Brief communication

Pan American Journal

of Public Health

Innovative in vitro methodologies for

establishing therapeutic equivalence
Lisa Murray,1 Antonio Arias,2 Jibin Li,3 Sid Bhoopathy,3 and Ismael J. Hidalgo3

Suggested citation

Murray L, Arias A, Li J, Bhoopathy S, Hidalgo IJ. Innovative in vitro methodologies for establishing
therapeutic equivalence. Rev Panam Salud Publica. 2016;40(1):2328.

ABSTRACT

To improve the quality of pharmaceutical products in their markets, several Latin American
countries have begun to require that new generic products demonstrate bioequivalence against
innovator or reference products. However, given the number of products involved, it is not
feasible to rely on clinical studies to comply with this requirement. Instead, it makes sense to
adopt or develop strategies that are appropriate to the characteristics of the region.
To streamline drug development and accelerate patients access to quality drug products,
15years ago the United States Food and Drug Administration (FDA) decided to grant
exemptions from clinical bioequivalence studies (i.e., biowaivers) for certain types of drug
products based on the Biopharmaceutics Classification System (BCS). Biowaivers can

significantly reduce development time and cost and can also prevent unnecessary human
exposure to potentially dangerous drugs while providing a robust, consistent standard for
therapeutic equivalence of generic drug products.
In addition, the limited success of translating in vitro dissolution data into in vivo
performance can be enhanced using innovative tools such as the in vitro dissolution and
absorption systems (IDAS). By integrating in vitro dissolution and permeability tests, these
systems can provide useful insights for formulation development. A thorough assessment of the
potential of in vitro techniques, along with formalization of their use through regulatory
science initiatives when appropriate, may lead to cost-effective tools to help address some of the
quality and regulatory challenges faced in the Latin American and Caribbean region.

Key words

Biopharmaceutics; dissolution; permeability; absorption; therapeutic equivalency;

quality control.

Cost control pressure, poor manufac

turing practices, and inadequate regu
lation in the Latin American and
Caribbean region contribute to the
prevalence of substandard and coun
terfeit medications. Two examples of
the potentially disastrous consequences
Provenir, LLC, Garnet Valley, Pennsylvania,
United States of America.
Absorption Systems Panam, Panama City,
Panama.
3
Absorption Systems, Exton, Pennsylvania, United
States of America. Send correspondence to:
Dr.Ismael J. Hidalgo, [email protected]
1

Rev Panam Salud Publica 40(1), 2016

of insufficient testing of pharmaceuti

cal products were experienced in Pan
ama when, in 2007, 365 deaths resulted
from counterfeit glycerin (diethylene
glycol) added to 260000 bottles of cold
medicine (1) and, in 2014, nine neo
nates died after receiving nutritional
heparin containing benzyl alcohol (2).
Attempts to control pharmaceutical
product quality by analyzing one or
more product lots during the registra
tion process (e.g., every 5 to 7 years),
with minimal or no additional evalua
tion of product lots produced in the

intervening years, do little to mitigate

the concern that the product lots actu
ally ingested by patients can be dif
ferent from those submitted for
registration. On the other hand, the in
discriminate use of quality control tests
not sensitive enough to monitor sub
standard or counterfeit medications
can compound the problem because
they may provide a false sense of secu
rity. To increase access to the therapeu
tic benefits of pharmaceutical products
there is a pressing need to identify
alternative tools and approaches that

23

Brief communication

permit evaluation and monitoring of

the bioequivalence of products in the
market.

Establishing Equivalence of
Generic Drug Products
The United States Food and Drug
dministration (FDA) and its counter
A
parts in all highly regulated pharmaceu
tical markets demand that generic drug
products meet the same standards of
quality, efficacy, and safety as their refer
ence listed drug (RLD) counterparts.
Consistent with this premise, procedures
have been established to demonstrate
that generic products are therapeutically
equivalent and interchangeable with
RLDs. Therapeutic equivalence (TE) is
generally achieved by assuring pharma
ceutical equivalence (PE) and bioequiva
lence (BE) of the generic to the RLD
products (3). Because implementation of
BE requirements based on clinical stud
ies would be prohibitively expensive,
there is an incentive to develop or iden
tify in vitro methods that can be used to
evaluate and monitor the registration
lots and also ensure the inter-lot consis
tency of a product.

In Vitro Tools for Establishing

Equivalence
In general, orally administered solid
drug products disintegrate and dis
solve in the stomach and are absor
bed in theintestine. The solubility and
permeability of the active ingredi

entand the drug product dissolution

the key determinants of intestinal
absorptionare extremely difficult to
determine in vivo. Therefore, the use of
in vitro tools is necessary to study these
characteristics.
Since drug product dissolution is a
prerequisite for the process of absorp

tion, dissolution tests are widely per

formed as an integral component of the
battery of routine quality control tests for
solid oral dosage forms. Thus, in princi
ple, the establishment of in vitroin vivo
correlations (IVIVCs), whereby the disso
lution rate may serve as a surrogate for
systemic exposure (e.g., bioavailability,
area under the curve (AUC), or Cmax), is
highly desirable because it could reduce
the number of BE studies required for
generic drug product development and
registration (4). Although IVIVCs can be
very advantageous to quality control

24

Murray et al. Innovative in vitro methodologies

efforts, they are difficult to demonstrate,

partly because in vitro dissolution tests
do not mimic either the rate or
mechanism(s) of drug release in vivo. The
implementation of in vitro methodologies
as alternatives to clinical BE studies has
been facilitated by progressive regula
tory guidelines such as the Biopharma
ceutics Classification System (BCS) and
could benefit from the inclusion of inno
vative technical a pproaches, such as the
in vitro dissolution absorption systems
(IDAS) discussed below.

Biopharmaceutics Classification
System
The BCS provides a scientific frame
work for drug classification based on
measurements of drug solubility and
permeability, the primary determinants
of drug absorption, and serves as an im
portant tool for the application of in vitro
measurements in support of BE require
ments. The BCS is an excellent example
of a successful regulatory initiative that
has resulted in biowaivers, exemptions
from clinical BE studies, for dozens of
oral products. For over 15 years, the FDA
permitted biowaivers for Class I drugs in
rapidly dissolving immediate-release
solid oral dosage forms (5), and in the re
cently updated BCS guidelines (6) it ex
panded biowaiver eligibility to Class III
drugs. According to a recent survey,
Classes I and III combined account for
63% of the top 200 selling drugs (7), sug
gesting that full implementation of the
BCS could result in a major reduction in
the number of clinical BE studies. In ad
dition to reducing costs, in vitro studies
prevent unnecessary exposure of healthy
subjects to potentially adverse drug
events and even deaths (7, 8) without
compromising the high quality stan
dards necessary to safeguard public
safety.

In Vitro Dissolution and

AbsorptionSystems
The in vitro dissolution absorption sys
tem 1 (IDAS1) is the product of major
modifications made to a device (the disso
lution/permeation, or D/P, system) origi
nally developed by Prof. Yamashita at
Setsunan University in Japan (9). IDAS1
represents a physiologically relevant
invitro system for the evaluation of drug
formulations. It comprises four compo
nents: dissolution-permeation chamber

(Figure 1A), magnetic stirring bar motor,

motor controller, and temperature block.
The dissolution-permeability chamber
consists of two half-chambers separated
by a cell membrane, typically polarized
epithelial cells such as human intestinal
cell Caco-2 cells or Madin-Darby canine
kidney cells grown on a microporous
membrane. While the internal design of
the IDAS1 chamber is very similar to that
of the D/P chamber, they differ in the
chamber locking mechanism, external
size and shape, type of motor (step versus
brushless), ability of the controller to dis
play the stirring speed (rpm), and the use
of a heating block as opposed to an incu
bator in the D/P system, which avoids the
need to open the incubator repeatedly for
sample withdrawal.
The potential utility of IDAS1 has been
shown in numerous studies performed
with the precursor D/P chamber system
(914). In vivo, drug product dissolution
does not need to be completed before
drug absorption can start; however,
product dissolution and drug permea
bility are measured independently,
largely under nonphysiological condi
tions. Thus, the strength of IDAS1 is its
ability to allow the concomitant evalua
tion of dissolution and permeability.
Invitro data obtained in a system that
replicates the in vivo dissolution-perme
ability interplay should be more translat
able into in vivo product performance.
Whereas other in vitro systems for per
meability measurement require adminis
tration of the drug as a solution or
suspension, IDAS1 is unique in that the
contents of a capsule or crushed tablet
may be applied in solid form into the
mucosal chamber.
To increase the physiological relevance
of these experiments, biorelevant media
are often used to mimic the gastrointestinal
environment. The apical (mucosal) cham
ber buffer can contain bile acids and leci
thin at concentrations to produce fasted
(FaSSIF) or fed (FeSSIF) state simulated in
testinal fluids, and the basolateral (serosal)
chamber contains 4.5% albumin to mimic
the blood plasma. Prior data with the D/P
system (9) and our own data with IDAS1
not only provided evidence of the impact
of dissolution rate on permeation but also
found a good correlation between in vitro
permeation and fraction absorbed in hu
mans, suggesting that this system is useful
for the study of oral absorption of drugs
with poor aqueous solubility (9). Kataoka
et al. reported that the albendazole

Rev Panam Salud Publica 40(1), 2016

Murray et al. Innovative in vitro methodologies

Brief communication

FIGURE 1. (A) Schematic representation of the in vitro dissolution absorption system 1 (IDAS1); (B) correlation between IDAS1
dissolution and permeability values, depicted as percent per 2 hours, and in vivo human absorption
(A)

(B)
Drug

Sampling

Mucosal
Solution

Stirring Bar

Caco-2 Monolayer

permeation (percent dose absorbed at

2hours) in vitro under simulated fed and
fasted conditions was in agreement with in
vivo findings and concluded that the sys
tem can be used to study foods effect on
drug absorption (10).
A good correlation between in vitro
permeation and systemic absorption
(AUC and Cmax) in the rat was observed
for fenofibrate (11, 13). The study com
pared six fenofibrate tablet formulations.
The in vitro data showed a good correla
tion with Cmax but not AUC in humans,
and the most likely explanation for the
apparent lack of correlation for AUC is
micellar entrapment of the drug. This
conclusion is supported by a recent
study that compared two capsule formu
lations containing nanosized and micro
nized fenofibrate formulations (15).
Using IDAS1, Class II drugs that were
completely dissolved within 2 hours
reached the highest experimental per
cent permeation values, ranging be
tween ~23 and ~28 (Figure 1B). This is
consistent with in vivo data since the ab
sorption in humans of these compounds
was at least 85% (16), the threshold de
fined by both the FDA and the European
Medicines Agency for complete absorp
tion (5, 17). For compounds with sub
stantial but incomplete dissolution (e.g.,
simvastatin and carbamazepine) experi
mental percent permeation at 2 hours

Rev Panam Salud Publica 40(1), 2016

Sampling

Serosal
Solution

Stirring Bar

Drugs

BCS
Class

%Diss.
(in 2h)

%Perm.
(in 2h)

%Abs.

Warfarin Sodium

II

100

27.5

93.5

Piroxicam

II

90

26.9

95

Amlodipine

I/III

100

6.78

6490

Atenolol

III

100

0.23

50

Carbamazepine

II

86.1

10.2

83

Albendazole

II

0.45

0.42

20

Ranitidine

III

100

0.15

50

Simvastatin

II

46.2

11.0

73

Ketoprofen

II

98.2

22.8

85

was ~10, and their absorption in

humansis slightly lower (73% and 83%,
respectively) (16, 1819). Albendazole,

known to have a low (20%) absorption

inhumans (16), had very low dissolution
and a low percent permeation at 2 hours
(0.42) in IDAS1. Since the main
absorption barrier for Class III drugs is
the cell membrane, values for percent
permeation at 2 hours were low
foratenolol and ranitidine (0.23 and
0.15,
respectively) despite complete
dissolution, consistent with a 50% oral
absorption in humans for both drugs
(16). These data illustrate the potential
versatility of this type of system, which,
as detailed above, has been successfully
applied to the evaluation of several
aspects of

formulation development
and/or characterization.
The IDAS1 device also makes it possi
ble to obtain dissolution/absorption
profiles for candidate formulations.

Dissolution can be affected by excipients,

crystal polymorphism, pH, and buffer
composition, whereas absorption can be
affected by formulation excipients and
buffer composition. These variables can
also affect the solubility of the active
ingredient(s). For example, the active

ingredient may have limited solubility

inbiological buffers, but the solubility

limit may never be reached if the
absorption rate equals or exceeds the rate

of dissolution. This situation can be

expected with some BCS Class I and II
drugs, but it is very unlikely for
ClassIIIand IV drugs, which have poor
absorption. Data from IDAS1 will

allow

scientists to assess the effect

ofexcipients on dissolution and permea
bility and to evaluate multiple itera
tionsof formulation modifications at a
higher throughput.
The in vitro dissolution absorption sys
tem 2 (IDAS2) is a more recent innovation
(20). It consists of a novel, specially
designed dissolution-vessel lid with an

attached permeability chamber that is

compatible with commercially available
dissolution apparatuses (Figure2A). Ex
periments with IDAS2 are performed in
two consecutive phases. In Phase 1, a tab
let or capsule is added to the dissolution
vessel that contains a biorelevant me
dium; the contents are stirred at a prede
termined speed (e.g., 25 to 50 rpm) and
allowed to undergo dissolution for 15 to
30 minutes. If the dissolution medium is
acidic (e.g., fasted-state simulated gastric
fluid, FaSSGF), it must be modified after
Phase 1 to mimic the intestinal content. To
this end, in a single step a concentrated
buffer is added to increase the pH to 6.5
and introduce bile acids and lecithin at
appropriate concentrations to mimic

theintestinal contents under fed or

fastedconditions. Immediately after this

25

Brief communication

Murray et al. Innovative in vitro methodologies

transfer, the IDAS2 chamber containing

the cell monolayer is introduced into the
dissolution medium, and the dissolutionpermeation phase (Phase 2) is initiated.
Donor samples are withdrawn from the
bulk fluid in the dissolution vessel at vari
ous time points during both phases to as
certain dissolution rate and donor
concentration. Multiple samples from the
receiver compartment are taken from the
IDAS2 chamber (basolateral, serosal)
during Phase 2 of the assay. A unique

feature of IDAS2 is that it permits the

assessment of intact, clinical-size dosage

forms. In addition, the use of 250 mL
dissolution media replicates the dose/

volume ratio expected in the gastrointesti

nal tract after the administration of a
tablet (or capsule) with a glass of water.
Recent experiments with propranolol
and warfarin tablets in IDAS2 high
light the potential utility of the system.
The initial dissolution rate of propra
nolol was slightly higher than that of
warfarin, but both products were
completely dissolved in 30 minutes

(Figure 2B). Despite having a higher in

trinsic permeability due to its initially
slower dissolution, the percent perme
ation of warfarin was almost the same

as that of propranolol. However, when

the dissolution of warfarin reaches a
solubilized amount comparable to that
of propranolol (i.e., after 30 minutes),
as expected warfarin had a much faster
rate of permeation than propranolol
(Figure 2C). This example demon
strates the ability of IDAS2 to reveal
the dissolution-permeability interplay.
Evolving experience with IDAS1 and
IDAS2 suggests that they have the
potential to become important tools in

formulation development and regulatory

oversight of drug product quality. Their
roles are naturally complementary; IDAS1
is primarily useful in excipient selection
and formulation development/optimiza
tion, whereas IDAS2 is mainly deployed
in the comparison of multiple intact prod
ucts (tablets or capsules). Even when clin
ical BE studies are necessary, the
information derived from IDAS1 and
IDAS2 could be used to inform the exper
imental design of the studies.

testing, along with the BCS classification,

have proved successful in numerous
jurisdictions in helping to assure equiva
lence, facilitate product development, and
reduce regulatory burden. Given the per
vasiveness of the problem, we believe that
two approaches could be undertaken im
mediately to help mitigate the conse
quences of poor quality and counterfeit
pharmaceutical drug products. First, tools
should be put in place that are capable of
detecting biopharmaceutically relevant
differences between different products of
the same drug, or large inter-lot variations
in the same product, in order to permit
both regulatory bodies and manufactur
ers to detect and correct important devia
tions in product or lot characteristics that
may result in differences in therapeutic
performance. Second, more effective pro
grams should be designed and imple
mented to monitor the similarity between
registration lots and commercial lots of
pharmaceutical products in order to as
sure continuity of product therapeutic
performance. Since the success of this
strategy depends on the availability of
tools and mechanisms capable of detect
ing therapeutically meaningful differ
ences in a time frame compatible with

Regulatory Science Initiatives for

Enhanced Quality
Sensitive and reproducible in vitro
methodologies such as dissolution

Figure 2. (A) Schematic representation of the in vitro dissolution absorption system 2 (IDAS2); (B) dissolution profiles of propranolol and warfarin tablets, as percent of dose over time; (C) permeation profiles of propranolol and warfarin associated with the
dissolution of their respective tablets
(B) Dissolution

(A)

120
Drug

100

Sampling
% of Dose

Sampling

Sampling

80
60

Propranolol
Warfarin

40
20
0
5

15

30

60

90

120

90

120

Time (min)

(C) Permeation
14
12
% of Dose

Permeation Chamber

Caco-2 Monolayer

8
6
4
2

Stirring Paddle

26

Propranolol
Warfarin

10

Dissolution Vessel

0
5

15

30
60
Time (min)

Rev Panam Salud Publica 40(1), 2016

Murray et al. Innovative in vitro methodologies

decision-making timelines, it is essential

to achieve a reasonable balance among
tool sensitivity, biopharmaceutical rele
vance of the test (e.g., simulation of in vivo
performance), and speed (e.g., days as op
posed to weeks).
Realistic approaches to guard product
quality must rely on an important in vitro
component, but commonly used tech
niques (single point dissolution, drug
content, etc.) lack sensitivity and/or rele
vance and/or speed to make them suffi
ciently useful for this purpose. Therefore,
the development or incorporation of
novel, physiologically relevant systems

Brief communication

like IDAS1 and IDAS2 would appear to

be useful in any strategy that seeks to
have a meaningful and long-term impact
on the quality of pharmaceutical prod
ucts in these markets. Following a more
robust evaluation of the potential of
IDAS1 and IDAS2, their utility, if war
ranted, could be formalized through re
gional regulatory science initiatives.
Since these tools appear to be technolog
ically and financially accessible, they
could aid Latin American and Caribbean
regulatory authorities efforts to safe
guard public health through improving
both the quality of products in

the market and the speed of regulatory

approval. Proper implementation of
these in vitro tools would present addi
tional cost-effective means to assist in
formulation development and optimiza
tion, which could also help bolster the
regional pharmaceutical industry.
Conflicts of interest. None declared.
Disclaimer. The authors hold sole
respon
sibility for the views expressed,
which may not necessarily reflect the
opinion or policy of the RPSP/PAJPH or
PAHO.

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Manuscript received on 15 March 2015. Revised

version accepted for publication on 4 January 2016.

27

Brief communication

Murray et al. Innovative in vitro methodologies

RESUMEN

Mtodos in vitro
innovadores para determinar
la equivalencia teraputica

Palabras clave

28

Para mejorar la calidad de los productos farmacuticos comercializados en su mer

cado, varios pases latinoamericanos han empezado a exigir que se demuestre la bio
equivalencia de los nuevos medicamentos genricos frente a los medicamentos inno
vadores o de referencia. Sin embargo, dado el gran nmero de medicamentos, resulta,
poco factible realizar estudios clnicos para cumplir con este requisito pero tiene sen
tido incorporar o elaborar estrategias que sean acordes a las caractersticas de la
regin.
Para simplificar el desarrollo de frmacos y optimizar el acceso de los pacientes a
medicamentos de buena calidad, hace 15 aos la Administracin de Alimentos y
Medicamentos de los Estados Unidos de Amrica (FDA) decidi conceder exenciones
a la realizacin de estudios clnicos de bioequivalencia (es decir, bioexenciones) a
algunos tipos de medicamentos conforme al Sistema de Clasificacin Biofarmacutica.
Las bioexenciones reducen significativamente el tiempo y el costo de desarrollo, y
tambin evitan la exposicin innecesaria de seres humanos a medicamentos que
podran ser nocivos, a la vez que constituyen una norma robusta y uniforme que
garantiza la equivalencia teraputica de los medicamentos genricos.
Por otra parte, los mtodos innovadores, como los sistemas de disolucin y absorcin
in vitro, permiten ampliar los resultados limitados obtenidos al aplicar los datos de
disolucin in vitro para simular los efectos in vivo. Dado que combinan las pruebas de
disolucin in vitro con las de permeabilidad, estos sistemas brindan conocimientos
tiles para el desarrollo galnico. Es probable que la evaluacin meticulosa del poten
cial de las tcnicas in vitro, junto con su formalizacin mediante iniciativas de nor
malizacin cientfica cuando corresponda, permita concebir mtodos eficaces en
funcin de los costos que ayuden a encarar algunos de los retos relativos a la calidad
y la regulacin de los medicamentos que enfrentan Amrica Latina y el Caribe.
Biofarmacutica; disolucin; permeabilidad; absorcin; equivalencia teraputica;
control de calidad.

Rev Panam Salud Publica 40(1), 2016