Pediatric Formulations: Need For New Excipients*

Pediatric Formulations: Need For New Excipients*

Mansoor A. Khan, R.Ph., Ph.D.

Director, Division of Product Quality Research

US Food and Drug Administration

ExcipienFest, April 28, 2015

Puerto Rico

*The views expressed are my own and do not necessarily represent the official policy of the FDA

Mansoor Khan 2015 2

Core Regulatory Tenet

Regulatory

Agency’s

Expectations

Facilitate

Accessibility

Efficacy Safety

Quality

Outline • Pediatric Oral Drug Products

– Challenges and special considerations

• Dosage forms of the regulated products

• New excipients for novel dosage forms

– BCS classification use in pediatrics

– Excipient challenges in pediatric products

• Excipient in Compounded Products

• New excipients safety qualification

• Some internal FDA studies

3 Mansoor Khan 2015

• Draft Guidance for Industry Pediatric Study Plans, July 2013: http://inside.fda.gov:9003/downloads/CDER/OfficeofNewDrugs/ImmediateOffice/

PediatricandMaternalHealthStaff/UCM360933.pdf

– Overview of the disease in pediatrics & the

drug/biologic

– Overview of extrapolation

– Info on waiver(s) and deferral(s)

– Info on the planned nonclinical & clinical studies

– Pediatric formulation development

4 Mansoor Khan 2015

– 2012 FDA Safety and Innovations Act (FDASIA)

– Permanent Reauthorization of BPCA and PREA

Pediatric Device Safety and Innovation Act

- Sponsor to submit Pediatric Study Plan (PSP)

http://inside.fda.gov:9003/downloads/CDER/OfficeofNewDrugs/ImmediateOffice/PediatricandMaternalHealthStaff/UCM360933.pdf

http://inside.fda.gov:9003/downloads/CDER/OfficeofNewDrugs/ImmediateOffice/PediatricandMaternalHealthStaff/UCM360933.pdf

5

FDA Collaboration with NIHCD

5 Mansoor Khan 2015

0

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Top Selling Drugs in US Market Bearing Pediatric Use Information in Label

6 Mansoor Khan 2015

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Platforms/Approved Pediatric Dosage forms

• Drops

• Syrups

• Suspensions

• Sprinkles

• Capsules

• Injectables

• Chewable tablets

• Orally disintegrating tablets

• Coated products

• MDIs and DPIs

• Orally dissolving films

• Minitabs

• Others (e.g., non oral drops, creams, ointment etc.)

Mansoor Khan 2015

API

Excipients

Product

Properties

Processing

Conditions

Environmental

Conditions

Container

Closure

System

Scale-Up

Dosage Form BLA/NDA/ANDA

Review/

Compliance

Solids, liquids,

semisolids, all

routes, All Analyti

–cal, evaluations

And measureme–

nts systems

Compatibility

Concentration

Solubility, Tg

Part. Size Dist.

Temperature, RH,

Light, Handling,

Storage

Ionic Strength

Buffer Choice,

Crystallization,

PS, Appearance

Viscosity, pH

Batch size, Yield

Moisture content

Impurities

Material, Geometry, Integrity

Headspace pressure, Leachables,

Fill volume, Terminal sterilization feasibility

Bioreactor/Synthetic

Mixing

Filtration

Sterilization,

Lyophilization

Freeze-thaw

Agitation

Filling

Spray Drying

Geometric,

Kinematic,

Heat

Transfer,

Mass

Transfer

Analytical

Methods

UV, HPLC, UPLC, MS, MS-

MS, DSC, TgA, X-ray

8 Mansoor Khan 2015

Pediatric Product: Special Considerations

• Minimal/safe excipients

• Stability under high heat/humidity – Physical, chemical, and microbiological

• Palatable – Flavor selection based on cultural preferences

• Easy-to-swallow or dissolvable dosage form

• Ability to titrate dose

• Adequate bioavailability

• Avoidance of extemporaneous compounding

• Commercially available

Anne Zajicek, NIH/NICHD 9 Mansoor Khan 2015

10 Mansoor Khan 2015

Understanding Product by QbD Approach

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Challenges of Solutions

• Main challenges are – Solubility

– Stability

– Taste masking

– Appropriate selections of excipients and packaging material

– Preservation

• Typical ingredients – Solubilizers, Stabilizers, viscosity builders,Sweeteners,

colorants, flavors, or complexing agents

• Selection of ingredients can be critical depending upon BCS classification

Mansoor Khan 2015


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Some Solubilization Methods for Poorly Soluble (BCS 2)

Compounds

• Cosolvents

• Salt formation

• Complexation

• Surfactants

• Nanosizing or micronizing

• Amorphous compounds

Mansoor Khan 2015

JBreitkreutz, J. Boos, Exp. Opin. Drug Deliv. 4: 37-45 (2007) 14 Mansoor Khan 2015

Safety of Preservatives

• Methyl & Ethyl parabens

• EFSA has assigned ADI of 10mg/kg/day • Propyl paraben

• EFSA has not assigned an ADI Reports of developmental problems in juvenile animals. Failure of testicular development. Must be seen as relevant to paediatric use, esp. lower age groups. • Optimal approach - propyl paraben should not

be used in paediatric medicines for neonates, infants and small children. Not even in the short term.

Piotr Kozarewicz European Medicines Agency 15 Mansoor Khan 2015

• The main excipients raising safety concerns were

parabens (especially propyl paraben), benzyl alcohol,

propylene glycol, ethanol, cyclodextrin, sorbitol,

polysorbate 80, and mannitol

Mansoor Khan 2014 1

6

Ruiz et al., Pediatric formulation issues identified in pediatric

investigation plans, Expert Rev. Clin. Pharmacol., Early Online 1-

6 (2014)

Safety of Excipients

• Deaths of neonates and low-weight infants up to the age of 6 months and severe, adverse drug reaction, such as seizures and plasma hyperosmolality, have been reported for propylene glycol [20,21]

─ Expt Opinion Drug Delivery; 4:37-45,2007

─ McDonald et.al., and Glassgow et.al- MV-12 parenteral: (reversible: “we can not as yet ascribe any clinical problems other than hyperosmolarity to propylene glycol




Mansoor Khan 2014 2

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Turner et al., Adv Drug Deliv Rev. 2013 Nov 13. pii: S0169-409X(13)00262-7

Risk assessment of neonatal excipient exposure: Lessons from food

safety and other areas.

From Abstract

….Many excipients have been used widely in neonates without obvious

adverse effects. Some excipients may be toxic in high amounts in which

case they need careful risk assessment. Alternatively, it is conceivable that

ill-founded fears about excipients mean that potentially useful medicines are

not made available to newborn babies….

From Background on Risk Characterization of Parabens

….The risk assessment of parabens needs to account for their beneficial

effects as antimicrobials. The withdrawal of parabens from multi-use

preparations may increase the incidence of infection in neonates who have

age-specific vulnerabilities to a number of microorganisms…

From Background on Risk Characterization of Propylene glycol

….Surveillance in routine clinical practice has shown that currently available

medicines that contain propylene glycol are not associated with an increase

incidence of adverse effects…

Mansoor Khan 2014 2

1

Turner et al., Adv Drug Deliv Rev. 2013 Nov 13. pii: S0169-409X(13)00262-7

Risk assessment of neonatal excipient exposure: Lessons from food

safety and other areas.

From Conclusions

Many excipients have been used without adverse events in the newborn

period and excipients will continue to be required in this age group. Rational

medicine use will depend on structured risk assessment…

We advocate a structured approach to identifying relevant information and

acknowledging uncertainties. We envisage that this will allow regulators,

manufacturers and clinicians to avoid or use excipients appropriately

Conflicts:

None: 15 authors from major hospitals and universities in UK, France,

Ireland, Estonia. Some are members of MHRA and EMA

FDA Approved

Products – Over

a 100 regulated

products in use


Pediatrics Product with Propylene Glycol – Sold in

Market

• Product 1 - >100,000 units/mo since 2007

• Product 2 - >15,000 units/mo since 2007

• Product 3 - .5000 units/mo since 2007

Too many to list all of them here….


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Composition of Some Compounding Vehicles

• Ora sweet contains water, sucrose, glycerin, sorbitol, flavouring, citric acid, sodium phosphate, methylparaben and potassium sorbate. pH 4.2

• Ora sweet SF contains purified water, glycerin, sorbitol, sodium saccharin, xanthan gum, flavouring, citric acid, sodium citrate, methylparaben, propylparaben, potassium sorbate. pH 4.2.

Mansoor Khan 2015

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Selection of Excipients

• Well known excipients – Monograph

– IIG List for adult products (http:/www.accessdata.fda.gov/scripts/cder/iig/index.cfm)

– Documented human use in the proposed level

– GRAS

• New excipients (Battery of tests needed) (http://www.fda.gov/cder/guidance/5544fnl.cfm)

Mansoor Khan 2015

http://www.fda.gov/cder/guidance/5544fnl.cfm

Inactive Ingredients Guide

• IIG lists the maximum amount of excipient used per dosage unit

– For multiple units, chronicity of dosing, maximum daily dose etc, the sponsors usually justify the use in the amounts used

• 21 CFR 314.94 (a)(9)ii states that “an applicant shall identify and characterize the inactive ingredients in the proposed drug products and provide information demonstrating that such inactive ingredients do not affect the safety or efficacy of the proposed drug product”

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How do we develop Pediatric IIG?

Mansoor Khan 2015

Guidance for Industry-Nonclinical studies for the safety

evaluation of pharmaceutical excipients

• May 2005

New excipient means any inactive ingredients

that are intentionally added to therapeutic and

diagnostic products, but that: (1) we believe are

not intended to exert therapeutic effects at the

intended dosage, although they may act to

improve product delivery (e.g enhance

absorption or control release of the drug

substance; and (2) are nor fully qualified by

existing safety data with respect to the currently

proposed level of exposure, duration of

exposure, or route of administration

Recommended strategies to qualify

new excipients

• Safety pharmacology – (ICH guidance S7A) –

potential pharmacological actions

• Excipient for short term use (14 or fewer days)

– Acute toxicity studies in rodent and mammalian non

rodent species

– ADME

– Genotox (ICH S2B)

– One month repeat dose study in both species

– Reproductive Tox (ICH S5A and S5B)

Excipient safety

• Excipient for intermediate term use (2 wks to 3 months)

– All the previous tests, except a three month repeat dose study instead of the one month study

• Excipient for long term use (>3 months)

– All the above tests except a 6-month repeat dose study instead of 3-month

– Other tests as recommended

• 2-Year Carcinogenecity tests

• For non oral excipients, other requirements

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Taste of Drugs

• Unpleasant and bitter - Alkaloidal subgroups/N- containing: e.g., pyrroles, pyrrolidines, quinolines, tropanes, imidazoles, purine, pyridines, steroids, alklylamines

• Astringents - Tannin sub-group/Polyphenols and non-nitrogens: gallates, pyrrolgallals, catechols etc.

• Bland taste - Lipid groups: Palmitates, stearates, caprates, laurates etc.

• Aromatic but bitter - Volatile oil groups: Limonene, menthol, carvone etc.

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Taste of Drugs

• Sweet - Glycerhitinic acids and carbohydrate

groups: Generally low MW sugars are sweet,

and high MW compounds are tasteless/bland

• Very bitter - Glycoside groups: Anthraquinones

(many antibiotics), cardiac glycosides, tropanes,

steroids. Aromatic - flavanoid and aldehydic

glycosides

Mansoor Khan 2015

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Examples of Bitter Tasting Drugs

• Anti-AIDS: Ritonavir, lopinavir, tenofovir

• Anti-malaria: Chloroquine

• Anticonvulsant: Lamotrigine

• Antihistamines: Brompheniramine

• Antibiotics: Amoxicillin, clindamycin, doxycycline

• Corticosteroids: Prednisone, Prednisolone and

many others..

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Methods for Taste Masking of Drugs • Flavor Enhancers: Natural and artificial - Cherry,

peppermint, bubble gum, orange, vanilla etc.

• Sweeteners: Saccharin, sucrose, fructose

• Coating: Acrylates, celluloses, others

• Complexation: Amberlite, cyclodextrins, tannates – Risperidone

• Salt Formation or Cocrystals: Lamotrigine, Cetirizine HCl, Hydrocodone bitartarate

• Pro-drug: Clindamycin Palmitate HCl, Tenofovir disoproxil fumarate

Mansoor Khan 2015

FDAs`Internal Pediatric Drug Taste-Masking Approaches

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Understanding and

Verification of the

selective formulation

approaches

Taste masking by

Complexation i.e.

Respiridone, Oseltamivir ,

Chlorpheniramine,

Brompheniramine

Taste Masking by

Drug Coating i.e.

Clindamycin HCL

Mansoor Khan 2015


Oseltamivir Phosphate (Drug)

Amberlite IRP 64 (Resin)

Drug: Resin Phy. Mix 1:1




Drug: Resin Comp 1:1




Differential scanning calorimetry (DSC)


Fourier Transform Infrared Spectroscopy (FTIR)


010000

20000

30000

40000

50000

60000

Counts

10 20 30 40 50

2Theta (Coupled TwoTheta/Theta) WL=1.54060

Oseltamivir Phosphate

Phy.Mixture 1:1

Phy.Mixture 1:2

Phy.Mixture 1:4

Phy.Mixture 1:6

Complex

1:6

Complex 1:4

Complex 1:2

Complex 1:1

Amberlite IRP 64

Powder X-Ray Diffraction (PXRD)


-0.2

0

0.2

0.4

0.6

0.8

1 Drug

Amberlite PM11

C11 C12

PM12

C14

PM14 PM16

C16

PLS Images of the Complexes and Physical Mixtures


0

20

40

60

80

100

120

0 10 20 30 40 50 60 70

Time (Min)C

um

ula

tive %

Dru

g R

ele

ase

PM11 C11 PM12 C12 PM14

C14 PM16 C16

0

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5 10 15 20

Time (Sec)

% D

rug

Re

leas

e

C11 C12 C14 C16

Complex Refer

ences

Distanc

es

p-

value

Pattern

discrimination

index (%)

Complex

1 Drug 85 0.07 95.23

Complex

2 Drug 130 0.05 97.63

Complex

4 Drug 154 0.02 98.3

Complex

6 Drug 263 0.01 98.95

Dissolution and Taste masking of oseltamivir phosphate

pH1.2 pH6.8


Mansoor Khan 2015 43

Taste Masking By Coating – an Internal FDA Study

• Solution of Drug and Binder spray coated onto the

substrate by fluidized-bed process

– Drug: Clindamycin Palmitate HCl (CPH)

– Binder: HPMC

– Substrate: MCC

• Eudragit L30D55 used as taste masking polymer


Coating Process

Inert

Substrate

Taste-masking

Polymer Layer

Seal Coat


Results of Drug Release Studies


New Technologies to Monitor Coating EndPoint

2500

API

20

16

12

8

4

0

% Wt Gain

-0.2

0.0

0.2

0.4

0.6

0.8

1100 1300 1500 1700 1900 2100 2300

Wavelength (nm)

NIR

Ab

so

rban

ce

Increasing API Peak

Characteristic

API peak

Pure API


E-Tongue Analysis of CPH Coated MCC Formulations


Taste-masked Orally Disintegrating Tablets

DPQR FDA Study, Tawakkal et al., Pharm. Dev, and Tech.,

2009;14(4):409-21.


• Through a collaborative multidisciplinary approach, progress can be made to provide medications for all ages within the pediatric population

• Well controlled, hypothesis-driven proactive research, not anecdotal data is needed for the exclusion of most commonly used excipient

• New excipients need to be qualified with safety evaluations

• Oral liquids continue to be the most popular pediatric dosage forms

• IIG needs to be developed for excipients used in pediatrics

• Many approaches exist to mask the taste of bitter drugs


Conclusions

Pediatric Formulations: Need For New Excipients*

Documents