Download Enhanced water solubility for enhanced oral drug delivery via the

Prodrug strategies to
overcome poor water solubility
and permeability
Pharmaceutical Technology
1
Prodrugs
A prodrug is a poorly active or inactive compound containing the
parental drug that undergoes some in vivo biotransformation through
chemical or enzymatic cleavage, enabling the delivery of the
active molecule at efficacious levels. Carrier-linked prodrugs can be
classified as bipartite prodrugs, in which the carrier is linked directly to
the parent drug, and tripartite prodrugs, in which a spacer links the
carrier to the parent drug . Carriers are commonly attached by chemical
groups such as ester, amide, carbamate, carbonate, ether, imine,
phosphate, among others Mutual prodrugs are a type of carrier-linked
prodrug in which two active compounds are linked each acting as the
carrier to the other. These prodrugs have increased effectiveness
Through synergistic action. Another type of carrier-linked prodrug is the
macromolecular prodrug; these prodrugs use polymeric backbones as
carriers.
2
3
Prodrugs
• Prodrugs also have been synonymously referred to as
latentiated drugs, bioreversible derivatives, and
congeners.
• However, the term prodrug gained wider acceptance and
usually describes compounds that undergo chemical
transformation within the body prior to exhibiting
pharmacologic activity. Some of the earliest examples of
prodrugs are methenamine (antibiotic, UTI) and aspirin.
4
In the late nineteenth century a chemist, Felix Hoffman in Bayar Company,
synthesized the antipyretic agent Aspirin (acetylsalicylic acid), which was
introduced for the first time in clinical practice in 1899; it can be considered a
less corrosive prodrug form of salicylic acid to minimize the gastric irritation and
ulcerogenicity associated with salicylic acid.
Methenamine was discovered in 1899 by Schering as inactive prodrug that
delivers the antibacterial formaldehyde. It is useful in the treatment of urinary
tract infection, when transported to urinary bladder it becomes acidified to
provide a medium in which formaldehyde is generated.
5
Rationale for Prodrug Design
• A large number of the new molecular entities with
promising therapeutic profiles are dropped from the
screening stage because of their inferior physicochemical
and biopharmaceutical properties.
• These undesired properties result in poor absorption,
extensive metabolism, and low bioavailability because of
physical, biological, or metabolic barriers.
• If the chemical structure of the drug or lead compound
can be modified to overcome these barriers and then
revert to the pharmacologically active form, the drug can
6 be delivered efficiently.
Rationale for Prodrug Design
• The objective of designing of prodrugs is to achieve:
– Favorable physicochemical characteristics (e.g.,
chemical stability, solubility, taste, or odor)
– Favorable biopharmaceutical properties (e.g., oral
absorption, first-pass metabolism, permeability across
biological membranes such as the blood-brain barrier,
or reduced toxicity)
– Favorable pharmacodynamic properties (e.g.,
reduced pain or irritation).
7
Enhancement of solubility/dissolution
through prodrug formation
• To solve the problem of poor solubility/dissolution of a
drug through prodrug formation we must understand the
reason why is the compound exhibiting poor solubility:
– Is the molecule one that displays high crystallinity, a
“brick dust” molecule, or
– is it a low melting or “grease ball” molecule?
• Obviously, a continuum exists, with most molecules not
fitting either extreme.
8
Enhancement of solubility/dissolution
through prodrug formation
• If the molecule has the characteristics of a “grease ball”
molecule and usual formulation approaches do not work,
solubility enhancement through the use of a polar
promoiety may prove useful.
• If one has a “brick dust” molecule a polar promoiety may
work, as might strategies that disrupt the intermolecular
interactions that led to the high crystallinity
9
Addition of polar functionalities
• Conventional wisdom dictates that placing a polar
functional group in the structure of a molecule with
limited aqueous solubility should enhance solubility.
• In the case of a prodrug, that functionality would have to
be removed/modified, either chemically or enzymatically,
to regenerate the parent drug.
10
Addition of polar functionalities
• Many prodrugs designed to increase water solubility
involve the addition of an ionizable promoiety to the
parent molecule.
• Because charged molecules have greater difficulty
crossing biological membranes, one must balance
increased water solubility with the potential for
decreased permeability.
11
Addition of polar functionalities
• One might argue that a phosphate ester of a drug with
an alcohol functionality in its structure would produce a
poorly, membrane permeable prodrug.
• However, phosphate esters have been shown to be very
effective at improving the delivery of poorly water-soluble
parent drug molecules after oral delivery.
12
Addition of polar functionalities
• For R–OH, a highly permeable drug, bioavailability after
oral dosing is limited by slow dissolution.
• The prodrug, R–OPO3= is much more soluble, rapidly
dissolves in the content of the GIT but is cleaved to R–
OH by the presence of the enzyme, alkaline
phosphatase, seen in abundance on the brush border
surface of the cells lining the small intestine, the
enterocytes.
• R–OH, being permeable, readily crosses the enterocyte
membranes and enters the systemic circulation.
13
Addition of polar functionalities
• limitations of this approach:
– The phosphate prodrug must be a good substrate for
alkaline phosphatase
– R–OH must be permeable once cleaved
– Too rapid a cleavage of a very insoluble R–OH can
result in precipitation of R–OH, and thus poor redissolution
14
Addition of polar functionalities
• Fosamprenavir, a phosphate prodrug of the HIV protease inhibitor,
amprenavir.
• Amprenavir was originally formulated in a 150 mg capsule
containing TPGS (d-alpha tocopheryl polyethylene glycol 1000
succinate ), PEG 400 and propylene glycol, requiring patients to
take 8 capsules to achieve a dose of 1200 mg twice a day. d-αTocopheryl polyethylene glycol 1000 succinate (simply TPGS or
Vitamin E TPGS) is formed by the esterification of Vitamin E
succinate with polyethylene glycol 1000. As novel Generally
Regarded as Safe (GRA) nonionic surfactant, it exhibits amphipathic
properties and can form stable micelles in aqueous vehicles at
acid 0.02 wt%.
concentration asSuccinic
low as
Tochopherol
PEG
•15 This puts amprenavir at a competitive disadvantage to other lower
dose and more conveniently administered antiAIDS drugs.
Addition of polar functionalities
• Amprenavir has a secondary alcohol group in its structure that was
synthetically phosphorylated to produce fosamprenavir.
• The commercial success of fosamprenavir has made an impact.
• Fosamprenavir is in the form of a calcium salt which is
approximately 10 times more soluble than amprenavir.
16
Addition of polar functionalities
• Because of this superior solubility, even more so at low
pH values where the calcium salt dissociates,
fosamprenavir can be formulated as a 700 mg tablet
(equivalent to 600 mg of amprenavir) thus reducing the
dosing to 2 tablets twice a day.
• The oral availability of amprenavir from fosamprenavir is
essentially equivalent to amprenavir from the original
capsules.
17
 A similar approach was not successful for propofol, a phenolic
compound used as a systemic anesthetic by injection or infusion. The
phosphat prodrug was too stable in blood after injection. Therefore, a
(phosphonooxy)methyl ester prodrug (fospropofol) was synthesized (see
Scheme 3), the disodium salt of which is >1000-fold more soluble than the
parent drug. The (phosphonooxy)methyl prodrug is readily cleaved in vivo by
phosphatases, followed by chemical hydrolysis yielding propofol, phosphate,
and formaldehyde.
18
Disulfide prodrugs
A paclitaxel prodrug containing a disulfide moiety was described as an anticancer
compound. The rationale behind the design of these molecules is based on the
recognition of disulfide subunit by the enzyme glutathione, which releases the
paclitaxel. High levels of this enzyme have been described in cancer cells, and one
hypothesis speculates that this enzyme is involved in resistance to many anticancer
drugs. The prodrug compounds were 6–100 times more soluble than paclitaxel.
Moreover, the most active compound 18 was 65 times more water soluble than
paclitaxel. For this molecule, superior antitumoral activity was identified in all types of
cells evaluated, except for MCF10A. After oral administration, the bioavailability in
mice was five-fold greater than that of the parental drug.
19
an intracellular sulfhydryl-containing species such as glutathione (GSH or its
thiolate anion GS- at biological pH) would attack the disulfide bond in the prodrug to
give the transient metabolites [M1] and [M2]. The thiolate anion in [M1] would trigger
intra-molecular cyclization by attacking the nearby carbonate group to release
paclitaxel (1) and the cyclic ethylene monothiolcarbonate [M3].The metabolite [M2]
could be excreted or metabolized further by plasma esterases if it isbonded to a
water-soluble group or moiety via an ester bond.
20
Macromolecular prodrug
Oridonin is a natural product is found in Rabdosia rubescens, a Chinese
medicinal plant, and it exhibited antitumoral activity against several types of cancer,
including leukemia. Exploring polyethylene glycol as carrier, the authors linked
oridonin to PEG, using succinic acid as a spacer. Four different molecular weights of
PEGs were tested to increase solubility in water. The greatest increase in solubility
was observed for a low PEG-molecular-weight (5 kDa) conjugate 10. This prodrug
had 99.2 times the solubility of oridonin. A chemical hydrolysis study showed a
sustained-release effect for the prodrugs. In vivo studies using the two intermediate
conjugates (10 and 20 kDa) demonstrated a successful use of this prodrug
approach, as these derivatives have better pharmacokinetic profiles than oridonin
21
Decreased crystal packing
• A strategy not often considered to effect better oral
delivery of poorly soluble drugs is one that attempts to
convert a “brick dust” molecule to a “grease ball”
molecule.
• Noyes–Whitney model describes the dissolution rate
(DR) of a drug under sink conditions,
22
Decreased crystal packing
• Although this equation has some limitations, it illustrates
that DR should be proportional to solubility, Cs, but
solubility in what?
• Because of the presence of mixed micelles of bile salts
and lecithin as well as food digestion products, the GIT
presents an environment favorable to dissolving the
poorly soluble, lipophilic compouds.
23
Decreased crystal packing
• The N–H at the 3-position of phenytoin is known to
hydrogen bond with the carbonyl of a second phenytoin
molecule. Thus, removing or blocking the N–H group at
the 3-position dramatically changes the properties of the
molecule.
• The melting points of a series of 3-acyloxymethyl
prodrugs of phenytoin is shown along with their solubility
in water, cyclohexane and in a bile salt/lecithin mixture
used to simulate the GIT contents (referred to by the
acronym SIBLM, for simulated bile salt, lecithin mixture).
24
Decreased crystal packing
25
Decreased crystal packing
• Note the melting behavior of the pentanoyl- (C4H8CO-)
and octanoyl- (C7H15CO-) derivatives, which have
melting points lower than their higher and lower
homologs, and the relationship between melting point
and the solubility of the various prodrugs in the
hydrocarbon solvent, cyclohexane.
• Clearly if one were to only consider water solubility and
DR in water, phenytoin itself would be the superior
candidate. When one considers the DR in the SIBLM
however, the choice becomes less clear, with the DR of
the octanoate prodrug superior to that of phenytoin in
this medium
26
Decreased crystal packing
• The oral, absolute bioavailability of phenytoin from
phenytoin, the pentanoate and the octanoate was
assessed in fed and fasted dogs.
27
Decreased crystal packing
• The bioavailability of phenytoin from the two prodrugs is
superior in both the fed and fasted state despite their
lower aqueous solubility. In the fed state, phenytoin
bioavailability from the pentanoate and the octanoate is
close to complete, even though the octanoate had
limited aqueous solubility and no measurable DR in
water.
28
Mutual prodrugs
• This azo bond is stable in the
upper GIT and is cleaved in
the colon by the azoreductases produced by the
microflora
• Sulphasalazine was introduced for
the treatment of rheumatoid
arthritis and anti-inflammatory
disease. Chemically it is
salicylazosulphapyridine (SASP),
where sulfapyridine is linked to a
salicylate radical by an azo bond
(mesalazine). When taken orally,
only a small proportion of the
ingested dose is absorbed from
the small intestine and the bulk of
the sulphasalazine reaches the
colon intact. There it is split at the
azo bond by the colonic bacteria
with the liberation of
sulphapyridine (SP) and 5-ASA
29
Enhancing Permeability and Absorption
 The transport of a drug to its site of action usually requires passage through
several lipid membranes; therefore, membrane permeability has a considerable
influence on drug efficacy. In oral drug delivery in particular, which is the preferred
route for the majority of drugs, the most common absorption routes are
unfacilitated and largely nonspecific, passive transport mechanisms. The
lipophilicity of poorly permeable drugs can be increased by modifying the
hydrocarbon moieties. However, good activity sometimes requires a structure,
which is far from ideal one for good membrane permeability. In such situation, the
prodrug strategy can be an extremely valuable option. Improvements of
lipophilicity have been the most widely studied and therefore now also the most
successful field of prodrug research. It has been achieved by masking polar
ionized or nonionized functional groups to enhance
Oral drug absorption.
 A hydrophilic hydroxyl, thiol, carboxyl, phosphate, or an amine group on the
parent drug can be converted to more lipophilic alkyl or aryl esters, and these
prodrugs are readily bioconverted to their active species by ubiquitous esterases,
which are present throughout the body. The attractiveness of this prodrug
approach is that the alkyl chain length can be modified to obtain precisely the
desired lipophilicity. Currently, a considerable number of ester prodrugs have
advanced into clinical use.
30
HA.PT
Oseltamivir (Tamiflu; Hoffmann-La Roche Inc., Nutley, NJ) is an orally active
ethyl ester prodrug of a selective inhibitor of viral neuraminidase glycoprotein
and used in the treatment of influenza types A and B . After absorption,
oseltamivir undergoes rapid bioconversion to its parent drug mostly by the action
of carboxylesterase The bioavailability of the more lipophilic oseltamivir
is almost 80%, whereas the corresponding value for free carboxylate is as low as
5%.
31
HA.PT
Adefovir dipivoxil (Hepsera; Gilead Sciences, Inc., Foster City, CA) represents
a more recent example of a prodrug, in which the ester promoiety is attached
to a phosphoryl group on the parent drug via a spacer. This pivaloyloxymethyl
phosphoric acid ester of the nucleotide reverse transcriptase inhibitor adefovir
(PMEA) is given orally to treat retro-, herpes-, and hepadnaviruses and has
almost four times greater bioavailability than adefovir itself.
32
HA.PT
The latest clinical example of a more lipophilic oral prodrug is dabigatran
etexilate (Pradaxa; Boehringer Ingelheim Pharma GmbH, Ingelheim,
Germany), a direct thrombin inhibitor for stroke prevention, which has been
available in Europe and many other countries since 2008. However, it was not
until the October 2010 when dabigatran etexilate became the first oral
alternative to warfarin to be approved in the United States. The active drug
dabigatran is a very polar, permanently charged molecule with a log P of -2.4
(noctanol/buffer, pH 7.4) and therefore it has zero bioavailability after oral
administration. In the more lipophilic bifunctional prodrug dabigatran
etexilate, the two polar groups, the amidinium moiety and carboxylate, are
masked by carbamic acid ester and carboxylic acid ester groups, respectively,
which results in better absorption with bioavailability of 7% after oral
administration
33
HA.PT
Another method to increase oral absorbtion is to design prodrugs, which have
structural features similar to substrates that are absorbed by carrier-mediated
transport. This strategy is particularly important when passive transcellular
absorption is negligible. Good examples of carrier-mediated of prodrugs are
midodrine (ProAmatine, Gutron; Shire Llc, Florence, KY) and valacyclovir (Valtrex;
SmithKline Beecham, Philadelphia, PA; Glaxo Wellcome Inc., Research Triangle
Park, NC).
Midodrine is a glycine prodrug of desglymidodrine (DMAE), a selective a1-receptor
agonist used in the treatment of orthostatic hypotension, in which the glycine
promoiety is attached to an amine group of DMAE. Midodrine is absorbed
via the intestinal proton-coupled peptide transporter 1 and is bioconverted by asyet-unknown peptidases, mainly in the liver and systemic circulation It has an oral
bioavailability of 93%, which is significantly more than the corresponding value for
DMAE (50%).
34
HA.PT
Valacyclovir is a L-valyl ester prodrug of acyclovir, a purine nucleoside used for the
treatment of herpes virus infections. Valacyclovir is a substrate, not only for
peptide transporter 1 but also for Na+-dependent neutral amino acid transporter.
After absorption, it is bioactivated by valacyclovir hydrolase.The bioavailability of
this prodrug is more than 50%, which is 20 to 35% better than the bioavailability of
acyclovir. Valacyclovir is actually apreprodrug or double prodrug, because after the
hydrolysis of the valine promoiety, acyclovir, like all nucleosides, requires
phosphorylation before it forms the active nucleotide triphosphate. The first
phosphorylation reaction is mediated by viral thymidine kinase, which is
far more effective than the endogenous enzyme in uninfected cells. This further
improves the selectivity of acyclovir. Cellular kinases subsequently phosphorylate
the nucleotide monophosphate to its active triphosphate form, which then can act
as a selective inhibitor of viral infection.
35
HA.PT
36
HA.PT