European Journal of Pharmaceutics and Biopharmaceutics
Research paperDifferent modalities of NaCl osmogen in biodegradable microspheres for bone deposition of risedronate sodium by alveolar targeting
Graphical abstract
Effect of varying NaCl concentration in either internal/external phase of the w/o/w emulsion on the morphology of risedronate sodium loaded PLGA microspheres.
Introduction
Porous or surface modified polylactide-co-glycolide (PLGA) microspheres are commonly employed as a suitable carrier for pulmonary administered drugs owing to their biocompatibility, controlled release behavior, and their well-known safety profile [1].
Various approaches have been attempted in the literature to incorporate water soluble drugs into biodegradable microspheres at high loading. However, the double (w/o/w) emulsion method remains the most commonly used method for achieving such purpose [2]. Upon using osmogens as NaCl in the preparation of these microparticles, the organic phase of a w/o/w emulsion acts as semipermeable membrane allowing the passage of water across the organic phase [3], [4], which in turn leads to the production of diverse modalities of microspheres, differing in their morphology, entrapment efficiency properties, release capabilities, and aerodynamic deposition in the lung.
Bisphosphonates (BPs), the gold-standard pharmacological treatment of osteoporosis [5], suffer extremely low bioavailability (less than 1%) upon their oral intake owing to their high polarity and hydrophilicity. Furthermore, they exhibit several gastric and esophageal side effects such as erosive esophagitis, gastritis, and ulcers. These adverse effects are hypothesized to be caused by the reflex of the acidic gastric contents along with the undissolved drug crystals back to the esophagus, exposing it to the free acid form of the drug, or due to the exacerbation of an existing esophageal disorder [6], [7]. They might also be caused by the local reaction of the mucosa upon contact with the concentrated form of the drug [8], [9], [10]. The local tissue damage and irritation at the sites of injection precluded the use of intra-muscular and subcutaneous routes of administration for delivery of BPs. Slow release of BPs is also critical, since it was reported that rapid injection of BPs can lead to renal failure due to the formation of complexes with calcium in the blood, which are held back in the kidney [10]. A model BP, risedronate sodium (RS), was used in our study, as it possessed a high anti-resorptive activity while causing less incidence of gastric damage [11].
Therefore, the aim of our work was to test the possibility for delivery of RS through an alternative route (the pulmonary route), taking advantage of the neutral pH of the lung environment with the possibility of using small dose to minimize possible local mucosal irritation. Different modalities for NaCl as osmogen through changing its concentration in the internal and external aqueous phases were attempted, in which the influence of the relative difference in osmotic pressure on the produced microspheres was studied through several experimental parameters. Sodium chloride was used as the osmogen of choice based on preliminary study conducted in our laboratory [12]. Cellular toxicity using MTT assay on Calu-3 cells as well as histological examination of lung tissue was performed in order to assess the safety of the optimized formula. In addition, instead of using the traditional chromatographic methods to test the bioavailability of our optimized formula, a novel radiolabeling technique was utilized to calculate the percentage of RS directly deposited in the bones after pulmonary administration.
Section snippets
Materials
Risedronate sodium was gifted by SPIC Pharma. Co., India. PLGA 50:50 and 75:25 of molecular weights 150,000 and 95,000 g/mole, respectively, were gifted by PURAC Biomaterials Co., the Netherlands. Polyvinyl alcohol (Mowiol®4-88) Molecular weight 31,000, MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide, HEPES buffer, fetal calf serum, gentamycin, phosphate buffered saline tablets (PBS), dimethyl sulfoxide (DMSO), sodium dodecyl sulfate (SLS), sodium pentobarbital, and
Preparation of RS loaded PLGA microspheres using NaCl as osmogen
Sodium chloride is commonly used as porogen owing to its osmotic effects. It is well known that water molecules may pass from one aqueous phase to the other, based on the difference in osmotic pressure [4]. Materials such as electrolytes and drugs in either aqueous phases are also known to exert a similar osmotic effect [3]. Therefore, in our study, the osmotic gradient was varied through changing the amount of NaCl in the internal and external aqueous phases, in order to study its effect on
Conclusions
The utilization of NaCl as an osmogen in the w/o/w double emulsion technique leads to morphologically diverse microspheres. The increased concentration of NaCl in the external phase was proven to be advantageous in producing dimpled microspheres of high EE%, suitable particle size both geometrically and aerodynamically, good flow properties, and a sustained release profile. While more work is needed to extrapolate these findings to better anti-osteoporotic efficacy by pulmonary route, regarding
Acknowledgment
The authors would like to thank SPIC Pharma Co., India, and PURAC company, the Netherlands, for their kind supply of risedronate and PLGA polymers, respectively.
References (46)
- et al.
Facile control of porous structures of polymer microspheres using an osmotic agent for pulmonary delivery
J. Control. Rel.
(2010) - et al.
The formulation and stability of multiple emulsions
Int. J. Pharm.
(1982) - et al.
Administration routes and delivery systems of bisphosphonates for the treatment of bone resorption
Adv. Drug Deliv. Rev.
(2000) - et al.
A reliable predictive factorial model for entrapment optimization of a sodium bisphosphonate into biodegradable microspheres
J. Pharm. Sci.
(2011) - et al.
Recombinant human erythropoietin (rhEPO) loaded poly(lactide-co-glycolide) microspheres: influence of the encapsulation technique and polymer purity on microsphere characteristics
Eur. J. Pharm. Biopharm.
(1998) - et al.
Characterisation of excipient-free nanoporous microparticles (NPMPs) of bendroflumethiazide
Eur. J. Pharm. Biopharm.
(2008) - et al.
Excipient-free nanoporous microparticles of budesonide for pulmonary delivery
Eur. J. Pharm. Sci.
(2009) - et al.
Insulin-loaded PLGA/cyclodextrin large porous particles with improved aerosolization properties: in vivo deposition and hypoglycaemic activity after delivery to rat lungs
J. Control. Rel.
(2009) - et al.
Cyclodextrins in the production of large porous particles: development of dry powders for the sustained release of insulin to the lungs
Eur. J. Pharm. Sci.
(2006) - et al.
Inhalable large porous microspheres of low molecular weight heparin: in vitro and in vivo evaluation
J. Control. Rel.
(2008)
Engineering gas-foamed large porous particles for efficient local delivery of macromolecules to the lung
Eur. J. Pharm. Sci.
Novel sustained release microspheres for pulmonary drug delivery
J. Control. Rel.
A comparative study of a range of polymeric microspheres as potential carriers for the inhalation of proteins
Int. J. Pharm.
New insights into the pore structure of poly(D,L-lactide-co-glycolide) microspheres
Int. J. Pharm.
Formulation of rifampicin-cyclodextrin complexes for lung nebulization
J. Control. Rel.
Aerodynamic deposition of combination dry powder inhaler formulations in vitro: a comparison of three impactors
Int. J. Pharm.
Biodegradable nano-micro carrier systems for sustained pulmonary drug delivery: (I) self-assembled nanoparticles encapsulated in respirable/swellable semi-IPN microspheres
Int. J. Pharm.
Preparation and in vitro evaluation of lipidic carriers and fillers for inhalation
Eur. J. Pharm. Biopharm.
Novel alternative methods for the delivery of drugs for the treatment of asthma
Adv. Drug Deliv. Rev.
PLGA microcapsules with novel dimpled surfaces for pulmonary delivery of DNA
Int. J. Pharm.
Mathematical modeling of bioerodible, polymeric drug delivery systems
Adv. Drug Deliv. Rev.
PLGA-based microparticles: elucidation of mechanisms and a new, simple mathematical model quantifying drug release
Eur. J. Pharm. Sci.
Mathematical modeling and simulation of drug release from microspheres: Implications to drug delivery systems
Adv. Drug Deliv. Rev.
Cited by (41)
Recent progress on polySarcosine as an alternative to PEGylation: Synthesis and biomedical applications
2024, International Journal of PharmaceuticsNanotechnologies and controlled release formulations for the administration of bisphosphonates and their potential in radiation protection
2023, Journal of Drug Delivery Science and TechnologySpanethosomes as a novel topical carrier for silymarin in contrast to conventional spanlastics: Formulation development, in vitro and ex vivo evaluation for potential treatment of leishmaniasis
2023, Journal of Drug Delivery Science and TechnologyNew repurposed rolapitant in nanovesicular systems for lung cancer treatment: Development, in-vitro assessment and in-vivo biodistribution study
2022, European Journal of Pharmaceutical Sciences