Drug Delivery Systems PDF 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 III. THE POLYMERIC APPROACH  Synthetic & natural-based polymers have found their way into the pharmaceutical & biomedical industries and their applications are growing at a fast pace.  Polymers have been used to develop devices for controlling drug delivery or for replacing failing natural organs.  In oral delivery, polymers are used as coatings, binders, taste maskers, protective agents, drug carriers, and release controlling agents.  In transdermal patches, polymers are used as backings, adhesives, or drug carriers in matrix or membrane products.  Controlled delivery of proteins and peptides has been made possible using biodegradable polymers.  4 POLYMERS IN GENERAL  Polymers in general  The word “polymer” means“ many parts”.  A polymer is a large molecule made up of many small repeating units.  The term “macromolecule” was used in reference to polymers.  However, macromolecules refer to any large molecule, not necessarily just those made of repeating units. And thus, Polymers are considered a subset of macromolecules.  A monomer is a small molecule that combines with other molecules of the same or different types to form a polymer.  The structure of a polymer is displayed by showing the repeating unit (monomer residue) and an “n” number that shows how many monomers are participating in the reaction.  5 POLYMERS IN GENERAL  Depending on the number of monomers attached to each other; In case of:  Two monomers: it is called a dimer,  Three monomers: it is called a trimer,  Four monomers: it is called a tetramer,  Five monomers: it is called a pentamer,  30 -100 monomers: it is called an oligomer,  > 200 monomers: it is called a polymer.  6 POLYMERS IN GENERAL  Polymers exist only as liquids or high solid materials (cannot exist in the gaseous state).  Polymers molecular weight can be adjusted for a given application.  For example silicone polymers are supplied:  As vacuum grease (low molecular weight),  As durable implants (very high molecular weight).  The physical and mechanical properties of the polymers can also be modified by blending them with other polymers.  Blending polymers can achieve superior properties that are unattainable from a single polymer.  7 POLYMERS IN GENERAL Silicone elastomer Silicone sheet  8 COPOLYMERS AND POLYMER BLENDS  Copolymers and polymer blends  Polymer systems can be physically blended or chemically reacted in order to modify their properties;  Polymer Blends: are simply made by physical blending of two different polymers in molten or in solution state.  Copolymerization: refers to a polymerization reaction in which more than one type of monomer is involved (generally two types of monomers).  9 COPOLYMERS AND POLYMER BLENDS  Copolymers and polymer blends  Types of copolymers are:  Alternate copolymer:  Random copolymer:  Block copolymer:  Graft copolymer:  A terpolymer (less common; involves 3 monomer types).  10 POLYMER TOPOLOGY  Polymer topology  The topology of the polymer can affect its properties.  Polymers can be linear, branched, or cross-linked. 1. Linear polymers:  Weak intermolecular forces hold the polymer chains together.  Linear polymer can show dual behavior, where:  Chains can freely move, offering the polymer a low melting temperature, or  Chains may have a higher chance of approaching each other in their solid state, which increases their crystallinity and melting temperature.  11 POLYMER TOPOLOGY  Polymer topology II. Branched polymers:  Short or long side groups are attached to the backbone of the polymer.  Branched polymer chains move with difficulty because of the steric hindrance induced by the side groups but they presumably possess weaker intermolecular forces, which apparently help them move freely.  12 POLYMER TOPOLOGY  Polymer topology III. Cross-linked polymers:  Chains are chemically linked and restricted from moving, depending on the level of cross-linking (very highly cross-linked polymers are very rigid structures).  Note that:  A branched polymer might display better solvent permeability compared to its linear counter part due to its side groups (e.g., gum Arabic is a highly branched polymer with very high solubility in water).  If a linear polymer is cross-linked, its solubility will be sacrificed at the expense of swell- ability.  Therefore, a cross-linked polymer can swell in a solvent to an extent that is inversely related to the amount of cross-linker.  13 POLYMER TOPOLOGY  Polymer topology  Thermoplastic and thermoset polymers  Thermoplastic polymers:  Linear or branched polymers generally behave as thermoplastics.  Can undergo melting and flow upon application of heat, which are useful in molding processes & thermoforming.  Gain more freedom to move as temperature increases (i.e., high process- ability).  Generally dissolves in an appropriates solvent. (water or alcohol)  Examples include: polystyrene, polyethylene, and poly (vinyl chloride).(PVC)  14 POLYMER TOPOLOGY  Polymer topology  Thermoplastic and thermoset polymers  Thermosetting polymers:  Are cross-linked polymers.  Do not soften upon heating and decompose with further application of heat.  Since there is no reversible melting and solidifying in thermoset polymers, they are very useful when a thermo-resistant polymer is desirable.  Addition of cross-links to a polymer structure will hinder its chain movement and reduce its solubility, and  Thus cross-linked polymers swell (rather than dissolve) when they are placed in a compatible solvent.  15 POLYMER PROPERTIES 1. CRYSTALLINE AND AMORPHOUS POLYMERS  Polymer properties I. Crystalline and Amorphous Polymers:  Polymers display different thermal, physical, and mechanical properties depending on their structure, molecular weight, linearity, intra- & inter-molecular interactions.  Polymers can exist in either crystalline (regular packing) or amorphous states (irregular packing).  16 POLYMER PROPERTIES 1. CRYSTALLINE AND AMORPHOUS POLYMERS  Polymer properties I. Crystalline and Amorphous Polymers:  Crystallinity increases polymer strength & stiffness (as a result of increased intermolecular interactions).  Crystallinity also increases the barrier properties of the polymer (drugs usually cannot penetrate or diffuse through crystalline domains).(less permeable)  Crystalline polymers display better barrier properties and durability in the presence of attacking molecules.  A less crystalline or an amorphous polymer is preferred when the release of a drug or an active material is intended.  17 POLYMER PROPERTIES 2. THERMAL TRANSITIONS  Polymer properties II. Thermal Transitions  Thermal transitions in polymers can occur in different ways: 1. Crystalline polymer melts, and show melting temperature (Tm).  (Solid liquid) 2. Amorphous polymer shows glass transition temperature (Tg).  (Glass  rubber)  18 POLYMER PROPERTIES 2. THERMAL TRANSITIONS  Polymer properties II. Thermal Transitions  Glass Transition Temperature (Tg)  Is an expression of molecular motion, which is influenced by the factors affecting the movement of polymer chains.  At temperatures > Tg, amorphous polymers exist is a rubbary state; they might flow.  The Tg values for linear organic polymers range from about -100 ˚C to above 300 ˚C.  19 POLYMER PROPERTIES 2. THERMAL TRANSITIONS  Polymer properties II. Thermal Transitions  The glass transition (Tg) of a polymer depends on many factors, the most important of which are: A. Length of polymer chains:  Longer chains provides smaller free volume than shorter ones, and thus corresponds to higher Tg values. B. Polymer chain side group:  Bulkier side group corresponds to higher Tg values (due to steric hindrance causing lower segmental motion in the polymer).  Polar side groups provide stronger intermolecular interactions that also affect the motion of polymer chains, and the polymer displays a higher Tg value.  20 POLYMER PROPERTIES 2. THERMAL TRANSITIONS  Polymer properties II. Thermal Transitions  The glass transition (Tg) of a polymer depends on many factors, the most important of which are: C. Polymer chain flexibility:  Flexible polymer chains displays higher desire to move (and thus lower Tg) than rigid chains. D. Polymer chain branching:  Linear polymer chains possess smaller free volume as opposed to branched ones, thus, higher Tg is expected for linear polymers.  Branches in branched polymers impose hindrance to chain motion, for which higher Tg is expected.  Thus, branching has no obvious effect on Tg, unless the whole structure of the polymer is known.  21 POLYMER PROPERTIES 2. THERMAL TRANSITIONS  Polymer properties II. Thermal Transitions  The glass transition (Tg) of a polymer depends on many factors, the most important of which are: E. Polymer chain cross-linking:  Cross-linking limits chain movement resulting in higher Tg values. F. Processing rate:  Rate of processing (as heating & cooling) can affect molecular motion in polymers. In fast processes, the chains cannot move to the extent that they are expected to and may display a high Tg for the same polymer. G. Plasticizers:  A plasticizer is added to a polymer to enhance its flexibility and help its processing; it facilitates the movement of polymer chains against each other.  Plasticizers results in reduction in the Tg of the mixture (i.e., lower the Tg).  22 POLYMER PROPERTIES 3. MOLECULAR WEIGHT  Polymer properties III. Molecular Weight  A polymer batch may contain polymer chains with different lengths (molecular weights) and hence different molecular weight distributions.  The molecular weight of all chains should be considered and must be averaged to have a more realistic figure for molecular weight of a given polymer.  23 POLYMER PROPERTIES  Polymer properties IV. Mechanical Properties  Depending on their structure, molecular weight, and intermolecular forces, polymers resist differently when they are stressed (i.e., against stretching, compression, bending, sudden stress, and dynamic loading).  By increasing the molecular weight and hence the intermolecular forces, polymers display superior properties under an applied stress.  As far as structure is concerned, a flexible polymer can perform better under stretching whereas a rigid polymer is better under compression.  A polymer is loaded and its deformation is monitored to measure its strength.  24 POLYMER PROPERTIES  Polymer properties  Molecular Weight and Polymer Properties  The mechanical properties of a given polymer generally increase with an increase in molecular weight.  As molecular weight increases, polymer chains are more likely entangled into each other at certain molecular weights.  This results in poor polymer flow either in solid state (as a melt) or in solution state (as a solution).  For many applications, there is a working range of molecular weights that a given polymer in solid or solution state can successfully be processed.  25 VARIETY OF POLYMERS  Variety of polymers  Depending on their applications, polymers may be classified as:  Rubbers: have unique elongation properties; they can be stretched without failure.  Plastics: possess completely different properties; their Tg is generally above the room temperature.  Fibers: fibrous polymers are required to have a crystalline structure with a very sharp melting point.  Adhesives: The required properties of polymers for adhesive and coating applications are tackiness and adhesiveness.  Coatings are used for protection purposes.(cover)  26 POLYMERS CLASSIFICATIONS  Polymers may also be classified according to their solubility into: 1. Hydrophobic polymers dissolve in organic solvent. 2. Water soluble polymers dissolve in water. 3. Hydrophilic polymers (water soluble with cross-linkage) / swell rather than dissolve. 4. Hydrogels  classified according to swelling rate. / Enormous swelling.  27 POLYMERIC DRUG DELIVERY SYSTEMS  All polymers used in drug delivery systems should be biocompatible.  Polymers could be either: 1. Soluble: such as Na-CMC and poly vinyl alcohol (PVA). 2. Insoluble: such as silicone elastomer, polyethylene vinyl acetate (EVA). 3. Biodegradable/ bioerodible: such as polyglycolic acid, polylactic acid and poly (lactide-co-glycolide).  28 POLYMERIC DRUG DELIVERY SYSTEMS Ethylene vinyl acetate granule Ethylene vinyl acetate in industrial applications (plasticizer &coloring)  29 POLYMERIC DRUG DELIVERY SYSTEMS  Polymeric drug delivery systems: 1. Diffusion-controlled systems  Reservoir systems  Monolithic systems 2. Solvent-controlled systems  Osmotically controlled systems  Swelling controlled systems 3. Chemically-controlled systems  Polymer erosion mechanisms: type I, type II and type III.  Drug release mechanisms  30 1. DIFFUSION-CONTROLLED POLYMERIC DDS  Polymeric drug delivery systems: 1. Diffusion-controlled systems  Reservoir systems  Monolithic systems 2. Solvent-controlled systems  Osmotically controlled systems  Swelling controlled systems 3. Chemically-controlled systems  Polymer erosion mechanisms: type I, type II and type III.  Drug release mechanisms.  31 1. DIFFUSION-CONTROLLED POLYMERIC DDS  There are two types of diffusion-controlled drug delivery systems.  The therapeutic agents are incorporated in two ways: A. Reservoir (or Capsule-type) drug delivery system, in which the drug is encapsulated in a core that is surrounded by a rate-controlling membrane. B. Monolithic (or matrix-type) drug delivery system, in which the drug is homogenously dispersed in a matrix system formed by the cross-linked polymer chains.  32 1. DIFFUSION-CONTROLLED POLYMERIC DDS  The diffusion of the drug from both systems is governed by Fick's first law of diffusion: Flux (J) = -D *dc (C2-C1)/dx (-) Minus means drug goes from high to low (decrease)  Where:  J is the flux which is defined as the quantity of drug diffused in a unit time in a unit area (dQ/dt. A) in g/cm2. sec.  dc/dx is the concentration of the drug across the diffusion path (x).  D is the diffusion coefficient of the drug in cm2/sec.  33 1. DIFFUSION-CONTROLLED POLYMERIC DDS A. CAPSULE DIFFUSION-CONTROLLED DS 1. Diffusion-controlled polymeric DDS A. Reservoir delivery systems include:  The Progestasert intrauterine device for contraception.  The Ocusert-Pilo insert; for controlled release of pilocarpine.  Since the drug is contained in a core that is surrounded by a rate- controlling membrane, then dc/dx is essentially constant & is invariant with time.  34 1. DIFFUSION-CONTROLLED POLYMERIC DDS B. MATRIX DIFFUSION-CONTROLLED DS 1. Diffusion-controlled polymeric DDS B. Matrix systems includes:  The vaginal ring for cyclic intravaginal contraception containing (Medroxyprogesterone Acetate).  The Nitro-Dur transdermal system for controlled release of nitroglycerin.  Here, the drug is homogenously dispersed in a matrix environment formed by the cross-linking of linear polymer chains.  dc/dx is time dependent, due to the fact that the thickness of the diffusional path (dx) grows progressively as time passes.  35 2. SOLVENT-CONTROLLED POLYMERIC DDS: A. OSMOTICALLY-CONTROLLED SYSTEMS 2. Solvent-controlled polymeric DDS: A. Osmotically-controlled systems  The driving force that generates constant drug release is the osmotic pressure.  The system is composed of a peripheral and central (i.e., core) compartments.  The central compartment may be made of a single chamber (for both the drug and the osmotic agent) or two separate chambers (one for the drug and the other for the osmotic agent).  The peripheral compartment is composed of a semipermeable membrane surrounding a core of an osmotically active drug, or a core of an osmotically inactive drug in combination with osmotically active salt.  36 2. SOLVENT-CONTROLLED POLYMERIC DDS: A. OSMOTICALLY-CONTROLLED SYSTEMS 2. Solvent-controlled polymeric DDS: A. Osmotically-controlled systems  A delivery orifice is drilled by means of laser or by high-speed mechanical drill, or by the incorporation of a pore-forming material (soluble polymer).  The size and the number of orifices can be controlled to control the release of drug.  When the osmotic system is exposed to water or body fluid, water will flow into the core due to an osmotic pressure difference across coating membrane.  37 2. SOLVENT-CONTROLLED POLYMERIC DDS: A. OSMOTICALLY-CONTROLLED SYSTEMS 2. Solvent-controlled polymeric DDS: A. Osmotically-controlled systems  Osmotic delivery systems provide the following advantages:  Operate independent of active agent properties.  Able to deliver macromolecules.  Constant delivery rates much higher than diffusional devices can be attained.  Drug release is independent of surrounding environment, as gastric pH or presence of food.  Zero-order drug release is achieved.  Can deliver soluble as well as insoluble drugs.  Can be formulated as single unit doses or as multicompartment system (e.g., pellets).  Can be made as sustained, pulsed or delayed release.  38 2. SOLVENT-CONTROLLED POLYMERIC DDS: B. SWELLING-CONTROLLED SYSTEMS 2. Solvent-controlled polymeric DDS:  Swelling controlled systems  The active agent is homogenously dispersed in a glassy polymer matrix (impermeable) where it is immobilized in the matrix and no diffusion takes place.  Upon placement of the device in an aqueous environment, water penetrates the matrix and swelling takes place.  As a consequence, chain relaxation occurs and drug begins to diffuse.  Examples of swellable polymers: Hydrogels as poly hydroxyethyl methacrylate (HEMA; PHEMA) and polymethyl methacrylate (MMA; PMMA).  39 3. Chemically-controlled systems A.a. Type I erosion 3. Chemically-controlled systems A. Polymer erosion mechanisms a. Type I erosion:  Water soluble macromolecules are cross-linked to form a 3D network (the net work is insoluble as the cross-links remain).  When placed in aqueous environment, the polymer swells to the extent allowed by the cross-link density.  Erosion occurs by either cleavage of the cross-links (Type IA) or cleavage of the water soluble backbone (Type IB), as illustrated in the next slide.  As bond cleavage takes place, matrix begins to swell and then dissolved.  40 3. Chemically-controlled systems A.a. Type I erosion  41 3. CHEMICALLY-CONTROLLED SYSTEMS A.b. TYPE II EROSION 3. Chemically-controlled systems A. Polymer erosion mechanisms b. Type II erosion:  Water insoluble macromolecules are converted to water soluble macromolecules by hydrolysis, ionization or protonation of pendant group.  No backbone cleavage occurs here, therefore solubilization does not result in significant changes in the MWt of the polymer.  Unless the backbone is also degraded, this will be useful for topical application.  42 3. CHEMICALLY-CONTROLLED SYSTEMS A.c. TYPE II EROSION 3. Chemically-controlled systems A. Polymer erosion mechanisms c. Type III erosion:  High MWt water insoluble macromolecules are converted to small water soluble molecules by hydrolytic cleavage of labile bonds in the polymeric backbone.  These polymers are converted to small water soluble molecules, therefore, they are useful for systemic administration from SC, IM or IP implantation sites.  43 DRUG RELEASE MECHANISM  Drug release mechanism  In general, drugs could be present in the polymeric delivery system as follows: i. Covalently attached to the polymer backbone (i.e., covalent bond). ii. Contained in a core surrounded by bioerodible rate-controlling membrane (i.e., non-covalent).(capsule type) iii. Homogenously dispersed in a polymer matrix.  44 DRUG RELEASE MECHANISM  Drug release mechanism i. In case of drugs covalently attached to polymer, the active agent is attached to polymer backbone and is released as its attachment to backbone cleaves by hydrolysis of bond A.  45 DRUG RELEASE MECHANISM  Drug release mechanism ii. In case of drug contained in a core surrounded by bioerodible rate- controlling membrane, the active drug is contained in a core surrounded by a bioerodible polymeric membrane.  The bioerodible polymeric membrane remains unchanged during drug delivery but bioerosion must occur after drug release has been completed.  46 DRUG RELEASE MECHANISM  Drug release mechanism homogenously dispersed in polymer matrix, the drug is iii. In case of drugs homogenously dispersed in a polymer and drug release from this monolithic system is controlled by diffusion, by erosion or by a combination of diffusion and erosion mechanisms.  47 DRUG RELEASE MECHANISMS  Drug release mechanism  Hydrophilic bioerodible polymers:  Undergo bulk erosion Type I (A & B)  Are unable to immobilize small molecules with appreciable water solubility.  Are useful for molecules of extremely low water solubility or macromolecules that physically entangled in the hydrogel.  Examples include: Copolymer of vinyl pyrrolidone and acrylamide.  48 DRUG RELEASE MECHANISMS  Drug release mechanism  Hydrophobic bioerodible polymers  Polymer erosion occurs by bulk erosion and surface erosion.  In bulk erosion: hydrolysis occurs throughout the bulk polymer and the kinetic of release combines both diffusion and erosion.  Example: Poly lactic acid and copolymer of glycolic and lactic acid.  In surface erosion: hydrolysis of the polymer is confined to the outer surface and the interior of the matrix remains unchanged.  Example: Poly orthoesters.