Transcript STABILITY STUDIES - WHO | World Health Organization

IMPROVING ACCESS TO APPROPRIATE
PAEDIATRIC ART FORMULATIONS
Development pharmaceutics
– formulations for paediatric ARVs
János Pogány, pharmacist, Ph.D.,
UNICEF/MSF/WHO, Geneva, 02 November 2004
E-mail: [email protected]
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FIFTH INVITATION FOR
EXPRESSION OF INTEREST
(EOI)
HIV and related diseases
Rev. 27/10/04
NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS
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Abacavir
Didanosine
Lamivudine
Stavudine
Tenofovir
Zidovudine
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NON-NUCLEOSIDE REVERSE
TRANSCRIPTASE INHIBITORS
 Efavirenz
 Nevirapine
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PROTEASE INHIBITORS
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Indinavir
Lopinavir + Ritonavir Nelfinavir
Saquinavir
Ritonavir
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FIXED DOSE COMBINATIONS
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Lamivudine + Stavudine
Lamivudine + Stavudine + Efavirenz
Lamivudine + Stavudine + Nevirapine
Lamivudine + Zidovudine
Lamivudine + Zidovudine + Efavirenz
Lamivudine + Zidovudine + Nevirapine
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BASIC REQUIREMENTS
SAFETY (no innovator for FDC-FPPs)
EFFICACY (no innovator for FDC-FPPs)
QUALITY (once safe and effective doses are
established, FDC-FPPs can be developed and
bioequivalence demonstrated)
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POTENTIAL PAEDIATRIC
APPLICATIONS
Innovator Antiretroviral
Finished Pharmaceutical
Products
Videx EC 125mg, 200mg, 250mg and
400mg Gastro-resistant Capsules
 Each gastro-resistant capsule, hard contains 125 mg, 200 mg, 250 mg
or 400 mg of didanosine.
 Sodium carmellose, diethyl phthalate, 30% methacrylic acid copolymer
dispersion (EUDRAGIT L30D-55), sodium starch glycolate and talc.
 Capsule shell - gelatin, sodium laurilsulfate, colloidal anhydrous silica
and titanium dioxide (E171).
 Capsule shell imprints (edible ink) shellac, ammonium hydroxide,
propylene glycol, simethicone and red iron oxide
 2 years
 Do not store above 25°C.
 Polyvinyl Chloride/Polyethylene/ACLAR/Aluminium foil blisters
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Videx EC 125mg, 200mg, 250mg and
400mg Gastro-resistant Capsules
Children: Safety data for children were generally similar to
those seen in adults. A higher haematotoxicity has been
reported with the combination with zidovudine compared to
didanosine monotherapy. Retinal or optic nerve changes have
been reported in a small number of children usually at doses
above those recommended. It is recommended that children
on didanosine treatment undergo dilated retinal examination
every 6 months or if a change in vision occurs.
There are no specific pharmacokinetic data from children
treated with Videx gastro-resistant capsules.
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SUSTIVA 30 mg/ml oral solution
 Each millilitre contains 30 mg efavirenz
 Medium chain triglycerides, benzoic acid (E210) and
strawberry/mint flavour.
 3 years.
 The oral solution should be used within one month of first
opening the bottle.
 No special precautions for storage.
 HDPE bottles with a child-resistant polypropylene closure
containing 180 ml of oral solution. An oral syringe with a
push-in bottle-neck adapter is included in the carton.
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Epivir 10 mg/ml oral solution
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Oral solution containing 10 mg/ml of lamivudine
Sucrose 20 %(3 g/15 ml)
Methyl parahydroxybenzoate
Propyl parahydroxybenzoate
Citric acid Anhydrous
Propylene glycol
Sodium citrate
Artificial strawberry flavour Artificial banana flavour
Purified water
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Epivir 10 mg/ml oral solution
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2 years
Discard the oral solution one month after first opening.
Do not store above 25°C.
240 ml oral solution in a white high density polyethylene
(HDPE) bottle, with a child resistant closure. A 10 ml
polypropylene oral dosing syringe and a polyethylene
adapter are also included in the pack.
 Zeffix oral solution contains 5 mg/ml lamivudine
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Epivir 10 mg/ml oral solution
Children
 Three months to 12 years of age: the recommended dose
is 4 mg/kg twice daily up to a maximum of 300 mg daily.
 Less than three months of age the limited data available
are insufficient to propose specific dosage
recommendations (see section 5.2)
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VIRAMUNE 50 mg/5 ml oral
suspension
 Oral suspension containing 10 mg/ml of nevirapine (active
substance) as 10.35 mg/ml nevirapine hemihydrate.
 VIRAMUNE 50 mg/5 ml oral suspension is a white to
off-white homogenous suspension.
 Carbomer, methyl parahydroxybenzoate, propyl
parahydroxybenzoate, sorbitol, sucrose, polysorbate 80,
sodium hydroxide and purified water.
 2 years.
 The product should be used within 2 months of opening.
 No special precautions for storage.
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VIRAMUNE 50 mg/5 ml oral
suspension
 White high density polyethylene (HDPE) bottle with two
piece child-resistant closure (outer shell white high
density polyethylene, inner shell natural polypropylene)
with a low density polyethylene (LDPE) foam liner. Each
bottle contains 240 ml of oral suspension.
 Clear polypropylene 5 ml dispensing syringe with silicone
rubber piston seal.
 Clear low density polyethylene bottle-syringe adapter.
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VIRAMUNE 50 mg/5 ml oral
suspension
 Infants under the age of 3 months: safety
data is available from clinical trials up to 6
weeks of treatment in 179 newborns and
infants < 3 months of age (see section 4.6).
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VIRAMUNE 50 mg/5 ml oral
suspension
Patients aged 2 months up to 8 years
 The recommended dose for patients 2 months up to 8
years is 4 mg/kg once daily for two weeks followed by 7
mg/kg twice daily thereafter. The total daily dose should
not exceed 400 mg for any patient.
Patients aged 8 years up to 16 years
 The recommended dose for patients 8 years up to 16 years
is 4 mg/kg once daily for two weeks followed by 4 mg/kg
twice daily thereafter. The total daily dose should not
exceed 400 mg for any patient.
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Zerit® 200 mg powder for oral solution
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The reconstituted solution contains 1 mg of stavudine per ml.
Cherry flavour
Methylparaben
Propylparaben
Silicon dioxide
Simethicone
Sodium carmellose
Sorbic acid
Stearate emulsifiers Sucrose
2 years.
After reconstitution with water, store the solution in tightly
closed bottles at 2°C to 8°C.
 HDPE bottle with child resistant screw cap, fill mark (200 ml
of solution after constitution) and measuring cup.
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Retrovir® 100 mg/10 ml, oral solution
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10 ml of solution contains: Zidovudine 100 mg
Retrovir 100mg/10ml oral solution/syrup:
A clear, pale yellow, strawberry-flavoured, sugar-free oral solution.
The pack contains an oral-dosing syringe which should be fitted to the bottle
before use.
Maltitol solution
Glycerol
Citric Acid
E211 Sodium Benzoate
Saccharin Sodium
Flavour Strawberry
Flavour White Sugar
Purified Water
2 years. Discard oral solution 1 month after first opening bottle.
Do not store above 30°C. Store the bottle in the original outer carton.
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Retrovir® 100 mg/10 ml, oral solution
 Retrovir Oral Solution/Syrup:
 200ml amber glass bottle with a plastic cap and polyethylene
wad. A 10ml oral-dosing syringe is included in the pack, with an
adaptor, which should be fitted to the bottle before use.
 Retrovir Oral Solution/Syrup (Neonate Pack):
 200ml amber glass bottle with a plastic cap and polyethylene
wad. A 1 ml oral-dosing syringe is included in the pack, with an
adaptor, which should be fitted to the bottle before use.
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Combivir film-coated tablets
 Each film-coated tablet contains 150 mg lamivudine and 300 mg
zidovudine.
 Tablet core: Microcrystalline cellulose (E460), sodium starch
glycollate, colloidal silicon dioxide, magnesium stearate
 Tablet film coat: Hypromellose (E464), titanium dioxide (E171),
macrogol 400, polysorbate 80
 2 years
 Do not store above 30°C
 Tamper-evident cartons containing opaque polyvinyl
chloride/foil blister packs or white high density polyethylene
(HDPE) bottle with a child-resistant closure. Each pack type
contains 60 film-coated tablets.
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TRIZIVIR film-coated tablets
 TRIZIVIR (300mg of abacavir as abacavir sulfate, 150mg
lamivudine and 300mg zidovudine) film-coated tablets.
 Core: microcrystalline cellulose, sodium starch glycollate
(type A), magnesium stearate.
 Coating: Opadry Green 03B11434 containing:
hypromellose, titanium dioxide, polyethylene glycol,
indigo carmine aluminium lake, iron oxide yellow.
 2 years
 Do not store above 30°C
 opaque PVC/Aclar blister packs HDPE bottles
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INNOVATOR PAEDIATRIC FPPs
 Efavirenz 30mg/ml oral solution
 Lamivudine 10mg/ml oral solution
 Nevirapine 50mg/5ml oral suspension
 Stavudine 200mg powder for oral solution
 Zidovudine 100mg/10ml, oral solution
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POTENTIAL PAEDIATRIC
APPLICATIONS
Generic Antiretroviral
Finished Pharmaceutical
Products
Potential paediatric dosage forms for
FDC-FPPs
 Powder for oral suspension (priority from
pharmaceutical development and stability points
of view)
 Film-coated tablets (priority from economic,
pharmaceutical development and stability points
of view)
 Powder for oral solution
 Chocolate pastilles (expensive and
storage/bioavailability may be a problem in
tropical climates and hot seasons)
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ILLUSTRATIVE R+D ISSUES
 Key physicochemical characteristics (e.g., water
content, solubility, particle size, etc.) of the APIs
that can influence the performance of the FPP
should be optimized and supported by
experimental data.
 The compatibility of APIs with each other should
be studied and the results documented.
 The compatibility of the APIs with excipients
should be documented.
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ILLUSTRATIVE R+D ISSUES
A discriminating dissolution method should be
developed for the final composition of the FPP.
Limits should be set for each API in fixed-dose
FPPs. The dissolution method should be
incorporated into the stability and quality control
programmes. Multipoint dissolution profiles of both
the test and the reference FPPs should be compared.
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% dissolved
HYPOTHETICAL DISSOLUTION
PROFILE OF A 2-FDC FPP
120
100
80
60
40
20
0
Series1
Series2
Series3
Series4
0
15
30
45
60
minutes
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EXISTING FDC-FPPs
Bracketing and Matrixing
Multiple strengths of identical
or closely related formulations
BRACKETING
Examples include but are not limited to
1. tablets of different strengths manufactured by
compressing varying amounts of the same
granulation, and
2. oral solutions/suspensions of different
strengths with formulations that differ only in
minor excipients (e.g., colourants,
flavourings).
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MATRIXING
Examples include but are not limited to
1. tablets of different strengths manufactured
by compressing varying amounts of the
same granulation, and
2. oral solutions/suspensions of different
strengths with formulations that differ only
in minor excipients (e.g., colourants or
flavourings).
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SmPC and PIL
 The results from pharmacokinetic
investigations must be described briefly in
the SmPC of the FPP.
 The SmPC and package insert should be
specific with regard to the HIVinfections
which can be reasonably treated with the
FPP.
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CONCLUSIONS
 Safe and effective paediatric doses for FDC-FPPs,
SmPCs and PILs should come from (literature
survey of) clinical studies.
 Film-coated tablets and oral solutions or
suspensions can be developed in about 18 months,
if pre-formulation is started soon.
 Development can be accelerated if paediatric FDCFPPs have the same ratio of APIs and compositions
are essentially similar to those already registered in
the ICH region or prequalified by WHO.
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