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Targeted DDS.targeted drug delivery system for pharmacy student
- 1. Targeted drug delivery system
- 2. Targeted drug delivery, sometimes called smart drug delivery, is a method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others. Therefore, it delivers the medication only to areas of interest within the body. This offers an improved efficacy of treatment and reduces side effects
- 3. Causes of using the targeted drug delivery systems 1. Low drug stability. 2. Poor drug absorption. 3. The short half-life of the drug. 4. The large volume of distribution of the drug. 5. Low drug specificity. 6. Narrow therapeutic index of the drug.
- 4. Need for Targeted Drug Delivery
- 5. Advantages of drug targeting The toxicity of the drug is decreased by targeting a specific site. The desired drug response can be reached by a small dose. Avoid the first-pass effect. Improvement in the drug absorption from the target site. Drug targeting resulted in no peak and valley plasma concentration.
- 6. Four principles of drug targeting first, the ability to load the drug to the target site second, avoid the degradation by body fluid, Third, reaching the target site and fourth, release the drug at the specific site at the predetermined time.
- 8. Different types of carriers applied for drug targeting The carriers are systems which required for transportation of entrapped drug to target sites. The carriers entrap the drug moiety and deliver it into the target site without releasing it in the non-target site.
- 9. Strategies for drug targeting
- 11. Brain Targeting Barriers in brain targeted drug delivery: The failure of systemically delivered drugs to effectively treat many CNS diseases can be rationalized by considering a number of barriers that inhibit drug delivery to the CNS. There are physical barriers that separate the brain extracellular fluid from the blood. 1. Blood-Brain Barrier 2. Blood-Cerebrospinal Fluid Barrier 3. Blood-Tumor Barrie
- 12. Blood - Brain Barrier (BBB) The blood brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system. The blood brain barrier is formed by capillary endothelial cells, which are connected by tight junctions with an extremely high electrical resistivity of at least 0.1 亮m. The blood brain barrier allows the passage of water, some gases and lipid soluble molecules by passive diffusion, as well as the selective transport of molecules such as glucose and amino acids that are crucial for neural function.
- 13. On the other hand, the blood brain barrier may prevent the entry of lipophilic potential neurotoxins by way of an active transport mechanism. Astrocytes are necessary to create the blood brain barrier. It is estimated that more than 98% of small molecular weight drugs and practically 100% of large molecular weight drugs (mainly peptides and proteins) developed for CNS pathologies do not readily cross the BBB. Endothelial cells restrict the diffusion of microscopic objects (e.g.bacteria) and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing the diffusion of small hydrophobic molecules (e.g. O2, CO2, hormones, etc.)
- 15. Blood - Cerebrospinal Fluid Barrier (BCSFB The second barrier, located at the choroids plexus, is represented by the blood-cerebrospinal fluid barrier that separates the blood from the cerebrospinal fluid (CSF) which, in turn, runs in the subarachnoid space surrounding the brain. However, this barrier is not considered as a main route for the uptake of drugs since its surface area is 5000-fold smaller than that of the BBB. CSF can exchange molecules with the interstitial fluid of the brain parenchyma, the passage of blood- borne molecules into the CSF is also carefully regulated by the BCB
- 16. Blood - Tumor Barrier Intracranial drug delivery is even more challenging when the target is a CNS tumor. For example, even when primary and secondary systemic tumors respond to chemotherapeutic agents delivered via the cardiovascular system, intracranial metastages often continue to grow. In CNS malignancies where the BBB is significantly compromised, a variety of physiological barriers common to all solid tumors inhibit drug delivery via the cardiovascular system.
- 17. Furthermore, as a tumor grows large, the vascular surface area decreases, leading to a reduction in transvascular exchange of blood-borne molecules. At the same time, intracapillary distance increases, leading to a greater diffusional requirement for drug delivery to neoplastic cells and due to high interstitial tumor pressure and the associated peritumoral edema leads to increase in hydrostatic pressure in the normal brain parenchyma adjacent to the tumor. As a result, the brain may be less permeable to drugs than normal brain endothelium
- 19. Mechanisms of Transfer of Drug via BBB Substances are able to cross the vascular BBB by a variety of mechanisms like transmembrane diffusion, saturable transport, adsorptive endocytosis and extracellular pathways
- 20. Transmembrane Diffusion Most drugs cross the BBB by transmembrane diffusion. This is a non- saturable mechanism that depend on the drug melding into the cell membrane. A low molecular weight and high degree of lipid solubility favour crossing by this mechanism. However, a drug taken up by the membranes that form the BBB must then partition into the aqueous environment of the brains interstitial fluid to exert an effect. As a result, a substance that is too lipid soluble can be sequested by the capillary bed and not reach the cells behind the BBB. The percent of administered drug entering the brain is determined by both the rate of transport across the BBB and the amount of drug presented to the brain. The largest substance found to cross the BBB by the mechanism of transmembrane diffusion is cytokine - induced neutrophil chemoattractant - 1 (CINC-1) at 7,800 Dalton
- 21. Saturable Transport System Some drugs or substances used for drug like effects cross the BBB by use of saturable transport system. L - DOPA and caffeine are examples. The uptake rate across the BBB for an endogenous ligand of a transporter is roughly about 10 times higher than would be expected if it crossed by transmembrane diffusion. Additionally, many of the transporter for regulatory molecules, such as peptides and proteins, are taken up selectively by specific brain regions. The rate at which saturable system transport their ligands across the BBB is often regulated. For flow-dependent substances such as glucose, transport rate is a function of cerebral blood flow. For substances that are more slowly transported, a variety of agent have been found to alter transport. For example, leucine regulates the transport rate of peptide transport system - 1 (PTS-1).
- 22. strategies Invasive Intracerebroventricular (ICV) infusion Convection-enhanced delivery (CED) Intra-cerebral injection or implants Disruption of the BBB. Non-invasive Chemical techniques Prodrug Colloidal Techniques Nanoparticles Liposomes. Miscellaneous techniques Intranasal delivery
- 23. Invasive Approach Drugs can be delivered to the brain by first drilling the hole in the head, and then implant is placed by intra- cerebral (IC) or infusion is given by intra-cerebro- ventricular (ICV). An advantage of this route is that a wide range of compound and formulation can be considered for ICV or IC administration. Thus both large and small molecules can be delivered, either alone or in various polymer formulations to achieve sustained release
- 24. Intra-cerebro-ventricular infusion (ICV) It has been reported that the concentration of a drug in the brain is only 12% of the CSF concentration at just 12 mm from the surface. Drugs could easily be distributed to the surface of the brain via intra ventricular drug infusion but not properly delivered to the brain parenchyma. Pharmacologic effects can be seen after ICV administration, if the target receptors of the drug are located near the ependymal surface of the brain.
- 25. Limitations The diffusion of the drug in the brain parenchyma is very low. Unless the target is close to the ventricles it is not an efficient method of drug delivery. Example: Glycopeptide and an aminoglycoside antibiotics used in meningitis.
- 26. Convection-enhanced delivery (CED) The general principle of CED involves the stereotactically guided insertion of a small-caliber catheter into the brain parenchyma. Through this catheter, infusate is actively pumped into the brain parenchyma and penetrates in the interstitial space. The infusion is continued for several days and the catheters are removed at the bedside. CED has been shown in laboratory experiments to deliver high molecular weight proteins 2 cm from the injection site in the brain parenchyma after as little as 2 hr of continuous infusion Limitations Some areas of the brain are difficult to saturate fully with infusate, particularly infiltrated tissues surrounding a cavity. Proper drug delivery depends on the placement of catheters.
- 27. Intra-cerebral injection or use of implants Delivery of drugs directly into the brain parenchymal space, the drugs can be administered by: Direct injection via intrathecal catheter. Control release matrices. Microencapsulated chemicals. The basic mechanism is diffusion. Useful in the treatment of different CNS diseases e.g. brain tumor, Parkinsons Disease etc Limitations Distribution in the brain by diffusion decreases exponentially with distance. The injection site has to be very precisely mapped to get efficacy and overcome the problem associated with diffusion of drugs in the brain parenchyma.
- 28. Disruption of the BBB This technique is used widely for CNS drug delivery and involves disruption of the BBB. Exposure to X- irradiation and infusion of solvents such as dimethyl sulfoxide, ethanol may disrupt BBB. By inducing pathological conditions such as hypertension, hypoxia, or ischemia, BBB may also be disrupted. The effects of alcoholic and hypoglycaemic coma on the BBB permeability are different. The effect depends on the energy metabolism process.
- 29. Some of the important techniques for disrupting BBB are: Osmotic disruption: The osmotic shock causes endothelial cells to shrink, thereby disrupting the tight junctions. Intracarotid administration of a hypertonic mannitol solution with subsequent administration of drugs can increase drug concentration in brain and tumour tissue to reach therapeutic concentration.
- 30. MRI-guided focused ultrasound BBB disruption technique: Ultrasound has been shown to be capable of BBB disruption. The combination of microbubbles (preformed microbubbles of ultrasound contrast agent, optison, with a diameter of 2-6 亮m) which is injected into the blood stream before exposures to ultrasound. This technique has been shown to increase the distribution of Herceptin in brain tissue by 50% in a mice model.
- 31. Limitations of Invasive approach: All these approaches are relatively costly, require anaesthesia and hospitalization. These techniques may enhance tumour dissemination after successful disruption of the BBB. Neurons may be damaged permanently from unwanted blood components entering the brain.