DRUG DELIVERY
APPROACHES WITH SPECIAL
EMPHASIS ON CHEMICAL
DRUG DELIVERY
Presented By : KIRAN.D
Department Of Pharmaceutics,
University College of Pharmaceutical Sciences,
kakatiya University.
CONTENT


Introduction
Targeted delivery of drugs
 Physical (or) Mechanical approach
 Biological approach
 Chemical approach

Prodrug approaches

Retro metabolic approach
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
•


Chemical drug delivery system (CDS)
Soft drug approaches
Chemical drug delivery approaches to Brain, Lung, Eye
Conclusion
References
Targeted delivery of drugs

Drug targeting:
Drug targeting is the delivery of
drugs to receptors (or) organs (or) any other
specific part of the body.
 In the past work was done mainly altering the
pharmacokinetics of the drugs, but later with the
advancement in “carrier technology”, approaches
based on specific site targeting came into focus.
Targeted delivery of drugs

The targeted delivery of drugs may be achieved
by different approaches, mainly classified into 3
categories.



Physical (or) Mechanical approach
Biological approach
Chemical approach
Physical (or) Mechanical approach




It involves formulation of drug using a particulate
delivery device, which will allow differential
release of the drug.
Carrier systems employed:
Solid particulates (such as microspheres,
nanoparticles, etc.,)
Liquid colloids (such as liposomes,etc.,)
Applications of Physical (or) Mechanical approach



Localization of particulate carriers:
Ex: 1) intravenously injected microparticulate carriers.
2) Orally adminstered microspheres taken up from the intestine by
payer’s patches present in the GIT.
Targeting to mononuclear phagocytic system:
Ex: 1) targetting of gamma interferon, or other
immunomodulators to macrophages which transform them into
competent host defence cells with capacity to kill tumour cells.
2) specific tageting of antivirals such as
azidothymidine(AZT) to macrophages using nanoparticles as colloid
drug carrier.
Targeting to pulmonary region:
Ex: IV adminstration of radiolabelled microspheres leads
to localisation in the lungs.

Extra vascular targeting:



Ex: pH sensitive nanoparticle suspension, which gels in neutral pH
environment of the cul-de-sac region of the eye.
Intra-articular adminstration of liposomes containing sterol
cortisol palmitate for arthritis.
Mucosal delivery of antigens:
Ex: orally adminstered vaccine loaded in
microspheres leading to induction of IgA antibody production.

Magnetic drug targeting:
Ex: epidoxorubicin chemically conjugated with
ferrofluid.
Biological approach

It involves the delivery of drugs using carrier system with
targeting moiety.

Strategies involved:


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Antibodies directed against specific cell surface antigens.
Endogenous carbohydrate-binding proteins (lectins)
Low molecular weight protein for renal targeting
Ex: Targeting of NSAID naproxen to kidney
using low molecular weight protein (lysozyme).

Hormones functioning as specific ligands for receptors on
specific targets.
Ex: Insulin for reduction in cholesterol ester.
CHEMICAL APPROACHES IN TARGETING

Chemical approach


Prodrug approaches
Retro metabolic approach





Chemical drug delivery system (CDS)
Soft drug approaches
Chemical approach represents a novel, systematic method to design
safe, localized delivery of drug compounds.
It allows targeting of molecules to specific target sites or organs, based
on predictable enzymatic activation.
It also involves incorporation of some groups in the structure of the
active molecule so as to deactivate and detoxify the drug subsequent to
exerting its biological effects.

ADVANTAGES:


Reduction in dose due to effective targeting
low frequent medication as the drug can be maintained for
longer duration of time. (sustained release)
Improved Therapuetic Index (TI).
Site enhanced specific delivery. (Drug targeting).

LIMITATIONS:

Hard to justify the pharmacokinetics of the intermediates along
with the active and inactive metabolites.
Enzymatic modification may effect the pharmacological
action.
Toxicity of separated moiety may also play a role leading to
adverse effects.




Targeted Prodrug Design to
Optimize Drug Delivery

Prodrugs are pharmacologically inert chemical derivatives that can be
converted in- vivo to the active drug molecules, enzymatically or
nonenzymatically, to exert a therapeutic effect.

Prodrugs are usually activated in single step enzymatic attack.

Enzyme-targeted prodrug approach has been used to improve oral drug
absorption, as well as site-specific drug delivery.
Targeted prodrug design is based on the following:



Targeting specific enzymes.
Targeting specific membrane transporters.
Classificastion Of Prodrug
• Carrier Linked Prodrug: In this type of prodrug, the active drug is covalently
linked to an inert carrier or transport moiety. Such prodrug has
modified lipophilicity due to attached carrier. The active drug is
released by hydrolytic cleavage either chemically or enzymaticaly. The
used moiety is ester or amides.
• Bioprecursor: These are obtained by chemical modification of active
drug but do not contain a carrier. Such type of prodrug has almost the
same lipophilicity as the parent drug and is bioactivated generally by
redox biotransformation.
APPLICATIONS




Brain targeting:
Dihydropridine pyridinium type redox system was
developed for brain specific sustained delivery of drug. The drug
containing amine group is made lipophilic by coupling to dihydropyridine
promoiety that facilitate penetration of prodrug through the blood brain
barrier. In the CNS dihydropridine group oxidize to polar pyridinium salt,
thus becomes poorly permeable to blood brain barrier and causes retention
at the site and cleavage provides sustained release for action .The same
process in periphery due to high hydrophilicity rapidly excreted and
toxicity eliminates.
Prodrug approach to prodrug activity in lung: In case of beta2-stimulants,
esterification of catechol function to improve lung uptake of the inactive
lipophilic drug that undergoes cleavage by lung esterase to release active
parent molecule.
Treatment of glaucoma. Propranolol is converted into prodrugpropranololoxime. On application to the eye it undergoes hydrolysis to
give propranolone followed by redution to give propranolol.

Sulphasalazine is a typical example of colon specific chemical drug
delivery, it is synthesized by coupling diazotized 2-sulphanilamide pyridine
and 5-amino salicylic acid, after reaching the colon, the prodrug is cleaved
into active 5-amino salicylic acid by azoreductase associated with colonic
microflora.This enables the selective delivery of 5-amino salicylic acid to
colon.

Kidney possesses high concentration of L-glutamyl transpeptidase and Lamino acid decarboxylase enzymes. These enzymes are used to provide
selective delivery of Dopamine to kidney in the form of its prodrug L-gglutamyl dopa. The prodrug is first cleaved by L-glutamyl transpeptidase
producing L-dopa, which is converted to dopamine by L-amino acid
decarboxylase. This leads to selective delivery of drug to kidney resulting
in desired renal vasodilatation avoiding systemic hypotension.

Recently, new therapies have been proposed which attempt the localization
of prodrug activation enzymes into specific cancer cells prior to prodrug
administration. These new approaches are referred to as


Anti-body directed enzyme prodrug therapy (ADEPT)
Gene directed enzyme prodrug therapy (GDEPT)
RETROMETABOLIC DRUG
DESIGN


This drug design approach were designated as
retrometabolic to emphasize the fact that metabolic
pathways are designed going backwards compared to actual
metabolic processes.
Retrometabolic drug design incorporates two major
systematic approaches:


The design of soft drugs (SDs) and
Chemical Delivery Systems (CDSs).
Both aim to design new, safe drugs with an improved
therapeutic index by integrating structural activity relationship
(SAR) and structural metabolism relationships (SMR).
The design of soft drugs (SDs)




DEFINATION:
Soft drugs SDs are newly designed, therapeutically active
compounds (most often close structural analogs of a known lead
compound) specifically designed to allow predictable metabolism into
inactive metabolites after exerting the desired therapeutic effect.
They produce targeted, localized pharmacological activity, but no
undesired systemic activity or toxicity as they are promptly deactivated
when they distribute away from this site.
The goal of a softdrug is not to avoid metabolism, but rather to control
and direct it in order to avoid the formation of toxic or active metabolic
products.
SDs rely on inactivation by hydrolytic enzymes.
SD approaches can be classified into five subclasses:
 (1) inactive metabolite-based SDs,
 (2) soft analogs,
 (3) active metabolite-based SDs,
 (4) activated SDs and

(5) pro-SDs.
 Of these approaches, the first two have proven to be
the most useful and successful strategies, and have been
applied the most frequently.


Inactive metabolite-based SDs:
These are active compounds
designed starting from a known inactive metabolite of an
existing drug. Sometimes, not an actually observed, but
an assumed (i.e., hypothetical) inactive metabolite can
also be used as a starting point. This is then converted
into a steric and electronic analog of the original drug that
is active, but allows facile, single-step metabolism back to
the very inactive metabolite the design started from.

Soft analog SDs:
These are close structural analogs
of known active drugs that have a specific
metabolically sensitive moiety built into their
structure to allow a facile single-step deactivation
after the desired therapeutic role has been
achieved. The two approaches overlap somewhat,
and certain SDs can be considered as resulting
from either of them.
Soft drug examples

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soft corticosteroids (e.g., loteprednol etabonate, etiprednol dicloacetate)
soft [beta]-blockers (e.g., adaprolol) and
soft anticholinergics (e.g., tematropium)
* soft tacrolimus analogs (e.g., MLD987) investigated at Novartis.
* soft benzodiazepine analogs (CNS7259X, CNS7056) that are
midazolam/bromazepam analogs originally developed at GlaxoSmithKline.
* intended soft mometasone furoate analogs investigated at Novartis.
"accidental" SDs: Methylphenidate, a methyl ester-containing piperidine
derivative that is structurally related to amphetamine and is now widely
used for the treatment of attention deficit hyperactivity disorder (ADHD).
Because methylphenidate is rapidly hydrolyzed into an inactive acidic
metabolite (ritalinic acid).
Natural SDs: such as steroid hormones or neurotransmitters (like dopamine,
GABA).
Chemical drug delivery system (CDS)





CDS approaches provide novel, systematic methodologies for targeting active
biological molecules to specific target sites or organs based on predictable,
multistep enzymatic activation.
The bioremovable moieties attached to the drug that is the subject of targeted
delivery include a targetor (T) moiety, which has to achieve the site-specific
targeting, and (optional) modifier functions ([F.sub.1]...[F.sub.n]), which
serve as lipophilizers, protect certain functions, or fine-tune the necessary
molecular properties to prevent premature, unwanted metabolic conversions.
Chemical Delivery Systems (CDS) are more advanced version of prodrugs in
which the drug is transformed into an inactive derivative, which then
undergoes sequential enzymatic transformations to deliver the drug at the site
of action.
Chemical delivery systems involve a cascade of enzymatic reactions for
activation.
Chemical delivery systems are utilized for sustained drug delivery as well as
site-specific targeted drug delivery.



The two main classes are represented by
The enzymatic physicochemical-based CDSs:
It exploit site-specific traffic properties
by sequential metabolic conversions that result in
considerably altered transport properties and are used for
brain targeting, and
Site-specific enzyme-activated CDSs:
It exploit specific enzymes found primarily,
exclusively, or at higher activity at the site of action and
are used for ocular targeting.
Applications of CDSs

Brain targeting:
CDSs are obtained by chemically attaching a T moiety
to the original drug structure and, if needed, some additional
modifier/protective functions. Upon administration, the resulting CDS is
distributed throughout the body. Predictable enzymatic reactions convert the
original CDS by removing some of the protective functions and modifying the
T moiety, leading to a precursor form ([T.sup. ]-D), which is still inactive, but
has significantly different physicochemical properties (Fig. 5). While the
charged [T.sup. ]-D form is locked behind the BBB into the brain, it is easily
eliminated from the body due to the acquired positive charge, which enhances
water solubility. After some time, the delivered drug (D) (as the inactive,
locked-in [T.sup. ]-D) is present essentially only in the brain, and carboxylic
esterases-mediated hydrolysis of this intermediary form provides sustained and
brain-specific release of the active drug.
Among the various existing models for brain targeting CDSs
are the only approaches which aim not only the influx of drug , but also the
efflux through the BBB once the molecule has entered.

Evaluation of a Brain-Targeting Zidovudine Chemical Delivery System

Redox targeting of LY231617, an antioxidant with potential use in the treatment
of brain damage.

Targeted drug delivery to the brain via phosphonate derivatives II. Anionic
chemical delivery system for zidovudine (AZT).

Improved brain delivery of antiviral agents through the use of redox targeting.

Delivery of peptide and protein drugs over the blood–brain barrier.

Targeting penicillins to the central nervous system: chemical delivery systems
and redox analogs.
Evaluation

Area-under-the-curve (AUC)-based site-targeting indexes,
STI = [AUC.sub.target]/[AUC.sub.blood],
provide pharmacokinetically accurate quantitative
measures of the effectiveness of delivery to the intended site of action.

Targeting enhancement factors,
TEF = [STI.sup.Delivery System]/[STI.sup.Drug Alone],
measure the relative improvement in the STI produced by
administration of the delivery system compared to administration of the drug
itself.

Estradiol-CDS ([E.sub.2]-CDS):
Among CDS approaches explored to date, estradiol CDS
([E.sub.2]-CDS) is in the most advanced investigation stage: it has recently completed phase I/II
investigation with a new buccal formulation [67]. Estradiol ([E.sub.2]) is the most potent human
estrogen, and because many of its pharmacological effects are CNS-mediated, there are several
potential therapeutic applications for a brain-targeted delivery system including the treatment of
menopausal vasomotor symptoms ("hot flashes"), the treatment and/or prevention of various types of
dementia including Alzheimer's disease, male or female sexual dysfunction, and possibly
neuroprotection.

Molecular packaging:
The CDS approach has also been extended to achieve successful brain deliveries
of neuropeptides such as Leu-enkephalin, thyrotropin-releasing hormone (TRH), and kyotorphin
analogs.
Occular targeting:β- blockers atenalol and metaprolol used in glaucoma .

lipophilic esters of adrenalone are effectively reduced within the eye ultimately
yielding epinephrine.

The soft methscopolamine analog 16 was significantly more potent than the corresponding
soft methatropine analog.

Lung targeting:
1,2 dithiolane-3pentyl moiety of lipoic acid was used as a targeting moiety
CONCLUSION

The targeting of chemical drug substances by
either of the different chemical approaches
involves proper understanding of SAR and
SMR which gives better targeting of drug
molecules with minimum of adverse effects
when compared to the other forms of drug
targeting approaches.
REFERENCES




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
Controlled drug delivery fundamentals & applications 2nd edition,
Joseph R.Robinson, Vincent H.L.Lee.
Controlled drug delivery concepts and advances, S.P.Vyas & Roop
k.Khar.
Andvances in controlled & novel drug delivery N.K.Jain.
Recent advances in retrometabolic design approaches N. Bodor*,
Center for Drug Discovery, University of Florida.
Retrometabolic drug design concepts in ophthalmic target specific drug
delivery, Nicholas Bodor, Center for Drug Discovery, University of
Florida.
Targeted drug delivery to the brain via phosphonate derivatives II.
Anionic chemical delivery system for zidovudine (AZT)
Gabor Somogyi , Peter Buchwald, Daishuke Nomi , Laszlo Prokai,
Nicholas Bodor.
Retrometabolic drug design concepts in ophthalmic targetspecific
drug delivery. Nicholas Bodor.
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