Matrixes for Drug Delivery Ready for a Prime Time Dr Alex Nivorozhkin NeoAdvent Technologies LLC USA 1 Traditional Uses of Amorphous Silica in Pharma NonPorous Particle Size Applications ID: 291509
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Silica-Based
Matrixes for Drug Delivery:Ready for a Prime Time?
Dr. Alex NivorozhkinNeo-Advent Technologies LLC, USA
1Slide2
Traditional Uses of Amorphous Silica in Pharma
Non-PorousParticle SizeApplications
FunctionSpherical5-50 micronsTablets
Flow, AnticakingFumed (Branched)
0.1-1 micronsGels, Semisolids
Viscosity Modifier
Porous
Particle
Size
Applications
Function
Spherical5-50 nmTabletsFiller, Oil/Wax AbsorbingSilicagel5-50 micronsDessicationMoisture Absorbing
Three Different Physical Attributes:-Shape/Size/ Porosity
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Fumed Silica – Viscosity Modifier
3
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Key Pathways to Producing the Silica
Silicagel, Precipitated SilicaNa2Si3O7 + H2SO4
→ 3 SiO2 + Na2SO4 + H2O
(different pH ranges, the product dehydrated )
Sol-Gel processSi
(OEt)4→
SiO2 (basic or acid hydrolysis)
Mesoporous Silica (MSN, Pore
Size 2-50 nm)
Si(
OEt
)4→ SiO2 in the presence of templating surfactant4Neo-Advent Technologies, LLC, Littleton, MA 01460; www.neo-adventtec.comSlide5
Toxicology of Silica
Plenty in nature (structural material), but not in humansWhen used orally up to 5 g/kg is safeSNP are more toxicToxicity depends on size, charge, shapeRole of increased solubility with decreased size?Lack of good in vitro-in vivo correlations
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Solubility of Silica
AmorphouspH-dependent, increase at pH>9Equilibrium solubility of Nonporous silica -70 ppm vs. Porous -120 ppmSi(OH)4 is excreted with urine
at 1.8 mg/dayCrystalline Forms
Soluble thru conversion to Si(OH)
4Insoluble at ambient conditions1 ppm at 400 o
CVery stable
6
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-Advent Technologies, LLC, Littleton, MA 01460;
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Mesoporous Silica Nanomaterials (MSN)
Key Properties of MSNOrdered pore structure (2-50 nm)Huge pore surface/volume (1 cm3/g, 1000 m2/g)
Commercial Availability MCM-41 (Aldrich $563/25 g) Preparation of MSN
Liquid Crystalline Templating
(“Mobil Process”, 1992) Variations in surfactant, inorganic framework, conditions
7
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SNP Surface Reactivity
Covalent Attachment OptionsNegative Zeta-potential for unmodified SNPProtonated amino groups after modification with 3-aminopropyl triethoxysilane Drug-SNP Conjugates
Convenient general chemistryCan it match potential for Polymer-Drug conjugates?Can it be produced economically: concentration limits, washout steps, density of conjugation?
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Surface Functionalization
Co-condensation (one-pot)Versatile post-process methodPossible pore cloggingGrafting Method
More homogeneous DistributionMaybe difficult to fit into the prep
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Drug Delivery Modalities
10Neo-Advent Technologies, LLC, Littleton, MA 01460; www.neo-adventtec.comSlide11
MSN-based Drug Delivery Vehicle
ChallengesHydrophilic surface (-Si-OH), low loading of hydrophobic drugs (many cancer, CNS leads) ca. 1%Hydrophobic surface modification results in sluggish and incomplete releaseFilling the pores with surfactant improves loading and release
Pore-loading with Capping
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MSN as Multifunctional Nanoplatform
Functionalization Domains:Silica framework
Mesopores Outermost surface of nanoparticles
Combination approach
12
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MSN Nanomotor
for DNA CaptureM. Vallet-Regi, Small, 201213
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What the Future Holds?
PotentialPossibly low toxicMay be cheap Versatile and compatible with various chemistriesCould be commercially as successful as liposomes?New Development ProductsPoorly soluble potent drugs (complement to non-MSN)Imaging
Targeted deliveryDelivery of biologics (little explored)Stimuli-triggered deliveryChallenges
Toxicity, particularly long-term
ManufacturingLow drug loads
“Smart” approaches bring add-on issues, may be all of the above
Driving ForcesSolid i
ndustrial baseAdvances in silica applications other than pharma, i.e. catalysis, ink,
polymers
Need for new drug delivery technologies
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Neo-Advent Technologies, LLC, Littleton, MA 01460; www.neo-adventtec.comSlide15
Thank
YouAlex Nivorozhkin, Ph.D.Founder, COONeo-Advent Technologies LLC, 410 Great Road, Littleton
, MA 1-508-970-4858www.neo-adventtec.comCo
-ChairFormulation Drug DeliveryCommittee, Massachusetts Biotechnology Council, Boston
Acknowledgements
Mr
. Nelson
LandrauDr
. Ken
Avery
Unilever, Port Sunlight, UK
Dr. Craig JonesDr. James MerringtonDr. David Mealing15Neo-Advent Technologies, LLC, Littleton, MA 01460; www.neo-adventtec.com