Overcoming Poor Water Solubility

Through Prodrugs

This webinar will begin at 12:30 EST

Conducted by Valentino J. Stella, Ph.D.

University Distinguished Professor of Pharmaceutical Chemistry, University of Kansas

Overcoming Poor Water Solubility

Through Prodrugs

Drug

Derivatization

Promoiety Drug Promoiety Drug

Transformation

Promoiety Drug +

B

A

R

R

I

E

R

Prodrugs represents a Chemical/Biochemical approach to the

Optimization of Drug Delivery

Prodrugs: Challenges and Rewards, Parts I and II

Volume 5 of the Biotechnology: Pharmaceutical Aspects

series.

Edited by Valentino Stella (University of Kansas),

Ronald T. Borchardt (University of Kansas),

Michael Hageman (Bristol-Myers Squibb),

Reza Oliyai (Gilead Sciences, Inc.),

Hans Maag (Roche Palo Alto, LLC),

Jefferson Tilley (Hoffmann-La Roche, Inc.).

This essential new volume provides a comprehensive

overview of prodrugs and will guide the reader

through the current status of the prodrug concept

and its many applications. The wealth of

information in this two-part reference work

highlights the many successes that have been

achieved in overcoming the formulation and

delivery of problematic drugs.

Drug Discovery Paradigm of the

1990s

Chemical

Libraries

Structural

Leads

High Affinity

Ligands or

Drug Candidates

HTS Optimization

Result - The High Affinity Trap

Poor clinical candidates

and

difficult to build in drug-like characteristics

(with permission from Ron Borchardt)

Drug Discovery Paradigm of the

FUTURE

Chemical

Libraries

Structural

Leads

High Affinity

Ligands or

Drug Candidates

HTS

of biological and

PHARMACEUTICAL

properties

Optimization of the

biological and

PHARMACEUTICAL

properties through combinatorial

chemistry and rational drug

design INCLUDING THE USE

OF PRODRUGS

“Drugs need to be Designed with Delivery in Mind”

Takeru Higuchi

(sometime during a coffee break in the late 1970s)

PRODRUG INTERVENTION

MUST

BECOME AN INTEGREL PART OF

THE DRUG DESIGN STRATEGUM

Dosage

Form Systemic

Circulation

Solubility* Stability* Permeability** First-Pass**

*May be amenable to fixing by “formulation”.

**Difficult to correct by “formulation”.

Key Pharmaceutical Properties Impacting the

Development of Drug Molecules

Solid Drug

Conce

ntr

atio

n

h

Cs

C

Bulk

Solution

Dissolution from Solids (Noyes-Whitney Equation)

Rate of Dissolution = (DA/h)[Cs-C] ≈ DACs/h

What do We Mean by

the Term SOLUBILITY?

Solubility can be thought of as a Three Step Process

1. Removal of a Molecule from its Crystal Lattice

2. Creating a Void in the Solvent

3. Release of Solvation Energy

∆G positive +

∆G positive +

+ ∆G Negative

Hildebrand & Scott, 1950. Solubility of Non-electrolytes, New York, Reinhold

Role of SIZE as a Determinant in Solubility (Solvent Cavity Size)

Butanol 2-Butanol tert-Butanol

Aqueous solubility

1.52 M 2.08 M Miscible

Packing and Symmetry

Melting Point 216°C 101°C

Benzene

Solubility 0.81 Mole% 20.7 Mole%

Packing

Fumaric Acid

Sublimes >200°C

Aqueous Solubility 1g/150mL

Maleic Acid

M.P. 138-39°C

Aqueous Solubility 1g/5mL

Drug MP°C Aq. Sol/30°C

Theophylline 270-76 4.5x10-2M

Caffeine 238 13.3x10-2M

7-Ethyl 156-7 17.6x10-2M

Theophylline

7-Propyl 99-100 104x10-2M

Theophylline

From Ed Kern

“even though the model considered

the effect of non-specific van der

Walls interaction present in the

crystal, it did not account for the

effect of highly specific hydrogen

bonding. Consequently, there is a

need for new molecular descriptors

that not only consider single

molecules but also capture the

intermolecular interactions.”

Carola Wassvik - University of Uppsala, 2006

Only 54% of aqueous

solubility estimates can be

accounted for by considering

only solvation as represented

by log P values

The results of determining the solubility

of a number of drug substances show,

“that connections between partition

coefficients and solubility in lipophilic or

aqueous phases do not exist”

Pfegel et al., Pharmazie 48, 741-744 (1993)

From Phil Burton

General Solubility Equation (GSE)

Log Sw = 0.5 - 0.01(TM-25) - log P

From Phil Burton

Solubility/Dissolution as a Barrier

THERE ARE SURPRISINGLY FEW EXAMPLES OF COMMERCIAL

SUCCESSES WHERE PRODRUGS HAVE BEEN USED TO IMPROVE THE

ORAL DELIVERY OF POORLY WATER-SOLUBLE DRUGS

Drug

Derivatization

Promoiety Drug Promoiety Drug

Transformation

Promoiety Drug +

B

A

R

R

I

E

R

PRODRUGS

Sulindac Sulindac Sulfide

Reduction

Oxidation

Drug Metab. Dispos. 1980 Jul-Aug;8(4):241-6

Dominguez et al., Il

Farmaco 50, 697-702

(1995)

Bioavailability of ABZS from

ABZS relative to ABZ is 226%

in rats and higher in humans

Fosamprenavir

(a phosphate prodrug of amprenavir)

Chemical

Modification

Biological

Transformation

(Brush Border

Gut Phosphatase)

Aqueous Sol’y = 41µg/mL

Aqueous Sol’y = 0.3 mg/mL

Banerjee and Amidon

In Design of Prodrugs

(H. Bundgaard, Ed)

Coupled Metabolism and Transport

Amprenavir

• Good bioavailability ≈ 80%

• High Percentage of Excipients due to Low Solubility

Requiring 8 Capsules b .i.d.

Fosamprenavir

• Bioavailability Same as Amprenavir

• Identical Preclinical safety Profile

• Due to High Solubility, Drug Load in Tablet can be Higher thus

Allowing Dosing of 2 Tablets versus 8 Capsules for Amprenavir

Alkaline

Phosphatase

Stain

Are all Hydroxyls Equal?

Ritonavir (RTV)

Lopinavir (LPV)

A-792611

DeGoey et al., J. Med. Chem., 52, 2964-70 (2009)

Ala

Glu

Phos

OMP

(oxymethylphosphate)

OEP

(oxyethylphosphate)

Very water soluble

Very chemically unstable

Very water soluble

Very chemically stable

Enzymatically labile

Very water soluble

Very chemically stable

Enzymatically stable

Marginally water soluble

Marginally chemically stable

Enzymatically stable

Marginally water soluble

Marginally chemically stable

Enzymatically stable DeGoey et al., J. Med. Chem., 52, 2964-70 (2009)

t1/2(min)

Rat & human

serum, & S9

Oral AUC

Rats

(ug.hr/mL)

A-79211 N/A 3.50

Ala No hydr. 0.57**

Glu No hydr. 0

Phos No hydr.* 0

OMP No hydr.*** 8.75

Prodrugs of A-792611

*Rat & human tissues **PD detected in plasma ***Cleaved by alkaline phosphatase

DeGoey et al., J. Med. Chem., 52, 2964-70 (2009)

Yagi et al., Pharm. Res., 16, 1041-46 (1999)

Solubility <0.001mg/mL <0.007 mg/mL

Chan et al., Pharm. Res.,

15, 1012-1018 (1998)

CAM-4451 was practically insoluble in water!

Phenytoin Plasma Levels after Fosphenytoin

versus Phenytoin

Epilepsy Res., 34, 129-133 (1999)

R-788 (fostamatinib)

Dapsone Prodrugs

Amino acid amides are good substrates for Peptidases

Pochopin et al., I.J.P. 121, 157-67 (1995) and Drug Met. Disp., 22, 770-75 (1994)

Drug/Prodrug Low M.P.

Low Aq. Sol’y

High Lipid Sol’y

Slow Dissolution

in Water Probable Improvement

in Oral Bioavailability

Perhaps Higher

Dissolution Rate in

Simulated Contents of

the GI Tract

Disrupted Packing

Role of Crystal Packing

mp 293°C

Aqueous Sol’y 25µg/mL

Cyclohexane Sol’y 39µg/mL

Predicted MP 165.3-189.3°C

(Bergstrom et al)

pentanoate

octanoate

acetate

Stella et al., J. Pharm. Sci., 87, 1235-1241 (1998)

“Would mp

estimates have

predicted this

behavior?”

R M.P.°C SolAqu SolC-Hex SolSIBLM DisAqu DisSIBLM

Mx105 Mx103 Mx104

Phenytoin (1)

293-295 8.0 0.16 5.5 1.01 2.87

C4H9 (2)

89-92 2.1 14.7 4.3 0.19 2.84

CH2OC2H5

120-2 3.4 0.14 1.0 0.31 0.87

C7H15 (3)

67.5-8.5 0.03 150 5.4 <0.01 5.59

Stella et al., J. Pharm. Sci., 88, 775-779 (1999)

Which drug would

have chosen to

develop if solubility

was the critical

variable?

In Vivo Performance in Fed and Fasted

Beagle Dogs

Fed Fasted

Stella et al., J. Pharm. Sci., 88, 775-779 (1999)

Fabsolute = 21.0±6.9 (1)

= 44.2±16.2 (2)

= 40.7±19.8 (3)

Fabsolute = 37.8±9.3 (1)

= 84.2±16.5 (2)

= 77.5±22.1 (3)

Another example

1 4b

m.p. (°C) >320 218-20

Sol. (pH7.4) 44µM 23µM

PC 7 92

t1/2 (plasma) 38 min

Higher bioavailability

despite lower aqueous

solubility!

Shaw et al., J. Med. Chem., 35, 1267-72 (1992)

I anticipate more and better

examples of Prodrugs to

enhance oral bioavailability of

sparingly water-soluble drugs

in the near future

The Greatest Successes with Prodrugs, from a

Commercial Viewpoint is the Partenteral

Delivery of Poorly Water-Soluble Drugs!

Cerebyx®

Could the POM technology be

applied to other classes of

drugs?

Phenytoin plasma concentration (mean, 12

subjects) versus time (first 6 h.) curves

after IV infusion over 30 min. of equimolar

doses (250 mg phenytoin) of sodium

phenytoin, open squares, and

fosphenytoin, open circles. Jamerson et

al., Epilepsia 31, 592-597 (1990).

Propofol

OH

Fospropfol Ready-to-use solution

Excellent substrate for enzymatic cleavage

t 1/2 in vivo 1-5 minutes

Excellent yields

Patented

O/W emulsion

Pain on injection

Significant blood pressure drop

Difficult to preserve

High lipid content

Application of the POM Technology to

Sterically Hindered Alcohols and Phenols

Aquavan® In vivo Behavior

Male beagle dogs

Equimolar iv doses

Slightly slower onset of action

versus Diprivan™ but very

interesting pharmacodynamics

Diprivan™: 10-12 secs

Aquavan®: 20-40 secs

Lusedra® has been licensed to

Eisei (via ProQuest, Guilford

and MGI).

Eur. J. Anaesthesiology 20:182-190 (2003) - rat PK/PD study

Anesthesiology 99: 303-313 (2003) - first human PK/PD study

Camptothecin POM Prodrug

Camptothecin

Potent anticancer agent

Low water solubility: 3 µg/mL

Currently no injectable form available

Camptothecin POM Prodrug

Rapid conversion to camptothecin in vivo

Solubility >10 mg/ml even as mono-sodium salt

Potential lyophile for reconstitution

CPT vs. TimeP-CPT and CPT IV Administration

1

10

100

1000

10000

0 20 40 60 80 100

TIME (minutes)

P-CPT IV CPT IV

Loxapine solubility (50 mM buffer, m = 0.2 with NaCl, 25 °C)

Loxitane® formulation 70 % (v/v) propylene glycol

05 % (v/v) polysorbate 80

Loxapine prodrug ionization

NO

N

NCH3

Cl

OP

O

OOH

NO

N

NCH3

Cl

OP

O

OO

pH 3 solubility = 290 mg/mlpH 7.4 solubility = 648 mg/ml

pKa2 = 4.7

Krise et al., J. Med. Chem., 42, 3094-3100 (1999)

Parenteral and Oral

Bioavailability of

Tertiary Amines?

• Amino acid (glycine) attached to urea nitrogen of CBZ.

• Hypothesized to convert to CBZ and glycine in vivo (in the body) by enzymatic cleavage of the acyl-urea bond.

• Release of potentially non-toxic entity upon bioreversion.

Acyl-Urea Amino Acid Prodrug Bioconversion

N

O N H

O +

_

N H 3 C l

N

O NH2

O

O

NH3+ _

in vivo +

Stability of N-Glycine-CBZ in plasma and buffer at 37 °C

N-Gly-CBZ in 80% plasma @37°C

k = 5.13 e-3 min-1

t1/2 = 153 min

N-Gly-CBZ in pH 7.4 buffer @37°C

k = 1.48 e-3 min –1

t1/2 = 467 min

Conversion of N-Gly-CBZ in 80% rat plasma

Time (min)

0 200 400 600 800 1000 1200

C (

mm

ol/L

)

0

5

10

15

20

25

30

35

N-Gly-CBZ

CBZ

PK Profile of N-Gly-CBZ and CBZ following IV Administration of N-Gly-CBZ to Rat 1.

N-Gly-CBZ is rapidly converted to CBZ in vivo.

Time (min)

0 100 200 300 400 500

Cp

(m

M)

0

10

20

30

40

N-Gly-CBZ

CBZ

PK of CBZ from N-Gly-CBZ

Cp(CBZ) = A1e-λ1t + A2e

-λ2t

A1 = -8.77 λ1 = 0.683 A2 = 8.68 λ2 = 0.0096

AUC = 893 µg·min/ml from N-Gly-CBZ

PK of CBZ from IV N-Gly-CBZ and Equiv. CBZ Control

Cp(CBZ) = A1e

-λ1t + A2e-λ2t

A1 = 5.03 λ1 = 0.042 A2 = 8.57 λ2 = 0.011

AUC = 936 µg·min/ml from CBZ

PK of CBZ from CBZ control

å=

-=

n

1i

të

ipieAC

Time (min)

0 100 200 300 400 500

Cp

(m

M)

0

2

4

6

8

10

12

14

CBZ from N-Gly-CBZ

y = A1e-l

1t + A2e

-l2t

CBZ control

y = A1e-l

1t + A2e

-l2t

Time (min)

0 50 100 150 200 250 300

Cp

(CB

Z)

(m

g/m

L)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

CBZ control

CBZ from prodrug

CBZ from Oral CBZ and Oral N-Gly-CBZ

Rat 13: AUCCBZ(N-Gly-CBZ) = 251 mg·min/mL AUCCBZ(control) = 119 mg·min/mL AUC’s by trapezoidal method.

Oral Prodrug vs. Oral CBZ control

AUCCBZ

(N-Gly-CBZ)

(mg·min/mL

)

AUCCBZ

(CBZ)

(mg·min/mL

) Relative F

Rat 10 505 513 0.98

Rat 11 232 109 2.12

Rat 12 272 166 1.64

Rat 13 251 119 2.11

Mean 315 227 1.72

SD 128 193 0.54

Basic Strategy Develop broad “functional group” based

prodrug platforms that will be applicable to

improving the formulation and delivery of a

a wide range of drug molecules containing

the problematic functional group.

For example, what novel promoieties could be

developed to overcome the hydrogen-bonding potential

of the following classes of functional groups?

Possible solution!

N-S Technology

In-vivo behavior

Some Carbamazepine Prodrugs

Jeff Hemenway and Victor Guarino

Quantitative and

complete release of

Carbamazepine in

vitro in whole blood

and in the presence

of glutathione and

cysteine

PK profile of CBZ from CBZ-cysteamine and CBZ control in same rat

• CBZ AUC from prodrug = 964 mg·min/ml • CBZ AUC from CBZ control = 959 mg·min/ml • No CBZ-cysteamine observed in plasma • No CBZ-cysteamine recovered unchanged in urine

PK of CBZ from IV CBZ-cysteamine and IV CBZ control

Time (min)

0 100 200 300 400 500

Cp

(m

g/m

L)

0

2

4

6

8

10

12

14

16

18

CBZ control

CBZ from CBZ-cysteamine

Could sulfenamides be used to better deliver drugs,

orally?

MDCK cell permeability characteristics of a sulfenamide prodrug: strategic implications in considering sulfenamide prodrugs for oral delivery of NH-

acids, V. R. Guarino, K. Nti-Addae, and V. J. Stella, Bioorg. Med. Chem. Let., early view. Hard copy will be in the January 2011 issue.

Boronic Acid Drugs

Lewis Acids

BROH

OH

Boron electronic configuration: 1s22s22px

3 bonding orbitals are

sp2 hybrids Empty 2pz orbital

BROH

OH O

H

H

BR

OH

OH

OH

+ + H

Velcade® (bortezomib)

http://www.communiquelive.com/siteimages/page441.jpg

•Approved by FDA May 2003

•Multiple myeloma

•2004 sales $143 million1

•2006 projected $225-2502

1. Sanchez-Serrano, I., Success in translational research: lessons from the development of bortezomib. Nat Rev

Drug Discov 2006, 5, (2), 107-14

2. http://investor.millennium.com/phoenix.zhtml?c=80159&p=irol-newsArticle_Print&ID=801177&highlight=

NH

HN B

OHN

N

O

O

OH

Velcade® (bortezomib)

Millennium Pharmaceuticals, I., VELCADE® (bortezomib) for Injection PRESCRIBING INFORMATION. In

Rev 1 ed.; Cambridge, MA, 2004

BO

O

OH

OH

OH

OH

R

O

BO

B

OB

R

RR

Bortezomib Solubility as a

Function of pH and Mannitol

pH

Solu

bili

ty, m

g/m

L

Solubility Results

Solubility of 4-MBBA Vs. pH

0.1

1

10

100

0.00 2.00 4.00 6.00 8.00 10.00 12.00

pH

So

lub

ilit

y (

mg

/mL

)

No Mannitol (solubility mg/mL) 500mM Mannitol (solubility mg/mL)

O B

OH

OH

Change in pKa with Mannitol

pKa: 7.99

pKa: 9.15

no mannitol

5 mM mannitol

Polyol Binding

Polyol Anion Binding

Constant:

KB2 (M -1)

Neutral Binding

Constant:

KB1 (M -1)

Mannitol 9670 ±2754 10.44 ±2.97

Xylitol 5351 ±1530 5.77 ±1.65

Erythritol 283 ±14.8 3.06x10-1 ±0.16x10-1

Glycerin 41.5 ±1.76 4.47x10-2

±0.19x10-2

Ethylene glycol 2.62 ±0.06 2.83x10-3

±0.06x10-3

HO

HO O H

HO O H

HO

ma nnitol

HO

O H

ethyl ene glycol

OH

HO

OH

glyce rin

OH

OH

OH

OH

erythritol

OH

OH

HO

HO

OH

xyli tol

Imagination is More Important than

Knowledge Albert Einstein

• The quality of imagination applied to prodrugs is surprisingly

NOT high.

• People seems to do the same thing. Some is driven by

historical precedence (safe but boring).

• Medicinal chemists are very creative in chemistry but

somewhat lacking in the biology/biochemistry.

• The biologist/biochemist often have poor organic and physical

chemistry backgrounds.

• Pharmaceutical chemists often know what needs to be done but

do not have the chemistry or the means to make sophisticated

molecules.

• For a prodrug strategy to work, a TEAM is necessary.

It Takes a Village to Raise a Child

(African proverb)

Lead

Molecule

Potential

Prodrugs

in vitro and extensive

in vivo testing of

ADME properties Design of new

potential prodrugs .

Prodrug

Candidate

10-25 “turns

of the wheel”

PRODRUG INTERVENTION

MUST

BECOME AN INTEGREL PART OF

THE DRUG DESIGN STRATEGUM

My favorite quote on prodrugs by Adrian Albert

“Although a detailed knowledge of permeability

and enzymes can assist a designer in finding pro-

agents…(s)he will have in mind and organisms

normal reaction to a foreign substance is to burn

it up for food”