Drug Targeting 1st Lecture PDF

Drug Targeting General principles of drug targeting; an overview BY: DR. AMIRA ABDEL HALIM BOSEILA P OST -DOC TOR AL F E L LOW AT P HA R MACEU TICS DE PA RTMENT, AT T HE EGYPTIA N DR UG AUT HOR ITY A S S ISTANT P ROF ESSOR AT FACU LT Y OF P HA R M ACY, S I N AI U N I V ERSI TY. co...

Drug Targeting General principles of drug targeting; an overview BY: DR. AMIRA ABDEL HALIM BOSEILA P OST -DOC TOR AL F E L LOW AT P HA R MACEU TICS DE PA RTMENT, AT T HE EGYPTIA N DR UG AUT HOR ITY A S S ISTANT P ROF ESSOR AT FACU LT Y OF P HA R M ACY, S I N AI U N I V ERSI TY. content Drug delivery systems Conventional drug delivery system Targeted drug delivery system Concept Definition Levels of drug targeting Ideal Characteristics of Targeted Drug Delivery System Advantages and Disadvantages Targeted drug delivery systems Strategies for drug targeting Drug delivery system (DDS) Drug delivery system is the method of administering pharmaceutical compound to achieve a therapeutic effect in humans or animals. Most common methods of drug delivery includes the oral (through the mouth), topical (skin), trans- mucosal (nasal, buccal, sublingual, vaginal, ocular, rectal), parenteral(injection into systemic circulation) and inhalation routes. The drug delivery system can further be divided into two main types: 1. Conventional drug delivery system. 2. Novel drug delivery system. ❖ Controlled release drug delivery system ❖Targeted drug delivery system CONVENTIONAL DRUG DELIVERY SYSTEM Conventional Drug Delivery System is the Classical methods for the delivery of Drug into the body. The Examples of these systems includes: Oral Delivery Buccal / Sublingual Delivery Rectal Delivery Intravenous Delivery Sub Cutaneous Delivery Intramuscular Delivery  Routes of drug administration 1. Oral route IT INCLUDES TABLETS, CAPSULES, SYRUPS ETC. TAKEN DIRECTLY THROUGH MOUTH AND TRAVELS THROUGH GASTROINTESTINAL TRACT (GIT). Advantages of Oral Delivery: Disadvantages of Oral Delivery: Convenience in Administration o unsuitable for unconscious patients Non invasive o Degradation of drug by Gastro-Intestinal fluid. Accurate and measured dose (as in topical ointments/creams the dose can’t o First pass metabolism (by liver) be calculated) o Irregular absorption (depends on fasted or Higher compliance fed state of patient) Low cost Importantly, drugs that are taken up into the body First-pass metabolism through the gastrointestinal mucosa will be transported to the liver via the portal vein before going into general circulation. As the liver is the main metabolic organ of the body, if the drug is susceptible to metabolic degradation in the liver, this may considerably reduce the activity of the drug. This phenomenon is known as the hepatic first-pass effect. The rectal route may also show varying degrees of the first-pass effect, while for other routes of administration (intravenous, vaginal, nasal, buccal, and sublingual) the drug is distributed in the body before reaching the liver, and therefore for certain drugs, these may be the preferred route of administration.  2. BUCCAL / SUBLINGUAL DELIVERY HERE TABLETS ARE PLACED UNDER THE TONGUE (SUBLINGUAL) OR BETWEEN THE CHEEKS (BUCCAL). Advantages By-pass First pass metabolism Rapid drug absorption Subjected to low enzymatic activity Disadvantages o Discomfort during drug release period o Probability of swallowing- lost of effect o Suitable for small doses  3. RECTAL DELIVERY HERE SUPPOSITORIES ARE PLACED INSIDE RECTUM AND IT MELTS AT BODY TEMPERATURE TO GIVE QUICK EFFECT. Disadvantages o Irregular absorption & bioavailability Advantages (depends on state of rectum) By-pass first pass metabolism o Degradation by bacterial flora Useful for: o Uncomfortable in application 1. Children 2. Vomiting patient 3. Irritant and bad taste drugs  4. INTRAVENOUS DELIVERY DRUG IN LIQUID FORM IS ADMINISTERED DIRECTLY INTO BLOOD BY INJECTING IN VEIN WITH THE HELP OF STERILE INJECTOR (SYRINGE). Disadvantages Advantages o Invasive Drug 100% bioavailable o Trained personnel is needed for Rapid response administration suitable for drugs that suffer from degradation in o Possible toxicity due to incorrect dosing GIT o Sterility By-passes First Pass Metabolism  5. SUBCUTANEOUS DELIVERY HERE LIQUID DRUG IS ADMINISTERED IN SUBCUTANEOUS TISSUE BY INJECTING WITH INJECTOR. Disadvantages Advantages o Invasive Patient self-administration o Irritation Slow, complete absorption o Inflammation By-pass 1st pass metabolism. o Small dosing volume (maximum dose volume - 2mL)  6. INTRAMUSCULAR DELIVERY THE LIQUID DRUG IS ADMINISTERED IN THE MUSCLE TISSUE BY INJECTING WITH INJECTOR. Advantages Disadvantages Drug is absorbed slowly, so prolong o Invasive – patient discomfort effect. o Irritation, Larger volume than subcutaneous o Inflammation By-pass first pass metabolism o May require some training for application Drawbacks of Conventional Drug Delivery System Difficulty in assessing diseased site (Diseases of central nervous system CNS, Cancer, etc…) High dose & frequent administration of drugs leads to toxic manifestation Inappropriate pharmaco-deposition Inactivation or decomposition of drug by GIT pH or by enzymes which digest food and metabolism by microbial flora In parenteral route deactivation & metabolism of drug, dose related toxicity frequently observed.  TARGETED DRUG DELIVERY SYSTEM (TDDS) Targeted 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. This improves the efficacy of the medication and reduces its side effects. Drug targeting is the delivery of drugs to receptors or organs or any other specific part of the body to which one wishes to deliver the drugs exclusively.  Concept of drug targeting: The concept of designing specified delivery system to achieve selective drug targeting has been originated from the perception of Paul Ehrlich, who proposed drug delivery to be as a “magic bullet”. Targeted drug delivery is as an event where a drug–carrier complex /conjugate delivers drug exclusively to the pre-selected target cell in specific manner. Definition The ability of a drug molecule to accumulate in the target organ or tissue selectively such that the concentration of the drug at the disease site is high, while its concentration in nontarget organs and tissues is low, preferably, below certain minimal level so as to prevent any toxic effect. Thus, drug targeting can overcome the non-specific toxic effect of conventional drug delivery system. Ideal Characteristics of Targeted Drug Delivery System Biochemically inert, non-toxic & non-immunogenic: The carrier must be biodegradable or readily eliminated from the body without problems Stability (physical & chemical), in-vivo & in-vitro Restricted delivery to target site/organ Uniform capillary distribution at the site of action Controlled & predictable rate of delivery Increase the therapeutic effect Minimal or low drug leakage Low cost of production  Advantages and Disadvantages Targeted drug delivery systems ADVANTAGES DISADVANTAGES Increase drug concentration at target site. o Requires highly sophisticated technology for the formulation. Selective targeting to infectious cells than (expensive) normal cells. o Requires skill in manufacturing, Enhancement of the absorption of storage & administration. targeted molecules such as peptides and particulates. o Stability issues. Drug can be administered in a smaller o Drug loading capacity. dose to produce the desired effect.  First Order Targeting Levels of Drug Targeting It involves the delivery of a drug to specific organ or a tissue Second Order Targeting It involves targeting towards the specific cell type within the tissue or organ (e.g. Tumor cells Vs Normal cell) Third Order Targeting It involves a delivery to a specific intracellular compartment in the target cell ( e.g. Lysosomes)  Dual targeting Passive Active targeting targeting Strategies for drug targeting Double Inverse targeting targeting Combination targeting  1. PASSIVE TARGETING Drug delivery systems which are targeted to systemic circulation are characterized as Passive delivery systems. In this technique drug targeting occurs because of the body’s natural response to physicochemical characteristics of the drug or drug carrier system. The ability of some colloid to be taken up by the Reticulo-Endothelial Systems (RES) especially in liver and spleen made them ideal substrate for passive hepatic targeting of drugs. Tumor vasculature. Local application, e.g. topical Enhanced Permeability and Retention (EPR)—Poorly formed tumor vasculature with leaky vessels and insignificant lymphatic drainage can be exploited by passively targeting the nanocarriers up to the size of 500 nm.  Obstacles facing Passive targeting based on the EPR effect Despite the fact that the “enhanced permeation and retention” EPR effect is really pronounced in mice models, this effect is not general in humans. There are tumors with a very pronounced EPR effect, such as Kaposi sarcoma “a type of cancer that forms in the lining of blood and lymph vessels” and multiple myeloma “a type of bone marrow cancer”, while other tumors barely exhibit this effect, as pancreatic cancer. Therefore, it is required to design strategies able to increase the nanoparticle accumulation in tumoral tissues where the EPR effect is weak. Additionally, even in the case where the EPR effect is present, there are other barriers that compromise the efficacy of nanoparticle-based therapies. One of these barriers is the elevated interstitial fluid pressure (IFP) present in the interstitial space of solid tumors, which approaches or even surmounts the intravascular pressure. This effect strongly compromises the diffusion of the nanoparticles into the tumor tissues.  2. INVERSE TARGETING In this type of targeting attempts are made to avoid passive uptake of colloidal carrier by RES (Reticulo-Endothelial Systems) and hence the process is referred to as inverse targeting. To achieve inverse targeting, RES normal function is suppressed by pre injecting large amount of blank colloidal carriers or macromolecules like dextran sulphate. This approach leads to saturation of RES and suppression of defense mechanism. This type of targeting is an effective approach to target drug(s) to non-RES organs.  3. ACTIVE TARGETING In this approach carrier system bearing drug reaches a specific site on the basis of modification made on its surface rather than natural uptake by RES. Surface modification technique includes coating the surface with either a bioadhesive, nonionic surfactant, or specific cell or tissue antibodies (i.e. monoclonal antibodies) or by albumin protein. 1. Targeting Mediated by External Stimuli (Physical) 2. Ligand Mediated Targeting 3.1) Targeting mediated by external stimuli In this type of targeting some characteristics of environment changes like pH, temperature, light intensity, ultrasound waves, and magnetic field are used to localize the drug carrier to a predetermined site. This approach was found exceptional for tumor targeting as well as cytosolic delivery of the entrapped drug or genetic material. External stimulus of focused ultrasound leads to ( a ) reversible disruptions and gaps in the epithelial cell layer allowing drugs/drug nanocarriers to escape the blood vessels into the target tissues, ( b ) disruptions to the nanocarriers to release the drugs around the target tissue  3.2) Ligand Mediated Targeting Ligands are carrier surface group(s), which can selectively direct the carrier to the pre-specified site(s) housing the appropriate receptor units to serve as ‘homing device’ to the carrier/drug. Most of the carrier systems are colloidal in nature & can be specifically functionalized using various biologically-relevant molecular ligands including antibodies, polypeptides, oligosaccharides and viral proteins. The ligands confer recognition & specificity upon drug carrier & endow them with an ability to approach the respective target selectivity & deliver the drug. EXAMPLES OF LIGANDS LIGANDS RECEPTOR SITE Folate (vitamin B9) Folate receptor Cancer cells Lactoferrin (glycoprotein) lactoferrin receptor Blood brain barrier (BBB) Galactose Asialo-glycoprotein Hepatocytes (Liver) receptor (ASGP-R)  4. Dual TARGETING Dual targeting delivery are designed to target two sites (for example, two different kinds of cells, tumor cells) and even target two receptors in the same cell type. Dual targeting is defined when the drug molecule in colloidal system is targeted to more than one location within the cell. For example, Nano-system carries two ligands, one for targeting the organ/tissue and the other for specific cells within that organ.  5. DOUBLE TARGETING This can be defined as the combination of site- and time-controlled drug delivery. The combination results in an improved therapeutic index. For this phenomenon, two effects are responsible. First, if drug release or activation occurs locally at therapeutic sites, selectivity is increased by a multiplication of the spatial selectivity with local activation. The second effect is the improvement in the therapeutic index by a combination of a spatially discriminating delivery and a desirable release pattern for a drug, such as zero-order release for a longer period of time  6. COMBINATION TARGETING These targeting systems are equipped with carriers, polymers, and homing devices of molecular specificity that could provide a direct approach to the target site. Example: Combination chemotherapy with ligand-targeted delivery of doxorubicin and vinorelbine. Conventional cancer chemotherapy results in the non-specific distribution of toxic therapeutic agents in the human body, which induces adverse side effects. To minimize such side effects, attempts have been made to encapsulate the drug in nanoparticles (e.g., liposomes with encapsulated doxorubicin). Although liposomal doxorubicin has fewer adverse effects than those of free drugs, its therapeutic efficacy is insufficient. The specificity of nanoparticles can be further enhanced through modification with targeting ligands. Some cancer cell types develop drug resistance over the course of drug treatment. The use of targeted nanoparticles to deliver multiple chemotherapeutics (with different mechanisms of action) specifically to cancer cells may simultaneously enhance therapeutic efficacy and reduce undesirable side effects