Inorganic Systems to Control Release: Applications of Biodegradable Silica in Parenteral Delivery of Large Molecules Dr. Lasse Leino, CEO LAI 2019 Conference, KU Leuven 1
Inorganic Systems to Control Release:
Applications of Biodegradable Silica in Parenteral Delivery of Large Molecules
Dr. Lasse Leino, CEOLAI 2019 Conference, KU Leuven
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Company & Business
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DelSiTech in Brief
• Private drug delivery & drug development company
• Based on biomaterial innovations made by academic research in Finland
• Head office and R&D in Turku, Finland
• Leading company in advanced biodegradable silica-based, controlled release parenteral drug delivery
• Research collaborations and licensing agreements with small to large (bio)pharmaceutical companies
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DelSiTech Technology License Agreement with Innovare
Confidential
Business Model
R&D services and licensing
of the technology
In-house supergeneric/
505(b)(2) drug products
DelSiTech develops and commercializes its proprietary drug delivery technology
Silica Matrix
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DelSiTech R&D Services
• Formulation Development:
• Development of controlled release formulations based on biodegradable silica matrix
• Analytical Support:
• State of the art analytics to support pharmaceutical development
• Manufacture and Process Development:
• Spray drying manufacture and process development with own bench top spray dryers
• GMP manufacture at pilot scale
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Inorganic Silicon (Si) in Drug Delivery
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Si
DelSiTech silica
-nonporousamorphous SiO2
-fully biodegradable
Silicone
-plastic
-nonbiodegradable
Bioglass
-dense amorphousSiO2
-slowly biodegradable
Mesoporoussilica
-highly porous SiO2
-biodegradable
Common Silicon (Si)-based Biomaterials
Na+
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DelSiTechTMSilica: Safety
• Essentially non-toxic when given orally (LD50 > 5g/kg)
• FDA recognizes silica in all its forms safe (GRAS status)
• Silicon dioxide is a compendial excipient used in oral drug products
• Human body contains several grams of silica mainly in the bone tissue
• In the body, silica dissolves into silicic acid (SiOx(OH)4-2x) such as orthosilicic acid that is excreted in the urine
• Amorphous silica is non-mutagenic and non-carcinogenic
• Supported by extensive in-house toxicology data package
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Drug Encapsulation in DelSiTechTMSilica
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DelSiTechTMSilica: Usability
Small drug molecules
d < 2 nm
Viruses: d = 20-300 nm
Adenovirus/lentivirus/
poxvirus
Peptides, proteins,
DNA,
polysaccharides
d = 2-20...100 nm
Cells and bacteria;
d = 1-100 mm
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3 Steps of Encapsulation in DelSiTechTMSilica
Sol-gel chemistry
Encapsulation of API
Form giving
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Sol-gel Chemistry: Background
• Sol-gel process is a wet-chemical method for producing solid material from small molecules via a colloidal solution (= Sol)
• The process involves formation of gel-like structure with continuous polymer networks
• Sol-gel process is used to produce metal oxides such as SiO2(first published in 1864 by T. Graham)
• Alkoxides are ideal precursors for sol-gel synthesis because they react ready with water
• Tetraethyl orthosilicate (TEOS) is the primary precursor and source of Si in Sol-gel synthesis of silica
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Triple Polymerisation of Silica in Sol-gel
Formation of nanoporousstructure
Oligomer aggregationby coagulation
Molecularpolymerisation
Oligomers with siloxanebond structure
Si
OR
OR
ORRO Si
OR
OR
OHHO Si
OH
OH
OO - - -- - -
TEOS
H2O, H+ H2O, H+
Nanosize silica aggregates
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Steps #1 & #2: Sol-gel Reaction and Encapsulation
Mixing liquidprecursors TEOS,H2O and HCl
Addition of API
Sol-gel formationand silica polymerisation
All-liquidsystem
Silicananoparticleformation
API entrappedinside silicaclusters
T = 0- 40°C15
Step #3: Form Giving of Drug Delivery Matrices
Casting Implant
ExtrusionImplant
Silica sol with API
Spray drying
Silica microparticle
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Drug Release from DelSiTechTMSilica
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DelSiTechTMSilica: Biodegradation
• Fully biodegradable and biodissolvable in body tissues
• Biodegradation based on surface erosion by body fluids
• Biodegradation adjustable from a day to many months
• Drug release strictly controlled by matrix erosion
• Initial burst controlled or eliminated
• Well established in vitro-in vivo correlation for biodegradation
rate
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DelSiTechTMSilica: Dissolution in Aqueous Solution
1921.2.2019 19
Si
O
OH
OH
OH
Si
OOO
Si
OSi
O
OH
OH
Si
O
O
O
SiSi
OSi
O
O
OH
Si
O
OO
+ H2O + H2O + H2O
Si
OH
OH
OH
OH
Si
OOO
OH
Silicic acid
• Dissolution takes place by surface erosion• Silicic acid is only weakly acidic with pKa 9.8
Effect of Water-to-TEOS Ratio in Sol-gel Process on DelSiTechTMSilica Dissolution In Vitro In Sink
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0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8
R3 R5 R10 R15
Cu
mu
lati
vesi
lica
dis
solu
tio
n/%
In vitro dissolution time/days
• Silica microparticles with various R-values (R = molar water-to-TEOS ratio in Sol-gel reaction)
• No differences in particles size (D50 3-5 microns)• Other process parameters (pH, temp., reaction time) identical
Incr
eas
ing
con
de
nsa
tio
n
In Vitro Case Study #1
Release control of 12 kDa protein in DelSiTechTMSilica
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Encapsulation And In Vitro Release of Cytochrome C Protein
• Cytochrome C is a 12 kDa protein with good water solubility (> 20 mg/ml)
• Cytochrome C was encapsulated in silica matrix using two different sol gel compositions: 1) R3 with 3-fold molar excess of water over TEOS2) R5 with 5-fold molar excess of water over TEOS
• All other parameters were kept same• The sols were spray dried in microparticles• Cytochrome C was measured in dissolution samples using RP-
HPLC method
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21.2.2019 Confidential 23
Cumulative in vitro in sink dissolution of silica and release of Cytochrome C protein in two silica microparticle formulations with different water-to-TEOS ratio
R3 silica microparticle with10 % protein payload
R5 silica microparticle with10 % protein payload
• In sink dissolution in 50 mM Tris pH 7.4 at 37 °C• Predicted in vivo dissolution after s.c. injection ca. 1 month for R3
microparticle and 4 months for R5 microparticle using IVIVC factor10 for s.c. dosing
Dosage Forms with DelSiTechTMSilica
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DelSiTechTMSilica Dosage Form #1:Injectable Silica-Silica Composite Depots
• API encapsulated in silica sol gel, followed by form giving in spray drying to produce microparticles
• Mixing microparticles with silica hydrogel to produce an injectable depot formulation
• Packing in prefilled syringe, ready-to-use
• Stable at rest, flowing upon injection
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Injectable Silica-Silica Composites Are Shear-
Thinning Material with Easy Injection
• Viscosity flow curves of silica microparticle-silicahydrogel depot formulations
• Microparticles mixed in at concentrations 0.5, 0.75 and 1.0 g/ml
Silica-silica composite depotafter injection into gelatin gel
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DelSiTechTMSilica Dosage Forms #2:Silica Monolithic Implants
• API encapsulated in silica sol gel, followed by form giving to produce an implant
• Form giving by casting in molds or extrusion
• Variable sizes and shapes, including micro-implants for e.g. intra-ocular use
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DelSiTechTMSilica Dosage Form #3:Ophthalmic Silica Composite Eye Drops
• API encapsulated either in silica microparticles or silica hydrogel, or both
• Packing in ready-to-use Single Dose Units
• One drop applied in conjunctiva cul-de-sac, where it stays for 24 hours maintaining therapeutic drug concentration in the eye
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DelSiTechTMSilica in Vivo Data
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In Vivo Case Study #2
Controlled Delivery of MR1 Humanized Antibody
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• Humanized anti-CD40L antibody (MW 150 kDa)• Target release time 6 months after subcutaneous
injection • Target dose at least 7 mg protein in 1 ml injection• Formulation strategy:
• Encapsulation of MR1 in silica microparticles only• Mixing MR1-silica microparticles with silica hydrogel• Protein load ca. 2.8 mass-% in the microparticles (8.4 mg in 1 ml
injection)
Development of Injectable Silica-Silica Composite Depot Formulation for MR1
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Cumulative concentration vs. time showingzero order release
In vivo serum concentration of MR1 in the mouse after s.c. depot and s.c. bolus injections (n=3 mice), measured by ELISA
In vivo release of MR1 from Injectable Silica Depot Formulation in the Mouse after Single S.C. Injection
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Summary
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Conclusions
• DelSiTechTMSilica is unique, versatile drug delivery vehicle that has proven safety, biocompatibility and material characteristics
• Combination of Sol-gel technology with spray drying is a powerful tool to produce controlled release formulations for parenteral use
• DelSiTechTMSilica is especially well suited for sustained release of therapeutic peptides and proteins even with high payloads
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Thank you – questions?
For more information, please contact:
Dr. Lasse Leino, CEO
Tel +358 40 8494 694
E-mail: [email protected]
www.delsitech.com36