Development and evaluation of olanzapine-loaded PLGA nanoparticles for nose-to-brain delivery: In vitro and in vivo studies
Graphical abstract
The images illustrate the histopathological condition of nasal mucosa after 2 h exposure of (A, negative control) PBS pH 6.4 (B, positive control) IPA (C) drug solution and (D) drug-loaded NP. The arrows in (B) indicate the change in histopathology of the mucosa. Some cilias were detached when treated with drug solution (C). No change in the mucosal histopathology was observed when treated with drug-loaded NP (D).
Introduction
The blood–brain barrier (BBB) prevents most substances from freely diffusing and penetrating into the central nervous system (CNS) from the bloodstream in order to maintain brain homeostasis. As this barrier is also the primary obstacle for delivery of drugs to the brain, various methods of circumventing the BBB have been attempted [1], [2], [3]. In the last decade, intranasal (IN) administration has attracted considerable interest, since it provides a non-invasive method for bypassing the BBB and delivering therapeutic drugs directly to the CNS [4], [5], [6].
Drugs administered to the nasal cavity can travel along the olfactory and trigeminal nerves to reach many regions within the CNS. Many substances have been shown to reach the cerebrospinal fluid (CSF), the olfactory bulb and other parts of the brain after nasal administration in experimental animals [7], [8], [9]. Intranasally administered peptide hormones (melanocortin and insulin) were reportedly delivered directly to the CSF in man [10]. Therefore, drug delivery via the nasal route provides potential for brain targeting. Although the nose-to-brain pathway has proved to be useful for a variety of CNS active drugs, the total amount of drug accessing the brain is reported to be low, with concentrations in the CSF and olfactory bulb in the nanomolar range or a bioavailability from 0.01% to 0.1% [11]. Poor brain uptake was found especially in the case of nasally applied large hydrophilic peptides and proteins [12], [13], because of their low membrane permeability, rapid mucociliary clearance from the nasal cavity and susceptibility to degradation either within the lumen of the nasal cavity or during passage across the epithelial barrier.
To overcome the nasal mucosal barrier, drugs with poor absorption need to be either co-administered with absorption promoters or encapsulated into an appropriate carrier system (liposomes, microspheres and nanoparticles) [14], of which nanoparticles (NP) based on biodegradable polymers have been extensively studied [15], [16]. NP offer an improvement to nose-to-brain drug delivery by protecting the encapsulated drug from biological and/or chemical degradation, and extracellular transport by P-glycoproteins. This increases the CNS availability of the drug.
The most commonly used degradable polymers in NP preparation are poly(lactic acid) (PLA), poly(glycolic acid) (PGA) or their copolymer poly(lactic-co-glycolic acid) (PLGA). These polymers are known to be biodegradable, biocompatible and non-toxic and have been used for biomedical application for more than two decades. PLGA has been widely investigated for formulation of NP because of its biocompatibility, safety [17], ability to promote mucoadhesion [18] and enhanced drug stability [19].
Atypical antipsychotic drugs have quickly supplanted the traditional antipsychotics as the first choice of treatment of schizophrenia, especially in the US [20], [21]. Olanzapine (OZ) is a second-generation or atypical antipsychotic which selectively binds to central dopamine D2 and serotonin (5-HT2c) receptors, appears more effective on the associated negative symptoms of schizophrenia and has a lower propensity to cause extrapyramidal symptoms. However, its clinical application is limited by poor bioavailability (40%) owing to hepatic first-pass metabolism [22] and low permeability into the brain owing to efflux by P-glycoproteins [23] thereby increasing dose and dosing frequency. Also, some major side effects seen with OZ include hypotension, dry mouth, tremor, akathisia and somnolence.
It is hypothesized that PLGA NP-based nasal delivery system of OZ would provide brain targeting and sustained release of OZ within the brain. This benefit would help to improve its clinical utility, decrease the dose and frequency of dosing, reduce side effects and improve therapeutic efficacy.
Section snippets
Materials
OZ was received as gift sample from Torrent Pharmaceuticals Ltd. (Ahmedabad, India). PLGA 50:50 was obtained as gift sample from Boerhinger Ingelheim Ltd. (Germany). Poloxamer 407 was a gift sample from BASF (Germany). All other chemicals were of analytical grade and obtained commercially.
Preparation of NP
OZ-loaded and empty PLGA NP were prepared using the nanoprecipitation method [24], [25]. Different formulation variables such as organic phase (acetone, acetonitrile, tetrahydrofuran), concentration of
Physicochemical characterization and effect of formulation variables
After preliminary study, acetonitrile was selected as the organic solvent, as it gave maximum encapsulation efficiency and minimum particle size. Acetone and tetrahydrofuran produced particles with less entrapment and greater particle size. Poloxamer 407 was selected as the stabilizer. It was tried at various concentrations ranging from 0.25% w/v to 1.0% w/v. Aggregates were observed when no stabilizer was used. However, particle size increased with decrease in entrapment efficiency when a
Conclusions
The prepared PLGA NP of OZ had high entrapment, small particle size, exhibited sustained release and followed Fickian diffusion-based release kinetics. MTDSC studies indicated broadening of the drug peak and a shift in the polymer peak, possibly due to physical interaction or H-bonding between the carbonyl groups of PLGA and the NH groups of OZ as well as to the plasticization effect of OZ on PLGA. XRD studies indicated the decrease in crystallinity of OZ or amorphization. PLGA NP showed no
Disclosures
The authors report no conflict of interest.
Acknowledgments
U. Seju would like to thank University Grants Commission, New Delhi, India, for providing a Junior Research Fellowship. The authors duly acknowledge Torrent Pharmaceuticals Ltd., Ahmedabad, India, for providing olanzapine as a gift sample, and Boehringer Ingelheim Ltd., Germany, for a gift sample of PLGA 50:50. The authors are grateful to Research Centre, IPCL, Vadodara, India, for DSC studies, and the Metallurgy Department, The Maharaja Sayajirao University of Baroda, Vadodara, India, for SEM
References (53)
- et al.
Cationic albumin-conjugated pegylated nanoparticles as novel drug carrier for brain delivery
J Controlled Release
(2005) Nasal drug delivery-possibilities, problems and solutions
J Controlled Release
(2003)- et al.
Nasal drug administration: potential for targeted central nervous system delivery
J Pharm Sci
(2005) - et al.
Profiles of methotrexate in blood and CSF following intranasal and intravenous administration to rats
Int J Pharm
(2003) - et al.
Intranasal administration of interferon beta bypasses the blood–brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis
J Neurochem
(2004) - et al.
Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents
Eur J Pharm Sci
(2005) Transport of drugs from the nasal cavity to the central nervous system
Eur J Pharm Sci
(2000)- et al.
Brain delivery of vasoactive intestinal peptide (VIP) following nasal administration to rats
Int J Pharm
(2003) - et al.
Thiomers: development and in vitro evaluation of a peroral microparticulate peptide delivery system
Eur J Pharm Biopharm
(2004) - et al.
PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug
J Controlled Release
(1999)
Comparative in vitro evaluation of several colloidal systems, nanoparticles, nanocapsules, and nanoemulsions, as ocular drug carries
J Pharm Sci
Body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on brain
J Controlled Release
Lecithin organogel as matrix for transdermal transport of drugs
J Pharm Sci
Determination of olanzapine in plasma by high-performance liquid chromatography using ultraviolet absorbance detection
J Chromatogr B Anal Technol Biomed Life Sci
Rivastigmine-loaded PLGA and PBCA nanoparticles: preparation, optimization, characterization, in vitro and pharmacodynamic studies
Eur J Pharm Biopharma
Effects of emulsifiers on the controlled release of paclitaxel (Taxol) from nanospheres of biodegradable polymers
J Controlled Release
PLGA nanoparticle formulations of risperidone: preparation and neuropharmacological evaluation
Nanomedicine
Haloperidol-loaded PLGA nanoparticles: systematic study of particle size and drug content
Int J Pharm
PLA/PLGA nanoparticles for sustained release of docetaxel
Int J Pharm
Thermoanalysis of microspheres
Thermochim Acta
Relation of glass transition temperature to the hydrogen-bonding degree and energy in poly(n-vinyl pyrrolidone) blends with hydroxyl containing-plasticizers. Part 1. Effects of hydroxyl group number in plasticizer molecule
Polymer
Ketoprofen-poly(vinylpyrrolidone) physical interaction
J Cryst Growth
Ketoprofen controlled release from composite microcapsules for cell encapsulation: effect on post-transplant acute inflammation
J Controlled Release
Quantifying drug release from PLGA nanoparticulates
Eur J Pharm Sci
Nanoparticles for direct nose-to-brain delivery of drugs
Int J Pharm
CNS drug design based on principles of blood–brain barrier transport
J Neurochem
Cited by (300)
A technological comparison of freeze-dried poly-ɛ-caprolactone (PCL) and poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with clozapine for nose-to-brain delivery
2024, Journal of Drug Delivery Science and TechnologyNose-to-Brain Targeted Delivery of Donepezil Hydrochloride via Novel Hyaluronic Acid-Doped Nanotransfersomes for Alzheimer's Disease Mitigation
2024, Journal of Pharmaceutical SciencesSodium alginate-based smart gastro-retentive drug delivery system of revaprazan loaded SLNs; Formulation and characterization
2023, International Journal of Biological MacromoleculesA Nanoemulgel for Nose-to-Brain delivery of Quetiapine – QbD-Enabled formulation development & in-vitro characterization
2023, International Journal of PharmaceuticsNose to Brain Delivery of Transferrin conjugated PLGA nanoparticles for clonidine
2023, International Journal of Biological MacromoleculesNiosomes for nose-to-brain delivery: A non-invasive versatile carrier system for drug delivery in neurodegenerative diseases
2023, Journal of Drug Delivery Science and Technology