Reagdfo lead Novel Drug Delivery System LESTE T ts | BUCO eye y a] PORE en ry) LUCKNow eR a Pres | Ganpati Katedeshmukh1. Contents Chapter 1: Controlled Drug Delivery Systems Controlled Drug Delivery Systems Introduction Terminologies/Definitions Rationale Advantages Disadvantages Differences Between Conventional, Sustained Release, and Controlled 20 Release Dosage Forms Selection of Drug Candidates 20 . Properties of Drugs Relevant to Controlled Release Formulations 21 .1, Physicochemical Properties 21 . Biological Properties 23 Approaches to Design Controlled Release Formulations 26 Introduction 26 ._ Rate-Programmed Drug Delivery System 26 . Dissolution-Controlled Drug Delivery System 26 . Diffusion-Controlled Drug Delivery System 27 .3, Erosion-Controlled Drug Delivery System 28 . Dissolution, Diffusion and/or Erosion-Controlled Drug Delivery 29 System Activated Modulated Drug Delivery System 30 . Activation by Physical Processes 31 . Activation by Chemical Processes 33 Activation by Biological Processes 34 Feedback Regulated Drug Delivery System 35, Site Targeting Drug Delivery System 36 Summary 36 Exercise 38 Chapter 2: Polymers 24. Polymers 39 2.1.1. Introduction 39 2.1.2. Classification 39 2.1.2.1. Based on the Source 39 2.1.2.2, Based on the Type of Polymerisation 40 2.1.2.3. Based on the Degradability 41 2.1.2.4. Based on the Nature of Polymer-Water Interaction 41 2.1.2.5. Based on the Structure of Polymers 41 2.1.2.6. Based on the Molecular Forces 42 2.1.2.7. Based on the Types of Monomer 43 2.1.2.8, Based on the Morphology 43 2.1.2.9. Based on the Tacticity 2.1.3. Properties 2.1.4. Advantages 21.5. Disadvantages @F utureP 4B harmacisty Telegram2.1.6. 2.2. 23. 31. 3.L1. 3.1.2. 3.13. 3.1.4. 3.14.1, 3.1.4.2 3.1.4.3, 3.1.4.4. 3.13. 3.1.6. 3.1.6.1. 3.1.6.2. 3.1.6.3. 3.1.64. 3.1.6.5. 3.1.6.6. 3.1.6.7, 3.1.6.8. 3.1.6.9. “8. Appl ante ms Summary Exercise Chapter 3: Microencapsulation Microencapsulation Introduction and Definition Advantages Disadvantages Microparticles Advantages Disadvantages Microspheres Microcapsules Formulation Methods of Microencapsulation Air Suspension Technique Coacervation-Phase Separation Method Multiorifice-Centrifugal Process Pan Coating Spray Drying and Spray Congealing Fluidised-Bed Technology Solvent Evaporation Polymerisation Rapid Expansion of Supercritical Fluids 3.1.6.10. Salting-Out Process 3.1.6.11 3.1.7. 3.1.8. 3.1.9. 3.2. 3.3, 41, Mee Complex Emulsion-Based Method Evaluation Applications Examples of Some Microencapsulated Drugs Summary Exercise Chapter 4: Mucosal D: i : rug Delivery System Mucosal Drug Delivery System ™ Introduction Advantages Disadvantages Principles and Concey i i inc Concepts of Bioadh ples of Bioadhesion onNscoaeson ies of Bioadhesion ee of Mucoadhesion ‘ors Affecting Mucosal Adhesi Pasmucsal Permeability esi ulation Considerations of i hen ‘ons of Buccal Delivery Systems Evaluation © Methods of Buccal Patches Summary Exercise cation of Polymers in Formulation of Controlled Release Dry S PSSSRRALSSSLSS9URRKeLSSees R-9- Chapter 5: Implantable Drug Delivery System Implantable Drug Delivery System (IDDS) ° Introduction Advantages Disadvantages Mechanism of Drug Release from Implantable Therapeutic System Concept of Implants - Non-Degradable Systems . Biodegradable Systems Applications Osmotic Pump Drug Delivery System Introduction Advantages Disadvantages Principle of Osmosis Basic Components of Osmotic Pumps Classification DUROS Technology . ALZET Osmotic Pumps . Rose and Nelson Pump . Higuchi-Leeper Pump . Higuchi-Theeuwes Pump .6. Mini Osmotic Pumps . Elementary Osmotic Pump (EOP) . Osmotic Pump with Non-Expanding Second Chamber . Push-Pull Osmotic Pump (PPOP) . Controlled Porosity Osmotic Pump (CPOP) - Osmotic Pump for Insoluble Drugs . Multi-Particulate Delayed Release Osmotic System . Monolithic Osmotic System . Colon Targeting Oral Osmotic System (OROS-CT) . Sandwiched Osmotic Tablets (SOTS) . Liquid Oral Osmotic System (L-OROS) . Osmotic Matrix Tablet (OSMAT) Evaluation Summary Exercise Chapter 6: Transdermal Drug Delivery System Transdermal Drug Delivery System (TDDS) Introduction Advantages Disadvantages Permeation Through Skin Factors Affecting Permeation Basic Components of TDDS . Polymer Matrix/Drug Reservoir . Membrane . Drug ill 11 lit 13 14 14 114 115 11s 17 119 119 120 120Permeation Pressure-Set lo- Enhancers nsitive Adhesives (PSAs) Backing Laminates Release Lin er “e8. Other Excipients Evaluation Summary Exercise Classification of TDDS . Rate-Progral Physical Sti Formulation Approaches :mmed Transdermal DSS/Transdermal Patches muli-Activated Transdermal DDS Chapter 7: Gastroretentive Drug Delivery System Gastroretentive Drug Delivery System (GRDDS) Introduction Advantages Disadvantages Factors Affecting Gastric Retention Time of the Dosage Form Applications Approaches for GRDDS Introduction Low Density or Floating Drug Delivery System . Mechanism of Floating Drug Delivery System Classification of Floating Drug Delivery System Effervescent System Non-Effervescent System High Density (Sinking) or Non-Floating Drug Delivery System Modified Shape or Unfolding System Bioadhesive or Mucoadhesive or Gastroadhesive Drug Delivery 144 System Super-Porous Hydrogel System Magnetic System Summary Exercise Chapter 8: Nasopulmonary Drug Deli System Nasal Routes of Drug Delivery initial Introduction Advantages Disadvantages Mechanism of Drug Absorption from Nose Factors Influencin; : ig Nasal Dru; corn Barriers to Nasal Absorption © SPO Strategies to Applications Pulmonary Introduction Advantages Improve Nasal Absorption Routes of Drug Delivery 135 136 136 136 137 137 138 138 141 143 144 145 145 145 1478.4. 91. 9.1.1. 9.1.2. 9.1.3. 9.1.4. 9.1.5. 9.1.6. 9.2. 9.2.1. 9.2.2. 9.2.3. 9.2.4. 9.2.5. 9.2.6. 9.2.7. 9.2.8. 93. 9.3.1. 9.3.2. 93.3. 93.4. 9.3.5. 9.3.6. 937. 9.3.8. 94. 9.4.1. 9.4.2. 9.4.3. 9.4.4, 9.45. 9.4.6. 9.4.7. “Jil Disadvantages Principal Mechanisms of Respiratory Deposition Formulation of Nasal Products Introduction Inhalers Nebulisers Squeezed Bottle Metered Dose Pump Sprays Dry Powders Pressurised MDIs Nasal Sprays Nasal Gels Summary Exercise Chapter 9: Targeted Drug Delivery System ‘Targeted Drug Delivery System Introduction Concept Approaches of Drug Targeting Components of Drug Targeting Advantages Disadvantages Liposomes Introduction Structure Types Methods of Preparation Evaluation Applications Introduction Structure Types Methods of Preparation Evaluation Applications Advantages Disadvantages Nanoparticles Introduction Structure Methods of Preparation Evaluation Applications Advantages Disadvantages 157 157 158 158 160 160 160 161 161 161 162 162 163 164 165 165 165 166 167 168 168 169 169 169 169 170 170 171 172 172 172 172 173 173 173 174 175 177 177 177 177 177 178 180 181 181 182~12- Monoclonal Antibodies Introduction Methods of Preparation Applications Summary Exercise Chapter 10: Ocular Drug Delivery System Ocular Drug Delivery System Introduction Advantages Disadvantages Ocular Drug Delivery Routes Intraocular Barriers Methods To Overcome- Preliminary Study Ocular Formulations Ocuserts Introduction Characteristics Approach Classification Insoluble Ocular Inserts Soluble Ocular Inserts Bioerodible Ocular Inserts Formulation Methods Evaluation Advantages Disadvantages Summary Exercise Chapter 11: Intrauterine Drug Delivery System Intrauterine Drug Delivery System Introduction Advantages Disadvantages Types of Intrauterine Devices Mechanism of Action Development of Intrauterine Devices q@uDs) Applications Summary Exercise Ig) 1) las 186 185 187 187 187 188 189 19 193 193 194 194 195 195 197 198 199 200 202 202 206 206 207 207 209 209 2 2 23Controlled Drug Delivery Systems (Chapter 1) 3 amr, CHAPTER Controlled Drug TT a Ay 1 CONTROLLED DRUG DELIVERY SYSTEMS 1.1.1. Introduction Controlled drug delivery system maintains suitable and desired drug release over an extended time period. A controlled dosage form is formulated using hydrophilic polymer matrix. An ideal controlled drug delivery system releases adequate amount of drug at regular time intervals and at the target site of action to maintain therapeutic levels of drug in blood plasma. The oral controlled drug delivery system offers potential advantages of controlled release rate and dose maintenance in plasma. The controlled release formulations are incorporated with swelling polymers or waxes or both for controlling the drug release rate. Reservoir system also provides the desired controlling release rate. Controlled release drug delivery system aims to reduce the dosing frequency. reduce the dose, and deliver the drug uniformly. Thus, controlled release dosage form releases the drugs continuously at a predetermined rate for a fixed time period, either systemically or locally to the target organ. Controlled release dosage forms provide better control of plasma drug levels, less dosage frequency, less side effects, increased efficacy, and constant delivery. 1.1.2. Terminologies/Definitions The related terminologies for controlled drug delivery or modified release delivery systems are as follows: 1) Controlled-Release Formulation: The controlled release system maintains aconstant supply of the drug at zero-order rate by continuously releas drug for a certain time period in amount equivalent to that elimin; y body. An ideal controlled drug delivery system delivers the drugs either locally or systematically at a predetermined rate for a specific time period. 2) Repeat Action Preparation: A drug dose, equivalent to a single dose of the conventional drug formulation, is initially released immediatly a’ administration. After a certain time period, a second single dose i 1 Tn some preparations, a third single dose is also released after a vertain time. 3) Extended-Release Formulation: This dosage form allows two-fold reduction in dosage frequency in comparison to the immediate-release (conventional) dosage form. Examples of extended-release dosage forms include controlled-release, sustained-release, and long-acting drug products.ion: is 2 form releases a gi -Release Preparation: This dosage : disc Dee of drug at a time or at specific time intervals afier administrag, te sithough one portion may be released immediately after administration, 9 at ample of delayed-release dosage form is enteric-coated dosage form, | + Thi: form releases drug a eted-Release Drug Product: This dosage f at oF p a Ae tnenaed physiological site of action. These dosage forms may either immediate or extended-release characteristics. Site-Specific Targeting System: This system targets a drug directly to a cer biological location. The target is adjacent to or in the diseased organ or tissue, 7) Receptor Targeting System: This system targets a drug directly 10 a certain biological location. The target is the particular receptor fora drug in an organ g, tissue, Site-specific targeting and receptor targeting systems satisfy the spat. al aspect of drug delivery and are considered as controlled drug delivery systems, Controlled Action System: This system provides a prolonged duration op drug release with predictability and reproducibility of drug release kinetics The drug absorption rate is equal to the drug removal rate from the body, Sustained Action System: This system initially provides a sufficien amount of drug to the body to produce the desired pharmacological action, The remaining drug amount is released periodically and maintains the maximum initial pharmacological activity for a desirable time period in excess of time expected from usual single dose. 10) Prolonged Action System: This system releases the drug over an extended time period during which pharmacological response is obtained, but it does not maintain the constant blood level. 1.1.3. Rationale The basic rationale for controlled drug delivery is to alter the pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and/or physiological parameters essential in a selected administration route. Thus, for designing optimum controlled release systems, a thorough understanding of the pharmacokinetics and pharmacodynamics of drug is required, 4) have 6) s 9 However, if the doses are not administered at scheduled time, the resulting peaks and valleys reflect less than optimum drug therapy. For example, if a drug administered at frequent doses, it will reach its Minimum Toxic Concentratios (MTC) and will also result in toxic side effects. If doses are missed, periods of Sub-therapeutic drug blood levels or those below the Minimum Effectiv® Concentration (MEC) will result, with no patient benefit. The medical rationale for the develo important for the following aspects: 1) Reduced Dosing Frequency: frequency of dosing, pment of controlled drug delivery system * ‘Use of conventional drug therapy vied the ‘ ie., a chance of skipping a dose; this problem resolved with the development of controlled release dosage form th# ‘leases the drug over an extended time period and maintains the desi" drug concentration in blood.Controlled Drug Delivery Systems (Chapter 1) 15 3) 4) By increasing the time interval between the doses, the number of doses can be reduced from 3-4 times to 1-2 times, Proteins and peptides can be delivered into the body using a controlled release system. Tumour therapies can also be improved with enhanced targeting. Therapeutic efficacy and safety of drugs are improved by targeting the drugs in the body in a more precise manner, and by reducing the dosing frequency. Reduced Drug Exposure to the Biological Environment: The CRDDS alters either the pharmacokinetic or pharmacodynamic profile of the active metabolites. Designing of such a system involves a property of rate controlling and achieving better plasma concentration. The CRDDS system controls the drug concentration in cells and tissues of the target sites. A drug is released in a controlled manner by either temporal control or distribution control. The temporal control allows the system to deliver the drug over an extended time period at specific intervals within the treatment regimen. This approach is useful for the drugs having a fast metabolism rate. Conversely, the distribution control allows the system to deliver the drug at the target sites within the body. Drugs like steroids, antibiotics, and hormones can be delivered using either of these approaches. Minimised Plasma Concentration Fluctuations: With the use of conventional tablets or capsules, only a single and transient type of burst occurs, when the drug effect is above minimum effective concentration. The response is observed pharmacologically, but a problem arises when the response is narrow; in this case, CRDDS is used to reduce the fluctuations in plasma levels by retarding the absorption rate, accompanied by slower drug release. The drug formulation is modified to reduce the fluctuations during the dosing interval. This approach is beneficial for the drugs having short half-lives and low therapeutic indices, for which maintenance of therapeutic drug concentrations is mandatory. Formulating such drugs (e.g., procainamide and quinidine) in CRDDS improves patient compliance and reduces the chances of toxicity. Better Patient Compliance: Development of any dosage form aims to provide better patient compatibility. Designing a dosage regimen for a drug influences its duration of action, bioavailability, absorption rate, and elimination rate. These factors in turn influence the therapeutic response of the dosage form. The CRDDS are ideal for delivering the drug at the target site of the body over an extended time period, and thus for maintaining relationship between the plasma concentration levels and the therapeutic Tesponse, and for improving patient compliance. Some drugs are unstable on oral administration, and thus are administered through a different route to improve the drug bioavailability and therapeutic Tesponse in the body, e.g., nitroglycerine. The CRDDS is more sophisticated than just delaying the release and delivering the drug with controlled release Tates within the specific time period. This system maintains the drug levels Within the required range with only few administrations.Novel Dr i ia 1 Drug Delivery Syqq, 5) Lower Adverse/Side Effects: The dose and dosing intervals of each ry designed as conventional dosage form are varied. Each drug Produces + different therapeutic response in plasma concentrations, the unbalan response results in improper therapeutic effect or undesirable side effects, rate-controlled dosage forms, the dosing intervals are increased fluctuations in plasma levels are reduced to minimise the risk of undesirabjy side effects. Incidences of side effects is a part of plasma concentration, 4 can be minimised by handling plasma drug concentration at a particular time, For example, by administering levodopa in the form of CRDDS, the risk of dyskinesis that the drug may cause is reduced. The CRDDS reduce the tisk of side effects in the GIT and produce effective results. For example, potassium chloride and ferrous sulphate cause GIT irritation, which can be reduced by slowing the drug release. 6) Augmented Efficacy: For designing an ideal drug delivery system, two prerequisites should be fulfilled. Firstly, the drug should be delivered at g rate that a body requires over a time period. Secondly, the action should be at the specific site at specific receptors. These goals can be achieved by using CRDDS. This system is biologically irresponsive to the external environment. The prolonged release dosage form slows down the absorption rate due to the slow release rate of the drug by small bursts over time, which improves the efficacy of CRDDS. By increasing the time interval between the doses, the total number of doses is reduced, thereby reducing the dosing frequency, and thus improving patient compliance. The biological rationale for the development of controlled drug delivery system is important for the following aspects: 1) Absorption: The extent and rate of drug absorption should be considered while developing a CRDDS. Drugs having a very slow absorption rate show poor bioavailability, and thus are not suitable candidates to be formulated into CRDDS. Drugs having rapid absorption rate, however, can be formulated into successful controlled release products. Absorption window also affects the bioavailability of drugs administered orally. It can ever hinder the development of CRDDS as some drugs undergo absorption in # specific region of GIT, which after absorption in the absorption window ca! go waste. Drug release is a rate-limiting step in CRDDS; therefore, fast drug absorption is required from a dosage form in terms of extent and rate of drug absorption especially for drugs administered orally. The amount of drug absorbed frot Conventional dosage forms is lower than that absorbed from CRDDS beca'S* of drug degradation due to metabolism or physical loss. For example Pilocarpine gets absorbed in the comea in 1% ratio of applied dose, # ! fuffers loss due to drainage and absorption in non-specific tissues: a bicavar ena oarvine into controlled release dosage form improves desired time. and maintains a constant level in specific tissuesControlled Drug Delivery Systems (Chapter 1) 7 Protein Binding: It is a reversible process. If the drug concentration in 2) aoe is decreased, ihe drug-protein complex dissociates and leaves free drug to maintain balance. This reversible process of drug-protein binding maintains the drug level in the blobd for an extended time period. Binding of drug with protein can function as a drug store for generating long-term action. For example, blood proteins recirculate in the body and are not eliminated; they act as a depot for drugs having controlled release profile; Quaternary ammonium compounds bind with mucin in the GIT, and the resultant complex then acts as a depot and enhances the absorption. 3) Distribution: Drug distribution in body is an important criterion to determine the overall elimination kinetics of the drug. Drugs whose volume of distribution (Vd) is higher than the real volume of distribution have a lesser half-life. While designing CRDDS, volume of distribution plays an important role as it affects the amount of drug in systemic circulation or reaching the target. The effect is not easy to determine because the volume of distribution is unpredictable. Designing of CRDDS demands knowledge of drug disposition, but the fate is decided on the basis of pharmacokinetic parameters, like the volume of distribution. It affects the drug concentration in blood, and also the elimination kinetics of a drug. A drug’s distribution property is described by volume of distribution by cither extent of distribution in the body or by relative distribution of the drug in compartments. These two parameters are independent of each other; for example, the relative distribution of procainamide is 10 times that of pentobarbital; however, both the drugs have same volume of distribution. Similarly, the relative distribution for procainamide is much larger than that of digoxin, and its volume of distribution at steady state is lower than that of digoxin. 4) Elimination: Every biological response parameter is beneficial in designing CRDDS. Most of the drugs undergo elimination within 20 hours of their administration. The zero-order rate of release is directly proportional to the elimination rate and is given by the biological half-lives. The drugs having short half-lives require frequent dosing, thus are suitable to be: formulated into CRDDS; while the drugs having long half-lives do not require frequent dosing, thus are considered poor candidates to be formulated into CRDDS. Drugs having half-lives < 1 hour (e.g. ampicillin and penicillin) and > 8 hours (e.g., digitoxin and digoxin) are also considered poor candidates to be formulated into CRDDS. 5) Dose-Dependent Bioavailability: Effect of dose is another factor that influences the designing of CRDDS. For example, bioavailability of Propoxyphene is dose-dependent, thereby restricting its use in CRDDs, because of the rate at which CRDDS should be able to achieve reproducible bioavailability, Bioavailability is another important factor that should be taken into account while formulating CRDDS. The CRDDS formulation Should be able to present about 80% of bioavailability ii conventional dosage form.Novel Drug Delivery Sy, my 6) Duration of Drug Residence within the Therapeutic Window: Duration 7 8 drug residence and the drug's half-life should be taken into considerag, while designing CRDDS. Most of the marketed drugs exhibit half-lives of | 20 hours. Drugs having short half-lives require frequent dosing to mainga;, the desired drug plasma concentrations, thus such drugs are formulated jg, CRDDS. ‘A drug's pharmacokinetic profile in a steady state concentration indicate, that the release rate of the drug is directly proportional to its elimination rate Drugs showing linear kinetics have a constant half-life and do not follow , change. Metabolism, distribution, and elimination are the factors influencin the half-life of drugs. The limit of half-life for CRDDS is not yet defined ang the exact half-life value for a good CRDDS is not known. The drug candidate with this half-life value has a ratio value of sustainin, dose to immediate dose of 2, if it shows release up to 12 hours. The controlled release product in this case can be developed for 1gm amount with the drug having a dose of 325mg. For example, due to its dose, procainamide is administered after every 3 hours to reduce fluctuations in plasma drug concentration. The CRDDS of procainamide maintains plasma level for 8 hours. Better Safety Margin: Therapeutic Index (TI) is the most common approach used for defining the safety margin of drugs by the following equation: (1) TI = Median toxic dose/Median effective dose This ratio provides a rough estimate of the relative safety of drugs; the drug candidate is considered safe if its TI value is > 10. Larger the ratio, safer the drug. This approach plays an important role in monitoring a drug therapy, especially for drugs having either narrow therapeutic index ot narrow therapeutic concentration, e.g., antiarrhythmic drugs, like digoxin and digitoxin. Individualisation in a Diseased Condition: The diseased state of a body is an important part in consideration of drug candidate for CRDDS. For example, aspirin is still used in the treatment of rheumatoid arthritis, but due to its biological half-life (6 hours), it is not considered a good candidate for formulation into CRDDS. Whereas, a controlled release dosage form tends 0 maintain a therapeutic concentration and provides release for up to 10 hours, which is more than non-controlled formulation. Safety margin of the drug can be made out using TI of the drug, along with its plasma concentratiot value. t0 make it therapeutically effective. This approach is valuable fo drugs having a narrow absorption window and a narrow therapeutic rang concentration, The drug release pattern should be precise to achieve safe therapeutic rang" other factors, like drug accumulation due to frequent dosing and variability # Patients, can alter plasma level. By controlling the TI, the drug concentratio® can be controlled. 7Controlled Drug Delivery Systems (Chapter 1) 1.1.4. Advantages Controlled drug delivery system has the following advantages over a conventional dosage form: 1) Itimproves patient convenience and compliance by reducing the dosing frequency. 2) It reduces fluctuation in steady-state levels, and provides better control of disease condition and reduced intensity of local or systemic side effects. It increases the safety margin of highly potent drugs due to better control of plasma levels. It allows maximum utilisation of drug, thereby reducing the total amount of dose administered. It reduces the healthcare costs through improved therapy, shorter treatment period, reduced dosing frequency, and reduction in personnel time to dispense, administer and monitor patients. 6) It maintains the drug levels within the desired range. 7) It offers slow release of water-soluble drugs and fast release of low solubility drugs. 8) Iteliminates the incidences of over- or under-dosing. 9) It improves the efficiency of treatment. 10) It obtains less potentiation or deduction in drug activity with chronic use. 11) It reduces drug accumulation with chronic dosing. 12) It improves bioavailability of drugs. 13) It maintains the required drug concentration in plasma, and thus eliminates failure of drug therapy and improves the efficiency of treatments. 14) Itis a suitable delivery system for drugs having a short biological half-life (3- 4 hours) and for drugs that undergo rapid elimination from the body. 1.1.5. Disadvantages Controlled drug delivery system has the following disadvantages: 1) It decreases systemic availability (in comparison to immediate release conventional dosage forms) due to incomplete release, increased first-pass metabolism, increased instability, insufficient residence time for complete release, site-specific absorption, pH-dependent solubility, etc. 2) It shows a poor in vitro-in vivo correlation. It may give rise to dose dumping due to food, physiologic or formulation variables, or chewing of oral formulations by the patients, and thus, increases the risk of toxicity. Retrieval of drug is difficult in case of toxicity, poisoning, or hypersensitivity reactions. 4 5) It reduces the potential for dosage adjustment of drugs administered in varying strengths. 6) Its formulation cost is high. 7) Its drug release period is influenced and limited by GI residence time. 8) It shows poor patient compliance as drugs having short half-lives require frequent administration, and some patients may miss the dose.20 9) The unavoidable fluctuations of drug concentration may result in unde, ® over-medication in narrow therapeutic index drug. 10) It gives a typical peak-valley plasma concentration-time profile due to Whig attainment of steady state condition is impossible. 11) Its major disadvantage is dumping, i.e., rapid release of a relatively | quantity of drag from a controlled release formulation. This phenomenon hazardous with potent drugs. 12) It is difficult to optimise the accurate dose and dosing interval. 13) Patient variability, like GI emptying rate, residential time, fasting or nop, Novel Drug Delivery 5 4 Co) fasting condition, etc., affects the drug release rate. 1.1.6. Differences Between Conventional, Sustaineg Release, and Controlled Release Dosage Forms Table 1.1 enlists the major differences between conventional, sustained release, and controlled release dosage forms: Table 1.1: Differences Between Conventional, Sustained Release, and Controlled Release Dosage Forms Conventional Dosage Forms Sustained Release Dosage Forms Controlled Release Dosage Forms The drug solubilises in the gastric contents. These dosage forms do not sustain either their dissolution or their absorption. These dosage — forms maintain the drug release rate over a sustained period. These dosage forms lead to predictable and constant plasma concentrations, independent of the biological environment of 3 the application site. These dosage forms release the drug in a single action following a first-order kinetics. ‘The dose in these dosage |forms is of less significance than the release rate from the | therapeutic system. These dosage forms release te drug in a pre-determined patten over a fixed time _ peried following zero-order kinetics. These dosage forms are related to all types of dosage forms. These dosage forms are related to oral dosage forms. The dosage forms are related oral, vaginal and transdermal dosage forms. = The time interval versus drug plasma concentration profile for these dosage forms is short and show {peak and valley effect. The drug concentration for these dosage forms is maintained for a certain time period and then reduced. _ The uniform drug concentrate for these dosage forms if maintained for a pre-determine! S time period without fluctuations. 1.1.7, should not be formulated reduce their absorption rate, to an active metabolite. Conversely, drugs having a long biological half-life in a controlled release formulation, sin development of a controlled release fo: patient and improves patient compliance. Selection of Drug Candidates Selection of drug candidates for cont important. Drugs that under; in unless j trolled release dosage forms is vital! ‘go or may undergo hepatic first-pass metabolist a controlled release dosage form, because this ¥!! justified by the fact that this process gives "™ a little medical justification exists for (ie., > 12 hours) and are to be formulate! ce these drugs are long-acting, unless mulation offers some convenience (0 "Controlled Drug Delivery Systems (Chapter 1) u Ideal Properties of a Drug Suitable for Sustained Release Drug Delivery System (SRDDS) 1) Wshould get effectively absorbed on oral administration and should remain stable in gastrointestinal fluid 2) It should have a short half-life (2-4 hours), sulphate, etc. fy captopril, salbutamol 3) Its dose should not be less than .5em and its maximum dose for designing SRDDS should be 1.0gm, e.g, metronidazole. 4) It should have a wide therapeutic range so that any variation in drug release does not result in concentration beyond the minimum toxic levels. Compounds that are Unsuitable for Controlled Release Drug Delivery System (CRDDS) Certain drug candidates are not considered suitable to be formulated in controlled release dosage forms owing to some of their properties. For example, drugs with an elimination half-life < 2 hours, or drugs having large doses to administer within the body, or drugs having a half-life > 8 hours are not required to be formulated as controlled release dosage form. Thus, drugs with the following properties are considered inappropriate for designing CRDDS: 1) Drugs with a short and long half-life, 2) Drugs undergoing hepatic first pass metabolism, 3) Drugs with a low solubility, and 4) Drugs requiring to be administered in a large number of doses. 1.1.8. Properties of Drugs Relevant to Controlled Release Formulations The release rate of drugs from controlled drug delivery system are affected by the following two major factors: 1) Physicochemical factors, and 2) Biological factors. 1.1.8.1. | Physicochemical Properties The following physicochemical properties of the drugs should be considered while selecting drug candidates for controlled and sustained release dosage forms: 1) Molecular Size and Diffusivity: Drugs formulated in sustained release dosage forms should diffuse through various biological membranes and also through a rate controlling membrane or matrix. Diffusivity is a drug’s ability to pass through membranes, and it is a function of its molecular size or weight. Molecular size of the diffusing species has a significant influence on the diffusivity value (D) of polymers. Thus, the value of D is related to the size and shape of the cavities and of the drugs. The diffusion coefficient values of drugs having intermediate molecular weight (150-400), through flexible polymers, range from 10” to 10%cm*/sec; and the values in 10 order are the most common. The diffusion coefficient values of drugs having molecular weight >500 are so small (ie., < 10-i ificatio 12cm’/sec) that their quanti } molecular weight should display very slo h polym release devices where diffusion through poly! release mechanism. 2) Aqueous Solubility formulated into sustained rele: Drugs are mostly weal nis difficult. Thus, drugs hay, Novel Drug Delivery, ' ing ww release kinetics in Sus eric membrane or Matrix ing k acids or weak bases. p, i ‘ gs ase dosage forms with very difficulty ify te ility i ile, it is difficult to delay the dissolution rat solubility is low. While, it is di Ene x ai big 4 high water solubility and rapid aeoo) ution rae Drs hav a high water solubility readily dissolve in water or gas! inal fluid, released in a burst, are quickly absorbed, and thus their Concentration rn i blood is more than the drugs having low wate noi ‘ncorpratn highly water-soluble drug in the dosage form and re ar ra eg Tee is a difficult task, especially when the drug dose is high. The PH depen solubility in physiological pH range is another problem “ sustained rel dosage forms due to the variation in pH of GIT and in dissolution rate, 3) pH and pKa: Highly ionised drugs are poor candidates for Oral sustaings release formulations. Unionised drugs undergo appropriate absorption, whi the ionised drugs undergo negligible permeation as their absorption Fate is 3. 4 times less than that of the unionised drugs. An acidic drug with py. sensitive ionisation has a pKa range around 3.0-7.5; while a basic drug with PH-sensitive ionisation has a pKa range around 7.0-11.0; and such drugs ae ideal for optimum positive absorption. The site to an extent 0.1-5,0%. 4) Partition Coefficient: adjacent aqueous phase, Partition coefficient drug should be unionised at the is the fraction of drug in an oil phase to that ina t (K) influences drug permeation across the biological membranes, and also drug diffusion across the ra controlling membrane or matrix between the drug admini drug elimination time, The drug should di membranes that act as lipid-like barriers, coefficient is the major Permeability (i.e. its ability to penetrate expressed as: C. = Equilibrium concentration of all forms of drug in an organic phase at equilibrium, Cy= Equilibrium Concentration of all forms of drug in an aqueous phase, Generally, the drugs having a high K value Partition into the n Membranes, Hansch cori between tissue Permeation and Pattition correlation de: : cribes @ parabolic relati Partition coefficient (figure 1.1), a evaluation criterion. of ration time and ffuse through various biologicd Apparent oil or water partition the drug's membrane these fipid membranes), and is Figure 1.1: Relationship betwee Drug Action and Partition Coefficient are highly oil-soluble and read! Telation defines the relationsh? Coefficient for the drug. Tm ip between the logarithms of ! «Controlled Drug Delivery Systems (Chapter 1) 2B 5) Permeability: Log P, expressed lipophilicity, and molecular size of the drug are the three drug properties that influence the drug’s permeability for passive transport across intestinal epithelium. Another important factor that determines the drug permeability is the polarity of drug, which is measured by the number of H-bond acceptors and H-bond donors on the drug molecule, Mechanism and Site of Absorption: Drugs to be absorbed by carrier- mediated transport are not suitable to be formulated as controlled release systems. For exampl min B,» (a water-soluble vitamin) is required for several metabolic reactions and for preventing medical problems, especially hematopoietic conditions and spinal cord related nevropathies. Vitamin Bo, ingested in its free or non-protein bound form, will bind to a carrier protein, namely R-binders or trans-cobalamin I, that is secreted by the salivary glands in oropharynx and by the gastric mucosal cells in stomach. Drug Stability: Loss of drug through acid hydrolysis and/or metabolism in GIT is an important factor for oral dosage forms. A solid drug degrades at a much slower rate than a drug in suspension or solution form; thus, the relative bioavailability of a drug that is unstable in stomach can be improved. The most appropriate controlling unit for the drugs that are unstable in intestine is the one ses its contents only in the stomach; therefore, drugs with stability problems in any particular part of the GIT are considered as poor candidates to be incorporated into controlled release systems that deliver their content uniformly throughout the length of GIT. In controlled drug delivery systems, the drugs are protected from enzymatic degradation as they are incorporated into a polymeric matrix; thus, these systems are beneficial for highly unstable drugs. 6 7 1.1.8.2. Biological Properties The following biological properties of the drugs should be considered while selecting drug candidates for controlled- and sustained-release dosage forms: 1) Absorption: Rate, extent and uniformity of drug absorption are the factors that should be taken into account for a drug to be formulated into « sustained release dosage form. Drug release from a dosage form (and not absorption) is the rate-limiting step in drug delivery from a sustained rel ystem; thus, rapid rate of drug absorption relative to its release is essential for sn efficient system. In controlled release dosage forms, Kr <<< Ka, and this is critical in case of oral administration. If a drug’s transit time through the absorption half-life is 4 hours, a minimum absorption rate constant (Ka) of 0.17-0.23 hour is necessary for a drug to undergo 80-95% absorption over a transit time of 9-12 hours. A drug having a rapid absorption rate (ie., Ka >> 0.23-1 hour) has the first-order release rate constant (Kr) < 0.17-1 hour, and this results in poor bioavailability in many patients. Therefore, slowly absorbed drugs are difficult to formulate as controlled release dosage forms, in which the drugs should essentially meet the Kr <<< Ka criteria. 2) Distribution: Drug distribution in tissues and cells lowers the concentration of circulating drug and can also be rate-limiting in its equilibrium with blood and extravascular tissue, thus it majorly affects the drug elimination kinetics. Distribution involves binding of a drug to the tissues and blood proteins. Protein-bound drug molecules are inactive and cannot permeate the biological3) 5) 6) Novel Drug Delivery ¢ Sy =i ding results in pp . ; of protein binding Pron 1e of vetribution (an important param, Re ‘ in binding in the bog, ."! * distribution and protein bin ody, the drugs) is the magnitude of Se ang concentration to the total ae iy the proportionality constant of pl i ie sustained release system, of drug in the body. Thus, Pret 10 TAT disposition. » Oe should gather information regarding " - s bind to plasma proteins and show relay Protein Binding: Many drugs Drug bound to blood proteins“! effects on the duration of drug action. Timinated). Drug bound to na mostly re-circulated (rather than getting elimunatee Plasn, 7 for a prolonged release of drug. The rate proteins serve as a drug depot for a pt by theidrile-interact ang extent of oral absorption of drug is also affected Ny 8 interaction ay; the binding period with mucin-like protein. : Metabolism: Drug metabolism involves either inactivation of an active dry or conversion of an inactive drug into an active metabolite. It Occurs ig various tissues, containing more enzymes. Drugs that get metabolised before absorption, either in the lumen or in the intestinal tissues, are Teleased aty slower rate, and thus result in reduced bioavailability. The intestinal wa enzyme systems are mostly saturable. As the drug is released to these regions at a slower rate, less total drug is presented to the enzymatic Process during « specific period, and thus the drug completely converts into its metabolite Formulating these enzymatically-susceptible compounds as prodrugs is another feasible solution. Drugs that can induce or inhibit enzyme synthesis are considered as poot ‘ candidates for sustained release delivery systems as they cannot maintain uniform blood levels. Also drugs whose bioavailability varies due to hepatic Ng first-pass metabolism or intestinal metabolism are not considered suitable candidates for sustained release delivery systems. Elimination or Biological Half-Life: An oral sustained release product aims to maintain therapeutic blood levels for an extended time period. For this, the drug should enter the blood circulation at a rate similar to its elimination rat ' (quantitatively described by the half-life), Each drug has its owl characteristic elimination rate, which is the sum of all elimination processes, ie., metabolism, urinary excretion, and the processes that eliminate the dr from blood circulation. Drugs having a short half-life are considered the bes! for sustained release delivery systems, as this reduces the dosage frequens} However, drugs having a very short biological half-life have limited use ® extremely large amounts of drug are required in each dosage unit in ordet ® maintain the sustained effect, thereby maki ieniting Jt In other words, drugs having a half he nine he dosage form limiting alf-life < 2 hours are considered unsuitib® cS rar deen Systems. Drugs having a long half-life, ie»? , considered unsuitabl i ie as their effect is already Sustained, © Rev uiainel lease einen 9 Duration of Action: The drug’ i i i g's dura the formulation of controlled release metabolism, and elimination of the drs of action. Half-life of the dra; a membranes. Also, a high degree therapeutic action. Apparent volum in action plays a significant ree delivery system. Distribut® ia ag UUB however, affect the drugs’ du" 5 18 ils residence time in the body. Drugs h#™Controlled Drug Delivery Systems (Chapter 1) 25 higher elimination half-lives (> 8 hours) are already sustained in the body, and thus are not formulated as controlled release dosage forms. On the other hand, drugs having shorter half-lives (< 2 hours) are also not formulated as controlled release dosage forms as it may require large amounts of drug. 7) First-Pass Metabolism: It is the intestinal and hepatic degradation or alteration of an orally administered drug, after its absorption, removing some of the active substances from the blood before it enters the systemic circulation. Liver is the major site of first-pass metabolism of an orally administered drug; however, GIT, blood, vascular endothelium, lungs, and the arm from which venous samples are taken are other potential sites. Amitriptyline, 5-fluorouracil, hydralazine, isoprenaline _ lignocaine, lorcainide, pethidine, metoprolol, morphine, neostigmine, nifedipine, pentazocine, and propranolol are the examples of drugs that undergo first- pass metabolism. Drugs undergoing extensive hepatic first-pass metabolism when administered in controlled release forms are not delivered to the body in desired concentrations. Drugs whose bioavailability varies due to first-pass metabolism cannot be easily formulated as controlled release systems as the problem of drug loss would be dose-dependent, and this will reduce the bioavailability if the drug is slowly released over an extended time period. If a drug undergoes extensive first-pass metabolism, the blood concentration to achieve the desired therapeutic effect is adversely affected. 8) Size of the Dose: For drugs to be administered orally, there is an upper limit to the bulk size of the dose. A single dose of 0.5-1.0gm is generally considered maximal for a conventional dosage form as well as for sustained release dosage forms. Drugs requiring large dosing size can be given in multiple amounts or formulated as liquid systems. The safety margin involved in the administration of large amounts of a drug with narrow therapeutic range is also considered. 9) Dosing Frequency: It is the number of times a drug dose is administered within a specific time period. The dose frequency is reduced in well-designed controlled release delivery systems. Also, such systems maintain the steady drug concentration in blood and in target tissue cells. For example, nanoformulation of natamycin suspension (5%) has reduced the dosing frequency; the initial dosing frequency was one or two drop(s) hourly, and this reduced to one drop in every 5 hours; this reduced the dose to one-fifth of the initial one, prolonged the release of natamycin, and also improved Patient compliance. 10) Margin of Safety/Therapeutic Index: It is the ratio of median toxic dose to median effective dose. Therapeutic index = LDso/EDso 11) A drug is considered to have a high safety margin if its therapeutic index is more than 10; thus indicating that larger the ratio, more safe is the drug. Safety margin of the drugs determined on the basis of therapeutic index is the range of plasma concentration in which the drug is considered to be safe