Prodrug design and its Applications in Pharma.

Prodrug

1. School Of Pharmacy &Research Center , Baramati Topic - Guided by - Mrs. Baravkar.M.G Prepared by – Ms. Yeole Siddhi Sanjay. Ms. Sawalkar Chaitali Vinod. PRODRUG

2. Content Defination . History. Importance of Prodrug Development. Designing of Prodrug. Degradation of Prodrug. Ideal Properties of Prodrug. Claasification of Prodrug. Applications of Prodrug.

3. Defination Prodrug is medication or a compound when administered, but after administration it get metabolized and converted into pharmacologically active drug. Prodrug is pharmacologically inactive chemical moiety which are used to change physicochemical properties of drug temporarily for improving efficacy and reducing their toxicity.

4. History Adrien Albert first introduced the term ‘Prodrug’ in 1958. The first intentionally designed prodrug is mostly ‘ Methenamine ’ was introduced in 1899 by Schering.

5. Importance of Prodrug Development The development of prodrug gives strategy to improve the physicochemical, biopharmaceutical and pharmacokinetic properties of drug. Prodrug development has great application in aqueous solubility, chemical instability, insufficient oral absorption, rapid pre-systemic metabolism, inadequate brain penetration, toxicity & local irritation.

6. Designing Of Prodrug Design of prodrug structure should be decided at early stages of pre-clinical development because after that it may alter tissue distribution, efficacy and toxicity of parent drug. For designing of prodrug following factors should be considered before developing a prodrug structure. Parent Drug Promoiety (Carrier)

7. a)Parent Drug :- It should be checked that what type of functional groups are able to chemical prodrug derivation. b) Promoiety (Carrier) :- This should be ideally safe & rapidly excreted from body. The selection of promoiety should be based on disease state, dose and duration of therapy. + Prodrug Parent Drug Carrier

8. Degradation of Prodrug These can affect chemical & physical stability and lead too formation of degraded product . Drug Carrier B A R R I E R Drug Carrier Drug Carrier

9. Ideal Properties Of Prodrug Pharmacologically inertness. Rapid Transformation (Chemically and Enzymatically). Non-toxic metabolic fragments.

10. Classification Depending upon constitution of lipophilicity method of bioactivation & catalyst used they are classified as- PRODRUG Carrier-linked Prodrug Bio Precursor Prodrug

11. A. Carrier linked Prodrug In this type active drug is covalently linked with the inert carrier. They are generally ester or amide. They have high modified lipophilicity due to joined carrier. Chemical prodrug formation covelent bond Chemical or Enzymatic clevage Active Drug Inert Carrier

12. Advantages

13. B.Bioprecursor Prodrug They are inert molecule obtained by chemical modification of active drug but do not contain carrier. Such moiety have some lipophilicity as that of parent drug and bioactivated generally using redox biotransformation only enzymatically. Bioprecursor doesn’t posses any temporary linkage between active compound and carrier but result in molecular modification of active drug.

14. Application Prodrug have wide range of applications such as to enhance pharmaceutical , organoleptic & chemical properties of parent drug with enhanced stability and patient compliance.

15. 1)Pharmacokinetic Applications Prodrug for improvement of bioavailability. Prodrug for site selective drug delivery. Prodrug for longer duration of action. Prodrug for minimizing toxicity. Prodrug for protection from pre-systemic metabolism .

16. a) Prodrug for improvement of bioavailability Chemical modification of drug is used to improve physicochemical properties such as solubility, lipophilicity , polarity & stability. For Improvement of Bioavailability Prodrug to increase L ipophilicity Prodrug to increase Polarity

17. I)Prodrug to increase lipophilicity The main reason behind the designing is to increase it’s bioavailability & intestinal absorption. Eg - Valacyclovir

18. II)Prodrug to increase Polarity Prodrugs are designed to increase aqueous solubility. This can be done by esterification with amino acid or phosphate group. Eg - Sulindac (NSAID)

19. b)Prodrugs for Site Selective Drug Delivery Site Selective Drug Delivery Tumor targeted drug delivery Prodrugs are applied for targeting drugs to a specific organ or tissue used in chemotherapy. Prodrugs are applied for targeting drugs to a specific organ or tissue used in Membrane Transporter prodrug targeting

20. 1.Tumor Targeted Drug Delivery Cancer chemotherapeutics are toxic & non-selective which limits their use for cancer therapy. In this method a gene encoding the activating enzyme is delivered to tumor cells, as first step. In second step inactivated prodrug is administered & converted to toxic drug by tumor enzyme. Eg - Doxorubicin

21. 2.Membrane Transporter Prodrug Targeting They target specific transporters which have an important role in drug absorption, distribution & elimination via prodrug. Eg - Acyclovir

22. c)Prodrug for Longer Duration of Action Drugs with short half life require frequent dosing to maintain blood concentration, which leads to poor patient compliance & fluctuation in the drug concentration. Eg – Fluphenazine decanoate

23. d)Prodrug Minimizing Toxicity For therapeutically active drug, it should be have minimum or no toxicity. Prodrugs have great application in minimizing the toxicity of drug. Eg – PEG conjugated paclitaxel 2 glycinate ( show antitumor effect by reducing toxicity)

24. e)Prodrug for protection from Pre-systemic metabolism Pre-systemic metabolism causes low oral bioavailability of drugs. Certain sites or groups in molecules are subjected to pre-systemic metabolism. Prodrugs can used to block these sites & increase oral bioavailability. Eg – Estradiol

25. Pharmaceutical Application For understanding organoleptic properties & physicochemical properties associated with them are resolved by prodrug formation. Taste Masking Odour Masking. Change of Physical form of drug. Reduction of GI Irritation. Minimizing Pain at injection site. Enhancement of Solubility & Dissolution Rate of Drug. Enhancement of Chemical Stability.

26. 1.Taste Masking Taste is an important factor in developing dosage form & masking bitter taste of oral drug , is crucial for patient especially for pediatric and geriatric patient. Eg – Various types of coating agents are used such as bees wax, shellac.

27. 2.Odour Masking Odour is an aesthetic concern for drugs with high vapour pressure or low boiling point which makes them difficult to formulate. Eg – Ethyl mercaptan

28. 3.Change of Physical form of Drug Some drug which are in liquid form are unsuitable for formulation as compared to solid dosage form, especially if there is high dose. The method of converting liquid form into solid form involves formation of symmetrical molecules having tendency to crystalize. Eg - Trichlorethanol

29. 4.Reduction of GI Irritation Several drugs cause irritation damage to gastric mucosa through direct contact, increased stimulation of acid secretion. Eg - Salsalate

30. 5.Minimizing Pain at Injection Site Pain at the injection site is caused by precipitation of drug that causes lysis & tissue injury. The problem may related to vehicle composition needed for formulation purpose. Eg - Fosphenytoin

31. 6.Enhancement of Solubility & Dissolution Rate The prodrug approach is also made useful for rectification of solubility problem & for better gastrointestinal absorption. Solubility can be enhanced by using phosphate ester. Eg – C hloramphenicol succinate

32. 7.Enhancement of Chemical Stability A drug may destabilize during it’s shelf life. The commonest conventional method is to lyophilize the solution into powder. The prodrug design of such agents is a good alternative to improve stability. Eg - Pivampicillin

33. Thank You!