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Emerging Technologies in 3D Printing of Pharmaceuticals:
Manufacturing unique dosage forms, accelerating drug development, and enabling personalized medicine
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
Kimberly Bone, PharmDVP Medical and Clinical Affairs
NABP-AACP District IV MeetingOctober 18, 2019
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Overview
Introduction to Aprecia Pharmaceuticals
Features of 3DP Technologies
Select Methods for 3DP Pharmaceuticals
Applying 3DP in the pharmaceutical industry
Benefits and Example applications
Looking ahead
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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Aprecia Facts
Privately held technology company
Founded in 2004
Headquartered in Blue Ash, Ohio
60+ employees
Innovative and patent-protected 3DP technology platform
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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Aprecia Milestones
2004
2007
2008
2011
2014
2015KEY
MILE
STON
ES
ZipDose® Technology development begins
Proprietary 3DP forming system built
Registration and launch facility opens in East Windsor, NJ
Filing of first NDA with the FDA
First product approved: SPRITAM® (levetiracetam)
SPRITAM is the first and onlyFDA approved 3DP
pharmaceutical product
2016
2017
Operations initiated
Next generation 3DP forming system built
Commercial manufacturing facility in Blue Ash, OH approved by FDA
East Windsor facility focused on R&D; new development machines built 2018
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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5CONFIDENTIAL © 2018, Aprecia Pharmaceuticals, LLC. All rights reserved.
Features of 3DP Technologies
Control of internal and external geometry
Spatial control of composition
Simpler, compact process
Rapid prototyping
Benefits for Pharmaceutical Industry
Dosage forms with unique properties– Instant dispersion–Ultra low dose–Complex release profiles–Combination therapy–Anti-counterfeit features
Agile, simplified supply chain
Accelerate development cycle
Key Advantages of 3DP Over Conventional Pharmaceutical Processes
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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6CONFIDENTIAL © 2018, Aprecia Pharmaceuticals, LLC. All rights reserved.
Example Device Demonstrating Various Features
PCL (Top Layer)
PEO (Middle Layer)
PCL (Bottom Layer)
Wu et al J. of Controlled Release 40 (1996) 77-87
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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Selected Methods for 3D Printing Pharmaceuticals
Fused Deposition Modeling(Material Extrusion)
Powder-Liquid Deposition(Binder Jetting)
Polyjet(Material Jetting)
Scopigno R., Cignoni P., Pietroni N., Callieri M., Dellepiane M. (2017). "Digital Fabrication Techniques for Cultural Heritage: A Survey". Computer Graphics Forum 36 (1): 6–21. DOI:10.1111/cgf.12781.
3D Printing: The action or process of making a physical object from a three-dimensional digital model, typically by laying down many thin layers of a material in succession.
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
http://vcg.isti.cnr.it/Publications/2017/SCPCD17/DigitalFabricationForCH.pdfhttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://doi.org/10.1111/cgf.12781
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8CONFIDENTIAL © 2018, Aprecia Pharmaceuticals, LLC. All rights reserved.
Aprecia’s 3DP Technology Platform
Utilizes powder-liquid or binder jetting 3DP TECHNOLOGY– Platform validated through FDA approval of first and only 3DP pharmaceutical product (Spritam®)
Pharmaceutical products are assembled layer-by-layer, without the use of compression forces or molds– Eliminates potential for disrupting particles of drug or particle coatings (e.g., modified release)
Spreading of thin layers of powder and depositing (“printing”) pre-programmed patterns of liquid droplets onto selected regions of each layer are carried out repeatedly until tablet is formed– Allows for controlling regional tablet hardness, dispersibility characteristics and overall form/shape
Interaction between powder and liquid during the 3DP process bonds the layered materials together– Dose forms can be designed to disperse on contact with liquid or to be swallowed whole
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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3DP Binder Jet Printing of Pharmaceuticals
Thin layer of powder is spread onto pallets upon successive passes
Newly spread powder layer is ready for printing
Printhead deposits droplets of liquid onto powder layer
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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Introducing ZipDose® Technology
ZipDose® disperses with a sip of water in less than 10 seconds, a previously unachievable rate for high-dose formulations.
The powder-liquid additive manufacturing process produces a porous formulation of high drug load and rapid dispersion with a sip of liquid.
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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11CONFIDENTIAL © 2018, Aprecia Pharmaceuticals, LLC. All rights reserved.
Harvesting the Dosage Forms
Printed ZDFs are dried and then harvested to remove unused powder
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved – not to be used without permission
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Components Necessary for 3DP Pharmaceutical Manufacturing
Printing Fluid• Aqueous Solution
• Deposition controls physical properties of
dosage form• Formulation depends on
product • Could incorporate API
Powder Blend• API along with functional fillers
• Controls performance properties of ZDF
• Particle size, shape, packing create the
matrix
ZDF
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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13CONFIDENTIAL © 2018, Aprecia Pharmaceuticals, LLC. All rights reserved.
Powder composition and compatibility
Powder flowability
Control of powder layer thickness and uniformity
Print fluid composition and compatibility
Deposition of printing fluid
Speed
Critical Elements
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved – not to be used without permission
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14CONFIDENTIAL © 2018, Aprecia Pharmaceuticals, LLC. All rights reserved.
Key Considerations for Applying 3DP to Pharmaceuticals
Achieving the speed and scale
Complying with regulatory requirements
Making economic sense
Identifying and meeting the unmet needs
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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Application Example: Rapidly Dispersing Dosage Forms
Controlled binding of powder allows instant dispersion upon contact with water Conventional pharma techniques were limited to low dose compounds
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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Application Example: Rapidly Dispersing Dosage Forms, ZipDose® Technology
Conventional pharma techniques were limited to low dose compounds
Source: U.S. Orange Book data All Rx ODTs, 258 total records
May 9, 2016
“Over/Under” for Freeze-Drying claims: 400 mg
First ZIPDOSE product:SPRITAM (levetiracetam)
Made by Soft Compression
(No new ODTs over 50 mg in OB in the interim as of Sept 2017)
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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Application Example: Highly Accurate Low Dose Products
Deposit metered amount of actives in
each tablet
No blending of actives
Complete encapsulation of actives
Physical separation of multiple actives
Safer process and product
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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Application Example: Zero-Order Release Profile
Introduce concentration gradient to achieve constant release
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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Application Example: Complex Release Profile
Spatial control of composition to achieve pulsed release
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Time (hours)
Rele
ase
Rate
Chl
orph
enira
min
e M
alea
te m
g/hr
empirical average ratetheoretical
Chlorpheniramine Maleate
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 2 4 6 8 10 12 14
Time (hours)
rele
ase
rate
dic
lofe
nac
mg/
hr
Diclofenac Sodium
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
Sheet3
If then statements based on geometry
like, if the radius is currently between these 2 numbers, add this concentration x volume to cumm and subtract the contribution from the height…
Sheet2
0.5405405405
5.94
55
each cell is 200 by 200 microns
radiallyvertically
hours it takeshours it takes
Ko (70:30HPMC)microns/hourerode 200 umerode 108 umCdrug
3.6 mg/harea294.480.680.3720mg/cc
erodedrelease in mgs
# of 200ums# of 108shoursrelease radialrelease vertical
10.370
10.68
20.74
31.11
21.36
41.48
51.85
32.04
62.22
72.59
42.72
82.96
93.33
53.4
103.7
114.07
64.08
200um124.44
74.76
134.81
145.18
85.44
155.55
165.92
96.12
176.29
186.66
106.8
197.03
207.4
117.48
217.77
228.14
128.16
238.51
138.84
248.88
259.25
149.52
269.62
279.99
1510.2
2810.36
2910.73
1610.88
3011.1
3111.47
1711.56
3211.84
3312.21
1812.24
3412.58
1912.92
3512.95
3613.32
2013.6
3713.69
3814.06
2114.28
3914.43
4014.8
2214.96
Sheet1
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3.58331.9
3.83332
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6.33333
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7.83333.6
8.08333.7
8.41673.8
8.753.9
9.08334
9.41674.1
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10.08334.3
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11.08334.6
11.41674.7
11.754.8
12.08334.9
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12.5
empirical average rate
theoretical
Time (hours)
Release Rate Chlorpheniramine Maleate mg/hr
0
0
0.013
0
0.074
0
0.218
0
0.371
0
0.467
0
0.431
0
0.386
0.5201585377
0.302
0.5201585377
0.18
0.5201585377
0.091
0.5201585377
0.086
0.5201585377
0.061
0.5201585377
0.1
0
0.17
0
0.241
0
0.254
0
0.289
0
0.292
0
0.3028719982
0
0.292
0
0.305
0
0.279
0
0.2689444789
0
0.287
0
0.272
0.2600792689
0.2590848318
0.2600792689
0.274
0.2600792689
0.259
0.2600792689
0.264
0.2600792689
0.277
0.2600792689
0.256
0.2600792689
0.264
0.2600792689
0.259
0.2600792689
0.2701284976
0.2600792689
0.261
0.2600792689
0.236
0.2600792689
0.208
0.2600792689
0.162
0.2600792689
0.14
0.2600792689
0.135
0.2600792689
0.1
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0.089
0.2600792689
0.069
0.2600792689
0.086
0.2600792689
0.058
0.2600792689
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0.2600792689
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Sheet1
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9.872.6476105.452615.639294744822.70142844370.55319509120.0890.0342.26922.77054982344.20.78023780660.26007926890.02600792690.78023780667.8297548309
10.083373.8165105.626915.890931022322.73895107450.25163627740.0690.0202.28922.96671270764.30.80624573350.26007926890.02600792690.80624573358.0907466586
10.416775.5725105.47716.268955920122.70668118150.37802489790.0860.0292.31723.25444275674.40.83225366030.26007926890.02600792690.83225366038.3517384863
10.7577.2623106.282116.632729537722.880.36377361760.0580.0192.33723.44843505154.50.85826158720.26007926890.02600792690.85826158728.612730314
11.083379.0166105.978617.010388466222.81466369220.37765892850.0530.0182.35423.62570387254.60.88426951410.26007926890.02600792690.88426951418.8737221417
11.416781.2375106.220317.488495240522.86669593470.47810677430.0250.0082.36323.70934632864.70.9102774410.26007926890.02600792690.9102774419.1347139694
11.7581.9262105.937317.636755916622.80577278770.14826067610.0130.0042.36723.75282736024.80.93628536790.26007926890.02600792690.93628536799.3957057971
12.083383.2499105.619717.921716940122.73740108640.28496102350.0080.0032.37023.77958491814.90.96229329480.26007926890.02600792690.96229329489.6566976248
50.98830122170.26007926890.02600792690.98830122179.9176894525
5.11.01430914850.26007926890.02600792691.014309148510.1786812802
5.21.04031707540.26007926890.02600792691.040317075410.4396731079
5.31.06632500230.26007926890.02600792691.066325002310.7006649356
5.41.09233292920.26007926890.02600792691.092332929210.9616567633
5.51.11834085610.26007926890.02600792691.118340856111.222648591
5.61.1443487830.26007926890.02600792691.14434878311.4836404187
5.71.17035670990.26007926890.02600792691.170356709911.7446322464
5.81.19636463670.26007926890.02600792691.196364636712.005624074
5.91.22237256360.26007926890.02600792691.222372563612.2666159017
61.24838049050.26007926890.02600792691.248380490512.5276077294
6.11.27438841740.26007926890.02600792691.274388417412.7885995571
6.21.30039634430.26007926890.02600792691.300396344313.0495913848
6.31.32640427120.26007926890.02600792691.326404271213.3105832125
6.41.35241219810.26007926890.02600792691.352412198113.5715750402
6.51.3784201250.26007926890.02600792691.37842012513.8325668679
6.61.40442805180.26007926890.02600792691.404428051814.0935586956
6.71.43043597870.26007926890.02600792691.430435978714.3545505233
6.81.45644390560.26007926890.02600792691.456443905614.615542351
6.91.48204610740.25602201770.02560220181.482046107414.8724626916
71.50721688530.25170777910.02517077791.507216885315.1250536558
7.11.53195990520.24743019960.024743021.531959905215.3733520316
7.21.55627883320.24318927950.02431892791.556278833215.6173946068
7.31.58017733510.23898501860.02389850191.580177335115.8572181693
7.41.60365907670.23481741690.02348174171.603659076716.092859507
7.51.62672772420.23068647450.02306864741.626727724216.3243554077
7.61.64938694330.22659219130.02265921911.649386943316.5517426593
7.71.67164040010.22253456740.02225345671.671640400116.7750580497
7.81.69349176030.21851360270.02185136031.693491760316.9943383667
7.91.714944690.21452929720.02145292971.7149446917.2096203983
81.73600285510.2105816510.02105816511.736002855117.4209409323
8.11.75666992150.20667066410.02066706641.756669921517.6283367566
8.21.77694955520.20279633640.02027963361.776949555217.831844659
8.31.7968454220.19895866790.01989586681.79684542218.0315014275
8.41.81636118780.19515765870.01951576591.816361187818.2273438499
8.51.83550051870.19139330870.01913933091.835500518718.4194087141
8.61.85426708050.1876656180.01876656181.854267080518.6077328079
8.71.87266453920.18397458650.01839745861.872664539218.7923529192
8.81.89069656060.18032021420.01803202141.890696560618.973305836
8.91.90836681070.17670250130.01767025011.908366810719.150628346
91.92567895550.17312144750.01731214481.925678955519.3243572372
9.11.94263666080.1695770530.01695770531.942636660819.4945292974
9.21.95924359250.16606931770.01660693181.959243592519.6611813145
9.31.97550341670.16259824170.01625982421.975503416719.8243500764
9.41.99141979920.1591638250.01591638251.991419799219.9840723709
9.52.00699640590.15576606740.01557660672.006996405920.140384986
9.62.02223690290.15240496920.01524049692.022236902920.2933247094
9.72.03714495590.14908053010.0149080532.037144955920.4429283292
9.82.05172423090.14579275040.0145792752.051724230920.589232633
9.92.06597839390.14254162980.0142541632.065978393920.7322744089
102.07991111070.13932716850.01393271692.079911110720.8720904447
10.12.09352604740.13614936650.01361493662.093526047421.0087175282
10.22.10682686980.13300822370.01330082242.106826869821.1421924474
10.32.11981724380.12990374010.0129903742.119817243821.2725519901
10.42.13250083530.12683591580.01268359162.132500835321.3998329442
10.52.14488131040.12380475070.01238047512.144881310421.5240720975
10.62.15696233490.12081024490.01208102452.156962334921.645306238
10.72.16874757470.11785239830.01178523982.168747574721.7635721535
10.82.18024069580.1149312110.01149312112.180240695821.8789066319
10.92.19144536410.11204668290.01120466832.191445364121.9913464611
112.20236524550.1091988140.01091988142.202365245522.1009284288
11.12.2130040060.10638760440.01063876042.21300400622.2076893231
11.22.22336531140.10361305410.01036130542.223365311422.3116659318
11.32.23345282770.1008751630.01008751632.233452827722.4128950427
11.42.24327022080.09817393110.00981739312.243270220822.5114134438
11.52.25282115660.09550935850.00955093592.252821156622.6072579229
11.62.26210930120.09288144510.00928814452.262109301222.7004652678
11.72.27113832030.0902901910.00902901912.271138320322.7910722665
11.82.27991187990.08773559610.00877355962.279911879922.8791157068
11.92.28843364590.08521766050.0085217662.288433645922.9646323766
122.2884336459002.288433645922.9646323766
12.12.2884336459002.288433645922.9646323766
12.22.2884336459002.288433645922.9646323766
12.32.2884336459002.288433645922.9646323766
12.42.2884336459002.288433645922.9646323766
12.52.2884336459002.288433645922.9646323766
Sheet1
empirical average rate
theoretical
Time (hours)
Release Rate mg/hr
average empirical
Theoretical
Time (hours)
mgs Chlorpheniramine Maleate
Chart8
00
0.08330.1
0.250.2
0.41670.3
0.470.4
0.690.5
0.91670.6
1.08330.7
1.250.8
1.41670.9
1.58331
1.751.1
1.91671.2
2.08331.3
2.33331.4
2.58331.5
2.83331.6
3.08331.7
3.33331.8
3.58331.9
3.83332
4.08332.1
4.33332.2
4.58332.3
4.83332.4
5.08332.5
5.33332.6
5.58332.7
5.83332.8
6.08332.9
6.33333
6.58333.1
6.83333.2
7.08333.3
7.33333.4
7.58333.5
7.83333.6
8.08333.7
8.41673.8
8.753.9
9.08334
9.41674.1
9.84.2
10.08334.3
10.41674.4
10.754.5
11.08334.6
11.41674.7
11.754.8
12.08334.9
5
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
6
6.1
6.2
6.3
6.4
6.5
6.6
6.7
6.8
6.9
7
7.1
7.2
7.3
7.4
7.5
7.6
7.7
7.8
7.9
8
8.1
8.2
8.3
8.4
8.5
8.6
8.7
8.8
8.9
9
9.1
9.2
9.3
9.4
9.5
9.6
9.7
9.8
9.9
10
10.1
10.2
10.3
10.4
10.5
10.6
10.7
10.8
10.9
11
11.1
11.2
11.3
11.4
11.5
11.6
11.7
11.8
11.9
12
12.1
12.2
12.3
12.4
12.5
Time (hours)
release rate diclofenac mg/hr
0
0.013
0
0.049
0
0.16
0
0.351
0
0.498
0
0.485
0
0.396
0.5840376564
0.274
0.5840376564
0.156
0.5840376564
0.011
0.5840376564
0.02
0.5840376564
0.01
0.5840376564
0.02
0
0.103
0
0.184
0
0.24
0
0.234
0
0.259
0
0.22
0
0.24
0
0.264
0
0.256
0
0.2689444789
0
0.237
0
0.272
0.2920188282
0.2590848318
0.2920188282
0.251
0.2920188282
0.259
0.2920188282
0.264
0.2920188282
0.277
0.2920188282
0.256
0.2920188282
0.24
0.2920188282
0.259
0.2920188282
0.2701284976
0.2920188282
0.261
0.2920188282
0.236
0.2920188282
0.24
0.2920188282
0.216
0.2920188282
0.172
0.2920188282
0.135
0.2920188282
0.154
0.2920188282
0.112
0.2920188282
0.115
0.2920188282
0.086
0.2920188282
0.058
0.2920188282
0.055
0.2920188282
0.044
0.2920188282
0.028
0.2920188282
0.018
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2920188282
0.2874633181
0.2826192607
0.2778163645
0.2730546296
0.2683340559
0.2636546435
0.2590163924
0.2544193025
0.2498633739
0.2453486065
0.2408750004
0.2364425555
0.2320512719
0.2277011496
0.2233921885
0.2191243887
0.2148977501
0.2107122728
0.2065679568
0.202464802
0.1984028084
0.1943819761
0.1904023051
0.1864637954
0.1825664469
0.1787102596
0.1748952336
0.1711213689
0.1673886654
0.1636971232
0.1600467422
0.1564375225
0.1528694641
0.1493425669
0.145856831
0.1424122563
0.1390088429
0.1356465908
0.1323254999
0.1290455702
0.1258068018
0.1226091947
0.1194527489
0.1163374642
0.1132633409
0.1102303788
0.107238578
0.1042879384
0.1013784601
0.098510143
0.0956829872
0
0
0
0
0
0
diclofenac
time343 mg4 mg3 inc4 inc''4 inc time adj4 cum adj4 cum mg4inc mgtime thcum thinc thinc adjcum adjcum adj mginc mginc with loading change
0000000.0000.0000.000000000000
0.08331.59051.7760.34239669710.38233042060.34239669710.0130.0010.0010.01215887720.13045614040.10000000
0.255.07964.95221.09351666931.06609048940.75111997220.0490.0080.0090.10387312280.49171929820.20000000
0.41678.60947.69641.85339838031.65685126660.7598817110.1600.0270.0360.40334821051.60561403510.30000000
0.4711.337610.58922.44071473942.27960207790.5873163590.3510.0190.0550.61340631583.52231578950.40000000
0.6913.88612.63722.98932444882.7204876080.54860970940.4980.1100.1641.84355368424.99747368420.50000000
0.916716.41115.12733.53289669663.25654671860.54357224780.4850.1100.2743.0780743864.86701754390.60000000
1.083318.966917.37254.08312097713.73988470310.55022428050.3960.0660.3403.81883059653.97389473680.70.05201585380.52015853770.05201585380.05201585380.58403765645.21983655390.5840376564
1.2520.659719.17694.44754042314.1283289660.3644194460.2740.0460.3864.33168168422.74961403510.80.10403170750.52015853770.05201585380.10403170751.16807531285.21983655390.5840376564
1.416722.580721.24454.86108588374.57343390840.41354546060.1560.0260.4124.62366989471.56547368420.90.15604756130.52015853770.05201585380.15604756131.75211296925.21983655390.5840376564
1.583324.312422.16215.23387957144.77097129240.37279368770.0110.0020.4144.64424645610.110385964910.20806341510.52015853770.05201585380.20806341512.33615062555.21983655390.5840376564
1.7525.801623.66515.55446879585.09453132750.32058922430.0200.0030.4174.68168084210.20070175441.10.26007926890.52015853770.05201585380.26007926892.92018828195.21983655390.5840376564
1.916727.051425.23545.82352091275.43257944660.2690521170.0100.0020.4194.70039803510.10035087721.20.31209512260.52015853770.05201585380.31209512263.50422593835.21983655390.5840376564
2.083328.426.49496.11384231215.70371974210.29032139940.0200.0030.4224.73780996490.20070175441.30.3120951226000.31209512263.504225938300
2.333330.11927.7336.48390199295.97025312820.37005968080.1030.0260.4485.02693277191.03361403511.40.3120951226000.31209512263.504225938300
2.583332.145529.40566.92015908616.33032399620.43625709320.1840.0460.4945.5434241.84645614041.50.3120951226000.31209512263.504225938300
2.833333.434130.95387.19756391726.66361451270.27740483110.2400.0600.5546.21710821052.40842105261.60.3120951226000.31209512263.504225938300
3.083335.552132.11617.65351877696.91382996760.45595485980.2340.0590.6126.87395031582.34821052631.70.3120951226000.31209512263.504225938300
3.333336.620233.07857.88345521967.12101172260.22993644270.2590.0650.6777.60096785962.59908771931.80.3120951226000.31209512263.504225938300
3.583338.551634.48548.29923955217.42388372080.41578433250.2200.0550.7328.21851171932.20771929821.90.3120951226000.31209512263.504225938300
3.833340.21935.94578.65819098427.73825146470.35895143210.2400.0600.7928.89219592982.408421052620.3120951226000.31209512263.504225938300
4.083341.348837.23368.90140996468.01550560250.24321898040.2640.0660.8589.63324856142.64926315792.10.3120951226000.31209512263.504225938300
4.333343.081538.20839.27441892858.2253352540.37300896390.2560.0640.92210.35184505262.56898245612.20.3120951226000.31209512263.504225938300
4.583344.106839.45769.49514155258.49427973290.2207226240.2690.0670.98911.10677692322.69888143732.30.3120951226000.31209512263.504225938300
4.833346.022940.27529.90763216018.67028950310.41249060750.2370.0591.04811.77204008112.37831578952.40.3120951226000.31209512263.504225938300
5.083346.932941.375610.10353344548.90717936510.19590128540.2720.0681.11612.5355488532.72954385962.50.33810304950.26007926890.02600792690.33810304953.79624476652.6099182770.2920188282
5.333348.35642.579110.40989291719.16626419690.30635947160.2590.0651.18113.26280452122.59993901372.60.36411097640.26007926890.02600792690.36411097644.08826359472.6099182770.2920188282
5.583350.197543.657210.80632392479.3983534010.39643100770.2510.0631.24413.96736592472.51880701752.70.39011890330.26007926890.02600792690.39011890334.38028242292.6099182770.2920188282
5.833351.527545.306411.09264118799.75338680740.28631726320.2590.0651.30914.69438346862.59908771932.80.41612683020.26007926890.02600792690.41612683024.67230125112.6099182770.2920188282
6.083352.899846.757711.388064631810.06581706610.29542344380.2640.0661.37515.43543610012.64926315792.90.44213475710.26007926890.02600792690.44213475714.96432007932.6099182770.2920188282
6.333354.624447.593511.759329858910.2457448620.37126522720.2770.0691.44416.21297995982.779719298230.46814268390.26007926890.02600792690.46814268395.25633890752.6099182770.2920188282
6.583355.956949.09212.046185312510.56833615440.28685545360.2560.0641.50816.9315764512.56898245613.10.49415061080.26007926890.02600792690.49415061085.54835773562.6099182770.2920188282
6.833357.575650.455912.394652796710.86195127870.34846748420.2400.0601.56817.60526066152.40842105263.20.52015853770.26007926890.02600792690.52015853775.84037656382.6099182770.2920188282
7.083358.2851.414412.546293308111.06829345680.15164051140.2590.0651.63318.33227820542.59908771933.30.54616646460.26007926890.02600792690.54616646466.1323953922.6099182770.2920188282
7.333359.762952.669212.865526292811.33842195440.31923298470.2700.0681.70019.09053363742.71076316943.40.57217439150.26007926890.02600792690.57217439156.42441422022.6099182770.2920188282
7.583361.466154.433913.232184610611.71831975470.36665831780.2610.0651.76619.82316521632.61915789473.50.59818231840.26007926890.02600792690.59818231846.71643304842.6099182770.2920188282
7.833362.536554.899713.462616188411.81859537970.23043157780.2360.0591.82520.48562135672.36828070183.60.62419024530.26007926890.02600792690.62419024537.00845187662.6099182770.2920188282
8.083363.888956.312313.753755637112.12269445180.29113944870.2400.0601.88521.15930556722.40842105263.70.65019817210.26007926890.02600792690.65019817217.30047070482.6099182770.2920188282
8.416765.294858.205114.056412359212.53016912540.30265672210.2160.0721.95721.96788830412.16757894743.80.6762060990.26007926890.02600792690.6762060997.5924895332.6099182770.2920188282
8.7567.218559.82314.470539065412.87846438860.41412670620.1720.0572.01422.61156661991.72603508773.90.70221402590.26007926890.02600792690.70221402597.88450836122.6099182770.2920188282
9.083368.93561.417614.840060555813.22174371790.36952149040.1350.0452.05923.11677925141.354736842140.72822195280.26007926890.02600792690.72822195288.17652718942.6099182770.2920188282
9.416770.0779103.846515.086099653722.35567343890.24603909780.1540.0512.11023.69326879531.54540350884.10.75422987970.26007926890.02600792690.75422987978.46854601762.6099182770.2920188282
9.872.6476105.452615.639294744822.70142844370.55319509120.1120.0432.15324.17528535671.12392982464.20.78023780660.26007926890.02600792690.78023780668.76056484582.6099182770.2920188282
10.083373.8165105.626915.890931022322.73895107450.25163627740.1150.0332.18624.5410902691.15403508774.30.80624573350.26007926890.02600792690.80624573359.0525836742.6099182770.2920188282
10.416775.5725105.47716.268955920122.70668118150.37802489790.0860.0292.21424.86302598830.86301754394.40.83225366030.26007926890.02600792690.83225366039.34460250212.6099182770.2920188282
10.7577.2623106.282116.632729537722.880.36377361760.0580.0192.23425.08008030410.58203508774.50.85826158720.26007926890.02600792690.85826158729.63662133032.6099182770.2920188282
11.083379.0166105.978617.010388466222.81466369220.37765892850.0550.0182.25225.28590767250.55192982464.60.88426951410.26007926890.02600792690.88426951419.92864015852.6099182770.2920188282
11.416781.2375106.220317.488495240522.86669593470.47810677430.0440.0152.26725.45061897070.44154385964.70.9102774410.26007926890.02600792690.91027744110.22065898672.6099182770.2920188282
11.7581.9262105.937317.636755916622.80577278770.14826067610.0280.0092.27625.55540381280.28098245614.80.93628536790.26007926890.02600792690.936285367910.51267781492.6099182770.2920188282
12.083383.2499105.619717.921716940122.73740108640.28496102350.0180.0062.28225.6227654970.18063157894.90.96229329480.26007926890.02600792690.962293294810.80469664312.6099182770.2920188282
50.98830122170.26007926890.02600792690.988301221711.09671547132.6099182770.2920188282
5.11.01430914850.26007926890.02600792691.014309148511.38873429952.6099182770.2920188282
5.21.04031707540.26007926890.02600792691.040317075411.68075312772.6099182770.2920188282
5.31.06632500230.26007926890.02600792691.066325002311.97277195592.6099182770.2920188282
5.41.09233292920.26007926890.02600792691.092332929212.26479078412.6099182770.2920188282
5.51.11834085610.26007926890.02600792691.118340856112.55680961232.6099182770.2920188282
5.61.1443487830.26007926890.02600792691.14434878312.84882844052.6099182770.2920188282
5.71.17035670990.26007926890.02600792691.170356709913.14084726862.6099182770.2920188282
5.81.19636463670.26007926890.02600792691.196364636713.43286609682.6099182770.2920188282
5.91.22237256360.26007926890.02600792691.222372563613.7248849252.6099182770.2920188282
61.24838049050.26007926890.02600792691.248380490514.01690375322.6099182770.2920188282
6.11.27438841740.26007926890.02600792691.274388417414.30892258142.6099182770.2920188282
6.21.30039634430.26007926890.02600792691.300396344314.60094140962.6099182770.2920188282
6.31.32640427120.26007926890.02600792691.326404271214.89296023782.6099182770.2920188282
6.41.35241219810.26007926890.02600792691.352412198115.1849790662.6099182770.2920188282
6.51.3784201250.26007926890.02600792691.37842012515.47699789422.6099182770.2920188282
6.61.40442805180.26007926890.02600792691.404428051815.76901672242.6099182770.2920188282
6.71.43043597870.26007926890.02600792691.430435978716.06103555062.6099182770.2920188282
6.81.45644390560.26007926890.02600792691.456443905616.35305437882.6099182770.2920188282
6.91.48204610740.25602201770.02560220181.482046107416.64051769692.56920340570.2874633181
71.50721688530.25170777910.02517077791.507216885316.92313695762.52590964240.2826192607
7.11.53195990520.24743019960.024743021.531959905217.20095332212.48298375780.2778163645
7.21.55627883320.24318927950.02431892791.556278833217.47400795172.4404257520.2730546296
7.31.58017733510.23898501860.02389850191.580177335117.74234200762.39823562490.2683340559
7.41.60365907670.23481741690.02348174171.603659076718.00599665112.35641337660.2636546435
7.51.62672772420.23068647450.02306864741.626727724218.26501304352.3149590070.2590163924
7.61.64938694330.22659219130.02265921911.649386943318.5194323462.27387251610.2544193025
7.71.67164040010.22253456740.02225345671.671640400118.76929571992.2331539040.2498633739
7.81.69349176030.21851360270.02185136031.693491760319.01464432642.19280317060.2453486065
7.91.714944690.21452929720.02145292971.7149446919.25551932682.15282031590.2408750004
81.73600285510.2105816510.02105816511.736002855119.49196188232.113205340.2364425555
8.11.75666992150.20667066410.02066706641.756669921519.72401315422.07395824290.2320512719
8.21.77694955520.20279633640.02027963361.776949555219.95171430382.03507902450.2277011496
8.31.7968454220.19895866790.01989586681.79684542220.17510649231.99656768480.2233921885
8.41.81636118780.19515765870.01951576591.816361187820.3942308811.95842422390.2191243887
8.51.83550051870.19139330870.01913933091.835500518720.60912863111.92064864170.2148977501
8.61.85426708050.1876656180.01876656181.854267080520.81984090391.88324093820.2107122728
8.71.87266453920.18397458650.01839745861.872664539221.02640886071.84620111350.2065679568
8.81.89069656060.18032021420.01803202141.890696560621.22887366271.80952916750.202464802
8.91.90836681070.17670250130.01767025011.908366810721.42727647111.77322510030.1984028084
91.92567895550.17312144750.01731214481.925678955521.62165844721.73728891180.1943819761
9.11.94263666080.1695770530.01695770531.942636660821.81206075241.70172060210.1904023051
9.21.95924359250.16606931770.01660693181.959243592521.99852454771.66652017110.1864637954
9.31.97550341670.16259824170.01625982421.975503416722.18109099461.63168761880.1825664469
9.41.99141979920.1591638250.01591638251.991419799222.35980125421.59722294530.1787102596
9.52.00699640590.15576606740.01557660672.006996405922.53469648781.56312615050.1748952336
9.62.02223690290.15240496920.01524049692.022236902922.70581785671.52939723450.1711213689
9.72.03714495590.14908053010.0149080532.037144955922.87320652211.49603619720.1673886654
9.82.05172423090.14579275040.0145792752.051724230923.03690364531.46304303860.1636971232
9.92.06597839390.14254162980.0142541632.065978393923.19695038761.43041775880.1600467422
102.07991111070.13932716850.01393271692.079911110723.35338791011.39816035770.1564375225
10.12.09352604740.13614936650.01361493662.093526047423.50625737421.36627083540.1528694641
10.22.10682686980.13300822370.01330082242.106826869823.65559994111.33474919180.1493425669
10.32.11981724380.12990374010.0129903742.119817243823.80145677211.3035954270.145856831
10.42.13250083530.12683591580.01268359162.132500835323.94386902851.27280954090.1424122563
10.52.14488131040.12380475070.01238047512.144881310424.08287787141.24239153350.1390088429
10.62.15696233490.12081024490.01208102452.156962334924.21852446211.21234140490.1356465908
10.72.16874757470.11785239830.01178523982.168747574724.3508499621.1826591550.1323254999
10.82.18024069580.1149312110.01149312112.180240695824.47989553221.15334478390.1290455702
10.92.19144536410.11204668290.01120466832.191445364124.60570233411.12439829150.1258068018
112.20236524550.1091988140.01091988142.202365245524.72831152881.09581967780.1226091947
11.12.2130040060.10638760440.01063876042.21300400624.84776427761.06760894290.1194527489
11.22.22336531140.10361305410.01036130542.223365311424.96410174191.03976608670.1163374642
11.32.23345282770.1008751630.01008751632.233452827725.07736508281.01229110930.1132633409
11.42.24327022080.09817393110.00981739312.243270220825.18759546160.98518401060.1102303788
11.52.25282115660.09550935850.00955093592.252821156625.29483403960.95844479060.107238578
11.62.26210930120.09288144510.00928814452.262109301225.3991219780.93207344940.1042879384
11.72.27113832030.0902901910.00902901912.271138320325.5005004380.9060699870.1013784601
11.82.27991187990.08773559610.00877355962.279911879925.59901058110.88043440320.098510143
11.92.28843364590.08521766050.0085217662.288433645925.69469356830.85516669830.0956829872
122.2884336459002.288433645925.694693568300
12.12.2884336459002.288433645925.694693568300
12.22.2884336459002.288433645925.694693568300
12.32.2884336459002.288433645925.694693568300
12.42.2884336459002.288433645925.694693568300
12.52.2884336459002.288433645925.694693568300
diclofenac
Time (hours)
release rate diclofenac mg/hr
Chlor. mal.
empirical average
theoretical
Time (hours)
mgs Diclofenac Sodium
time343 mg4 mg3 inc4 inc''4 inc time adj4 cum adj4 cum mgtime thcum thinc thinc adjcum adjcum adj mg
0000000.0000.0000.00000000000
0.08331.59051.7760.34239669710.38233042060.34239669710.0130.0010.0010.01086699650.01086699650.1000000
0.255.07964.95221.09351666931.06609048940.75111997220.0740.0120.0130.13465783160.12379083510.2000000
0.41678.60947.69641.85339838031.65685126660.7598817110.2180.0360.0500.49933894040.36468110880.3000000
0.4711.337610.58922.44071473942.27960207790.5873163590.3710.0200.0700.69777577540.19843683510.4000000
0.6913.88612.63722.98932444882.7204876080.54860970940.4670.1030.1721.72878068771.03100491230.5000000
0.916716.41115.12733.53289669663.25654671860.54357224780.4310.0980.2702.70928602810.98050534040.6000000
1.083318.966917.37254.08312097713.73988470310.55022428050.3860.0640.3343.35461843510.6453324070.70.05201585380.52015853770.05201585380.05201585380.52198365540.5219836554
1.2520.659719.17694.44754042314.1283289660.3644194460.3020.0500.3853.85981887020.50520043510.80.10403170750.52015853770.05201585380.10403170751.04396731080.5219836554
1.416722.580721.24454.86108588374.57343390840.41354546060.1800.0300.4154.16093171230.30111284210.90.15604756130.52015853770.05201585380.15604756131.56595096620.5219836554
1.583324.312422.16215.23387957144.77097129240.37279368770.0910.0150.4304.31306966320.152137950910.20806341510.52015853770.05201585380.20806341512.08793462160.5219836554
1.7525.801623.66515.55446879585.09453132750.32058922430.0860.0140.4444.45693468770.14386502461.10.26007926890.52015853770.05201585380.26007926892.6099182770.5219836554
1.916727.051425.23545.82352091275.43257944660.2690521170.0610.0100.4544.55897848420.10204379651.20.31209512260.52015853770.05201585380.31209512263.13190193240.5219836554
2.083328.426.49496.11384231215.70371974210.29032139940.1000.0170.4714.72616304560.16718456141.30.3120951226000.31209512263.13190193240
2.333330.11927.7336.48390199295.97025312820.37005968080.1700.0430.5135.15265427370.42649122811.40.3120951226000.31209512263.13190193240
2.583332.145529.40566.92015908616.33032399620.43625709320.2410.0600.5745.75726830880.60461403511.50.3120951226000.31209512263.13190193240
2.833333.434130.95387.19756391726.66361451270.27740483110.2540.0640.6376.39449637890.63722807021.60.3120951226000.31209512263.13190193240
3.083335.552132.11617.65351877696.91382996760.45595485980.2890.0720.7097.11953146670.72503508771.70.3120951226000.31209512263.13190193240
3.333336.620233.07857.88345521967.12101172260.22993644270.2920.0730.7827.85209287020.73256140351.80.3120951226000.31209512263.13190193240
3.583338.551634.48548.29923955217.42388372080.41578433250.3030.0760.8588.61192963760.75983676741.90.3120951226000.31209512263.13190193240
3.833340.21935.94578.65819098427.73825146470.35895143210.2920.0730.9319.34449104110.732561403520.3120951226000.31209512263.13190193240
4.083341.348837.23368.90140996468.01550560250.24321898040.3050.0761.00710.10966647970.76517543862.10.3120951226000.31209512263.13190193240
4.333343.081538.20839.27441892858.2253352540.37300896390.2790.0701.07710.80961384810.69994736842.20.3120951226000.31209512263.13190193240
4.583344.106839.45769.49514155258.49427973290.2207226240.2690.0671.14411.48433420740.67472035932.30.3120951226000.31209512263.13190193240
4.833346.022940.27529.90763216018.67028950310.41249060750.2870.0721.21612.20435175130.72001754392.40.3120951226000.31209512263.13190193240
5.083346.932941.375610.10353344548.90717936510.19590128540.2720.0681.28412.88673771620.68238596492.50.33810304950.26007926890.02600792690.33810304953.39289376010.2609918277
5.333348.35642.579110.40989291719.16626419690.30635947160.2590.0651.34913.53672246960.64998475342.60.36411097640.26007926890.02600792690.36411097643.65388558780.2609918277
5.583350.197543.657210.80632392479.3983534010.39643100770.2740.0691.41714.22412597840.68740350882.70.39011890330.26007926890.02600792690.39011890333.91487741550.2609918277
5.833351.527545.306411.09264118799.75338680740.28631726320.2590.0651.48214.87389790820.64977192982.80.41612683020.26007926890.02600792690.41612683024.17586924310.2609918277
6.083352.899846.757711.388064631810.06581706610.29542344380.2640.0661.54815.53621369770.66231578952.90.44213475710.26007926890.02600792690.44213475714.43686107080.2609918277
6.333354.624447.593511.759329858910.2457448620.37126522720.2770.0691.61716.23114352230.694929824630.46814268390.26007926890.02600792690.46814268394.69785289850.2609918277
6.583355.956949.09212.046185312510.56833615440.28685545360.2560.0641.68116.87338913630.6422456143.10.49415061080.26007926890.02600792690.49415061084.95884472620.2609918277
6.833357.575650.455912.394652796710.86195127870.34846748420.2640.0661.74717.53570492580.66231578953.20.52015853770.26007926890.02600792690.52015853775.21983655390.2609918277
7.083358.2851.414412.546293308111.06829345680.15164051140.2590.0651.81218.18547685560.64977192983.30.54616646460.26007926890.02600792690.54616646465.48082838160.2609918277
7.333359.762952.669212.865526292811.33842195440.31923298470.2700.0681.88018.86316764790.67769079233.40.57217439150.26007926890.02600792690.57217439155.74182020930.2609918277
7.583361.466154.433913.232184610611.71831975470.36665831780.2610.0651.94519.51795712160.65478947373.50.59818231840.26007926890.02600792690.59818231846.0028120370.2609918277
7.833362.536554.899713.462616188411.81859537970.23043157780.2360.0592.00420.11002729710.59207017543.60.62419024530.26007926890.02600792690.62419024536.26380386470.2609918277
8.083363.888956.312313.753755637112.12269445180.29113944870.2080.0522.05620.63185185850.52182456143.70.65019817210.26007926890.02600792690.65019817216.52479569240.2609918277
8.416765.294858.205114.056412359212.53016912540.30265672210.1620.0542.11021.17385497430.54200311583.80.6762060990.26007926890.02600792690.6762060996.78578752010.2609918277
8.7567.218559.82314.470539065412.87846438860.41412670620.1400.0472.15721.64211223740.46825726323.90.70221402590.26007926890.02600792690.70221402597.04677934780.2609918277
9.083368.93561.417614.840060555813.22174371790.36952149040.1350.0452.20222.09364602690.451533789540.72822195280.26007926890.02600792690.72822195287.30777117550.2609918277
9.416770.0779103.846515.086099653722.35567343890.24603909780.1000.0332.23522.42821585150.33456982464.10.75422987970.26007926890.02600792690.75422987977.56876300320.2609918277
9.872.6476105.452615.639294744822.70142844370.55319509120.0890.0342.26922.77054982340.34233397194.20.78023780660.26007926890.02600792690.78023780667.82975483090.2609918277
10.083373.8165105.626915.890931022322.73895107450.25163627740.0690.0202.28922.96671270760.19616288424.30.80624573350.26007926890.02600792690.80624573358.09074665860.2609918277
10.416775.5725105.47716.268955920122.70668118150.37802489790.0860.0292.31723.25444275670.28773004914.40.83225366030.26007926890.02600792690.83225366038.35173848630.2609918277
10.7577.2623106.282116.632729537722.880.36377361760.0580.0192.33723.44843505150.19399229474.50.85826158720.26007926890.02600792690.85826158728.6127303140.2609918277
11.083379.0166105.978617.010388466222.81466369220.37765892850.0530.0182.35423.62570387250.17726882114.60.88426951410.26007926890.02600792690.88426951418.87372214170.2609918277
11.416781.2375106.220317.488495240522.86669593470.47810677430.0250.0082.36323.70934632860.08364245614.70.9102774410.26007926890.02600792690.9102774419.13471396940.2609918277
11.7581.9262105.937317.636755916622.80577278770.14826067610.0130.0042.36723.75282736020.04348103164.80.93628536790.26007926890.02600792690.93628536799.39570579710.2609918277
12.083383.2499105.619717.921716940122.73740108640.28496102350.0080.0032.37023.77958491810.02675755794.90.96229329480.26007926890.02600792690.96229329489.65669762480.2609918277
50.98830122170.26007926890.02600792690.98830122179.91768945250.2609918277
5.11.01430914850.26007926890.02600792691.014309148510.17868128020.2609918277
5.21.04031707540.26007926890.02600792691.040317075410.43967310790.2609918277
5.31.06632500230.26007926890.02600792691.066325002310.70066493560.2609918277
5.41.09233292920.26007926890.02600792691.092332929210.96165676330.2609918277
5.51.11834085610.26007926890.02600792691.118340856111.2226485910.2609918277
5.61.1443487830.26007926890.02600792691.14434878311.48364041870.2609918277
5.71.17035670990.26007926890.02600792691.170356709911.74463224640.2609918277
5.81.19636463670.26007926890.02600792691.196364636712.0056240740.2609918277
5.91.22237256360.26007926890.02600792691.222372563612.26661590170.2609918277
61.24838049050.26007926890.02600792691.248380490512.52760772940.2609918277
6.11.27438841740.26007926890.02600792691.274388417412.78859955710.2609918277
6.21.30039634430.26007926890.02600792691.300396344313.04959138480.2609918277
6.31.32640427120.26007926890.02600792691.326404271213.31058321250.2609918277
6.41.35241219810.26007926890.02600792691.352412198113.57157504020.2609918277
6.51.3784201250.26007926890.02600792691.37842012513.83256686790.2609918277
6.61.40442805180.26007926890.02600792691.404428051814.09355869560.2609918277
6.71.43043597870.26007926890.02600792691.430435978714.35455052330.2609918277
6.81.45644390560.26007926890.02600792691.456443905614.6155423510.2609918277
6.91.48204610740.25602201770.02560220181.482046107414.87246269160.2569203406
71.50721688530.25170777910.02517077791.507216885315.12505365580.2525909642
7.11.53195990520.24743019960.024743021.531959905215.37335203160.2482983758
7.21.55627883320.24318927950.02431892791.556278833215.61739460680.2440425752
7.31.58017733510.23898501860.02389850191.580177335115.85721816930.2398235625
7.41.60365907670.23481741690.02348174171.603659076716.0928595070.2356413377
7.51.62672772420.23068647450.02306864741.626727724216.32435540770.2314959007
7.61.64938694330.22659219130.02265921911.649386943316.55174265930.2273872516
7.71.67164040010.22253456740.02225345671.671640400116.77505804970.2233153904
7.81.69349176030.21851360270.02185136031.693491760316.99433836670.2192803171
7.91.714944690.21452929720.02145292971.7149446917.20962039830.2152820316
81.73600285510.2105816510.02105816511.736002855117.42094093230.211320534
8.11.75666992150.20667066410.02066706641.756669921517.62833675660.2073958243
8.21.77694955520.20279633640.02027963361.776949555217.8318446590.2035079024
8.31.7968454220.19895866790.01989586681.79684542218.03150142750.1996567685
8.41.81636118780.19515765870.01951576591.816361187818.22734384990.1958424224
8.51.83550051870.19139330870.01913933091.835500518718.41940871410.1920648642
8.61.85426708050.1876656180.01876656181.854267080518.60773280790.1883240938
8.71.87266453920.18397458650.01839745861.872664539218.79235291920.1846201114
8.81.89069656060.18032021420.01803202141.890696560618.9733058360.1809529168
8.91.90836681070.17670250130.01767025011.908366810719.1506283460.17732251
91.92567895550.17312144750.01731214481.925678955519.32435723720.1737288912
9.11.94263666080.1695770530.01695770531.942636660819.49452929740.1701720602
9.21.95924359250.16606931770.01660693181.959243592519.66118131450.1666520171
9.31.97550341670.16259824170.01625982421.975503416719.82435007640.1631687619
9.41.99141979920.1591638250.01591638251.991419799219.98407237090.1597222945
9.52.00699640590.15576606740.01557660672.006996405920.1403849860.1563126151
9.62.02223690290.15240496920.01524049692.022236902920.29332470940.1529397234
9.72.03714495590.14908053010.0149080532.037144955920.44292832920.1496036197
9.82.05172423090.14579275040.0145792752.051724230920.5892326330.1463043039
9.92.06597839390.14254162980.0142541632.065978393920.73227440890.1430417759
102.07991111070.13932716850.01393271692.079911110720.87209044470.1398160358
10.12.09352604740.13614936650.01361493662.093526047421.00871752820.1366270835
10.22.10682686980.13300822370.01330082242.106826869821.14219244740.1334749192
10.32.11981724380.12990374010.0129903742.119817243821.27255199010.1303595427
10.42.13250083530.12683591580.01268359162.132500835321.39983294420.1272809541
10.52.14488131040.12380475070.01238047512.144881310421.52407209750.1242391534
10.62.15696233490.12081024490.01208102452.156962334921.6453062380.1212341405
10.72.16874757470.11785239830.01178523982.168747574721.76357215350.1182659155
10.82.18024069580.1149312110.01149312112.180240695821.87890663190.1153344784
10.92.19144536410.11204668290.01120466832.191445364121.99134646110.1124398291
112.20236524550.1091988140.01091988142.202365245522.10092842880.1095819678
11.12.2130040060.10638760440.01063876042.21300400622.20768932310.1067608943
11.22.22336531140.10361305410.01036130542.223365311422.31166593180.1039766087
11.32.23345282770.1008751630.01008751632.233452827722.41289504270.1012291109
11.42.24327022080.09817393110.00981739312.243270220822.51141344380.0985184011
11.52.25282115660.09550935850.00955093592.252821156622.60725792290.0958444791
11.62.26210930120.09288144510.00928814452.262109301222.70046526780.0932073449
11.72.27113832030.0902901910.00902901912.271138320322.79107226650.0906069987
11.82.27991187990.08773559610.00877355962.279911879922.87911570680.0880434403
11.92.28843364590.08521766050.0085217662.288433645922.96463237660.0855166698
122.2884336459002.288433645922.96463237660
12.12.2884336459002.288433645922.96463237660
12.22.2884336459002.288433645922.96463237660
12.32.2884336459002.288433645922.96463237660
12.42.2884336459002.288433645922.96463237660
12.52.2884336459002.288433645922.96463237660
empirical average rate
theoretical
Time (hours)
Release Rate mg/hr
average empirical
Theoretical
Time (hours)
mgs Chlorpheniramine Maleate
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20
Application Example: Anti-Counterfeit Features
Place designed markers within dosage forms
Control location, amount, and shape of the marker
Use invisible markers increase the level of difficulty
for counterfeiting
Fluorescein feature width: 225µm
5.05 mm
scan across digital image
x
output: distributioncollapse and average
pixel count over position
X - position
gree
n pi
xel n
umbe
r
scan across digital image
x xx
output: distributioncollapse and average
pixel count over position
X - position
gree
n pi
xel n
umbe
r
X - position
gree
n pi
xel n
umbe
r
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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21
Pharmaceutical Solutions Provided by 3DP Technology
Solution Provided by 3DP Problem Being Addressed
Rapidly dispersing tablets containing dose loads up to 1000mg (ZipDose®) address patient swallowing difficulties
Dose ceiling is a major limitation of commercially available fast melt manufacturing technologies
Drug particles and particle coatings are better protected in a compression free manufacturing process like 3DP
Compression forces used in conventional tableting processes can disrupt drug particles and particle coatings
Control over print image and fluid deposition enablestargeted drug delivery with the optimal dispersion time
Conventional manufacturing technologies lack flexibility to control tablet hardness, disintegration time, size & shape
Rapid dispersion of high drug loads and the ability to print drug-loaded solutions means more room to deliver multiple actives in the same dosage form
Large tablets that do not disintegrate rapidly in the mouth are difficult to swallow and pose design space limitations when using
Amenable to multiple taste masking strategies Less limitations on design space; no compression forces
Rapid adjustment of formulated dose through layered production technique Difficulty in rapidly changing doses in adaptive trials
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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22
Pharmaceutical Solutions Provided by 3DP Technology
Solution Provided by 3DP Problem Being Addressed
Rapidly dispersing tablets containing dose loads up to 1000mg (ZipDose®) address patient swallowing difficulties
Dose ceiling is a major limitation of commercially available fast melt manufacturing technologies
Drug particles and particle coatings are better protected in a compression free manufacturing process like 3DP
Compression forces used in conventional tableting processes can disrupt drug particles and particle coatings
Control over print image and fluid deposition enablestargeted drug delivery with the optimal dispersion time
Conventional manufacturing technologies lack flexibility to control tablet hardness, disintegration time, size & shape
Rapid dispersion of high drug loads and the ability to print drug-loaded solutions means more room to deliver multiple actives in the same dosage form
Large tablets that do not disintegrate rapidly in the mouth are difficult to swallow and pose design space limitations when using
Amenable to multiple taste masking strategies Less limitations on design space; no compression forces
Rapid adjustment of formulated dose through layered production technique Difficulty in rapidly changing doses in adaptive trials
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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23
Pharmaceutical Solutions Provided by 3DP Technology
Solution Provided by 3DP Problem Being Addressed
Rapidly dispersing tablets containing dose loads up to 1000mg (ZipDose®) address patient swallowing difficulties
Dose ceiling is a major limitation of commercially available fast melt manufacturing technologies
Drug particles and particle coatings are better protected in a compression free manufacturing process like 3DP
Compression forces used in conventional tableting processes can disrupt drug particles and particle coatings
Control over print image and fluid deposition enablestargeted drug delivery with the optimal dispersion time
Conventional manufacturing technologies lack flexibility to control tablet hardness, disintegration time, size & shape
Rapid dispersion of high drug loads and the ability to print drug-loaded solutions means more room to deliver multiple actives in the same dosage form
Large tablets that do not disintegrate rapidly in the mouth are difficult to swallow and pose design space limitations when using
Amenable to multiple taste masking strategies Less limitations on design space; no compression forces
Rapid adjustment of formulated dose through layered production technique Difficulty in rapidly changing doses in adaptive trials
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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24
Pharmaceutical Solutions Provided by 3DP Technology
Solution Provided by 3DP Problem Being Addressed
Rapidly dispersing tablets containing dose loads up to 1000mg (ZipDose®) address patient swallowing difficulties
Dose ceiling is a major limitation of commercially available fast melt manufacturing technologies
Drug particles and particle coatings are better protected in a compression free manufacturing process like 3DP
Compression forces used in conventional tableting processes can disrupt drug particles and particle coatings
Control over print image and fluid deposition enablestargeted drug delivery with the optimal dispersion time
Conventional manufacturing technologies lack flexibility to control tablet hardness, disintegration time, size & shape
Rapid dispersion of high drug loads and the ability to print drug-loaded solutions means more room to deliver multiple actives in the same dosage form
Large tablets that do not disintegrate rapidly in the mouth are difficult to swallow and pose design space limitations when using
Amenable to multiple taste masking strategies Less limitations on design space; no compression forces
Rapid adjustment of formulated dose through layered production technique Difficulty in rapidly changing doses in adaptive trials
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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25
Pharmaceutical Solutions Provided by 3DP Technology
Solution Provided by 3DP Problem Being Addressed
Rapidly dispersing tablets containing dose loads up to 1000mg (ZipDose®) address patient swallowing difficulties
Dose ceiling is a major limitation of commercially available fast melt manufacturing technologies
Drug particles and particle coatings are better protected in a compression free manufacturing process like 3DP
Compression forces used in conventional tableting processes can disrupt drug particles and particle coatings
Control over print image and fluid deposition enablestargeted drug delivery with the optimal dispersion time
Conventional manufacturing technologies lack flexibility to control tablet hardness, disintegration time, size & shape
Rapid dispersion of high drug loads and the ability to print drug-loaded solutions means more room to deliver multiple actives in the same dosage form
Large tablets that do not disintegrate rapidly in the mouth are difficult to swallow and pose design space limitations when using
Amenable to multiple taste masking strategies Less limitations on design space; no compression forces
Rapid adjustment of formulated dose through layered production technique Difficulty in rapidly changing doses in adaptive trials
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
-
26
Pharmaceutical Solutions Provided by 3DP Technology
Solution Provided by 3DP Problem Being Addressed
Rapidly dispersing tablets containing dose loads up to 1000mg (ZipDose®) address patient swallowing difficulties
Dose ceiling is a major limitation of commercially available fast melt manufacturing technologies
Drug particles and particle coatings are better protected in a compression free manufacturing process like 3DP
Compression forces used in conventional tableting processes can disrupt drug particles and particle coatings
Control over print image and fluid deposition enablestargeted drug delivery with the optimal dispersion time
Conventional manufacturing technologies lack flexibility to control tablet hardness, disintegration time, size & shape
Rapid dispersion of high drug loads and the ability to print drug-loaded solutions means more room to deliver multiple actives in the same dosage form
Large tablets that do not disintegrate rapidly in the mouth are difficult to swallow and pose design space limitations when using
Amenable to multiple taste masking strategies Less limitations on design space; no compression forces
Rapid adjustment of formulated dose through layered production technique Difficulty in rapidly changing doses in adaptive trials
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
-
3D printing is another approach to advanced manufacturing. These methods are capable of manufacturing pre-determined 3D geometric
structures of solid drug products in various shapes, strengths and distributions of active and inactive ingredients. This approach provides a unique opportunity to produce medicines that are tailored for individual needs of patients. - Scott Gottlieb, FDA Commissioner (blog of July 13,
2018) 3D printing of drug products could offer several advantages for pharmaceutical applications. For example, it has the potential to produce unique dosage forms with characteristics that cannot be
achieved in conventional dosage forms, such as instantaneous disintegration of an active ingredient, and other complex drug release profiles. To date, one FDA-approved drug—Spritam®--is
manufactured using 3D printing technology. Spritam® tablets, for the treatment of epilepsy, are designed so that a large dose of active
ingredient (1000 mg of levetiracetam) disintegrates within seconds after taking a sip of water. - Ahmed Zidan, FDA Spotlight on
Science
Emerging technologies such as 3D printing can be an enabler of personalized medicine by promoting agile manufacturing, an approach to production that is focused on meeting the needs of a specific patient
while controlling manufacturing efficiency. 3D printing technologies have the potential for producing final dosage forms that allow patients to
be given a personalized regime, which could include multiple active ingredients, either as a single blend or potentially as layers in a multi-layer printed tablet, based on their treatment needs. - Kristofer Baumgartner,
CDER Spokesperson in PharmaTech.com (August 2, 2016)
Delivering the Next Generation of Medicine Today
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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28CONFIDENTIAL © 2018, Aprecia Pharmaceuticals, LLC. All rights reserved.
Examples of Unmet Needs
Accelerating drug development cycle (e.g. adaptive clinical trials)
Solving the “last mile” issue
Optimized dose and release profiles
Personalized medicine and reducing pill burden
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
Design
Make
Test
Analyze
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29
Adaptive Clinical Trials
Definition: “A study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of date (usually interim data) from subjects in the study” – FDA
Example: First in Human (FIH) Dose Ranging Study (estimate dose 0.5 to 100mg)
Traditional design: Dose ten subjects at each dosing level in a progressive manner. May be planned for 5-10 or more dose levels
Adaptive Design:– Two to five subjects receive 0.5mg dose and blood samples taken. Drug concentrations
measured overnight.– Based on results of these five, next dose is determined and process is repeated until desired
concentrations achieved.
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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30
How Could 3DP of Pharmaceuticals Aid an Adaptive Clinical Trial?
Benefits:
Dosage strength could be printed on-site, as needed.
No need for large scale, manufacturing of all possible doses.
Just enough tablets for each step of trial could be produced.
Less worry about tablet stability.
Reduced cost and time.
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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31CONFIDENTIAL © 2018, Aprecia Pharmaceuticals, LLC. All rights reserved.
What if Pharmaceuticals Could be “Printed” at the Point of Sale?
Would obviate the need for large production facilities
Could use clinical data from individual patients–Electronic monitoring of patient parameters
• E.g., blood pressure, heart rate, glucose, weight, compliance, etc.
• Patient privacy issues?
Would allow for personalized doses for each individual patient
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Potential Role of 3DP in Precision Medicine
Dosage forms containing patient-specific amounts of active ingredient manufactured either from a regional location or at the point of care.– Theoretically could adjust dose as often as every dose– Could allow for “near real-time” dosage adjustments– Could simplify dosage titration
Creation of combo medications with patient-specific doses of each drug.– Expands possibilities beyond traditional fixed dose combinations– Potential for release of different active ingredients at different times or in different parts of GI tract
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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33
The “Multi-Pill”
JAMA 2018;320:566-579.
Could this be a precursor to a customized “one-tablet” regimen?
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
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34
Summary
Powder liquid 3DP offers unique advantages and opportunities for the pharmaceutical industry, as recognized by FDA and other industry leaders.
3DP for pharma offers formulation advantages over traditional methods, opening doors for oral drug delivery in ways otherwise unachievable.
3DP offers flexibility and efficiency in early stage development work from animal studies to clinical trials
3DP can help address unmet patient needs and transform how medicines are delivered
Because of the customization possible with 3D printing of pharmaceuticals, it may provide a platform for precision medicine
© 2019 – Aprecia Pharmaceuticals, LLC All Rights Reserved
-
Questions
Kimberly Bone, PharmDVP Medical and Clinical Affairs
Aprecia [email protected]
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36
Thank You!
Slide Number 1OverviewAprecia FactsAprecia MilestonesSlide Number 5Example Device Demonstrating Various FeaturesSlide Number 7 Aprecia’s 3DP Technology Platform Slide Number 9Introducing ZipDose® TechnologySlide Number 11Components Necessary for 3DP Pharmaceutical ManufacturingSlide Number 13Key Considerations for Applying 3DP to PharmaceuticalsApplication Example: Rapidly Dispersing Dosage FormsApplication Example: Rapidly Dispersing Dosage Forms, ZipDose® TechnologyApplication Example: Highly Accurate Low Dose ProductsApplication Example: Zero-Order Release ProfileApplication Example: Complex Release ProfileApplication Example: Anti-Counterfeit FeaturesPharmaceutical Solutions Provided by 3DP TechnologyPharmaceutical Solutions Provided by 3DP TechnologyPharmaceutical Solutions Provided by 3DP TechnologyPharmaceutical Solutions Provided by 3DP TechnologyPharmaceutical Solutions Provided by 3DP TechnologyPharmaceutical Solutions Provided by 3DP TechnologyDelivering the Next Generation of Medicine TodaySlide Number 28Adaptive Clinical TrialsHow Could 3DP of Pharmaceuticals Aid an Adaptive Clinical Trial?What if Pharmaceuticals Could be “Printed” at the Point of Sale?Slide Number 32Slide Number 33SummaryQuestionsSlide Number 36