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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
Presented By : KIRAN.D
Department Of Pharmaceutics,
University College of Pharmaceutical Sciences,
Drug targeting is the delivery of drugs to receptors (or) organs (or) any other specific part of the body.
Ex: 1) intravenously injected microparticulate carriers.
2) Orally adminstered microspheres taken up from the intestine by payer’s patches present in the GIT.
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.
Ex: IV adminstration of radiolabelled microspheres leads to localisation in the lungs.
Ex: orally adminstered vaccine loaded in microspheres leading to induction of IgA antibody production.
Ex: epidoxorubicin chemically conjugated with ferrofluid.
Ex: Targeting of NSAID naproxen to kidney using low molecular weight protein (lysozyme).
Ex: Insulin for reduction in cholesterol ester.
• 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.
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.
Both aim to design new, safe drugs with an improved therapeutic index by integrating structural activity relationship (SAR) and structural metabolism relationships (SMR).
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.
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.
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.
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)
It exploit site-specific traffic properties by sequential metabolic conversions that result in considerably altered transport properties and are used for brain targeting, and
It exploit specific enzymes found primarily, exclusively, or at higher activity at the site of action and are used for ocular 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.
STI = [AUC.sub.target]/[AUC.sub.blood],
provide pharmacokinetically accurate quantitative measures of the effectiveness of delivery to the intended site of action.
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.
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 . 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.
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.
1,2 dithiolane-3pentyl moiety of lipoic acid was used as a targeting moiety
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.