Controlled drug delivery system Part 1

Introduction, Definitions, Advantages and Disadvantages, Selection of drug candidates for designing controlled drug release systems and rationale biological and medical rationale

1. NL1 CONTROLLED DRUG DELIVERY SYSTEM Introduction, Terminology/Definitions and Rationale, Advantages, Disadvantages, Selection of drug candidates PART - I Nabeela Moosakutty Lecturer Dept. of Pharmaceutics K.T.N College of Pharmacy

2. INTRODUCTION What is Drug Delivery System? Drug delivery refers to approaches used to deliver drugs at the target sites inside our body An Ideal drug delivery system should be Inert Biocompatible Mechanically strong Comfortable for the patient Capable of achieving high drug loading Safe from accidental release Simple to administer and remove Easy to fabricate and sterilize

3. Overview of the drug delivery system development from basic research to clinical applications. The main components of drug delivery systems and processes are shown in bold face and a solid box, and subsections of each component are shown in a dotted box

4. Limitations of Conventional Drug Delivery Systems Poor patient compliance as the complete dosage regimen needs more than twice or thrice a day administration, which multiplies the chances of missing a dose, especially in the case of geriatric and pediatric patients Due to the frequent dosing with fluctuating drug concentration-time intervals between the doses, the plasma drug concentration profile encompasses a combination of alternate peaks and valleys, which posses a prominent hindrance for the attainment of the desired steady-state profile Due to the immeasurable fluctuations in plasma drug concentration profile, there may be chances of under or overmedication , that is, at certain points during the therapy the plasma drug concentration may fall below the minimum effective concentration or may rise above the maximum safe concentration

5. What is Novel Drug delivery System? Novel Drug delivery System (NDDS) refers to the approaches , formulations , technologies and systems for transporting a pharmaceutical compound in the body as needed to safely achieve its desired therapeutic effects Simply, NDDS is a system for delivery of drug other than conventional drug delivery system NDDS is a combination of advance technique and new dosage forms which are far better than conventional dosage forms Advantages of Novel Drug Delivery System are: Optimum dose at the right time and right location Efficient use of expensive drugs Excipients and reduction in production cost Beneficial to patients with better therapy and improved comfort Basic modes of Novel drug delivery systems are: Targeted Drug Delivery System Controlled Drug Delivery System Modulated Drug Delivery System

6. The conventional dosage forms, for example, tablets and capsules, provide only a single and transient bursting of the drug The problem arises when the results obtained from drugs are above the limit of the range. So, one of the main reasons for development of CRDDS is to reduce side effects and improve the safety of drug usage CRDDS employs drug-encapsulating devices from which therapeutic agents may be released at controlled rates for long periods of time , ranging from days to months Mechanism of CRDDS Controlled Drug Delivery System

7. What is the difference between SRDDS and CRDDS? Sustained release dosage forms follow first order kinetics whereas Controlled forms follow zero order kinetics In sustained forms the dosage is sustained for prolonged period of time and drug release is not definite per unit time but in controlled forms, drug release is very definite per unit time Synonyms CRDDS: Programmed release, Timed release, Repository dosage forms SRDDS: Prolonged release, Extended release, Depot formulations

8. To get a basic idea of CDDS

9. Drug levels in the blood with- Traditional drug dosing The level rises after each administration of the drug and then decreases until the next administration Controlled delivery dosing

10. TERMINOLOGY/ DEFINITIONS

11. Controlled Drug Delivery System ADVANTAGES Tailoring of drug release rates Protection of fragile drugs Increased patient comfort and compliance Enhanced efficiency Favorable reach in plasma levels Breached side effects and Adverse reactions System imparts long-term action Greater drug potential Interprets the movement of drugs across biological membranes and ensures a better understanding of drug transport methods Carriers delivering drugs to specific target sites More uniformity in effect Reduction in total drug usage when compared with conventional therapy Reduction in drug accumulation with chronic therapy Stabilization of medical condition (because of more uniform drug levels) DISADVANTAGES Possible toxicity or non-biocompatibility of the materials used Undesirable by-products of degradation Surgery required to implant or remove the system Chance of patient discomfort from the delivery device Delay in onset of drug action Possibility of dose dumping in the case of a poor formulation strategy Increased potential for first pass metabolism Greater dependence on GI residence time of dosage form Possibility of less accurate dose adjustment in some cases Cost per unit dose is higher when compared with conventional doses Not all drugs are suitable for formulating into CR dosage form

12. Comparison between Conventional and Controlled release system

13. Parameters to be considered while designing into CRDDS

14. Properties of a drug that make it unsuitable for designing CRDDS Selection of drug candidates for CRDDS Some properties of drug candidates make it a poor choice for consideration in designing of the controlled release system

15. Rationale for Designing Controlled Drug Delivery Systems Rationale: An underlying reason – the basis It is a necessary justification for any scientific study 2 types Medical Rationale Biological Rationale Medical Rationale Reduction in Dosing Frequency Lesser Drug Exposure to the Biological Environment Minimal blood plasma concentration fluctuation Better Patient Compliance Lower Adverse/Side Effects Augmented Efficacy Biological Rationale Absorption Drug protein binding Distribution Elimination Dose dependent bioavailability Duration of drug residence Better safety margin Individualization in a diseased condition

16. 1. Reduction in Dosing Frequency The conventional therapy usage shows a limitation of frequent dosing, that is, a chance of skipping a dose ; this problem can be reduced if the dosage forms are developed into CRDDS form thereby releasing the drug for a long time and maintaining the drug concentration in blood When the time period between the doses is increased, the number of doses is reduced from 34 times to 12 times. The novel systems like proteins and peptides can be delivered into the body using a controlled delivery approach. Tumor therapies also can be improved by enhanced targeting Medical Rationale

17. 2. Lesser Drug Exposure to the Biological Environment The basic rationale behind the CRDDS is the alteration of active metabolites either pharmacokinetically or pharmacodynamically by using new drug delivery approaches or by modifying the molecular structure and or physiological parameters The controlled release of a drug can be achieved by either temporal control or by distribution control Temporal control: Enables the system to deliver the drug over an extended time for a specific period within the treatment regimen. This control proves to be beneficial for the drugs with a fast metabolism Distribution control : Involved in the targeted delivery of the drug in the body (i.e.; to control the concentration of drug on the cells and tissues of target sites) various drugs like steroids, antibiotics, and hormones benefit from both of these approaches of CRDDS

18. 3. Minimal blood plasma concentration fluctuation Minimization of Plasma Concentration Fluctuations With the use of conventional tablets or capsules there occurs only a single and transient type of burst, when the effect of the drug is above minimum effective concentration. The response is observed pharmacologically, but when the response is narrow a problem arises; in this case CRDDS reduce fluctuation in plasma levels by retarding the rate of absorption, which is accompanied by slower drug release The modification of drug formulation should be achieved in such a way that fluctuations during the dosing interval are reduced . This approach is required for the drugs having short half-lives and low therapeutic index , for which maintenance of therapeutic drug concentrations are mandatory. This approach results in better patient compliance and reduced chances of toxicity Ex: Procainamide and Quinidine

19. The development of any dosage form deals with the aim of providing better patient compatibility The designing of a drug dosage regimen influences the duration of action of the drug. Factors like bioavailability, absorption rate, and elimination rate content affect the therapeutic response of a dosage form The CRDDS are the ideal drug delivery system to deliver the drug at the needed part of the body over a period a time and have a clear relationship between the plasma concentration levels and the therapeutic response thereby improved patient compliance To improve the bioavailability and therapeutic response of drugs in the body the drugs that are unstable through the oral route are administered through a different route, for example, nitroglycerine The CRDDS is more sophisticated than merely delaying the release, it delivers the drug with controlled release rates within the specific time period. This system maintains the drug levels within the required range, requiring few administrations 4. Better Patient Compliance

20. 5. Lower Adverse/Side Effects In conventional dosage forms, the dose and dosing intervals of each drug are varied. Each drug shows a different therapeutic response in plasma concentrations; the unbalanced response can result in improper therapeutic effect or unwanted side effects Generally, with rate-controlled dosage forms, the dosing intervals are increased and fluctuations in plasma levels are decreased thereby decreasing the risk of unwanted side effects The occurrence of side effects is a part of drug plasma concentration and its properties , which can be minimized by handling drug concentration in plasma at a particular time Example: Levodopa, when administered in the form of CRDDS, reduces the possibility of dyskinesia caused by the drug The CRDDS are able to reduce side effects occurring in the GIT and are known to produce effective results Example: the drug candidates like potassium chloride and ferrous sulfate tend to cause irritation in the GIT, but on slowing the release of these drugs the irritant effect can be reduced

21. Physicochemical Properties of Drug – occurrence of side effects Different physicochemical properties of drug-like solubility, partition coefficient, and its stability tend to affect the therapeutic responsiveness of a drug and occurrence of side effects Dissolution of the drug in body fluids is the first step required in the drug delivery process; the drug molecules with low solubility in aqueous medium additionally manifest poor bioavailability. Hence, a drug should be extensively dissolved at a rapid dissolution rate to achieve utmost convenience in therapeutic response Partition coefficient explains the distribution of the drug in two phases, between the lipid phase and water phase. This property demonstrates permeation of drugs through biological membranes and its interaction with receptors

22. The higher value of partition coefficient enables a drug to penetrate easily through membranes but does not enable it to process further because of a lack of affinity with aqueous surroundings The drug candidates with low partition coefficient value show a greater affinity towards the aqueous surroundings of the body but cannot reach the biological membrane. So to achieve a proper distribution of drug among biological membrane an optimum range of partition coefficient value is required After administration of the drug into the body, the body fluids come in contact with the drug and affect its stability . During this event, the drug is likely to face the chemical and enzyme degradation, which can cause a reduction in performance of the drug within the body. The drugs that show poor stability in acidic pH can be coated with enteric polymer materials to bypass the acidic pH effect in the stomach and can release the drug in the lower gastrointestinal tract. The drugs can also be modified chemically to form prodrugs , to be protected from enzymatic cleavage reactions. Also the molecular interactions among drugs, drugs and metals, and drugs and proteins show important factors that can bring a change in the pharmaceutical performance of a drug candidate. These factors should be considered while designing CRDDS

23. 6. Augmented Efficacy While designing the ideal drug delivery system two requisites are necessary to fulfill The drug should get delivered at a rate that a body requires over a period of time The action should be at the specific site at specific receptors The CRDDS can achieve these goals. These systems are capable of maintaining the drug level in the body for the extended time period 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 affects and improves the overall efficacy of the CRDDS The reduction in fluctuations of plasma drug concentration is desirable for constant drug levels, which can be achieved by reducing the adverse effect and by increasing minimum effective concentrations and thereby increasing the efficacy

24. BIOLOGICAL RATIONALE FOR CRDDS Absorption For developing a CRDDS the extent and rate of absorption of the drug are very important factors. Drugs with a very slow rate of absorption show poor bioavailability, which in turn makes them poor candidates to be formulated into CRDDS The drug candidates with more rapid absorption than release promise a successful controlled release product formulation Absorption window (they need transporter- mediated absorption or only soluble at particular pH) is another factor that affects the bioavailability of orally administered drugs and can be a hindrance to the development of conventional drug delivery system. This is because some drugs have the property of absorption in a specific region of the GIT, which after absorption in the absorption window can go waste

25. Absorption efficiency differs throughout the GIT, which directly affects the extent of drug absorption from the site. Most of the drugs are poorly soluble and poorly permeable, thereby less absorbable. Thus, in such cases, the use of CRDDS enables them to be carried out into the cell easily The release of the dosage form is a rate-limiting step in case of CRDDS rather than absorption . The amount of drug absorbed from conventional dosage forms can be low compared with CRDDS due to various reasons like degradation or metabolism or physical loss For example, Pilocarpine gets absorbed across the cornea in about 1% ratio of applied dose; the loss occurs due to drainage and absorption in nonspecific tissue. The prepared controlled release product improves its bioavailability and maintains a constant level of drug in specific tissue for the time required

26. 2. Drug-Protein Binding One of the major problem with conventional dosage form is the lesser availability of the drug in the blood due to higher protein binding. This binding decreases the action of drug and thereby the effective therapeutic effect diminishes But in case of CRDDS, the problem can be solved by formulating it in several carriers which will further help in delivering the drug in required quantity at the desired site The binding of the drug with proteins is a reversible process. With the decrease in the concentration of the drug in the blood the drug-protein complex dissociates and leaves free drug to maintain balance. This reversible process of drug binding maintains the drug level in the blood for a long time. The binding of the drug with protein can function as a drug store for generating long-term action For example, the blood proteins keep recirculating in the body and are not eliminated; they act as a depot for drug candidates showing controlled release profile. The quaternary ammonium compounds have the tendency to bind with mucin in the GIT, and the drugs that get bound to mucin act as a depot and enhance the absorption

27. 3. Distribution The drug distribution in the body is an important criterion in determining the overall elimination kinetics of the drug The distribution comes with the drug binding to tissue and protein in circulation. Generally the drug in the bound condition is termed as inactive and is not able to cross the membranes The high binding of the drug shows the prolonged release For designing of the CRDDS, one needs to have knowledge of drug disposition but the fate is usually decided on the basis of pharmacokinetic parameters such as volume of distribution (Vd). It plays an important rol e as it affects the amount of drug in systemic circulation or reaching the target. The drugs having a volume of distribution (Vd) higher than the real volume of distribution show lesser half-life The Vd affects the concentration of the drug in the blood also it has effects on elimination kinetics of a drug candidate. The information on Vd allows to act as a guide for studies in drug dosing. The distribution property of a drug is described well by Vd by either extent of distribution in the body or by relative distribution of the drug in compartments

28. These two parameters are independent of each other, for example The relative distribution of procainamide is almost 10 times that of pentobarbital though the volume of distribution for both the drugs is the same Similarly, the relative distribution for procainamide is much larger than digoxin and the volume of distribution at steady state is lower than that of digoxin Distribution from the conventional dosage form directly gets distributed throughout the body, and gets accumulated to some of the off- sites, which may lead to toxicity. Such instances can be prevented by CRDDS, which can be specific and site- targeted and thus preventing accumulation in other sites and also helps the complete drug to be reached to the required site 4. Elimination The elimination of most of the drugs occurs within 20 h of administration. The zero order rate of release is directly proportional to the rate of elimination and is given by the biological half-lives; the drug candidate with short half-life requires frequent dosing making it desirable to be prepared into CRDDS and the case is opposite with drugs having a long half-life The drugs with a half-life less than 2 h and more than 8 h are not suitable for developing into a CRDDS. For example drugs with a half-life, less than 2 h include ampicillin and penicillin whereas drugs with half-life more than 8 h include digitoxin and digoxin

29. 5. Dose-Dependent Bioavailability Another factor influencing the design of CRDDS is the effect of dose Due to low bioavailability of most drugs, higher and sometimes repeated doses are given at certain intervals of time. This leads to patient inconvenience and most importantly the changes of missing the dose. Such problems can be eliminated by using the CRDDS as the tool For example, due to the dose of procainamide , it has to be administered after every 3 h to reduce fluctuations in plasma drug level. The CRDDS of procainamide is able to maintain plasma level for a period of about 8 h Bioavailability is another important criterion in consideration for the formulation of CRDDS. A drug candidate like propoxyphene whose bioavailability is dose dependent restricts its use in CRDDS, because of the rate at which CRDDS should be able to achieve reproducible bioavailability. It is desired that the CRDDS formulation should be able to show around 80% of bioavailability than that of the conventional dosage form

30. 6. Duration of Action/ Drug Residence (Half-life) The pharmacokinetics of a drug in a steady state concentration implies that the release rate of the drug is directly proportional to its elimination. The drugs showing linear kinetics have a constant half-life and do not follow a change. Mostly the factors that influence the half-life of drugs are metabolism, distribution, and elimination Within the Therapeutic Window The duration of drug residence and the half-life of the drug play an important role in the designing of CRDDS. Most of the drugs available in the market show half-life of around 20 h. The drugs having short half-life require frequent dosing to maintain drug plasma concentrations. So, for such drugs, CRDDS are desirable. In case of higher half-life, the CRDDS approach is not required, as it already have the ability to remain in the body for longer periods For example, due to the dose of procainamide , it has to be administered after every 3 h to reduce fluctuations in plasma drug level. The CRDDS of procainamide is able to maintain plasma level for a period of about 8 h

31. 7. Better Safety Margin In conventional dosage form, the margin of safety is quite low compared to CRDDS, due to accumulation at off-sites, less target specific, protein binding etc. When it comes to safety, again the major concern comes is the elimination of the polymers and other excipients used in the CRDDS without accumulation or side effects The types of polymers used must be biodegradable enough so that the alternate effects of its metabolites are less and without toxic effects Among myriad approaches to defining the safety margin of drugs, the therapeutic index (TI) is the most common criteria to be followed This ratio merely provides a crude estimate of the relative safety of drugs; the drug candidate is considered safe if the TI is in value exceeding 10. The larger the ratio is, then safer the drug This approach plays an important role in the monitoring of a drug therapy, especially in case of those drug candidates that have either narrow therapeutic index or have narrow therapeutic concentration like antiarrhythmic drugs (e.g., digoxin and digitoxin)

32. 8. Individualization in Diseased Condition The Individualization in disease state of a body is not among drug characteristics but it is an important part in consideration of drug candidate for CRDDS Individualization: Patient research by themselves (if requested patients should be given information about the purpose, harms and benefits of particular treatment) Individual needs- From burdensome medication regimens (as in Long term treatment) For example, aspirin is still used in RA for treatment but is not considered as a good candidate in conventional drug delivery due to its biological half-life (6 h). Whereas a controlled dosage form tends to maintain a therapeutic concentration and is able to provide release up to 10 h, which is more than non-controlled formulation The safety margin of the drug can be made out using TI of the drug along with its plasma concentration value, to make it therapeutically effective. This approach is valuable for the drug with a narrow absorption window and narrow therapeutic range concentration The pattern of drug release should be precise, to achieve safe therapeutic range; also other factors like an accumulation of drug due to frequent dosing and variability in patients can alter plasma level. By controlling the TI is possible to control drug concentration