Drug Delivery Systems Past Paper PDF 070114120 Fall 2023

CHAPTER 2: Approaches in Drug Delivery DRUG CARRIERS: LIPOSOMES Drug Delivery Systems Msc Suhad Anabousi 070114120 Fall 2023  2 APPROACHES IN DRUG DELIVERY  Approa...

CHAPTER 2: Approaches in Drug Delivery DRUG CARRIERS: LIPOSOMES Drug Delivery Systems Msc Suhad Anabousi 070114120 Fall 2023  2 APPROACHES IN DRUG DELIVERY  Approaches in Drug Delivery I. The Chemical Approach/ Prodrugs II. The Biological Approach III. The Polymeric Approach 2  3 I. THE CHEMICAL APPROACH  The Chemical Approach/ Prodrugs  The chemical approach was used for optimization of drug delivery by means of chemical modification of the drug:  There are two chemical derivatives that generally have been used:  The design of an analog, which is basically a new drug with new pharmacological and pharmacokinetic characteristics. Fentanyl versus morphine.  The design of a prodrug, which has the same pharmacological characteristic as the parent compound but processes different pharmacokinetic properties. (delivering the drug itself) 3  4 PRODRUGS  The Chemical Approach/ Prodrugs  The prodrug approach can be defined as an alteration of the physicochemical properties of an agent through bio-reversible chemical modification.  The prodrug is inactive, and the parent drug molecule is regenerated in vivo.  The prodrug approach is used in order to overcome barriers that might limit the ability of a drug to reach its site of action.  i.e., the drug is chemically modified to increase it is usefulness. 4  5 PRODRUGS  The Chemical Approach/ Prodrugs  A drug must reach and interact with a site of action (target).  Thus, barriers that might limit the ability of the drug to reach its site of action or interact with it must be removed.  Once the barrier to the drug usefulness has been removed, the parent drug may be regenerated in vivo.  i.e., parent drug molecule is ideally regenerated immediately after the barrier is overcome. 5  6 DRUG ACTION & BARRIERS  Aspect of drug action & barriers that could limit the usefulness of drugs: 1. The pharmaceutical phase:(in vitro) 2. The pharmacokinetic phase:(once enter the body) 3. The pharmacodynmic phase: (once drug reach the target site)  With prodrug design  we can overcome barriers in the pharmaceutical stage and pharmacokinetic stage but not the pharmacodynamics stage. 6  7 DRUG ACTION & BARRIERS  Aspect of drug action & barriers that could limit the usefulness of drugs: 1. The pharmaceutical phase:  This is involved with the development of a potential drug entity into a successful drug delivery system. It includes:  The economics of drug development.  The aesthetic properties of the drug and dosage form (as appearance and taste).  Formulation problems due to the physicochemical properties of drug that could represent the barrier.  Oral  bad taste.  Volatile drug and heat.  Injection  pain.  Photosensitive drug. 7  Skin  texture (suitable).  8 DRUG ACTION & BARRIERS  Aspect of drug action & barriers that could limit the usefulness of drugs: 2. The pharmacokinetic phase:  This stage describes the fate of the drug or dosage form in vivo (i.e., after administration).  Barriers which could limit the utilization of a drug can result from incomplete absorption of the drug from its delivery system due to: 1. Dosage form factors &/or physicochemical properties of the drug, as poor solubility. 2. Physicochemical drug properties affecting transport across the GI barrier and other membrane. 3. The drug is undergoing rapid absorption, when longer duration of action is required.  9 DRUG ACTION & BARRIERS  Aspect of drug action & barriers that could limit the usefulness of drugs: 2. The pharmacokinetic phase:  This stage describes the fate of the drug or dosage form in vivo (i.e., after administration).  Barriers which could limit the utilization of a drug can result from incomplete absorption of the drug from its delivery system due to: 4. Metabolism of drug before reaching systemic circulation. 5. Drug toxicity related to local irritation or distribution in tissue other than the target organ. 6. Poor site specificity of drug.  10 DRUG ACTION & BARRIERS  Aspect of drug action & barriers that could limit the usefulness of drugs: 3. The pharmacodynmic phase:  This stage deals with the drug receptor interactions, and not with drug delivery.  11 THE PRODRUG APPROACH  In summary, the prodrug approach can be used to: 1. Overcome specific problems associated with drug molecules such as:  Absorption problems  Solubility problems  Toxicity problems  Poor patient acceptance of product.  Stability and formulation problems. 2. Promote site specific delivery. 3. Achieve controlled/ sustained release effects.  12 SYNTHESIS OF PRODRUGS  Before synthesizing a prodrug, the following points should be taken into consideration:  What functional groups in the parent drug that can undergo chemical modification. (alcoholic, hydroxyl, thiol, amine groups and carboxylic acid group)?  Are the synthetic methods available for selectively modifying drug molecule?  Are the chemical intermediate available at reasonable cost?  13 SYNTHESIS OF PRODRUGS  Before synthesizing a prodrug, the following points should be taken into consideration:  Synthesis and purification of prodrug should be simple (one to two steps of synthesis is optimal).  The prodrug should be chemically stable in bulk form and compatible with the ingredient in the dosage formulation.  Toxicity of the derivative portion of the prodrug should be considered.  The parent drug molecule must be regenerated from the prodrug in vivo (i.e., should be bio-reversible).  14 THE CHOICE OF A DERIVATIVE  The choice of a derivative  Before choosing a derivative, we need to: 1. Know what physicochemical properties of the drug that are required in the prodrug design. 2. Select the chemical linkage that alters this effect.  15 THE CHOICE OF A DERIVATIVE 1. PHYSICOCHEMICAL PROPERTIES / PRODRUG DESIGN  The choice of a derivative 1. Determination of physicochemical and pharmacological properties that are required to be modified.  For example: I. In case where we need to: 1. Mask bitter taste or odour of a drug, (chloramphenicol palmitate (nonpolar)) 2. Improve absorption, 3. Eliminate or decrease pain on injection, 4. Eliminate or decrease gastric distress;  Then, rapid generation of the parent drug is necessary after passing the barrier (i.e., short half life for prodrug is required).  16 THE CHOICE OF A DERIVATIVE 1. PHYSICOCHEMICAL PROPERTIES / PRODRUG DESIGN  The choice of a derivative 1. Determination of physicochemical and pharmacological properties that are required to be modified.  For example: II. In case where we need to: 1. Achieve depot action (long acting), 2. Enhance localized drug activity;(Methenamine)  Then, the pharmacokinetics of the parent drug via the prodrug becomes necessary (i.e., longer or extended half-life of the prodrug is required).  17 THE CHOICE OF A DERIVATIVE 1. PHYSICOCHEMICAL PROPERTIES / PRODRUG DESIGN  The choice of a derivative 1. Determination of physicochemical and pharmacological properties that are required to be modified.  For example: III. In case where:  The drug is intended to be hydrolyzed in gastric content;  Then, acetal, ketal and ether linkages can be used, where they are stable in basic media and hydrolyzed in acidic media.  Amides and Phosphamides don’t hydrolyze in the stomach, but later on they noticed that amides concentrate in cancer tissue  so it’s a good choice for targeted treatment of cancer. Also, amide linkage remains stable until it reaches the tissue.  18 THE CHOICE OF A DERIVATIVE 1. PHYSICOCHEMICAL PROPERTIES / PRODRUG DESIGN  The choice of a derivative 1. Determination of physicochemical and pharmacological properties that are required to be modified.  For example: IV. In case where the drug is intended to exhibit slow hydrolysis (or depot activity);  Then, include long chain aliphatic ester and derivatives sterically hindered at or near the site of hydrolysis.  19 THE CHOICE OF A DERIVATIVE 1. PHYSICOCHEMICAL PROPERTIES / PRODRUG DESIGN  The choice of a derivative 1. Determination of physicochemical and pharmacological properties that are required to be modified.  For example: V. In case where we need to enhance the bioavailability of the parent drug of low water solubility;  Then, water soluble prodrugs can be synthesized.  Note that the aqueous solubility of a prodrug:  Increases with phosphate ester  more polar.  Decreases with each addition -CH2 unit, also Decreases with branching.  20 THE CHOICE OF A DERIVATIVE 1. PHYSICOCHEMICAL PROPERTIES / PRODRUG DESIGN  The choice of a derivative 1. Determination of physicochemical and pharmacological properties that are required to be modified.  For example: VI. In case where we need to improve drug passive absorption through biological membranes;  Then, The HLB of the parent drug molecule may be adjusted, so as to increase the partitioning of the drug between the biological membrane and water, also  The ionization of the drug may be altered (unionized drugs are absorbed more effectively than ionized ones). hydrophobic moiety.  21 THE CHOICE OF A DERIVATIVE 2. SELECTION OF A PRODRUG LINKAGE.  The choice of a derivative 2. Selection of a prodrug linkage.  The selection of a potential prodrug linkage requires knowledge of what enzymes or enzyme systems would catalyze the hydrolysis of the prodrug.  For example:  Orally administered prodrugs rely on enzymes present in the gut, liver and blood.  Whereas parenterally administered prodrugs encounter enzyme found in the systemic circulation.  Enzymes that are endogenous to a specific tissue can provide the rationale for the design of site-activated prodrugs.  22 THE CHOICE OF A DERIVATIVE 2. SELECTION OF A PRODRUG LINKAGE.  The choice of a derivative  Prodrug derivatives include the following: 1. Aliphatic and aromatic esters: can improve the absorption and duration of action. 2. Carbonate esters: provide rapid hydrolysis. 3. Hemiesters: can increase the aqueous solubility. 4. Phosphate ester: provide very high aqueous solubility and can be used for localization of action.  23 THE CHOICE OF A DERIVATIVE 2. SELECTION OF A PRODRUG LINKAGE.  The choice of a derivative  Prodrug derivatives include the following: 5. Amides: have limited applications due to their relative stability in vivo. 6. Peptides (amino acid): are hydrolyzed by peptidase or proteolytic enzymes. 7. Azo products: are hydrolyzed by azo-reductase (in microflora of the colon). 8. Phosphamides: used in cancer chemotherapy as they provide selective activity on receptor site.  24 PRODRUG EXAMPLES  To overcome absorption problems, the absorption barrier should be defined.  Poor absorption could be due to:  Poor lipid solubility;  Very low water solubility;  First-pass metabolism.  25 PRODRUG EXAMPLES A. For example: Drugs with poor lipid solubility  Dopamine is polar and incapable of crossing the BBB due to its presence in ionized state at the physiological pH.  L-dopa is a prodrug of dopamine which was found to be effective in Parkinson's disease because it is absorbed from GIT.  26 PRODRUG EXAMPLES B. For example: Drug with very low aqueous solubility  Allopurinol has very low water solubility. Its low solubility is due to the intermolecular H-bonding in its crystal lattice. Its oral absorption may be enhanced by increasing its water solubility.  So preparing prodrug that could disrupt the crystal lattice would increase its aqueous solubility.  27 PRODRUG EXAMPLES 3. To overcome poor patient acceptance.  For example: Drugs with unpleasant taste  Acetaminophen has an unpleasant taste which prevented its use in chewable tablet formulations for pediatric patients.  2-(p-acetaminophenoxy) tetra-hydropyran is a prodrug of acetaminophen, which has low water solubility than acetaminophen and is converted to the parent drug under the acidic condition of the stomach.  28 PRODRUG EXAMPLES 4. To promote site specific delivery of drug.  Formaldehyde is used in urinary tract infections, however, it is irritant to the GIT.  Methenamine is a prodrug of formaldehyde which offers site specificity for formaldehyde at the urinary tract.  It is converted to formaldehyde under acidification in urine.  Methenamine is administered in enteric coated tablet to prevent acidification in the stomach and thus prevent GI irritation.  29 PRODRUG EXAMPLES 5. To prolong or sustain drug release.  For example: Steroid therapy  Longer duration of action of testosterone from I.M injection is achieved by acylation of 17-B- hydroxy group, which provides a duration of action of the drug for more than 3 months.  30 PRODRUG EXAMPLES 6. To overcome stability and formulation problems.  Penicillins are unstable in aqueous solution due to B-lactam ring hydrolysis.  So by preparing slightly soluble salts of penicillin, the degradation becomes zero- order since the concentration remains small and constant, due to its presence in suspension.  31 PRODRUG EXAMPLES 7. To improve efficacy of ophthalmic drugs.  For example: Enhance ocular absorption  Dipivefrin (Propine®) is a prodrug of epinephrine (not optimum Pc), that is used to treat open-angle glaucoma.  Dipivefrin is used to enhance Corneal permeability and increase therapeutic effectiveness.  32 II. THE BIOLOGICAL APPROACH  The biological approach  The biological approach includes the use of biological material for controlled drug delivery.  Drug targeting using biological carriers have been used to enhance the effectiveness and reduce side effects of drugs.  Biological carriers include: liposomes, polysaccharides, albumin, antibodies, IgG, DNA, lipoprotein, and glycoproteins.  Drugs incorporated into biological carriers include: methotrexate and Adriamycin as well as agents which are of macromolecular size such as enzymes and nucleic acids.  33 II. THE BIOLOGICAL APPROACH: DRUG CARRIERS  Drug carriers may provide the following:  Localized drug action, by introducing the carrier directly into the target organ.  Controlled drug release.  Drug targeting  Protection of drugs from degradation.  protein. gene, enzyme, vaccines.  Reduction in nonspecific cytotoxicity and side effect of drugs.  Changing the drug’s solubility.  Reduction in immunogenicity & antigenicity of enzymes.  Generally, drug carriers can be combined with antibodies to develop more specific target drug carrier complexes (liposomes).  34 CHARACTERISTICS OF A CARRIER SYSTEM  The properties of a carrier system may vary from one application to another depending on the drug used.  However there are general characteristics that a drug-carrier system must possess:  The carrier-agent conjugate must retain the agent’s activity (unless it can be degraded at the site of desired action with the release of the agent in its active form).  The carrier must be biocompatible (i.e., non-toxic, non-immunogenic and non antigenic) should not change the antigenicity of the compound carried.  The carrier must be biodegradable  The carrier must retain its own desirable characteristics following conjugation with a drug.  35 TYPES OF CARRIERS  Types of carriers 1. Specific: carriers of highly specific binding to cell surface receptors. These are used to direct drugs or enzymes to cells bearing specific receptors, such as antibodies. 2. Non-specific: Carriers that do not have high specificity of binding. The majority of carriers are of this type. Such carriers are normally taken by cells by phagocytosis.  In this case, the target cells should have a well-developed phagocytic function.  36 EXAMPLE: PHAGOCYTOSIS OF MICRO-PARTICLES  SEM images showing the phagocytosis of microparticles by macrophages:  (d) Micro-particles lying on the cell surface,  (e & f) being phagocyted and  (g & h) allegedly located inside the cell.  37 TYPES OF CARRIERS  The cross-linking between the carrier & drug molecules could be: 1. Covalent binding.  Need chemical interaction  Strongest & less leakage but may delay release. 2. Non - covalent (i.e., entrapment or encapsulation of the drug).  Easier but leakage is higher.  May protect the drug by encapsulation.  38 TYPES OF CARRIERS  The desirable characteristics of the cross linkage reaction: 1. The reaction should allow effective control of the size of drug - carrier complex. 2. It should maintain the site specificity of the carrier portion. 3. It should not change the normal activity of the drug or enzyme. 4. The cross-linking must be readily broken if the drug is to be released.  39 THE DISTRIBUTION OF NON- SPECIFIC CARRIERS  The distribution of non-specific carriers in vivo depends on the following properties: 1. Size & size distribution of the carrier  0.1- 7.0 μm  goes for liver, spleen and kidney  < 0.1 μm  to bone marrow (nanoparticle)  > 7 μm  lung (circulation, monocyte) 2. Lipophilicity & hydrophilicity of the carrier  The more hydrophobic carriers go to the liver. 3. Surface charge of the carrier  The more negatively charged carriers go to the liver.