BIOAVAILABILITY

Formulation approaches to enhance bioavailability

 Formulation approaches to enhance
bioavailability
■ To date, the majority of studies aimed at overcoming food effect have focused on
poorly water-soluble, BCS class II compounds.
■ This has provided a focus for the development of bio-enabling formulations to
improve dissolution and bioavailability, ultimately with the aim of ensuring BCS class
II compounds will behave more like BCS class I compounds in vivo.
 Formulation
approaches to
enhance
bioavailability
Nanosized
preparations
■ Nanosizing refers to the reduction of API
particle size to the submicron range,
typically <500 nm production techniques,
it is possible to achieve particle size in
the 100–200 nm range.
■ The reduction in particle size leads to an
increase in surface area available for
solvation and increases the rate of
dissolution.
■ Nanonisation of API has proven useful in
enhancing the bioavailability of PWSD
(Poorly-Water Soluble Drugs), and
numerous commercial examples exist.
Nanosized
preparations
■ Fenofibrate has been widely investigated as a model PWSD
displaying positive food effect bioavailability.
■ Originally marketed as a comicronised capsule, with an API
particle size of 5–15 µm, which required dosing with food to
achieve maximal absorption of a 200 mg dose, it has
repeatedly been reformulated using different bio-enabling
approaches.
■ Two nanonised preparations of fenofibrate have so far reached
market, namely Tricor®(also marketedas Lipantil® Supra;
prepared using NanoCrystal ® milling technique developed by
Elan Nanosystems) and TriglideTM (prepared via high-pressure
homogenisation).
■ Comparison of absorption from 145 mg nanosised Tricor®
formulation in the fasted and fed state to that of the 160 mg
microcoated tablets demonstrated similar exposure in the fed
state, while absorption from the nanonised tablet was
increased in the fasted state and resulted in the elimination of
a food effect
 Nanosized preparations
■ Aprepitant is a BCS class IV compound which was formulated as a nanoparticle, using
NanoCrystal® technology, during drug development to enhance fasted state dissolution.
■ The final preparation was marketed as EMEND® and was found to improve fasted state
exposure and eliminate the positive food effect seen with early tablet formulations in clinical
development
Nanosized preparations
■ Megestrol acetate is a steroidal progestin which is licensed for use as an appetite
stimulant in anorexia and cachexia. Thus, the positive food effect seen with the original
Megace® oral suspension, along with the 800 mg dose in the relatively large volume of
20 ml suspension was seen as problematic in patients with decreased appetite.
■ Reformulation as the nanocrystalline Megace® ES demonstrated a reduction of food
effect, but also allowed dose reduction to 625 mg administered in 5 ml of the new
formulation.
■ Several other nanocrystalline
preparations have also
demonstrated enhanced fasted state
bioavailability in the fasted state and
elimination of food effect in
preclinical animal models, including
ziprasidone, lurasidone and the
novel gamma secretase inhibitor
ELND006.
 Amorphisation and solid dispersion
■ By reducing the drug particle size to the
molecular level rapid dissolution can be
facilitated, and production of an amorphous
form will improve the apparent solubility, while
solid dispersion can also confer improved
wettability, increased porosity and, ultimately,
improved biopharmaceutical performance
■ Solid dispersions are being used increasingly
often as bio-enabling formulations for PWSD to
enhance oral bioavailability and numerous
commercial preparations exist. These
preparations most often exist as amorphous
drug dispersed in an inert carrier matrix, and
this narrow definition has been used to
describe their behaviour.
■ Kaletra®, (lopinavir/ritonavir) originally been formulated
as a soft gelatin capsule containing lipid excipients
required to be taken with food, with a 48% increase in
bioavailability.
■ Poor solubility of the API was limited to an 80/20 mg
strength capsule
■ Solid dispersion technology, specifically hot-melt
extrusion using PVP/VA production of a 200/50 mg
tablet reducing the pill burden from 10 capsules daily to
four tablets daily AND allowing food-independent dosing.
lopinavir/ritonavir
 Que es la extrusión en caliente (hot-
melt extrusion)
■ En el proceso de hot-melt extrusion, los
ingredientes farmacéuticos activos (IFA) y
excipientes se mezclan y funden a alta
temperatura para formar una masa
homogénea y viscosa, que luego se extruye a
través de una boquilla para obtener una
estructura continua y uniforme, como
filamentos, gránulos o películas. La extrusión
en caliente permite la incorporación de IFA y
excipientes en una matriz amorfa o
cristalina, lo que puede mejorar
significativamente sus propiedades de
solubilidad y liberación controlada
Ventajas de la hot-melt extrusion en
medicamentos:
■ Mejora de la solubilidad: La técnica HME puede convertir IFA con baja solubilidad en
agua en una forma amorfa o dispersa, lo que aumenta su solubilidad y, por lo tanto, su
biodisponibilidad.
■ Liberación controlada: La extrusión en caliente permite la formulación de sistemas de
liberación modificada, donde el medicamento se libera gradualmente en el cuerpo, lo
que puede mejorar la eficacia del tratamiento y reducir la frecuencia de dosificación.
■ Estabilidad: La matriz amorfa formada durante el proceso de HME puede mejorar la
estabilidad química y física del medicamento.
■ Formulación de combinaciones: La HME permite la formulación de medicamentos
combinados, donde múltiples ingredientes farmacéuticos activos o excipientes pueden
combinarse en una sola formulación.
■ Reducción de dosis: La mejor solubilidad y biodisponibilidad pueden permitir la
reducción de la dosis necesaria para lograr el efecto terapéutico deseado.
■ Lynparza® (olaparib) has been olaparib in
Gelucire®, to a hot-melt extrusion based
dispersion as a carrier.
■ While the original formulation, relatively low
drug loading (10%) led to a significant pill
burden for patients (16 capsules daily).
■ The development of the melt extrusion tablet
formulation (reformulated from a lipid-based,
crystalline solid dispersion of micronized using
copovidone ) both increased Olaparib
bioavailability and drug loading, allowing a dose
reduction from 400 to 300 mg twice daily, and
reduced the pill burden to four tablets daily.
■ The food effect was also reduced, with a 20%
increase in exposure observed for the capsule
compared to a 9% increase with the tablet
formulation.

■ Ver patente
■ ziprasidone solid dispersion via hot-melt extrusion,
which retained crystalline characteristics of ziprasidone
while suspending the drug in a hydrophilic matrix to
improve wettability and dissolution, resulting in a nearly
10-fold increase in solubility.
■ The enhanced dissolution translated to improved
bioavailability in fasted healthy volunteers, while
simultaneously eliminating the positive food effect
observed with the commercial Zeldox® formulation
Lipid-based formulations
■ The ability of food to enhance the absorption of PWSD
has long been attributed to the ability of meal
components, and in particular lipids, to enhance drug
solubilisation, dissolution and absorption.
■ Thus, the addition of exogenous lipids to pharmaceutical
preparations was proposed and investigated as a viable
option to enhance the bioavailability of PWSD.
■ Charman et al. demonstrated that the approximately
threefold increase in Cmax and AUC observed for a
commercial danazol capsule formulation (Danocrine®)
was eliminated using a lipid emulsion of danazol in
glycerol mono-oleate.
■ The commercial success of self-emulsifying drug delivery system (SEDDS) formulation of
Neoral® owing principally to its elimination of the food effects and reducing intersubject
variability relative to the crude lipid emulsion formulation of Sandimmune®.
■ Delivery as a crude emulsion was not sufficient to overcome the food effect, which required a
more elaborate SEDDS formulation.
 Que son los self-emulsifying drug delivery system (SEDDS)
(sistemas de liberación autoemulsificables)
■ Los sistemas de liberación autoemulsificable
(también conocidos como sistemas de liberación
autoemulsionante) son formulaciones
farmacéuticas diseñadas para mejorar la
solubilidad y la biodisponibilidad de medicamentos
con baja solubilidad en agua o baja permeabilidad
intestinal.
■ Estos sistemas emplean la formación espontánea
de emulsiones en el tracto gastrointestinal para
facilitar la absorción del medicamento y, en
consecuencia, mejorar su eficacia terapéutica
 SEDDS

Consisten en tres componentes

principales:
1. Aceite: Un compuesto lipofílico
(soluble en lípidos) que transporta el
principio activo del medicamento.
2. Emulsionante: Un surfactante o
mezcla de surfactantes que ayuda a
dispersar y estabilizar el aceite en el
agua para formar una emulsión.
3. Cosurfactante (o coemulsionante):
Un componente adicional que puede
mejorar la estabilidad de la emulsión y
su capacidad para formarse en el
tracto gastrointestinal.
 SEDDS

Cuando el sistema de liberación autoemulsificable

entra en contacto con el contenido gástrico, las
contracciones intestinales y la acción de las enzimas
digestivas facilitan la formación de microemulsiones o
emulsiones de tamaño nanométrico.
Estas emulsiones aumentan significativamente la
superficie de contacto entre el medicamento y las
membranas mucosas, lo que mejora la absorción a
través de la barrera intestinal y, por lo tanto, aumenta
la biodisponibilidad del principio activo.
■ Roaccutane® is a soft gelatin capsule,
which contains isotretinoin solubilised
in water-insoluble solvents, namely
beeswax, soya bean oil and
hydrogenated soya bean oil, which
displays an approximately 2.7-fold
increase in bioavailability in the fed
compared to fasted state.
■ Absorica® is a novel isotretinoin
formulation developed using Lidose®
technology, which enhanced the
fasting state bioavailability and
reduced the food effect to a 1.5- fold
increase, which is not considered to
be clinically significant and allows
food-independent dosing
■ Fortovase®, a SEDDS formulation
designed to improve the oral
bioavailability of saquinavir,
relative to the conventional
capsule formulation, Invirase®.

■ While bioavailability was

enhanced approximately
threefold by Fortovase®, a
significant food effect was still
evident, with a similar increase in
the fed state to that observed
with Invirase® (6.7-fold increase).
 Otros
fármacos que
han mejorado
su BD con
SEDDS
Otros fármacos
que han
mejorado su
BD con SEDDS
Otros fármacos que
han mejorado su
BD con SEDDS
 ■ Cyclodextrins have been widely used to enhance the
oral bioavailability of lipophilic and poorly water-soluble
Ciclodextrinas drugs, in both preclinical animals and in humans.
■ The bioavailability enhancing effects are mainly due to
enhanced dissolution kinetics, increased solubility and
potential reduction in degradation as well as increased
permeability.
■ Las ciclodextrinas son oligosacáridos cíclicos
que se utilizan en la industria farmacéutica y
en otros campos para mejorar la solubilidad,
estabilidad y biodisponibilidad de ciertos
medicamentos y compuestos.
■ Estas moléculas son anillos cíclicos formados
por la unión de glucosas mediante enlaces
glucosídicos. La estructura cíclica de las
ciclodextrinas crea una cavidad hidrofóbica
en su interior y una superficie hidrofílica en
el exterior, lo que les confiere la capacidad
única de capturar moléculas hidrofóbicas en
su interior formando inclusiones. Esta
característica es la que permite que las
ciclodextrinas se utilicen como excipientes en
formulaciones farmacéuticas
Las ciclodextrinas más comúnmente utilizadas en
medicamentos son la alfa-ciclodextrina (α-
ciclodextrina), la beta-ciclodextrina (β-
ciclodextrina) y la gamma-ciclodextrina (γ-
ciclodextrina).
¿Cómo se usan las ciclodextrinas en los
medicamentos?
■ Mejora de la solubilidad: aumentan la
solubilidad de los farmacos poco solubles en
agua, facilita absorción y biodisponibilidad.
■ Protección de principios activos: pueden
proteger de la degradación química, lo que
mejora la estabilidad del medicamento.
■ Mejora de la estabilidad: Al formar complejos
de inclusión con moléculas inestables, pueden
protegerlas de la luz, el oxígeno y otras
condiciones que podrían degradar el principio
activo.
Las ciclodextrinas más comúnmente utilizadas en
medicamentos son la alfa-ciclodextrina (α-
ciclodextrina), la beta-ciclodextrina (β-ciclodextrina) y
la gamma-ciclodextrina (γ-ciclodextrina).
¿Cómo se usan las ciclodextrinas en los
medicamentos?
■ Modificación del perfil de liberación: permitiendo
la liberación sostenida y controlada en el
organismo.
■ Enmascaramiento de sabor y olor: pueden
enmascarar sabores y olores desagradables de
ciertos medicamentos, mejorando así la
aceptabilidad del producto.
■ Reducción de interacciones no deseadas: pueden
reducir las interacciones no deseadas entre
medicamentos y excipientes en formulaciones
farmacéuticas, lo que mejora la compatibilidad y
la estabilidad general del producto
■ Sporanox® (itraconazole) has been formulated both as
an amorphous solid dispersion, which displayed
significant, positive food effect and as an oral solution
solubilised by hydroxypropyl-b-cyclodextrin inclusion
complex.
■ Sporanox® cyclodextrin solution has demonstrated
higher bioavailability than Sporanox capsules in the fed
state and has also been demonstrated to show
enhanced bioavailability in the fasted state,
eliminating the need for fed state dosing
■ have demonstrated that a sulfobutyl ether- β -
cyclodextrin (SBE-β-CD) inclusion complex
enhanced fasted bioavailability and eliminated food
effect for ziprasidone relative to the comercial
preparation Geodon® in beagle dogs.
■ Have recently demonstrated similar results with an
SBE-β-CD complex of amiodarone
What is a bioenhancer?
■ Is an agent capable of enhancing bioavailability and bioefficacy of a particular drug
with which it is combined.
■ Piperine is the world's first bioavailability enhancer coined and scientifically
validated
■ The benefits of adding a bioenhancer include reduced drug dosage, reduced cost of
the drug, reduced incidence of drug resistance and reduced risk of adverse drug
reaction/side effects, reduced requirement of raw material for drug manufacture.
Mechanism of action of bioenhancers
May increase the bioavailability of nutraceuticals
by:
■ acting on gastrointestinal tract to enhance
absorption, or by acting on drug metabolism
process i.e. inhibiting or reducing the rate of
biotransformation of drugs in the liver or
intestines,
■ modifying the signaling process between host
and pathogen ensuring increased
accessibility of the drugs to the pathogens,
■ inhibiting efflux mechanisms frequently
encountered with antimalarials, anticancer,
antimicrobials etc
CLASSIFICATION
OF THE
BIOENHANCERS
 Solubilizers as bioenhancers
Fulvic Acid
■ is characterized by having a sponge-like structure
punctured by voids of about 200-1000 Å in diameter
and a molecular weight, (Mw) of about 700 – 2500.
■ A water-insoluble ingredient can be added to the
purified fulvic acid carrier in an amount of about 0,5
to 40% by weight of the fulvic acid carrier filling its
voids and this potentiates the bioactivity of a drug,
nutritional or cosmetic ingredient.
■ This can be done physical mixing of drug and carrier
and/or chemical bonding of drug and carrier like
ligand-complex/chelation, reversible covalent
bonding and/or charge-transfer complexes etc.
 Gelucires
■ Gelucires are polyethylene glycol (PEG)
glycerides composed of mono-, di- and
triglycerides and mono- and diesters of PEG.
■ They are inert semi-solid waxy amphiphilic
excipients with surfaceactive properties that
spontaneously form a fine dispersion or
emulsion upon contact with water to
produce immediate-release solid dosage
forms for poorly water-soluble drugs.
 Gelucires
■ Peroral bioavailability of silymarin, a
herbal hepatoprotectant through the
formation of semisolid dispersion
system with Gelucire 44/14
■ Binary systems were prepared by the
solvent –fusion method and confirmed
by DSC. Increase in solubility of
silymarin semisolid dispersion was
observed (1.5 to 7.0 folds relative to
pure silymarin at 1% to 15% Gelucire
44/14 concentrations) which in turn
increased the dissolution rate of
silymarin-Gelucire system (91% within
10 minutes).
Gelucires
■ Carotenoid compositions of enhanced
solubility and bioavailability are
described in patent literature. The
carotenoid can be β-carotene,
lycopene or lutein.
■ The bioenhanced products were made
by dry blending and solvent spray
drying methods where a mixture
comprising of the carotenoid, a
solubility-enhancing polymer and a
solvent was used and the solvent was
removed to produce an amorphous
form of the carotenoid.
■ These bioenhanced compositions of
carotenoids can be used in
pharmaceuticals, nutraceuticals,
cosmetic, and personal care products
for man and animal.
P-glycoprotein
inhibitors as
bioenhancers
■ P-gp inhibitors reduce P-gp
active drug transport across
the luminal membrane and
prevent return of drugs
absorbed into the cytoplasm of
the enterocytes back to the
lumen of the gut.
■ This increases bioavailability
by increasing net drug
absorption in the gut
P-glycoprotein inhibitors as
bioenhancers
Inhibitors of cytochrome P450 3A drug
biotransformation as bioenhancers
■ The liver and enterocytes lining the lumen of the
intestine contains many isoforms of cytochrome
P450 but mostly dominated by a single family of
isozymes, 3A, the most important isoforms in
drug metabolism.
■ Inhibition of CYP3A by bioenhancers in gut
epithelia will lead to a total increase in drug
bioavailability in the serum.
■ Fewer drug molecules will be metabolized by
phase I enzymes in the gut and will not be
available for phase II conjugation enzymes.
 Gallic acid esters
■ investigated the potential
pharmacokinetic interactions of
rosuvastatin (RSV) with herbal
bioenhancers (such as piperine,
gallic acid and cinnamic acid) in
healthy male C57 BL/6 mice. After
per oral (p.o.) coadministered of RSV
(5 mg/kg) with piperine, gallic acid
and cinnamic acid (5 mg/kg)
intravenous exposure (AUClast)
significantly increased by 174.51%,
176.65% and 181.08% respectively
than alone group (control).
Compared with the control (alone) group, p.o. co-
administered of piperine, gallic acid and cinnamic
acid (5 mg/kg) significantly increased the oral
exposure (AUClast) of RSV (25 mg/kg) by 1.35-
fold, 1.66-fold and 1.62 –fold respectively.
The absolute oral bioavailability of rosuvastatin
alone increased from 33 % upto 45, 56 and 54%
with rosuvastatin co-administered with per oral
dose of piperine, gallic acid and cinnamic acid
respectively showing 15, 19 and 18% increase in
oral availability of rosuvastatin when co
administered with piperine, gallic acid and
cinnamic acid respectively in C57BL/ 6 male mice
BCRP inhibitors as bioenhancer
■ Breast Cancer Resistance Protein (BCRP) is a protein
overexpressed in breast carcinoma cell lines.
■ The oral administration of BCRP inhibitors together with
pharmaceutical compounds enhances the
bioavailability of the latter.
■ Thus, bioenhancer being an inhibitor of BCRP mediated
or related transport for enhancing the bioavailability of
an orally administered drug in tumor cells, could be a
useful target to approach with a view to increasing oral
bioavailability of drugs
■ The BCRP inhibitor inhibits drug back flux from the
blood or epithelial lumen.
■ Thus, the return of drugs absorbed into the cytoplasm
of enterocytes back to the lumen of the gut is inhibited
GRACIAS