solid dosage forms for heterogeneous patient groups ...1 3 3 march 15, 2019 solid dosage forms for...

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March 15, 2019

Solid Dosage Forms for Heterogeneous Patient Groups: Challenges and SolutionsVeronique Henner-KulkarniTechnical Sales Manager

Email: [email protected]

1. What kind of Patients are we?

2. Need of a Patient Centric Approach

3. Solid Dosage Forms with Cellulose Derivatives

− Technical Challenges and Solutions

233

What kind of Patients are we?

Children

Require help = Care-giver

Rejecting Medicine

Swallowing Issue

Young-Adults

Hypo-salivation

Swallowing Issue

Discontinua-tion when

feeling better

Pill burden

Elderly

Require help = Care-giver

Hypo-salivation

Swallowing Issue

Forgetting Medicine

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26%

61%

13%

20%

55%

25%

World population 2017-2050

0-14 years old 15-59 years old

> 60 years old

Statista.com/statistics world population

Inner circle: year 2017Outer circle: year 2050 estimation

Challenges in Pediatric/Geriatric

− Heterogeneous patient groups

→ Need of patient centric approach

→ Assure medicine is taken

− Pediatric and geriatrics common challenges:

− Palatability linked to Acceptability

− Swallowability, Dysphagia

− Regulatory for excipients:− Safety and toxicity data

433

Source: pixabay.com/de/muffinsHealthline.com/

Patient Centric Approach

Palatability

SwallowabilityAcceptability

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Improved Palatability

• Masking Taste and Odor

• Appearance

Improved Swallowability

• Reducing tablet size (mini-tablets)

• Oral dispersible tablets

• Dispersible tablets

Acceptability

• Reducing Dose frequency

• Fixed Dose Combination (Capsules, Pellets)

Cellulose Derivatives …− Are well established in the

pharmaceutical developments of solid dosage forms

− Non toxic, no teratogenic

− Maximal doses are available (US/JP)

− Based on a biorenewable polymer

− Produced by Shin-Etsu decades

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Cellulose Derivatives − Solutions within Shin-Etsu’s

Product portfolio for solid dosage forms

− Hypromellose / Methyl Cellulose− High viscous for sustained release

(SR) dosage forms− Low viscous for coating

− L-HPC− IR dosage forms− Oro-dispersible or dispersible

dosage forms

− HPMCAS/HPMCP + MC− Taste Masking 7

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HPMC/MC HV

Metolose®

Tylopur

HPMC/MC LV

Pharmacoat®

Tylopur

HPMCAS

AQOAT®

L-HPC

HPMCP

HPMC

Metolose® SR

Tylopur SR

Shin-EtsuProduct Portfolio

SmartExTM

Cellulose Derivatives: Safety

− HPMC, L-HPC and recently HPMCAS are listed in the STEP database for pediatric formulations

− http://step-db.ucl.ac.uk

833

Source: EuPFI, STEP Database

http://step-db.ucl.ac.uk/

Solid Dosage Forms

Advantages

− Flexible dosage form (size, color)

− Easy, cost efficient production (DC, capsule filling)

− Good stability

Acceptability

− Age limitation

− Swallowability

− Dysphagia

− Administration

− Texture, mouth feeling

− Taste/Smell

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Solid Dosage Forms: Challenges andSolutions− How to improve acceptability of solid dosage forms− Improving Palatability by taste masking

− Solid Dosage Forms to ease swallowing − Mini-Tablets

− Oral Disintegrating Tablets and Mini-Tablets (ODMT)

− Fix Dose Combination− Bi-Layer Tablets

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Mini-Tablets− Solid dosage form 1-4 mm,

− Prepared on standard rotarytablet press

− IR/SR/delayed release

− Advantages− Versatile dosage form which

allows dose flexibility− Possibility of further processing

(e.g capsule)− Easy and cost-efficient to

formulate by direct compression− Easy administration compared to

syrups (e.g. dose accuracy) 1133

3 mm mini-tablets and tooling

Mini-Tablet Challenges: Coating

− Challenges:

− Agglomeration of mini-tablets during coating process

− Abrasion of mini-tablets in coating pan or fluid bed

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− Example:Enteric coating with AQOAT® HPMCASa)

Photographs of typical agglomerates formed: drum coating (left) and fluid bed coating (right)

Trial First Trial Optimized

Drum Coating Agglomeration [%]

3.9 <0.1

Fluid Bed Agglomeration [%]

11.5 0.6

Buffer change dissolution test after process optimizationa)Coating Formulation see Shin-Etsu Technical Information A-049 2016.

Mini-Tablet Challenges: Coating

− SEM Pictures Tablets − SEM Pictures Cross-Section

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Tablet Surface of a tablet prepared in the perforatedpan (left) and in the fluid bed wurster process (right). The film surface is smooth for both processes.

Cross-section of the tablet edge. The edge feature iswell preserved for the perforated pan coating process(left), while for the fluid bed process, the edge issmoothened due to abrasion (right).

− Careful process optimization required− e.g. drum with increased rotation speed, more dry process

− Coating in fluid bed using wurster also possible

Taste Masking of Mini-Tablets

− Taste masking of Dosage Forms− Mostly needed to cover bitterness which induces

− Poor patient acceptance

− Children reject medicine

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Source: Wikimedia.org/indiatimes.com

Most Common TM technologies

Flavor/sweetener addition

Microencapsulation Granulation

Ion Exchange Resin Adsorption Pro-drug approach

Bitternessinhibitors

Coating …..


− Taste Masking by Coating

− Analytical challenge: Laboratory Dissolution test for screening efficiency of taste masking

− Dissolution test according USP or EP in water or pH relevant buffers− Determination of lag time

− Small volume: Oral cavity model test

− Small volume: Dissolution in simulated saliva in comparison with quinine (bitter substitute)

− Electro-tongue ($$$)

− Tasting panel (gold standard)

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Measure/ Quantify

Improve/Reformulate

Apply Taste

Masking

Challenge: Fast feedback for lab development


− Taste masking− Enteric polymers combined with a water soluble pore former

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HPMCP (Phthalate) HPMCAS (Acetate-Succinate)Methyl Cellulose (MC) / Hypromellose (HPMC)

Enteric Enteric Pore Former

= Phthalyl= Succinoyl= Acetyl = Methoxy or HPO


− Mini-Tablets Caracteristics

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− Tablet weight: 19.9mg

− Hardness: 42 N /Friability: 0.01%

− Disintegration in water 37°C: 3 Min.

− Coating Formulations

− Tablets were coated in a Solid lab 1 (Bosch) until 20% weight gain

Material w/w[%]

Caffeine 20.0

L-HPC (NBD-021) 15.0

Lactose (Flowlac 90) 63.75

Silicon dioxide (Aerosil®) 0.25

Magnesium stearate* 1.0

Total 100.0*Magnesium stearate added before tableting

Material Content [%]

F1 F2 F3 F4

HPMCAS AS-HG(Shin-Etsu AQOAT®)

6.3 3.5 0.7 -

Hypromellose (Tylopur®

606)0.7 3.5 6.3 -

Ammonia (as NH3) 0.08 0.045

0.009

-

Eudragit® EPO ReadyMix - - - 15.0

Purified Water (H2O) 92.92

- 92.92

85.0

Total 100.0

100.0

100.0

100.0


Low-Volume Dissolution

− Quinine threshold used as referenceequivalent to 2.5 µg/mL caffeine (UV analysis)

− Detection 5 ml simulated saliva(pH=6.2) + 1 coated mini-tablet putinto the Ultra Turrax drive vessel at 400 rpm for 5 Min. (n=6)

Threshold Reference*

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− In vitro/in vivo tools available forpre-screening study on taste

− Correlation with human taste panelstill difficult

− Examples:− Quinine : 0.0025 mg/mL (0.000008 M)

− Acetaminophen: min 0.2mg/mL up to5mg/mL

− Naproxen-Na: av.=1.124mg/mL

*Mohamed-Ahmed A.H., Soto J., Ernest T., Tuleu C., Non-human tools for the evaluation of bitter tastein the design and development of medicines: a systematic review, Drug

Discov. Today, 21 (2016)


Dissolution Results Conclusion

− Low volume dissolution in simulated saliva:

− Taste masking was achieved from 15% weight gain with the HPMCAS/HPMC

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− Dissolution profile in acidmedia (0.1 N HCl)

− F1 (9:1/ AS:HPMC) − no dissolution observed

− F2 (5:5/ AS:HPMC) − delayed release of API at

pH=1.2

− F3 (1:9/ AS:HPMC) − short lag time of around 5

min then immediate dissolution 2

033

Summary Mini-Tablets

Mini-Tablets Coating

− Possible in fluid bed or coating pan depending on mini-tablet size− Adjustment of coating parameters

− Attrition higher during fluid bed coating− Very low mini-tablet friability

required− Less coating efficiency, loss of

spray solution− Risk of content inhomogeneity

Taste Masking

− Possible with cellulose derivatives − Enteric Polymer AQOAT® HPMCAS

or HPMCP with pore former methyl cellulose

− Challenge of TM analysis to support rapid lab development− Simulated saliva, oral cavity

model, electronic tongue….2133

ODT: Oral-Dispersible-Tablets

− Disintegrates within the oral cavity and powder is swallowed

− ODTs advantages − Easy administration

− No need of water

− Avoid first pass metabolism

− Fast absorption of drug due to pre-gastric absorption

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Disintegration in 30 secondsFDA: < 30 secondsEP: < 180 seconds

ODT with SmartExTM

− Co-processed excipient by Shin-Etsu, manufactured by Freund corporation

− Pharmaceutical excipients used

− DMF #030193

− Complies with EP Chapter “co-processed excipient”

− Two grades QD-50/100

− ODT by easy DC process 2333

ODT: Content of UniformityF1 F2 F3 F4 F5 F6

Acetaminophen* (AAP) 1 5 10 15 20 30

SmartExTM QD-50 98 94 89 84 79 69

Magnesium stearate 1 1 1 1 1 1

Total 100 100 100 100 100 100

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*Acetaminophen passed through a mesh opening of 106 mm

Shin-Etsu Technical Information L-035 2017.

ODT: Content of Uniformity

Compression Parameters Tablet Properties

− Tablet weight deviation: n=10

− Content Uniformity: − UV detection (244 nm) / n=10

− Friability [%]: < 1,0%

− Disintegration time: n=6

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Machine Virgo (KikusuiSeisakusho Ltd.)

Punch 12 punches

Tablet size 8 mm-d, 12 mm-R,200 mg/Tab

Compression force Adjusted for 50 N of tablet hardness

Rotation speed 40 rpm


Disintegration Time Tablet Weight Deviation

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0

2

4

6

8

10

12

14

16

18

5 10 15

Dis

inte

grat

ion

tim

e [

sec.

]

Tablet press running time [min.]

1%

5%

10%

15%

20%

30%

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

5 10 15

Tab

let

we

igh

t C

V [

%]


1%

5%

10%

15%

20%

30%


Content of Uniformity

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− Over a broad AAP dosage(1 to 30%), SmartEx showedexcellent disintegrationability and tablet weightdeviation

− Only extremely low AAP concentration affected thecontent uniformity of thetablets− Solved by sequential

blending of AAP andSmartEx™

− For AAP >5%, tablets showedexcellent content uniformity

0

0.5

1

1.5

2

2.5

3

1 5 10

AA

P c

on

ten

t C

V[%

]


1%

5%

10%

15%

20%

30%

ODMT: Analysis

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− Challenges(e.g. oral-dispersible mini-tablets):− Very low hardness observed

<10 N

− Very fast disintegration time<10 s

− Standard equipment cannot follow subtle changes in hardness or disintegration time

− Modified analysis methods required (texture analyzer)(a-d)

− Example: SmartExTM placebo 3 mm mini-tablets

0

2

4

6

8

10

0 5 10 15 20

Dis

inte

grat

ion

tim

e [

s]

Tablet Hardness [N]

Analysis via the texture analyzer (a-d)

a) Mitwollen, J.-P. Doctoral Thesis, 60-61 (2002); b) Stoltenberg, I. Doctoral Thesis, 104-105 (2012); c) Bohnacker, R.; Streil, A., Schweizer, S. Müller, I.; Pharm. In. 67, 327-335 (2005); d) Münster, M.; Pfeifer, C.; Breitkreutz, J., Development and Characterization of Orodispersible Mini-tablets Manufactured by Direct Compression, Poster presentation, 1st European Conference on Pharmaceutics, Reims (2014).

Bi-Layer Tablets− Advantages:

− Combination therapy:− Two APIs in different layers

− Avoid chemical incompatibilitiesbetween APIs by physicalseparation

− Drug release profile modulation

− Decrease of administrationfrequency− Reduced pill burden

− Easy and cost-efficient toformulate by direct compression 2

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Source bi-layer tablets: picswe.com

Bi-Layer Tablets

Formulation Screening Study

− In a previous study, L-HPC: LH-31 (micronized grade) has beenfound as most effective grade avoiding lamination at different compaction forces.

− Lamination was observed whenthe IR layer was compressed first.

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Formulation Layer 1

(sustain release)

FormulationLayer 2

(immediate release)

Acetaminophen

60% Acetaminophen 60%

Hypromellose(Metolose90SH-400SR)

40% L-HPC (LH-31) 10%

Riboflavin 1% Lactose 60%

Magnesiumstearat

0.5% Magnesium stearat

0.5%

Shin-Etsu Technical Information L-006 2010.

Bi-Layer Tablets

Compaction Parameters− FlexiTab®: Manesty

− Tablet: 10 mm flat

− Weight: 200 mg per layer

− Compression forces: 2.5/10/15 kN

Results− Even at very low compression force,

tablets showed very high hardness

− IR layer fully released after 1h

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Compressionforce [kN]

Hardness[kgf]

Lamination

1st layer

2nd layer

2.5 2.5 4.0 No

2.5 5.0 9.5 No

2.5 10.0 14.5 No

Summary

Mini-Tablets

− Aqueous enteric coating − Shin-Etsu AQOAT®

− Taste masking tailored released− Shin-Etsu AQOAT®

with pore former

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ODT/ODMT

− Direct compression− Co-processed

excipient SmartExTM

− Very low API dosage possible

Bi-Layer Tablets

− Avoiding lamination− L-HPC

− Solutions with Cellulose Ether excipients for

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solid dosage forms for heterogeneous patient groups ...1 3 3 march 15, 2019 solid dosage forms for...

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