New and Emerging Uses of Polymeric Excipients to … · • Container closure system evaluated: ......

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Ashland Specialty Ingredients

New and Emerging Uses of Polymeric Excipients to

Overcome Drug Delivery Challenges

Thomas Dürig

[email protected]

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Critical Importance of Excipients Biopharmaceutical factors modulated by excipients

Fraction of dose

absorbed

Dissolution Luminal reactions

Absorption

•API solid state

•API surface area

•API particle size

•API solubility

•Product disintegration

•Transit times

•Intrinsic permeability

•Stability of the API

•pH

•Enzymatic reactions

•Bile salts

Adapted from Kubbinga et al Eur J Pharm Sci 61 (2014) 27-31

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Innovation in Excipients : bioavailability, ease of administration, reduced dosing, stability

Challenges in Drug Delivery and Dosage Form Development

Parenteral drug delivery

• Rise in bio-

pharmaceutical

• Need to stabilize

proteins and peptides

• Aggregation inhibitors

• Also stabilizing and

solubilizing small

molecules

• oral bioavailability

enhancers for peptides

and proteins

Efficient Manufacturing

processes

• Continuous processing

• Rise of twin screw hot

melt extrusion

• Other Twin screw

extrusion

• Re-evaluation of direct

compression

processes

Importance of Patient

Compliance

• CR for reduced

dosing & side effects

• Pediatric and

geriatric friendly

(taste) ease of us

• Rise of abuse

resistant dosage

forms

• Improved patient

monitoring - Ingestible

microchips

Low Biovailability/ Solubility

• 70% of oral drug pipeline solubility challenged

• Fewer compounds progressing through early stage development

• Growth in solid dispersions and alternate technologies

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Selected Areas of Focus in Polymeric Excipient

Research

New and emerging uses in hot melt extrusion processing

• Solubilization-solid dispersions

• Taste masking

• Controlled release

New and emerging uses in continuous manufacturing and direct compression

New and emerging uses in injectable and liquid systems

• Stabilizing API’s

• Solubilizing API’s

• Protein excipient interactions

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Hot melt extrusion for solubilization / solid dispersions

Individual drug molecules

dispersed in solid polymer

phase

Intrinsic drug solubility

Supersaturated concentration

HPMCAS, HPMC & Copovidone are leading solid dispersion polymers but….

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New HPMC AS Analogs: Improved Thermal

Processing for Hot Melt Extrusion

A A

C

A A C

B

B D

D

Solid Dispersion of Drug

in the polymer

HPMC AS

New Analog Crystalline Drug

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Improved melt rheology of new HPMCAS analogs

• Lower viscosity of AquaSolve HPMCAS samples as temperature increases

• New grades melt extrudable at lower temperatures than commercial grade

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M

A

H

S

M

H

A S

A M

A A

S

S A

S

H

H M

M

Original HPMC AS

New HPMC AS with more selective

and better drug interaction ability

New HPMC AS Analogs: Improved Solubilization

New synthesis

method

A

Drug molecule

Better interaction

and solubilization

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Improved Solubilization and Sustainment Rapid Crystallizer Ezetimibe

0

20

40

60

80

100

120

140

160

0 50 100 150 200

Eze

tim

ibe

Co

nc

en

tra

tio

n (

µg

/ml)

Time (minutes)

AquaSolveHPMCAS new gradeAquaSolve HPMCAS new gradeAquaSolve HPMCAS HGEzetimibe

• Ezetimibe has a high recrystallization potential giving lower overall solubility (8.5 µg/mL)

• Solid Dispersions were prepared as 60% ezetimibe load

• New HPMCAS grade samples show >7X solubilization enhancement of ezetimibe

compared to drug alone

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New HPMC Analogs: Improved Thermal

Processing for Hot Melt Extrusion

Affinisol ™ HPMC* – altered synthesis method results in enhanced

thermoplasticity and greater hydrophobicity.

Tg 110-120˚C vs 180˚ C. Extrudable at 150˚C.

More organosoluble

Low and high molecular viscosity types for solubilization and controlled

release

*Third party trade name

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Pressurized CO2 -Reversible polymer plasticizer and

foaming aid in HME for improved solubility

Inexpensive, non toxic, non flammable high purity solvent

Good solvent for most small non-polar molecules

P-Co2 acts as a plasticizer by reducing Tg for most polymers

Secondary foaming effects can be achieved resulting in highly porous

structures with desirable mechanical and dissolution properties.

(courtesy M. Repka, Univ of Missipppi)

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API Polymer Extrusion

process Zone / Temp. (oC)

Screw

speed

(rpm)

Torque (Nm)

Ketoprofen

15% w/w

Klucel™

HPC ELF

without CO2 All Zones 140 ℃

100

21-22

with CO2 Zone 2-5 (140 ℃) &

rest 120 ℃ 18-18.5

* Processing Temperature for extrusion with P-CO2 was lower by 20oC for all zone except Zone 2-5

Case Study- Ketoprofen and HPC

B

Polarized Light Microscopy Images (3X Magnification) of Klucel™ ELF HPC

(A) Without CO2 (B) With CO2

A

Klucel™ ELF HPC Without CO2 injection With CO2 injection

Surface area (m2/Kg) 100 10116

Pore volume cm3 STP 0.143 1.547

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P-CO2 assisted HME demonstrated significant enhancement in the drug release rate

: with CO2 : without CO2 : physical mixture

Drug Release Studies

Ketoprofen/ELF

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Drug embedded in EC

via HME

Maintain the Crystallinity

via Modified screw design

Desirable release in Gastric

via Pore forming agent

Taste masked with

preferable release

Caffeine citrate and sildenafil citrate

Ethylcellulose (Aqualon EC N7 )

chosen as barrier due to low mp

Poreformers, calcium phosphate and

mannitol to promote gastric release

Physical

Blend

HME Milling ODT

Tablet

Use of Polymers in Taste Masking via HME

J. Pharm Sci Manuscript, in press, Morrot et al

(Repka group and ASI)

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Mixing Zone

Modified Design

Temperature: 125 – 130°C

Screw Speed: 50 rpm

Torque: 30-35 %

Modified Screw design:

--Will help to maintain the API

in a crystalline form & reduce

the torque

Standard Design

Modified screw design to maintain crystallinity

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Oral Release (Artificial Saliva )

Both in Vitro dissolutions indicated that the optimized

extruded formulation was sufficiently taste masked as well as

attained desired drug release profiles.

Sildenafil release from ODT tablets

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0 : no taste, 1 : threshold, 2 : slightly unpleasant/bitter, 3 : bitter,

4 : moderately bitter , 5 : extremely bitter

F1: 20% API + 60% EC-N7 + 5% TEC + 3% Mannitol

F2: 20% API + 60% EC-N7 + 5% TEC + 15% Calcium Phosphate

Note: Two HME ODT Tablets were significantly better than PM.

Human Taste Panel Evaluation

10 Healthy human volunteers (ages 18-42yrs) (Protocol number VIPS/2013/12).

(API: Caffeine citrate)

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Extruded Solid Dispersions for Simultaneous

Solubilization and Controlled Release • Case study:

– Develop amorphous solid dispersion in pellet form to achieve 8h t80% release for low soluble drug (Nifedipine (BCS class II) as the model drug)

• Approach:

– Extrusion using typical controlled release grades of HPMC (BenecelTM K type) and copovidone (PlasdoneTM S-630) polymers

– Formulation Design Factors

• Drug loading level

• Ratio of hypromellose to copovidone

• Hypromellose molecular weight

• Pellet size

• Plasticizer

Tm(ºC) Tg(ºC) MW

(g/mol) Solubility (mg /mL)

173 42 346.3

pH 6.8 Buffer 0.0038

DI Water 0.0033

pH 4.6 +1% SLS 0.4020

FaSSIF pH 6.5 0.0160

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Hang - Glider Effect

New drug delivery platform with programmable drug release while

simultaneously solubilizing and preventing drug crystallization

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Effect of HPMC Grade

• 20% drug loading

• 40% HPMC, 40%

CoPVP

• K4M, K15M, K100M

and K200M

Molecular Weight

(Dalton) for BenecelTM

K4M Mw: 400,000

K15M Mw: 575,000

K100M Mw: 1,000,000

K200M Mw: 1,200,000

Higher MW of HPMC will help sustain degree of supersaturation and delay the

drug release

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Dissolution Stability, 40ºC/75%RH

Product stable throughout 6 month accelerated stability

• Container closure system evaluated:

60cc HDPE bottle, 0.04” inch wall thickness

• F2 values > 50 throughout 6M

F5: 20%API, 40%HPMC,

40% Copovidone

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Use of Excipients in Continuous Processing

DISPENSING

TABLET COATER

DRY MIXING

WET GRANULATION

FLUID

BED

DRYER

DRY MILL

MIXING (LUBRICANT)

TABLET PRESS

DIRECT

COMPRESSION

DRY GRANULATION

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Continuous Granulation of Acetaminophen

Feed Rate

120 RPM

Extruder Speed 150 RPM

Temperature 55°C

Feed Rate

15 kg/hour

Extruder Speed 400 RPM

Temperature 40°C

Mixer Speed

750 RPM

Chopper Speed 1500

RPM

Temperature 25°C

Leistritz ZSE 18HP

Extruder

GEA/Niro

ConsiGmaT*-1 Glatt 5L High-shear

Granulator2

* Trademark owned by a third party

Ingredients Percentage Comments

Acetaminophen 90.00

Intragranular 10%

water Various binders 4.00

Microcrystalline cellulose q.s.

Fumed Silica 0.20

Croscarmellose sodium 4.00

Extragranular Magnesium stearate 0.25

Total 100.00

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Effect of Different Processes on Tablet Strength

• Process selection: continuous granulation shows advantages over

traditional wet granulation for tablet strength

• Conventional twin-screw extrusion is best

• Binder selection: HPC shows stronger profiles

4% Binder

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Effect of Different Processes on Granule Morphology

Leistritz ZSE18HP ConsiGmaT*-1 Glatt HSG

Plasdone™

K-29/32

PVP

Klucel™

EXF HPC

Twin-screw extruded (Leistritz) granules have a distinctly different morphology.

* Trademark owned by a third party

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Direct compression HPMC for controlled release

•High MW (CR grade) HPMC particles are typically fibrous and

moderately flowable.

•New forms with modified morphology

•Methocel™DC2 HPMC

•Benecel ™DC PH HPMC

•Different approaches:

•More spherical and densified, Methocel™ DC2 HPMC

•Surface modification, Benecel ™DC PH HPMC

*Registered trademark Dow Chemical Co.

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Case study

Parameter Settings

Machine Model (Elizabeth

Hata)

HT-CTX-

MS-U

Stations 38

Turret Speed (RPM) 30

Feeder Speed (%) 50

Precompression Force (kN) 2

Main Compression Force (kN) 15

Tablet Target Weight (mg) 500

Metformin CR formulations compressed on a production scale press

Comparison of standard HPMC CR grade vs HPMC DC

Improved weight and content uniformity, improved tablet strength.

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Stable In-Process Force Control

Average compression force was recorded every minute

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Lower in-process Weight Variation

Formulation # 2 Concentration (%)

Metformin HCl 50.0

Benecel K100M 49.5

Mg Stearate 0.5

Formulation with Benecel DC has better flow and smaller weight variability

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Better Mechanical Properties

Formulations with Benecel DC have higher tablet hardness

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Acknowledgements

• Professor Mike Repka and graduate students at Ole Miss

• John Lian ASI Pharma

• Divya Tewari ASI Pharma

• Kapish Karan ASI Pharma

• Brad Beissner ASI Pharma

• Vivian Bi ASI Pharma

• Stu Porter ASI pharma

• Todd Brugel ASI Molecular Science

• Jenny Titova ASI Process Research

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Thank you !

New and Emerging Uses of Polymeric Excipients to … · • Container closure system evaluated: ......

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