Transcript Evaluation of novel CR-GRDF formulation of levodopa in dogs

lipid-based delivery systems for oral
administration
• Lipid-based delivery systems range from simple oil
solutions to complex mixtures of oils, surfactants, cosurfactants and cosolvents.
• The latter mixtures are typically self-dispersing systems
often referred to as self-emulsifying drug delivery
systems (SEDDS) or self-microemulsifying drug delivery
systems (SMEDDS)
1
lipid-based delivery systems for oral
administration
• Formulations which disperse to form transparent
colloidal systems are usually referred to as SMEDDS,
though in scientific terms this distinction is somewhat
arbitrary.
• Whether these dispersions are thermodynamically stable
microemulsions is usually unknown, though the
dispersions formed by both SEDDS and SMEDDS are
often stable in practice for months.
• he particle sizes of dispersions formed by SMEDDS are
lower than those formed by SEDDS.
2
lipid-based delivery systems for oral
administration
• The performance of lipid-based delivery systems is
governed by their fate in the gastrointestinal tract, rather
than the particle size of the initial dispersion.
• This concept can be appreciated by considering the fate
of long-chain triglycerides, which have no practical ability
to self-disperse but are digested rapidly in the intestine.
• Subsequent to lipolysis their fatty acid and
monoglyceride digestion products are solubilised by bile
salt–lecithin mixed micelles, a fine colloidal dispersion
which promotes absorption and.
3
lipid-based delivery systems for oral
administration
• It is likely that the powerful digestive system in the
intestine will play a part in determining the fate of all
lipid-based delivery systems.
• Even when non-digestible excipients are used the
interaction of a dispersed formulation with bile is likely to
change its physical form.
• Formulators need to have a good understanding of
gastrointestinal digestion and are increasingly making
use of relevant in vitro tests which can predict the fate of
the formulation, and most importantly the drug, after oral
administration
4
The Lipid Formulation Classification
System
• The Lipid Formulation Classification System (LFCS)
main purpose is to enable in vivo studies to be
interpreted more readily, and subsequently to facilitate
the identification of the most appropriate formulations for
specific drugs, i.e. with reference to their
physicochemical properties
5
The Lipid Formulation Classification
System
6
The Lipid Formulation Classification
System
• Many of the marketed products are Type III systems but
this group is particularly diverse as a result of the wide
variation in the proportions of oily and water-soluble
materials used
• This group has been further divided into Type IIIA and
Type IIIB, to distinguish between formulations which
contain a significant proportion of oils (Type IIIA) and
those which are predominantly water-soluble (Type IIIB).
7
The Lipid Formulation Classification
System
• At present the sub-classification of Types III formulations
is ill-defined, particularly when one considers that a Type
III formulation could contain 3–5 excipients, including
water-insoluble and water-soluble surfactants, as well as
water miscible cosolvents.
8
The Lipid Formulation Classification
System
Precipitation of a lipophilic drug after 1/100 dilutions of Types II, IIIA, IIIB and IV lipidbased formulations of the drug in water. The graph shows the % of the dose of drug
which remained in solution (mean ± s.d. n = 4) as a function of time after initial dispersion.
Prior to dispersion the drug was dissolved at 80% saturated solubility in each formulation.
Formulations: Type II—15% w/w Miglyol 812, 35% Imwitor 988, 50% Tween 85; Type
IIIA—15% w/w Miglyol 812, 35% Imwitor 988, 50% Tween 80; Type IIIB—50% Imwitor
308,950% Tween 80; Type IV—50% Tween 80, 50% propylene glycol.
Excipients for lipid formulations
• A wide range of triglycerides, partial glycerides,
semi-synthetic oily esters, and semi-synthetic nonionic surfactants esters are available from excipient
suppliers.
10
Excipients for lipid formulations
11
Excipients for lipid formulations
• Water-insoluble surfactants penetrate and fluidize
biological membranes and water-soluble surfactants
have the potential to solubilize membrane components.
• All surfactants are potentially irritant or poorly tolerated
as a result of these non-specific effects.
• In general terms cationic surfactants are more toxic than
anionic surfactants which in turn are more toxic than
non-ionic surfactants.
12
Excipients for lipid formulations
• Lipid-based delivery systems usually only include nonionic surfactants so it is pertinent to compare the toxicity
of non-ionic surfactants.
• In general bulky surfactants such as polysorbates
(derived from PEG-ylated sorbitan (a derivative of
sorbitol) esterified with fatty acids) or polyethoxylated
vegetable oils (Cremophor EL®) are less toxic than
single-chain surfactants, and esters are less toxic than
ethers (which are non-digestible).
13
Excipients for lipid formulations
• Non-ionic surfactants are generally considered to be
acceptable for oral ingestion.
• The oral and intravenous LD50 values for most non-ionic
surfactants are in excess of 50 g/Kg and 5 g/Kg
respectively, so 1 g surfactant in a formulation is welltolerated for uses in acute oral drug administration.
• More careful consideration needs to be given to
formulation of a product which is intended for chronic
use, and it is noteworthy that most marketed lipid
products for chronic use generally do not include
surfactants
14
Excipients for lipid formulations
• However the marketed HIV protease inhibitors products,
such as Agenerase (Amprenavir), Kaletra (lopinavir and
ritonavir) and Norvir (ritonavir), contain a considerable
mass of surfactants in each capsule, and several
capsules are administered 2–4 times daily, so that
patients are ingesting 2–3 g Cremophor or TPGS
(Tocopheryl polyethylene glycol 1000 succinate ) daily.
• Sandimmune® Neoral® Capsules.
15
Excipients for lipid formulations
• Although most non-ionic surfactants have similar LD50
values, in practice formulators are predictably cautious
when choosing surfactants and usually turn to one of a
few tried and tested materials which have been used in
marketed products.
• In this respect a useful resource is the US FDA Center
for Drug Evaluation and Research ‘Inactive Ingredients
Database’ which states the masses or concentrations of
ingredients used in marketed pharmaceutical products.
•
16
http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm
Excipients for lipid formulations
• Another practical consideration relates to the chemical
complexity of excipients.
• The use of vegetable oils from different plants is an
immediate source of diversity, and subsequent chemical
derivation by hydrolysis and esterification introduces
more diversity.
• Further processing is required to produce non-ionic
surfactants, usually esters of polyoxyethylene or
polyglycerol, or products of reaction with ethylene oxide.
17
Excipients for lipid formulations
• The polyoxyethylene or polyglycerol chains are
polymeric in nature, which means that a typical
surfactant product based on mixed glycerides is
comprised of dozens of separate chemical entities in
different proportions.
• For practical purposes these products are usually given
a simple chemical name which represents their ‘average’
composition but which hides their complexity.
18
HO-CH2-(CH2-O-CH2-)n-CH2-OH
Polyoxyethylene
Polyglycerol monooleate n=2 or 3
19
Polyglycerol mono laaurate n = 2 or 3
Excipients for lipid formulations
• The formulator of lipid-based products has to accept that
there will be differences between excipient products
which appear to have the same chemical name, and
there will also be a finite level of diversity between
batches of the same product.
• Establishing a relationship with the excipient suppliers to
set product specifications is an important strategy, but
the formulator should also build a degree of latitude ‫حرية‬
‫ االختيار‬into formulation design (robustness), so that the
product is not compromised by inevitable variation in
chemical composition of the excipients used.
20
Excipients for lipid formulations
• Trace contaminants are an issue with lipid excipients
and surfactants, particularly in relation to the chemical
stability of the dissolved drug.
• Care should be taken to select excipients with low level
of peroxides, aldehydes etc. and to ascertain at an early
stage in preformulation studies whether the drug of
interest is sensitive to the presence of particular trace
contaminants.
• Chemical stability of drugs in lipid vehicles is poorly
understood. Formulators should exercise caution but the
prevalence of stability problems is not clear from the
published literature.
21
Triglycerides
• Triglyceride vegetable oils have many advantages as the
foundation of lipid-based delivery systems: They are
commonly ingested in food, fully digested and absorbed,
and therefore do not present any safety issues.
• Vegetable oils are glyceride esters of mixed unsaturated
long-chain fatty acids, commonly known as long-chain
triglycerides (LCT).
• Oils from different vegetable sources have different
proportions of each fatty acid.
22
Triglycerides
• The fatty acid compositions of coconut and palm kernel
oils are noteworthy in that they are unusually rich in
saturated medium-chain oils (C8, C10 and particularly
C12).
• Coconut oil is distilled to produce the generic product
‘medium-chain triglycerides’ (MCT) (also known as
glyceryl tricaprylate/caprate) which is available from
several suppliers and commonly comprises glyceryl
esters with predominantly saturated C8 (50–80%) and
C10 (20–45%) fatty acids.
23
Triglycerides
• Triglycerides are highly lipophilic and their solvent
capacity for drugs is commonly a function of the effective
concentration of the ester groups, thus on a weight basis
MCT generally has higher solvent capacity than LCT.
• In addition MCT is not subject to oxidation, so MCT is a
popular choice for use in lipid-based products.
• Castor oil is noteworthy as the only common source of
glyceryl ricinoleate, which uniquely has a hydroxyl group
coupled to the alkyl chain.
24
Mixed glycerides and polar oils
• Partial hydrolysis of triglycerides is used to produce a
wide range of mixed glyceride excipients, containing
various proportions of monoglycerides, diglycerides and
triglycerides.
• The chemical composition of mixed glyceride products
depends on the source of triglyceride starting material as
well as the extent of hydrolysis induced.
• Care needs to be taken with excipient names.
‘Monoglyceride’ products often contain substantial
quantities of diglycerides and triglycerides, so the
manufacturers datasheet should be consulted in detail.
25
Mixed glycerides and polar oils
• ‘Glyceryl monooleate’ is a waxy material but its physical
form will be very dependent on the di-and trigyceride
content.
• Since waxes create technical challenges, mixed mono
and diglycerides of long-chain fatty acids are a good
option, allowing liquid formulations to be produced.
• Trace amounts of saturated monoglycerides sometimes
produce a hazy product.
26
Mixed glycerides and polar oils
• In general, mixed long-chain glycerides are popular
excipients. They are usually much better solvents for
drugs than triglycerides, unless the drug is highly
lipophilic, and they are also useful components of Type II
and Type III self-emulsifying systems, promoting mutual
miscibility and emulsification.
• Medium-chain mixed glycerides have become popular
excipients, having even greater solvent capacity,
enhanced ability to promote emulsification, and lack of
susceptibility to oxidation.
• However there are complications with medium-chain
excipients in relation to digestion.
27
Mixed glycerides and polar oils
• In addition to mixed glycerides there are a wide variety of related
materials which may be useful, including esters of propylene glycol,
and esters formed between fatty acids and fatty alcohols.
• Other more polar oily excipients are of interest to improve the
solvent capacity and dispersibility of the formulation. Some
excipients which are traditionally thought of as hydrophobic
surfactants, such as sorbitan fatty acid esters (Spans), are very
similar in physical properties to mixed glycerides or propylene glycol
esters.
• The more lipophilic sorbitan fatty acid esters, such as sorbitan
trioleate (Span 85) are alternative polar oils.
• Sorbitan monooleate (Span 80) which has more hydroxyl groups
has also been used widely in pharmaceutical products.
28
Mixed glycerides and polar oils
• In the context of formulation and the desire to promote
mutual miscibility, free fatty acids can be considered to
belong to this general group of polar oils or ‘cosurfactants’.
• Oleic acid has been used in a number of marketed
products.
29
Water-insoluble surfactants
• Non-ionic esters which are not polyethoxylated or
polyglycerylated can be considered to be polar oils.
• In the context of oral lipid-based formulations we refer to
a group of excipients of intermediate HLB (8–12), which
adsorb strongly at oil–water interfaces, as ‘waterinsoluble surfactants’.
• These materials are insufficiently hydrophilic to dissolve
in water and form micelles but nevertheless are
sufficiently hydrophilic to be capable of driving selfemulsification.
30
Water-insoluble surfactants
• The constituents of water-insoluble surfactants will have
a finite solubility in water depending on their degree of
ethoxylation, but solubility is generally very low.
• These surfactants are sometimes described as
‘dispersible’ in water, meaning that they can form an
emulsion if subject to shear. These materials typically
are predominantly oleate esters, such as
polyoxyethylene (20) sorbitan trioloeate (polysorbate
85—‘Tween 85’) or polyoxyethylene (25) glyceryl
trioleate (‘Tagat TO’).
• These two examples have HLB values between 11 and
11.5 and are particularly useful for formulation of Type II
31 systems.
Water-insoluble surfactants
• It should be noted that the properties of these
surfactants cannot necessarily be recreated by blending
materials of different HLB values.
• Polysorbate 80 can be blended with sorbitan monooleate
(i.e. classical Tween 80/Span80 mixtures) to give a
average HLB of 11 but such a blend will contain a
mixture of water-soluble and water-insoluble molecules,
and will not behave in the same way as Tween 85 which
consists predominantly of water-insoluble molecules.
• Tween 85 is polymeric so it will contain a finite fraction of
water-soluble components, but this fraction will not
dominate the fate of the formulation components after
32 dispersion or digestion.
Water-soluble surfactants
• The most commonly used surfactants for formulation of
SEDDS or SMEDDS are water-soluble, though by
definition these materials can only be used in Type III or
Type IV formulations.
• Above their critical micelle concentration these materials
dissolve in pure water at low concentrations to form
micellar solutions.
• This implies an HLB value of approximately 12 or
greater. The fatty acid components can be either
unsaturated or saturated.
33
Water-soluble surfactants
• The popular castor oil derivative Cremophor RH40, is a
typical example of a product with saturated alkyl chains
resulting from hydrogenation of materials derived from a
vegetable oil.
• Its close relative Cremophor EL, which has also been
used widely, has a slightly lower degree of ethoxylation
but is not hydrogenated and is therefore unsaturated.
• Relatively few of the available water-soluble ester
surfactants have been used in pharmaceutical products.
This is a function of their proven safety profile rather than
particular advantages they offer in physicochemical
performance.
34
Water-soluble surfactants
• One intriguing issue in relation to oral bioavailability which has not
been satisfactorily resolved is the extent to which bioavailability is
affected by direct effects of surfactants on drug efflux by Pglycoprotein.
• Cremophors have been implicated as inhibitors of efflux pumps, but
the mechanism of inhibition has not been determined.
• This could be a non-specific conformational change caused by
penetration of surfactant molecules into the plasma membrane,
adsorption of surfactants to the external surface of the efflux pump,
or even interaction of small molecules with the intracellular domains
of the efflux pump.
• The chemical heterogeneity of surfactants such as Cremophors will
make it difficult to establish a precise mechanism.
35
Co solvents
• Several marketed lipid-based products contain watersoluble cosolvents.
• The most popular materials have been PEG 400,
propylene glycol, ethanol and glycerol, though other
approved cosolvents have been used in experimental
studies.
36
Co solvents
• There are at least three reasons why cosolvents have
been included in lipid-based formulations:
37
– Ethanol was used in early cyclosporin products at a low
concentration to aid dissolution of the drug during manufacture.
– More commonly it has been assumed that cosolvents could be
included to increase the solvent capacity of the formulation for
drugs which dissolve freely in cosolvents. However to enhance
the solvent capacity significantly the cosolvent must be present
at high concentration and this is associated with the risk of drug
precipitation when the formulation is dispersed in water.
Cosolvents lose their solvent capacity quickly following dilution.
For many drugs the relationship between cosolvent
concentration and solubility is near to logarithmic.
– A third reason for inclusion of cosolvents is to aid dispersion of
systems which contain a high proportion of water-soluble
surfactants. There are practical limits on the concentrations of
cosolvents which can be used, governed by issues of
immiscibility with oil components and also possible
incompatibilities of low molecular weight cosolvents with capsule
shells.
Additives
• Lipid-soluble antioxidants such as -tocopherol, βcarotene, butylated hydroxytoluene (BHT), butylated
hydroxyanisole (BHA) or propyl gallate could potentially
be included in formulations to protect either unsaturated
fatty acid chains or drugs from oxidation.
38
Choice of Excipients-Mutual Miscibility
• Mutual miscibility of excipients is necessary to produce a clear,
stable, liquid formulation.
• LCT oils are not usually miscible with hydrophilic surfactants or
cosolvents so in practice it is often necessary to blend these
materials with a polar oil (or co-surfactant) to promote mutual
solubility for Type III systems.
• The inclusion of polar oils, such as mixed glycerides, usually has the
added benefit of enhancing dispersion of Type III systems.
• Water-insoluble surfactants are usually miscible with MCT and LCT
oils so that Type II systems can be formulated with just these two
components. Nevertheless polar oils can be added to optimise the
performance of Type II systems.
39
Choice of Excipients-Mutual Miscibility
• Interestingly the affinity of mixed glycerides for both lipophilic and
more polar materials allows mutual solubility to be achieved using
three-component mixtures of MCT oils, medium-chain
mono/diglycerides and cosolvents.
• The chemical diversity of lipid excipients can lead to immiscibility on
long-term storage, so long-term physical stability tests should be
carried out routinely during commercial development projects.
• Problems may result from the common practice of heating waxy
excipients prior to and during blending. This can lead to dissolution
of saturated fatty acid components at elevated temperature, leading
to supersaturation at ambient temperature. Re-crystallization of the
waxy components may take weeks or months once excipients have
been blended.
• Temperature cycling tests may help to identify potential problems
with supersaturation, but anticipation of potential problems is vital.
40
Choice of Excipients-Solvent Capacity
• Triglycerides are poor solvents for all but highly lipophilic
compounds, so most lipid-based formulations contain polar oils,
surfactants and/or cosolvents to improve the solvent capacity of the
anhydrous formulation.
• Many poorly-water soluble drugs are much more soluble in
cosolvents than oils, and such compounds also dissolve in the
polyoxyethylene-rich environment present in water-soluble non-ionic
surfactant materials.
• This naturally encourages formulators to add water-soluble
surfactants and cosolvents at the expense of lipids, ultimately
resulting in the complete exclusion of lipid excipients to produce
Type IV formulations.
• The formulator must balance the advantage of including cosolvents
with the risk of inducing drug precipitation on dispersion.
41
Choice of Excipients-Capsule
compatibility
• Low molecular weight polar molecules present in
capsule formulations are able to penetrate and plasticize
gelatin capsule shells, which restricts the concentration
of propylene glycol and related cosolvents that can be
used in capsule fills.
• Surfactants can also destabilise capsule shells.
42
Solid self-emulsifying drug delivery
system
• SEDDS can exist in either liquid or solid states.
• SEDDS are usually, however, limited to liquid dosage
forms, because many excipients used in SEDDS are not
solids at room temperature.
• Given the advantages of solid dosage forms, S-SEDDS
have been extensively exploited in recent years, as they
frequently represent more effective alternatives to
conventional liquid SEDDS.
43
Solid self-emulsifying drug delivery
system
• From the perspective of dosage forms, S-SEDDS mean
solid dosage forms with self-emulsification properties.
• S-SEDDS focus on the incorporation of liquid/semisolid
SE ingredients into powders/nanoarticles by different
solidification techniques (e.g. adsorptions to solid
carriers, spray drying, melt extrusion, nanoparticle
technology, and so on).
• To some extent, S-SEDDS are combinations of SEDDS
and solid dosage forms, so many properties of S-SEDDS
(e.g. excipients selection, specificity, and
characterization) are the sum of the corresponding
44
properties of both SEDDS and solid dosage forms.
Solidification techniques for transforming
liquid/semisolid SEDDS to S-SEDDS
•
•
•
•
Spray cooling
Spray drying
Adsorption to solid carriers
Melt granulation
• Melt extrusion/extrusion spheronization
45
Spray cooling
• Spray cooling also referred to as spray congealing is a
process whereby the molten formula is sprayed into a
cooling chamber.
• Upon contact with the cooling air, the molten droplets
congeal and re-crystallize into spherical solid particles
that fall to the bottom of the chamber and subsequently
collected as fine powder.
• The fine powder may then be used for development of
solid dosage forms — tablets or direct filling into hard
shell capsules.
46
Spray cooling
• The main parameters for spray cooling are:
– the melting point of the excipient that should range
between 50 and 80 °C,
– the viscosity of the formulation during atomization,
– and the cooling air temperature inside the atomizer to
allow a quick and complete crystallization of droplets.
47
Spray cooling
• The spray cooling technique can be used for
bioavailability enhancement and or sustained release
formulations — depending on the choice of lipid matrix,
and the drug behavior in that matrix (solution or
dispersion).
• The drug loading capacity is limited by formulation
viscosity as dispersions generally tend to be more
viscous than solutions. A maximum of 30% drug loading
capacity has been reported in the literature
48
Spray cooling
• The main class of excipient used with this technique are
polyoxylglycerides and more specifically stearoyl
polyoxylglycerides (Gelucire® 50/13) facilitating the
production of microparticles with narrow size distribution
that exhibit significantly enhanced drug release profiles
for poorly soluble drugs.
49
Spray drying
• Spray drying is defined as a process by which a liquid
solution is sprayed into a hot air chamber to evaporate
the volatile fraction, i.e. the organic solvent or the water
contained in an emulsion.
• The process yields solid microparticles.
50
Spray drying
• This technique involves the preparation of a formulation
by mixing lipids, surfactants, drug, solid carriers, and
solubilization/dispersing them in an organic / aqueous
phase before spray drying.
• The liquid formulation is then atomized into a spray of
droplets. The droplets are introduced into a drying
chamber, where the volatile phase (e.g. the water
contained in an emulsion) evaporates, forming dry
particles under controlled temperature and airflow
conditions.
•51 Such particles can be further prepared into tablets or
capsules.
Spray drying
• The conventional organic solvent used in spray drying is
dichloromethane, a harmful solvent that could be
carcinogenic. However, other solvents could be used
with that technique.
• If the formula is dispersed (emulsified with an aqueous
phase), the product is referred to as a dry emulsion.
• Dry emulsion technology solves the stability problems
associated with classic emulsions (phase separation,
contamination by microorganism, etc.) during storage
and helps also avoid using harmful or toxic organic
solvents. Dry emulsions may be redispersed into water
before use.
52
Spray drying
• The atomizer, the temperature, the most suitable airflow
pattern and the drying chamber design are selected
according to the drying characteristics of the product and
powder specification.
53
Adsorption to solid carriers
• Free flowing powders may be obtained from liquid SE
formulations by adsorption to solid carriers.
• The adsorption process is simple and just involves
addition of the liquid formulation onto carriers by mixing
in a blender.
• The resulting powder may then be filled directly into
capsules or, alternatively, mixed with suitable excipients
before compression into tablets.
• A significant benefit of the adsorption technique is good
content uniformity.
• SEDDS can be adsorbed at high levels (up to 70%
54 (w/w)) onto suitable carriers
Adsorption to solid carriers
•
–
–
–
–
Solid carriers can be:
Microporous inorganic substances,
High-surface-area colloidal inorganic adsorbent
substances,
Cross-linked polymers
Nanoparticle adsorbents,
• For example, silica, silicates, magnesium trisilicate,
magnesium hydroxide, talcum, crospovidone, crosslinked sodium carboxymethyl cellulose and cross-linked
polymethyl methacrylate, porous silicon dioxide (Sylysia
550), carbon nanotubes, carbon nanohorns, fullerene,
charcoal and bamboo charcoal have been used.
55
Adsorption to solid carriers
• These carriers should be selected for their ability to:
– Adsorb a great quantity of liquid excipients (to allow for a high drug
loading and high lipid exposure) and for
– the flowability of the mixture after adsorption.
• The down side of this formulation technique however,
may be the reduced drug loading capacity in the final
dosage form. This is due initially to dilution of the lipid
formulation during mixing with the solid carrier and
subsequent dilution by addition of excipients to obtain
compressible mixtures for tableting.
56
Melt granulation
• As a ‘one-step’ operation, melt granulation offers several
advantages compared with conventional wet granulation,
since the liquid addition and the subsequent drying
phase are omitted.
• Moreover, it is also a good alternative to the use of
solvent.
57
Melt granulation
• The technique necessitates high shear mixing in
presence of a meltable binder which may be sprayed in
molten state onto the powder mix as in classic wet
granulation process.
• This is referred to as “pump-on” technique.
• Alternatively, the binder may be blended with the powder
mix in its solid or semi-solid state and allowed to melt
(partially or completely) by the heat generated from the
friction of particles during high shear mixing — referred
to as “melt-in” process.
• The melted binder forms liquid bridges with the powder
particles that shape into small agglomerates (granules)
58 which can, by further mixing under controlled conditions
transform to spheronized pellets.
Melt granulation
59
Melt granulation
60
Melt granulation
• The progressive melting of the binder allows the control
of the process and the selection of the granule's size.
• Variations of this technique have also been reported in
the literature. For example, fluid bed equipment outfitted
with a rotor may be used as an alternative technique to
produce pellets by melt granulation.
• Also, the melt granulation process may be used for
adsorbing semi-solid self-emulsifying systems on solid
neutral carriers (mainly silica and magnesium
aluminometasilicate).
61
Melt granulation
62
Melt granulation
• The melt granulation technique, also described as
“thermoplastic pelletization”, is effortlessly adaptable to
lipid-based excipients that exhibit thermoplastic
properties.
• A wide range of solid and semi-solid lipids can be
applied as meltable binder for solid dispersions.
• Generally, lipids with low HLB and high melting point are
suitable for sustained release applications.
• Semi-solid excipients with high HLB on the other hand
may serve in immediate release and bioavailability
enhancement.
63
Melt granulation
• A wide range of solid and semisolid lipids can be applied
as meltable binders.
• Gelucire®, a family of vehicles derived from the mixtures
of mono-/di-/tri-glycerides and polyethylene glycols
(PEG) esters of fatty acids, is able to further increase the
dissolution rate compared with PEG usually used before,
probably owing to its SE property.
• Other lipid-based excipients evaluated for melt
granulation to create solid SES include lecithin, partial
glycerides, or polysorbates.
64
Melt granulation
 The melt granulation process was usually used for
adsorbing SES (lipids, surfactants, and drugs) onto solid
neutral carriers (mainly silica and magnesium
aluminometa silicate)
 The main parameters that control the granulation
process are impeller speed, mixing time, binder particle
size, and the viscosity of the binder.
 The main advantages of melt granulation/pelletization
with lipids are:
65
 Process simplicity (one-step)
 Absence of solvents
 The potential for the highest drug loading capacity − 85%
theoretically, and up to 66% actually reported in the literature.
Melt extrusion/extrusion
spheronization
• Extrusion is a procedure of converting a raw material
with plastic properties into a product of uniform shape
and density, by forcing it through a die under controlled
temperature, product flow, and pressure conditions.
• The size of the extruder aperture will determine the
approximate size of the resulting spheroids.
• The extrusion–spheronization process is commonly used
in the pharmaceutical industry to make uniformly sized
spheroids (pellets).
66
Melt extrusion/extrusion
spheronization
• The extrusion–spheronization process requires the
following steps:
– dry mixing of the active ingredients and excipients to
achieve a homogenious powder;
– wet massing with molten binder;
– extrusion into a spaghetti-like extrudate;
– spheronization from the extrudate to spheroids of
uniform size;
– sifting to achieve the desired size distribution
67
Melt extrusion/extrusion
spheronization
• Melt extrusion is a solvent free process that allows high
drug loading as well as content uniformity for low dose
high potency actives.
68
In vitro dissolution
• Unlike conventional dosage forms, from which the drug
substance simply dissolves in the aqueous dissolution
test media, lipid-based formulations release the drug
from an oily solution which is often immiscible with water.
• In evaluating drug release from a lipid-based formulation,
quantification of the surface area of the dispersed oil
droplets is deemed more critical in assessing formulation
performance than is solubilization of drug in the aqueous
test media which, if it occurs at all, is unlikely to be
reflective of in vivo formulation performance.
69
In vitro dissolution
• There are no standard pharmacopoeial methods for
testing lipid-based formulations.
• Release and absorption of drugs from oily dispersions in
vivo is thought to occur subsequent to lipid digestion and
micellization or possibly, via direct transfer from the oil
droplets to the intestinal epithelia, the efficiency of both
processes being proportional to the total oil droplet
surface area.
70
In vitro dissolution
• In the case of formulations which incorporate large
amounts of surfactant (e.g., self-emulsifying
formulations), evaluation of the oil droplet size formed in
a biorelevant aqueous test medium could prove of value
in anticipating drug release in vivo.
• However, in instances where the formulation depends on
gastrointestinal processing for emulsification (e.g., a
simple oily solution of drug), design of a meaningful
release test will require evaluation of drug release from
the formulation in the presence of lipolytic enzymes that
catalyze GI lipid digestion in vivo.
71
In vitro dissolution
• Dispersion testing, i.e. emulsification capacity and
analysis of particle size distribution is often used to
assess the effectiveness of self-emulsifying formulations.
• Emulsification capacity is generally evaluated visually
and particle size distribution can be measured either by
optical microscopy, laser light diffraction or Photon
Correlation Spectroscopy (PCS) depending on the
fineness of the dispersion.
• Dispersion testing is vital for Type III and Type IV
formulations, which may lose solvent capacity on
dispersion due to migration of water-soluble components
into the bulk aqueous phase
72
In vitro dissolution
• Digestion testing is of even greater significance because
it offers the opportunity to predict the fate of the
formulation and drug in the intestinal lumen prior to
absorption.
• Digestion tests are essential for evaluation of Type I,
Type II, and Type III formulations, and given that
surfactants are subject to digestion, probably for Type IV
formulations as well.
73