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: lasse.leino@delsitech.com

www.delsitech.com36