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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5480_Библиотеки_им_академика_М_И_Перельмана.pdf
Biopharmaceutics
69
6.7. Ionic Diffusion (or Electrochemical Diffusion)
One may take cognizance of the fact that the inherent charge residing on the membrane infl uences the
actual permeation of drug substances. Nevertheless, the usual molecular forms of solutes (or drug mol-
ecules) are found to be quite unaffected by the corresponding membrane charge and, therefore, perme-
ate even faster vis-à-vis the ionic forms. Interestingly, it has been duly observed that the anionic solute
permeates more rapidly than the cationic solute.
Hence, at a given pH, the observed rate of permeation will be of the following order:
Unionized molecules > anions > cations
6.7.1. Permeation Profile of Cationic Drug Molecules
The permeation profi le of cationic drug molecule solely depends upon either the ensuring ‘electrical
gradient’ or the prevailing ‘potential difference’ as the critical driving force occurring across the mem-
brane. Obviously, a cationic drug gets dully repelled because of the specifi c positive charge residing
fi rmly on the outer region of the membrane. Consequently, only such particular cationic drug molecules
having a distinct ‘high–kinetic energy status’ would be able to penetrate the ionic barrier with great ease
and fervour. Importantly, once the cations have an access inside the membrane, they usually get attracted
to the negatively charged intracellular membrane thereby raising a distinct ‘electrical gradient’.
Thus, in the above situation it may be said that the ‘drug’ is moving towards the ‘downhill direction’
along with the electrical gradient,
Electrochemical Diffusion: It refers to a situation when the ‘drug moves from a higher to a lower
concentration, i.e., the drug moving down the electrical gradient’.
The ionic or electrochemical diffusion continues till such time an equilibrium is accomplished (viz.
very much akin to passive diffusion.
6.8. Ion-Pair Transport
The ion-pair transport mechanism rightly and explicitly clarifi es and explains the critical absorption of
drugs, such as:
∑ quaternary ammonium compounds, e.g., Demecarium bromide—a quaternary ammonium anti-
cholinesterase drug; Pilocarpinenitrate—a quaternary ammonium cholinomimetic drug
∑ sulphonic acids.
The above-mentioned drugs do have a tendency to undergo ionization under all pH conditions.
Following are some of the typical examples of carrier-mediated intestinal transport process:
1. P-Glycoprotein [or P-Gp]: P-Glycoprotein is an intestinal transmembrane protein that
causes the specifi c reduction of the ensuring intestinal epithelial cell permeability from
lumen to the circulating blood for a good number of cytotoxic and lipophilic drugs.
2. Amino Acid Transporters: These are duly present in the intestines. A number of oral
cephalosporins are adequately absorbed via the amino acid transporters.
Examples
Essentials of Biopharmaceutics and Pharmacokinetics
70
Mechanism of Action: Though the quaternary ammonium compounds as well as the sulphonic acids essen-
tially possess low o/w partition coeffi cient values, yet such typical drug entities do exhibit a tendency to
penetrate the membrane by the formation of typical reversible neutral complexes specifi cally with the
endogenous ions of the GIT, e.g., mucins.
48
In fact, such neutral complexes do possess
∑ requisite lipophilicity and
∑ aqueous solubility
in order to undergo passive diffusion effi caciously and, hence, such a phenomenon is invariably termed
as the ‘ion-pair transport’ as illustrated in Figure 2.18.
6.9. Endocytosis
Endocytosis refers to a method of ingestion of a foreign substance by a cell. The cell membrane invagi-
nates to form a space for the material and then the opening closes to trap the material inside the cell.
In another words, endocytosis is a minor transport mechanism that essentially involves the critical
engulfi ng of the extracellular materials very much within a specifi c region of the cell membrane to give
rise to the formation of a ‘saccule’ or a ‘vesicle’ that gets detached intracellularly at the end of the phe-
nomenon as depicted in Figure 2.19. It is, therefore, also known as ‘vesicular transport’ or ‘corpuscular
transport’ alternatively.
Pinocytosis refers to the engulfment of the small solutes or fl uids, whereas, phagocytocis refers to the
engulfment of larger macromolecules or particles invariably by means of the respective macrophages.
Besides, endocytocis and exocytocis are the specifi c processes related to moving the ‘macromolecules’
either into or out of a cell, respectively.
Mechanism of Action: These essentially include the following:
1. First of all, in the course of pinocytosis or phagocytosis, the respective cell membrane duly invagi-
nates to crucially surround the material and subsequently engulfs the material right inside the cell.
48
Mucins: These are high molecular weight glycoproteins and form major constituents of gastric juice, saliva,
intestine juice and other secretions.
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Figure 2.18 Diagrammatic representation of ion-pair transport of a cationic drug.
Biopharmaceutics
71
2. Consequently, the cell membrane comprising the material duly generates a vesicle (or vacuole)
within the cell.
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Figure 2.19 Diagrammatic representation of an endocytic uptake of macromolecules.
Following are two typical examples:
1. Sabin Polio Vaccine and other Large Proteins: The proposed process for the special-
ized products, viz. orally administered Sabin Polio Vaccine, sub-cutaneously administered
Erythropoietin 4000 U, are accomplished duly via the vesicular transport (or endocytosis).
2. Insulin: The transport of ‘insulin’ (a protein) from the respective insulin-producing cells of the
pancreas occurs due to exocytosis, into the specifi c extracellular space. The probable mecha-
nism of action may be expatiated by the following two cardinal steps in a sequential manner:
∑ insulin molecules being packaged into the intracellular vesicles and
∑ subsequent ‘fusion’ with plasma membrane to release insulin outside the cell.
Examples
6.10. Summary of Important Transport Processes vis-à-vis Critical Absorption
of Drugs by Different Mechanism
It is, however, pertinent to state at this point in time that a drug molecule may get duly absorbed in vivo
by defi nitely more than one mechanism. This fact may be further expatiated and substantiated by the
most glaring example of the well-known cardiac glycosides, such as Lanoxin
®
, Crystodigin
®
that are
absorbed so meticulously by two entirely different transport mechanism, namely ‘passive diffusion’ (see
Section 2(6.1)) and ‘active transport’ (see Section 2(6.4)). It has also been established that the ensuing
transport mechanism solely depends on the actual site of drug administration.
Figure 2.20 records the summary of certain important transport processes vis-à-vis the critical absorp-
tion profi le of a few specifi c categories of drug substances by different mechanism in an orderly manner.
Essentials of Biopharmaceutics and Pharmacokinetics
72
7. Drug Absorption vs. Bioavailability
7.1. Preamble
After haring studied the intricacies and critical aspects of ‘drug absorption mechanism’ (under Section 2(6)),
one would be rather tempted and inclined to have an exhaustive inquiry into the absorption profi le of
drugs from various known solid-dosage forms (viz. tablets, capsules, dragees).
Importantly, to understand thoroughly and accomplish the conceptualized therapeutic objective(s), the
eventful ‘drug product’ (or dosage form) should be able to deliver the active drug with a reasonable success both
∑ at an ‘optimized rate’ and
∑ at a ‘suffi cient quantum’.
Nevertheless, these two cardinal aspects could be duly addressed by the meticulous ‘biopharmaceutic
design’ of the drug product bearing in mind the crucial rate and the degree of absorption, invariably
termed as ‘bioavailability’. Indeed, the so-called ‘systemic delivery of a drug substance’ right inside a
human body may be achieved in two ways, namely:
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Figure 2.20 Diagrammatic representation of the summarized status of important transport phenomena and
drugs absorbed via these mechanisms.
Biopharmaceutics
73
∑ a fast, rapid and complete absorption of drug and/or
∑ a slow, sluggish and sustained absorption of drug
that depends exclusively upon the desired/predicted therapeutic aims and objectives.
7.2. Pharmaceutical Factors (or Biopharmaceutic Considerations)
Affecting Drug Bioavailability
The various pharmaceutical factors (or biopharmaceutic considerations) intimately associated with the ultimate
design and judicious manufacture of drug product so as to enable the critical delivery of the ‘active drug’
having the desired and pre-empted bioavailability characteristic features. These are comprised essentially
with four cardinal aspects, namely:
∑ type of drug product (viz. solution, suspension, suppository),
∑ nature of excipients used in the drug product,
∑ physicochemical characteristic features of drug molecules and
∑ route of drug administration.
Importantly, the critical and important criteria for the adequate absorption of ‘active drugs’ from the
solid-dosage forms could be duly ascertained by the following two vital aspects, such as:
∑ rate-determining step and
∑ Noyes–Whitney dissolution rate law
which will be treated individually in the following sections.
7.2.1. Rate-Determining Step (RDS)
Importantly, in the discussion under Section 2(5.2 through 5.4), the ensuing absorption phenomenon
actually commenced almost instantaneously the moment the ‘drug’ came in contact with the site for
absorption effectively. However, this is not the path followed by a ‘drug’ when it is administered ade-
quately in the typical solid-dosage form.
Evidently, in order to facilitate the ‘drug’ to undergo absorption, it should fi rst of all be subjected to
dissolution in an appropriate medium (preferably water).
The above analogy may be best explained by assuming the typical absorption of an acidic drug
[HA] from a tablet. The four common steps invariably involved in the ensuing absorption phenom-
enon are, namely:
∑ drug in tablet form [A],
∑ drug particles in stomach [B],
∑ drug in solution form [C] and
∑ drug in circulating blood
that are explicitly given in Figure 2.21(a). However, the ‘tablet’ on being administered orally (or swal-
lowed) undergoes the following three functional procedures in the body:
Disintegration–Dissolution–Absorption
as illustrated in Figure 2.21(b).
Essentials of Biopharmaceutics and Pharmacokinetics
74
At this point in time, it is absolutely necessary to have a clear distinction between the following two
important phenomena, such as:
∑ disintegration and
∑ dissolution.
Disintegration Disintegration may be defi ned as ‘the critical breaking apart of the compressed tablet
into the respective primary particulate matters’.
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Figure 2.21(a) Four common steps involved in absorption phenomenon of a drug.
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Figure 2.21(b) Diagrammatic representation of normal steps involved in absorption of a drug following oral
ingestion of a tablet: disintegration-dissolution-absorption.
Biopharmaceutics
75
The incorporation of certain known disintegrants
49
(or disintegrating agents) in the original formula,
one may form a tablet which would eventually undergo a massive explosion on being submersed in an
aqueous environment.
Note
It is worthwhile to mention here that though disintegration is an absolute pre-requisite to the
process of ‘absorption’ as well as fast and rapid disintegration, yet it certainly increases a speedy
onset of action, however, it fails to ensure absorption.
Obviously, in case the ‘drug particulate matters’ never get dissolved adequately even after the disinte-
gration comes into play, the ‘drug’ will never gain an access into the circulating blood stream.
Incidentally, two different situations may arise with respect to the phenomenon of disintegration, namely:
1. Negative Disintegration: The negative disintegration test distinctly and certainly provides the
evidence of a reasonably poor tablet, which is signifi cantly based on the fact that
∑ if the very ‘fi rst step’ fails to materialize,
∑ the subsequent ‘dissolution’ will be rather diffi cult, and under these circumstances, the follow
up absorption process may not ever commence.
2. Fast Disintegration: It invariably helps in the appropriate prediction of a uniform behav-
ioural profi le from the tablets; however, it may not ensure and ascertain, in itself, the overall
effi caciousness ultimately.
Dissolution Dissolution may be defi ned as ‘a process by which a solute is rendered homogenous with a
solvent’.
In other words, a ‘drug substance’ must undergo dissolution before absorption may take place. However,
in actual practice, the phenomenon of dissolution rate is found to be usually the slowest and most sluggish
step observed soon after the ‘oral administration’ of a solid-dosage form (viz. tablets, capsules, dragees).
49
Disintegrant: It refers to a substance usually added to a tablet granulation during its preparation and after
granulation to facilitate the breaking apart of the tablet into the granules, and splitting of the granules respectively
when it is duly subjected to the fl uids of the GI tract.
Note
A universal ‘rule of thumb’ suggests prominently that drug substance with an aqueous solubility <1%
of pH value 1–7 at 37 ± 1°C are critically predisposed to certain typical bioavailability problems.
Predictor of Dissolution–Rate-Limited Absorption: Nevertheless, under the infl uence of iden-
tical experimental parameters, a typical and critical rate of dissolution which being <0.1 mg mL
–1
cm
−2
,
employing a rotating disk with a constant surface area represents the so-called ‘predictor of dissolution–
rate-limited absorption’.
Various Absorption Steps Immediately after Oral Ingestion of Coated Tablets or Capsules The following
Scheme A illustrates explicitly the various absorption steps that are followed immediately after the oral
ingestion of the coated tablets or capsules (see Figure 2.22).
Essentials of Biopharmaceutics and Pharmacokinetics
76
It is, however, pertinent to state here that such drug entities whose solubility properties are observed to
be distinctly less than the ideally required optimized formulations in order to skip over the exacerbation
of an inherent bioavailability problem. Therefore, Scheme A may duly come into play in the steps imme-
diately preceding the disintegration process so as to result in the requisite formation of ‘drug particulate
matters in the ensuring suspension.’
Rate-Limiting Steps vis-à-vis Risk for Incomplete Bioavailability In a broader perspective, the drug bio-
availability may be caused duly by the critical failure of the following two vital and important features,
namely:
∑ coating of tablet to expose the intended drug contents and
∑ administered tablet to undergo rapid disintegration.
Amazingly, if the aforesaid two steps are fairly and reasonably rapid, the observed dissolution of particu-
late matters duly present in the ‘suspension’ shall be expected to render into a rate-limiting feature.
Interestingly, one may genuinely encounter greater hits in the ‘potential-limiting steps’ corresponding
to the ‘more complex nature’ of the drug product (or dosage form) and, therefore, entails greater risk
for ‘incomplete bioavailability’. The most informative perception, knowledge and understanding with
regard to the extent to which a desired formulation may exert overwhelmingly these criteria, such as:
∑ typical infl uence upon the rate of absorption and
∑ pivotal role in accomplishing bioavailability,
are predictable effectively upon these fundamental basis.
Figure 2.23: Scheme B explicitly records the useful anticipated results pertaining to ‘absorption’ vis-à-vis
‘bioavailability risk’ pertaining to an array of specifi cally designed/formulated drug products.
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Figure 2.22 Scheme A: Absorption steps involved immediately after oral ingestion of coated tablets or capsules.
The various aspects of Scheme B essentially include the following:
1. Solutions: Drug substances that are administered usually in solution form, viz. elixirs, syr-
ups and solutions, do ascertain fast and rapid absorption of the drug, since the rate-limiting
dissolution gets eliminated almost completely by the drug product itself.
Explanation
Biopharmaceutics
77
2. Sustained Release (or Prolonged Release or Delayed Release) Dosage Forms: These
drug products would be duly expected to exhibit the lowest level of absorption by virtue of
the underlying fact that the ‘release pattern of the active drug’ has been retarded intentionally.
3. Enteric-Coated Tablets: These specially designed dosage form are intended to check and
prevent particularly the drug-release profi le just prior to its arrival in the intestinal passage.
4. Coated Tablet: In this instance, fi rst and foremost, the ‘coating’ should get dissolved, which
is subsequently followed by the core tablet itself. Thus, the rapid dissolution of the active
drug contained in the core tablet will not commence till such time the tablet itself undergoes
disintegration.
5. Capsules: They invariably do have the ‘capsule shell’ (made up of hard gelatin) which must
get dissolved before the active drug contents are duly available for dissolution. Nevertheless,
the contents of a capsule more or less behave as
∑ a ‘tablet’ (very much akin to a compressed one) and
∑ a ‘suspension’ (resemblance more closer)
and get distributed rather quickly right inside the GI fl uids.
6. Suspensions: They essentially possess no coatings at all to be removed; besides, no tablet to
undergo disintegration, and no capsule-shell to get dissolved. Importantly, the suspensions are
observed to be distinctly slower and more sluggish in nature vis-à-vis the emulsion, due to the
fact that the suspended drug substance should still undergo dissolution process in the GI fl uids.
7. Emulsions: They normally contain the dissolved drug substance that should critically
undergo partition between the two existing immiscible phases.
8. Solutions: They ultimately present the drug almost directly upon the gastrointestinal (GI)
wall for causing the necessary absorption.
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Figure 2.23 Scheme B shows useful anticipated results pertaining to absorption vis-à-vis bioavailability risk.
Important Features: They essentially include the following:
1. Any one of the other drug products (or dosage forms), as discussed above from (1) through (7), may
be bioavailable as speedily as the solutions provided the various steps preceding the absorption
phenomenon are fast and rapid enough.
2. Importantly, an ‘active drug’ presented in one of the non-solution dosage forms may not be
absorbed more rapidly and completely vis-à-vis its respective solution form.
Essentials of Biopharmaceutics and Pharmacokinetics
78
7.2.2. Noyes–Whitney Dissolution Rate Law
50
Preamble The critical presence of a ‘fast disintegrant’ amalgamated with a ‘rapidly absorbed drug’,
the overall net dissolution rate of the ensuring drug particulate matters would themselves impose a limit
upon the very rate of appearance of the drug duly present in the circulating blood. However, the afore-
said conditionalities may fall within the scope of a ‘normal instance’. Besides, it has been observed that
one may suitably augment the rate of absorption of a drug by simply enhancing the rate of dissolution.
As the rate of dissolution determines the ‘limiting factor’, it follows obviously that one could control
and modulate the absorption profi le of a drug by controlling the dissolution rate accordingly. Interestingly,
it accomplishes the ultimate goal and targeted objective of various aspects related to drug development
in a methodical way so as to control/monitor the ensuing behavioural profi le of the ‘product’ under
investigative studies in a clinic.
Importantly, in the case of a solid-dosage form, it is required necessarily to look into the following cri-
teria intimately,
∑ infl uence of dissolution rate and
∑ design and applicability of the drug product,
must be able to control the desired ‘dissolution rate of the drug’.
According to Noyes–Whitney dissolution rate law, dm/dt is given by the following expression:
sg
()
d
d
DA C C
m
th
−
=
where
dm/dt is the rate of dissolution of drug particles,
D is the diffusion coeffi cient of drug in solution in GI fl uids,
A is the effective surface area of drug particles,
h is the thickness of the diffusion layer (i.e., the stationary layer of the solvent) around the drug particles,
C
s
is the saturation solubility of the drug in the diffusion layer and
C
g
is the concentration of the drug in solution duly present in the bulk of GI fl uids.
Figure 2.24 shows the schematic representation of the ensuing relationship of the various terminolo-
gies, as per the Noyes–Whitney equation stated above, to the ensuring dissolution process. It may, however,
50
Noyes AA and Whitney WR: J. Am. Chem. Soc., 19: 930, 1897.
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Figure 2.24 A schematic diagram of dissolution phenomenon.