DRUG DELIVERYAPPROACHES WITH SPECIAL

EMPHASIS ON CHEMICALDRUG 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

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 ofdrugs to receptors (or) organs (or) any otherspecific part of the body.

In the past work was done mainly altering thepharmacokinetics of the drugs, but later with theadvancement in “carrier technology”, approachesbased on specific site targeting came into focus.

Targeted delivery of drugs

The targeted delivery of drugs may be achievedby different approaches, mainly classified into 3categories.

Physical (or) Mechanical approach

Biological approach

Chemical approach

Physical (or) Mechanical approach

It involves formulation of drug using a particulatedelivery device, which will allow differentialrelease 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 bypayer’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 intocompetent host defence cells with capacity to kill tumour cells.

2) specific tageting of antivirals such asazidothymidine(AZT) to macrophages using nanoparticles as colloiddrug 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 sterolcortisol 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 withtargeting moiety.

Strategies involved: 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 kidneyusing 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 designsafe, localized delivery of drug compounds.

It allows targeting of molecules to specific target sites or organs, basedon predictable enzymatic activation.

It also involves incorporation of some groups in the structure of theactive molecule so as to deactivate and detoxify the drug subsequent toexerting its biological effects.

ADVANTAGES: Reduction in dose due to effective targeting

low frequent medication as the drug can be maintained forlonger duration of time. (sustained release)

Improved Therapuetic Index (TI).

Site enhanced specific delivery. (Drug targeting).

LIMITATIONS:

Hard to justify the pharmacokinetics of the intermediates alongwith the active and inactive metabolites.

Enzymatic modification may effect the pharmacologicalaction.

Toxicity of separated moiety may also play a role leading toadverse effects.

Targeted Prodrug Design toOptimize Drug Delivery

Prodrugs are pharmacologically inert chemical derivatives that can beconverted in- vivo to the active drug molecules, enzymatically ornonenzymatically, to exert a therapeutic effect.

Prodrugs are usually activated in single step enzymatic attack.

Enzyme-targeted prodrug approach has been used to improve oral drugabsorption, 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 hasmodified lipophilicity due to attached carrier. The active drug isreleased by hydrolytic cleavage either chemically or enzymaticaly. Theused 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 thesame lipophilicity as the parent drug and is bioactivated generally byredox biotransformation.

APPLICATIONS

Brain targeting:Dihydropridine pyridinium type redox system was

developed for brain specific sustained delivery of drug. The drugcontaining amine group is made lipophilic by coupling to dihydropyridinepromoiety that facilitate penetration of prodrug through the blood brainbarrier. In the CNS dihydropridine group oxidize to polar pyridinium salt,thus becomes poorly permeable to blood brain barrier and causes retentionat the site and cleavage provides sustained release for action .The sameprocess in periphery due to high hydrophilicity rapidly excreted andtoxicity eliminates.

Prodrug approach to prodrug activity in lung: In case of beta2-stimulants,esterification of catechol function to improve lung uptake of the inactivelipophilic drug that undergoes cleavage by lung esterase to release activeparent molecule.

Treatment of glaucoma. Propranolol is converted into prodrug-propranololoxime. On application to the eye it undergoes hydrolysis togive propranolone followed by redution to give propranolol.

Sulphasalazine is a typical example of colon specific chemical drugdelivery, it is synthesized by coupling diazotized 2-sulphanilamide pyridineand 5-amino salicylic acid, after reaching the colon, the prodrug is cleavedinto active 5-amino salicylic acid by azoreductase associated with colonicmicroflora.This enables the selective delivery of 5-amino salicylic acid tocolon.

Kidney possesses high concentration of L-glutamyl transpeptidase and L-amino acid decarboxylase enzymes. These enzymes are used to provideselective delivery of Dopamine to kidney in the form of its prodrug L-g-glutamyl dopa. The prodrug is first cleaved by L-glutamyl transpeptidaseproducing L-dopa, which is converted to dopamine by L-amino aciddecarboxylase. This leads to selective delivery of drug to kidney resultingin desired renal vasodilatation avoiding systemic hypotension.

Recently, new therapies have been proposed which attempt the localizationof prodrug activation enzymes into specific cancer cells prior to prodrugadministration. These new approaches are referred to as Anti-body directed enzyme prodrug therapy (ADEPT) Gene directed enzyme prodrug therapy (GDEPT)

RETROMETABOLIC DRUGDESIGN

This drug design approach were designated asretrometabolic to emphasize the fact that metabolicpathways are designed going backwards compared to actualmetabolic processes.

Retrometabolic drug design incorporates two majorsystematic approaches: The design of soft drugs (SDs) and

Chemical Delivery Systems (CDSs).

Both aim to design new, safe drugs with an improvedtherapeutic 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 leadcompound) specifically designed to allow predictable metabolism intoinactive metabolites after exerting the desired therapeutic effect.

They produce targeted, localized pharmacological activity, but noundesired systemic activity or toxicity as they are promptly deactivatedwhen they distribute away from this site.

The goal of a softdrug is not to avoid metabolism, but rather to controland direct it in order to avoid the formation of toxic or active metabolicproducts.

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 bethe most useful and successful strategies, and have beenapplied the most frequently.

Inactive metabolite-based SDs:

These are active compoundsdesigned starting from a known inactive metabolite of anexisting drug. Sometimes, not an actually observed, butan assumed (i.e., hypothetical) inactive metabolite canalso be used as a starting point. This is then convertedinto a steric and electronic analog of the original drug thatis active, but allows facile, single-step metabolism back tothe very inactive metabolite the design started from.

Soft analog SDs:

These are close structural analogsof known active drugs that have a specificmetabolically sensitive moiety built into theirstructure to allow a facile single-step deactivationafter the desired therapeutic role has beenachieved. The two approaches overlap somewhat,and certain SDs can be considered as resultingfrom either of them.

Soft drug examples 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 widelyused for the treatment of attention deficit hyperactivity disorder (ADHD).Because methylphenidate is rapidly hydrolyzed into an inactive acidicmetabolite (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 activebiological 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 targeteddelivery include a targetor (T) moiety, which has to achieve the site-specifictargeting, and (optional) modifier functions ([F.sub.1]...[F.sub.n]), whichserve as lipophilizers, protect certain functions, or fine-tune the necessarymolecular properties to prevent premature, unwanted metabolic conversions.

Chemical Delivery Systems (CDS) are more advanced version of prodrugs inwhich the drug is transformed into an inactive derivative, which thenundergoes sequential enzymatic transformations to deliver the drug at the siteof action.

Chemical delivery systems involve a cascade of enzymatic reactions foractivation.

Chemical delivery systems are utilized for sustained drug delivery as well assite-specific targeted drug delivery.

The two main classes are represented by

The enzymatic physicochemical-based CDSs:

It exploit site-specific traffic propertiesby sequential metabolic conversions that result inconsiderably altered transport properties and are used forbrain targeting, and

Site-specific enzyme-activated CDSs:

It exploit specific enzymes found primarily,exclusively, or at higher activity at the site of action andare used for ocular targeting.

Applications of CDSs Brain targeting:

CDSs are obtained by chemically attaching a T moietyto the original drug structure and, if needed, some additionalmodifier/protective functions. Upon administration, the resulting CDS isdistributed throughout the body. Predictable enzymatic reactions convert theoriginal CDS by removing some of the protective functions and modifying theT moiety, leading to a precursor form ([T.sup. ]-D), which is still inactive, buthas significantly different physicochemical properties (Fig. 5). While thecharged [T.sup. ]-D form is locked behind the BBB into the brain, it is easilyeliminated from the body due to the acquired positive charge, which enhanceswater solubility. After some time, the delivered drug (D) (as the inactive,locked-in [T.sup. ]-D) is present essentially only in the brain, and carboxylicesterases-mediated hydrolysis of this intermediary form provides sustained andbrain-specific release of the active drug.

Among the various existing models for brain targeting CDSsare the only approaches which aim not only the influx of drug , but also theefflux 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 treatmentof brain damage.

Targeted drug delivery to the brain via phosphonate derivatives II. Anionicchemical 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 systemsand redox analogs.

Evaluation Area-under-the-curve (AUC)-based site-targeting indexes,

STI = [AUC.sub.target]/[AUC.sub.blood],

provide pharmacokinetically accurate quantitativemeasures 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 byadministration of the delivery system compared to administration of the drugitself.

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/IIinvestigation with a new buccal formulation [67]. Estradiol ([E.sub.2]) is the most potent humanestrogen, and because many of its pharmacological effects are CNS-mediated, there are severalpotential therapeutic applications for a brain-targeted delivery system including the treatment ofmenopausal vasomotor symptoms ("hot flashes"), the treatment and/or prevention of various types ofdementia including Alzheimer's disease, male or female sexual dysfunction, and possiblyneuroprotection.

Molecular packaging:

The CDS approach has also been extended to achieve successful brain deliveriesof neuropeptides such as Leu-enkephalin, thyrotropin-releasing hormone (TRH), and kyotorphinanalogs.

Occular targeting:β- blockers atenalol and metaprolol used in glaucoma . lipophilic esters of adrenalone are effectively reduced within the eye ultimatelyyielding 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

The targeting of chemical drug substances byeither of the different chemical approachesinvolves proper understanding of SAR andSMR which gives better targeting of drugmolecules with minimum of adverse effectswhen compared to the other forms of drugtargeting approaches.

CONCLUSION

REFERENCES 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 drugdelivery, Nicholas Bodor, Center for Drug Discovery, University ofFlorida.

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 targetspecificdrug delivery. Nicholas Bodor.

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