Physiological and BiochemicalPhysiological and Biochemical Barriers to Drug Delivery
Xiaoling Li, Ph.D.P f d A i t DProfessor and Associate Dean
Thomas J Long School of Pharmacy and Health SciencesUniversity of the Pacific,
Stockton CAStockton, CA
Outline
Definition of barriers Methods and mechanisms of drug crossing Methods and mechanisms of drug crossing
the barriers Permeation through biological membranes Permeation through biological membranes Overcoming the barriers and dosage form
d idesign 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 ith l 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 ptarget Physical barriers (Permeation barriers) 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 titransporters, immunological reaction
Ad i i i R d B iAdministration Routes and BarriersTransporters
GI LiverEfflux Enzymes
E
p
OralIV
BrainBBBEnzymes
Target
Parenteral
Blood
IMSC
M b
TissueTissue gBlood
CirculationTransmucosal/Transdermal/
Membranes
Inhalation
Physicochemical Properties of DrugPhysicochemical Properties of Drug and Barriers
Partition coefficient, P Molecular weight/molecular volume, MW/MV Dissociation constant, Ka
Hydrogen bond, HBA/HBD/HBT Polar surface area, PSA/HCPSA Solubility, Sy, Permeability, Kp
……….……….
Crossing the Barriers
Invasive means Injections Injections Surgical implant
Non invasive delivery Non-invasive delivery Permeation/transportation
Diffusion Diffusion Facilitate transport/active transport
Barriers to Drug Delivery
Drug Molecules Target
GI walls Enzymes Cellular membranesSkin pgp
Mechanisms of Drug across Barriers
Diffusion Fick’s laws Fick s laws
Carrier mediated transport
pH partition theory Transcellular and paracellular pathways
Carrier Mediated Transport
~400 transporters ~20 have therapeutic or toxicity implicationsp y p ATP (ABC) transporters Solute Carriers (SLC) Solute Carriers (SLC)
EffluxRat
e
Passive Diffusion
TransporterAbs
orpt
ion
Carrier-mediated Transport
pA
Drug Conc. at Absorption Site
Diffusion
Passive Driving force
CD
g Concentration gradient
dC CR
dxdCDJ
)( DR CCh
DKJ
R
)( DRh
hDKK p
J
CD
Permeability
Apparent permeability is a net result of Passive diffusion Passive diffusion Paracellular permeation Endocytosis Endocytosis Active transport (uptake) Efflux transport Efflux transport
Permeability FDA Guidance for Industry:
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 ) ghumans 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 pcan 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 y pwhen 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
Amidon et al. Pharm Res 12 (1995) 413
T ll l d P ll l P hTranscellular and Paracellular Pathways
Multiple pathways Multiple barriers
Transcellular
Multiple barriers
111ParacellularpParapTranspABLpT KKKK
111
A B d LBarriers in series
Parallel pathways
Aqueous Boundary LayerBarriers in series
What is the dominant pathway?
pParapTranspABLpT KKKK
111
Aqueous boundary layer-limited transcellular routelimited transcellular route
Transcellular routeP ll l t Paracellular route
Avdeef and Tam. J Med Chem 2010, 53, 3566–3584
Contribution of Ionized Species Permeation100 5
l iO
NHS
O
O
CH3
40
60
80
2
3
4
%J i
x( g
/(cm
2 .hr)
)Buccal Intestine
NO2
0.0 0.2 0.4 0.6 0.8 1.00
20
0
1
fi
Flux
MW 308.3
filogP 2.6
logD6.8 1.7
pK 6 5 CACO 280
100
4
5
m2 .h
r))
80
100
4
5
cm2 .h
r))
SublingualpKa 6.5 CACO-2
20
40
60
1
2
3%
J i
otal
Flu
x( g
/(cm
20
40
60
1
2
3To
tal F
lux( g
/(c
%J i
g
0.0 0.2 0.4 0.6 0.8 1.00
20
0
1
fi
To
0.0 0.2 0.4 0.6 0.8 1.00
20
0
1 T
fi
Contribution of Ionized Species Permeation
O CH
Barriers Ionized % Ji/JT
Small intestine 50 0.1O
NHS
O
O
CH3
85 0.5
Buccal 50 0.1NO2
85 0.5
Sublingual 50 0.13
75 0 575 0.5
CACO-2 50 0.25
82 0 582 0.5
Relationship between Permeation and pThermodynamic Activity
Assumption: The ionized and unionized species permeate through
ipiupuiuTpTT CKCKJJCKJ
Assumption: The ionized and unionized species permeate through different pathways across buccal epithelium
max,max,
max,max,
:i
ii
u
uuT
saturationC
CJC
CJJ
Degree of Degree of
max,
:
i
uu
CJJJ
CCsaturation
gSaturation of Ionized Species
gSaturation of Unionized Species
max,max,max,,
iiusatT C
JJJ
JT , Ju and Ji = total flux, flux of the unionized and the ionized species
J and J = maximum possible flux of the unionized and ionized speciesJu,max and Ji,max = maximum possible flux of the unionized and ionized species
Cu and Ci = concentrations of the unionized and ionized species
Cu,max and Ci,max = solubilities of the unionized and ionized species
0.0025 7
1 0
Contribution of Ionized Species to Drug TransportSaturated
6.0e-5 0.8Sub-saturatedS
of Io
nize
d
0.0010
0.0015
0.0020
x (
g/(c
m2 .h
r))
3
4
5
6
of U
nion
ized
0.6
0.8
1.0
of Io
nize
d
3.0e-5
4.0e-5
5.0e-5
( g/
(cm
2 .hr)
)
0.4
0.5
0.6
0.7
of U
nion
ized
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
DS
0.0000
0.0005
Flux
0
1
2
DS
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
DS
0.0
1.0e-5
2.0e-5 Flux
0.0
0.1
0.2
0.3
DS
o
0.0
0.2
0.4
pH
DS of Ionized pH vs Total Flux DS of Unionized
6
Total Flux vs. Thermodynamic Activity
pHDS of Ionized Total Flux DS of Unionized
1820
Steady state flux (%)
O
NHS
O
O
CH3
0
1
2
3
4
5
0.8
1.0Tota
l Flu
x (
g/hr
.cm
2 )
ed S
pecie
s
68
10121416O
NO20
0.2
0.4
0.6
5.0e-41.0e-3
1.5e-32.0e-3
Activi
ty of
Uni
onize
d
Activity of Ionized Species0
1 2
3 4
pH 5 pH 6.5 pH 8
Ju
JiJt
0246
JuJiJt
Permeability and Pore SizeBarriers Permeabilit Aq eo s Pore Si e RefBarriers Permeability
(cm/sec)Aqueous Pore Size
(Å)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
3Skin 10-5-10-8 6.8-17 3
Cornea 10-5-10-7 7.3-10 4
CACO 2 10 4 10 7 12 5CACO-2 10-4-10-7 12 5
1. Gastroenterology 108 (1995) 983-9892 T Goswami U of the Pacific Ph D Dissertation 20082. T. Goswami, U of the Pacific Ph.D. Dissertation 20083. J Control Rel 58 (1999) 323–3334. J Controlled Release 49 (1997) 97-1045. J Pharm Sci 83 (1994) 1529-1536
Relative Permeability
6
7e
Perm
eabi
lity
4
5
Rel
ativ
e
1
2
3
Region
Skin Palate Gingiva Buccal Sublingual 0
1
g
R. Birudaraj, R. Mahalingam, X. Li, B.R. Jasti. 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 pEpithelia
Law S, Wertz PW, Swartzendruber DC, Squier CA. Arch Oral Biol 40 (1995 ) 1085-91
In Silico ModelsIntestineIntestine
HBD0 239 D5.5 log 0.192
PSA 0.010-2.883- sec)/( log p
cmK
CLOGP0 1623 067sec)/(logHBD 0.278-
PSA 0.011--2.546sec)/( logHBD0.239-
p
cmK
cmK
S. Winiwarter et al. J. Med. Chem. 41 (1998 ) 4939-4949.
CACO 2HBD 0.235- PSA 0.010 -
CLOGP0.162-3.067sec)/( log p cmK
CACO-2 p
HCPSA0.00484-
2.0 D log 1.8-0.252 -4.392 log K
rotb1.060 0.193rgyr -
f
T. J. Hou et al. J. Chem. Inf. Comput. Sci. 44 (2004) 1585-1600
In Silico ModelsSublingual
bilit
y co
effic
ient
(cm
/sec
)
55
-5.0
-4.5
-4.0
Sublingual
6.8p logD0.53 HBD0.24-5.08-)/(log scmK
log
pred
icte
d pe
rmea
b
-7.0
-6.5
-6.0
-5.5
Buccal
log experimental permeability coefficient (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. Jasti. Pharm Res 26(2009)1130-1139
In Silico ModelsSkinSkin
R. O. Potts abd R. H. Guy. Pharm Res 9(1992) 663-669.
Cornea
4.7log277.0
183.0885.3)/(log
D
HBscmK totp
a.
0.8log265.0
169.0002.4)/(log
D
HBscmK totp
b.
H. Kidron, K-S. Vellonen, E. M. del Amo, A. Tissari, A. Urtti. , , , ,Pharm Res 27(2010) 1398–1407
Key Parameters for Overcoming Barriers
h i l l/d Therapeutic level/dose Permeability
Invasive delivery-non issue Invasive delivery-non issue 10-4-10-9 cm/sec
Bioavailability Residence time Absorption area
Eli i i Elimination rate Solubility Dissolution rate Dissolution rate
Overcoming Permeation BarriersD d i h Drug design approach Alternating chemical structure of lead
compounds Formulation approach Formulation approach Increasing drug
solubility/thermodynamicsolubility/thermodynamic activity/residence timeM d l i b i i Modulating barrier properties
Modulating Barrier Properties
Surfactants Chemical enhancers Cell penetrating peptides Sonophoresisp Iontophoresis Microneedle array Microneedle array Ligand/vector targeted delivery Prodrug Prodrug
D F D iDosage Form Design
Disease state/clinical needs Administration routes Biopharmaceutical properties of drug
Half life Half-life BioavailabilityPh i h i l d h i l ti Physicochemical and chemical properties of drug
l d i i iPer Oral Administration
Parotid gland
Submandibular glandSublingual gland
Pharynx
Oral cavity
Oesophagus
Liver
Duodenum
Gall bladder Stomach
PancreasDuodenum
Jejunum
Ileum
Ascending colon
Pancreas
Transverse colon
Descending colon
Ileum
Caecum
Appendix
Sigmoid colon
Rectum
Anus
O l C i G i i lOral Cavity-Gastrointestinal TractOral Mucosa/ Stomach Small Intestine Large IntestineEsophagus
SEROSACircular
Oblique Muscle
Epithelium
Stratified epithelium
Longitudinal Muscle
MuscleMUSCULARIS EXTERNA SUBMUCOSA
Muscularis Mucosae
Lamina Propria
MUCOSA
Adventitia (Fibrous coat)
Mucosae
Relevant Dimensions for Oral Absorption
Lumenal radius 1 cmLumenal radius 1 cm
Aqueous boundary layer 100-900 µm
Mucus layer 100-500 µmy µ
Villus height 500-800 µm
Microvillus height 1.4 µ
Glycocalyx 0.1-0.2 µm
Epithelial cell height 30 µm
Epithelial cell width 8 µm
Mucosal bilayer membrane thickness 10-11 nm
BL bilayer membrane thickness 7 nmTransport Processes in Pharmaceutical Systems, Marcel Dekker Inc.
Enzymes and Efflux/Influx Transporters y pin 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 × 106 1.5-7 Up to 38 hrMouth Cavity 15-20 700Esophagus 20 200Stomach 25
Fasted state 65 1.4-2.1 0.5-1.5 hrF d 660 2 5 2 6 hFed state 660 2-5 2-6 hr
Small Intestine 370-630 2.1-5.9 × 106* 4.4-7.4 3 ± 1 hr
Duodenum 20-30 1.13-2.83x105 4.9-6.4 3-10 min
Jejunum 150-260 2.70-7.50x105 4.4-6.4 0.5-2 hr
Ileum 200-350 3.60-10.50x105 6.5-7.4 0.5-2.5 hr
Large Intestine 150 15000 5.5-7.4 Up to 27 hrLarge Intestine 150 15000 5.5 7.4 Up to 27 hr
Caecum 7 500 5.5-7Colon 90-150 15000 7.4Rectum 11-16 150 7
X. Li and B. Jasti. 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 Increase available drug Increase available drug
protecting drugs in absorption site and in circulationcirculation
Increasing drug solubility Increasing dissolution rate Increasing dissolution rate
Buccal and Sublingual MucosaEpithelium
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 MucosaBuccal mucosa Sublingual mucosaBuccal 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 cellbasa e
Melanocyte
Summary
Barriers are part of the protection mechanisms for the human body.y
Understanding the transport mechanisms is essential for drug discovery andessential for drug discovery and development.
The barriers to drug delivery can be The barriers to drug delivery can be overcome through drug design and formulation design approachesformulation design approaches.
Acknowledgements
AAPS Bhaskara Jasti Ph D Bhaskara Jasti, Ph.D. Amit Kokate, Ph.D.
T G i Ph D Tarun Goswami, Ph.D. Dan Su, M.S.