absorption of drugs - PowerPoint PPT Presentation

About This Presentation
Title:

absorption of drugs

Description:

routes of absorption – PowerPoint PPT presentation

Number of Views:11284

less

Transcript and Presenter's Notes

Title: absorption of drugs


1
ABSORPTION PROCESS AND FACTORS EFFECTING ORAL
DRUG ABSORPTION
BY VENKATA NAVEEN KASAGANA SWATHI SREE
KARUMURI M-PHARM -PHARMACEUTICS S.B. COLLEGE OF
PHARMACY SIVAKASI TAMIL NADU INDIA E-MAILnaveen.k
asagana_at_gmail.com
2
Absorption Absorption may be defined as the
process by which a compound penetrates one or
more biological membranes to gain entry into the
body. An orally administered drug that undergoes
extensive firstpass hepatic clearance may give
rise to poor oral bioavailability despite being
efficiently absorbed from the gastrointestinal
(GI) tract.
3
  • Mechanism of drug absorption
  • Following the administration of a drug in a
    dosage form, drug molecules must somehow gain
    access to the bloodstream, where the distribution
    process will take it to the site of action.
  • For absorption to occur, therefore, the drug
    molecule must first pass through a membrane.
  • Membrane physiology the gastrointestinal barrier
  • It is made up of lipids, proteins, lipoproteins
    and polysaccharide material
  • It is semipermeable in nature or selectively
    permeable (i.e. allowing rapid passage of some
    chemicals while restricting others).

4
INTRODUCTION
  • DRUG ABSORPTION Movement of unchanged drug from
    site of administration to systemic circulation.

Fig- Plots showing significance of rate extent
of absorption in drug therapy
5
GASTROINTESTINAL ABSORPTION OF DRUGS
  • Oral route is most common ROA for systemically
    acting drugs so more emphasis is given to GI
    drug absorption.
  • It includes all aspects of variability observed
    in drug absorption.
  • CELL MEMBRANE - Cell membrane structure
    Physiology

6
MECHANISM OF DRUG ABSORPTION
  • Passive diffusion
  • Pore transport
  • Facilitated diffusion
  • Active transport
  • Ionic or Electrochemical diffusion
  • Ion-Pair transport
  • Endocytosis

7
(No Transcript)
8
Figures showing different types of
transport Mechanisms.
9
  • Passive diffusion
  • The membrane plays a passive role in drug
    absorption during passive diffusion most drugs
    pass through membrane by this mechanism.
  • The rate of drug transfer is determined by the
    physicochemical properties of the drug and the
    drug concentration gradient across the membrane.
  • The driving force for the movement of drug
    molecules from the gastrointestinal fluid to the
    blood is the drug concentration gradient (i.e.
    the difference between the concentration of drug
    in the gastrointestinal fluid and that in the
    bloodstream).
  • The passage of drug molecules through the
    membrane being a continuous process, there will
    always be an appreciable concentration gradient
    between the gastrointestinal tract and the
    bloodstream (because of volume differences),which,
    in turn, will yield a continuous drug transfer
    and maintain a so-called sink condition.
  • Passive diffusion or transfer follows first-order
    kinetics (i.e. the rate of transfer is directly
    proportional to the concentration of drug at
    absorption and/or measurement sites).

10
(No Transcript)
11
  • Active transport
  • Chemical carriers in the membrane combine with
    drug molecules and carry them through the
    membrane to be discharged on the other side.
  • This process is called active transport because
    the membrane plays an active role.
  • Important features are that chemical energy is
    needed and that molecules can be transferred from
    a region of low concentration to one of higher
    concentration (i.e. against a concentration
    gradient.)
  • The striking difference between active and
    passive transport, however, is that active
    transport is a saturable process and, therefore,
    obeys laws of saturation or enzyme kinetics.
  • The rate of absorption reaches a saturation
    point, at which time an increase in drug
    concentration (larger doses) does not result in a
    directly proportional increase in the rate of
    absorption.
  • This is because of a limited number of carriers
    in the membrane.

12
(No Transcript)
13
(No Transcript)
14
  • where Vmax is the theoretical maximum rate of the
    process
  • Km is the MichaelisMenten constant (i.e. the
    concentration of drug at the absorption site when
    the absorption rate is half of Vmax)
  • 3. Ca is the concentration of drug at the
    absorption site (e.g. in the gastrointestinal
    tract) at a given time.
  • At low solute concentration (i.e. at low
    doses)KmCa

15
  • pH--partition theory of drug absorption
  • The dissociation constant, expressed as pKa, the
    lipid solubility of a drug, as well as the pH at
    the absorption site often dictate the magnitude
    of the absorption of a drug following its
    availability as a solution.
  • The interrelationship among these parameters (pH,
    pKa and lipid solubility) is known as the
    pHpartition theory of drug absorption.
  • This theory is based on the following
    assumptions
  • 1. The drug is absorbed by passive transfer
  • 2. The drug is preferentially absorbed in
    unionized form
  • 3. The drug is sufficiently lipid soluble.
  • The fraction of drug available in unionized form
    is a function of both the dissociation constant
    of the drug and the pH of the solution at the
    site of administration.
  • The dissociation constant, for both acids and
    bases, is often expressed as log Ka, referred to
    as pKa.

16
For weak acids Ionization of weak acids is
described by an adaptation of a classical
HendersonHasselbalch equation.
  • This equation clearly indicates that the ratio of
    ionized/unionized species, a/(1a), is solely
    dependent upon pH and the pKa.
  • For weak acids
  • when pH¼pKa, a¼0.5, or 50 of the drug is in
    ionized form
  • when pH is 1 unit greater than pKa, a¼0.909,or
    90 of the drug, is in ionized form
  • when pH is 2 units greater than pKa, a¼0.99, or
    99 of the drug, is in ionized form
  • when pH is 1 unit below pKa, 1a¼0.9, or 90 of
    the drug, is in unionized form
  • when pH is 2 unit below pKa, 1a¼0.99, or 99 of
    the drug, is in unionized form.

17
For weak bases For weak bases, the
HendersonHasselbalch equation is
  • when pH¼pKa, a¼0.5, or 50 of the drug is in
    the ionized form
  • when pH is 1 unit below pKa, a¼0.909, or 90
    of the drug, is in the ionized form
  • when pH is 2 units below pKa, a¼0.99, or 99
    of the drug, is in the ionized form
  • when pH is 1 unit above the pKa of the
    drug,1a¼0.909, or 90 of the drug, is
  • present in unionized form
  • when pH is 2 units above pKa, 1a¼0.99, or 99
    of the drug, is present in unionized
  • form.
  • As the pH of the solution increases, the degree
    of ionization (percentage ionized) decreases.
  • Therefore, weak basic drugs are preferentially
    absorbed at higher pH.
  • Examples
  • Aspirin, a weak acid with pKa of 3.473.50,has a
    greater fraction ionized in a more alkaline
    (higher pH) environment
  • Erythromycin, a weak base with pKa of 8.7, has a
    greater fraction ionized in a more acidic (lower
    pH) environment.

18
(No Transcript)
19
  • Physicochemical properties of drug substances
  • Drug solubility Dissolution rate
  • Particle size Effective surface area
  • Polymorphism Amorphism
  • Pseudo polymorphism ( hydrates/ solvates)
  • Salt form of the drug
  • Lipophilicity of the drug
  • pKa of the drug p H
  • Drug stability

20
  • Dissolution rate
  • In order for absorption to occur, a drug or a
    therapeutic agent must be present in solution
    form.
  • This means that drugs administered orally in
    solid dosage forms (tablet, capsule, etc.) or as
    a suspension (in which disintegration but not
    dissolution has occurred) must dissolve in the
    gastrointestinal (GI) fluids before absorption
    can occur

21
  • There are two possible scenarios for drug
    dissolution
  • Absorption from solution takes place following
    the rapid dissolution of solid particles. In this
    case, the absorption rate is controlled by the
    rate of diffusion of drug molecules in GI fluids
    and/or through the membrane barrier.
  • 2. Absorption from solution takes place following
    slow dissolution of solid
  • particles. In this process, the appearance of
    drug in the blood (absorption) is
  • controlled by the availability of drug from
    solid particles into the GI fluid
  • (i.e. dissolution is the rate-limiting step).
  • Hence, the rate of absorption and bioavailability
    are dependent upon how fast the drug dissolves in
    the GI fluid.
  • Generally, for hydrophobic drugs, the rate of
    absorption and bioavailability may be improved by
    increasing the rate of dissolution.

22
Noyes--Whitney equation and drug dissolution The
NoyesWhitney equation was developed from careful
observation of the dissolution behavior of
solids in a solvent system
  • The specific dissolution rate constant (K1) is a
    constant for a specific set of conditions,
    although it is dependent on temperature,
    viscosity,agitation or stirring (which alters the
    thickness of diffusion layer) and volume of the
    solvent.
  • The NoyesWhitney equation tells us that the
    dissolution rate (dC/dt) of a drug in the GI
    tract depends on
  • 1. diffusion coefficient (D) of a drug
  • 2. surface area (S) of the undissolved solid drug
  • 3. saturation, or equilibrium, solubility (Cs) of
    the drug in the GI fluid
  • 4. thickness of the diffusion layer (h).
  • dCdt ¼ KDShCs

23
  • Surface area and particle size
  • Of all possible manipulations of the
    physicochemical properties of drugs to yield
    better dissolution, the reduction of the particle
    size of the drug has been the most thoroughly
    investigated.
  • A drug dissolves more rapidly when its surface
    area is increased.
  • This increase in surface area is accomplished by
    reducing the particle size of the drug.
  • This is the reason why many poorly soluble and
    slowly dissolving drugs are marketed in
    micronized or microcrystalline form (i.e.
    Particle size of 210 mm).
  • Drugs where bioavailability has been increased as
    a result of particle size reduction
  • Aspirin
  • Bishydroxycoumarin
  • Chloramphenicol
  • Digoxin
  • Fluocinolone acetonide
  • Griseofulvin

24
Solubility of a drug in the diffusion layer If
the solubility of a drug can be appreciably
increased in the diffusion layer, the drug
molecules can rapidly escape from the main
particle and travel to the absorption site.
This principle is used to increase the
solubility of weak acids in the stomach. The
solubility of weak acids increases with an
increase in pH because the acid is transformed
into an ionized form, which is soluble in aqueous
GI content. The pH of a solution in the
diffusion layer can be increased by using a
highly water-soluble salt of a weak acid
mixing or combining a basic substance into a
formulation (e.g. NaHCO3 sodium
bicarbonate,calcium carbonate, magnesium
oxide,and magnesium carbonate MgCO3)
25
Crystalline forms Many drugs exist in more than
one crystalline form, a property known as
polymorphism. Drug molecules exhibit different
spacelattice arrangement in crystal form in each
polymorph. Though chemically the same, polymorphs
differ substantially with regards to
physicochemical properties.These properties
include solubility, dissolution rate, density and
melting point, among others.Solubility and
dissolution rate, in turn, will likely influence
the rate of Examples are 1.sulfameter This
sulfanilamide is reported to have six polymorphs.
State of hydration The state of hydration of a
drug molecule can affect some of the
physicochemical properties of a drug. One such
property that is significantly influenced by the
state of hydration is the aqueous solubility of
the drug. Often the anhydrous form of an organic
compound is more soluble than the hydrate (with
some exceptions). Complexation Formation of a
complex of drugs in the GI fluid may alter the
rate and, in some cases, the extent of
absorption. The complexing agent may be a
substance normal to the GI tract, a dietary
component or a component (excipient) of a dosage
form.
26
(No Transcript)
27
Complexing with a substance in the
gastrointestinal tract Intestinal mucus, which
contains the polysaccharide mucin, can avidly
bind streptomycin and dihydrostreptomycin. This
binding may contribute to the poor absorption of
these antibiotics. Bile salts in the small
intestine interact with certain drugs, including
neomycin and kanamycin, to form insoluble and
non-absorbable complexes.
28
Absorption of drug from Non-per oral route
  • Buccal/Sublingual Administration
  • Rectal Administration
  • Topical Administration
  • Inhalation Administration
  • Intramuscular Administration
  • Subcutaneous Administration
  • Intranasal Administration
  • Intraocular Administration
  • Vaginal Administration

29
Buccal/Sublingual Administration
  • In buccal route the medicament is placed between
    the cheek and the gum.
  • In sublingual the drug is placed under the
    tongue.
  • Barrier to drug absorption from these route is
    epithelium of oral mucosa.
  • Absorption of drug is by passive diffusion.
  • Eg lozenges
  • nitrates and nitrites,

30
Rectal Administration
  • An important route for children and old patients.
  • The drug may be administered as solution or
    suppositories.
  • Irritating suppositories bases such as PEG
    promotes defecation and drug loss, and presence
    of fecal matter retards drug absorption.
  • By passes the presystemic hepatic metabolism.
  • Drug administered by this route includes
  • ExAspirin, paracetamol, few barbiturates.

31
Topical Administration
  • Skin is the largest organ in the body weighing
    around 2kg and 2mtsq in area and receives about
    1/3rd of total blood circulating through the
    body.
  • Topical mode of administration is called as
    percutaneous or transdermal delivery.
  • The drug act either locally or systemically.
  • Drug that administered precutaneously include
    lidocaine, testosterone , estradiol, etc.

32
Inhalations Administration
  • All drugs intended for systemic effect can be
    administered by inhalation since the larger
    surface area of alveoli, higher permeability to
    the alveolar epithelium rapid absorption just
    exchange of gases in blood.
  • Route has been limited for drugs such as
    bronchodilators, anti-inflammatory steroids and
    antiallergics.
  • Drug do not under go first pass metabolism.
  • lipid soluble drugs absorption rapid by passive
    diffusion and polar drug by pore transport.
  • Generally administered by inhalation either as
    gases or aerosols

33
Intra muscular injection
  • degree of absorption will be Armsgt Thighgt
    Buttocks.
  • These are given to the patients those who are
    unable to take oral medication.
  • These route is used for the drugs that are poorly
    absorbed from the GIT.
  • Lipophilic drugs absorbed rapidly by passive
    diffusion whereas hydrophilic drugs are slowly
    absorbed through capillary pores
  • Ex-digoxin

34
Subcutaneous injection
  • Application of heat increase the blood flow.
  • Local co administration of vasodilators.
  • Absorption of the drug can be slowed by
    co-injection of a vasoconstrictor.
  • Ex epinephrine
  • Insulin, local anesthesia.

35
Intraocular Administration
  • Mainly for the treatment of local effects such as
    mydriasis, meiosis, anesthesia and glaucoma.
  • The barrier in the occular membrane is called
    cornea which contains both hydrophilic and
    lipophilic characters.
  • Thus for optimum intra occular permeation drug
    should posses biphasic solubility.
  • pH of formulation influences lacrimal output.
  • The addition of viscosity increasing agents in
    the ophthalmic solution will increases occular
    bio availability.
  • Ex pilocarpine, timmolol, atropine.

36
Vaginal Administration
  • Available in various forms tablets, creams,
    ointments, douches and suppositories.
  • Used for systemic delivery of contraceptive and
    other steroids.
  • By passes first pass metabolism.
  • Factors effecting drug absorption are
  • -pH of the lumen fluid
    4-5.
  • -vaginal secretions.
  • -microbes at vaginal
    lumen.
  • Bio availability of vaginal product was about 20
    more compared with oral.
  • Ex steroidal drugs and contraceptives.

37
Intra Nasal application
  • Used for the systemic administration of drugs.
  • Mainly contain decongestants, anti histamines,
    corticosteroids.
  • Nasal mucosa are more permeable than gastric
    mucosa.
  • Drugs directly traveled through blood stream no
    first pass metabolism.
  • Peptides are not actively absorbed from nasal
    mucosa but can be promoted by surface active
    agents.
  • Ex desmopressin acetate

38
Physiological factors
  • 1.Age

    2.Gastric Empting
    3.Intestinal Transit

    4.GI pH

    5.Blood Flow to GIT
    6.Diseased State

    7.GI Content
    8.First pass
    effect

39
1. Age
  • In infants GI pH is high and intestinal surface
    and blood flow to GIT is low as compared to
    adults results in poor drug absorption.

  • In elderly people, alteration in drug absorption
    becuase of alteration in gastric emptying, and
    incidents of achlorhydria and bacterial over
    growth in small intestine.

40
2. Gastric emptying
  • Defined, as passage of contents of stomach into
    the intestine.
  • Rapid gastric emptying is advisable where
  • Rapid onset action is required, eg sedatives.
  • Dissolution of drug occurs in intestine.
    eg Enteric coated tablets.
  • Drug is unstable in gastric fluids.
  • Drug is best absorbed from distal part of small
    intestine, eg vitamin B 12 .

41
Kinetics of GI emptying
  • GI emptying is first-order kinetics many
    parameters are used to quantify a gastric
    emptying

  • 1.Gastric
    emptying rate Is the speed at which the stomach
    contents are emptied into the intestine.


  • 2.Gastric emptying time Time required for the GI
    content to empty into small intestine.

  • 3.G.E.t1/2
    Is time taken for half the stomach contents to
    empty.

42
Factors affecting GI emptying
  • 1.Volume of meals

    2.Composition of meal
    3.Physical state of
    meal
    4.GI ph
    5.Body posture

    6.Emotional state

    7.Exercise
    8.Drugs

43
  • 1.Volume of meal Larger the bulk of the meal,
    longer the gastric time and however an initial
    rapid rate of emptying is observed with large
    meal volume and initial lag phase in emptying of
    small volume meals.
  • 2.Composition of meal The rate of gastric
    emptying for various food materials in the
    following order carbohydratesgtproteinsgtfats.
  • 3.Physical state Liquid meal takes less
    time as compared to solid meals.


  • 4.GI ph Gastric emptying is
    retarded at low stomach pH and promoted at
    alkaline pH.

44
  • 5.Exercise Vigorous physical training retards
    gastric empting.
  • 6.Body posture Gastric emptying is favored
    while standing and by lying on right side.
  • 7. Emotional state Stress and anxiety
    promotes GI motility, where as depression retards
    it.
  • 8.Drugs That retards gastric emptying are
    antacids, anti cholinergic, narcotic analgesics
    and tri cyclic antidepressants.

45
3. Intestinal transit
  • Defined as, the residence time of drug in small
    intestine.
  • Delayed intestinal transit is desirable for
  • 1.Sustained release dosage forms,
  • 2.Drug that only release in intestine ie ,enteric
    coated formulations,
  • 3.Drugs absorbed from specific sites in
    intestine, eg several B vitamins

46
4. GI pH
  • GI pH influence in several ways

    1.Disintegration
    Disintegrating of some dosage forms is pH
    sensitive, enteric coated tabs dissolve only in
    alkaline pH.

    2.Dissolution A large no. of drugs either weak
    acids or weak bases, their solubility is greatly
    affected by GI pH.

    -weakly
    acidic drugs dissolve rapidly in alkaline pH.

    -basic drugs soluble in acidic pH..

    3.Absorption Depending upon drug pKa whether
    its an acidic or basic drug the GI pH influences
    drug absorption.
  • 4.stability of drug GI pH influence the
    stability of drug.
  • Eg erythromicin

47
5. Blood flow to git
  • GIT is extensively supplied by blood capillary,
    about 28 of cardiac output is supplied to GIT
    portion, most drug reach the systemic
    circulation via blood only.
  • Any factor which affects blood flow to GIT may
    also affect absorption.

48
6. Disease state
  • Several disease state may influence the rate
    and extent of drug absorption.
  • Three major classes of disease may influence
    bioavailability of drug.
  • GI diseases
  • CVS disease
  • HEPATIC disease

49
GI diseases
  • A. GI infections
  • 1.Celiac disease (characterized by destruction
    of villi and microvilli) abnormalities associated
    with this disease are increase GI emptying rate
    and GI permeability, alter intestinal drug
    metabolism.
  • 2.Crohns disease alter gut transit time and
    decreased gut surface area.
  • B. GI surgery
  • Gastrectomy may cause drug dumping in intestine,
    osmotic diarrhoea and reduce intestinal transit
    time.

50
CVS diseases
  • In CVS diseases blood flow to GIT decrease,
    causes decreased drug absorption.

Hepatic diseases
Disorders like hepatic cirrhosis influences
bioavailability of drugs which under goes first
pass metabolism.
51
7. Gastro intestinal contents
  • 1.Food- drug interaction In general
    presence of food either delay, reduce, increase
    or may not affect absorption.
  • Aspirin Delayed
  • Penicillin's Decreased
  • Griseofulvin Increased
  • Methyldopa Unaffected
  • 2.Interaction of drug with normal GI contents
    GIT contains no. of normal constituents such as
    mucin, bile salts and enzymes, which influence
    the drug absorption. Eg Inhibitory action of
    bile on GI motility.



52
  • 3.Drug-Drug interaction in the GIT
  • Physico chemical drug- drug interaction
  • Adsorption Eg anti diarrhial preparations
    contains adsorbents like kaolin, prevents a
    absorption of many drugs co-administered with
    them.
  • Complexation Eg penicillin derivative with
    ca-gluconate.

  • pH changes Basic drugs changes gastric pH
  • Eg tetracycline with antacids

53
8. First pass metabolism
  • Four primary systems which affect pre systemic
    metabolism of a drugs.
    1. Luminal enzymes.

    2.Gut wall enzymes or mucosal enzymes.
    3. Bacterial enzymes.
    4.
    Hepatic enzymes.

54
Pharmaceutical Factors
  • Different dosage forms-
  • Solutions Suspensions
  • Tablets Capsules
  • Coated tab Enteric coated tab
  • Disintegration test
  • Dissolution test
  • Excipients and adjuvant
  • Product age and storage conditions.

55
FACTORS INFLUENCING DRUG ABSORPTION
  • By proper biopharmacetic design, the rate
    extent of drug absorption (BA) / systemic
    delivery of drug to the body can be varied from
    rapid complete absorption to slow sustained
    absorption depending upon desired therapeutic
    objective.
  • Sequence of events that occur following
    administration of solid dosage form until its
    absorption in systemic circulation.
  • Rate at which drug reaches systemic circulation
    is determined by slowest of the various steps
    involved in sequence. Such a step is called as
    Rate- determining/ Rate- limiting step (RDS)

56
(No Transcript)
57
Dosage forms
  • Order of bioavailability of drugs.
  • Solutionsgtsuspensionsgtcapsulesgttabletsgtcoated
    tablets
  • SOLUTIONS
  • Drugs absorbed more rapidly in this form.
  • When this formulation is taken after meal gastric
    emptying is the rate limiting step.
  • Factors influencing are
  • Nature of the solvent, viscosity, surfactant,
    solubilisers, stabilizers.
  • Drugs which are poorly soluble can be converted
    to water soluble by the addition of co solvents
    such as alcohol, propylene glycol etc

58
Suspensions
  • Dissolution is the rate limiting step for the
    absorption of the drug from suspension.
  • Factors to considered for drug bioavailability
    are,
  • particle size ,
  • wetting agents ,
  • viscosity of the medium,
  • suspending agents.

59
(No Transcript)
60
  • For hard gelatin capsules the shell should
    disrupt quickly and expose the contents to the GI
    fluids.
  • Factors influencing are particle size, density,
    crystal form of the drug, selection of diluents.
  • soft elastic capsule dissolve faster than hard
    gelatin capsule tablets. Which shows better
    bioavailability from oily solutions, emulsions,
    or suspensions.
  • The problem with SGC is high water content of
    shell, moisture migrate in to the shell causes
    crystallization of the drug results in altered
    dissolution characteristics .

Capsules
61
Tablets
  • This is the most widely used dosage form.
  • Problem with this arises from reduction in the
    effective surface area due to granulation
    subsequent compression in to dosage form.
  • Tab disintegration and granule deaggreation are
    the imp steps in absorption process.
  • Compression force also may be an important
    factor.
  • Disintegration is the rate limiting step for
    this.

62
(No Transcript)
63
Coated tablets
  • Coat is generally used to mask unpleasant taste
    odor to protect the ingredients from
    decomposition during storage.
  • This adds an additional barrier between GIT
    drug. It should get dissolve before tablet
    disintegration dissolution.
  • Sugar film coatings
  • Sugar coating will take more time than film
    coating.
  • Care should be taken while selecting the coating
    material
  • Ex methyl cellulose which retards the dissolution

64
Enteric coated tablets
  • It is a special film coated design to restricts
    the gastric fluids to dissolve in small
    intestine.
  • Protect the drug from the degradation in the
    stomach Ex erythromycin.
  • Minimize the gastric distress caused by some
    drugs. Ex aspirin.
  • These tablets must empty the stomach before the
    drug absorption can begin.
  • The polymers with pKa values ranging from 4-7
    have been found to use.
  • Thickness of coating will effects the
    bioavailability in these formulations.

65
Pharmaceutical Excipients
Excipients are add to ensure the acceptability,
physiochemical stability, bioavailability and
functionability of the drug product. More the
number of excipients in a dosage form, the more
complex and greater the absorption and
bioavailability problems.
66
Commonly used excipients Diluents
Binders Disintegrants Lubricants
Coatings Suspending agents Surfactants Buffers C
omplexing agents Colorants Sweeteners.
67
Product Age and Storage Condition
  • A number of changes, especially in the
    physiochemical properties of a drug in a dosage
    from, can result due to aging and alteration in
    storage conditions which can adversely affect
    bioavailability.
  • Solution dosage form.
  • Solid dosage form.

68
DISINTEGRATION
  • It is provided to determine the compliance with
    the limit on disintegration stated in the
    individual monograph.
  • Formulation tested are
  • un coated tab, plain coated, enteric
    coated, buccal, sub lingual, hard gelatin capsule
  • For un coated tab and capsules the time is 30
    mins. where as for coated tab it is 2 hrs.
  • Disintegration can be aided by incorporating
    disintegrants in suitable amount during
    formulation .

69
DISSOLUTION
  • The development of this test predicts the drug
    absorption.
  • It shows close relation b/w drug absorption and
    dissolution rather than disintegration.
  • By using USP apparatus
  • type1- basket method
  • type2- paddle method
  • Basket method- the basket containing tab and
    capsules are immersed in the dissolution fluid
    and rotated .
  • Paddle method-the dosage form is placed directly
    in the dissolution medium and paddle is rotated.
  • Fluids may be water , HCL, buffer maintained at
    370c.
  • The samples are removed at desired interval and
    assayed for drug content.

70
METHODS OF DETERMINING ABSORPTION
  • IN-SITU AND IN-VIVO

  • METHODS

71
  • IN-SITU METHODS
  • These absorption models permits the
    study of individual organ processes site
    specific absorption.
  • The tissue is maintained intact with
    blood flow to the organ. Samples of drug solution
    from in-situ loop experiments can be obtained to
    measure the drug disappearance metabolite
    formation.

72
DIFFERENT METHODS USED
  • 1) Absorption from small Intestine
  • A) Perfusion technique.
  • B) Intestinal loop technique.
  • 2) Absorption from stomach.
  • 3) Perfusion Intestine-Liver
  • preparation.

73
  • 1) ABSORPTION FROM SMALL INTESTINE
  • Perfusion Technique
  • Method-1
  • In this method adult male rats are fasted for
    about 16-24 hours before the experiment.
  • The animal is anaesthesised, a midline abdominal
    incision is made the small intestine is
    isolated cannulated at the duodenal ileal
    ends with polyethylene cannulas of internal
    diameter 2.5mm external diameter of 3.5mm.
  • The stomach cecum are closed off by ligature
    the intestine is then replaced in the rats
    abdominal cavity.

74
  • The incision is closed the duodenal cannula is
    attached to an infusion pump.
  • Initially the intestine is cleared off
    particulate matter using drug free buffer at a
    rate of 1.5 ml/min for 30 minutes.
  • Next, buffer solution containing the drug is
    perfused at a rate of 1.5 ml/minute for 30
    minutes.
  • Then, samples at 10 minutes interval are
    collected from the ileal cannula.

75
  • The samples are assayed for drug content the
    relative rate of absorption is calculated from
    the difference in the drug concentration entering
    leaving the small intestine.
  • This method was used to demonstrate the validity
    of the pH partition hypothesis for the intestinal
    absorption of a variety of weakly acidic basic
    drugs.

76
  • Method-2
  • Doluisio and coworkers have reported a
    simple reproducible method for studying
    intestinal absorption of drugs in rats.
  • A rat that has been fasted overnight is
    anaesthetized ( intraperitoneally with urethane),
    a midline abdominal incision is made the
    intestinal segment (usually jejunal) to be
    perfused is identified.
  • A-L shaped glass inlet cannula is secured into
    the segment the outlet cannula is placed
    approximately 15-50 cm from the inlet cannula.

77
  • These are secured with sutures the intestine
    is replaced in the abdominal cavity.

Rat perfusion technique
78
  • A 30 ml hypodermic syringe equipped with a three
    way stopcock containing perfusion solution at
    37C is attached to the duodenal cannula.
  • Then the intestinal lumen is cleared off
    particulate matter by introducing the solution
    from the syringe.
  • The syringe is then filled with drug solution
    10ml volume is introduced into the intestine.

79
  • An identical syringe is affixed to the ileal
    cannula.At appropriate time intervals,the
    solution in the intestine is pumped into either
    syringe a 0.1ml sample is removed assayed for
    drug content.
  • Alternatively, the compound is perfused through
    the segment with an infusion pump at a constant
    rate for 120 minutes. Outflow samples are
    collected at predetermined time intervals both
    influent effluent are assayed for the
    compound.

80
  • B) Intestinal Loop Technique
  • Adult male rat are fasted over night.
  • Under anesthesia an abdominal midline incision
    is made the small intestine is exposed.
  • A proximal ligature is loosely placed around the
    intestine about 6 from the pylorus a distal
    ligature is secured at a distance of
    approximately 4 distal to proximal ligature.

81
  • The drug solution is introduced into the lumen
    of loop by means of a syringe which is secured by
    the proximal ligature.
  • After injection, needle is removed, the proximal
    ligature is tightened, the loop is replaced into
    the abdominal cavity the incision is closed.
  • After a predetermined period of time, the animal
    is sacrificed, the intestinal loop is rapidly
    excised homogenized the amount of drug
    unabsorbed is determined.

82
  • 2) ABSORPTION FROM STOMACH
  • Fasted adult male rats are anaesthetized,
    stomach is exposed the cardiac end is ligated.
  • An incision is made in the pylorus in which a
    cannula is introduced ligated.
  • The lumen is washed several times with saline
    subsequently with 0.1N HCl solution containing
    0.15M NaCl.
  • The drug solution of known concentration is
    introduced into stomach.

83
  • After 1hr, the solution is removed from the
    gastric pouch assayed for drug content.
  • The percentage of drug absorbed in 1hr may be
    calculated.
  • The gastric pouch may also be
    homogenized analyzed for drug.
  • In order to obtain number of samples as
    a function of time, the following modification is
    done.
  • Drug solution is introduced into the gastric
    lumen via cardiac cannula.

84
  • A polyethylene tubing connected to a 2ml syringe
    equipped with a three way stopcock is attached to
    the duodenal L shaped glass cannula.
  • At appropriate intervals the stomach contents
    are sampled by withdrawing about 0.5ml of
    solution into the syringe, removing 0.1ml of
    aliquot returning the reminder.

85
3) PERFUSED INTESTINE-LIVER PREPARATIONS
  • This technique use a direct approach to examine
    the contribution of each organ/tissue in the
    first pass metabolism can be used to study the
    sequential processing of drug metabolites by
    the intestine liver.

86
  • A schematic illustration of the once through
    vascularly perfused rat intestine-liver
    preparation is shown in below figure.

87
  • where, QHV Hepatic venous flow
  • QPV Hepatic portal flow
  • QHA Hepatic artery flow
  • CPV Steady- state drug
  • concentration in the
    portal vein
  • CHV Steady- state drug
  • concentration in the
    hepatic vein
  • The superior mesentric artery the hepatic
    artery are cannulated for the inflow of
    oxygenated perfusate to the intestine liver
    respectively.

88
  • The bile duct can also be cannulated to obtain
    or to permit full collection of bile.
  • The portal vein is cannulated for sampling of
    venous perfusate from the intestine.
  • In addition, the outflow from the hepatic vein
    can be sampled.
  • The model is flexible permits manipulation of
    the flow, intestinal site concentration
    perfusate.

89
Some Applications of perfused intestine liver
studies.
  • Application
  • Measuring extraction ratios
  • 2) Investigate intestinal metabolism
  • Examples
  • Determine the steady-state extraction ratio of
    enalpril in the intestine liver.
  • The intestine is responsible for the formulation
    of most of 4-methylumbeliferone glucuronide.

90
IN-VIVO METHODS
  • IN-VIVO Methods can classified into-
  • Direct method.
  • Indirect method.
  • 1)DIRECT METHOD
  • In this method, the drug levels in blood or urine
    is determined as a function of time.
  • A blank urine or blood sample is taken from the
    animal before experiment.
  • The test dosage form is then administered

91
  • to the animal at appropriate intervals of
    time the blood or urine samples are collected
    assayed for drug content.
  • From the data, we can determine the rate
    extent of drug absorption.
  • 2) INDIRECT METHOD
  • In this method, the pharmacologic response is
    taken as the index of drug absorption.
  • Here, Assumption is made that the pharmacologic
    response of a drug is related to the amount of
    drug in the body, the response is determined
    after the administration of a test dosage form.
  • LD50 appears to be dependent on the rate of
    absorption of the drug hence on the rate of
    dissolution.

92
References
  1. Peter.G.Welling et.Al pharmacokinetics 2nd
    edition marcel dekker inc new york32-33.
  2. Dr.Shobha rani r.Hiremath textbook
    biopharmaceutics and pharmacokinetics prism
    books private limited banglore28-31
  3. D.M.Brahmankar, sunil b. Jaswal biopharmaceutics
    and pharmakokinetics. Ist ed., Vallabh
    prakashan-delhi 1995. P.39-71.

93
THANK U ALL
Write a Comment
User Comments (0)
About PowerShow.com