Download What is a peptide?

Thinking beyond the Tablet –
Enabling Formulation Development for
non-oral routes
Liping Zhou
Ipsen BioSciences
Routes of Drug Delivery
the preferred route
Factors governing the choice of route:
2
•
Local vs. systemic effect
•
Drug properties (physical & chemical)
•
Drug metabolism
•
Rapidity of the desired response
•
Rate & extent of absorption from
various routes
•
Accuracy of the dosage
•
Convenience and patient centricity
Routes of Drug Delivery
EFFECTS
LOCAL
SYSTEMIC
Internal
Oral
Sublingual (buccal)
Rectal
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Parenteral
Injections
(IV/IM/SC/ID…)
Inhalational
transdermal
Intranasal
Ocular
Mucosal-throat
Vaginal
Inner-ear
Inhalational
Transdermal
Intrathecal
……
Routes of Drug Delivery
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What can we do beyond oral routes?
Drug properties
Medical
needs
Route of
administration
Case examples:
Suitable delivery devices
-- sustained release of peptide drugs
-- device-aid controlled release
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Example#1:
PEPTIDE FORMULATION
DEVELOPMENT FOR SUSTAINED
RELEASE
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Why Peptides?
Craik et al., Chem Biol Drug Des., 2013, 81(1):136-47.
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What is a peptide?
It is not a large small
molecule:
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
It is not a small protein:
Molecular weight >>500
Amorphous
Many are amphiphilic
Tendency to self aggregate
Surface activity
Maximum instability
 Number of residues is usually less than 50
 Lack of organized tertiary or higher order structure
 Some amount of secondary structure, likely to be
metastable
 Fluxional behavior. There may be rapid inter-conversion
of many metastable conformations
 Less common motifs, such as 310 helices (in comparison
with a-helices)
 Side chains are fully solvent exposed – subject to
degradation
Challenging to formulate!
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Why Peptides?
40-49
With sustained release form
30-39
Glatiramer (COPAXONE)
Leuprolide (LUPRON) (9-mer)
20-29
1-9
Goserelin (ZOLADEX) (10-mer)
Octreotide (SANDOSTATIN) (8-mer cycl.)
Teriparatide (FORTEO) (34-mer)
10-19
Exenatide (BYETTA) (39-mer)
Triptorelin (DECAPETYL) (10-mer)
Desmopressin (9-mer cycl.)
Size distributions of peptide drugs on the market
in 2010 (in terms of amino acid numbers)
Bivalirudin (ANGIOMAX) (20-mer)
Eptifibatide (INTEGRILIN) (6-mer cycl.)
Calcitonin (MIACALCIN) (32-mer)
Craik et al., Chem Biol Drug Des., 2013, 81(1):136-47.
Lanreotide (SOMATULINE) (8-mer cycl.)
Enfuvirtide (FUZEON) (36-mer)
0
500
1000
1500
2000
2500
3000
3500
Worlwide Sales (US $ Millions)
Global annual sales of major peptide drugs
Peptide Therapeutics Foundation, 2010, “Development Trends for Peptide
Therapeutics“
Routes of delivery of marketed peptide
products (PharmacircleTM)
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Lews AL, Richard J; Ther. Deliv. (2015), 6, 149-163
Sustained Release of Peptide Drugs
 Micro particulates
 Depot injections

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PLGA based rod implants
In situ gel formation due to peptide self assembly
Thermo gelling system
Polymer-tocopherol conjugate based depot
FluidCrystal (naturally occurring polar lipids) self-assembly system
 Device-aid release control
 Other emerging technologies
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Polymer micro-particle design
PLGA: poly
lactic and
glycolic acids
copolymer
Mitragotri et. al.,
Nature
Reviews/Drug
Discovery, 2014,
13, 655
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Example: SOM230
 Pasireotide (SOM230) is a
cyclohexapeptide.
 For chronic disease, bid SC
injections may not be
convenient
 Long-acting release (LAR)
was achieved by less soluble
salt form with biodegradable
polymers – once-monthly IM
administration
 Drug
release
rate
is
controlled in LAR with less
peak-to-trough
fluctuation
than sc injections, thereby
minimizing adverse effects
 “Burst effect”
Dietrich et. al., Eur J Endo (2012), 166, 821
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Effect of particle size on particle disposition
 Particulates do not across most epithelial or endothelial cells
 Particulates greater than 10mm do not redistribute from an IM depot
 Particulates greater than 0.2mm do not leave the vascular system
(except via endocytosis)
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Depot injections

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PLGA based rod implants
In situ gel formation due to peptide self assembly
Thermo gelling system
Polymer-tocopherol conjugate based depot
FluidCrystal (naturally occurring polar lipids) self-assembly
system
carrier
API
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compliance
Example: PLGA based rod implant – Goserelin acetate
carrier
API
 SC administration of PLGA biodegradable
implant (rod)
 Ready-to-use drug product
 Stable peptide/polymer
 One-month and three-month implants
available
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http://my-journal-entries.blogspot.com/2007/11/attended-urologists-surgery-in-st.html
compliance
Example: liquid based implant – Eligard
carrier
API
compliance
 Ease of administration
 The liquid drug product solidifies in the
body and slowly releases the drug over
time as the polymer is degraded by
normal biological processes
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http://www.medscape.org/viewarticle/438957_4
carrier
Physical Stability of Peptides
API
Jorgense et. al., Expert opin. Drug deliv. (2009), 6(11),1219
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compliance
carrier
Physical Stability of Peptides
API
compliance
 Colloidal Stability
 How strong are API-API interactions?
 Interfacial Stability
 Does exposure to interfaces cause
damage?
 All 3 aspects are
closely related
 They are linked to
immunogenicity*
 Conformational Stability
 Is the 3-D structure maintained?
* (1) Wang et al., Int J Pharm, 2012, 431, 1-11; (2) Ratanji et al., J Immunotox, 2014, 11,
99-109; (3) den Engelsman et al., Pharm Res, 2011, 28, 920-933
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carrier
Physical Stability of Peptides
API
compliance
Aggregates are complex entities
 Aggregates can be caused by:
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Impurities
Stress
Batch to batch variation
formulation
Different manufacturing procedures
 Not all aggregates are the same:
 The aggregates exist as an aggregate mixture, rather than a single form
 The size of the aggregates can be very small (not readily detectable) to be in
the subvisible range
 Aggregates may not have a consistent profile through product lifecycle:
 The time to reach thermodynamic stable stage varies.
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carrier
Sustained Release of somatuline
Nanofabrication by molecular self-assembly
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API
compliance
Extended release
Sustained release
Autogel
Suspension of PLGA micro particle
monthly
10-14 days
SC
IM
Pre-filled syringe
Powder in a vial + solvent in a vial
Re-constitution required prior to injection
WFI + acetic acid (for pH
adjustment)
Mannitol
Carmellose Sodium
Polysorbate 80
Sustained Release of somatostatin analogues
Nanofabrication by molecular self-assembly
 Spontaneously self-assemble into mono-disperse nanotubes.
Pouget et. al., JACS (2010), 132, 4230
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Peptide Aggregation
Degarelix – mechanism of fibrillation
 The gelling process is
mainly influenced by
the concentration of
degarelix, time,
temperature, salt
content and proteins.
http://www.researchgate.ne
t/profile/Gregoire_Schwach
/publications
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Peptide Aggregation
Sustained release of degarelix via gel formation
Degarelix, a potent peptide self-depoting GnRH receptor blocker
FDA approval: Dec 24, 2008; EMA approval: Feb 19, 2009
Polarization microscopy
schematic illustration
 After administration, in contact with body fluids such as plasma, degarelix
spontaneously forms a gel (naturally forming prolong-release form)
http://www.researchgate.net/profile/Gregoire_Schwach/publications
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Peptide Aggregation
Sustained release of degarelix via gel formation
Long acting of the degarelix depot
 Gradual release of monomeric functional analogs at termini  controlled & slow release
 No apparent toxicity to dermal cells observed
http://www.researchgate.net/profile/Gregoire_Schwach/publications
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Peptide Aggregation
Case example: changes caused by fluorescent tag
ID
Peptide A
Sequence
30 AA
Solubility
1mg/mL in water
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Peptide B
TAMRA-Peptide A
1mg/mL in DMSO
Peptide Aggregation
Case example: changes caused by fluorescent tag
 Data collected using SECMALS
Mn=8.8X104 (22-23mer)
 10 times higher concentration
used for un-tagged peptide (5
mg/mL vs. 0.5 mg/mL);
Mn=5.6X104
 Aggregation observed with the
tagged peptide only
Solid line: LS signal
Dotted line: calculated molar mass
Red: Peptide B (tagged peptide)
Blue: Peptide A
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Peptide Aggregation
Case example: changes caused by fluorescent tag
Peptide A
Peptide B
Rh=4.02±0.25nm
Rh <0.5nm
 Data from QELS
 Size of the aggregate determined
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Peptide Aggregation
Case example: concentration dependent aggregation
Peptide C: a 39 aa peptide with lipid at the N-terminal
1 mg/mL in PBS
0.1 mg/mL in PBS
0.01 mg/mL in PBS & PBS
control
 Data from DLS
 Aggregation is concentration dependent
 Aggregates are not necessarily uniform; multiple forms can co-exist
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Example#2:
DEVICE-AID DRUG DELIVERY
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Novel Delivery & Patient Centricity
Convenient & personalized
Insulin
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Delivery Devices – controlled release
External pump
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Infusion pumps used in
hospital
settings
delivering
aqueous
solutions via existing IV
lines
MiniMed-Medtronic SC
insulin infusion
Pump + bio-sensor +
electronics: Enabling the
delivery of the right dose
at the right time
Implantable pump
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Duros (Alza) osmotic pump
Viadur
leuprolide
acetate
implant, 12 months dose
Telemedicine: Chip
based delivery

API stability at 37C over
dosing period is required
Limited
internal
volume:
~150uL;
high
drug
concentration
Titanium tube administered by
a trocar / minor surgery;
remove through minor incision
Release rates are independent
of
agent
properties
or
environmental conditions

A self-contained hermeticallysealed device that can store
100’s of therapeutic dose.
Chips are communicated with
over a special frequency
Drug administration or dose
change is controlled with a
code; cells are opened
individually
Bidirectional communications
link between the chip and the
receiver enables the update
of information including dose
delivery, battery life etc.
Delivery Devices – controlled release
• Evaluation of the Duros (Alza) osmotic pump in
rodent study
API #1
API #2
Poor PK outcome
Decreased API release rate
due to chemical degradation
Constant release of
the API within the
required time-frame
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Delivery Devices – controlled release
• Evaluation of the Duros (Alza) osmotic pump in
rodent study
API#3
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•
No major chemical degradation found within the 7-day period.
•
Temperature dependent gelling has been identified – current formulation
is not suitable for osmotic pump.
Nose-to-Brain Drug Delivery
Classical devices for local and systemic
delivery. Devices often commercially
established,
fulfilling
regulatory
requirements; however limited ability of
nose-to-brain delivery.
Nasal spray pumps
Single dose
Multiple dose
Pressurized
Advanced
http://www.impelneuropharma.com/pod-technology/
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Innovative device designed
for nose-to-brain delivery.
Device has not established
commercially and fulfilment
for regulatory requirements is
needed.
Alternative (POD)
Nose-to-Brain Drug Delivery
Impel Neuropharma’s Pressurized Olfactory Device (POD) for
nose-to-brain peptide delivery, bypassing BBB.
Delivery of MAG3 (a technetium-99m labeled 3-aa peptide) with POD:
 POD administration led to significantly higher MAG3 signal in all brain regions examined.
 The POD device technology results in greater than 50 % deposition of drug in the olfactory
region of the nasal cavity, whereas standard devices deposit < 5 %.
http://www.impelneuropharma.com/pod-technology/
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Conclusions
 Non-oral routes provide alternatives to improve patient centricity and quality of
life. Innovative technologies made the non-oral deliveries of drugs more
convenient, and/or more effective. Early consideration of drug delivery
strategy can improve the compatibility of new drug products.
 Enabling formulation development is essential to optimize the efficacy and
safety profiles for each API
 Understanding the benefits and limitations of each delivery systems to enable
the design for delivery.
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