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Edit Comment Close Premium member Presentation Transcript Seminar on prodrugProdrug : Seminar on prodrugProdrug Presented by :-ABDUL RAZZAQ M.Pharm Pharmaceutical chemistry Submitted under the guidance of : Mr.Gubbi sudheendra sir M.Pharm , (Ph.D) PROFFESOR Luqman College of pharmacy, Gulbarga Content : Content Definition of PRODRUG Ideal properties of prodrug Classification of prodrug Application of prodrug Choice & function of pre-moiety Reference Prodrug : Prodrug The term prodrug was first introduced by “Albert -1958”,to describing “The compound that undergo biotransformation before exhibiting their p`cological effect, which are previously chemically modified in to inert substance. Or A prodrug is chemically modified inert drug precursor which upon biotransformation librates the pharmacologically active parent compound. Basically prodrug designs constitute an area of the drug concern with the optimization of drug delivery. By attachment of pro-moiety to the active moiety a prodrug is formed that in designed to overcome the barriers that restricts the optimal use of the active principle .usually the use of term prodrug implies a covalent link between an ‘active moiety’& a carrier moiety. Slide 4: Active drug prodrug (inactive) Active drug Schematic illustration of the prodrug concept Slide 6: Administration of the prodrug is one of the avenues when attempting to control drug delivery & to generate predictable drug concentration Vs time modified at specific drug receptor. Slide 9: A] Barrier related to physico-chemical properties of drug: Poor aqueous solubility – which being prevent the drug from administrated in the form of injectables. Low lipophilicity – which limits the design lipid bond formulation. Chemical instability – which prevent the drug to incorporate in to adequate forms. There are two types of barriers to drug delivery Slide 10: B] Barriers in the pharmacokinetic phase: Incomplete absorption across biological membrane such as GIT mucosa & BBB. Low & variable bioavailability due to extensive first pass effect. Too rapid absorption or excretion when longer duration of the action is desired. Lack of site-specificity. Slide 11: Ideal properties of prodrug: It should not have intrinsic pharmacological activity. It should rapidly transfer chemically or enzymatically in to the active form where desire. The metabolic fragment apart from the active drug should be non-toxic. Slide 12: Prodrug designing is requiring overcoming the following drawbacks: Unpleasant taste or odor. A wide range of adverse effect. Shorter duration of action. Instability. Site non-specificity. Poor absorption & distribution. Poor water solubility. Some compound are more active but unable to reach the site of action (e g. GABA) Slide 14: Classification of prodrug: Depending upon constitution of the constitution, lipophilicity, method of bioactivation & catalyst involved; they are classified in 2 groups, 1. Carrier linked Prodrugs 2. bioprecursor /Metabolic precursor Slide 15: 1. Carrier linked Prodrugs – They are one where the active drug is covalently linked to an inert carrier. They are generally ester or amide. Such prodrugs have greatly modified lipophilicity due to the attached carrier. The active drug is released by hydrolytic cleavage either chemically or enzymatically. E.g. Ditrimethylethanoate groups of dipivaloyladrenaline hydrolyse to original-OH groups on adrenalin in presence of esterase enzyme. Slide 16: (Adrenaline) Slide 17: 2. Bioprecursor/Metabolic precursor – This prodrug does not contain carriers but ready up on metabolism to induce the necessary functionally active species. E.g. The NSAID agent Sulindac is inactive as Sulphoxide & must be reduce metabolically to active sulphide. Slide 18: R= COOC2H5 Enalapril R=COOH Enalaprilic acid Enalapril (Prodrug) →Enalaprilic acid (Active) Slide 19: Pro-prodrug- Here the prodrug is further derivatised a fashion such that only enzymatic conversion to prodrug is possible. E.g. Diester of pilocarpic acid. Slide 21: Mutual prodrug In such type of prodrug two pharmacologically active agents are coupled to form a single molecule which acts as carrier for others. Eg.benorylate is a mutual prodrug of Aspirin & Paracetamol. Slide 23: Application of Prodrug – A- Pharmaceutical Application: -Improvement of taste. -Improvement of odour. -Change of physical form for preparation of solid dosage forms. -Reduction of pain on injection. -Enhancement of drug solubility and dissolution rate. B. pharmacokinetic application: - Enhancement of bioavailability (lipophilicity), - Prevention of presystemic metabolism, - Prolongation of duration of action, - Reduction of toxicity, - Site-specific drug delivery. Pharmaceutical application- : Pharmaceutical application- 1) Improvement of taste- one of the reason for poor patient compliance , particularly in case of children ,is the bitterness, acidity or causticity of the drug .two approaches can be utilized to overcome the bad taste of drug. 1) Reduction of the drug solubility in saliva. 2) To lower the affinity of drug towards taste receptor: Thus making the bitterness or causticity imperceptible. Slide 26: Clindomycin (Bitter taste) Clindomycin-2-palmitate (Bland taste) Slide 27: 2)Improvement of odour: - the odor of the compound depends upon the pressure of vapor's liquid with high vapor pressure (& low B.P.) will have string odour. E.g. ethylmercapto (ethaneethol) is one such drug which is foul smelling liquid at B.P. 35c the drug useful in treatment of leprosy is converted into its phthalate ester. Diethyldithio-isopthalate Slide 28: Which has high B.P. & odourless. The prodrug is administered by rubbing on skin after absorption the esters are metabolized to parent drug by thioesterase. Slide 29: 3)change of physical form of drug :- Some drugs which are in liquid form are unsuitable for formulation as a tablet especially if their dose is high. The method of converting such liquid drug in solid prodrug involves formation of symmetrical molecule having higher tendency to crystallize. Example: - ester of ethyl mercapto & trichloro –ethanol Slide 30: Slide 31: 4) Reduction of GIT irritation: several drug cause irritation & damage to the gastric mucosa through direct contact increased stimulation of acid secretion or through interference with protective mucosal layer. The NSAID’s especially salicylates have such a tendency. They lower gastric PH & induce ulceration. Slide 32: Examples of prodrug design to overcome such problems of gastric distress are given below Slide 33: 5) Reduction of pain on injection: Intramuscular injections are particularly painful when the drugs precipitate in to the surrounding cell or when the solution is strongly acidic, alkaline or alcoholic. For example: the low aqueous solubility of clindomycin hydrochloride & alkaline solution of the phenytoin are responsible for the pain on injection. This can be overcome by use of more water soluble prodrug of such agent like the 2-phosphate ester of clindomycin. Slide 34: Clindomycin 2-phosphate with increase aqueous solubility means reduces the pain after injection. Slide 35: 6)Enhancement of solubility& dissolution rate (hydrophilicity) of drug: water soluble drug are desire where dissolution is the rate limiting step in the absorption of poorly absorbed aqueous soluble agents or when parenteral or ophthalmic formulation of such agent are desired. Drug with hydroxyl function can be converted in to their hydrophilic form by use of half-esters such as hemisuccinates, hemigluratarates or hemiphthalates. The other half of these acidic carriers can forms sodium, potassium or amine salts & render the moiety water soluble for phenolic drugs & some alcohols as in the case of steroidal drug such as cortisol, prednisolone, betamethasone & dexamethasone. Slide 36: The sodium succinate salts have poor chemical stability & hence phosphate esters are preferred. Glycoside prodrugs of some agent & lysine ester of benzodizepines are also water soluble. Such hydrophilic promoieties when mint for parenteral use are advantageous over propylene glycol solution. Which are toxic & painful. Slide 37: 7) Enhancement of chemical stability: A drug may stabilize either during its selflife or in the GIT when used orally. Selflife stability is particularly important in case of the drug for I.V. use. The convential approach is to lyophilize such solution in to powder which can be reconstituted before use. The prodrug design of such agent is also a good alterative to improve stability. An example of anti-neoplastic drug azacytidine. The aqueous solution of this drug is readily hydrolyzed but the bisulfite prodrug is stable to such as degradation at acidic PH & is more water soluble than the parent drug. The prodrug converts to the active drug at the physiological PH of 7.4. Slide 38: Slide 39: 8) Enhancement of bio-availability: (lipophilicity) Most drugs are absorbed by passive diffusion for which lipophilicity is an important prerequisite. A big advantage of increased bioavailability through increased lipophilicity is the reduction in new dosage. For example: bacampicillin is as effective as ampicillin in just one-third of the dose of latter. Slide 40: 9) Prevention of presystemic metabolism: Several corticosteroids undergo extensive first-pass hepatic metabolism which can be prevent by use of their esters or either prodrugs. For example: triamcinolone 10) Prolongation of duration of action: Frequent dosing is required for drug having short biological half-lives. This can be overcome by use of both controlled release & prodrug approaches. Slide 41: The two rate controlling steps in enhancement of duration of action of drug are:- 1] The rate of release of prodrug from the site of application or administration in to the systemic circulation. 2] The rate of conversion of prodrug in to active drug in the blood. Slide 42: Rate limiting steps in the release of a drug from prodrug Slide 43: 10) Reduction of toxicity: An important objective of a drug design is to develop one which high active & low toxicity. Example of drug for systemic use with local side effect such as gastric distress with NSAID’s which can be overcome by prodrug design have already been discussed. Another example is bioprecursor sulindac. As a sulfoxide it does not cause any gastric distress & is absorbed better in blood, it is converted to its active sulfide form. Slide 44: 11) Site-specific drug delivery: after its absorption in to the systemic circulation. The drug is distributed to the various part of body including target site as well as non-targeted tissue. A distribution pattern has various several disadvantages: 1] The drug may lead undesirable toxic effect on non-targeting tissue. 2] A smaller fraction of the drug will reach its site because of dilution. 3] If target site has long distribution time, drug may be eliminated without reaching such site. These problems can be overcome by targeting the drug to its site of action by altering its deposition characteristics. There are several approaches to drug targeting & prodrug design is one of them. Slide 45: e.g. Slide 46: Choice & function of pre-moiety: - drug candidates may posses a variety of functional groups available for bioreversible chemical derivation. E. g. Type of ester derivative 1.Drug containing a carboxylic 2. Drug containing hydroxyl functional acid group Slide 47: Simple drug derivatives are obtained by direct attachment of functional group of the active agent. The types of sufficiently labile drug pro-moiety linkage formed in this way are limited for each chemical functional group as for example: - A carboxylic group on the ether band, within a particular type of prodrug candidates such as carboxylic acid ester exhibiting significantly different properties might be designed dependently on the transport moiety chosen. Slide 48: Slide 49: Thus the derived rate and mechanism of cleavage of prodrug band might be accomplished by section of an appropriate transport moiety influences the physiochemical and pharmacokinetic characteristics of the designed prodrug as outlined below. Rational prodrug design, these consist if three basic groups. Identification of the drug delivery problem. Initiation of the physico -chemical properties require for maximum efficiency or delivery. Selection of transport moiety providing a prodrug derivatives exhibiting the proper physico-chemical characteristics and which can be cleaned up the desired biological compartment. Slide 50: Bio-reversible derivatives for various functional groups. The most common type of prodrug is ester derived from hydroxy carboxyl group present in the parent drug molecules. In another cases however other strategies are required, since the drug to be modify dose most net content such groups readily available to esterification. An outline of the most commonly used of derivatives given in following section. Slide 51: 1)Esters as a prodrug for compounds containing hydroxyl group. The popularity of using esters as a prodrug type for drug containing carboxyl or hydroxyl function and atom primary from the fact that the organization is rich in enzyme capable of hydrolyzing ester bond. According to a significant no. of carboxylic acid drug containing a alcohol groups have been modified for a multitude of reasons employing the ester producing approach. The pH-dependent Rate of hydrolysis of simple ester derivatives in vitro can often be described by the general rate eqn. Slide 52: Where, Kobs Is the observed pH dependent pseudo 1st Order rate count for hydrolytic cleavage of the 2nd order, KH+ and KoH represent the 2nd order rate count for specific acid and base catalysis irrespectively. Ko the apparent first order rate count for the spontaneous depression. aH+ & ago- refers to the hydrogen & hydroxide ion activity respectively. Plot the log kobs against PH yields the characteristics U shaped curve or U shaped profile in case the continuous & the spontaneous reduction to kobs become insignificant. Slide 53: Ester prodrug having carboxyl group. E.g.pivampicillin i.e. alpha acyloxyalkyl ester of ampicillin. Slide 54: Ester prodrug having hydroxy group: E.g. bambutenol Slide 55: 2)prodrug for amides, Imides & other NH-acidic compounds- A) N-Mannich bases: N-Mannich bases can function as a prodrug candidate for NH-acidic compounds like various amides, imides & hydantoins as well as for aliphatic formed by reacting an NH-acidic compound with formaldehyde. Slide 57: The structural effect on the decomposition rate of N-mannich bases derived from carboxamide, sulphonamide or imides & aliphatic or aromatic involves- 1] Steric effect 2] Basicity of the amine compound 3] Acidity of amide compound e.g. Slide 58: B) N-a-acyloxyalkyl derivative: Is commonly used approach, hydantoin, uracil & tertiary or heterocyclic amines. By variation of the acyl portion of this type of derivative. It is possible to control the rate of generation of the parent drug & to obtain prodrug with varying physico-chemical properties, where as the derivative which can be in vitro comparable to that of esters they are generally rapidly cleaved in vivo by virtue of enzymatic hydrolysis. Slide 59: The activation of the parent NH-acidic compound is accomplished by two step reaction. Slide 60: C) N-acyl derivative: N- acyl derivative of amide & imides type compound may be useful prodrug approach in some particular cases. In accessing N- acetyled amide as imides as potential prodrug it is important to consider the possibility of drug regeneration afford by enzyme-catalyzed hydrolysis. Thus N2-acetyl-5-fluroracil and N-ethoxy-carbonyl-5-flurourasil hydrolysis with half lives of 40 & 550min. respectively at pH 7.4 and 37oC. In 80% human plasma however half life of about 2-4 min have been observed. As a result of their altered physioco-chemical properties and easy bioconvention, these prodrug derivatives of 5fu have shown improved ocular and rectal absorption as compared to the parent drug. Slide 61: Carbonyl compounds like hydrolysable derivatives. Slide 62: The most common prodrug of aldehyde and ketone are amines, oxime, and acetals (Ketone) enol esters, oxazolidines and thiazolidines prodrug analogs of carbonyl compound. Slide 63: Ref.: Drug design by V.M. Kulkarni. Medicinal chemistry by Wilson and Gisvold’s. Pharmaceutics and pharmacokinetics by D.M.Brahmankar. Organic chemistry of drug design action by Richard B.Silverman. Biopharmaeutics and pharmacokinetics by Jaiswal and Brahmankar. Text book of drug designing and discovery by Prof. Krogsgard-larsen. Controlled drug delivery by S. P. Vays, Roop K. Khar www.Google.Com Slide 64: THANK YOU You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.