Physiological andBiochemical Physiological and Biochemical

Barriers to Drug Delivery

Xiaoling Li, Ph.D.
P f dA i t D Professor and Associate Dean
Thomas J Long School of Pharmacy and Health Sciences
University of the Pacific,
Stockton CA Stockton, CA
Outline
Definition of barriers
Methodsandmechanismsof drugcrossing Methods and mechanisms of drug crossing
the barriers
Permeationthroughbiological membranes Permeation through biological membranes
Overcoming the barriers and dosage form
d i design
Summary
Goals of Drug Delivery
Achieve the therapeutic objectives by
delivering sufficient amount of the pharmaceutical
active agents to intended target
maintaining therapeutic level of pharmaceutical agents
M i ff t ithl t d Maximum effects with lowest dose
Minimum toxicity
Optimum pharmaceutical agent profile at target site
Pharmaceutical Relevant Barriers
Physical, physiological, or biochemical
obstacles along the path to therapeutic g p p
target
Physical barriers(Permeationbarriers) Physical barriers (Permeation barriers)
Skin, mucosal, epithelium, blood brain barrier,
cellular membranes
Biological and Pathophysiological barriers
Enzymes, first hepatic metabolism, efflux
t t i l i l ti transporters, immunological reaction
Ad i i i R dB i Administration Routes and Barriers
Transporters
GI Liver
Efflux
Enzymes
E
p
Oral
IV
Brain BBB
Enzymes
Target
Parenteral
Blood
IM
SC
M b
Tissue
Tissue g
Blood
Circulation
Transmucosal/
Transdermal/
Membranes
Inhalation
Physicochemical Propertiesof Drug Physicochemical Properties of Drug
and Barriers
Partition coefficient, P
Molecular weight/molecular volume, MW/MV
Dissociation constant, K
a
Hydrogen bond, HBA/HBD/HBT
Polar surface area, PSA/HCPSA
Solubility, S y,
Permeability, K
p
. .
Crossing the Barriers
Invasive means
Injections Injections
Surgical implant
Non invasivedelivery Non-invasive delivery
Permeation/transportation
Diffusion Diffusion
Facilitate transport/active transport
Barriers to Drug Delivery
Drug Molecules Target
GI walls Enzymes
Cellular membranes
Skin pgp
Mechanisms of Drug across Barriers
Diffusion
Fickslaws Fick slaws
Carrier mediated transport
pH partition theory
Transcellular and paracellular pathways
Carrier Mediated Transport
~400 transporters
~20 have therapeutic or toxicity implications p y p
ATP (ABC) transporters
SoluteCarriers(SLC) Solute Carriers (SLC)
Efflux
R
a
t
e
Passive Diffusion
Transporter
A
b
s
o
r
p
t
i
o
n


Carrier-mediated Transport
p
A
Drug Conc. at Absorption Site
Diffusion
Passive
Driving force
C
D
g
Concentration gradient
dC
C
R
dx
dC
D J =
) (
D R
C C
h
DK
J =
R
) (
D R
h
h
DK
K
p
=
J
C
D
Permeability
Apparent permeability is a net result of
Passivediffusion Passive diffusion
Paracellular permeation
Endocytosis Endocytosis
Active transport (uptake)
Effluxtransport Efflux transport
Permeability
FDA Guidance for I ndustry:
B. Permeability
The permeability class boundary is based indirectly
on the extent of absorption (fraction of dose
absorbed, not systemic BA) of a drug substance in , y ) g
humans and directly on measurements of the rate of
mass transfer across human intestinal membrane.
Alternatively, nonhuman systems capable of
predicting the extent of drug absorption in humans p g g p
can be used (e.g., in vitro epithelial cell culture
methods). In the absence of evidence suggesting
instability in the gastrointestinal tract, a drug
substance is considered to be highly permeable g yp
when the extent of absorption in humans is
determined to be 90% or more of an administered
dose based on a mass balance determination or in
comparison to an intravenous reference dose. p
Good absorption: 2-4x10
-4
cm/sec
Amidonet al. PharmRes 12 (1995) 413
T ll l dP ll l P h Transcellular and Paracellular Pathways
Multiple pathways
Multiplebarriers
Transcellular
Multiple barriers
1 1 1
Paracellular
pPara pTrans pABL pT
K K K K +
+ =
1 1 1
A B d L
Barriersinseries
Parallel pathways
Aqueous Boundary Layer
Barriers in series
What is the dominant pathway?
pPara pTrans pABL pT
K K K K +
+ =
1 1 1
Aqueous boundary layer-
limitedtranscellular route limited transcellular route
Transcellular route
P ll l t Paracellular route
Avdeef and Tam. J Med Chem2010, 53, 35663584
Contribution of Ionized Species Permeation
100 5
l i
O
N H
S
O
O
CH
3
40
60
80
2
3
4
%
J
i
x
(

g
/
(
c
m
2
.
h
r
)
)
Buccal Intestine
NO
2
0.0 0.2 0.4 0.6 0.8 1.0
0
20
0
1
fi
F
l
u
x
MW 308.3
fi
logP 2.6
logD
6.8
1.7
pK 65
CACO 2
80
100
4
5
m
2
.
h
r
)
)
80
100
4
5
c
m
2
.
h
r
)
)
Sublingual
pK
a
6.5
CACO-2
20
40
60
1
2
3
%
J
i
o
t
a
l

F
l
u
x
(

g
/
(
c
m
20
40
60
1
2
3
T
o
t
a
l

F
l
u
x
(

g
/
(
c
%
J
i
g
0.0 0.2 0.4 0.6 0.8 1.0
0
20
0
1
fi
T
o
0.0 0.2 0.4 0.6 0.8 1.0
0
20
0
1 T
fi
Contribution of Ionized Species Permeation
O CH
Barriers I onized % J
i
/J
T
Small intestine 50 0.1
O
N H
S
O
O
CH
3
85 0.5
Buccal 50 0.1
NO
2
85 0.5
Sublingual 50 0.13
75 05 75 0.5
CACO-2 50 0.25
82 05 82 0.5
Relationship between Permeation and p
Thermodynamic Activity
Assumption: The ionized and unionized species permeate through
i pi u pu i u T pT T
C K C K J J C K J + = + = =
Assumption: The ionized and unionized species permeate through
different pathways across buccal epithelium
max ,
max ,
max ,
max ,
:
i
i
i
u
u
u T
saturation
C
C
J
C
C
J J - + - =
Degree of Degree of
max ,
:
i
u u
C
J J J
C C
saturation
- + =
=
g
Saturation of
Ionized Species
g
Saturation of
Unionized
Species
max ,
max , max , ,
i
i u sat T
C
J J J - + =
J
T
, J
u
and J
i
=total flux, flux of the unionized and the ionized species
J andJ =maximumpossiblefluxof theunionizedandionizedspecies J
u,max
and J
i,max
=maximum possible flux of the unionized and ionized species
C
u
and C
i
=concentrations of the unionized and ionized species
C
u,max
and C
i,max
=solubilitiesof the unionized and ionized species
0.0025 7
1 0
Contribution of Ionized Species to Drug Transport
Saturated
6.0e-5 0.8
Sub-saturated
S

o
f

I
o
n
i
z
e
d

0.0010
0.0015
0.0020
x

(

g
/
(
c
m
2
.
h
r
)
)
3
4
5
6
o
f

U
n
i
o
n
i
z
e
d
0.6
0.8
1.0
o
f

I
o
n
i
z
e
d

3.0e-5
4.0e-5
5.0e-5
(

g
/
(
c
m
2
.
h
r
)
)
0.4
0.5
0.6
0.7
o
f

U
n
i
o
n
i
z
e
d
0.6
0.8
1.0
pH
4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5
D
S
0.0000
0.0005
F
l
u
x
0
1
2
D
S

0.0
0.2
0.4
pH
4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5
D
S

0.0
1.0e-5
2.0e-5
F
l
u
x

0.0
0.1
0.2
0.3
D
S

o
0.0
0.2
0.4
pH
DS of Ionized
pH vs Total Flux
DS of Unionized
6
Total Flux vs. Thermodynamic Activity
pH
DS of Ionized
Total Flux
DS of Unionized
18
20
Steady state flux
(%)
O
N H
S
O
O
CH
3
0
1
2
3
4
5
0.8
1.0
T
o
t
a
l

F
l
u
x

(

g
/
h
r
.
c
m
2
)
e
d

S
p
e
c
i
e
s
6
8
10
12
14
16
O
NO
2
0
0.2
0.4
0.6
5.0e-4
1.0e-3
1.5e-3
2.0e-3
A
c
t
i
v
i
t
y

o
f

U
n
i
o
n
i
z
e
d
Activity of Ionized Species 0
1
2
3
4
pH 5
pH 6.5
pH 8
J u
J i
J t
0
2
4
6
J u
J i
J t
Permeability and Pore Size
Barriers Permeabilit Aq eo sPoreSi e
Ref
Barriers Permeability
(cm/sec)
Aqueous Pore Size
()
Ref
Small intestine 10
-3
-10
-5
8-13
1
Buccal 10
-4
-10
-7
18-22
2
Sublingual 10
-4
-10
-7
30-53
2
3
Skin 10
-5
-10
-8
6.8-17
3
Cornea 10
-5
-10
-7
7.3-10
4
CACO 2 10
4
10
7
12
5
CACO-2 10
-4
-10
-7
12
5
1. Gastroenterology 108 (1995) 983-989
2 T Goswami U of thePacificPhD Dissertation2008 2. T. Goswami, U of the Pacific Ph.D. Dissertation 2008
3. J Control Rel 58 (1999) 323333
4. J Controlled Release 49 (1997) 97-104
5. J PharmSci 83 (1994) 1529-1536
Relative Permeability
6
7
e

P
e
r
m
e
a
b
i
l
i
t
y
4
5
R
e
l
a
t
i
v
e

1
2
3
Region
Skin Palate Gingiva Buccal Sublingual
0
1
g
R. Birudaraj, R. Mahalingam, X. Li, B.R. J asti. Crit Rev Ther Drug Carrier Syst 2005;22: 295-330.
Y. Kurosaki, T. Kimura. Crit Rev Ther Drug Carrier Syst 2000;17:467-508.
Biochemical Composition of Different p
Epithelia
Law S, Wertz PW, Swartzendruber DC, Squier CA. Arch Oral Biol 40 (1995 ) 1085-91
In SilicoModels
Intestine Intestine
HBD 0239
D5.5 log 0.192
PSA 0.010 - 2.883 - sec) / ( log
p
+
= cm K
CLOGP 0162 3067 sec) / ( log
HBD 0.278 -
PSA 0.011 - -2.546 sec) / ( log
HBD 0.239 -
p
+
=
cm K
cm K
S. Winiwarter et al. J . Med. Chem. 41 (1998 ) 4939-4949.
CACO 2
HBD 0.235 -
PSA 0.010 -
CLOGP 0.162 -3.067 sec) / ( log
p
+ = cm K
CACO-2
| |
p
HCPSA 0.00484 -
2.0 D log 1.8 - 0.252 -4.392 logK < < + =
rotb
1.060
0.193rgyr -
f +
T. J . Houet al. J . Chem. Inf. Comput. Sci. 44 (2004) 1585-1600
In SilicoModels
Sublingual
b
i
l
i
t
y

c
o
e
f
f
i
c
i
e
n
t

(
c
m
/
s
e
c
)
55
-5.0
-4.5
-4.0
Sublingual
6.8 p
logD 0.53 HBD 0.24 - 5.08 - ) / ( log + = s cm K
l
o
g

p
r
e
d
i
c
t
e
d

p
e
r
m
e
a
b
-7.0
-6.5
-6.0
-5.5
Buccal
logexperimental permeabilitycoefficient (cm/sec)
-7.5 -7.0 -6.5 -6.0 -5.5 -5.0 -4.5 -4.0
Buccal
A. Kokate, X. Li, P. J . Williams, P. Singh, and B.R. J asti.
PharmRes 26(2009)1130-1139
In SilicoModels
Skin Skin
R. O. Potts abdR. H. Guy. PharmRes 9(1992) 663-669.
Cornea
4 . 7
log 277 . 0
183 . 0 885 . 3 ) / ( log
D
HB s cm K
tot p
+
=
a.
0 . 8
log 265 . 0
169 . 0 002 . 4 ) / ( log
D
HB s cm K
tot p
+
=
b.
H. Kidron, K-S. Vellonen, E. M. del Amo, A. Tissari, A. Urtti. , , , ,
PharmRes 27(2010) 13981407
Key Parameters for Overcoming Barriers
h i l l/d Therapeutic level/dose
Permeability
Invasivedelivery-nonissue Invasive delivery-non issue
10
-4
-10
-9
cm/sec
Bioavailability
Residence time
Absorption area
Eli i i Elimination rate
Solubility
Dissolutionrate Dissolution rate
Overcoming Permeation Barriers
D d i h Drug design approach
Alternating chemical structure of lead
compounds
Formulationapproach Formulation approach
Increasing drug
solubility/thermodynamic solubility/thermodynamic
activity/residence time
M d l i b i i Modulating barrier properties
Modulating Barrier Properties
Surfactants
Chemical enhancers
Cell penetrating peptides
Sonophoresis p
Iontophoresis
Microneedlearray Microneedlearray
Ligand/vector targeted delivery
Prodrug Prodrug
D F D i Dosage Form Design
Disease state/clinical needs
Administration routes
Biopharmaceutical properties of drug
Half life Half-life
Bioavailability
Ph i h i l d h i l ti Physicochemical and chemical properties
of drug
l d i i i Per Oral Administration
Parotid gland
Submandibular gland Sublingual gland
Pharynx
Oral cavity
Oesophagus
Liver
Duodenum
Gall bladder Stomach
Pancreas Duodenum
Jejunum
Ileum
Ascending colon
Pancreas
Transverse colon
Descending colon
Ileum
Caecum
Appendix
Sigmoid colon
Rectum
Anus
O l C i G i i l Oral Cavity-Gastrointestinal Tract
OralMucosa/ Stomach SmallIntestine LargeIntestine
Esophagus
SEROSA
Circular
Oblique
Muscle
Epithelium
Stratified
epithelium
Longitudinal
Muscle
Muscle
MUSCULARIS
EXTERNA
SUBMUCOSA
Muscularis
Mucosae
Lamina
Propria
MUCOSA
Adventitia (Fibrous
coat)
Mucosae
Relevant Dimensions for Oral Absorption
Lumenal radius 1cm Lumenal radius 1 cm
Aqueous boundary layer 100-900 m
Mucus layer 100-500 m y
Villus height 500-800 m
Microvillus height 1.4
Glycocalyx 0.1-0.2 m
Epithelial cell height 30 m
Epithelial cell width 8 m
Mucosal bilayer membrane thickness 10-11 nm
BL bilayer membrane thickness 7 nm
Transport Processes in Pharmaceutical Systems, Marcel Dekker I nc.
Enzymes and Efflux/Influx Transporters y p
in Intestine
W Huang, S L Lee, and L X. Yu. The AAPS J . 11(2009) 217-224
Region of the
GI tract
Physical Characteristics
Length (cm) Surface area (cm2) pH Average residence time
Entire GI tract 530-870 2 10
6
1.5-7 Up to 38 hr
Mouth Cavity 15-20 700
Esophagus 20 200
Stomach 25
Fasted state 65 1.4-2.1 0.5-1.5 hr
F d 660 2 5 2 6h Fed state 660 2-5 2-6 hr
Small Intestine 370-630 2.1-5.9 10
6
* 4.4-7.4 3 1 hr
Duodenum 20-30 1.13-2.83x10
5
4.9-6.4 3-10 min
J ejunum 150-260 2.70-7.50x10
5
4.4-6.4 0.5-2 hr
Ileum 200-350 3.60-10.50x10
5
6.5-7.4 0.5-2.5 hr
LargeIntestine 150 15000 5.5-7.4 Upto27hr Large Intestine 150 15000 5.5 7.4 Up to 27 hr
Caecum 7 500 5.5-7
Colon 90-150 15000 7.4
Rectum 11-16 150 7
X. Li and B. J asti. Design of Controlled Drug Delivery Systems.
McGraw-Hill, New York, New York, 2006
Barriers in GI
Aqueous boundary layer
Epithelium Epithelium
Lipid bilayer
E Enzymes
Transporters
Chemical degradation/pH
Drug Formulation
Increase residence time in GI
Increaseavailabledrug Increase available drug
protecting drugs in absorption site and in
circulation circulation
Increasing drug solubility
Increasingdissolutionrate Increasing dissolution rate
Buccal and Sublingual Mucosa
Epithelium
Gum (Gingiva)
Upper lip
H d l t (R f f th M th)
Region Thickness Keratinization
Buccal mucosa Thick NK
Buccal mucosa
(Cheek)
Hard palate (Roof of the Mouth)
Soft palate
Transitional zone of
lip
Thin K
Gingiva Thick K,PK
Sublingual mucosa Thin NK
Tongue
Sublingual (Floor of the mouth)
Sublingual mucosa Thin NK
Ventral surface of
tongue
Thin NK
Gum (Gingiva)
Lower lip
Dorsum of tongue
(anterior 2/3)
Thick K (primarily)
Dorsum of tongue
(posterior (1/3)
Variable NK
(posterior (1/3)
Soft palate Thick NK
Hard palate Thick K
Buccal and Sublingual Mucosa
Buccal mucosa
Sublingual mucosa
Buccal mucosa
Sublingual mucosa
100
microns
Epithelium
Basal Lamina
Connective tissue
Basal Lamina
Barrier: Epithelium, membrane coating granules
Skin
Barrier:
Stratum corneum
Epithelium
S
Lipid regions
Stratum
corneum
Corneocyte
Injections
Transdermal
Topical
Stratum
granulosum Lamellar
granules
p
Patches
Stratum
spinosum
Langerhans cell
Keratinocyte
Stratum
basale Merkel cell basa e
Melanocyte
Summary
Barriers are part of the protection
mechanisms for the human body. y
Understanding the transport mechanisms is
essential for drugdiscoveryand essential for drug discovery and
development.
Thebarrierstodrugdeliverycanbe The barriers to drug delivery can be
overcome through drug design and
formulationdesignapproaches formulation design approaches.
Acknowledgements
AAPS
BhaskaraJ asti PhD Bhaskara J asti, Ph.D.
Amit Kokate, Ph.D.
T G i PhD Tarun Goswami, Ph.D.
Dan Su, M.S.