novel nanoparticles for pulmonary drug administration. J Drug Target, 2001; 9:295–302.
19.
El-SherbinyIM, McGillS, SmythHDC. Swellable microparticles as carriers for sustained pulmonary drug delivery. J Pharm Sci, 2010; 99:2343–2356.
20.
El-SherbinyIM, SmythHDC. Novel cryomilled physically crosslinked biodegradable hydrogel microparticles as carriers for inhalation therapy. J Microencapsul(in press).
21.
EvoraC, SorianoI, RogersRA, ShakesheffKN, HanesJ, LangerR. Relating the phagocytosis of microparticles by alveolar macrophages to surface chemistry: the effect of 1,2-dipalmitoylphosphatidylcholine. J Control Release, 1998; 51:143–152.
22.
Gonzalez-RothiRJ, StraubL, CacaceJL, SchreierH. Liposomes and pulmonary alveolar macrophages: functional and morphologic interactions. Expt Lung Res, 1991; 17:687–705.
23.
McDonaldKJ, MartinGP. Transition to CFC-free metered dose inhalers—into the new millennium. Int J Pharm, 2000; 201:89–107.
24.
VervaetC, ByronPR. Drug–surfactant–propellant interactions in HFA-formulations. Int J Pharm, 1999; 186:13–30.
25.
BlondinoFE, ByronPR. Surfactant dissolution and water solubilization in chlorine-free liquified gas propellants. Drug Dev Indust Pharmacy, 1998; 24:935–945.
26.
CourrierHM, ButzN, VandammeTF. Pulmonary drug delivery systems: recent developments and prospects. Crit Rev Ther Drug, 2002; 19:228.
SmythHDC, BeckVP, WilliamsD, HickeyAJ. The influence of formulation and spacer device on the in vitro performance of solution chlorofluorocarbon-free propellant- driven metered dose inhalers. AAPS PharmSciTech, 2004; 5Article 7.
29.
SmythHDC. The influence of formulation variables on the performance of alternative propellant-driven metered dose inhalers. Adv Drug Deliv Rev, 2003; 55:807–828.
30.
EganME, PearsonM, WeinerSA, RajendranV, RubinD, Glöckner-PagelJ, CannyS, DuK, LukacsGL, CaplanMJ. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science, 2004; 304:600–602.
31.
AmmonHPT, WahlMA. Pharmacology of Curcuma longa. Planta Medica, 1991; 57:1–7.
32.
ChengAL, HsuCH, LinJK, HsuMM, HoYF, ShenTS, KoJY, LinJT, LinBR, Ming-ShiangW, YuHS, JeeSH, ChenGS, ChenTM, ChenCA, LaiMK, PuYS, PanMH, WangYJ, TsaiCC, HsiehCY. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res, 2001; 21:2895–2900.
33.
HuangM, NewmarkHL, FrenkelK. Inhibitory effects of curcumin on tumorigenesis in mice. J Cell Biochem, 1997; 67:26–34.
34.
SethiG, SungB, AggarwalBB. The role of curcumin in modern medicine. Herbal Drugs: Ethnomed Modern Med, 2009; 97–113.
35.
AggarwalBB, KnightJV. Aerosol delivery of curcumin. Research Development Foundation, 2009; EP1658061.
OchsM, NyengaardJR, JungA, KnudsenL, VoigtM, WahlersT, RichterJ, GundersenHJ. The number of alveoli in the human lung. Am J Respir Crit Care Med, 2004; 169:120–124.
38.
RidderKB, Davies-CuttingCJ, KellawayIW. Surfactant solubility and aggregate orientation in hydrofluoroalkanes. Int J Pharm, 2005; 295:57–65.
39.
SelvamP, ChokshiU, WuL, GouchA, PorcarL, da RochaSRP. Ethoxylated copolymer surfactants for the HFA134a-water interface: interfacial activity, aggregate microstructure and biomolecule uptake. Soft Matter, 2008; 4:357–366.
40.
RoguedaP. Novel hydrofluoroalkane suspension formulations for respiratory drug delivery. Expert Opin Drug Deliv, 2005; 2:625–638.
41.
WuL, PeguinRPS, da RochaSRP. Understanding solvation in hydrofluoroalkanes: ab initio calculations and chemical force microscopy. J Physiol Chem B, 2007; 111:8096–8104.
42.
PeguinRPS, da RochaSRP. Solvent–solute interactions in hydrofluoroalkane propellants. J Physiol Chem B, 2008; 112:8084–8094.
43.
ChokshiU, SelvamP, PorcarL, da RochaSR. Reverse aqueous emulsions and microemulsions in HFA227 propellant stabilized by non-ionic ethoxylated amphiphiles. Int J Pharm, 2009; 369:176–184.
44.
WuL, BharatwajB, PanyamJ, da RochaS. Core–shell particles for the dispersion of small polar drugs and biomolecules in hydrofluoroalkane propellants. Pharm Res, 2008; 25:289–301.
ShaikhJ, AnkolaD, BeniwalV, SinghD, KumarMR. Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer. Eur J Pharmaceut Sci, 2009; 37:223–230.
47.
PeguinRPS, WuL, da RochaSRP. The Ester group: how hydrofluoroalkane-philic is it?Langmuir, 2007; 23:8291–8294.
