Two-piece capsules for Liquid-fill Formulations

Transcription

LUFERCOMP
QSA022 - 2006E
Two-piece capsules for
Liquid-fil l Formulations
F4SHIO001_8p_liquid_3V2.indd Sec2:1
23/2/06 14:16:02
Liquid-fill Applications
An innovative
solution
for formulation
challenges
The changing nature of the NCE (New Chemical
Entity) and NME (New Molecular Entity) that are being
produced currently by the research groups in the
pharmaceutical industry means that the formulator is
faced with new challenges to produce effective products.
Solid oral dosage forms (SODF) are the most popular for
medicines because patients like their simplicity and ease
of use. Thus the formulator needs to find ways in which to
utilise their acceptability and at the same time devise new
types of formulation. The hard two-piece capsule is the oral
dosage form that is the most versatile, because it can be filled
with formulations that have wide range of physical forms, from
dry powders, through pellets to semi-solid matrices (SSM) and
non-aqueous liquids. It is really a tool for the latest formulation
technologies. Recent research to improve absorption of poorly
soluble actives has focused on lipid systems: an application for which
the hard capsule is well suited.
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Qualicaps manufactures a range of hard two-piece
capsules with different shell formulations each designed
for specific applications:
Qualicaps® Gelatin capsules
❚ The standard gelatin capsules for liquid fill formulations compatible
with many excipients.
Qualicaps® PEG/Gelatin capsules
❚ First developed by Qualicaps in Japan, standard gelatin capsules
containing 5% w/w Polyethylene Glycol (PEG) 4000 as an additional
plasticizer. Suitable for slightly hygroscopic excipients.
Quali-V® capsules
❚ The first hypromellose capsules to be produced with properties
suitable for pharmaceutical applications. Compatible with a wide
range of excipients. Made from non-animal materials with a lot of
interesting properties for the liquid formulations.
www.qualicaps.com
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The pharmaceutics
of liquid-filled capsules
Liquid Formulation
There are two types of liquid-fill formulations:
1) Liquids mobile at temperatures below 35°C: mixtures of oils and lipids and
solutions or suspensions of actives in oils or lipids.
2) Liquids that are non-mobile solids below 35°C: are liquefied for filling by
the use of heat, thermosoftening mixtures, or by the use of shear stress,
thixotropic mixtures. In these semi-solid matrix formulations, the active
is presented either in solution or as a suspension: in the former they
are in a thermosoftening base, and in the latter in a liquid base to which
viscosity modifying ingredients have been added.
A formulation-tree (Chart 1) shows how SSM formulations are developed.
Chart 1. Formulation selection based on the water solubility of
the active.
ACTIVE INGREDIENT
ACTIVE
PROPERTY
GOOD SOLUBILITY
POOR SOLUBILITY
RELEASE
REQUIRED
STANDARD
RELEASE
PROLONGED
RELEASE
STANDARD
RELEASE
PROLONGED
RELEASE
NATURE OF
FORMULATION
HYDROPHILIC
/NEUTRAL
HYDROPHOBIC
HYDROPHILIC
HYDROPHOBIC
/NEUTRAL
EXCIPIENT
PROPERTIES
SSM: HLB>7
PEG >1500
SiO2
SSM: HLB<5
SSM: HLB >10
PEG >1500
SiO2
SSM: HLB 5-10
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This demonstrates that a range of release characteristics can be obtained
by matching the solubility of the active to the properties of the excipients.
For example, if a prolonged release product is required for a soluble active
then the SSM formulation needs to be hydrophobic and an SSM base with
an Hydrophilic/Lipophilic Balance (HLB) value less than 5 is required. The
excipients used for this technology are widely used in pharmaceutical
products and are well documented (Table 1).
Table 1. Excipients used for liquid-fill hard capsules.
MATERIAL TYPE
EXAMPLES
Natural oils
Lipophilic liquids
Propylene glycol laurate
Glyceryl monolineate
Glyceryl monooleate
Arachis (groundnut), Castor,
Cottonseed, Soybean
Hydrogenated oils
Medium chain
triglycerides
Caprylic/capric triglycerides
Macrogols
(Polyethylene Glycol)
Macrogol Glycerides
Arachis, Castor, Cottonseed,
Maize (corn), Olive, Soybean,
Sunflower
Lauroglycol FCC
Maisine 35-1
Peceol
Bergabest, Captex 300 & 350,
Labrafac CC, Miglyol 810 & 812,
Myritol, Neobee M5, Nesatol,
Waglinol 3/9280
Carbowax, Lipoxol, Lutrol E,
Pluriol E
Oleoyl-6,
Linoleoyl-6,
Caprylocaaproyl-8,
Lauroyl-32,
Stearoyl-32
Glyceryl esters of
fatty acids
Labrafil M 1944 CS,
Labrafil M 2125 CS,
Labrasol,
Gelucire 44/14,
Gelucire 50/13
Gelucire 33/01, 39/01, 43/01
Transcutol HP,
Solubilizers, surfactants
Diethylene glycol
monoethyl ether,
Glyceryl monostearate,
Polyglycerol-6 dioleate,
Polyoxyethylene castor oil
derivatives
Viscosity enhancers
Colloidal silicon dioxide
Aerosil, Cab-O-Sil, Wacker HDK
Imwitor,
Plurol oleique CC497,
Cremophor RH40
www.qualicaps.com
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Equipment for Liquid Filling
The liquid filling of hard capsules is done using volumetric pumps that give
better dose uniformity than for powder-filled products. Equipment is available
to fill hard capsules at all scales from the bench to full-scale production.
Initial trials can be carried out using a hypodermic syringe, and the product
produced will have the same properties as one filled on a high-speed
automatic machine.
Sealing of Capsules
Certain liquid-filled hard capsules need to be sealed after filling to prevent
the liquid leaking out. The sealing of capsules brings additional benefits to
the encapsulated product because it reduces the amount of oxygen that can
penetrate through the shell and interact with the formulation. It can retain
within the shell any strong odours generated by the product.
There is equipment available to carry out band-sealing on the bench-scale.
Preparation of products on the small-scale can replicate filling on high-speed
machines.
Major Capsule Properties
Less brittle
Qualicaps® PEG/Gelatin and Quali-V® capsules were developed by Qualicaps
to try and overcome the well-known problems of standard gelatin capsules
associated with their water content. Water in a gelatin film acts as the
plasticizer and when the moisture content of a capsule falls below its
specification limit they become brittle. This can happen when capsules are
exposed to low humidities during storage or if the formulation filled in to
them is hygroscopic.
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Brittleness (% broken)
Qualicaps® PEG/Gelatin capsules contain PEG 4000 as an additional
plasticizer that allows their moisture content to fall to below about 10%
without brittleness: Gelatin capsules become brittle at about 12%
(see Figure 1).
Quali-V® capsules are made from
hypromellose and the water in
their shell walls does not act as a
0%''ELATIN
plasticizer. Thus if they lose water
when they are exposed to low
humidities during storage or if
the formulation filled in to them
is hygroscopic then they do not
become brittle (see Figure 1).
% moisture content
Figure 1. The effect of capsule moisture content on brittleness of empty capsules: a comparison of
capsule types.
Test conditions: capsules stored in sealed bottles at 45°C, number of replicates = 5. Brittleness
determined by dropping 50 g weight from 10 cm on to capsules placed on a flat anvil.
This is of particular use because it extends the number of excipients that
can be used in formulations. Several of the more useful ones are slightly
hygroscopic. For example, the effects of slightly hygroscopic SSM excipients
on the moisture content and brittleness are shown in (Figures 2 & 3).
Figure 2 shows that both Qualicaps® Gelatin capsules and Quali-V®
capsules lose equivalent amounts of water, when filled with the same SSM
excipients.
QUALICAPS® Gelatin capsules
% moisture content
% moisture content
QUALI-V® capsules
Time, weeks
Time, weeks
Figure 2. Effect of SSM fill materials on the moisture content of Qualicaps® Gelatin and Quali-V®
capsules.
Filled capsules stored in sealed bottles at 45°C, n=5. Moisture content determined by Karl Fischer.
Redrawn from information in Nagata, S. and Tochio, S., Poster CRS meeting, Seoul, South Korea, 2002.
www.qualicaps.com
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% Brittleness
Figure 3 shows that the Qualicaps® Gelatin capsules became extremely
brittle over the course of this trial and the more water that was removed
from the shells the more brittle they became. On the other hand, none of the
Quali-V® capsules showed any signs of brittleness during this test.
Time, Weeks
Figure 3. Liquid-fill hard capsules, the effect of liquid-fill excipients and storage on Qualicaps® Gelatin
capsule brittleness.
Filled capsule stored in sealed bottles at 45°C, number of replicates = 5. Brittleness determined by
dropping 50g weight from 10 cm on to capsules placed on a flat anvil.
Redrawn from information in Nagata, S. and Tochio, S., Poster CRS meeting, Seoul, South Korea, 2002.
Water Vapour and Gas Permeability
Rate, g/m2 / 24hr: Thickness, microns
The capsule shell wall is permeable to gases and water vapour. The
stability of the formulation can be affected if components contained in the
formulation are readily hydrolysed or oxidized.
Figure 4. The rate of water vapour transmission through capsule shell films. Comparison of capsule
types.
Redrawn from data in Nagata, S., Drug. Del., Technol., 2002, 2(2), 34-39.
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This is an important consideration during formulation. The rate of which
water vapour penetrates through the shell is different for Gelatin,
PEG/Gelatin and Hypromellose capsules (Figure 4). The rate at which
water diffuses through Quali-V® capsule films is about half of the rate for
Qualicaps® Gelatin capsule films.
In addition, Quali-V® capsules do not change their physical properties when
exposed to low humidities. Thus, they are more suitable for products that
are moisture sensitive because their water content can be reduced before
filling.
On the contrary, the rate at which gases such as oxygen penetrate through
shell walls is about three fold slower for Qualicaps® Gelatin than for
Quali-V® capsules (Table 2).
Table 2. The rate of oxygen diffusion through capsule shell films:
a comparison of capsules types.
Films
O2 concentration after 3 days
Gelatin
PEG/Gelatin
Hypromellose
0.1%
0.0%
0.3%
Data from Nagata, S., Shionogi Qualicaps, Co., Ltd, 1999.
However, to put this into perspective it must be remembered that the bulk of
the oxygen will enter the capsule through the gap between the cap and the
body. Thus if the Quali-V® capsules are band-sealed, the amount penetrating
into the capsule will be significantly reduced. If this amount is still a problem
for the product then an anti-oxidant could be included in the formulation.
Product-Shell Interaction
When considering the potential for product-shell interactions, there is a
significant difference between a powder-filled capsule and a liquid-filled
capsule, because the contact area between the products and capsule shell
is significantly greater in the case of the liquid-filled capsule. The types of
interaction that can occur will be either partitioning or migration from the
contents to the shell or vice-versa. These interactions are well documented
for soft gelatin capsules. However, the potential for this to happen in a hard
capsule is significantly less than for soft gelatin capsule because of the much
smaller hydrophilic phase in the shell from which materials can migrate in to
or out of.
www.qualicaps.com
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For example, consider the case of a size 0 capsule with a fill volume of
about 0.7 ml, a hard gelatin capsule would have a hydrophilic phase of
15 mg, which is its moisture content, and a hypromellose capsule one of
5 mg. Whereas a soft gelatin capsule with the same fill volume would have
a shell wall that is approximately 4 times as thick, weighing about 400 mg,
and its hydrophilic phase, which is a mixture of water and plasticizer, would
be about 150mg.
Qualicaps® Gelatin capsules filled with liquid will react in a slightly different
way to the ones filled with powder if the contents are hygroscopic, because
the stresses will build up in a different way (Figure 5).
RH inside cap dome
Stresses caused by
Cap shrinkage and
Body expansion
Body expansion by
migration of fill
Figure 5. Stress points for liquid-filled Qualicaps® Gelatin capsule.
The filling capacity of a capsule for a liquid-fill product is approximately 90%
of the powder capacity to avoid spillage of liquid during filling. In the case
of a SSM formulation, the material will solidify in the body. This is in contrast
to a powder-filled capsule where the material will be more evenly spread
through out its internal space. Therefore in a SSM-filled capsule there will be
an air space in the dome of the cap. If the RH in this space is reduced, water
will be drawn from the cap, causing it to shrink on to the body. The stresses
will increase if material migrates in the body shell causing it to swell slightly.
The result of these stresses will bring a longitudinal split in the cap.
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Applications & Benefits
of liquid-filled capsules
Expand Product
Development Possibilities
The liquid-filled capsule provides a very flexible vehicle for the formulator
to solve many of the challenges currently facing the pharmaceutical
and nutraceutical industries:
❚ Improves the absorption of poorly soluble drugs through utilising
lipid-based formulations.
❚ Makes easier the handling of toxic and potent actives in production
areas. Once mixed in a SSM base, it prevents contamination of areas
enabling operator-friendly environments to be created without great
expense.
Reduce Time for Product
Development and for Scale-up
Many of the formulations developed for liquid filling are simple mixtures of
active plus excipient. It reduces the number of tests and process validations
that have to be performed. Liquid formulations in hard capsules are typically
easier to scale-up than other solid oral dosage forms because liquid systems
are much less complex. They involve two steps, mixing and filling: the filling
process is typically scaled-up just by using more pumps rather than by
pumping faster. Thus products prepared on the small-scale will have the
same properties as those filled on high-speed production machines.
Give Good Product Appearance
The two-piece capsule has always been regarded as a pharmaceutically
elegant dosage form. Liquid-filled capsules bring an extra cachet to a product
by their ability to make it eye-catching
(Figure 6). Hard capsules can be bandsealed to give the possibility of adding a
third colour to the product: thus giving
it a more distinctive appearance with
patient appeal and at the same time
making it more difficult to copy.
Figure 6. Liquid-filled capsule.
www.qualicaps.com
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For the Liquid-Fill applications
Qualicaps recommends
the following range:
QUALICAPS® Gelatin capsules
Our Gelatin two-piece capsules for liquid-fill formulations
❚ Compatible with a wide range of excipients for improving bioavailability
of poorly soluble drugs.
❚ Leak-proof capsules for liquid formulations with our patented bandsealing technology.
❚ Tamper evident capsule with our band-sealing technology
❚ Band-sealed
penetration.
capsules
provide
an
excellent
barrier
to
oxygen
❚ Can be filled with SSM formulations up to 70°C.
QUALICAPS® PEG/Gelatin capsules
Our Gelatin with PEG 4000 two-piece capsules
for liquid-fill formulations
❚ Suitable for use with slightly hygroscopic excipients.
❚ Recommended for products that may be exposed to low humidity
conditions.
❚ Leak-proof capsules for liquid formulations with our patented band
sealing technology.
❚ Tamper-evident capsules with our band-sealing technology.
❚ Band-sealed
penetration.
capsules
provide
an
excellent
barrier
to
oxygen
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QUALI-V® capsules
Our hypromellose two-piece capsules
for liquid-fill formulations
❚ Plant derived materials.
❚ Maintain shell mechanical strength at low moisture contents.
❚ Suitable for products with hygroscopic tendencies without the problem of
shell brittleness.
❚ Extend the range of excipients that can be used for liquid-fills.
❚ Compatible with a wider range of excipients for improving bioavailability
of poorly soluble drugs.
❚ Leak-proof capsules for liquid formulations with our band-sealing
technology.
❚ Tamper evident capsule with our band-sealing technology.
www.qualicaps.com
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Liquid-filled capsules are an innovative solution for
formulation challenges.
The filling of liquids in to hard two-piece capsules has been known of
since the 19th century. There has been a resurgence in the interest in
using this simple technique because its provides a means of handling
compounds that are difficult to formulate in terms of both stability and
availability. Two types of liquid formulation can be used: those that
are mobile at ambient temperatures and those that are solids (SSM).
The excipients for liquid and SSM formulations have a wide range of
chemical and physical properties. The choice is greater than for soft
gelatin capsules because materials can be used with melting points
higher than 35ºC.
Hard two-piece capsules are now available made with shell
formulations that are better adapted to liquid filling than the traditional
gelatin shell capsules. Qualicaps® PEG/Gelatin capsules give an
improved performance compared to the standard gelatin capsules in
situations where its moisture content is reduced, i.e., when exposed
to low humidities or filled with slightly hygroscopic formulations.
Quali-V® hypromellose capsules are the premium grade of capsules
for liquid filling because the problems of brittleness with gelatin based
capsules, associated with water loss, do not occur. This means that
a more extensive list of excipients is available for use to solve the
formulator challenges.
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www.qualicaps.com
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Qualicaps, Co., Ltd.
6505 Franz Warner Parkway
Whitsett, NC 27377-9215
USA
Tel: +1 336 449 3900
Fax: +1 336 449 3333
E-mail: [email protected]
321-5 Ikezawacho
Yamatokoriyama
Nara, 639-1032 Japan
Tel: +81 743 56 0651
Fax: +81 743 56 5113
E-mail: [email protected]
QSA022 - 2006E
Qualicaps, Inc.
Calle de la Granja, 49
28108 Alcobendas
Spain
Tel: +34 91 663 08 00
Fax: +34 91 663 08 30
E-Mail: [email protected]
LUFERCOMP
Qualicaps Europe, S.A.
www.qualicaps.com
23/2/06 14:15:50

Two-piece capsules for Liquid-fill Formulations

Transcription

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