Transcript BIOPHARMACEUTICS & PHARMACOKINETICS

BIOPHARMACEUTICS
&
PHARMACOKINETICS
• Bio – life
• Pharmaceutics
– general area of study concerned with
the formulation, manufacture, stability
and effectiveness of pharmaceutical
dosage forms.
Biopharmaceutics
• study of the factors
influencing the
bioavailability of a drug
in man and animals and
the use of this
information to optimize
pharmacological or
therapeutic activity of
drug products in clinical
application.
Biopharmaceutics
• study of the influence of formulation on
therapeutic activity of a drug product.
Biopharmaceutics
• study embracing this relationship between the
physical, chemical and biological sciences as they
apply to drugs, dosage forms, and to drug
action.
Biopharmaceutics
• Modern biopharmaceutics is the study of the
relationship of the physico-chemical properties
and in vitro behavior of the drug and drug
product on the delivery of the drug to the body
under normal or pathologic conditions.
Drug
•
•
agent intended for use in the diagnosis,
mitigation, treatment, cure or prevention of
disease in man or in other animals.
It may be:
1. synthetic
4. biological
2. semi-synthetic
5. natural
3. chemical
Drug
• Modern drugs are potent chemical substances
that must be fabricated into a drug product
before use.
• Generally, the drug is combined with other
ingredients into a drug formulation, which may
be a solution, tablet, capsule or suppository.
Rationale
• The development of biopharmaceutic principles
allowed for the rational design of drug products,
which would enhance the delivery of active
drug, and optimize the therapeutic efficacy of
the drug in the patient.
Drug Product
• a finished dosage form that contains an active
drug ingredient generally, but not necessarily, in
association with inactive ingredient.
• formulation or matrix in which the drug is
contained
• The term may also include a dosage form that
does not contain an active ingredient intended
to be used as placebo.
Drug Action
result of an interaction between the drug
substance and functionally important cell
receptors or enzyme systems.
 This response is due to the alteration in
the biologic processes that were present
prior to the drug administration.

In vitro – glass
 referring to a process or reaction carried
out in a culture dish or test tube
 In vivo – in the living organism

Effects of Biopharmaceutics

Generic equivalency
 Drug availability
 Therapeutic efficacy
 Drug substitution
BIOPHARMACEUTICS
&
PHARMACOKINETICS
Effects of Biopharmaceutics

Drug product selection
*drug product should be
cost-effective
*drug product selection
should be according to
the patient’s capability
*drug product selection
should be based upon
the patient’s diagnosis
Aim

The aim of biopharmaceutics is to adjust
the delivery of drug to the general
circulation in such a manner as to
provide optimal therapeutic activity for
the patient.
Aim

Biopharmaceutic studies allow drugs to
be formulated rationally based on
pharmaceutic properties.
Some Pharmaceutic Properties

Some drugs are intended for topical or
local therapeutic action at the site of
administration. For these drugs, systemic
absorption is undesirable.
Some Pharmaceutic Properties

Drugs intended for local activity generally
have a direct pharmacodynamic action
without affecting other body organs.
These drugs may be applied topically to
the skin, nose, eyes, mucous
membranes, buccal cavity, throat and
rectum.
Factors Affecting Biopharmaceutics

a. physical state of the drug
- according to the 4 states of matter
 The
crystal or amorphous forms and/or
the particle size of a powdered drug
have been shown to affect the
dissolution rate, and thus the rate of
absorption, for a number of drugs.
Factors Affecting Biopharmaceutics

By selective control
of the physical
parameters of a
drug, biologic
response may be
optimized.
b. dosage form
- delivery system the drug could be
available or administered.
b. dosage form
Each of dosage unit is designed to contain
a specified quantity of medication for
ease and accuracy of dosage
administered.
 Each
product is a formulation unique
unto itself

Biopharmaceutic considerations often
determine the ultimate dose and dosage
form of a drug product.

Biopharmaceutic considerations often
determine the ultimate dose and dosage
form of a drug product.
☺ For
example, the dosage for a drug
intended for local activity, such as a topical
dosage form, is often expressed in
concentration or as % of the active drug in
the formulation.
☺ The
amount of drug is not specified
because it is the concentration of the drug
at the active site that relates to the
pharmacodynamic action.
Biopharmaceutics

Biopharmaceutic
studies must be
performed to ensure
that the dosage form
does not irritate,
cause an allergic
response or allow
systemic drug
absorption.
The dosage of a drug intended for
systemic absorption is given on the basis
of absolute amount, such as mg or g.
c. route of administration

each route of drug application presents
special biopharmaceutic considerations
in drug product design.
c. route of administration

by carefully choosing the route of drug
administration and properly designing the drug
product, the bioavailability of the active drug
can vary from rapid and complete absorption
to a slow, sustained rate of absorption or even
virtually no absorption, depending on the
therapeutic objective.
Example

The design of a
vaginal tablet
formulation for the
treatment of a
fungus infection
must consider
ingredients
compatible with
vaginal anatomy and
physiology.
Example

An eye medication may require special
biopharmaceutic considerations
including appropriate pH, isotonicity,
local irritation to the cornea, draining by
tears, and concern for systemic drug
absorption.
Scope of Biopharmaceutics
1. Encompasses all possible effects observed
following the administration of the drug
in the various dosage forms.
2. Encompasses all possible effects of various
dosage forms on biological response
3. Encompasses all possible physiological
factors which may affect the drug in
various dosage forms.
A primary concern in
biopharmaceutics is the
bioavailability of drugs.
Bioavailability
refers to the measurement of the rate and extent of
active drug that reaches the systemic circulation.
means access to the bloodstream
Drug Bioavailability Process
Drug in the drug product
Solid drug particles
Drug in solution
Drug in the body
Pharmaceutic Factors Affecting Drug
Bioavailability
1. type of the drug product
2. nature of excipients in the drug product
3. physico-chemical properties of the drug
- measurable characteristics by which a
compound interacts with other systems
Physico-Chemical
Properties of the Drug
1. Particle size of a drug in a solid dosage form
2. Particle size of a dispersed phase in an emulsion
3. Tablet disintegration
4. Tablet & capsule adjuncts
5. Tablet coating
6. Crystalline drug properties
Something to ponder….
1. Particle size of a drug in a solid
dosage form
In order to affect dissolution rate based
on one’s objective, there should be a
change in particle size.
 ↓ particle size → larger surface area to
be wetted → ↑ dissolution rate → faster
rate of absorption
 But for local effect, increased particle
size is required

2. Particle size of the dispersed
phase in an emulsion

2-phase system in which one should be
uniformly dispersed into another.

Dispersed phase should be in small
particle size so it can readily mix with
dispersion medium.
3. Tablet Disintegration
Disintegration is the physical break-up of
an intact dosage form to its component
aggregates.
 Disintegration depends on the
disintegrant used.

Starch
 Microcrystalline cellulose

It was generally recognized some years
ago that a solid drug product had to
disintegrate into small particles and
release the drug before absorption could
take place.
 For the purpose of monitoring tablet
disintegration, USP established an official
disintegration test.

USP Specifications

Separate specifications are given for
uncoated tablets
 plain coated tablets
 enteric coated tablets
 buccal tablets
 sublingual tablets

USP Specifications
Solid drug products exempted from
disintegration tests
 Troches
 Tablets which are intended to be chewed
 Drug products intended for SR, or
prolonged or repeat action

4. Tablet & Capsule Adjuncts

Excipients
– added to the active ingredient to
form a dosage form that is convenient for
control purposes.
- it should be inert, inactive, neither
enhances nor diminishes the therapeutic
effect of the drug
Roles/Effects of Excipients
1.
2.
3.
4.

may affect drug absorption
may increase solubility
may increase retention time of drug in the
GIT
may act as carriers to increase diffusion
across intestinal wall
In contrast, most excipients may retard
drug dissolution and decrease drug
absorption
Different Excipients used in Tablets
1. Diluents – added to increase the bulk/mass
of the dosage form
 ex. Lactose, Dibasic Ca Phosphate, starch,
microcrystalline cellulose
2. Binder – makes the diluent adhere to the
tablet to form a compact mass. Pressure is
applied to make the tablets contact.
 Ex. Acacia, alginic acid, gelatin, povidone,
etc.
Different Excipients used in Tablets

3. Lubricant
– helps to have an easier transfer from one
stage of manufacture to another
- assist the smooth tableting process.
 Ex. Mag. Stearate, stearic acid, talc,
hydrogenated vegetable oil

excessive magnesium stearate (a hydrophobic
lubricant) in the formulation may retard drug
dissolution and cause slower drug absorption.
5. Tablet Coating

protection
 uneven coating can cause uneven release of
active ingredient

Example:
a. enteric coatings – employed to permit safe
passage of tablet thru the acid environment of
the stomach where certain drugs may be
destroyed, to the more suitable juices of the
intestines where tablet dissolution safely takes
place. ( shellac, cellulose acetate phthalate)

b. film-coatings
– employed to protect the drug substance
from the destructive influences of moisture, light
and air throughout their period of storage or to
conceal a bad or bitter taste from the taste buds
of the patient. (hydroxypropylmethylcellulose)
c. sugar-coatings – conceal bitter taste (liquid
glucose, sucrose)
4. Surfactants
Low conc. of surfactant = decrease
surface tension = rate of dissolution?
High conc. of surfactant = formation of
micelles = rate of dissolution?
6. Crystalline Drug Properties


Polymorphism
– refers to the arrangement of a drug in various crystal
forms or Polymorphs
Polymorphs
– have the same chemical structure but different
physical properties such as:
solubility, density, hardness and compression
characteristics

Some polymorphic crystals may have
much lower aqueous solubility than the
amorphous forms, causing a product to
be incompletely absorbed.
Ex. Chloramphenicol

Crystal with the LOWEST free energy is
stable
Solvate
Drug + solvent = crystal

Hydrates
Drug + H2O = crystal

In general, the crystalline form of drugs are more
rigid and thermodynamically more stable than
the amorphous form. The crystal form with the
lowest free energy is the most stable polymorph.
 A change in crystal form may cause problems in
manufacturing the product. For example, a
change in crystal structure of the drug may
cause cracking in a tablet or even inability for a
granulation to be compressed to form a tablet.
Example
☺

Erythromycin dehydrate dissolves faster
than the monohydrate & anhydrous form
less hydrated – faster dissolution
☺
Ampicillin anhydrous would have faster
dissolution than trihydrate but it is less
absorbed
Clathrates- cages the drug to make it
more stable (protective) and soluble
(reacts with the solvent)
e.g. gallic acid, urea, zeolite

Drugs with narrow therapeutic
window
Size of dose (mg/kg)
 Dosing frequency (bid, tid, od)

Size of the dose
Determined by:
 Inherent potency of the drug
 Dosing strengths


E.g. score in tablets for fractured dosing.
Paper tablets
Dosing frequency
Dependent on:
1. Clearance of the drug (elimination)
2. Target plasma drug concentration
(MEC)
e.g. Drug with a short half-life or rapid
clearance  how frequent is the
dosing?

Sustained release (SR) tablets

Devised to minimize fluctuating plasma
concentration and good patient
compliance
Route of administration
Formulation given in IM, IV and oral only
changes the rate of absorption but NOT
the rate of elimination
Sublingual  rapid onset but shorter
duration of action
Maraming
salamat
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