Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive...
Transcript of Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive...
![Page 1: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/1.jpg)
Novel Formulation and Biopharmaceutical Challenges of Oral Cancer Therapy
Gavin HalbertCancer Research UK Formulation Unit
Strathclyde Institute of Pharmacy and Biomedical SciencesUniversity of Strathclyde
![Page 2: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/2.jpg)
Synopsis
• Introduction• Oral administration• Cancer and chemotherapy developments• Barriers requiring carriers• Pharmaceutical nanolandscape• Amorphous, anthracyclines and taxanes• Nanotechnology issues• Conclusions
![Page 3: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/3.jpg)
Gavin Halbert• Pharmacist, Chemist & Qualified Person• Drugs into patients• Range of research, formulation and product experience• Drug delivery sympathies – practical realities
FormulationUnit
CMAC OrBiTo
MMIC
Introduction
![Page 4: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/4.jpg)
Formulation Unit• Established in 1983 – unique within UK• Develop novel anti-cancer drugs selected by Cancer Research UK• Antibodies – Alkylating Agents – Antisense• Drug Delivery Systems
LiposomesADEPT
Introduction
![Page 5: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/5.jpg)
Drug Delivery in Cancer
Chemotherapy
• Long history of delivery/targeting drugs to cancer
1958 – methotrexate conjugated to polyclonal antibody
• Early rationale
Alleviation of toxicity
• Multiple systems tested
Liposomes
Microspheres
Nanoparticles
Polymeric conjugates
Chen, Y., et.al., J.Cont.Rel., 1988;8;93-101
Microscopy Transferrin/Albumin/Polyaspartic acid microspheres
Introduction
![Page 6: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/6.jpg)
Oral Nanoparticulate Systems
• Uptake of nanoparticles after gastro-intestinal administration
Jani, P., et.al., J.Pharm.Pharmacol., 1990;42;821-826Jani, P., et.al., J.Pharm.Pharmacol., 1989;41;809-812
Introduction
Dawson, G.F., Halbert, G.W., Pharm.Res., 2000;17;1420-1425
![Page 7: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/7.jpg)
Cancer and chemotherapy developments
![Page 8: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/8.jpg)
Cancer Research
• Massive increase in biological understanding• Imatinib – 2001 – targeted treatment
• Tumour heterogeneity
• Agile combination therapy• Personalised therapy
Cancer and chemotherapy developments
Burrell, R., et.al., (2013) Nature 501: 338-345
![Page 9: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/9.jpg)
Molecular Complexity
BCS Issues
sorafenib
nilotinib
imatinib Solubility 200mg/ml
Oral Bioavailability 98%
Solubility sparingly
Oral Bioavailability 31%
Solubility (1:2 DMSO:PBS) 0.3mg/ml
Oral Bioavailability 50%
Cancer and chemotherapy developments
![Page 10: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/10.jpg)
Intestinal Solubility Variation• Impact of simulated gastrointestinal fluid composition
Khadra, I., et.al., (2015) Eur. J. Pharm. Sci., 67: 65-75 (Fasted data only)
CRUK1
2/05
CRUK0
7/13
felodip
ine
fenofib
rate
probu
col
aprep
itant
tadala
fil
zafirlu
kast
carved
ilol
AZD-424
CCTxx736
0.00001
0.0001
0.001
0.01
0.1
1
10
100
Solu
bility
(mM
)
Cancer and chemotherapy developments
![Page 11: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/11.jpg)
Oral administration
![Page 12: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/12.jpg)
Cancer Chemotherapy TherapyRoutes of Administration
• Oral therapy – always presentChlorambucil, tamoxifenTraditional formulation presentations
Not always optimal• Parenteral therapy – main route
Alkylating agents, doxorubicinBioavailabilityAcute therapy
Toxicity, pharmacokinetics
Oral administration
![Page 13: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/13.jpg)
Oral Therapy - Temozolomide
• DacarbazineIV administration
• TemozolomideOral administration
Dacarbazine
Temozolomide
N N
NN
NNH2
O
O
Oral administration
Pro-drug approach
![Page 14: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/14.jpg)
Advantages and switch to oral
Pare
nter
al/O
ral R
atio
0
2
4
6
1995 2010
Formulation Unit Survey
“Biotechs” not included
“the most frequently reported attributes contributing to preference included convenience, ability to receive treatment at home, treatment schedule, and side effects.”
Oral administration
EeK, D., et.al., Patient Preference and Adherence 2016;10;1609-1621
Shih, Y-C.T., et.al., J.Clin.Oncol., 2015;33;2190-2196
![Page 15: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/15.jpg)
Bioavailability
• Poor bioavailability - always an issue• Chemical stability• Poor solubility• Efflux pumps
Paclitaxel
Methotrexate
Doxorubicin
Oral administration
![Page 16: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/16.jpg)
Barriers requiring carriers
![Page 17: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/17.jpg)
Gastrointestinal transit route
DosageForm
Intestinal Fluid
PortalCirculation
SystemicCirculation Tumour
Un-dissolvedDegraded
Un-absorbed
IntestinalMembrane
Liver
MetabolisedExcreted
Kidney Liver
TumourVasculatureNormal
Organs
Toxicity
Drug in solution
Barriers requiring carriers
ReviewsBlanco, E., et.al., Nat.Biotechnol., 2015;33;941-951Malhaire, H., et.al., Adv.Drug.Deliv.Rev., 2016;106;320-336
![Page 18: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/18.jpg)
Gastrointestinal transit route
DosageForm
Intestinal Fluid
PortalCirculation
SystemicCirculation Tumour
Un-dissolvedDegraded
Un-absorbed
IntestinalMembrane
Liver
MetabolisedExcreted
Kidney Liver
TumourVasculatureNormal
Organs
Toxicity
Drug in solution
SolubilityDissolution
Stability
Pumps
Metabolism Excretion
Toxicity
Barriers requiring carriers
![Page 19: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/19.jpg)
How far do you need to go?
DosageForm
Intestinal Fluid
PortalCirculation
SystemicCirculation Tumour
IntestinalMembrane
Liver
TumourVasculatureNormal
Organs
Drug in solution
Passive
Active
Stability
Absorbtion
Drug
Solubilisation
Metabolism
Excretion
Toxicity
Targeting
Use an excipient (carrier) to usurp or circumvent the barrier
Barriers requiring carriers
![Page 20: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/20.jpg)
Pharmaceutical nano-landscape
![Page 21: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/21.jpg)
Pharmaceutical nano-landscapeNano Systems
Molecular Amphiphile Polymer-isable
Intrinsic Particulate
Nanocrystal
Vesicular EmulsionMicelle
Solid Capsular Liposome Niosome Simple Multiple Particulate Capsular
Talelli, M., et.al., Nano Today 2015;10;93-117
Nanocrystals
Micelles
Pharmaceutical nano-landscape
![Page 22: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/22.jpg)
Amorphous systems
• Are they nanobased?
Drug dispersed in polymer – nano sized domains
Molecular dispersion or solution
• Route to increased kinetic solubility
• Systems variability possible
Nano-crystalline to amorphous
Polymer characteristics
• Extreme particle size reduction
Down to the molecule
NB also applicable for other systems
Martinez-Marcos, L., et.al., Int.J.Pharm., 2016;499;175-185
Albendazole polymer –
amorphous dispersion
Pharmaceutical nano-landscape
Review
Jermain, S.V., et.al., Int.J.Pharm., 2018;535;379-392
![Page 23: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/23.jpg)
Development of polymeric systemsHydrophilicHydrophobic
Polymer BPolymer A
Drug
Polymer BPolymer A
DrugDrugDrug
Polymer BPolymer A
DrugDrugDrug
Polymer BPolymer A
DrugDrugDrug
Direct chemical attachment
Triggered release mechanism
Additional Modifier
HydrophilicHydrophobicDrug
Additional moleculesPendant spacer
Physical mix
Polymer BPolymer A
DrugDrugDrug
Targeting Ligand
ReviewsPerez-Herrero, E., et.al., Eur.J.PharmSci., 2015;93;52-79Biswas, S et.al., Eur.J.PharmSci., 2016;83;184-202 Pharmaceutical nanolandscape
![Page 24: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/24.jpg)
Amorphous, anthracyclines and taxanes
![Page 25: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/25.jpg)
Amorphous systems• Increased interest
Poorly soluble drugs• Range of manufacturing techniques
Hot melt extrusion, solvent precipitation
• Example marketed systemsVemurafenibRegorafenibEvorlimus
• Solubility assistance only
Native drug
Martinez-Marcos, L., et.al., Int.J.Pharm., 2016;499;175-185
Solid dispersion
Dissolution of Albendazole
Amorphous, anthracyclines and taxanes
![Page 26: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/26.jpg)
PAMAM-Doxorubicin dendrimer
Amorphous, anthracyclines and taxanes
Data from: Ke, W., et.al., J.Pharm.Sci., 2008;97;2208-2216
• Oral administration 20mg/kg in rat• Particle size ≈ 4nm• Doxorubicin
Cmax (µM) = 0.20AUC (µg/mL)*h = 0.78
• Doxorubicin-PAMAMCmax (µM) = 7.63AUC (µg/mL)*h = 247
• Doxorubicin IV Cmax (µM) ≈ 10
Data from: Rahman, A., et.al., Cancer.Res., 1986;46;2295-2299
Relative not Absolute!
![Page 27: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/27.jpg)
Surface decorated nanoparticles
• PLGA Nanoparticles• Surface –polyethylene glycol or mannosamine• Epirubicin @ 10mg/kg in rats• Particle Size ≈ 250nm
Data from: Tariq, M., et.al., Int.J.Pharm., 2016;501;18-31
Amorphous, anthracyclines and taxanes
![Page 28: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/28.jpg)
Docetaxel microemulsion
• o/w microemulsion oral in ratsCapryol 90/cremophor/transcutol
• Droplet size ≈ 30nm
Yin, Y-M., et.al., J.Cont.Rel., 2009;140;86-94
iv 8mg/kg
po 10 mg/kg
Amorphous, anthracyclines and taxanes
![Page 29: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/29.jpg)
Paclitaxel nanomicelle
• Dual functional system – in ratsMucosal penetration & P-gp inhibition
• Particle size ≈ 250nm
Lian, H., et.al., Colloids and Surfaces B: Biointerfaces, 2017;155;429-439
po 15 mg/kg
Amorphous, anthracyclines and taxanes
![Page 30: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/30.jpg)
Nanotechnology issues
![Page 31: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/31.jpg)
Nanotechnology issues• Complex systems• Production
Solvent, dialysis, sonication, centrifugation• Issues of scale up
Working volume approx 10mL• Control of complex polymers
Synthesis and impact on properties• Stability
Chemical and physical• Cost of goods
Greater than drug costs?• Toxicity
Nanotechnology issues
O
OH
NH2
HO OOO
OH
NH2
HO OO
OH
NH2
HOO O
OH
NH2
HO OO
OH
NH2
HO O
n
HO
O
Realistic values ≈ 10n
![Page 32: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/32.jpg)
Conclusions
• Not yet - “set the heather alight!”Struggling to break through
• Amorphous systemsIncreasing acceptance – solubility only – or maybe not?
• Experimental promise – not realized clinically• Not simply drug – but whole system
Efficacy, variability, biological interaction, manufacture and control• Likely to arrive
Bioavailability improvement• Watch this space
Recent QuoteDespite the demonstrated advantages by the preclinical studies, further studies on improved understanding of the interactions of SLNCs with biological tissues of the target site is necessary for efficient designing functional nanoparticles for clinical applications. Mu, H., Holm, R., Expert Opinion Drug Delivery 2018;15;771-785
ReviewsTran, S., et.al., Clin.Trans.Med., 2017;6;44Ventola, C.L., P&T., 2017;42;742-755
![Page 33: Novel Formulation and Biopharmaceutical Challenges of Oral ... · Cancer Research • Massive increase in biological understanding • Imatinib – 2001 – targeted treatment •](https://reader033.fdocuments.us/reader033/viewer/2022053020/5f2bcae2d8400d5733398fb6/html5/thumbnails/33.jpg)
Thank you
• Funder – Cancer Research UK
• CollaboratorsMany and varied
Local, national and international
• Organisers - Invitation
• You for listening