emerging technologies in 3d printing of pharmaceuticals · benefits for pharmaceutical industry...

1

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

2

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


3

Aprecia Facts

Privately held technology company

Founded in 2004

Headquartered in Blue Ash, Ohio

60+ employees

Innovative and patent-protected 3DP technology platform


4

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


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



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


7

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.


http://vcg.isti.cnr.it/Publications/2017/SCPCD17/DigitalFabricationForCH.pdfhttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://doi.org/10.1111/cgf.12781


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


9

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


10

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.



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

12

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



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


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


15

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


16

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)


17

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


18

Application Example: Zero-Order Release Profile

Introduce concentration gradient to achieve constant release


19

Application Example: Complex Release Profile

Spatial control of composition to achieve pulsed release

0.000

0.100

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0 2 4 6 8 10 12 14

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


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

progfluidla1la2la3la4la5la1sla2sla3sla4sla5score1core2core3

a1-a5L100Layer 1

a1-a5both2

a1-a5, a1=a5both3

a1-a5, a1=a5L1004

a1-a5L1005

a1-a5L1006

a1-a5L1007

a1-a5L1008

a1-a5L1009

a1-a5L10038 layers10

a1-a5L100200 microns each11

a1-a5L1007.6cm before pressing12

a1-a5L1004.2436464088cm after pressing13

a1-a5L10014

a1-a5L10015

a1-a5L100active soln16

a1-a5, coreboth25% CM17

a1-a5, corebothin ethanol18

a1-a5, coreboth19

a1-a5, corebothbinder20

a1-a5, coreboth3%L10021

a1-a5, corebothin ethanol22

a1-a5L10023

a1-a5L10024

a1-a5L10025

a1-a5L10026

a1-a5L10027

a1-a5L1000.342105263228

a1-a5L1001.62529

a1-a5L1000.210526315830

a1-a5L1000.684210526331

a1-a5L1002.5532

a1-a5L10033

a1-a5L10034

a1-a5, a1=a5both35

a1-a5, a1=a5both36

a1-a5both37

a1-a5L10038

Chart1

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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

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6.9

7

7.1

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8

8.1

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9

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10

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11

11.1

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11.5

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11.7

11.8

11.9

12

12.1

12.2

12.3

12.4

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

0.2600792689

0.089

0.2600792689

0.069

0.2600792689

0.086

0.2600792689

0.058

0.2600792689

0.053

0.2600792689

0.025

0.2600792689

0.013

0.2600792689

0.008

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2600792689

0.2560220177

0.2517077791

0.2474301996

0.2431892795

0.2389850186

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0.2306864745

0.2265921913

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0.2185136027

0.2145292972

0.210581651

0.2066706641

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0.1989586679

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0.1913933087

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0.1767025013

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0.0852176605

0

0

0

0

0

0

Sheet1

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0000000.0000.0000.0000000000

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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


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

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6.41.35241219810.26007926890.02600792691.352412198113.57157504020.2609918277

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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

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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


theoretical

Time (hours)

Release Rate mg/hr

average empirical

Theoretical

Time (hours)

mgs Chlorpheniramine Maleate

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


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


22














23














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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



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


Design

Make

Test

Analyze

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.


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.



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

32

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


33

The “Multi-Pill”

JAMA 2018;320:566-579.

Could this be a precursor to a customized “one-tablet” regimen?


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


Questions

Kimberly Bone, PharmDVP Medical and Clinical Affairs

Aprecia [email protected]

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

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