DRUG DELIVERY APPROACHES WITH SPECIAL EMPHASIS ON CHEMICAL DRUG DELIVERY

1. DRUG DELIVERY APPROACHES WITH SPECIAL EMPHASIS ON CHEMICAL DRUG DELIVERY Presented By : KIRAN.D Department Of Pharmaceutics, University College of Pharmaceutical Sciences, kakatiya University.

2. 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

3. 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.

4. 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

5. 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.,)

6. 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.

7. 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.

8. Biological approach • It involves the delivery of drugs using carrier system with targeting 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 kidney using low molecular weight protein (lysozyme). • Hormones functioning as specific ligands for receptors on specific targets. Ex: Insulin for reduction in cholesterol ester.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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 prodrug-propranololoxime. On application to the eye it undergoes hydrolysis to give propranolone followed by redution to give propranolol.

14. 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 L-amino acid decarboxylase enzymes. These enzymes are used to provide selective delivery of Dopamine to kidney in the form of its prodrug L-g-glutamyl 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)

15. 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).

17. 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.

18. 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.

19. 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.

20. 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.

21. 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 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).

22. 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. Chemical drug delivery system (CDS)

23. 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.

24. 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.

25. 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.

26. 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.

27. 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 areeffectively reduced within the eye ultimately yielding epinephrine. • The softmethscopolamine analog 16 was significantlymore potent than the corresponding soft methatropineanalog. Lung targeting: 1,2 dithiolane-3pentyl moiety of lipoic acid was used as a targeting moiety

28. 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.

29. 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 deliveryN.K.Jain. Recent advances in retrometabolic design approachesN. 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. www.sciencedirect.com REFERENCES

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