DRUG DELIVERY SYSTEMS AND

ROUTES OF DRUG
ADMINISTRATION

1 Mr Ernest Simpemba
BPharm. MSc
OUTLINE
2.1 Biopharmaceutics considerations in drug product design

2.2 Different types of drug delivery systems (dosage forms)

2.3 Different routes of drug administration and the effect on drug

absorption

2.4 Oral dosage forms and oral route of administration.

2.5 Non Oral routes of drug administration and other drug

delivery system 2
INTRODUCTION
 Biopharmaceutics is the study of the physicochemical properties
of the drug and the drug product, in vitro, as it relates to the
bioavailability of the drug, in vivo, and its desired therapeutic
effect.

 Biopharmaceutics thus links the physical and chemical properties of

the drug and the drug product to their clinical performance, in vivo.

 A primary concern in biopharmaceutics is the bioavailability of

drugs.

 Bioavailability refers to the measurement of the rate and extent of 3

active drug that becomes available at the site of action.
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

Importance of Biopharmaceutics in the Overall

Development Process:
 Biopharmaceutics is an integral component of the overall
development cycle of a drug.

 compound selection,
 preclinical efficacy and safety testing,
 formulation development,
 clinical efficacy studies,
 and post approval stages 4
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

Importance of Biopharmaceutics in the Overall

Development Process:
 multiple disciplines are involved
 Biopharmaceutical specialists,
 Discovery chemistry and biology,
 drug safety assessment,
 clinical development,
 Pharmaceutical development,
 regulatory affairs,
 marketing,
5
 and manufacturing.
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

Discovery and Preclinical Development: Candidate

Selection
 The process to identify a potential drug candidate is not an
easy one

 Discovery scientists strive to synthesize candidate

compounds with appropriate activity and maximal potency
at the intended target, maximal safety profile, and
desirable ADME properties.
6
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

Preclinical Development: Preparation for Phase I

Clinical Studies
 Once a drug candidate is chosen for clinical development,
additional biopharmaceutical assessment is conducted to
build on existing knowledge and experience.

 A clinical candidate must be tested in formal animal safety

studies in multiple species in order to establish a safety
profile and provide guidance on the choice of clinical doses.
7
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

Early Clinical Development

 The primary goals in early clinical development are to
establish safety, PK, and pharmacodynamics, and also to
provide guidance on a dose range expected to be
efficacious, in both single-dose and multiple-dose studies.

 The plasma drug concentration time profiles are used to

determine AUC, half-life, Cmax, tmax, dose-
proportionality, and extent of accumulation upon multiple
dosing. 8
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

Advanced Clinical Development

 As a compound moves from Phase I into Phase II and
eventually into Phase III, the objectives of the clinical
development program evolve from primarily safety and PK
to safety and efficacy.

9
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

Postapproval Considerations
 Changes to the formulation, manufacturing process or site,
or dosing regimen must be assessed for impact on the
biopharmaceutical behavior.

 Enhancements or extensions, including different dosage

forms (e.g., capsule to tablet or oral liquid), new strengths,
modified-release (e.g., for less frequent dosing to improve
patient compliance), or alternate routes of administration
(e.g., addition of an injectable dosage form for use as a
loading dose or for emergency use, or long acting depot 10
injection).
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

Regulatory Considerations
 biopharmaceutics knowledge base contributes to the
establishment of a product’s “design space,” reflecting the
ranges of multiple, interrelated material properties and
manufacturing parameters within which acceptable
product performance is assured with a high degree of
confidence.

11
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

 For the majority of orally administered drugs, the site of

action is within the systemic circulation and the drug must
be absorbed to achieve a pharmacological response.

 Oral drug absorption involves at least three distinct steps:

1. drug release or dissolution from the drug product in the body’s
fluids,
2. permeation of the drug across the gastrointestinal (GI) linings
into the systemic circulation, and
3. drug disposition during GI transit (eg, GI stability, motility,
12
metabolism, etc).
2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN

 Drug disposition may occur in the systemic circulation and

thus reduce the concentration of drug available to the
target tissues.

 Changes in oral bioavailability affect changes in the

pharmacodynamics and toxicity of a drug because the
systemic blood circulation ultimately delivers
therapeutically active drug to the tissues and to the drug’s
site of action.
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2.1 BIOPHARMACEUTICS CONSIDERATIONS IN
DRUG PRODUCT DESIGN
 A drug product may also be designed to deliver the drug directly to the site
of action before reaching the systemic circulation, which is often termed
locally acting drug.

 Some examples of products in this class include ophthalmic, pulmonary,

and nasal drug products.

 Local drug bioavailability is strongly influenced by physicochemical

properties of the drug and drug product, the rate and extent of drug
release from the drug product, and permeation at the target site (eg, skin
physiology compared with that in the cornea).

 Regardless of the intended site of drug action, biopharmaceutics aims to

balance the amount and extent of drug delivered from the drug product to
achieve optimal therapeutic efficacy and safety for the patient. 14
2.2 DIFFERENT TYPES OF DRUG DELIVERY
SYSTEMS (DOSAGE FORMS)
 In broad terms, the factors affecting drug bioavailability may be related to the
formulation of the drug product or the biological constraints of the patient.

 Drugs are not usually given as pure chemical drug substances, but are formulated
into finished dosage forms (ie, drug products).

 Drug products include the active drug substance combined with selected additional
ingredients (excipients) that make up the dosage form.

 Excipients are important in the manufacture of the drug product and provide
functionality to the drug product with respect to drug release and dissolution.

 Some common drug products include liquids, tablets, capsules, injectables,

suppositories, transdermal systems, and topical creams and ointments.

15
2.2 DIFFERENT TYPES OF DRUG DELIVERY
SYSTEMS (DOSAGE FORMS)
 The design of the dosage form, the formulation of the drug
product, and the manufacturing process require a thorough
understanding of the biopharmaceutic principles of drug
delivery.

 Considerations in the design of a drug product to deliver the

active drug with the desired bioavailability characteristics and
therapeutic objectives include
(1) the physicochemical properties of the drug molecule,
(2) the finished dosage form (eg, tablet, capsule, etc),
(3) the nature of the excipients in the drug product,
(4) the method of manufacturing, and
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(5) the route of drug administration
2.3 DIFFERENT ROUTES OF DRUG ADMINISTRATION
AND THE EFFECT ON DRUG ABSORPTION
 Each route of drug administration presents special biopharmaceutic
considerations in drug product design.

 For example, the design of a vaginal tablet formulation for the treatment
of a fungal infection must use ingredients compatible with vaginal
anatomy and physiology.

 An eye medication requires special considerations for formulation pH,

isotonicity, sterility, the need to minimize local irritation to the cornea,
potential for drug loss from draining by tears, and residual systemic drug
absorption.

 For a drug administered by an extravascular route (eg, intramuscular

injection), local irritation, drug dissolution at the application site, and
drug absorption from the intramuscular site are some of the factors that 17
must be considered.
2.3 DIFFERENT ROUTES OF DRUG ADMINISTRATION
AND THE EFFECT ON DRUG ABSORPTION
 Systemic absorption after extravascular administration is
influenced by the anatomic and physiologic properties of the site
and the physicochemical properties of the drug and the drug
product.

 On the other hand, if the drug is given by an intravascular route

(eg, IV administration), systemic drug absorption is considered
complete or 100% bioavailable, because the drug is placed
directly into the general circulation.

 However, drug disposition can be altered by modifying the

composition of the drug product (eg, addition on mannitol may 18
change the renal clearance of the drug).
2.3 DIFFERENT ROUTES OF DRUG ADMINISTRATION
AND THE EFFECT ON DRUG ABSORPTION
 By choosing the route of drug administration carefully and properly
designing the drug product, the bioavailability of the active drug can be
varied from rapid and complete absorption to a slow, sustained rate of
absorption or even virtually no absorption, depending on the therapeutic
objective.

 Once the drug is systemically absorbed, normal physiologic processes for

drug distribution and elimination occur.

 These intrinsic factors may also be influenced by the specific formulation

of the drug (eg, encapsulated drug in liposome or microspheres may
change the drug distribution and systemic clearance).

 The rate of drug release from the product and the rate and extent of drug
absorption are important in determining the onset, intensity, and duration 19
of drug action.
SUMMARY POINTS
 Biopharmaceutic considerations often determine the ultimate dose and
dosage form of a drug product.

 For example, the dosage form for a locally acting drug such as a topical
drug product (eg, ointment) is often expressed in concentration or as a
percentage of the active drug in the formulation (eg, 0.5%
hydrocortisone ointment).

 The amount of drug applied is not specified because the concentration

of the drug at the active site relates to the pharmacodynamic action.

 However, biopharmaceutic studies must be performed to ensure that

the drug product does not irritate, cause an allergic response, or allow
significant systemic drug absorption.
20
SUMMARY POINTS
 In contrast, the dosage form for a systemically acting drug is
expressed in terms of mass, such as milligrams or grams.

 In this case, the dose is based on the amount of drug that is

absorbed systemically and dissolved in an apparent volume of
distribution to produce a desired drug concentration at the
target site.

 The therapeutic dose may also be adjusted based on the weight

or surface area of the patient, to account for the differences in
the apparent volume of distribution, which is expressed as mass
per unit of body weight (mg/kg) or mass per unit of body surface 21
area (mg/m2).
SUMMARY POINTS
 For many commercial drug products, the dose is
determined based on average body weights and may be
available in several dose strengths, such as 10-mg, 5-mg,
and 2.5-mg tablets, to accommodate differences in body
weight and possibly to titrate the dose in the patient.

22
2.4 ORAL DOSAGE FORMS AND ORAL ROUTE OF
ADMINISTRATION.

 REVISION

23
2.5 NON ORAL ROUTES OF DRUG ADMINISTRATION
AND OTHER DRUG DELIVERY SYSTEM

 REVISION

24
CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
THE PLASMA MEMBRANE
 The plasma membrane retains the contents of the cell and
acts as a permeability barrier.

 It allows only certain substances to enter or leave the cell,

and the rate of entry is strictly controlled.

25
CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
EPITHELIA
 With a few exceptions, all internal and external body
surfaces are covered with epithelium.

 This consists of a layer of structural protein, normally

collagen, called the basal lamina, on which sit one or more
layers of epithelial cells.

26
CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
 There are several morphologically distinct common epithelial types

(a) simple squamous (b) simple columnar (c) transitional

27
(d) stratified squamous epithelium
CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
Simple squamous epithelium:
 This forms a thin layer of flattened cells and consequently
is relatively permeable.

 This type of epithelium lines most of the blood vessels.

Simple columnar epithelium:

 A single layer of columnar cells is found in the epithelium
of organs such as the stomach and small intestine.
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CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
Transitional epithelium:
 This is composed of several layers of cells of different shapes and it lines
epithelia which are required to stretch.

Stratified squamous epithelium:

 These membranes are several cells thick and are found in areas which
have to withstand large amounts of wear and tear, for example the inside
of the mouth and oesophagus, and the vagina.

 In the skin the outer cells become filled with keratin, and then die and
slough off from the outside.

 This type of epithelium is termed keratinized and provides a major 29

permeability barrier as well as protection from the environment.
CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
Cell junctions
 Tight junctions

 Gap junctions

 Desmosomes

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CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
TRANSPORT ACROSS CELL MEMBRANES
 Passive diffusion

 Facilitated and carrier mediated diffusion

 Co-transport

 Uptake of macromolecules and particles

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CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
INTERCELLULAR ROUTES OF ABSORPTION
 As well as being absorbed through the epithelial cells,
molecules can pass through tissues via the intercellular or
paracellular route through junctional gaps between cells.

32
CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
PERSORPTION
 There is a special mode of permeation across the intestinal
wall in which the cell membranes are not involved.

 Intestinal cells are continuously produced in the crypts of

Lieberkühn and migrate towards the tip of the villus.

 During digestion the cells are sloughed off leaving a

temporary gap at the cell apex, and through this gap large
particles can slip into the circulation through the
intercellular gaps. 33
CELL MEMBRANES, EPITHELIAL BARRIERS AND
DRUG ABSORPTION
MUCUS
 An epithelium containing mucosal cells is called a mucosal
epithelium or simply mucosa.

 Mucus has several functions:

 It restricts the penetration of large molecules
 prevents the tissue from dehydrating
 It keeps the tissue surface clean by its continuous removal
 lubricates the passage of materials such as food through the
gastrointestinal tract 34
PARENTERAL DRUG DELIVERY
INTRAVENOUS DELIVERY
 Intravenous delivery involves the direct injection of the
formulation into the venous circulation.

Advantages of intravenous delivery:

 rapidity of action
 more predictable response than is obtained from other
routes
Disadvantages of intravenous delivery:
 need for extensive training of medical staff
35
 Sterility must be maintained
PARENTERAL DRUG DELIVERY
Complications include:
 Air embolism, or the injection of air into a vessel.

 Thrombosis, the formation of a clot in a blood vessel, can be particularly dangerous

if the clot circulates in the bloodstream.

 Haemolysis, the breakdown of red cells with the release of haemoglobin, can cause
kidney damage if severe.

 Phlebitis is the inflammation of the vein wall due to irritation from the
formulation; it can be caused by the formulation itself, or may be due to
precipitation of the drug if injection is too rapid.

 Extravasation, or the leakage of the injection from the vein into the surrounding
tissue, can lead to extensive damage since there may be no mechanism to rapidly
clear it from the injection site. 36
PARENTERAL DRUG DELIVERY
Formulation considerations
 intravenous formulations must be sterile

 Ideally all injections would be formulated at pH 7.4 and be

isotonic with blood

 solvents, especially to aid the solubility of a drug (for example

deoxycholate, which is used to solubilize amphotericin B in the
injectable Fungizone®)

 drug may precipitate in the bloodstream leading to

37
unpredictable pharmacokinetics
PARENTERAL DRUG DELIVERY
INTRAMUSCULAR DELIVERY
 Intramuscular delivery involves the injection of the dose
form into a muscle, from where it is absorbed due to the
perfusion of the muscle by blood.

 The formulation forms a local depot which is partly mixed

with interstitial fluid, and partly forms a bolus within the
muscle, particularly if the injected volume is large.

38
PARENTERAL DRUG DELIVERY
Pharmacokinetics
Intramuscular delivery involves a number of steps:
 release of the drug from the dose form into the intercellular fluid
(ICF),
 absorption from the ICF into the blood and lymphatics,
 transport from the local blood volume into the general
circulation,
 metabolism.

39
PARENTERAL DRUG DELIVERY
Formulation considerations
 The possible formulations include aqueous solutions, aqueous
suspensions, oily solutions, oil in water emulsions, water in oil
emulsions, oily suspensions, and dispersions in polymer or solid
implants.

 If the drug is extremely hydrophobic it will not dissolve in the ICF,

while if it is strongly ionized or extremely water soluble it will not be
able to cross the capillary membrane.

 Drugs which are strongly protein-bound will also be slowly absorbed

since their activity in solution will be reduced.

 Drug precipitates after dilution and change in pH resulting in slow 40

absorption.
PARENTERAL DRUG DELIVERY
SUBCUTANEOUS DELIVERY
 A subcutaneous injection (SC) is made into the connective
tissue beneath the dermis
 An intradermal injection is made into the dermal layer,
often between the dermis and the epidermis.

41
DRUG DELIVERY TO THE ORAL CAVITY OR MOUTH
 The oral cavity is the point of entry for oral drug
formulations but usually their contact with the oral
mucosa is brief.

 In order to take advantage of some of the properties of the

oral mucosa or to locally treat the mucosa, delivery
systems have been designed to prolong residence in this
area.

 The total surface area available for drug absorption is

quite limited, being only approximately 100 cm2 42
DRUG DELIVERY TO THE ORAL CAVITY OR MOUTH
 Drugs which are absorbed through the oral mucosa enter
the systemic circulation directly via the jugular vein,
thereby initially avoiding passage through the liver where
they might otherwise be metabolized.

 The oral cavity is rich in blood vessels and lymphatics, so a

rapid onset of action and high blood levels of drug are
obtained quickly

43
DRUG DELIVERY TO THE ORAL CAVITY OR MOUTH
Disadvantages
 Only small lipophilic molecules are well absorbed.

 Polar drugs, for example those which are ionized at the pH of the
mouth (6.2–7.4), are poorly absorbed.

 the dose form must be kept in place while absorption is occurring, since
excessive salivary flow may wash it away.

 The taste of the drug must be bland, otherwise it will not be acceptable

 drug must also be non-irritant,

44
 drug should not discolour or erode teeth.
DRUG DELIVERY TO THE ORAL CAVITY OR MOUTH
Effect of position on drug delivery
 Within the oral cavity, delivery of drugs can be classified
into four categories:
 Sublingual delivery in which the dosage form is placed on the
floor of the mouth, under the tongue,
 buccal delivery, in which the formulation is positioned against
the mucous membranes lining the cheeks,
 local oropharyngeal delivery to treat mouth and throat
 periodontal delivery, to treat below the gum margin.

 Variations in epithelia thickness and composition will

45
undoubtedly affect drug absorption.
DRUG DELIVERY TO THE ORAL CAVITY OR MOUTH
DOSAGE FORMS FOR THE ORAL CAVITY
 Chewable formulations

 Fast-dissolving dosage forms

 Bioadhesive dosage forms

 Dental systems
46
DRUG DELIVERY TO THE ORAL CAVITY OR MOUTH
DRUGS ADMINISTERED VIA THE ORAL MUCOSA
 Nitrates

 Steroids

 Analgesics

 Antibiotics

 Antifungals

 Lorazepam for anxiety and insomnia

 Nicotine for smoking cessation

 Ergotamine for migraine treatment

47
DRUG DELIVERY TO THE ORAL CAVITY OR MOUTH
 Metronidazole
 Metoclopramide
 Phenazocine
 Propranolol,
 Timolol
 Salbutamol
 Fenoterol
 Insulin.
 Calcium channel blockers (nifedipine, verapamil)
 Oxytocin. 48
TRANSDERMAL DRUG DELIVERY
STRUCTURE OF THE SKIN

49
TRANSDERMAL DRUG DELIVERY
 FACTORS AFFECTING PERCUTANEOUS ABSORPTION
 Individual variation
 Age
 Site
 Occlusion
 Temperature
 Race
 Disease

50
NASAL DRUG DELIVERY
 REVISE ANATOMY AND PHYSIOLOGY OF THE NOSE

 INTRANASAL ADMINISTRATION OF DRUGS

 Currently, intranasal drug delivery is primarily employed to
treat allergies and infections which cause nasal irritation,
sneezing and congestion by the topical action of drugs.

51
PULMONARY DRUG DELIVERY
 REVISE ANATOMY AND PHYSIOLOGY OF THE PULMONARY
SYSTEM

52
PULMONARY DRUG DELIVERY

53
PULMONARY DRUG DELIVERY
 Lung permeability
 The alveolar epithelium and the capillary endothelium have a very high
permeability to water, most gases and lipophilic substances.

 There is an effective barrier however for many hydrophilic substances of large

molecular size and for ionic species.

 The alveolar type 1 cells have tight junctions, effectively limiting the penetration of
molecules to those with a radius of less than 0.6 nm.

 Endothelial junctions are much larger, with gaps of the order of 4 to 6 nm.

 The normal alveolar epithelium is almost totally impermeable to proteins and small
solutes.

 The microvascular endothelium, with its larger intercellular gaps, is far more
permeable for all molecular sizes and there is normally an appreciable leak of 54
protein into the systemic circulation.
PULMONARY DRUG DELIVERY
 DOSAGE FORMS FOR PULMONARY DRUG DELIVERY
 Pressurized inhalation aerosols
 Dry powder inhalers
 Nebulizers
 DRUGS ADMINISTERED VIA THE PULMONARY ROUTE
 Anti-allergy agents
 Beta receptor agonists
 Adrenocorticosteroids
 Leukotriene inhibitors

55
OCULAR DRUG DELIVERY
REVISE ANATOMY AND PHYSIOLOGY OF THE EYE

56
OCULAR DRUG DELIVERY
 FACTORS INFLUENCING DRUG RETENTION
 Proper placement of the eyedrops
 Influence of instilled volume
 Preservatives
 Effect of systemically administered drugs

 ROUTES OF DRUG ADMINISTRATION

1. Topical—drops or ointment
2. Systemic—oral or injection
3. Intra-ocular injection 57
OCULAR DRUG DELIVERY
 Increasing the residence time of an ophthalmic formulation on the corneal surface increases
the drug bioavailability and therefore reduces frequency of administration.

 Frequent administration is necessary with eye drops.

 The retention of a drug on the corneal surface is determined by the amount of tear flow and by
the blink frequency, which can be stimulated by different factors.

 The most important factor influencing the retention of a drug on the corneal surface appears to
be the properties of the drug itself.

 If a drug irritates the eye, it is difficult to obtain a long retention.

 If the drug is non-irritant, retention time can be increased by instillation of small drops, by
adjustment of the osmolarity, tonicity, pH and by choosing the appropriate preservatives and
adjuvants.
58
VAGINAL AND INTERUTERINE DRUG DELIVERY
REVISE ANATOMY AND PHYSIOLOGY

59
VAGINAL AND INTERUTERINE DRUG DELIVERY
DRUG ABSORPTION THROUGH THE VAGINA/UTERUS
 A wide range of drugs have been studied for vaginal absoprtion.

 These include steroid hormones such as progesterone and

oestrogen.

 A recently reported observation is that drugs administered

intravaginally accumulate in uterine tissue.

 These findings have lead to the hypothesis that there is a direct

transport mechanism from vagina to uterus or a “uterine-first
60
pass effect
VAGINAL AND INTERUTERINE DRUG DELIVERY
DRUG DELIVERY (Vaginal)
 Challenges to vaginal drug delivery;
 Epithelium is highly sensitive to oestradiol
 Epithelium thickness changes throughout the menstrual cycle
 The extent and rate of drug absorption vary
 Gender specificity
 Personal hygiene
 Influence of sexual intercourse.

61
VAGINAL AND INTERUTERINE DRUG DELIVERY
 Creams and gels
 Pessaries or tablets

 Vaginal rings

 Bioadhesive delivery systems

 Intrauterine Devices

62
VAGINAL AND INTERUTERINE DRUG DELIVERY
 Vaginal delivery has the advantage that self-insertion and removal of delivery
devices is possible.

 This route does avoid first-pass metabolism, but the mucosa is not as permeable as
the uterus to peptides and proteins and the variability in bioavailability is too high
to be used clinically.

 In contrast, the uterus appears to be very permeable to a wide variety of

substances, but insertion and removal of devices has to be performed by medically
qualified personnel.

 Possible consequences of pregnancy occurring whilst the devices are in situ has to
be studied thoroughly since the local concentration of the drug is likely to be high.

 Drugs absorbed from the uterus also avoid first-pass metabolism.

63