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DRUG TARGETING

DRUG TARGETING. DRUG TARGETING. Drug targeting is the ability of the drug to accumulate in the target organ or tissue selectively and quantitatively, independent of the site and methods of its administration. Drug targeting.

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DRUG TARGETING

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  1. DRUG TARGETING

  2. DRUG TARGETING Drug targeting is the ability of the drug to accumulate in the target organ or tissue selectively and quantitatively, independent of the site and methods of its administration.

  3. Drug targeting The main problems currently associated with systemic drug administration are: • Even bio-distribution of drug throughout the body; • The lack of drug specific affinity toward a pathological site; • The necessity of a large total dose of a drug; • Non-specific toxicity and other adverse side-effects. Drug Targeting May solve Many Of These Problems.

  4. Drug Targeting • Advantages of drug targeting: • Drug administration protocols may be simplified; • Drug quantity may be greatly reduced as well as the cost of therapy; • 3. Drug concentration in the required sites can be sharply increased without negative effects on non-target compartments.

  5. Strategy for drug targeting The concept of drug targeting allow the development of drugs which are potent and non-toxic and targeted drugto its particular site of action through: Use Cell-specific enzymes and ligands Development of prodrug-based technologies Use of smart polymeric systems

  6. Strategy for Site-Specific drug Delivery

  7. PRODRUGS • A prodrug is a pharmacologically inactive compound which undergo chemical or enzymatic metabolism to give the active compound. • Most chemically designed prodrugs consist of two components, which are the active drug chemically linked to a pharmacologically inert moiety .

  8. After administration or absorption of the prodrug, the active drug is usually released by either chemical or enzymatic hydrolytic or reductive processes. • The prodrug must be sufficiently stable to withstand the pharmaceutical formulation while permitting chemical or enzymatic cleavage at the appropriate time or site.

  9. The prodrug must be readily transported to the site of action, rapid uptake and essentially perfusion rate limited. Once at the site, the prodrug must be selectively cleaved to the active drug relative to its conversion at other sites. Once selectively generated at the site of action, the active drug must be retained by the tissue. Factors for optimizing site-specific drug delivery:

  10. Prodrug used to solve a wide range of pharmaceutical problems including: • Un palatability • gastric irritation • pain on injection • insolubility • instability. • poor drug adsorption and drug distribution • by increasing the lipophilicity of the drug molecule.

  11. Advantages • Overcome biological & pharmaceutical barriers which separate the site of administration from the site of action of drug. • Enhance efficacy of drug. eg, the administration of the methoxy methyl ester of hetacillin(derivative of ampicillin) gaiv more distribution of ampicillin in the tissues than occurs on administration of ampicillin itself. • Prodrugs are decreases toxic side-effects by restricting the action of a drug to a specific target site in the body.

  12. SITE-SPECIFIC ENZYME-BASED DELIVERY SYSTEMS Are prodrug designed to ensure the release of the active drug only at its site of action by utilizing enzyme or chemical activity of a particular cell. For example, the prodrugcyclophosphamide is initially activated by hepatic cell enzymes to generate 4-hydroxycyclophosphamide which is then specifically converted to the alkylatingcytotoxicphosphoramidemustard in the hepatic target cells.

  13. • can used for site-specific delivery to tumor cells. • As the blood supply to large solid tumors is disorganized, the internal regions are often non-vasculated and the cells termed hypoxic cell ( poor O2) • The absence of molecular oxygen enhances the reductase activity in hypoxic tissues providing means of targeting the internal regions of solid tumors using a selective chemical prodrug-delivery system. • For example, the 2-nitro-imidazole compound is selectively cytotoxic to cultured hypoxic cells.

  14. SITE-SPECIFIC REDOX-BASED DRUG DELIVERY SYSTEMS Use of lipophilicprodrugs overcome the impenetrability of some barriers as blood-brain barrier to highly polar drugs, however the increased lipid solubility may enhance uptake in other tissues with a result in increase drug toxicity.

  15. These problems overcome by utilizing a drug delivery system which "trapping" a prodrug in the brain by oxidizing the prodrugto a less membrane permeable derivative. • This approach used to enhance the CNS penetration of a non-polar prodrugwhich crosses the blood-brain barrier but is then rapidly oxidized to the active form and trapped in the CNS. • Dihydropyridine-pyridinium salt redox systems of phenylethylamine and dopamine illustrate this technology.

  16. Dihydropyridine-pyridinium salt redox system for site-specific delivery to the brain. • The 1,4 dihydro-prodrug is delivered directly to the brain, where it is oxidized and trapped as the prodrug of quaternary ammonium salt. • The quaternary ammonium salt is slowly cleaved by chemical/enzymatic action with the release of the biologically active phenylethylamine .

  17. SITE-SPECIFIC ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY (ADEPT) • It is also possible to target drugs to specific cells th • use specific cell surface ligands – prodrugthat use antibody-directed enzyme for cleavage to active drug. • The approach has been used to target drugs to tumor cells by employing an enzyme, not normally present in the extracellular fluid or on cell membranes, conjugated only to an tumor antibody which localizes in the tumor via an antibody-antigen interaction on administration.

  18. Following clearance of any unbound antibody conjugate enzyme from the systemic circulation, a prodrugwhich is specifically activated by the enzyme conjugate, is administered. • The bound enzyme-antibody conjugate ensures that the prodrug is only converted to the cytotoxic parent compound at the tumor site thereby reducing systemic toxicity. • Example: • using cytosine deaminaseto generate 5-fluorouracil from the 5-fluorocytosine prodrugat tumor sites increases the delivery to the tumor by 17 fold compared to that achieved on administration of 5-fluorouracil alone. 1 2

  19. DRUG TARGETING USING DRUG DESIGN POLYMERIC SYSTEMS

  20. Gastrointestinal tract TARGETING SYSTEMS TARGETING SYSTEMSstomach Orally administered controlled release dosage forms are subjected to 2 complications: 1- short gastric residence time 2- irregular gastric emptying rate. Gastric emptying of dosage forms is valuable asset for dosage forms, which need to be residence in the stomach for a longer period of time.

  21. Advantages of Prolonged gastric retention • improves bioavailability of drug • reduces drug waste • improves solubility for drugs that are less soluble in a high pH environment. • It has a local drug delivery to the stomach and proximal small intestines. • The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of : • mucoadhesion, floating drug delivery systems (FDDS), sedimentation,expansion,modified shape systems, simultaneous administration of pharmacological agentsthat delay gastric emptying.

  22. Factors affecting gastric residence time of solid dosage forms : • Size and shape of dosage unit • Tetrahedron- and ring-shaped dosage have a better gastric residence time as compared with other shapes. • Dosage forms having a diameter of more than 7.5 mm show a better gastric residence • Several formulation parameters can affect the gastric residence time.

  23. The density of a dosage form also affects the gastric emptying rate. • A buoyant (floating) dosage form • having a density of less than that of the gastric fluids and it • is floats. Since it is away from the pyloric sphincter, the • dosage unit is retained in the stomach for a prolonged • period.

  24. Applications of Floating Drug Delivery Systems • Floating drug delivery offers several applications: • For drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. • It retains the dosage form at the site of absorption and thus enhances the bioavailability.

  25. Sustained Drug Delivery • HBS systems remain in the stomach for long periods and hence can release the drug over a prolonged period of time. • These systems have a bulk density of <1 as a result of which they can float on the gastric contents. • These systems are relatively large in size and passing from the pyloric sphincter is prohibited.

  26. Site-Specific Drug Delivery • These systems are particularly advantageous for drugs that are specifically absorbed from stomach or the proximal part of the small intestine, eg, riboflavin and furosemide. • By targeting drugs to the stomach, desired therapeutic levels achieved and drug waste could be reduced • FDDS serves as an excellent drug delivery system for the eradication ofHelicobacter pylori, which causes chronic gastritis and peptic ulcers. The treatment requires high drug concentrations within the gastric mucosa.

  27. Absorption Enhancement • Drugs that have poor bioavailability because of site-specific absorption from the upper part of the gastrointestinal tract are potential candidates to be formulated as floating drug delivery systems, thereby maximizing their absorption. • As increase in the bioavailability of floating dosage forms of enteric-coated LASIX-long product (42.9%) could be achieved as compared with commercially LASIX tablets (33.4%)

  28. On comparison of floating & nonfloating dosage units, • The floating dosage units remained floating on the gastric contents throughout their residence in the gastrointestinal tract, Floating units away from the gastro-duodenal junction were protected from the peristaltic waves during digestive phase • While the non floating dosage units sink and remained in the lower part of the stomach, And stayed close to the pylorus and were subjected to propelling and retropellingwaves of the digestive phase.

  29. Intragastric residence positions of floating and nonfloating units

  30. Design Floating Dosage Forms • Single-Unit Floating Dosage Forms: • The globular shells withpopcorn, poprice, and polystyrolhave been used as drug carriers, having lower density than that of gastric fluid used for drug controlled release. • Sugar polymeric materials such as methacrylic polymer and cellulose acetate phthalate have been used to coat these shells.

  31. These are coated with a polymer mixture. • The polymer of choice can be either ethyl cellulose or hydroxypropyl cellulose depending on the type of release desired. • Finally, the product floats on the gastric fluid while releasing the drug gradually over a prolonged period. • A buoyant dosage form can also be obtained by using a fluid-filled system that floats in the stomach. As Hydro dynamically balanced systems (HBS)

  32. Design Floating Dosage Forms • multiple-Unit Floating Dosage Forms: • This systems are classified depending on formulation : • Effervescent • Non-effervescent systems.

  33. Effervescent Floating Dosage Forms • a) matrix types systems • prepared with the swellable polymers such as methylcellulose and chitosan and various effervescent compounds eg, sodium bicarbonate, tartaric acid, and citric acid. • They are formulated in a way that when in contact with the acidic gastric contents, CO2 is liberated and entrapped in swollen hydrocolloids, which provides buoyancy to the dosage forms.

  34. Effervescent Layer inner & outer sublayer Conventional sustained release pill Swelable membrane layer Sublayers membrane polyvinyl acetate & purified shellac sodium bicarbonate & tartaric acid methylcellulose &chitosan • Multiple-unit oral floating drug delivery system. • Working principle of effervescent floating drug delivery system.

  35. The effervescentlayer containing sodium bicarbonate and tartaric acid was divided into 2 sublayers to avoid direct contact between the 2 agents. • These sublayerswere surrounded by a swellable polymer membrane containing polyvinyl acetate and purified shellac. • When this system was immersed in the buffer at 370C, it settled down and the solution permeated into the effervescent layer through the outer swellable membrane. CO 2 was generated by the neutralization reaction between the 2 effervescent agents, producing swollen pills with a density less than 1.0 g/mL. • It was found that the system had good floating ability independent of pH and viscosity.

  36. Effervescent floating drug delivery system based on ion exchange resin b) ion exchange resin floating system Use resin that was loaded with bicarbonate by mixing the resine beads with 1 M sodium bicarbonate solution. The loaded resine beads were then surrounded by a semipermeable membrane to avoid sudden loss of CO2

  37. Effervescent floating drug delivery system based on ion exchange resin Upon coming in contact with gastric contents an exchange of chloride and bicarbonate ions took place that resulted in CO2 generation thereby carrying beads toward the top of gastric contents and producing a floating layer of resin beads . The gastric residence time was prolonged considerably (24 hours) compared with uncoated beads (1 to 3 hours).

  38. Non-Effervescent Floating Dosage Forms Non-effervescent floating dosage forms use a gel forming hydrocolloids of swellable cellulose type , polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, poly methacrylate , and polystyrene and bioadhesion polymers like chitosan and carbopols.

  39. The formulation method includes: a simple mixing the drug and the gel-forming hydrocolloid. Working principle of non effervescent floating drug delivery system: After oral administration in contact with gastric fluids this dosage form swells and attains a bulk density of < 1. The air entrapped within the swollen matrix imparts buoyancy to the dosage form. The formed swollen gel-like structure acts as a reservoir and allows sustained release of drug.

  40. Intragastric floating drug delivery device. The system composed of a drug reservoir encapsulated in a microporous compartment having pores on top and bottom surfaces. The peripheral walls of the reservoir compartment were completely sealed to prevent any physical contact of the undissolved drug with walls of the stomach. Tablets of 2 kg/cm2and4 kg/cm2hardness after immersion into the floating media floated immediately for 3 to 4 minutes and then came to the surface. And remained floating for 24 hours. The tablet with 8 kg/cm2hardness showed no floating capability.

  41. TARGETING SYSTEMSintestinal • Small intestinal transit time is an important parameter for drugs that are incompletely absorbed. • Intestinal target solid dosage forms (enteric coated tablets) is intended to: • Prevent destruction of the drug by gastric juices. • To prevent irritation of the stomach lining by the drug. • To promote drug absorption

  42. TARGETING SYSTEMSColon • Colon-specific diseases are inefficiently treated by oral therapy, because most orally administered drugs are absorbed before arriving in the colon. • Advantages of Colon-specific drug delivery systems include: • used for the local treatment of colonic disorders such as Crohn`s disease, ulcerative colitis and irritable bowel syndrome • deliver drugs to the lower gastrointestinal tract without releasing them in the upper GI-tract, with expected decrease in the side-effects of the drugs.

  43. colon is a preferable site for the absorption of liable compounds such as peptides and proteins, because the hydrolytic enzyme activities of the colon are lower than that of the small intestine thus improve the bioavailability of such drugs. • Disadvantages • colon is not suitable site for drug absorption as the small intestine, because the water content in the colon is much lower and the colonic surface area for drug absorption is narrow in comparison with the small intestine.

  44. Methodologies For Colon Site-Specific Drug Release: • pH-sensitive delivery systems • Methods based on pH-Sensitive Polymer Coated Drug Delivery to the Colonsuch as enteric coated dosage forms However failure of pH-dependent system may be expected due to: • inter and intra subject variation of GI pH • pH variation due to pathological conditions and diet composition. • such methods release the drug in the upper small intestine after gastric emptying,

  45. Delayed Release Drug delivery to Colon (Time Controlled • Release System) (TCRS) : In (TCRS) the location of drug release depends on the transit time in GIT. such as sustained release dosage forms. • Disadvantages • Due to the large variation in the gastric emptying time due amount of food intake and peristalsis in the stomach thus in this approach the colon arrival time of dosage forms cannot be accurately predicted, resulting in poor colonical availability. • The approach is affected by the changes in diet, environmental conditions, and state of disease.

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