Multiparticulate Formulation Strategies for Pediatric Drugs...Webinar| Multiparticulate Formulation...

Multiparticulate Formulation Strategies for Pediatric DrugsThursday, July 12, 2018Presented by: Sven Stegemann, Ph.D. & Jaspreet Arora, Ph.D.

Webinar| Multiparticulate Formulation Strategies for Pediatric Drugs| July 2018

Sven Stegemann, Ph.D., Lonza and Graz University of Technology.

Jaspreet Arora, Ph.D., Lonza Pharma and Biotech

Jaspreet Arora, Ph.D., is a senior engineer, product development at Lonza Pharma and Biotech at their Bend, OR site. His work focuses on formulation, manufacturing, and analytical characterization of immediate and controlled release multiparticulates.

Prof. Dr. Sven Stegemann is director, pharmaceutical business development at Lonza, and professor of patient centric drug design and manufacturing at the Graz University of Technology, Austria. Over the course of his 21-year career at Lonza (formerly Capsugel), Dr. Stegemann has worked as an advisor to major pharmaceutical companies on ways to improve the design, development and manufacture of pharmaceutical products so they better address the individual needs of patients. In his academic role, Dr. Stegemann’s focuses his research on the rational development of patient centric drug products and their associated manufacturing technologies, as well as education and training of students and young scientists. Dr. Stegemann is the founder and chair of the AAPS Focus Group on Patient-Centric Drug Development, Product Design, and Manufacturing as well as the founder and President of the Geriatric Medicine Society.

Speakers

Webinar| Multiparticulate Formulation Strategies for Pediatric Drugs| July 2018 2


Flexible Model Across the Product Development CycleSmall Molecule Technologies Integrated Offer

DESIGNSmall / Lab-Scale (non-GMP)

DEVELOPClinical Scale

MANUFACTURECommercial Scale

Drug Substance Intermediates – early and GMP intermediates

Drug substances – full range of API inclusive of HPAPI, cytotoxic payloads for ADC’s

Drug Product Intermediates – multiparticulates (MP), micronized API, spray dried dispersions

Drug Products - tablets (IR and MR), encapsulated powder and MP, soft gels, liquid-fill hard caps

> 300

Projects

> 200

Products

4

Key Focus AreasSmall Molecule Technologies


Agenda



Why do we need special pediatric formulation?

• The pediatric population is highly vulnerable and in need for effective therapy

• Physiology, pharmacology and toxicology might differs from „mature“ humans

• Different disease patterns and trajectories

• Treatment of pediatric patients requires

Individualized dosing regimen (e.g. by age, body weight, ...)

Excipient that are proven to be safe in pediatric patients with limited/immature ADME

Suitable formulation to overcome immature swallowing functions

Achieving our public health goals

Data are separated into deaths of neonates aged 0–27 days and children aged 1–59 months. Causes that led to less than 1% of deaths are not presented.

Black et al Lancet 2010


Why do we need special pediatric formulation?

• Swallowing function development is closely related to the age of the child

• It includes use and function of the lips, tongue, jaw, teeth and hard/soft palates and coordination with breathing

Swallowing development in the pediatric population

Age CapabilityAfter birth to 3 month • Development of sucking and suckling reflex

• Response to stimulus in and around the mouth

Three to six months • Up- and down munching movement • Transfer of food from front to back

Six to twelve months • Beginn to control of position of bolus• Start chewing

Twelve to eighteen months • Coordinates sucking, swallowing and breathing

Eighteen to thirtysix months • Fine tuning swallowing skills

Thirtysix to sixty months • Progress towards advanced chewing and swallowing skills

Insert reference


Balancing between industrial requirements and patient needs

• The increasing level of individualization of pharmaceutical products (e.g. pediatrics, geriatrics) require flexible industrial manufacturing platforms

Approaches to pediatric formulation

Multiparticulate Chewable tablets Liquids/ powder for reconsitution

Oral dispersible tablets/films

Dose accuracy +++ +++ +(user dependent dose

measurment)

+++

Dose flexibility +++ - ++(limited by volume)

-

Stability +++ +++ +/- ++

Transportability +++ +++ - +++

Excipients +++ +++ +/- +++

Taste ++ ++ +/- ++

Technology availability +++ +/- + ++

Manufacturing simplicity +++ ++ +++ -

Pediatric coverage +++ + ++ +++


Moving toward „universal design“

• Standard SODF (e.g. tablets, capsules) are suitable for adult patients with intact physical functioning

• For pediatric, geriatric, multimorbid or patient populations with specific diseases (e.g. Parkinson, stroke) these forms a not suitable due to limited or impaired physical functioning

• Drug omission, (inappropriate) altering and medication errors are consequences of standard SODF

• In contrast to this, dosage forms suitable for patients with impaired physical functioning are also suitable for unimpaired patients (universal design = suitable for all user groups)

Leveraging pediatric formulation platform technology

Uncomplicated patient(e.g. Single disease adult)

Specific disease patient(e.g. M. Parkinson)

Complex patient(e.g. Multimorbid, high age)

Standard product

Patient centered product

Universal product

Stegemann Exp Opin Drug Del 15(6):619-627 (2018)


Targeting patients and care-givers

Target population

• The pediatric patient

• The young and engaged care giver

Target product requirements

• Dose adjustment/flexibility

• Oral administration (swallowability, swallowing safety, swallowed dose accuracy)

• Neutral or positive patient experience (acceptability)

• Transportability and storage/stability

Considerations for pediatric formulation

Klingmann et al AAPS PharmSciTech 18(2):263-66 (2017)

Acceptability of coated/uncoated minitablets and 15% glucose sirup from 3 performed clinical studies


Multiparticulates in pediatrics

Development

• Provide a broad range of release profiles

• Ease of dose adjustments and dose strength development (same principle formulation)

• Standard technology and processes

• Technology knowledge and know how

• Availability of excipients safe for pediatric use

The role of multiparticulates in universal design

Manufacturing

• Technology availability and accessability (Technology Platform)

• Ease of finish product manufacturing (e.g. Sprinkle capsules, sachets, etc)

• Flexibility of dose strength based on a single multiparticulate bulk

• Standard storage and supply chain

Patient use/acceptability

• Metered dose or dose adjustment

• Ingestability by sucking, chewing, swallowing

• „Medicine hiding“ into preferred alimentation/taste

• Ingested dose precision

• Swallowing safety

• „Standardization“ to ease medicine use

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• Jim will provide

Market Data


13

Product drivers: distinction from monolithic dosage forms

Drivers for Multiparticulate Use in Drug Delivery

Economic drivers:

Sustained release needs in

cardiovascular, CNS & mood disorders

505(b)(2) pathway

Patent extensions Pediatric regulation

↑ Geriatric population

Combination products


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Commercial Product ExamplesMultiparticulate Final Dosage Form Flexibility

Pulsatile releaseRitalin LA®

Solubility enhanced ERFocalin XR®

Pediatric sachetLamisil®

Solubility enhancedSporanox®

Taste masking + ERZmax®

Orally disintegrating + DRPrevacid®

Extended releaseDetrol LA®

Fixed dose combinationNuedexta®

Delayed releaseNexium®

Capsules Mixed & ODTs

Suspensions & Sprinkles

+ recent pediatric launches


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• Multiparticulates (MP) allow the administered drug dose to be subdivided across multiple discrete units that are easily swallowed, and are compatible with a range of final dosage forms

• Particles, pellets, beads, granules / mini-tablets

• Discrete units range from a few hundred microns to a few millimeters in size

• Produced in various processes including fluid bed coating, extrusion / spheronization, melt / congeal processing, mini-tabs

• Multiparticulates offer a number of advantages vs. monolithic dosage forms, especially in meeting the need for more specialized meds.

Multiparticulate Technology


16

Distinguished by Particle Size & Processes

• Rank technology options against criteria for:

• the spectrum of patients,

• the desired dosage form(s),

• and the drug properties

MP Technology Options

Technology Description

Lipid Multiparticulates

Spray Layered Dispersions Pellets Mini Tablets

MP Image

PrimaryProcess(es)

Melt Spray Congeal

Fluid Bed Coating & Drying

Wet Granulation &Spheronization

Dry Granulation & Compression

NominalParticle Sizes 0.1 – 0.4 mm 0.2 – 1.0 mm 0.5 – 1.5 mm 1.5 – 3 mm

TypicalDrug Loadings 5 – 60% 1 – 40% 10 – 80% 10 – 80%

Present matrix options


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• Cylindrical, typically 2-3 mm tablets produced using conventional tableting machines (rotary presses)

• Smooth tablet surface amenable for coating using either conventional perforated coating pans or fluid bed

• Solid Finished Multiparticulate Product MP advantages, e.g. safety, gut distribution, ‘swallow-ability’ format options: suspension, sachet, capsule, compression into larger tablet

• Flexibility & Range Use for either IR, CR, DR, combination release profiles, taste masking, applications in pediatric and geriatric delivery

• Other features Optimal storage/transport, chemical stability, excipient tolerability, dosing flexibility – potential to count number of tablets

Mini-tablet Technology (Oral Granules)

Commercial products:


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• API layered onto core as an amorphous dispersion or in crystalline form

– Solubility enhancement through high energy dispersion or small particle size

• Modified release layers added for additional functionality

– Taste concealment, delayed release, controlled release

Spray Layered Dispersions

API, polymer, solvent OR

DYNO-MILL

Milled API, binder, solvent

Spray Layered Dispersions

Amorphous API – polymer

Microcrystalline cellulose or sucrose core

Crystalline API - binder


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Features & Benefits

• LMPs are • spherical, smooth multiparticulates, 75-1200 μm in diameter• primarily delivering crystalline API • produced from GRAS and/or USFA lipid excipients• produced from a solvent-free melt process• precedented for acceptable mouthfeel, even in pediatric populations, due to size, shape, and materials

Lipid Multiparticulate (LMP) Technology:

Commercial precedence:

Established Manufacturing Process LMP produced from melt-spray-congeal process that has commercial precedence

Flexibility High and low compound loading capacity (5% up to 60%) and can be readily coated for additional functionality

Solid Finished Multiparticulate Product

• Pediatric-compliant dosage forms with personalizable doses: suspension, sachet, capsule fill options

• MP advantages, e.g. safety, gut distribution.


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Drug Form & Release for Bioperformance

• Narrow down & further rank technology options based on success probability around:

• Bioperformance and achievable formulation designs

• Robust formulation release and stability

• Reproducible and scaleable processes

Select a Base-Model Multiparticulate

Immediate Modified

Crystalline

Amorphous

Desir

ed D

rug

Form

Desired Release Target


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Lipid Multiparticulate Example

• Selecting correct technology for the problem statement and target product profile is critical to successful programs

• Define drug delivery needs and identify the appropriate attributes of the drug to get started

• Identify the right formulation approach within a technology for speed and risk-based decisions during development

Technology Selection & Formulation Groundwork


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Apply Coatings for Additional FunctionalityWhen the Base-Model Isn’t Enough

Surface / CosmeticFlow, product appearance,

patient compliance

Extended ReleaseTaste masking, metered drug release through a permeation-

limiting membrane

pH Target ReleaseTaste masking, gastric protection, small or

large intestine release, colonic release

Enteric ColonicReverse Enteric

Time Target ReleaseTaste masking, time dependent

release regardless of pH


Coated API core

API in core

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• Example in vitro release profiles for coated multiparticulates• All multiparticulates are coatable; from aqueous or organic solvent based formulations are possible• Our approach is fluid bed coating for microspheres and pellets & pan coating for mini tablets

Coatings to Further Tailor Bioperformance & Compliance Targets

IR / DR combination

IR in target intestinal chambers

Fixed Dose CombinationpH-Trigger Release

pH sensitive polymer coat

Controlled Release

Diffusion coating

CR over 4-8 hours

Stom

ach

Duo

denu

m

Jeju

num

/Ileu

m

Enteric coating

Taste-concealing

Osmotic rupture

Taste conceal 5-60 min

Reverse enteric coating


24

Problem Statement Considerations

Patient(s) Pediatric, <6 mos – 12 years

Dose Range & Frequency

10-50 mg, BID

Dosage Form Constraints

5 mg dosing increments,<5 units to achieve dose,<500 mg total burden

Desired PK Bioequivalence

Release Target Immediate release

Desired Drug Form Amorphous for enhanced solubility

Taste Masking No

Amorphous spray layered multiparticulate

Mini-tablet of an amorphous solid dispersion

- OR -

Final Outcome Further Influenced by:• Drug molecule &

properties• Dissolution rates; size

and surface area• Excipient compatibility &

safety• Preferred dosage form

for patient and/or caregiver

• Method & means of administration

• Process & storage stability; both physical and chemical


In-Vitro: %Release vs. Time PK: Concentration vs. Time

Stomach→Intestine

3

21

100 µm

Goal Deliver 3 MR products to clinic for Ph1 healthy volunteer study & supporting stability

Patient Pediatric

Drug Form Crystalline

Dose 50-100 mgA/g, Q.D.

Dosage Form Enteric coated lipid multiparticulate

Release Profile Modified release, tunable core

Target Site Upper GI, gastric dose dumping mitigated by coating.

Particle Size < 0.4 mm

Stability Predicted >2 years at room temperature

3

2

1

25

Case Study A: Coated Lipid MultiparticulateProduct Development Examples


26

Case Study B: Spray-Layered DispersionProduct Development Examples

1.00 mm

In-Vitro: %Release vs. Time PK: Concentration vs. Time

Crystal

SLD

Crystal

SLD

Goal Deliver a single IR product to clinic for Ph1 healthy volunteer study & supporting stability

Patient Pediatric, oncology

Drug Form Amorphous

Dose 400-600 mgA/g, B.I.D.

Dosage Form Spray-layered dispersion

Release Profile Immediate with sustained solubility

Target Site Stomach

Particle Size < 0.4 mm

Stability Predicted >2 years at room temperature


Summary


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Thank youContact us: [email protected]

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Extra Slides

30

Multiparticulate Case StudiesLeverage our Know-How & Experience

Case Study Core Dose Solubility (mg/mL) Taste

MaskingTrigger/ Release Coating Stability -

Shelf Life

Release Profile(Time vs. DrugRelease)

A< 10% Active

LMP2-15 mgA

pH <210-100

pH 6.50.1-1.0

NopH

3-8 hr CREnteric 2 yr +

B60% Active

LMP20-600 mgA

Capsules

pH <210-100

pH 6.50.1-1.0

YesCoating

pH

IRReverse Enteric 3 yr +

C< 10% Active

LMP5-20 mgACapsules

pH <21-10

pH 6.5< 0.1

YesCoating IR Enteric 2 yr +

D10% Active

SLM1 mgA

Oral Film 100 YesCoating

Time Delay2hr DR

Osmotic Rupture 6 mo +

E30% Active

Mini-tablets60 mgA

Capsules < 0.1 No IR None --

IntestineStomach

StomachMouth

IntestineStomach


CongealingMelt Atomization

• Heat transfer rates control the solidification time and physical form of the formulation

• Fundamental understanding of atomization drives optimization, scale-up and process robustness

• Proper atomization allows for precise control of particle size distribution

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LMPs Atomization & Congealing

Direct Drop(4 kg/hr)

Ligament(15kg/hr)

Ligament(7kg/hr)


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• Atomization and congealing process consistent across all scales

• Same atomizer size and design across all scales

• Batch sizes from less than 20 gram to 100’s of kilograms, and continuous processing

• Continuous flow rates of 10-15 kg/hr typical, with up to 50 kg/hr demonstrated commercially

• Higher flow rates are possible with a larger atomizing disk

LMPs – Design, Develop and Manufacture


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Zmax® approved for use in US, Japan, Canada and New Zealand

Case Study Summary

0.0

2.0

4.0

6.0

8.0

10.0

0 15 30 45 60 75 90 105

In Vitro % Released at 30 min

AU

C(0

-4 h

r) m

cg.h

r/mL

2% poloxamer

3% poloxamer

4% poloxamer

Immediate release sachet

35 70

Acceptable tolerability demonstrated

Acceptable bioavailability demonstrated

0.0

2.0

4.0

6.0

8.0

10.0

0 15 30 45 60 75 90 105

In Vitro % Released at 30 min

AU

C(0

-4 h

r) m

cg.h

r/mL

2% poloxamer

3% poloxamer

4% poloxamer

Immediate release sachet

35 70

Acceptable tolerability demonstrated

Acceptable bioavailability demonstrated

Faster in vitro release

Incr

ease

d BA

Human Clinical DataMean serum azithromycin concentration following administration of 1 x 2 g sustained release or 2 x 1g commercial sachet azithromycin to health subjects under fasting conditions

Commercial sachet

Release testing

In Vitro – In Vivo Relationship:

LMP particles consisting of the

compound suspended in a

glyceryl behenate and poloxamer

matrix 0

25

50

75

100

0 20 40 60

% D

isso

lved

Time (min)

Release mechanism: Aqueous pore diffusion


34

• High loading of suspended water-soluble drug embedded within a lipid matrix that does not melt at body temperature

• Release is governed by “Aqueous pore diffusion” whereby dissolution of water-soluble drug and poloxamer enhances water ingress and drug release from a hydrophobic LMP matrix

Mechanism of Release: Aqueous Pore Diffusion

Cavity formed by dissolved-away drug crystal

Surface PoresMicrosphere Surface

Water-soluble-Filled Pore(connecting at point of closest approach)

Drug crystal

30-minute soak (52% released)



SEM Images of hydrated LMP: Schematic drawing of release:


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• LMP release rates can be controlled through formulation & process, without coatings

• An in-depth understanding of factors that impact release rate is essential to achieve the target release profile

Meeting the Target Release Profile

0

20

40

60

80

100

0 30 60 90 120 150 180

Time (min)

Dru

g Re

leas

ed (%

)

Increased APIparticle size gives slower release

0

20

40

60

80

100

0 30 60 90 120 150 180

Time (min)

Dru

g Re

leas

ed (%

)

Faster release due to more pore formation

0

20

40

60

80

100

0 30 60 90 120 150 180

Time (min)

Dru

g Re

leas

ed (%

)

Increased LMPparticle size gives slower release

0

20

40

60

80

100

0 30 60 90 120 150 180

Time (min)

Dru

g Re

leas

ed (%

)

Acid-soluble drug with pH-dependent dissolution rates

Increasing % dissolution enhancer: Increasing basic excipients:

Changing compound particle size: Changing LMP particle size:

Impact of particle size

Impact of formulation


Multiparticulate Formulation Strategies for Pediatric Drugs...Webinar| Multiparticulate Formulation...

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