`
`EDITION
`
` Remington's
`
`ALFONSO R GENNARO
`Editor, and Chairman
`of the Editorial Board
`
`LUPIN EX. 1035
`
`Lupin v. iCeutica
`
`US Patent No. 8,999,387
`
`Page 1
`
`LUPIN EX. 1035
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
`

`

`Pharmaceutical
`
`Sciences
`
`
`
`199o
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042
`
`Page 2
`
`Page 2
`
`

`

`of approximately one, according to others. Yet, the pene-
`tration of ethanol and dibromomethane are nearly equal,
`and other such enigmas exist.
`It is not surprising, then, that
`the effects of vehicles are not altogether predictable.
`A general statement might be made that if a drug is quite
`soluble in a poorly absorbed vehicle, the vehicle will retard
`the movement of the drug into the skin. For example, sali-
`cylic acid is 100 times as permeant when absorbed from
`water than from polyethylene glycol and pentanol is 5 times
`as permeant from water as from olive oil. Yet, ethanol
`penetrates 5 times faster from olive oil than from either
`water or ethanol, all of which denies the trustworthiness of
`generalizations about vehicles.
`‘
`Since the 1960s, there has been much interest in certain
`highly dielectric aprotic solvents, especially dimethyl sulfox-
`ide (DMSO). Such substances generally prove to be excel-
`lent solvents for both water- and lipid-soluble compounds
`and for some compounds not soluble in either water or lipid
`solvents. The extraordinary solvent properties probably
`are due to a high polarizability and van der Waals bonding
`
`“adjuvant” is not an adjuvant but rather it is only a nonde-
`terrent.
`Other Factors—A number of other less-well-defined fac-
`tors affect the absorption of drugs, some of which may oper-
`ate, in part, through factors already cited above. Disease or
`injury has a considerable effect upon absorption. For exam-
`ple, debridement of the stratum corneum increases the per-
`meability to topical agents, meriingitis increases the perme-
`ability of the blood—brain barrier, biliary insufficiency de-
`creases the absorption of lipid-soluble substances from the
`intestine and acid—base disturbances can affect the absorp-
`tion of weak acids or bases. Certain drugs, such as ouabain,
`that affect active transport processesmay interfere with the
`absorption of certain other drugs. The condition of the
`ground substance, or “intracellular cement,” probably bears
`on the absorption of certain types of molecules. Hyaluroni-
`dase, which depolymerizes the mucopolysaccharide ground
`substance, can be demonstrated to facilitate the absorption
`of some, but not all, drugs from subcutaneous sites.
`
`Drug Disposition
`
`‘The term drug disposition is used here to include all
`proc_esses_ which tend to lower the plasma concentration of
`drug,‘as opposed to drug absorption, which elevates the
`plasma level. Consequently, the distribution of drugs to the
`various tissues will be considered under Disposition. Some
`authors use the term disposition synonymously with elimi-
`nation, that is, to include only those processes which de-
`crease the amount of drug in the body.
`In the present
`Cfimtext, disposition comprises three categories of processes:
`distribution, biotransformation and excretion.
`
`Distribution, Biotransformation and Excretion
`
`It denotes the
`, _=T1_19 term distribution is self-explanatory.
`Dfirtitioning of a drug among the numerous locations where a
`df‘-lg may be contained within the body. Biotransforma-
`twns are the alterations in the chemical structure of a drug
`Phat are imposed upon it by the life processes. Excretion is,
`m,-359.1186, the converse of absorption, namely, the transpor-
`t".‘t19n Of the drug, or its products, out of the body. The term
`ggpliils Whether or not special organs of excretion are in-
`qve .
`.
`
`Distribution
`
`C’O‘E11;:b0dy may be considered to comprise a number of
`rtments: enteric (gastrointestinal), plasma, intersti-
`tial
`stmjaczrebrospinal fluid, bile, glandular secretions, urine,
`0 this Vesicles, cytoplasm or intracellular space, etc. Some
`Orp
`9 C0Inpartments,” such as urine and secretions, are
`0:2?“-ded, but since their contents relate to those in the
`cl
`Compartments, they also must be included.
`
`At first thought, it may seem that if a drug were distribut-
`ed passively (ie, by simple diffusion) and the plasma concen-
`tration could be maintained at a steady level, the concentra-
`tion of a drug in the water in all compartments ought to
`become equal.
`It is true that some substances, such as
`ethanol and antipyrine, are distributed nearly equally
`throughout the body water, but they are more the exception
`than the rule. Such substances are mainly small, un-
`charged, nondissociable, highly water-soluble molecules.
`The condition of small size and high water solubility al-
`lows for passage through the pores without the necessity of
`carrier or active transport. Small size also places a limit on
`van der Waals binding energy and configurational comple-
`mentariness, so that binding to proteins in plasma, or cells, is
`slight. The presence of a charge on a drug molecule makes
`for unequal distribution across charged membranes, in ac-
`cordance with the Donnan distribution (see below). Disso-
`ciability causes unequal distribution when there is a pH
`differential between compartments, as discussed under The
`pH Partition Principle (see below). Thus, even if a drug is
`distributed passively, its distribution may be uneven
`throughout the body. When active transport into, or a rapid
`metabolic destruction occurs within, some compartments,
`uneven distribution is also inevitable.
`The pH Partition Principle——-An important conse-
`quence of nonionic diffusion is that a difference in pH be-
`tween two compartments will have an important influence
`upon the partitioning of a weakly acidic or basic drug be-
`tween those compartments. The partition is such that the
`un-ionized form of the drug has the same concentration in
`both compartments, since it is the form that is freely diffus-
`ible; the ionized form in each compartment will have the
`
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`Page 3
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`pass through the lipid phase, as explained above for the
`morphinans and mecamylamine. Furthermore,
`ion-pair
`formation in carrier transport also bypasses nonionic diffu-
`sion. All processes that tend toward an equal distribution of
`drugs across membranes, and among compartments, will
`cause further deviations from theoretical predictions of pH
`partition.
`'
`Electrochemical and Donnan Distribution—-A drug
`ion may be distributed passively across a membrane in ac-
`cordance with the membrane potential, the charge on the
`drug ion and the Donnan effect. The relationship of the
`membrane potential to the passive distribution of ions is
`expressed quantitatively by the Nernst equation (Eq 7, page
`709) andalready has been discussed. Barring active trans-
`port, pH partition and binding, the drug will be said to be
`distributed according to the electrical gradient or to its
`“equilibrium” potential.
`If the membrane potential is 90
`mv, the concentration of a univalent cation will be 80 times
`as high within the cell as without; if the drug cation is
`divalent, the ratio will be 890. The distribution of anions
`would be just the reverse.
`If the membrane potential is but
`9 mv, the ratio for a univalent cation will be only 1.4 and for a
`divalent cation only 2.0.
`It, thus, can be seen how important
`membrane potential may be to the distribution of ionized
`drugs.
`a
`It was pointed out under Membrane Potentials, page 707,
`that large potentials derive from active transport of ions but
`that small potentials may result from Donnan distribution.
`Donnan membrane theory is discussed in Chapter 14.‘ Ac-
`cording to the theory, the ratio of the intracellular/extraceL
`lular concentration of a permeant univalent anion is equal to
`the ratio of extracellular/intracellular concentration of a
`permeant univalent cation. A more general mathematical
`expression that includes ions of any valence is
`
`At,
`
`1/Z,
`
`<A—> =<a>
`
`Ce
`
`1/Z,
`
`where A, is the intracellular and Ae the extracellular concen-
`tration of anion, Z, is the valence of cation, Z, is the valence
`of anion, C; is the intracellular and Ce the extracellular con-
`centration of cation and r is the Donnan factor. The value of
`r depends upon the average molecular weight and valence of
`the macromolecules (mostly protein) within the cell and the
`intracellular and extracellular volumes. Since the macro-
`molecules within the cell are charged negatively, the cation
`concentration will be higher within the cell,’ that is, C, > Ce.
`Since a Donnan distribution results in a membrane poten-
`tial, the distribution of drug ion also will be in keeping with
`the membrane potential.
`The Donnan distribution also applies to the distribution
`of a charged drug between the plasma and interstitial com-
`partment, because of the presence of anionic proteins in the
`plasma. Eq 8.applies by changing the subscript i to p, for
`plasma, and e to i, for interstitial. The Donnan factor, r, for
`plasma—interstitial space partition is about 1.05:1.
`Binding and Storage—Drugs frequently are bound to
`plasma proteins (especially albumin),
`interstitial sub-
`stances, intracellular constituents and bone and cartilage.
`If binding is extensive and firm, it will have a considerable
`impact upon the distribution, excretion and sojourn of the
`drug in the body. Obviously, a drug that is bound to a
`protein or any other macromolecule will not pass through
`the membrane in the bound form; only the unbound form
`can negotiate among the various compartments.
`The partition among compartments is determined by the
`binding capacity and binding constant in each compart-
`ment. As long as the binding capacity exceeds the quantity
`of drug in the compartment, the following equation general-
`ly applies:
`
`Page 4
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`7 1 6
`
`CHAPTER 35
`
`concentration that is determined by the pH in that compart-
`ment, the pK and the concentration of the un-ionized form.
`The governing effect of pH and pK on the partition is known
`as the pH partition principle.
`To illustrate the principle, consider the partition of sali-
`cylic acid between the gastric juice and the interior of a
`gastric mucosal cell. Assume the pH of the gastric juice to
`be 1.0, which it occasionally becomes. The pK,, of salicylic
`acid is 3.0 (Martinm provides one source of pK values of
`drugs). With the Henderson—Hasselbach equation (see
`page 242) it may be calculated that the drug is only 1%
`ionized at pH 1.0.* The intracellular pH of most cells is
`about 7.0. Assuming the pH of the mucosal cell to be the
`same, it may be calculated that salicylic acid will be 99.99%
`ionized within the cells. Since the concentration of the un-
`ionized form is theoretically the same in both gastric juice
`and mucosal cells, it follows that the total concentration of
`the drug (ionized + un-ionized) within the mucosal cell will
`be 10,000 times greater than in gastric juice. This is illus-
`trated in Fig 35-11.
`‘ Such a relatively high intracellular
`concentration can have important osmotic and toxicologic
`consequences.
`
`Had the drug been a Weak base instead of an acid, the high
`concentration would have been in the gastric juice.
`In the
`small intestine, where the pH may range from 7.5 to 8.1, the
`partition of a weak acid or base will be the reverse of that in
`the stomach, but the concentration differential will be less,
`because the pH differential from lumen to mucosal cells, etc,
`will be less. The reversal of partition as the drug moves
`from the stomach to the small intestine accounts for the
`phenomenon that some drugs may be absorbed from one
`gastrointestinal segment and returned to another. The
`weak base, atropine, is absorbed from the small intestine,
`but, because of pH partition, it is “secreted” into the gastric
`Juice.
`
`The pH partition of drugs has never been demonstrated to
`be as marked as that illustrated in Fig 35-11 and in the text.
`Not only do many drug ions probably pass through the pores
`of the membrane to a significant extent, but also some may
`
`* The relationship of ionization and partition to pH and pK has been
`formulated in several different ways, but the student may calculate the
`concentrations from simple mass law equations. More sophisticated
`calculations and reviews of this subject are available.5»“'1"
`
`
`
`MUCOSAL CELL
`CYTOPLASM
`
`GASTRIC JUICE
`
`.
`
`pH 7.0
`
`"I133
`
`pH l.0
`
`, 1=[Un—ionized]v__ __ EUn-lonizedIl=1\
`
`2i
`
`99.99= Elonizedll
`
`it
`
`E Ionized] = 0.01
`
`nZ(
`
`17
`:u
`
`>2r
`
`n
`
`Fig 35-11. Hypothetical partition of salicylic acid between gastric
`juice and the cytoplasm of a gastric mucosal cell.
`It is assumed that
`the ionized form cannot pass through the cell membrane. The
`intragastric concentration of salicylic acid is arranged arbitrarily to
`provide unit concentration of the un-ionized form. Bracketed values:
`concentration; arrows:
`relative size depicts the direction in which
`dissociation-association is favored at equilibrium.
`
`Page 4
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