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lipid-based delivery systems for oral administration

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Title: lipid-based delivery systems for oral administration


1
lipid-based delivery systems for oral
administration
  • Lipid-based delivery systems range from simple
    oil solutions to complex mixtures of oils,
    surfactants, co-surfactants 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)

2
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.

3
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 saltlecithin mixed micelles, a fine
    colloidal dispersion which promotes absorption
    and.

4
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

5
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

6
The Lipid Formulation Classification System
7
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).

8
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 35 excipients, including water-insoluble
    and water-soluble surfactants, as well as water
    miscible cosolvents.

9
The Lipid Formulation Classification System
  • Precipitation of a lipophilic drug after 1/100
    dilutions of Types II, IIIA, IIIB and IV
    lipid-based 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 II15 w/w Miglyol 812, 35
    Imwitor 988, 50 Tween 85 Type IIIA15 w/w
    Miglyol 812, 35 Imwitor 988, 50 Tween 80 Type
    IIIB50 Imwitor 308, 50 Tween 80 Type IV50
    Tween 80, 50 propylene glycol.

10
Excipients for lipid formulations
  • A wide range of triglycerides, partial
    glycerides, semi-synthetic oily esters, and
    semi-synthetic non-ionic surfactants esters are
    available from excipient suppliers.

11
Excipients for lipid formulations
12
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.

13
Excipients for lipid formulations
  • Lipid-based delivery systems usually only include
    non-ionic 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).

14
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 well-tolerated 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

15
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 24 times daily, so that
    patients are ingesting 23 g Cremophor or TPGS
    (Tocopheryl polyethylene glycol 1000 succinate )
    daily.
  • Sandimmune Neoral Capsules.

16
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.
  • http//www.accessdata.fda.gov/scripts/cder/iig/in
    dex.cfm

17
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.

18
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.

19
HO-CH2-(CH2-O-CH2-)n-CH2-OH
Polyoxyethylene
Polyglycerol monooleate n2 or 3
Polyglycerol mono laaurate n 2 or 3
20
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 ???? ????????
    into formulation design (robustness), so that
    the product is not compromised by inevitable
    variation in chemical composition of the
    excipients used.

21
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.

22
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.

23
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 (5080) and C10 (2045) fatty
    acids.

24
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.

25
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.

26
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.

27
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.

28
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.

29
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 co-surfactants.
  • Oleic acid has been used in a number of marketed
    products.

30
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 (812), which adsorb strongly at oilwater
    interfaces, as water-insoluble surfactants.
  • These materials are insufficiently hydrophilic to
    dissolve in water and form micelles but
    nevertheless are sufficiently hydrophilic to be
    capable of driving self-emulsification.

31
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 85Tween 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 systems.

32
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 dispersion or
    digestion.

33
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.

34
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.

35
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 P-glycoprotein.
  • 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.

36
Co solvents
  • Several marketed lipid-based products contain
    water-soluble cosolvents.
  • The most popular materials have been PEG 400,
    propylene glycol, ethanol and glycerol, though
    other approved cosolvents have been used in
    experimental studies.

37
Co solvents
  • There are at least three reasons why cosolvents
    have been included in lipid-based formulations
  • 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.

38
Additives
  • Lipid-soluble antioxidants such as -tocopherol,
    ß-carotene, 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.

39
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.

40
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.

41
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-ric
    h 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.

42
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.

43
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.

44
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 properties of both SEDDS and solid
    dosage forms.

45
Solidification techniques for transforming
liquid/semisolid SEDDS to S-SEDDS
  • Spray cooling
  • Spray drying
  • Adsorption to solid carriers
  • Melt granulation
  • Melt extrusion/extrusion spheronization

46
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.

47
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.

48
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

49
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.

50
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.

51
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.
  • Such particles can be further prepared into
    tablets or capsules.

52
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.

53
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.

54
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
    (w/w)) onto suitable carriers

55
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, cross-linked 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.

56
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.

57
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.

58
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) which can, by further
    mixing under controlled conditions transform to
    spheronized pellets.

59
Melt granulation
60
Melt granulation
61
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).

62
Melt granulation
63
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.

64
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.

65
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/pelletizat
    ion with lipids are
  • 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.

66
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 extrusionspheronization process is commonly
    used in the pharmaceutical industry to make
    uniformly sized spheroids (pellets).

67
Melt extrusion/extrusion spheronization
  • The extrusionspheronization 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

68
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.

69
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.

70
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.

71
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.

72
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

73
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.
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