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Dosage Form Options for the Oral Delivery
of Liquid Lipid-based Formulations: Key
Considerations for Selection, Benefits,
Limitations, and Future Prospects
CATALENT PHARMA SOLUTIONS
Presentation Outline
•
Overview of Dosage Form Options
—
Dosage Form Types, Designs and Compositions
—
Methods of Manufacture
•
Key Considerations for the Selection of a Suitable Dosage
Form
•
Summary of Benefits and Limitations
•
Future Prospects
—
Targeted Drug Release
—
Controlled Released of Drugs
—
Liquid Versus Solid LBDDS
1
Overview of dosage form options
Types of Dosage Forms
•
Soft Elastic Capsules (SECs)
—
—
—
—
•
Seamed SECs using Rotary Die Process
Seamless SECs using Drop Formulation Process
Gelatin Shells (SGC)
Gelatin-free Shells (GF-SEC)
•
Starch-Carrageenan
•
Starch
Liquid-filled Hardshell Capsules (LFHCs)
—
—
Gelatin Shells (HGC)
•
Gelatin with plasticizers (PEG)
Gelatin-free Shells
•
Hypromellose (HPMC)
•
HPMC with gelling aids
—
—
—
•
•
•
Carrageenan/KCl
Gellan gum/EDTA or Citric Acid
Pectin and glycerin
Pullalan (Carrageenan/KCl)
PVA copolymer (Carrageenan/KCl)
Starch
SEC and LFHC Dosage Forms: General Benefits
•
Minimal or no adverse impact on performance properties of
encapsulated lipid-based formulations
—
—
•
A wide variety of fill formulations with drugs solubilized or suspended
in liquid and semi-solid lipid-based excipients can be encapsulated
—
—
•
Excellent CU for low dose drugs
Better safety and containment
Direct filling of lipid-based formulations into capsule (pumpable at RT
or with application of heat) … no downstream processing necessary
—
—
•
Enhanced bioavailability
Improved stability
Reduced development times/costs
Facilitates easier process scale-up for larger batch sizes
Capsule shells are available with gelatin or plant-derived excipients
—
Global regulatory and consumer acceptance
Composition of a SEC
GELATIN
+
Plasticizer
water
Lipophilic,
Hydrophilic,
or
Mixed Vehicle
Colors,
Opacifiers
Solution, Suspension
or highly viscous
formula of Drug
SEC Method of Manufacture: Rotary Die Process
SEC Method of Manufacture: Drop Formation Process
Principle of seamless capsule production
Vibrator
Double Nozzle
Fill
Gel
Overflow of MCT
Supply of MCT
MCT
(Streamline Flow)
Seamless capsule
Shell Compositions of Commercially Available GF-SEC
Technologies
•
•
Starch-carrageenan shells
—
Vegicaps® Capsule (Catalent) is comprised of modified starch
(hydroxypropyl starch)/iota-carrageenan, plasticizer, sodium phosphate
dibasic buffer and water
—
SeaGel™ Capsule (FMC) is comprised of kappa-2-carrageenan or iotacarrageenan, a secondary film former or bulking agent (starch), optionally
a plasticizer, and a pH controlling agent
Starch shells
—
VegaGels™ (Swiss Caps) is comprised of an amorphous starch (GT 50%
amylopectin), water and at least one organic softener
SEC Method of Manufacture: Vegicaps® Capsules
SEC Method of Manufacture: SeaGels™
SEC Method of Manufacture: VegaGels™
US Patent 6,790,495
Design & Composition of a LFHC
Shell Composition
•
•
LFHC Design
Gelatin
—
Licaps® (Capsugel)
—
Coni-Snap® (Capsugel)
—
Qualicaps® Capsules
(Shionogi Qualicaps)
—
EMBROCaps® (Suheung)
HPMC
—
Vcaps Plus® (Capsugel)
—
Vcaps® (Capsugel)
•
—
Quali-V® (Shionogi Qualicaps)
•
—
HPMC/Gellan gum
HPMC/Carrageenan
EMBROCaps®-VG (Suheung)
•
HPMC/Pectin and glycerin
Richardson, et al., Tablets & Capsules, Jan 2007
12
Dipping Process for LFHC
The Manufacturing Process
Jones, 2008 AAPS Presentation, Atlanta,GA
Sealing LFHCs: Banding
Sealing LFHCs: LEMS
Richardson, et al., Tablets & Capsules, Jan 2007
Key considerations in the selection of a
suitable dosage form
Physical State of the Formulation
•
•
•
Liquid fills
—
Surface tension
—
Viscosity
Viscous liquid and semi-solid fills ⇒ Must be pumpable on the
filling equipment
—
Melting point and viscosity (temperature-viscosity profiles)
—
Shear thinning or shear thickening
Maximum filling viscosity
—
•
Suspensions
—
•
Up to 9,000 to 12,000 cps
Maximum particle size ~180 microns
Potential process issues
—
Sealing, stringing at filling nozzle, gravity flow feed systems, thermally
labile APIs
—
LFHC leaking ⇒ fill volume/MOC/equipment contamination
Physical State of the Formulation
Example: Extremely low viscosity, low surface tension vehicle
such as co-solvents and surfactants (n-methyl pyrrolidine)
• Potential impact on SEC
—
•
Sealing process ⇒ weak seals and leaking capsules
Potential impact on LFHC
—
Sealing process (banding or LEMS) ⇒ leaking capsules, lower fill volumes
—
Equipment contamination due to leakage ⇒ sealing problems/material on
outside of capsule ⇒ higher rejection rates
Example: High melting point fill formulation requiring hot filling
such as PEG 6000 (MP 60°C)
• Potential impact on SEC
•
—
Gelatin-free shell would be required
—
Temperature requirements for gravity feed or pumping
Potential impact on LFHC
—
Rapid dissipation of heat to prevent HGC sticking
—
Temperature requirements for gravity feed or pumping
Physical State of Formulation
Rheological profiles of high viscosity or high melting point
fill formulations
PEG 6000 vehicle, 40% Ibuprofen
SAIB vehicle, 40% Ibuprofen
80
8
7
G'
70
6
Viscosity
60
Viscosity
50
Pa
5
Pa
G'
Solid
4
40
3
30
2
20
1
10
0
0
50
55
60
65
70
Temperature, C
75
80
40
45
50
Temperature, C
55
60
Fill Formulation Melting Point: An Important
Property Influencing Dosage Form Selection
Liquid
40°C
Melting Point
of Fill
Formulation
Gelatin
SEC
20
Semi-Solid
LF HC
Gelatin-Free
SEC
75°C
Fill-Shell Dynamics
Fill-shell dynamics increase with fill formulation HLB/polarity (Types
II, III and IV)
H2O
Lipid-Based
Formulations
Solution or Suspension
or Semi-Solid
Surfactant
Low M.W.
H2O
Plasticizer
Type I
Type II
Type III A-B
Type IV
H2O
Low
Solvent
M.W.
Solvent
Fill-Shell Dynamics
•
SEC
—
—
•
Shell formulation variables (degrees of freedom) to optimize dosage
form/mitigate unwanted effects due to fill-shell dynamics
•
Gelatin or plant polysaccharide – type/amount
•
Plasticizer – type/amount
•
Water – amount
•
All 3 are varied to achieve desired compatibility
Fill formulation and process variables (degrees of freedom) to optimize
dosage form/mitigate unwanted effects due to fill-shell dynamics
LFHC
—
—
Shell formulation variables (degrees of freedom) to optimize dosage
form/mitigate unwanted effects due to fill-shell dynamics
•
Gelatin or HPMC
•
Capsule design provided by supplier
Fill formulation and process variables (degrees of freedom) to optimize
dosage form/mitigate unwanted effects due to fill-shell dynamics
Fill Formulation Melting Point and Polarity (HLB) As
Factors Influencing Dosage Form Selection
Liquid
Melting Point
of Fill
Formulation
Lipophilic
Amphiphilic
Hydrophilic
23
Semi-Solid
40°C
Gelatin-Free
Gelatin LF HC
SEC
SEC
75°C
Fill-Shell Dynamics: Excipient Incompatibilities –
Need to Perform Compatibility Studies
•
Low M.W. or shorter C chain ingredients (co-solvents, cosurfactants) can potentially plasticize the shell
•
Excipient compatibility varies with shell type (gelatin-based or
gelatin-free) and shell formulation
•
Lipid excipients are often a mixture of components some of which
can potentially plasticize the shell
•
Mechanical aspects (capsule design, shell thickness, seal quality,
etc.) of the dosage form and excipients often play an important role
in physical stability
Excipient Level
Excipient
SGC
GF-SEC
HGC
HPMC
Ethanol
Low
Low
High
High
Moderate
Moderate
Low
Low
Glycerin
Low
Low
Low
High
Water
Low
Low
Low
Low
Propylene glycol
Excipient Compatibility Studies: HGC
Ku, S., et al., International J. of Pharm., 386 (2010)
Excipient Compatibility Studies: HPMC
Ku, S., et al., International J. of Pharm., 386 (2010)
GF-SECs (starch/carrageenan shell) for Type IIIB and
IV Lipid Formulations (SEDDS and SMEDDS)
Self-emulsifying formulations can be formulated with higher
concentrations of “low” m.w. ingredients that plasticize gelatin-based
SECs or LFHCs
—
Co-solvents
—
Solubilizers
—
Penetration enhancers
Example ingredients: octanoic acid (caprylic acid, C8), propylene
glycol, sodium caprate (penetration enhancer), lauric acid and its
sodium or potassium salt
Gelatin-free
versus gelatin
SEC with ‘neat’
caprylic acid
Chemical Stability Requirements: Oxidation
Minimizing oxidation of labile API and fill ingredients
•
Limit exposure of API and fill ingredients to oxygen
—
Closed manufacturing process/equipment with inert gas flush
—
Protective properties offered by SECs and LFHCs
•
SEC – no headspace and low oxygen transmission rates through shell
•
LFHC – use inert gas to displace oxygen in capsule headspace and low
oxygen transmission rates through shell
•
Addition of anti-oxidants to the fill formulation
•
Utilize protective primary packaging
Chemical Stability Requirements: Oxidation
Oxygen transmission rates: SEC and LFHC Shells
•
•
SEC shell
—
Plasticizer type and water levels in the shell
—
Shell thickness: ~500 microns
LFHC shell
—
Proper sealing of body and cap
—
Shell thickness: ~100 microns
SEC (right) has larger channels than HGC, as shown in these freeze etchings taken
from a scanning electron microscope (1.6 x 10-6 magnification).
Oxygen Transmission Rates: SEC and LFHC Shells
•
Effect of plasticizer type on oxygen permeability of SEC
shells:
Glycerol > Sorbitol Special Blend > Polysorb
•
Oxygen permeability of SEC films (plasticized with glycerol)
at a thickness of approximately 500 microns:
< 5 ml O2/m2 d bar (20°C/30%RH)
•
Oxygen permeability of HGC films at a thickness of
approximately 100 microns:
< 10-20 ml O2/m2 d bar (20°C/30%RH)
Commercialized SEC Products Containing APIs That
Undergo Oxidation
•
Vitamin D Analogs
•
Retinoids
•
Omega-3 Oils
•
Other Oxygen Sensitive Vitamins (A, E, etc.)
Chemical Stability Requirements : Hydrolysis
Minimizing hydrolysis of labile API and fill ingredients
•
SEC Fill Moisture Content
— Oil
•
fill
•
During encapsulation ⇒ 0.1-0.3%
•
Following drying ⇒ 0.1-0.3%
LFHC Shell Moisture Content
— Gelatin-based
— HPMC
⇒ 13-16%
⇒ 2-5%
•
Lipid or hydrophilic semi-solid fills in a LFHC
•
Lipid semi-solid fills in a GF-SEC
Shell Rupture/Disintegration/Dissolution Times
In-vitro
•
Gelatin-based capsules generally faster than GF-SECs
(starch/carrageenan) or LFHCs (HPMC) (37°C) which exhibit a lag
time
—
Disintegration Time: SGC ⇒ 2–8 minutes and GF-SEC (starch/carrageenan)
⇒ 10–20 minutes
—
Disintegration Time: HGC faster than HPMC
•
HPMC gelling aids – HPMC fastest, HPMC/carrageenan slower,
HPMC/gellan slowest
•
HPMC disintegration/dissolution media – HPMC lag time greatest in pH
6.8 phosphate buffer, HPMC/carrageenan and HPMC/gellan affected by K
and Ca
•
HGC disintegration/dissolution media temperature – HGC does not
dissolve below (30°C)
Shell Rupture/Disintegration/Dissolution Times
In-vivo
•
•
Human scintigraphic studies (Cole, et al.)
—
HCG disintegration ⇒ 8–14 minutes
—
HPMC/gellan disintegration ⇒ 28–41 minutes
Human scintigraphic studies (Tuleu, et al.)
—
HCG disintegration ⇒ 7 minutes
—
HPMC disintegration ⇒ 9 minutes
•
No reported human PK profile difference between HPMC/carrageenan
and HPMC (Ku, et al.)
•
No reported dog PK profile difference in fed and fasted state with
HPMC (Ku, et al.)
Cole, E., Pharm. Res. 21 (2004)
Tuleu, C., Eur. J. Pharm. Sci. 30 (2007)
Ku, S., et al., International J. of Pharm., 386 (2010)
Shell Rupture/Disintegration/Dissolution Times:
Cross-linking
Minimizing cross-linking in gelatin-based SECs and LFHCs
• Fill excipients with low impurity levels (aldehydes, peroxides)
• Use high quality gelatin from reliable suppliers
• Minimize exposure of fill to oxygen
—
—
Closed manufacturing process/equipment in an inert gas atmosphere
Protective properties offered by SECs and LFHCs
• SEC – no headspace and low oxygen transmission rates
• LFHC – use inert gas to displace oxygen in capsule headspace
Eliminating cross-linking potential in SECs and LFHCs
• SECs
—
—
•
Modified starch/carrageenan
Starch
LFHCs
—
—
HPMC
HPMC/gelling aid
LFHC Spontaneous Cracking/Breaking
•
Failures (cracking/breaking) have been observed in the capsule cap
—
Capsule design
•
—
Manufacturing room conditions
•
—
High tensile stress areas and stress risers increase the incidence of
cracking/breaking
Higher RH’s increase the incidence of cracking/breaking
Fill formulation composition
•
Hygroscopic excipients and migration of ingredients into the shell causing
plasticization increase the incidence of cracking/breaking
LFHC Spontaneous Cracking: The Impact
of Cap Shoulder Thickness
Cracking observations after 4 hours with 41 percent DMA in
Cremophor EL fill
Fulper, D., et al., Tablets & Capsules 6, (2009)
LFHC Spontaneous Cracking: The Effect of Humidity
During Manufacture
Effect of humidity on capsule cracking
Fulper, D., et al., Tablets & Capsules 6, (2009)
LFHC Spontaneous Cracking: A Cascade of Events
Moisture gradient across
capsule shell wall when
filled with hygroscopic
material
Gelatin plasticity gradient
across capsule shell wall
when filled with
hygroscopic material
Fulper, D., et al., Tablets & Capsules 6, (2009)
Stress distribution across
capsule shell wall when
filled with hygroscopic
material
LFHC Design Considerations
Fulper, D., et al., Tablets & Capsules 6, (2009)
LFHC Design Considerations
Fulper, D., et al., Tablets & Capsules 6, (2009)
Fill Capacity/Size & Shape
SEC Ovals
2 Oval
minims: 1.5-1.8
cc: 0.092-0.1111
12 Oval
minims: 8.3-12.0
cc: 0.511-0.739
SEC Oblongs
3 Oblong
minims: 2.3-3.0
cc: 0.142-0.185
22 Oblong
minims: 18.3-22.0
cc: 1.109-1.355
SEC Rounds
1 Round
minims: 0.75-1.00
cc: 0.046-0.062
9 Round
minims: 7.0-9.0
cc: 0.431-0.554
LFHCs
Size
Body
volume
Liquid-fill
capacity
Total
volume
Liquid-fill
Air volume
00
0.93
0.84
1.16
0.32
4
0.21
0.19
0.25
0.06
All values in mL: Data Qualicaps
API Usage Requirements
SEC
• Lab-scale encapsulation machine (non-GMP)
—
•
Minimum fill required for Minicap Machine: 250 g
•
0.1%(w/w) – 250 mg
•
1%(w/w) – 2.5 g
•
10%(w/v) – 25 g
Full-scale encapsulation machine (GMP)
—
Minimum fill required for 7th Generation Machine: 750 g
•
0.1%(w/w) – 750 mg
•
1%(w/v) – 7.5 g
•
10%(w/v) – 75 g
LFHC
• No lower limit
Comparison of SGC versus GF-SEC: Benefits and
Limitations
Gelatin-based SEC
Gelatin-free SEC
SHELL COMPOSITION
• Gelatin, plasticizer, water, etc.
• Carrageenan (extract of red seaweed),
modified starch, plasticizer, water, etc.
FILL FORMULATION
OPTIONS
• Maximum fill temperature: 35°-40°C
(primarily liquids)
• Maximum fill temperature: 65°-75°C
(viscous liquids and semi-solids)
• Fill pH: slightly acidic to slightly basic
• Fill pH: slightly acidic to highly alkaline
• Type I – IV lipid formulations
• Type I – IV lipid formulations (potential
improvement for Type IIIB – IV)
COMPATIBLITY WITH
FILL EXCIPIENTS
• Wide range: lipophilic ⇒ hydrophilic
• Wide range: lipophilic ⇒ hydrophilic
• Potentially fewer limitations: low MW and
short-medium C chain lengths
(cosolvents/cosurfactants ⇒ SMEDDS)
SHELL
DISINT./DISSO.
• Fast, potential cross-linking
• Fast, short lag-time, no potential crosslinking
OXYGEN
TRANSMISSION RATE
• Minimal
• TBD
SMALL-SCALE
MANUFACTURE
• Minimum fill required: ~250 g (nonGMP)
• Minimum fill required : ~750 g
(nonGMP/GMP)
• Some limitations: low MW and shortmedium C chain lengths
• Minimum fill required : ~750 g (GMP)
• 100’s – 1000’s capsules
• 100’s – 1000’s capsules
RELIABLE LARGESCALE MANUFACTURE
• Accepted (Pharma & H&N products)
• Accepted (H&N products)
NDA APPROVED
PRODUCTS
• 49
• None – OTC/H&N only
Comparison of HGC versus HPMC LFHCs: Benefits and
Limitations
HGC
HPMC
SHELL COMPOSITION
• Gelain, water (13 – 16%)
• HPMC, HPMC/gelling aid, water (2 – 7%)
FILL FORMULATION
OPTIONS
• Maximum fill temperature: 75°C
• Maximum fill temperature: 75°C
• Fill pH: slightly acidic to slightly basic
• Fill pH: acidic to alkaline
• Type I – IV lipid formulations
• Type I – IV lipid formulations
• Wide range: lipophilic ⇒ hydrophilic
• Wider range: lipophilic ⇒ hydrophilic
• Some limitations: low MW and shortmedium C chain lengths
COMPATIBLITY WITH
FILL EXCIPIENTS
• Some limitations: low MW and shortmedium C chain lengths
• Better compatibility with low MW alcohols
• Incompatible with low MW alcohols
PHYSICAL STABILITY
• Potential brittleness/cracking at lower
shell moisture contents (environment,
hygroscopic fill excipients, capsule
design)
• Less affected at lower shell moisture
contents (environment, hygroscopic fill
excipients, capsule design)
SHELL
DISINT./DISSO.
• Fast, potential cross-linking
• Fast, short lag-time (varies based on gelling
aid), no potential cross-linking
OXYGEN
• Minimal
TRANSMISSION RATE
• Minimal (3X HGC)
MACHINABILITY
• Good machinability – improved quality
(tighter dimensional tolerances) with
lower reject rates
• Moderate machinability – improving quality
(dimensional tolerances less controlled)
with higher reject rates
RELIABLE LARGESCALE MANUFACTURE
• Accepted (H&N products)
• Accepted (H&N products)
NDA APPROVED
PRODUCTS
• 3
• None – OTC/H&N only
Comparison of SEC versus LFHC: Benefits and
Limitations
SEC
LFHC
SHELL COMPOSITION
• Gelatin/plant polymers, plasticizer, water, • Gelatin/plant polymers, water, etc.
etc.
FILL FORMULATION
OPTIONS
• Maximum fill temperature: 40°C (gelatin); • Maximum fill temperature: 75°C
75°C (gelatin-free)
• Type I – IV lipid formulations
• Type I – IV lipid formulations (GF-SEC
potential improvement for Type IIIB – IV)
COMPATIBLITY WITH
FILL EXCIPIENTS
• Wide range: lipophilic ⇒ hydrophilic
• Some limitations (fewer for GF-SEC): low
MW and short-medium C chain lengths
• Better compatiblity with low MW alcohols
• Wide range: lipophilic ⇒ hydrophilic
• Some limitations (fewer for HPMC): low MW
and short-medium C chain lengths
• Incompatible with low MW alcohols
SHELL FORMULATION
OPTIONS
• Gelatin/Gelatin-free: Varied depending on • Gelatin/Gelatin-free: Fixed
fill
• Design differences depending on supplier
OXYGEN
TRANSMISSION RATE
• Minimal
• Minimal (3X HGC)
IN-HOUSE
DEVELOPMENT
• Fill formulation – Yes
• Yes
• Shell/manufacture - No
• Advantageous for early, rapid, in-house
screening of lipid-based formulations
SMALL-SCALE
MANUFACTURE
• Minimum fill required: ~250 g (nonGMP);
minimum fill required : ~750 g (GMP)
• No lower limit
• 100’s – 1000’s capsules
SIZE/SHAPE
• Customized; greater maximum fill volume • Fixed; reduced maximum fill volume
RELIABLE LARGESCALE MANUFACTURE
• Accepted (Pharma & H&N products)
• Accepted (H&N products)
NDA APPROVED
PRODUCTS
• 49
• 3
Future prospects
Targeted Delivery
Targeted delivery using film-coated SECs and LFHCs
• Delivery applications
—
•
Post-gastric delivery of poorly soluble and/or poorly permeable compounds
Delivery approach
—
Utilize a functional film coating to deliver the formulation/API to the site of
absorption
—
Following dissolution of the film coat, a rapid release of the formulation to
provide a high local concentration of API and permeation enhancers
Modified Release
Encapsulation of semi-solid matrix for modified release
• Delivery applications
•
—
Poorly soluble and/or poorly permeable compounds
—
Eliminating spikes in blood concentrations to reduce associated side effects
—
Extending API release to reduce dosing frequency
—
Providing abuse resistance for controlled substances
Delivery approach
—
Lipid-based semi-solid matrix filled into a GF-SEC
—
Hydrophilic or lipid-based semi-solid matrix filled into a HGC or HPMC
capsule
Comparing Liquid LBDDS and Solid LBDDS
Liquid LBDDS
• Starts with the drug in solution
•
•
Offers a wider range of lipid fill formulation options to enhance
bioavailability
—
In-vivo drug solubilization using digestible lipid excipients
—
Improving permeation using lipid excipients that increase absorption
•
via transcellular or paracellular transport
•
Via modulation of drug transport or metabolism processes
Often results in reduced cycle times/costs
—
Liquids are relatively easy to scale-up
—
No downstream processing is required
Solid LBDDS
•
Potentially beneficial for drugs unstable in liquid state or extremely
sensitive to water (hydrolysis)
•
Provides the opportunity to utilize in-house development and
manufacturing capability and capacity
discover more.
CATALENT PHARMA SOLUTIONS
14 SCHOOLHOUSE ROAD
SOMERSET, NJ 08873
+ 1 888 SOLUTION
www.catalent.com