Drug Delivery Systems PDF - Fall 2023

Chapter 1: Drug Delivery system DRUG CARRIERS: LIPOSOMES Drug Delivery Systems Msc Suhad Anabousi 070114120 Fall 2023  2 INTRODU...

Chapter 1: Drug Delivery system DRUG CARRIERS: LIPOSOMES Drug Delivery Systems Msc Suhad Anabousi 070114120 Fall 2023  2 INTRODUCTION  Attention has been focused on the development of new drug delivery systems for the following reasons:  Therapeutic efficacy & safety of drugs administered by conventional methods can be improved by precise spatial and temporal placement within the body, thereby reducing both the size and the number of doses.  Possibility of re-patenting successful existing drug by applying the techniques and concepts of CDDS.  The increasing expenses in bringing new drugs to the market has encouraged the development of new DDS.  New systems are needed to deliver the novel, genetically engineered pharmaceuticals (Biopharmaceuticals, Peptides & Proteins) to their sites of action without significant immunogenic or biological inactivation.  Treatment of enzyme deficient diseases and cancer therapy can be improved by better targeting.  3 DRUG DELIVERY  Drug delivery refers to approaches, formulations, technologies, and systems for transporting a pharmaceutical compound in the body as needed (place and rate) to safely achieve its desired therapeutic effect.  Drug delivery is concerned with both quantity and duration of drug presence inside the body.  Drug delivery is often approached via a drug’s chemical formulation (prodrug), but it may also involve medical devices or drug-device products.  Drug delivery is a concept heavily integrated with dosage form and route of administration.  4 DRUG DELIVERY TECHNOLOGIES  Drug delivery technologies modify drug release profile, absorption, distribution and elimination for the benefit of improving product efficacy and safety, as well as patient convenience and compliance.  Current efforts in the area of drug delivery include the development of: 1. Controlled release drug action, in which drug is released from formulation in controlled manner.  sustained, delayed, pulsed. 2. Targeted delivery systems, in which the drug is only active in the target area of the body.  important in cancer therapy. 3. Localized drug action, in which the action of the drug is confined to a particular diseased tissue or organ (i.e., spatial control).  intrauterine device & ophthalmic drug delivery (Ocuserts)  5 1. CONTROLLED RELEASE FORMULATION  When the drug is either injected or ingested into the body, the systemic drug level could exceed the therapeutic level for a brief period of time then gradually declines to ineffective levels.  This could lead to a fluctuation in the drug level which is undesirable, specially in potent drugs with low level of therapeutic index.  The magnitude of these fluctuations depends on the rate of drug absorption (Kabs), distribution, rate of drug elimination (Kel) and on dosing intervals.  Therefore, plasma drug concentration may not be maintained above the minimum therapeutic level for a very long period of time.  The administration of another dose, before the entire drug of the first dose has been eliminated, results in the drug accumulation in the body, which could reach a concentration above the toxic level.  6 1. CONTROLLED RELEASE FORMULATION  Each drug has a therapeutic window in which the drug - plasma concentration below the therapeutic level is insufficient and above which results in undesirable or toxic effects.  In the ideal profile, the therapeutic concentration of the drug is maintained relatively constant during the whole length of treatment.  7 1. CONTROLLED RELEASE FORMULATION  To achieve ideal profile, the drug should be given continually to the body in a way that the Kel = Kabs.  Controlled release systems can reduce undesired fluctuations of drug levels, thus diminishing side effects while improving the therapeutic outcomes. Immediate- versus controlled-release dosage form  8 THE TERMINOLOGY OF DRUG DELIVERY AND TARGETING  The terminology describing drug delivery and targeting is extensive and ever-growing.  Systems are diversely referred to as “controlled release”, “sustained release”, “zero- order”, “reservoir”, “monolithic”, “membrane-controlled”, “smart”, “stealth” (RES) etc.  Unfortunately, these terms are not always used consistently and, in some cases, may even be used inaccurately.  9 THE TERMINOLOGY OF DRUG DELIVERY AND TARGETING  Some common terms could be defined as follows: 1. Prolonged/sustained release: the delivery system prolongs therapeutic blood or tissue levels of the drug for an extended period of time. 2. Zero-order release: the drug release does not vary with time; thus the delivery system maintains a (relatively) constant effective drug level in the body for prolonged periods. 3. Variable release: the delivery system provides drug input at a variable rate. 4. Bio-responsive release: the system modulates drug release in response to a biological stimulus (e.g. blood glucose levels triggering the release of insulin from a drug delivery device).  10 THE TERMINOLOGY OF DRUG DELIVERY AND TARGETING  Some common terms could be defined as follows: 5. Pulsatile-release: the systems releases the drug in pulse(s), according to the circadian rhythm of the body, where a constant drug release is not desired.  (release insulin as needed) 6. Delayed release: the system releases a discrete portion or portions of drug at a time other than promptly after administration (e.g. enteric coated).  This would ensure that the drug is released into the body at the correct time which may solve compliance issues as drug administration in the middle of the night.  (nocturnal asthma) 7. Modulated/self-regulated release: the system delivers the necessary amount of drug under the control of the patient.  11 THE TERMINOLOGY OF DRUG DELIVERY AND TARGETING  Some common terms could be defined as follows: 8. Temporal-drug delivery: the control of delivery to produce an effect in a desired time-related manner. 9. Spatial drug delivery (Targeted delivery systems): the delivery of a drug to a specific region of the body (thus this term encompasses both route of administration and drug distribution).  The term “drug delivery system” (DDS) is used as a general term to denote any type of advanced delivery systems, which represent a more sophisticated system and may incorporate one, or a combination, of advanced technologies such as rate- control, pulsatile release or bio-responsive release to achieve spatial and/or temporal delivery.  12 COMMONLY USED ABBREVIATION Abbreviation Meaning Abbreviation Meaning CD Controlled delivery MR Modified release CR Controlled release SA Sustained action (may mean short-acting) DR Delayed release SR Sustained release ER (XL, XR, XT) Extended release TR Timed release IR Immediate release LA Long-acting ES and XS Extra strength LAR Long-acting release (used as suffixes; but refer to dose rather than release rate)  Note that there is no industry standard for these abbreviations, and confusion & misreading have sometimes caused prescribing errors.  13 2. TARGETED DRUG DELIVERY  Conventional dosage forms normally medicate the whole body, reaching healthy areas as well as diseased ones.  The effect of a drug on the body results from its action on a target (or receptor) site, whereas toxic effects or undesirable side effects result from the drug action on non- target sites.  Some drugs are specific in their action (as hormones & enzymes) and interact with receptors that are located in only one or few cell types.  However, many drugs are not specific and interact with both target and non-target cells.  14 2. TARGETED DRUG DELIVERY  The availability of a drug molecule to the cell is governed by a sequence of pharmacokinetic processes including drug release, absorption, distribution and elimination, which could result in inefficient bioavailability of the drug to target tissues.  The administration of high drug doses (to compensate for incomplete absorption, first pass metabolism, and distribution to non-target sites) can result in high drug levels that could be associated with local & systemic side effects.  Actually, the dose in conventional dosage forms is always in excess than the body needs, in order to achieve the therapeutic effect, which could result in toxic effects in non-target tissues.  15 2. TARGETED DRUG DELIVERY  As a result, new controlled drug delivery systems are now available for restricting drug action to the target sites (i.e., where it is needed).  Thus, improving the quality of treatment by promoting the therapeutic effect of drugs and minimizing their undesirable toxic effects; by increasing the amount of drug in target cells while reducing its concentration in non-target tissues.  Drug targeting is very important particularly in cases of cancer chemotherapy, treatment of intracellular parasitic diseases, gene therapy and enzyme replacement therapy.  These dosage forms could be immediate or extended-released (i.e., one can combine the technology of drug targeting and controlled release).  16 2. TARGETED DRUG DELIVERY  Definition: Targeted drug action includes the use of carriers to exclusively deliver drugs to particular or selected target cells.  Examples of drug carriers (natural & synthetic) are: albumin, antibodies, liposomes, micro/nanoparticulate carriers, cyclodextrins, viruses, and RBCs, in which the drug may be bound to the carrier by covalent or non covalent link.  In vivo distribution of drug-carrier complexes is dictated by the physicochemical properties of the carrier alone (and not the drug).  Carriers could be specific or non specific in their distribution.  17 2. TARGETED DRUG DELIVERY  Specific distribution:  when there is chemical recognition between the carrier and the target site (e.g. antibodies).  None-specific distribution depends on the following properties of the carrier:  Size and size distribution.  Lipophilicity/ hydrophilicity  Surface charge  Carriers could also provide the following advantages:  Protect encapsulated drugs from premature degradation.  Protect the body from the immunogenicity and antigenicity of encapsulated proteins or peptides.  Help save drugs of limited supply.  Enhance the solubility of incorporated drugs.  18 Antibodies DRUG CARRIERS Stealth A Liposome (unilamellar) Matrix A Micelle / single chain  19 3. LOCALIZED DRUG ACTION  Site of application is the site of action.  Localized drug action involves placing the delivery system directly into the affected tissue/ or organ.  One can combine the technology of localized drug action with controlled release.  Actually, it is usually a rate controlled dosage form.  Localized drug action is important in case of anticancer and anti-fertility drugs (IUDs).  Other examples include ophthalmic drug delivery (Ocuserts), dermal therapy, treatment of local GIT problems, and drug delivery to the lower respiratory tract.  20 THE RATIONAL OF CDDS  On summary, an ideal drug delivery system should:  Deliver the drug at a rate dictated by the needs of the body over the period of treatment  Direct the drug solely to the site of action; or localize the drugs to a diseased tissue or organ.  Thus, the basic rationale for CDDS is to alter the pharmacokinetics of the drug by using novel delivery systems, or by modifying the molecular structure of the drug or a physiological parameter inherent in a selected route of administration. In order to:  Control drug delivery, ensure safety and improve efficacy of drug as well as patient compliance.  21 AVAILABLE DRUG DELIVERY SYSTEM  At present, there are no available drug delivery system that could achieve all these goals:  Conventional and prolonged-released dosage forms are unable to control either the rate or the site of action, while controlled release dosage forms are capable of delivering drugs at some predetermined rate either systemically or locally for specific period of time.  In order to maintain a constant drug level in plasma or target tissue, the release rate from the controlled release dosage form should be equal to the elimination rate from plasma or target tissue.  The most conventional method of achieving constant plasma levels is by using IV infusion.  However this is inconvenient for most therapeutic situation.  Thus other non-invasive routes as oral and transdermal are preferred.  22 TYPES OF THERAPEUTIC SYSTEMS  Three types of therapeutic systems are available:  Passive pre-programmed: in which the release rate is predetermined and is irresponsive to external biological environment.  Active pre-programmed: in which the release is altered by a source external to the body.  include most metered insulin pumps, whose release rate can be altered by a source external to the body  Active self-programmed: which modulate drug release rate in response to information registered by a sensor. sensor, on the changing biological environment such as blood sugar level in diabetes  23 ADVANTAGES OF CONTROLLED DRUG DELIVERY SYSTEM  Rationale for controlled release dosage forms 1. Reduction of dosing frequency. 2. Reduction of fluctuation of circulating drug levels. 3. Avoidance of night time dosing and decreasing patient care time. 4. Enhancing therapeutic action of certain drugs by appropriate control of drug levels, where continuous exposure of drug to target cells is provided. Reduction of undesirable local &/or systemic side effects, such as GI irritation and drowsiness. 5. Increasing patient acceptance and compliance, specially to long term therapy, and thus improving the success of therapy.  The success of therapy depends critically on the ability of the patient to comply with the drug regimen; noncompliance is a common cause of failure to respond to drug treatment that can specially occur with long term therapy.  24 PATIENT COMPLIANCE  Many factors would affect patient compliance such as:  Awareness of the disease process.  Faith in the therapy.  Understanding the need to adhere to strict treatment schedule.  Complexity of the regimen.  Cost of the therapy.  Magnitude of local and systemic side effect.  25 PATIENT COMPLIANCE  The problem of lack of patient compliance can be resolved with the use of CDDS by the following:  Minimizing the need for frequent drug intake and thus reducing the complexity of regimen and patient care time.  Avoidance of night-time doses which makes the treatment more convenient to the patient.  Minimizing local and systemic side effects of drugs.  Improving the efficacy of treatment and obtaining uniform pharmacological responses.  The unit cost of medication may be reduced (and may be not !!!!!!!!!!!!!!!).  26 ECONOMICAL ADVANTAGES  Economical advantages:  The low cost of introducing new DDS of existing successful drugs compared to introducing new drugs to the market.  The FDA requirements for new DDS are less restricted compared to those for introducing new drugs.  Re-patenting the existing successful drugs with new DDS.  27 LIMITATION OF CONTROLLED DRUG DELIVERY SYSTEM  Some of the following limitations are sometimes restricted to certain routes, while others are general: 1. Possibility of dose dumping (an un-intentional release of the drug in large amounts due to faulty formulation). 2. Reduced potential for accurate dose adjustment: it is easier to prepare a medication that works for a short time (e.g. hours) than one that works for a long period of time (e.g. days or even longer). 3. There is an increased potential for first-pass metabolism.  28 LIMITATION OF CONTROLLED DRUG DELIVERY SYSTEM 4. Unpredictable & poor in vitro-in vivo correlation. 5. Slow absorption, which can delay the onset of action of drug. 6. Toxicity and effect of polymer additives should be taken into consideration. 7. It can be more expensive to formulate CDDS than conventional dosage forms. 8. In oral dosage forms, drug release period is restricted to residence time in GIT and absorption window. 9. Controlled release delivery may not be suitable to all drug types. 10. Not all diseases are appropriate candidate for formulation in CDDS.  29 DRUGS THAT MAY BE DIFFICULT TO FORMULATE IN CDDS  Drugs that may be difficult to formulate in CDDS include: 1. Drugs with short biological half-lives (t1/2 > 8 hr). 3. Potent drug with narrow therapeutic indices (for fear of dose dumping that can be dangerous). 4. Drug given in large doses. 5. Poorly absorbed drugs which may result in poor bioavailability and delayed onset of action. 6. Poorly or slightly soluble drugs, in which the rate of dissolution is the rate limiting step in their release.  30 DRUGS THAT MAY BE DIFFICULT TO FORMULATE IN CDDS  Drugs that may be difficult to formulate in CDDS include: 7. Drugs undergoing extensive 1st pass metabolism. 8. Drugs that show delayed pharmacological effects relative to their blood profiles (provide no clinical advantages). 9. Actively absorbed may pass quickly and not being absorbed in sufficient amount from GIT. 10. Drugs that have absorption windows would result in reduced absorption efficiency.  31 EXAMPLE OF CDDS  Many drugs are now being formulated as controlled delivery systems.  Examples of some drugs and substances that are available in controlled release dosage forms are shown in the table below: Substances Examples Vitamins, minerals, and hormones Potassium, Pyrodixine, Methyltestosterone Diuretic and CV drugs Nitroglycerin, procainamide, acetazolamide, isosorbide dinitrate CNS drugs Diazepam, Phenobarbital, amphetamine sulfate Respiratory drugs Aminophylline, phenylpropanolamine HCl  32 SOME APPLICATION OF CDDS  Cancer therapy: to control the pharmacokinetic behavior of antitumor drugs and their tissue distribution in order to reduce the severe adverse effects associated with antitumor agents.  Fertility control: mainly using synthetic polymers in the area of contraception. E.g. intra uterine (IUD) and intra vaginal (IVD) contraceptive devices that consist of sustained release systems for progestins and/or estrogens.  33 SOME APPLICATION OF CDDS  Treatment of glaucoma: in conventional ophthalmic preparations, there is poor penetration into ocular space and rapid loss of the dose to systemic circulation and outside ocular cavity. Synthetic polymer devices (as Ocuserts) and prodrugs have been used to enhance the effectiveness of drug therapy & minimize the side effects.  Enzyme replacement therapy: The problems concerned with conventional enzyme replacement therapy involve in vivo stability of exogenous enzymes and their cellular uptake by the cells that are mostly effected by the disease. Using carrier complexes for enzyme replacement therapy is promising.  34 FACTORS INFLUENCING THE DESIGN AND PERFORMANCE OF CDDS  Factors influencing the design and performance of sustained/controlled release products: 1. Drug properties: The physicochemical (in vitro exp.) and biological properties (in vivo study/kinetics) of drugs (solubility, partition coefficient, stability, protein binding, …etc) could play a dominant role in the design of CDDS 2. Route of drug delivery: The area of the body in which the drug will be administered can be restrictive on a basis of suitable controlled release mechanism or device: Sometimes the DDS in certain route of administration can exert negative influence on drug efficiency.  Also the performance of a controlled release system may be influenced by physiological constraints presented by a particular route such as first-pass metabolism, GI motility, and blood supply.  35 FACTORS INFLUENCING THE DESIGN AND PERFORMANCE OF CDDS  Factors influencing the design and performance of sustained/controlled release products: 3. Target site: maximizing the fraction of dose reaching the target organ will minimize unwanted side effects. This can be partially achieved by local administration of the drug to the required site of action (i.e., localized action) or by the use of carriers (i.e., targeting). 4. Acute or chronic therapy: Consideration of whether one expect to achieve a cure or to control the condition and the expected length of drug therapy are important factors in designing CDDS  For e.g.: Attempts to generate one year contraceptive implants present significantly different problems in the design than do antibiotics for acute infections.  Also long term toxicity of rate-controlling DDS is usually different from that of conventional dosage forms.  36 FACTORS INFLUENCING THE DESIGN AND PERFORMANCE OF CDDS  Factors influencing the design and performance of sustained/controlled release products: 5. The disease state: Pathological changes during the coarse of disease can play significant role in design a suitable DDS.  For e.g.:  In attempting to design an ocular CR product for external inflammation, the time coarse of changes in protein content in ocular fluids and the integrity of ocular barrier should be taken into consideration.  The higher plasminogen activator level in tumor cells can lead to preferential bioconversion of peptidyl prodrug in these cells.  The higher tyrosinase level in melanoma cells has been demonstrated to allow targeting and preferential bioconversion of 2,4-dihydroxy phenylalanine.  37 FACTORS INFLUENCING THE DESIGN AND PERFORMANCE OF CDDS  Factors influencing the design and performance of sustained/controlled release products: 6. The patient: Whether the patient is ambulatory or bedridden; young or old can influence the design of controlled release products.  For e.g.:  An implant or IM injection of drug to a bedridden patient (altered abs. and blood flow) with little muscle movement may perform differently from the ambulatory patient.  All these factors are equally important in the design of a CDDS.  38 A. PHYSICOCHEMICAL AND B. BIOLOGICAL PROPERTIES  The physicochemical and biological properties of the drug can influence:  The drug release characteristics; the availability of the drug is controlled by drug release rather than its absorption.  The availability of the drug to its target site (in vivo distribution). complete knowledge of the  Therefore, the development of a CDDS requires a intrinsic properties of the drug and the ways in which it can influence the design of these systems.  39 A. PHYSICOCHEMICAL PROPERTIES OF DRUGS  Physicochemical properties of a drug influencing drug product design and performance:  The performance of a drug in its release pattern from the dosage form as well as in the body proper is a function of its properties.  The drug’s physicochemical properties can restrict its placement in a CDDS and may also restrict its route of administration.  Some of these properties are discussed here: 1. Aqueous solubility. 2. The partition coefficient and molecular size. 3. The stability of drugs. 4. Protein binding.  40 A. PHYSICOCHEMICAL PROPERTIES OF DRUGS 1. Aqueous solubility:  For drugs to be absorbed, they must be in solution.  Drug with very low aqueous solubility usually suffer oral bioavailability problems; because of limited GI transit time of and limited solubility at absorption site.  For most drugs, the site of maximum absorption will be also the site in which the drug is least soluble.  Slightly water soluble drugs are considered poor candidate for diffusional CDDS.  The aqueous solubility also limits the loading efficiency of drugs into different carriers (such as liposomes) and most of water soluble drugs tend to leak out rapidly from their carrier systems.  41 A. PHYSICOCHEMICAL PROPERTIES OF DRUGS  In conventional dosage forms, the rate limiting step in drug availability is usually drug absorption through biological membranes.  While, in control release (CR) systems the rate limiting step is the release of drug from the dosage form.  Drug release from CRS can be controlled by different mechanisms such as:  Dissolution  Diffusion  Degradation  Swelling  Osmotic pressure  Complexation  Ion-exchange  Others  42 A. PHYSICOCHEMICAL PROPERTIES OF DRUGS 2. The partition coefficient and molecular size:  Following administration, the drug must traverse a variety of membranes to gain access to the target area.  The partition coefficient and molecular size influence the permeability of drugs through biological membranes, as well as their diffusion across rate- controlling membranes and matrix delivery systems.  A balance in the partition coefficient and water solubility is thus required to obtain an optimum flux of the drug for penetrating through biological membranes (i.e. absorption) and through rate-controlling membranes (i.e. release).  The partition coefficient at which max flux occurs = 1000 for many body tissues such as GIT, Skin, and Eye.  43 A. PHYSICOCHEMICAL PROPERTIES OF DRUGS 3. The stability of drugs:  In vitro stability  physical, chemical ,microbiological stability.  Physical stability such as particles size, odor, color, precipitation.  Chemical stability such as degradation ,hydrolysis, oxidation.  In vivo stability  metabolism and degradation  Drugs should be stable in the environment to which they are exposed.  Drugs that are unstable in stomach can be placed in slightly soluble form or have their release delayed until they reach the small intestine (e.g., enteric coated).  For drugs that undergo extensive GI metabolism, a different route should be chosen (e.g., nitroglycerin).  44 A. PHYSICOCHEMICAL PROPERTIES OF DRUGS 4. Protein binding:  Many drugs can bind to plasma proteins that will influence their duration of action; drug- protein binding can serve as depot action for that drug.  Drugs can also bind to mucin, which could influence their absorption and could act as depots too.  On the other hand, drugs with high degree of binding will be poor candidates for CR products.  45 B. BIOLOGICAL PROPERTIES OF DRUGS  A comprehensive picture of the drug disposition should be known.  Every pharmacokinetic property and biological parameter has a useful range for the design of a CDDS and outside this range the design becomes difficult.  Biological factors influencing design and performance of sustained/controlled release products 1. Absorption  Drugs must be uniformly released & uniformly absorbed.  To maintain constant blood or tissue level of drug, it must be uniformly released from the controlled release system and then uniformly absorbed.  The rate limiting step from CR products is the release of the drug from the dosage form rather than its absorption through biological membranes, which means rapid absorption relative to drug release.  46 B. BIOLOGICAL PROPERTIES OF DRUGS 1. Absorption  Although it is preferred to be completely absorbed, as long as the drug is uniformly absorbed, even incomplete, a successful CR system can be formulated.  If the drug is erratically absorbed (e.g., in case of variable absorptive surfaces), the design gets more difficult or even prohibitive.  Drugs absorbed by specialized transport processes or drugs absorbed at specific sites of GIT are considered poor candidates for CR systems.  Slowly absorbed oral drug are poor candidates for CR because drug availability is limited by GI transit time (e.g., iron).  47 B. BIOLOGICAL PROPERTIES OF DRUGS 2. Distribution  Drug distribution can be an important factor in the overall drug elimination kinetics because it does not only lower the drug concentration in blood but also can be rate limiting in its equilibrium with blood and extra-cellular fluids.  One aspect of distribution is binding of drugs to tissues and blood proteins.  48 B. BIOLOGICAL PROPERTIES OF DRUGS 3. Metabolism  Metabolism can either inactivate or activate drugs.  The liver is the organ mostly responsible for the metabolism of orally given drugs (Metabolism could occur anywhere).  Drugs that upon chronic use are capable of either inducing or inhibiting enzyme synthesis are also poor candidates for CR systems.  Drugs extensively metabolized by GIT or by liver are considered poor candidates for CR systems.  The metabolism process is a saturable process and, therefore, metabolism will be more in slow release systems than in conventional dosage forms.  49 B. BIOLOGICAL PROPERTIES OF DRUGS 4. Duration of action  The biological half life (t ½) and duration of action play a major role in designing CDDS.  Drugs with biological half-lives of 4-6 hr are considered good candidates for CR systems. 5. Margin of safety  Drugs with narrow therapeutic indices (i.e., potent) are considered poor candidates for oral and parenteral CR delivery systems.  50 B. BIOLOGICAL PROPERTIES OF DRUGS 6. Side effects  Local and systemic side effects can be minimized by using CDDS. 7. Role of disease state and circadian rhythm  The disease state and circadian rhythm are very important in the design of CDDS.  Diseases with circadian rhythm include: Rheumatoid arthritis, epileptic seizures, asthma attack and acute MI.  CR products should be designed to release their contents in accordance with the circadian rhythm.  51 SELECTED ROUTES OF DRUG ADMINISTRATION  The route of administration has a significant role on the therapeutic outcomes of the drug.  Many dosage forms are designed for different routes.  The delivery system should be suitable for the route of administration.  The oral route is the preferred route of administration.  However, many drugs are unsuitable for oral delivery and must be given parenterally.  Alternative non-injectable routes, as buccal, sublingual, transdermal, nasal and pulmonary, are gaining greater interest for systemic delivery.  52 ROUTE OF DRUG ADMINISTRATION  Properties of an “ideal” route of administration  In order to maximize the amount of drug absorption from the site of administration, the delivery site should possess certain properties, as follows: 1. Large surface area  Large surface area facilitates absorption.  E.g.,: Villi & microvilli makes the surface area of small intestine very large, making it extremely important for oral drug delivery.  The surface area of the lungs is very extensive, making it promising alternative route to parenteral and oral routes. 2. Low metabolic activity  Poor bioavailability may be expected from an absorption site in which enzyme activity is high, such as the GIT.  Other routes (nasal, buccal etc.) avoid intestinal first-pass effects, and has lower metabolic activity than GIT, thus they are highly attractive for delivery of enzymatically labile drugs.  53 ROUTE OF DRUG ADMINISTRATION 3. Contact time  Contact time between drug and absorbing tissue influences the amount of drug absorbed.  In the buccal cavity, the administered dosage form is washed daily with 0.5–2 liters of saliva.  In the nasal cavity the “mucociliary clearance” is responsible for removing foreign substances from the nasal cavity.  In the eye, materials are diluted by tears and removed via the lachrymal drainage system. 4. Blood supply  Adequate blood flow from the absorption site is required to carry the drug to the site of action post-absorption and also to ensure that “sink” conditions are maintained.  54 ROUTE OF DRUG ADMINISTRATION 5. Accessibility  Certain absorption sites (as alveolar region of lungs) are not readily accessible and thus may require quite complex delivery devices to ensure the drug reaches the absorption site. Other sites (as skin) are highly accessible. 6. Lack of variability  Lack of variability is essential to ensure reproducible drug delivery, particularly for the delivery of highly potent drugs with a narrow therapeutic window. E.g.,  Due to extremes of pH, enzyme activity, intestinal motility, presence of food, etc., the GIT can be a highly variable absorption site.  Diseases (as common cold & hay-fever) alter the physiological conditions of the nose, contributing to the variability of this site.  Cyclic changes in the female menstrual cycle mean that large fluctuations in vaginal bioavailability can occur.  55 ROUTE OF DRUG ADMINISTRATION 7. Permeability  A more permeable epithelium facilitates greater absorption.  Some epithelia are relatively more permeable than others. E.g.,  Skin is extremely impermeable barrier, whereas the permeability of the lung membranes towards many compounds is much higher than the skin and is also higher than that of the small intestine and other mucosal routes.