Download Soft Capsules: A Versatile Drug Delivery System

rp scherer softgel
Soft Capsules: A Versatile
Drug Delivery System
Norman Stroud
Director, Technology Development
28th January 2014
© 2014 Catalent Pharma Solutions. All rights reserved.
Presentation Topics
Soft Capsules
• General overview of soft capsule technology
• Features and versatility of soft capsules
• Recent developments: expanding the soft capsule
technology platform
 OptiShell™
• Summary
• Q&A
© 2014 Catalent Pharma Solutions. All rights reserved.
1
Soft Capsules: A Versatile Drug Delivery System
SHELL MATRIX FORMER(S),
+
Plasticizer,
Water
Lipophilic,
Colors,
Hydrophilic,
or
Mixed vehicle
Opacifiers,
Flavors
Solution, suspension,
or highly viscous fluid
• Seamed or seamless… a variety of form
• Gelatin or polysaccharide shell formers
• Wide variety of fill types
© 2014 Catalent Pharma Solutions. All rights reserved.
2
Soft Capsule (Softgel) History
Rotary-die
encapsulation
process
Gelatin
Capsules
Enhanced Solubility
Formulations
Chewable capsules
Gelatin-glycerol
capsules
1846
1834
Unit-dose, twist off
capsules
Vegicaps®
OptiShell™
US 1,970,396
2000
1934
Lehuby
Robert P Scherer
Mothes &
Dublanc
FP 5648
© 2014 Catalent Pharma Solutions. All rights reserved.
3
Overview of Softgel Technology
Gelatin capsules and OptiShell™ capsules
•
Both types of capsule are formed
using the rotary-die encapsulation
process
•
Both types of encapsulating film have
the ability to undergo thermoreversible gel formation
•
Gelatin is the shell matrix-former in
conventional soft capsules
•
The gel and shell of OptiShell™
capsules comprises a plasticized blend
of modified starch and iotacarrageenan; both plant-based
polysaccharides
© 2014 Catalent Pharma Solutions. All rights reserved.
4
Overview of Softgel Technology
Preparation of the gel mass
Preparation of capsule fill
Vacuum
Vacuum
Addition of
colourants and
flavors
Gel
mass
Capsule
fill
Drying in tumble dryers....
and on trays
Encapsulation
© 2014 Catalent Pharma Solutions. All rights reserved.
5
Overview of Softgel Technology
Rotary-die encapsulation
•
Formation of encapsulating
films
•
Precision injection of fill
material via injection wedge
•
“Paired” machine rolls with
cavities
•
‘Gel-sol-gel’ transition; form-fillseal formation of the capsules
Solution
Gel I
Decrease Temp
Gel II
© 2014 Catalent Pharma Solutions. All rights reserved.
6
Features and Versatility of Softgels
Routes of Administration
•
Primary
—
•
Variety of sizes,
shapes & colors
Oral
•
Swallowable
•
Chewable
95+% Oral
Secondary
—
Vaginal
—
Rectal
—
Topical dermatological
© 2014 Catalent Pharma Solutions. All rights reserved.
7
Features and Versatility of Softgels
ORAL FORMULATIONS
Liquid/solubilized systems
Liquid API’s
Simple solutions
Solubility enhanced systems
Drug/drug salt pairs
Nano-, Micro-emulsions
(SEDDS/SMEDDS/SNEDDS)
Permeability enhanced systems
Permeation/penetration enhancers
(OptiGel Bio™ & OptiShell™)
Abuse deterrent systems
High viscosity/viscoelastic systems
(OptiLock™ & OptiShell™)
Semi-solid/CR systems
(OptiShell™)
Enteric-Coated Capsules
Chewable Softgels
© 2014 Catalent Pharma Solutions. All rights reserved.
Delivers Key
Benefits
Improved and/or
more consistent
absorption
Improved content
uniformity of low dose
API’s
Enhanced stability
(against hydrolysis,
oxidative-deg’n &
photo-deg’n)
Improved tamper
evidence
Solve/minimize
process challenges
(containment,
scalability)
8
Features and Versatility of Softgels
• Softgel solutions to solubility challenges
 Solubility enhancement – drugs dissolved in hydrophilic
vehicles
o
Concentrated solutions of API(s)

Drug/drug salt pairs of ionizable drugs

Use of basic salts
 Lipid-based formulations for poorly water-soluble drugs
o
Emulsions (SEDDS, SMEDDS)
© 2014 Catalent Pharma Solutions. All rights reserved.
9
Drugs Dissolved in Hydrophilic Vehicles
Drug/drug salt pairs of ionizable drugs
• Cumulative solubility allows for
the development of highly
concentrated solutions
• Solution formulations typically
provide for more consistent
absorption and enhanced
bioavailability
• A number of patents have been
granted that describe this
formulation technique
Patent or
Application
Inventor (s)
5,071,643
Yu et al *
5,360,615
Yu et al *
5,376,688
Morton et al *
5,912,011
Makino et al *
6,365,180
Meyer et al
6,383,471
Chen, F.J., & Patel, M.V.
6,387,400
Tindal et al *
2007/053868
Chidambaram et al
2013/0011470
Lopez et al
* Assigned to R.P. Scherer
© 2014 Catalent Pharma Solutions. All rights reserved.
10
Drug/Drug Salt Pairs of Ionizable API’s
Example: Ibuprofen/potassium ibuprofen
CH3
• Solubilities in polyethylene glycol
— Ibuprofen  23%; K ibuprofen  36%
CH3
COOH
H3C
• Solubilization of one species results in a change in the solvation
properties of the “vehicle”, allowing for enhanced solubilization of
the second species
• Optimum solubility and improved stability is achieved at mole ratios
in the region 0.5 - 0.7
• However, for gelatin shell softgels, basic vehicles (pHapp  7.6) can
lead to time-dependent destabilization of the gelatin
© 2014 Catalent Pharma Solutions. All rights reserved.
11
Drugs Dissolved in Hydrophilic Vehicles
Use of basic salts of organic acids to enhance drug
solubility
• The presence of basic salt(s),
e.g. potassium acetate,
modifies the solvation potential
and pHapp
• This formulation technique has
been used successfully for very
weak acids (pKa  9.6)
• Patents and applications that
describe this formulation
technique are shown in the
table
Patent or
Application
Inventor(s)
5,505,961
Shelley et al *
2002/0187195
Sawyer et al
7,029,698
Waranis et al *
* Assigned to R.P. Scherer
Acetaminophen (APAP)
HO
O
N
H
© 2014 Catalent Pharma Solutions. All rights reserved.
CH3
12
Use of Alkaline Salts
• Solubilities in polyethylene glycol
— APAP  22%
• The incorporation of potassium acetate and/or sodium lactate
in a PEG-based vehicle results in an enhancement of APAP
solubility ( 32 - 35%)
• The combined incorporation of potassium acetate and
potassium hydroxide results in a further improvement in APAP
solubility
• “High” pH (10-12) formulations, however, possess a tendency
to destabilize gelatin
© 2014 Catalent Pharma Solutions. All rights reserved.
13
Drugs dissolved in hydrophilic vehicles
Summary
• The solubility enhancement techniques utilizing drug/drug salt, and
or basic salt systems are still very useful for certain API’s
• The OptiShell™ capsule shell is resistant to “high” pH formulations
and enables the pharmaceutical formulator to develop solution or
suspension capsule formulations utilizing basic/alkaline systems
• There is renewed interest in these formulation techniques, since
some of the emerging biomolecules and ‘permeation enhancers’ are
alkaline salts and/or benefit from an alkaline environment
© 2014 Catalent Pharma Solutions. All rights reserved.
14
Self-emulsifying Drug Delivery Systems
Formulation of self-emulsifying drug delivery systems
• Lipid-based “preconcentrate” of solubilized drug
• Typical composition
—
Lipid excipients
—
Surfactants (hydrophilic, high HLB)
—
Co-surfactants (lipophilic, low HLB)
—
Co-solvents (ethanol)
Desired characteristics upon dilution with G.I. fluids
• Spontaneous formation of micro/nanoemulsion
• Drug stays in solution and does not precipitate out
© 2014 Catalent Pharma Solutions. All rights reserved.
15
SEDDS, example: Cyclosporin A (the Neoral® story)
• API Physical-chemical properties
—
MW, 1202.63; log P, 2.92; calcS 9g/mL H2O
—
Poorly soluble in G.I. fluids
• API pharmacokinetic characteristics
—
Poor and variable absorption
• Initially introduced as a lipid-based formulation in a softgel Sandimmune®
• Reformulated as a microemulsion pre-concentrate in a softgel Neoral®
—
Polyoxyl 40 hydrogenated castor oil, propylene glycol, mono-and diglycerides of corn oil, alcohol, DL--tocopherol, API
•
•
•
Rapid gastric dispersion due to self-emulsifying properties
The system maintains the drug in solution (minimal precipitation)
A high drug concentration is presented to the site of absorption
Neoral and Sandimmune are registered trademarks of Novartis Ag
© 2014 Catalent Pharma Solutions. All rights reserved.
16
Pharmacokinetic Profiles for Cyclosporin A Formulations
Sandimmune
Neoral
1600
1200
800
400
0
1200
(µg/L)
Concentrationin
inthe
theblood
blood
Concentration
1600
(µg/L)
Concentration
Concentration in
in the
the blood
blood
12 Fasting Human Volunteers; 150mg Dose
800
400
0
0
2
4
6
8
Time (hours)
(hours)
Time
© 2014 Catalent Pharma Solutions. All rights reserved.
10
12
0
2
4
6
8
10
12
Time (hours)
Time
(hours)
17
Effect of food intake on the
absorption of Sandimmune® and Neoral®
AUC (µL-1 h)
1000
800
Fed
Fasted
Neoral®
600
Sandimmune®
400
200
0
0
4
8
12
Time (Hours)
16
20
24
Neoral® is less affected by food intake
© 2014 Catalent Pharma Solutions. All rights reserved.
18
OptiShell™ - Wider Compatibility Range with SMEDDS
The OptiShell™ film-formers are polysaccharides and have improved
resistance to certain solvents, surfactants and formulation types
• Formulations containing high concentrations of “products of
digestion”, e.g. monocaprylates and caprylic acid
Co-solvents
Solubilizers
Penetration enhancers
Example:
octanoic acid
(caprylic acid, C8)
• Formulations containing solubilizing agents that cross-link gelatin
Co Q10 SMEDDS
© 2014 Catalent Pharma Solutions. All rights reserved.
19
OptiShell™: Other Benefits
% w/w
Ingredient
Gel
Shell
Modified starch/
-carrageenan blend
31
52.5
Plasticizer
22
37.5
Water *
47
10
Patent-protected OptiShell™
technology expands the range of
fill formulations that can be
encapsulated
* Includes buffer salt
OptiShell™ Capsules
SHELL
COMPOSITION
FILL
FORMULATION
PROPERTIES
Soft Gelatin Capsules
• Carrageenan (extract of red seaweed),
modified starch, plasticizer, water
• Gelatin, plasticizer, water
• Higher temperature encapsulation of fill
formulations (‘hot fill’) -> semi-solid and
highly viscous liquid fills
• Lower temperature encapsulation of fill
formulations (up to 40˚C) -> liquids, pastes
or low melting point semi-solids
• Fill formulations that cross-link hard or
softgel capsule shells
• Potential cross-linking
• Higher pH fill formulations
• Slightly acidic to neutral pH fill formulations
© 2014 Catalent Pharma Solutions. All rights reserved.
20
OptiShell™: Other Benefits
OptiShell™ ‘hot fill’ capability is suitable for:
•
Formulations that are highly viscous/viscoelastic at room
temperature
•
Formulations that are semi-solid, solid-like at room
temperature but exist as mobile fluids at elevated
temperature
•
•
The OptiShell™ capsules are formed by filling and sealing at
temperatures in the range 55° - 75°C
This process capability is particularly useful for CR, matrix
type formulations
© 2014 Catalent Pharma Solutions. All rights reserved.
21
OptiShell™: ‘Hot fill’ Encapsulation
75°C
40°C
Melting
Point
Softgels
Softgels
VegiCaps®®
VegiCaps
OptiShell™
technology
Soft
Soft
SAIB
0
10
20
30
minutes
© 2014 Catalent Pharma Solutions. All rights reserved.
22
OptiShell™: Overall Benefits
Differences in the properties of OptiShell™ capsule
shell expands the capabilities of softgel technology
•
OptiShell™ is compatible with a wide range of conventional,
liquid, fill formulation types:
—
•
Lipophilic, amphiphilic, hydrophilic
OptiShell™ is compatible with a range of formulation types
that are problematic for gelatin-based shells
—
Semi-solids, higher melting point and/or high viscosity
formulations
—
Formulations that contain low m.w. co-solvents
(SEDDS/SMEDDS)
—
Fill formulations that contain ingredients or impurities that react
with and cross-link gelatin
—
Formulations that are alkaline in nature or contain alkaline salts
© 2014 Catalent Pharma Solutions. All rights reserved.
23
In Summary
• Soft capsules are suitable for a wide variety of dosage and
delivery systems and often can be used to enhance therapeutic
performance
• The development of the OptiShell™, soft capsule technology has
expanded our encapsulation capability with respect to many
different types of fill formulation
• The OptiShell™ capsule shells can be used for the development
of liquid, suspension, and semi-solid formulations that would
otherwise prove extremely challenging or impossible to formulate
using conventional, gelatin shell technology
• Work is underway to investigate the feasibility of using
OptiShell™, and other novel encapsulation approaches, to further
enhance the delivery and absorption of challenging API’s
(including macromolecules)
© 2014 Catalent Pharma Solutions. All rights reserved.
24
Acknowledgements
Catalent colleagues
Jeff Browne, Keith Tanner, Irena McGuffy,
Rickey Shelley, Stephen Tindal,
Elizabeth Youngblood, Didier Kiyali,
Jing Lin, Julien Meissonnier,
Nathalie Sicre and Thomas Pointeaux
© 2014 Catalent Pharma Solutions. All rights reserved.
25
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Questions
© 2014 Catalent Pharma Solutions. All rights reserved.
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rp scherer softgel
rp scherer softgel
Back-up slides
© 2014 Catalent Pharma Solutions. All rights reserved.
OptiShell™ soft capsule technology
OptiShell™ Soft Capsule Manufacture

Specialized gel melters are required to process the high-melting point, high
viscosity gel mass formulations

The gel to film process is accomplished using ‘melt-on-demand’ and
extrusion technology (GMPU, HISV, ICDMS)
Patented process US 6,884,060
© 2014 Catalent Pharma Solutions. All rights reserved.
29
OptiShell™ Technology:
Expanding the Softgel Technology Platform
• The OptiShell™ polysaccharide-based shell is unaffected by fill
formulations that are alkaline in nature (US patent 8,231,896)
Effect of storage at 40ºC/75% RH (in HDPE bottles) on the physical stability of an alkaline
acetaminophen fill formulation encapsulated in A) a gelatin softgel and B) an OptiShell™
softgel
A
B
A.
The gelatin-based capsules showed signs of physical instability and leakage after
one months storage at 40ºC and 75% RH
B.
The OptiShell™ capsules exhibited satisfactory physical and chemical stability after
3 and 6 months storage at 40ºC and 75% RH
© 2014 Catalent Pharma Solutions. All rights reserved.
30
OptiShell™ Technology:
Expanding the Softgel Technology Platform
The polysaccharide-based shell is unaffected by the cross-linking agents that

react with gelatin
IR and MR products do not exhibit any significant time- or temperature-

dependent changes in dissolution performance
Ibuprofen, 400mg, solution formulation, dissolution profile
110
100
100
90
90
80
80
70
% Ibuprofen
% Ibuprofen
25/60
110
Q+5 = 80%
60
Initial
50
40
6 mo's, 25/60
30
6 mo's, 30/65
20
6 mo's, 40/75
10
70
Q+5 = 80%
60
Initial
50
6 months
40
30
12 months
20
24 months
10
0
0
0
5
10
15
20
25
30
Time, minutes
35
© 2014 Catalent Pharma Solutions. All rights reserved.
40
45
50
0
5
10
15
20
25
30
Time, minutes
35
40
45
50
31
Technology comparison:
OptiShell™ and gelatin capsules
 Viscosity of starch/carrageenan (S/C) gel mass is
typically 6–10x greater than that of gelatin-based gel
mass
Gel mass
 Gelatin-based gel masses melt at about 45–57C
S/C gel masses melt at 87–92C
 Specialized, “Melt-on-Demand” equipment is required to
process the OptiShell™ gel
 Maximum sealing temperature of gelatin-based films is
approximately 40C
Encapsulating
film
 Maximum sealing temperature of OptiShell™ films is
65-70C
 Both film systems are thermo-reversible; sealing occurs
predominantly by gel-sol-gel transition
© 2014 Catalent Pharma Solutions. All rights reserved.
32
Other Technical Needs Addressed by Softgels…
Compounds that exist in the liquid-state or semisolid-state or have a
low melting point
Highly potent compounds (mcg or mg dose) where achieving
uniformity of dose is challenging
Highly potent or toxic compounds (cytotoxic or hormone) where
safe handling is a concern
Compounds that exhibit poor stability (oxidation, photo,
hydrolysis)
Compounds that exist as multiple polymorphic forms
Compounds that are likely to pose lengthy scalability issues as a
conventional solid dosage form (uniformity of dose, polymorphs)
© 2014 Catalent Pharma Solutions. All rights reserved.
33