Advanced Drug Delivery System PDF

Advanced Drug delivery system 9/28/2024 1 Introduction A drug (API) is a substance (recognized in official pharmacopoeia) intended for use in the diagnosis, cure, treatment, or prevention of disease. Drug delivery systems can describe the way that drugs are ‘packaged’—...

Advanced Drug delivery system 9/28/2024 1 Introduction A drug (API) is a substance (recognized in official pharmacopoeia) intended for use in the diagnosis, cure, treatment, or prevention of disease. Drug delivery systems can describe the way that drugs are ‘packaged’—like a micelle or a nanoparticle The encapsulation of drugs in nanoparticles, including micelles, liposomes, nanocapsules, nanospheres and others, improves the therapeutic index and reduces the adverse side effects. 9/28/2024 2  Classification of drug delivery systems (DDS) Basically, the DDSs can be divided into two main types: Conventional DDSs /immediate release formulations. The immediate release formulations are typically provides rapid onset of action for some drugs like analgesics, antipyretics and vasodilators. The conventional drug delivery forms include simple oral, topical, inhaled, or injection methods. 9/28/2024 3 Limitation of conventional DDS 9/28/2024 4 Drug plasma levels and release profiles. 9/28/2024 5 Novel drug delivery systems Currently, scientists and researchers are focused on discovering new methods/routes to control the pharmacokinetics (ADME), pharmacodynamics, non-specific toxicity, immunogenicity, and drug efficacy of drugs. These new strategies are often called novel drug delivery systems (NDDS) Novel drug delivery systems try to deliver drugs having complications that cannot be minimized by conventional drug delivery systems Novel drug delivery system (NDDS) sometimes called controlled DDS is a combination of advanced techniques and new dosage forms. 9/28/2024 6 TERMINOLOGY Rate controlled delivery: Drug delivered at predetermined rate either systemically or locally for a specific period of time. Sustained /prolonged /extended drug delivery: It is designed to release the drug slowly and to provide a continuous supply of drug over an extended period. It allows at least a two fold reduction in dosage frequency as compared to that drug presented as an immediate release Targeted drug delivery: (magic bullet,) Drug is delivered to specific sites in the body. 9/28/2024 7  Zero-order release: Drug release does not vary with time and relatively constant drug level is maintained in the body for longer periods. Timed (delayed) release DDS (delayed): Timed release DDS are used to obtain the drug release after a lag time of about 4-5 hrs. E.g., Enteric coated dosage (colon-specific dosage form) forms of cellulose acetate phthalate are designed to provide protection in the stomach. Application of a thick coat causes a delay in the drug release 9/28/2024 8 9/28/2024 9 Rationale (Goal) of developing SR DDS To extend the duration of action of the drug To reduce the frequency of dosing To minimize the fluctuations in plasma level To improve drug utilization To minimize the adverse effects To improve patient compliance. 9/28/2024 10 Conventional vs controlled release DDS 9/28/2024 11 Advantages of Sustained/Controlled Disadvantages of Sustained Release Dosage Forms: /Controlled Release Dosage Forms: Reduction in frequency of drug Unpredictable or poor in vitro/in vivo administration correlation. Reduced fluctuations in circulating drug Reduced potential for dose adjustment. levels. Possibility of dose dumping Avoidance of night time dosing. Delay in onset of drug action Increased patient compliance. Poor systemic availability in general More uniform effect. Cost of single unit higher than Reduced toxicity due to overdose conventional dosage forms Improve of bioavailability The requirement for additional patient education for proper medication 9/28/2024 12 Parameters for drug selection Elimination half-life: 2- 8 h Molecular weight/ size: < 1000 daltons  600 daltons Solubility: > 0.1 µg/ml for pH 1 to pH 7.8 Dose: maximum 1.0 g in controlled release form Stability in GIT; stable at both gastric and intestinal pH Apparent partition coefficient: High (1-2) Absorption rate constant: high General absorbability: From all GI segments Release: Should not be influenced by pH and enzymes 9/28/2024 13 Examples of drugs which are poor candidates for S.R/C.R release systems: Drugs, limited in the absorption by their dissolution rates are: Digoxin, Warfarin, Griseofulvin, and Salicylamide. Low or slow solubility Short elimination half-life, i.e., t1/2 8 hrs Narrow therapeutic index large doses Drug showing high plasma protein binding are not a good candidate for CRDDS Poor absorption (high ionization) Extensive first-pass clearance. 9/28/2024 14 Classification of Controlled Release Drug Delivery Systems Controlled release drug delivery systems are classified based on the mechanism of drug release from the dosage form. 9/28/2024 15  1. Diffusion-Controlled Drug Delivery Systems Diffusion systems are characterized by the release rate of a drug being dependent on its diffusion through an inert membrane barrier. Diffusion process shows the movement of drug molecules from a region of a higher concentration to one of the lower concentration The drug release is governed by Fick’s laws of diffusion. The rate-limiting step in diffusion-controlled systems is the diffusion of drugs. 9/28/2024 16  The rate of drug released (dm/dt) can be calculated using the following Ficks” first law equation: dm/dt = ADK ΔC/L Where, A = Area, D = Diffusion coefficient, K = Partition coefficient of the drug between the drug core and the membrane, L = Diffusion path length and ΔC= Concentration difference across the membrane. 9/28/2024 17  Fig. Diffusion-controlled reservoir (a) and matrix (b) systems 9/28/2024 18 A. Reservoir device, the drug is contained in the core as a reservoir and is covered by a thin polymeric membrane. The water-insoluble membrane could be either porous or non-porous. The polymers commonly used in such devices are Ethyl cellulose and Poly-vinyl acetate, PVC, hydrogel. The release of drugs is by diffusion through the membrane The rate of release is governed by membrane thickness, porosity and physicochemical characteristics of drugs (partition coefficient, molecular size and diffusivity, protein binding). If the reservoir membrane accidentally ruptures, a large amount of drug may be suddenly released into the bloodstream (known as “drug dumping”). the rate of drug release does not vary with time and zero-order controlled release is attained Difficult to deliver high molecular weight compound, Fig. Reservoir device (Membrane-controlled drug delivery systems) 9/28/2024 19 B. Matrix devices the drug is either dissolved or dispersed homogenously throughout the polymer matrix. The rate of release of drug is dependent on the rate of drug diffusion It is easier to produce than reservoir or encapsulated devices, can deliver high molecular weight compounds. The drug release is through diffusion when the outside layer that is exposed to the solution gets dissolved first, allowing drugs to diffuse out of the matrix 9/28/2024 20  Difference between Reservoir type /matrix type Reservoir type Matrix type Advantage Advantages Zero order delivery is possible, Easier to produce than reservoir or Release rates variable with polymer type, encapsulated devices, thickness. can deliver high molecular weight Maintain drug stability compounds. Disadvantage No danger of dose dumping Rupture can result in dose dumping System must be physically removed from Disadvantages implant sites. Cannot provide zero order release, Difficult to deliver high molecular weight removal of remaining matrix is compound necessary for implanted system. potential toxicity if system fails. 9/28/2024 21 Examples of commercial diffusion-controlled reservoir and matrix devices 9/28/2024 22 2. Swelling Controlled Systems Swelling controlled release systems are initially dry and when placed in the body absorbs water or other body fluids and swells. Swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment. 9/28/2024 23  Most water-swellable polymers used in hydrophilic matrices are based on cellulose and include hydroxypropyl methylcellulose (HPMC) and methylcellulose (MC). HPMC offers many advantages for hydrophilic matrix formulation, including fast and uniform gel formation, which is crucial to protect the matrix from disintegration and premature drug release. The gel formed by HPMC is strong and viscous, which provides the necessary diffusional barrier to control drug release. The release of drug is controlled by the rate of swelling of the polymer matrix. 9/28/2024 24  Different chemistries (degree of methoxyl and hydroxypropyl substitution) and viscosities of HPMC allow customization of the desired release profile. It may also be combined with other polymers to offer further flexibility and control of release. Combinations with water-insoluble ethyl cellulose (EC) polymers can be used to delay release rates, whereas combinations with soluble polyvinylpyrrolidone (PVP), and poly(ethylene oxide) (PEO) polymers can be used to enhance solubility and dissolution rate 9/28/2024 25  3. Osmosis-controlled drug release OROS™ (i.e., ORal OSmotic) technology uses osmotic pressure as the mechanism to control drug release from the delivery system. It consists of a drug-containing core, a semipermeable membrane made of water- permeable cellulose polymers, and laser-drilled orifice Water is drawn into the system by osmosis, displacing drug in the core, which is then released through the orifices. Polymers, such as cellulose acetate, ethylcellulose, polyurethane, poly-vinyl chloride, and PVA, are used to prepare semipermeable membranes This type of drug system dispenses drug solutes continuously at a zero order rate. 9/28/2024 26  Figure. Schematic of the OROS Push-Pull and elementary osmotic system 9/28/2024 27 Advantages of the OROS system No risk of dose dumping (early release of most of the drug dose) Drug release significantly less affected by factors such as pH, food intake, GI motility, and differing intestinal environments The following example demonstrates some of the advantages gained by using osmotically controlled tablets to deliver drugs. Nifedipine delivered by an Oros Push-Pull system (Procardia XL). as single 60-mg dose of Procardia XL (administered once a day) provides a steady plasma level throughout the day and eliminates the rapid rise in plasma concentration seen with immediate-release nifedipine 9/28/2024 28 Key parameters that influence the design of osmotic controlled drug delivery systems Orifice size Solubility, drugs should have sufficient solubility to be delivered by osmotic delivery. Osmotic pressure., To achieve a zero-order release rate, it is essential to keep π constant by maintaining a saturated solute solution. Thickness of semipermeable membrane Type and level of osmogent (sodium chloride, lactose, dextrose, bicarbonate) 9/28/2024 29 4. Chemically Controlled Release Systems Chemically controlled release systems are the systems that change their chemical structure, when exposed to biological fluid. Mostly, biodegradable polymers are designed to degrade as a result of hydrolysis of the polymer chains into biologically safe and progressively smaller moieties. e.g. Erodible systems Two major advantages of erodible systems are (1) polymers do not have to be removed from the body after the drug supply is exhausted, and (2) the drug does not have to be water-soluble 9/28/2024 30 Two types of biodegradations are reported Bulk Erosion process polymer degradation may occur through bulk hydrolysis When the polymer is exposed to water hydrolysis occurs Hydrolysis degrades the large polymers into smaller biocompatible compounds e.g. poly lactide, polyglycolic acid Surface Erosion process Polymers like polyanhydrides degradation occurs only at the surface of the polymer 9/28/2024 Fig : Bulk Erosion and Surface Erosion 31 Factors affecting degradation of polymers 1. Chemical structure and composition 2. Molecular weight of polymer 3. Polymer concentration 4. Hydrophilicity/hydrophobicity 5. Carrier morphological properties such as size, shape, and porosity 6. Additives in the system (acidic, basic, monomers, drugs) 7. Microenvironmental climate such as pH 8. Method of preparation 9. Sterilization 9/28/2024 32  Today, many synthetic biodegradable polymers are being employed successfully for drug delivery applications: E.g., polylactic acid and polyglycolic acid, polycaprolactone (polyesters: aliphatic homo-polymer). All biodegradable polymers possess some common characteristics: (1) stability and compatibility with the drug molecule, (2) biocompatible and biodegradable, (3) ease of manufacture on a larger scale, (4) amenability to sterilization, and (5) flexibility to yield multiple release profiles. 9/28/2024 33  Polyesters and their copolymers have been tested extensively as rate controlling membranes and erodible polymeric excipients for injectable drug delivery systems Polyesters have been tested as implants, nanoparticles, and microspheres for the delivery of various drugs, such as narcotic antagonists, contraceptives, local anesthetics, cytotoxics, and antimalarial agents. Polylactic acid has been studied extensively for controlled release applications ranging from the oral delivery of simple drugs such as indomethacin to the parental administration of complex proteins such as insulin 9/28/2024 34 5. Magnetic nanoparticle-based drug delivery is a means in which magnetic particles such as iron oxide nanoparticles are a component of a delivery vehicle for magnetic drug delivery, 9/28/2024 35  Conventionally used systemic antineoplastic agents are unable to achieve ideal tumor specificity. Magnetically responsive drug carrier systems, composed of albumin and magnetic microspheres, have been developed for use in cancer chemotherapy Because of their magnetic characteristics, these microspheres are theoretically capable of enhanced area-specific localization. This carrier system is capable of accommodating a wide variety of drugs. Major advantages of the magnetically responsive carrier system over other drug delivery systems are its high efficiency for in vivo targeting and its controllable release of a drug at the microvascular level. zero-order drug delivery profile is achieved 9/28/2024 36  6. Target drug delivery Targeted drug delivery is the delivery of a drug to its target site without having an effect on other tissues. Interest in targeted drug delivery has grown drastically in the treatment of cancers and other chronic diseases. In order to achieve efficient targeted delivery, the designed system must avoid the host's defense mechanisms and circulate to its intended site of action. A number of drug carriers have been studied to effectively target specific tissues, including liposomes, nanogels, and other nanotechnologies. 9/28/2024 37  Advantage of Target DDS 9/28/2024 38 7. Hydro-dynamically balanced drug delivery system In various controlled delivery systems short duration of the gastric residence is very problematic. Various techniques can use for the reduction of gastric emptying for a dosage form, like floating drug delivery system. The system has less bulk density as compared to the gastric fluids. Floating systems floats over the gastric fluid for longer period that enhance the bioavailability of therapeutic agents 9/28/2024 39  8. Microencapsulated drug delivery system Solids, liquids, or gases can be entrapped by this technique. A thin layer formation takes place around the material to be encapsulated. These micro-capsules have a number of benefits such as converting liquids to solids, separating reactive compounds, providing environmental protection, improved material handling properties. Gelatin is used commonly for encapsulation but synthetic polymers such as polyvinyl alcohol, ethyl cellulose, polyvinyl chloride, and enteric resin as shellac, CAP other materials can be used. Various proteins, lipids, insulin, and other drugs can be encapsulated by 9/28/2024 these materials 40