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.