pediatric formulations: need for new excipients*
TRANSCRIPT
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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
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Core Regulatory Tenet
Regulatory
Agency’s
Expectations
Facilitate
Accessibility
Efficacy Safety
Quality
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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
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• Draft Guidance for Industry Pediatric Study Plans, July 2013: http://inside.fda.gov:9003/downloads/CDER/OfficeofNewDrugs/ImmediateOffice/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
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– 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)
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FDA Collaboration with NIHCD
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0
5
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1
1/3
3
?
2
2/4
4
BCS
0
20
40
60
80
100
120
140
160
Tablets Capsules Injection Solution
Nu
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Dru
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ou
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BCS
Top Selling Drugs in US Market Bearing Pediatric Use Information in Label
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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.)
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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
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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
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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
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Some Solubilization Methods for Poorly Soluble (BCS 2)
Compounds
• Cosolvents
• Salt formation
• Complexation
• Surfactants
• Nanosizing or micronizing
• Amorphous compounds
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JBreitkreutz, J. Boos, Exp. Opin. Drug Deliv. 4: 37-45 (2007) 14 Mansoor Khan 2015
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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
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• 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
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Ruiz et al., Pediatric formulation issues identified in pediatric
investigation plans, Expert Rev. Clin. Pharmacol., Early Online 1-
6 (2014)
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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
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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…
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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 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
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FDA Approved
Products – Over
a 100 regulated
products in use
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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.
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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)
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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?
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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
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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)
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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
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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
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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
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Oseltamivir Phosphate (Drug)
Amberlite IRP 64 (Resin)
Drug: Resin Phy. Mix 1:1
Drug: Resin Phy. Mix 1:2
Drug: Resin Phy. Mix 1:4
Drug: Resin Phy. Mix 1:6
Drug: Resin Comp 1:1
Drug: Resin Comp 1:4
Drug: Resin Comp 1:6
Drug: Resin Comp 1:2
Differential scanning calorimetry (DSC)
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Fourier Transform Infrared Spectroscopy (FTIR)
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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)
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-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
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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
5
10
15
20
25
30
35
40
45
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
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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
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Coating Process
Inert
Substrate
Taste-masking
Polymer Layer
Seal Coat
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Results of Drug Release Studies
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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
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E-Tongue Analysis of CPH Coated MCC Formulations
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Taste-masked Orally Disintegrating Tablets
DPQR FDA Study, Tawakkal et al., Pharm. Dev, and Tech.,
2009;14(4):409-21.
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• 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
50 Mansoor Khan 2015
Conclusions