Translational formulation of nanoparticle therapeutics from laboratory discovery to clinical scale.

Translational formulation of nanoparticle therapeutics from laboratory discovery to clinical scale.

Publication date: Jun 14, 2019

“Nanomedicine” is the application of purposely designed nano-scale materials for improved therapeutic and diagnostic outcomes, which cannot be otherwise achieved using conventional delivery approaches. While “translation” in drug development commonly encompasses the steps from discovery to human clinical trials, a different set of translational steps is required in nanomedicine. Although significant development effort has been focused on nanomedicine, the translation from laboratory formulations up to large scale production has been one of the major challenges to the success of such nano-therapeutics. In particular, scale-up significantly alters momentum and mass transfer rates, which leads to different regimes for the formation of nanomedicines. Therefore, unlike the conventional definition of translational medicine, a key component of “bench-to-bedside” translational research in nanomedicine is the scale-up of the synthesis and processing of the nano-formulation to achieve precise control of the nanoscale properties. This consistency requires reproducibility of size, polydispersity and drug efficacy.

Here we demonstrate that Flash NanoPrecipitation (FNP) offers a scalable and continuous technique to scale up the production rate of nanoparticles from a laboratory scale to a pilot scale. FNP is a continuous, stabilizer-directed rapid precipitation process. Lumefantrine, an anti-malaria drug, was chosen as a representative drug that was processed into 200 nm nanoparticles with enhanced bioavailability and dissolution kinetics. Three scales of mixers, including a small-scale confined impinging jet mixer, a mid-scale multi-inlet vortex mixer (MIVM) and a large-scale multi-inlet vortex mixer, were utilized in the formulation. The production rate of nanoparticles was varied from a few milligrams in a laboratory batch mode to around 1 kg/day in a continuous large-scale mode, with the size and polydispersity similar at all scales.

Nanoparticles of 200 nm were made at all three scales of mixers by operating at equivalent Reynolds numbers (dynamic similarity) in each mixer. Powder X-ray diffraction and differential scanning calorimetry demonstrated that the drugs were encapsulated in an amorphous form across all production rates. Next, scalable and continuous spray drying was applied to obtain dried powders for long-term storage stability. For dissolution kinetics, spray dried samples produced by the large-scale MIVM showed 100% release in less than 2 h in both fasted and fed state intestinal fluids, similar to small-batch low-temperature lyophilization.

These results validate the successful translation of a nanoparticle formulation from the discovery scale to the clinical scale. Coupling nanoparticle production using FNP processing with spray drying offers a continuous nanofabrication platform to scale up nanoparticle synthesis and processing into solid dosage forms.

Open Access PDF

Feng, J., Markwalter, C.E., Tian, C., Armstrong, M., and Prud’homme, R.K. Translational formulation of nanoparticle therapeutics from laboratory discovery to clinical scale. 04797. 2019 J Transl Med (17):1.

Concepts Keywords
Amorphous Nanoparticle
Batch Mode Nanomedicine
Bioavailability Solid lipid nanoparticle
Clinical Trials Flash
Coupling
Differential Scanning Calorimetry
Diffraction
Flash
Inlet
Jet
Kinetics
Lumefantrine
Lyophilization
Malaria
Mass Transfer
Mixer
Momentum
Nanofabrication
Nanomedicine
Nanoparticle
Nanoparticles
Nanoscale
Polydispersity
Precipitation
Reproducibility
Small Batch
Spray Dried
Spray Drying
Temperature
Translational Medicine
X Ray

Semantics

Type Source Name
drug DRUGBANK Artemether
gene UNIPROT RTRAF
gene UNIPROT EIF2B5
disease DOID cle
disease DOID cle
gene UNIPROT ENG
drug DRUGBANK Curcumin
gene UNIPROT MBNL1
gene UNIPROT CHIA
gene UNIPROT ARHGEF1
gene UNIPROT POC1A
gene UNIPROT DUOXA1
disease DOID cryptosporidiosis
disease MESH cryptosporidiosis
gene UNIPROT APPL1
gene UNIPROT ACSS2
gene UNIPROT ACCS
gene UNIPROT PLA2G15
drug DRUGBANK (S)-Des-Me-Ampa
gene UNIPROT NLRP5
gene UNIPROT CYREN
drug DRUGBANK Nonoxynol-9
drug DRUGBANK Ibuprofen
gene UNIPROT F11R
gene UNIPROT NSF
gene UNIPROT IP6K1
gene UNIPROT IP6K2
gene UNIPROT PTPRF
gene UNIPROT ADHFE1
gene UNIPROT PLEKHG5
gene UNIPROT FES
gene UNIPROT CTBP1
gene UNIPROT SPEN
gene UNIPROT TNF
disease MESH dif
gene UNIPROT NT5E
gene UNIPROT TBPL1
disease MESH bile
gene UNIPROT ACIN1
gene UNIPROT NF2
gene UNIPROT BBS9
disease MESH separation
gene UNIPROT COL17A1
gene UNIPROT FBLIM1
gene UNIPROT TUBE1
gene UNIPROT GAST
gene UNIPROT PAGR1
gene UNIPROT GALNS
gene UNIPROT LRP1
drug DRUGBANK Nitrogen
gene UNIPROT SERPINB6
gene UNIPROT SORBS1
gene UNIPROT BRD4
gene UNIPROT HACD1
gene UNIPROT LNPEP
gene UNIPROT CAP1
gene UNIPROT KAT5
gene UNIPROT ITFG1
gene UNIPROT TIPRL
gene UNIPROT METTL8
gene UNIPROT NR1H4
gene UNIPROT ADRB2
gene UNIPROT BFAR
gene UNIPROT CES2
gene UNIPROT CASP1
gene UNIPROT FASTK
drug DRUGBANK Clofazimine
drug DRUGBANK Microcrystalline cellulose
gene UNIPROT IDE
drug DRUGBANK Activated charcoal
gene UNIPROT GRAP2
drug DRUGBANK Copper
gene UNIPROT TNMD
gene UNIPROT CYLD
drug DRUGBANK Tretamine
gene UNIPROT MENT
drug DRUGBANK Trestolone
gene UNIPROT TNFSF14
gene UNIPROT PADI1
gene UNIPROT PDIA2
gene UNIPROT P4HB
gene UNIPROT FURIN
gene UNIPROT CTNND1
gene UNIPROT CSE1L
gene UNIPROT BCAR1
gene UNIPROT MARK1
gene UNIPROT SERPINF2
drug DRUGBANK Alpha-1-proteinase inhibitor
gene UNIPROT ARID1A
gene UNIPROT DEPP1
gene UNIPROT GOPC
drug DRUGBANK Water
gene UNIPROT CEL
gene UNIPROT DSC3
gene UNIPROT LMNB1
gene UNIPROT AMBP
gene UNIPROT PTPN5
drug DRUGBANK Coenzyme M
gene UNIPROT CBARP
drug DRUGBANK Succinic acid
drug DRUGBANK Methylcellulose
gene UNIPROT SFRP4
gene UNIPROT EMD
gene UNIPROT NPS
gene UNIPROT SLC26A3
gene UNIPROT OXCT2
pathway BSID Reproduction
gene UNIPROT NPL
gene UNIPROT COL9A3
gene UNIPROT COMP
gene UNIPROT COL9A1
gene UNIPROT COL9A2
gene UNIPROT SCN8A
pathway BSID Release
gene UNIPROT RAB35
gene UNIPROT SH3YL1
disease MESH multi
gene UNIPROT FBXL15
pathway BSID Malaria
disease DOID malaria
disease MESH malaria
drug DRUGBANK Lumefantrine
gene UNIPROT EGR3
gene UNIPROT CASP8AP2
gene UNIPROT FBN1
drug DRUGBANK Spinosad
gene UNIPROT LARGE1
gene UNIPROT SET
disease MESH development
pathway BSID Translation

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