development of pilosebaceous gland-targeted drug products
TRANSCRIPT
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Development of pilosebaceous gland-targeted drug products and
potential impact on BE testing
Guang Wei Lu, Ph.D. Allergan
March 12, 2013
PQRI Workshop on the Evaluation of New and Generic Topical Drug Products – Current Challenges in Bioequivalence, Quality, and Novel Assessment Technologies March 11-13, 2013, U.S. Pharmacopeia Meeting Center, Rockville, MD 20852
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I. Development process of dermal drug products and BE considerations II. Methods explored for the investigation of pilosebaceous gland-targeted drug products
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Developing a new dermal drug product
• Parachuting – Minoxidil: from a oral product for treating hypertension to a topical
solution for treating hair loss – Retinoids: topical tretinoin, tazarotene, adapalene for treating acne and
psoriasis
• Product enhancement – Microsponge drug delivery systems for tretinoin and benzoyl peroxide – New combination products: clindamycin/tretinoin, adapalene/benzoyl
peroxide
• Discovery of new molecule for dermal indication – Androgen receptor antagonist for the topical treatment of excess sebum
and androgenetic alopecia – Tyrosinase inhibitor for treating skin hyperpigmentation – Estrogen receptor agonist for reduction of wrinkles – Inhibitor of the intracellular esterification of cholesterol with CoA-
activated fatty acids to produce cholesterol esters for excessive sebum production
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First generation Second generation Third generation
Tazarotene
Bexarotene
Adapalene
Discovery and Development of Retinoids
Tretinoin
Retinol
Isotretinoin
Alitretinoin
Etretinate
Acitretin
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Recently approved new molecules for dermal indications
Molecule Product Manufacturer Indication Date approved by FDA
Ingenol mebutate Picato gel Leo Actinic keratosis 1/23/2012
Spinosad Natroba Parapro Head lice 1/18/2011
Retapamulin Altabax GSK Skin infection 4/12/2007
Sinecatechins Veregen Medigene External genital warts 10/31/2006
Sertaconazole Ertaczo Valeant Skin infection 12/10/2003
Pimecrolimus Elide Valeant Eczema 12/13/2001
Docosanol Abreva GSK Cold sores/fever blisters 7/25/2000
Aminolevulinic acid HCI
Levulan/ Kerastick
DUSA Non-hyperkeratotic actinic keratoses
12/3/1999
Alitretinoin Panretin Eisai Visceral Kaposi-s sarcoma
2/2/1999
Tazarotene Tazorac Allergan Acne, Psoriasis 6/17/1997
Penciclovir sodium Denavir Novartis Cold sores 9/24/1996
Butenafine HCl Mentax Mylan Fungal infection 10/18/1996
Azelaic acid Azelex Allergan Acne 9/13/1995
Adapalene Differin Galderma Acne 5/31/1996
Calcipotriene Dovonex Leo Scalp Psoriasis 12/29/1993
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year
1 2 3 4 5 6 7 8 9 10 11 12
Timeline and Stages of Drug Product Development
Bridge from 1 2 4 to 5
3
R&D Research Early Development Late Development Commercialization
Clinical Development Hit to lead Pre-clinical Phase I Phase II Phase III NDA - Phase IV
Drug Product Development Research Formulation Tox Formulation Phase I/II Formulation Phase III Formulation Final Drug Product
Drug Product Production Scale Lab batch, <10 g GLP, 1-5 kg GMP, 5-20 kg GMP, >20 kg Commercial Scale
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Key Activities in Early-stage Development of Dermal Products
Functions Lead selection Pre-clinical
Phase I/II
Chemistry -Identify leads -Synthetic feasibility
- Structural alert - Scale up (steps, raws, stereocenters, COG, Impurities )
- API scale up -Process optimization
Pharmaceutics - Initial solubility - Calculated Log P/pKa
-Solubility/Excipient compatibility/Solid form characterization & selection - UV spectrum for phototoxicity assessment/ Analytical method -Vehicle/formulation development for tox/Phase I/II -API and formulation stability
-Develop and validate analytical and microbial methods for quality control - GLP/GMP manufacture -Stability
ADME - Systemic exposure in animal models/Skin permeation and retention - Clearance in animal models/Major clearance mechanisms and metabolites - Plasma protein binding - PK/PD assessment/Prediction ADME in human and clinical dose/dosing regimen
Pharmacology - In vitro functional binding/assay
-In vitro assay - in vivo efficacy models/Biomarker
Safety -Acute dose study -Safety pharmacology: neuro, pulmonary and cardiovascular functions -Repeated-dose studies: rats and minipigs -Genetic tox studies -Special studies: photoirritation, local lymph node assay, reversibility
Bridging study if formulation is changed
Clinical - IND strategy/Early clinical development plan - Protocol for Phase I/II
- Clinical trials -Bridging study if formulation is changed
Regulatory -IND strategy/Pre-IND meeting -IND filing
Legal Freedom to operate and patent opportunity for indications/molecules/API solid form/formulation
Commercial/ Marketing
- IND strategy - Input to Target Product Profile
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Acceptable
Formulation /
Packaging?
Y
Formulation/Packaging Stability Studies
Vehicle
Related?
Systemically &
Topically Safe
Terminate
N
NN
N
Safe
Evaluate
Formulation
against MI
Criteria
Terminate
File IND/
CTX
Phase 1
Clinical
Supplies
& Studies
Y
lead
Formulation
& Analytical
Development
Phase 2a
Clinical
Supplies &
Studies
Lead Compound
Identified
Safety StudiesCandid
ate
N
Late
Dev
Late
Dev
Pre-Clinical
Studies
Phase 2b
Clinical
Supplies &
Studies
N
Terminate
Y
N
Y
Safe
Manufacture
Phase 2b Clinical
Supplies
POC
N
Early
Formulation
Development
Y Y
Bridging Safety
Studies
(if needed)
MIF
Packaging
Development
Y Market Image
Consumer
Evaluation
Delivery
Equivalency
Studies
Y
Decision
to Initiate MIF
Development
MIF
Formulation
Development
Phase 3
API, <100 g
Manufacture
& Release
Y
N
Phase 2b
API Manufacture
& Release
API, <10 g
Manufacture &
Release
Packaging/
Applicator
Development
$
Y
$
Supply Chain/
Outsourcing
Manufacture
Late dev team
API, 1-5 kg
Manufacture
& Release
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Research and Early Development Formulation
• Developed for non-clinical studies and Phase I/II studies • Limited quantity of API
– Starting with 50-100 mg – Effect of impurities
• Short development timeline – < 1 month for research formulation – 3-9 months for early development formulation depending on front-loading
or staged strategy
• Simple formulation preferred – Solutions, simple gels or ointments
• Excipients selection – Solubilizer, stabilizer, volatile solvent – Permeation enhancer or retarder (BE effect if changes) – Safety – Antimicrobial activity – Aesthetics (cosmetic elegancy)
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Change of formulations
• Dosage form change • Excipient change
– Change of excipient manufacture process – Different grade
• Stability Issue – Short term stability for Phase I/II, and long term stability for Phase III – Packaging compatibility or change
• Efficacy issue – Proof of mechanism (POM) vs. Proof of concept (POC) – Potency – Drug delivery profile – Placebo effect
• Safety issue – Irritation and sensitization – Systemic exposure
• In-use compatibility with other topical products
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Approaches in developing dermal products
• Targeted dermal drug concentration
– Established effective drug concentrations in dermal tissue following oral dosing
– Set the target drug concentrations for evaluation of topical delivery
• In vitro study
– Skin flux and disposition of topically applied drug
– Targeting the pilosebaceous gland
• In vivo study
– Rodents, minipigs and monkeys
– Drug concentrations in skin tissues and systemic exposure
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Summary I
• Development of topical products for dermal indications requires additional studies
• Vehicle/formulation effect on development process impacts the process, timeline, and resource of development from early discovery stage to commercialization
• Bridging among animal model and human subjects and understanding formulation BE are critical in each development stage
• There is unmet needs for non-invasive, target-specific quantification methods
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Methods explored for the investigation of pilosebaceous gland-targeted drug
products
I. Drug permeation through various skin models
II. Drug permeation through sebum
III. NIR Spectrometry for the qualification of drug in skin
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SKIN FLUX STUDY
Apparatus: Franz diffusion cell or alternatives
Membrane: Cadaver Skin or pig skin
Receptor Phase: Appropriate fluid at sink condition
Donor Phase: Saturated solution or formulations
Amount applied
Occlusive or non-occlusive
Temperature: 32°C
Duration: 24 hr or 48 hr
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Follicular Transepidermal
Systemic
Topical drug delivery to target site
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Franz Cell Flow Cell
Sid-by-side Cell Hanson’s Microette System
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Comparison of drug distribution in various skin samples
Compound (0.5%)
Vehicle Apparent Skin Flux (µg/cm²/hr)
Human Minipig Hamster ear
A Ethanol/Water/Propylene glycol/propylene carbonate
70/20/5/5 (% v/v)
0.057 ± 0.018 0.0317 ± 0.0053 0.878 ± 0.149
B Ethanol/Water/Propylene glycol 60/35/5 (% v/v)
0.0074 ± 0.0042 0.0007 ± 0.0032 0.127 ± 0.029
C Ethanol/Water/PEG 400 50/25/25 (% v/v)
0.011 ± 0.006 0.0005 ± 0.0005 0.060 ± 0.030
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Comparison of drug distribution in various skin samples
0
5
10
15
20
25
Human Minipig Hamster
Stratum corneum Skin Penetrated
0
5
10
15
20
25
Human Minipig Hamster
Stratum corneum Skin Penetrated
0
5
10
15
20
25
Human Minipig Hamster
Stratum corneum Skin Penetrated
% o
f d
ose
d
% o
f d
ose
d
% o
f d
ose
d
Compound A Compound B
Compound C
Compound A B C
MW 298 388 434
Log P 3.5 4.88 5.74
Dose 0.5% API, 5 -10 µL/cm²
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Comparison of drug distribution in skin tissues between female and male hamster
0
10
20
30
40
50
Surface Stratum corneum Skin Penetrated
Female hamster Male hamster
0
10
20
30
40
50
Surface Stratum corneum Skin Penetrated
Female hamster Male hamster
0
10
20
30
40
50
Surface Stratum corneum Skin Penetrated
Female hamster Male hamster
% d
ose
d
% d
ose
d
Compound A Compound B
Compound C
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Drug concentration effect on skin permeation, local and systemic exposure, and activity
% A Vehicle Human Skin (single dose) Hamster model (repeated doses)
Flux (µg/cm²/hr)
Derm conc. (µg/g)
SG conc.* (µg/g)
Plasma conc. (ng/mL)
% Reduction of WE**
0.5 EtOH/PG/W/Klu 60/20/20/0.5
0.062 ± 0.017 0.816 ± 0.085 30.1 ± 15.9 1.24 ± 0.55 80
1 EtOH/PG/W/Klu 60/20/20/0.5
0.099 ± 0.075 1.26 ± 0.69 21.0 ± 7.6 1.29 ± 0.43 77
Drug precipitation was observed after dosing 1% formulation
* Drug concentration in the sebaceous glands; ** efficacy model
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Formulation effect on skin flux and in vivo activity
Drug Vehicle Skin flux
(µg/cm2/hr) % Reduction of WE
0.5% B EtOH/W/PEG400/PG 50/25/15/10
0.0137 ± 0.0061 78
0.5% B EtOH/W/PEG1000/PG 50/25/15/10
0.0054 ± 0.0010 73
0.5% C EtOH/W/PG 50/30/20
0.0375 ± 0.0171 88
0.5% C EtOH/W 60/40
0.0064 ± 0.0058 86
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In vivo follicular drug delivery measurement
• Cyanoacrylate casting and differential stripping
• Follicular blocking techniques
– Microparticles
– Nail varnish
2. Press on to skin, glue spreads across
skin surface and into follicle openings
and dries
1. Drop of ‘Supaglue’ on microscope slide
3. Pull off to harvest stratum corneum
and contents of the follicle where glue
has penetrated
Glue
droplet
Drug
molecule
Dry
glue
Drug
molecules
set in glue
2. Press on to skin, glue spreads across
skin surface and into follicle openings
and dries
1. Drop of ‘Supaglue’ on microscope slide
3. Pull off to harvest stratum corneum
and contents of the follicle where glue
has penetrated
Glue
droplet
Drug
molecule
Dry
glue
Drug
molecules
set in glue
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Nonionic lipid effect on the topical delivery of minoxidil to hamster sebaceous glands
Topical delivery systems for active agents S Niemiec et al. US 6419913 B1, Jul 6, 2002
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Diffusion properties of model compounds in artificial sebum S Valiveti & G Lu, Int J Pharm 2007, 345: 88-94
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Drug Diffusion through artificial sebum
TransWell Insert
Donor solution or suspension (150 L)
Artificial sebum (5 L)
Receptor fluid (10% HP--CD in CPB, pH 5.5)
0.4 m membrane
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In vitro diffusion through the artificial sebum
A 24 well Transwell® plate (polycarbonate, 0.33 cm2 area, 0.44 μm pore size)
A 5 μL of artificial sebum was loaded on to the each well
A 150 μL of drug suspension (10 mg/ml) was loaded on to the each well, citrate-phosphate buffer pH 5.5 used as receiver solution
Samples were withdrawn at 10 min interval for 2h
At each time point entire receiver solution was replaced with fresh buffer
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Influence of receiver solution on lidocaine diffusion through the artificial sebum from water
0.00
10.00
20.00
30.00
40.00
50.00
0 20 40 60 80 100 120
cum
ula
tive a
mount
transp
ort
ed
(ug/c
m2)
Time (min)
pH 5.5 CPB buffer
5% HP-CD in CPB buffer pH 5.5
10% HP-CD in CPB buffer pH 5.5
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Lidocaine and minoxidil diffusion through the artificial sebum from water
lidocaine Flux = 34.89 mcg/cm2/min
Minoxidil Flux = 1.51 mcg/cm2/min
0
500
1000
1500
2000
2500
3000
3500
4000
0 20 40 60 80 100 120
cu
mu
lati
ve
am
ou
nt
tra
ns
po
rte
d (
mc
g/c
m2)
Time (min)
Drug transport profiles through artificial sebum from water
Lidocaine suspension in water
Minoxidil suspension in water
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Effect of solvent system on the minoxidil diffusion through the artificial sebum
Minoxidil Flux = 3.60 mcg/cm2/min
Minoxidil Flux = 1.51 mcg/cm2/min
0
200
400
600
0 20 40 60 80 100 120
Time (min)
cu
mu
lati
ve
am
ou
nt
tra
ns
po
rte
d (
mc
g/c
m2)
5% Minoxidil in ethanol:water:PG (60:20:20:)
5% Minoxidil in Water
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Effect of the solvent system on the lidocaine diffusion through the artificial sebum
Liodocaine permeation profiles through artificial sebum
Lidocaine Flux = 149.60 mcg/cm2/min
Lidocaine Flux = 34.89 mcg/cm2/min.
0
5000
10000
15000
0 20 40 60 80 100 120
Time (min)
cu
mu
lati
ve a
mo
un
t tr
an
sp
ort
ed
(m
cg
/cm
2)
Saturated solution of lidocaine in
ethanol:water:PG (60:20:20:)
Suspension of lidocaine in water
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Influence of volume of donor solution on the minoxidil flux through artificial sebum
Flux from 10 uL = 3.77 mcg/cm2/min
Flux from 15 uL = 4.388 mcg/cm2/min
Flux from 20 uL = 5.1235 mcg/cm2/min
Flux from 25 uL = 6.0152 mcg/cm2/min
0
200
400
600
0 20 40 60 80 100 120
Time (min)
cum
ulat
ive
amou
nt t
rans
port
ed (
ug/c
m2)
10 uL 15 uL
20 uL 25 uL
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NIR Spectrometry Method
• J Medendorp et al. Pharm Res. 23: 835-843 (2006)
• Econazole nitrate (EN) and 4-cyanophernol (4-CP) exhibit strong NIR chromophores. The NIR spectrum at 1470-1870 nm for 4-CP, and at 1936-2336 nm for EN were selected for quantification .
• Hairless guinea pig skin, MatTek permeation device and Technicon InfraAlyzer 500 were used for the study.
• Scattering data were analyzed using principle component regression (PCR), interval PCR and PCR-uninformative variable elimination models
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Estradiol distribution in skin tissues after application of topical formulations using NIR spectra method
• J Medendorp et al. AAPS AM posters, 2007
• Estradiol was formulated in gel, suspension and nanosuspension
• Estradiol distribution in hairless guinea pig skin was investigated using NIR method
• Scattering data were analyzed using principle component method
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Principal component ellipses calculated from multiplicative scatter corrected data in the mid-IR region (4,000 – 2,000 cm-1) demonstrating the tendency of like-data to cluster in the same region of multidimensional hyperspace. These clusters included those spectra of tissues harvested from the left side of the guinea pig.
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2% Estradiol Gel
0
20
40
60
80
100
120
140
160
0 5 10 15 20 25
ng
/mL
Time (h)
Hartley (shaved)
IAF Hairless
Hartley (hair removed)
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Hairy Guinea Pigs
0
20
40
60
80
100
120
140
160
0 5 10 15 20 25Time (h)
ng
/mL
Milled
Gel
Large Particle
Baseline
D.C. Hammell et al. AAPS AM poster, 2007
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Summary II
• Skin permeation and disposition studies in various models are commonly used for the development of dermal drug products.
• Sebum model provides a complementary tool for molecule and formulation screening, particularly for those targeting pilosebaceous glands.
• The correlation among rodent models for efficacy and irritation, minipig model for tolerance, and human subjects in clinical trials needs to be carefully assessed at discovery and early development stages.
• The MIR/NIR instrumentation presented in this research have proven to be effective means for visualizing estradiol distribution in human tissue, and demonstrated the formulation effect on the distribution. Further investigation for the application is needed.
• Hairy and hairless guinea pigs were used as the animal models for the investigation of hair follicular drug delivery.