Characterization of polymer/drug films as models for

Transcription

Polymer/drug films as a model system for a drug
eluting coronary stent coating layer
Valeria Ciarnelli
Prof. Clive Roberts
Prof. Morgan Alexander, Prof. Martyn Davies
School of Pharmacy
The University of Nottingham
14 September 2012
PharmSci_APS
Introduction: what is a coronary stent?
The coronary artery stent is a tubular device, in the form of a coil or mesh, that
is inserted at the site of arterial obstruction via a catheter.
This device widens the coronary artery improving blood flow to the ischemic
heart muscle.
2 types:
Bare metal stent (BMS)
Drug eluting stent (DES)
A
Obstruction: plaque.
The stent is placed via catheter
B
Balloon inflated
The artery is expanded
C
Scaffolding action
The blood flow is re-established
Targets
Drug eluting stent
+
Drug/Polymer coating layer
Characterization of films as models for drug eluting coronary
stent coating layer
Characterization of the actual drug eluting coronary stent coating layer
This work is a part of analytical support to develop a medical device
Optimization of manufactoring process
Methods. Spun cast film preparation and
equipments used
Spin casting
Spray coating
AFM
(XPS)
3
(ToF-SIMS)
Spun cast or spray coated film
Sample ID
Series 1*
Series 2*
Casting Procedure
Spun cast
Spun cast
Drying Step
Room condition
Bake in oven (50°C for 45 min)
Series 3*
Spray coated
Warm air (50°C for 15 sec each
2nd spray cycle)
Series 4*
Spun cast in argon
atmosphere
Bake in oven (50°C for 45
min under vacuum)
*The films were made from solutions at different drug polymer weigh ratio precisely at 1:3; 1:1 and 3:1. Pure
polymer and drug films were also made as references models.
Methods. Atomic Force Microscopy
(AFM)
A) Ball and stick model of pentacene B) STM images, C) and
D) NC-AFM image of pentacene
A
5Å
C
5Å
1.3 Å
B
5Å
- 2 Hz
- 7 Hz
0Å
+ 1 Hz
D
20 Å
Leo Gross et al, Science, 2009
Leo Gross et al, Science, 2009, 324, 1428
- 5 Hz
Methods. Time of flight Secondary Ion Mass
Spectroscopy (ToF-SIMS)
Sputter Ion
Beam
Analysis Ion
Beam
100 µm
300 µm
y
x
Intensity
Depth
z
Anna Belu et al. Chemical imaging of drug eluting coatings: Combining
surface analysis and
confocal Raman microscopy
Methods. X-Ray Photo-electron
Spectroscopy (XPS)
Photoemission peak
Photo emission
Inelastic scattering tail
Free electron
X-rays
X-Ray
Valence electrons
eV
Core electrons
Nucleus
X-Ray
Coronene Molecule (C24H12)
Results. AFM characterization. Series 1 and 2
Series 1. Spun cast film without heating step. Tapping mode.
Topography
Topography
Phase
220nm
63°
0 nm
- 90°
1 µm
Topography
Phase
134nm
60°
0 nm
- 90°
2 µm
1 µm
0 nm
1:3 d:p wr
Phase
41°
150nm
- 90°
1: 1 d:p wr
3: 1 d:p wr
Increasing drug loading
• Film at 1:3 wr shows circular pit features (diameter approximately 10 - 250 nm). Clear evidence of phase separation
• Film at 3:1 drug polymer weight ratio shows globular surface features
Series 2. Spun cast film with heating step (50°C for 45 min). QNM mode.
Topography
Topography
DMT modulus
330nm
Topography
DMT modulus
200 nm
250
MPa
DMT modulus
145 nm
137
MPa
3 GPa
c
2 µm
1 µm
0 nm
1:3 d:p wr
0 MPa
1 µm
0 nm
1: 1 d:p wr
0 MPa
0 nm
0 GPa
3: 1 d:p wr
• Film at 1:1 shows network structure surrounding deeper areas, globular features with a diameter of approximately 100 nm
Results. AFM characterization. Series 2 and 3
Series 3. Spray coated film on silicon wafer with heating step.
(QNM mode)
167 nm
Topography
1 µm
DMT modulus
5.8 GPa
551 nm
Topography
DMT modulus
2.6 GPa
1 µm
0 nm
1 GPa
DMT modulus
1 µm
2.4 GPa
0 nm
1:3 d:p wr
216 nm
Topography
0 nm
0 GPa
1: 1 d:p wr
75 MPa
3: 1 d:p wr
Increasing drug loading
• Presence of globular features (diameter ≈ 100 nm) showing mechanical heterogeneity
• Features organized in globular domains also observed in the spun cast films.
• These features occur at a higher incidence with increasing drug concentration
Series 4. Spun cast film on silicon prepared in argon atmosphere with heating step (50°C for 45 min) under
vacuum. ( tapping mode RH = 5%)
Topography
2 nm
Phase
120°
1 µm
Topography
8 nm
Phase
-15°
1:3 d:p wr
100°
33 nm
-15°
Phase
1 µm
2µm
0 nm
Topography
0 nm
1: 1 d:p wr
-27°
0 nm
3: 1 d:p wr
• Different morphology although still presence of globular domains with diameter ranging from 100 nm to 350 nm
-21°
Results. ToF-SIMS characterization.
Depth profiling of spun cast films series 1
Series 1. Spun cast film on silicon wafer
1:3 d:p weight ratio
Bulk
14000
9000
Film at 1:1 drug polymer weight ratio without heating step
18000
Polymer
PLA
Interface
Drug
12000
Everolimus
Intensity (ion count)
20000
Silicon x 5
10000
8000
6000
4000
16000
Polymer
PLA
14000
Drug
Everolimus
Silicon x 10
12000
10000
8000
6000
Everolimus
Drug
6000
4000
3000
2000
2000
1000
0
0
Surface
200
Depht (nm)
300
400
500
Silicon x 5
5000
4000
100
PLA
Polymer
7000
2000
0
8000
16000
0
0
100
200
300
400
500
0
100
Depht (nm)
Drug
Polymer
200
300
Depht (nm)
400
500
600
Silicon x n
(n= 5,10 and 5 for 1:3, 1:1 and 3:1 respectively)
• This indicates that the drug migrates to the surface and to an extent at the substrate interface leaving the
polymer relatively concentrated in the bulk.
• Overall relative ion peak intensities for drug and polymer markers are consistent with the respective
concentration
Sputter time
(sec)
277
Sputter rate
(nm/sec)
0.90
Sample ID
Thickness (nm)
1:3 d:p wr
250
1:1 d:p wr
315
351
0.90
3:1 d:p wr
288
342
0.85
Series 2. Spun cast film on glass slide.
The films underwent a drying step in the oven at 50°C for 45 min
60000
90000
70000
Film at 1:1 drug polymer weight ratio with heating step
80000
Polymer
PLA
Silicon
Drug
Everolimus
50000
40000
30000
50000
Polymer
PLA
40000
Intensity
(ion(ions)
count)
Counts
Silicon
60000
Count (ions)
70000
60000
50000
Counts
(ions)
Intensity
(ion
count)
Drug
Everolimus
30000
20000
Silicon
40000
Polymer
PLA
Drug
Everolimus
30000
20000
20000
10000
10000
10000
0
0
0
50
100
150
200
250
300
0
0
Depth (nm)
Polymer
Drug
The drug migrates to the surface
forming a surface-enriched drug
region for all the films at different
loadings
Polymer
The polymer is concentrated in the
bulk region of the film
1:1 d:p wr
50
100
150
Depth (nm)
200
250
Drug
300
350
0
50
Silicon
100
150
200
Depth (nm)
250
300
350
Series 3. Spray coated film on silicon.
The films underwent a drying step (warm air 50°C)
200000
70000
Spray coated film at 1:3 drug polymer wr.
180000
40000
Spray coated film at 1:1drug polymer wr
Silicon
120000
Polymer
100000
Drug
Silicon
80000
60000
40000
50000
Polymer
40000
Drug
Silicon x 5
140000
30000
20000
10000
20000
0
500
1000
1500
Depth (nm)
2000
Drug
Polymer
Polymer
The drug surface
enrichment is less
pronounced than
the one observed
for the spun cast
films
1:1 d:p wr
Polymer
25000
Drug
20000
15000
10000
0
0
2500
30000
5000
0
0
Spray coated film at 3:1 drug polymer wr
35000
60000
160000
500
1000
1500
Depth (nm)
2000
Drug
2500
3000
0
1000
Silicon
2000
Depth (nm)
3000
4000
Results. XPS characterization. Surface
analysis of spun cast films series 2 and
spray coated films series 3
XPS spectra of drug powder
2
O 1s
80
3
O 1s
x 10
25
C 1s
x 10
XPS spectra of polymer powder
70
20
60
CPS
15
40
C 1s
CPS
50
10
30
N 1s
20
5
10
0
0
1200
900
600
Bi ndi ng E nerg y (eV)
30 0
1 200
0
C
Spun cast films (series 2)
S ( hi
i
b
9 00
di
di
C
S
/
i
6 00
Bi ndi ng E n ergy (eV)
)
Spray coated films (series 3)
3 00
0
Spun cast films (series 4)
1:3
(25%)
1:1
(50%)
3:1
(75%)
1:3
(25%)
1:1
(50%)
3:1
(75%)
1:3
(25%)
1:1
(50%)
3:1
(75%)
0.37
0.74
1.1
0.37
0.74
1.1
0.37
0.74
1.1
N % (experimental) ± SD
1.3 ± 0.02
1.2 ± 0.04
1.1 ± 0.01
0.4 ± 0.04
1.0 ± 0.10
1.3 ± 0.05
1.29 ± 0.06 1.44 ± 0.04 1.39 ± 0.03
Experimental Drug %
(w/w) ± SD
85.4 ± 1.0
83.3 ± 2.4
76.4 ± 0.7
27.2 ± 2.7
64.7 ± 7.0
88.5 ± 0.2
88.5 ± 4.0
Drug/polymer wr (Drug
loading)
N % (theoretical)
Drug enrichment
Less pronounced drug enrichment
99.5± 2.4
96.3± 1.7
Results. XPS characterization.
Depth profiling of spun cast films: series 4
Series 4. Spun cast film on silicon. 50ºC for 45 min, Ar atmosphere and controlled humidity
1.6
80
1.4
70
1.6
70
1.2
1.2
50
1
40
0.8
30
0.6
20
10
0
50
100
Depth (nm)
0.2
10
C 1s
Drug enrichment at the
surface and interface
(film/silicon). The same is
observed for the other drug
polymer concentrations.
0.6
30
20
150
0.8
40
0.4
1.2
1.2
70
70
1
50
0.4
0
0
60
1.4
1.4
80
80
N1s %
1.4
60
90
90
11
60
60
50
50
0.8
0.8
40
40
0.6
0.6
N1s %
%
N1s
90
1.8
C1s,
& Si2p
Si2p %
%
C1s, O1s
O1s &
2
80
C1s, O1s & Si2p %
90
N1s %
C1s, O1s & Si2p %
30
30
0.4
0.4
20
20
0.2
0
0
0
20
40
O 1s
60
Depth (nm)
80
100
N 1s
120
0.2
0.2
10
10
00
00
00
50
50
100
150
100
150
Etching
Etching time
time(sec)
(sec)
Si 2p
The drug profiles obtained from XPS
and ToF-SIMS depth profiling are
consistent.
200
200
Conclusions
9We are able to characterize this particular drug polymer coating layer using
complementary surface analysis techniques.
9AFM shows the presence of globular features (diameter 100-150 nm) occurring at higher
incidence with increased drug loading
9ToF-SIMS depth profiling on the model films showed the drug and polymer distribution as
a function of depth, with the drug preferentially located at the surface
9The XPS analysis confirmed the existence of an enrichment of drug on the surface of the
model films (series 2 and 3) at higher percentage compared to the bulk drug loading. In the
case of the spray coated films the drug at the surface increased with the drug loading
9 The drug enrichment is more pronounced in the spun cast films than the spray coated
films.
9We have gained an understanding of the distribution of the drug
Acknowledgements
Supervisors
Prof Clive J Roberts
Prof Morgan R Alexander
Prof Martyn C Davies
Thanks to:
Prof Chen Xinyong
Dr David J Scurr
Mrs Emily Smith
From Kratos Analytical
Chris Blomfield
Simon Hutton
THANKS FOR
LISTENING
Results. ToF-SIMS Depth profiling of spun
cast films: series 4
Series 4. Spun cast film on silicon wafer. Silicon substrate, 50 ºC for 45 min, Ar atmosphere
and controlled humidity
60000
50000
40000
45000
35000
Silicon
40000
Polymer
Drug
30000
20000
35000
Silicon
30000
Polymer
25000
Drug
40000
50000
20000
15000
10000
10000
50
100
150
200
250
Polymer
20000
Drug
15000
10000
0
0
0
Silicon
25000
5000
5000
0
30000
0
50
Depth (nm)
100
150
Depth (nm)
200
250
0
50
100
150
Depth (nm)
• The drug migrates to both the surface and the interface (film/silicon)
• The polymer is concentrated in the bulk region.
• Relative ion peak intensities for drug and polymer markers are consistent with the respective concentration
84
Sputter time
(sec)
115
Sputter rate
(nm/sec)
0.81
1:1 d:p wr
93
93
1
3:1 d:p wr
83
95
0.87
Sample ID
Thickness (nm)
1:3 d:p wr
200
250
Results. AFM characterization
Globular features
Peak force QNM mode
Series 3. 1:1 drug polymer wr
185 nm
Topography
Topography
a
Deformation
DMT modulus
3.5 GPa
1
1 µm
0 nm
a
1µm
Diameters: ≈ 100 nm
1.5 x 1.5 µm
2 x 2 µm
1
230 MPa
b
b
2 x 2 µm
Diameters: ≈ 200 nm
Topography
216 nm
1µm
1 GPa
1 µm
0 nm
1.5 x 1.5 µm
Series 2. 2 areas of spun cast film at 1:1 drug polymer weight
ratio. Globular features with a diameters of approximately 100200 nm can be observed. Their formations is probably due to the
dry step at 50°C for 45 min.
2
2
DMT modulus
75 MPa
Series 3. Granular structure of the domain. The size
of the globular structure varies between 100 and 200
nm.

Characterization of polymer/drug films as models for

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