The AAPS Journal, Vol. 14, No. 1, March 2012 ( # 2011)
`DOI: 10.1208/s12248-011-9307-4
`
`Review Article
`Theme: Established Drug Delivery Technologies-Successes and Challenges
`Guest Editors: Bruce Aungst and Craig K. Svensson
`
`Absorption Enhancers: Applications and Advances
`
`Bruce J. Aungst1,2
`
`Received 11 May 2011; accepted 20 October 2011; published online 22 November 2011
`Abstract. Absorption enhancers are functional excipients included in formulations to improve the
`absorption of a pharmacologically active drug. The term absorption enhancer usually refers to an agent
`whose function is to increase absorption by enhancing membrane permeation, rather than increasing
`solubility, so such agents are sometimes more specifically termed permeation enhancers. Absorption
`enhancers have been investigated for at least two decades, particularly in efforts to develop non-injection
`formulations for peptides, proteins, and other pharmacologically active compounds that have poor
`membrane permeability. While at least one product utilizing an absorption enhancer for transdermal use
`has reached the market, quite a few more appear to be at the threshold of becoming products, and these
`include oral and transmucosal applications. This paper will review some of the most advanced absorption
`enhancers currently in development and the formulation technologies employed that have led to their
`success. In addition, a more basic review of the barriers to absorption and the mechanisms by which those
`barriers can be surmounted is presented. Factors influencing the success of absorption-enhancing
`formulations are discussed. If ultimately successful, the products now in development should offer non-
`injection alternatives for several peptide or protein drugs currently only administered by injection. The
`introduction of new absorption enhancers as accepted pharmaceutical excipients, and the development of
`formulation technologies that afford the greatest benefit/risk ratio for their use, may create opportunities
`to apply these enabling technologies more broadly to existing drugs with non-optimal delivery properties.
`
`KEY WORDS: absorption; bioavailability; enhancer; permeability.
`
`INTRODUCTION
`
`Oral dosing is generally considered to be the most patient-
`friendly and convenient route of drug administration. However,
`many pharmacologically active compounds cannot be adminis-
`tered orally because of inadequate oral bioavailability, and this
`may limit the usefulness of these compounds. Poor oral
`bioavailability can be caused by poor aqueous solubility,
`degradation within the gastrointestinal contents, poor membrane
`permeability, or presystemic metabolism. Compounds can have
`poor membrane permeation due to large-molecular weight, as is
`the case with proteins and other macromolecules, or insufficient
`lipophilicity to partition into biological membranes, as with many
`hydrophilic, low-molecular weight compounds. There are nu-
`merous pharmacologically effective compounds currently used
`that must be administered by injection because of inadequate
`bioavailability by non-injection routes. Others are used orally
`even though their oral bioavailability is low, and inter-individual
`variability in systemic exposure is high, making therapy with
`these drugs less than optimal. Absorption enhancement is the
`
`1 QPS, LLC, 110 Executive Drive, Suite 7, Newark, Delaware 19702,
`USA.
`2 To whom correspondence should be addressed. (e-mail: bruce.
`aungst@qps.com)
`
`1550-7416/12/0100-0010/0 # 2011 American Association of Pharmaceutical Scientists
`
`10
`
`technology aimed at enabling non-injection delivery of poorly
`membrane-permeable compounds.
`This review provides a summary of the current status of
`various absorption enhancement technologies, particularly
`focusing on those that are currently in clinical trials or are
`already used in marketed products. Much of the discussion is on
`gastrointestinal absorption enhancement, which if successful,
`could have the greatest impact on drug therapy. However,
`absorption enhancement has also been applied to delivery by
`the transmucosal and transdermal routes, and these will also be
`discussed to some extent. The agents and technologies reviewed
`are mainly those that alter drug permeation through the
`biological membrane that acts as the barrier to absorption.
`While one approach to improve membrane permeability and
`absorption is to chemically modify the structure of the active
`compound, this review will be restricted to those technologies in
`which the active ingredient is not chemically altered, but is
`combined with an another agent or a specific formulation
`composition to increase permeability. Technologies that en-
`hance absorption by increasing dissolution or solubility are not
`the subject of this review. Technologies intended for reducing
`presystemic metabolism are only considered here for those
`compounds that require membrane permeability enhancement
`and stabilization on the way to or at the absorption site.
`This review focuses on the progress that has been made
`in this field in the last decade toward marketed products. For
`
`Grün. Exhibit 1095
`Grünenthal v. Antecip
`PGR2017-00022
`
`

`

`Absorption Enhancers
`
`11
`
`a more thorough and fundamental discussion of absorption
`enhancement and the earlier literature, the reader is referred
`to previous reviews of this subject (1–4). Since the impact of
`absorption-enhancing technologies will be determined by the
`benefits and successes of the commercially available products,
`now or in the near future, a component of this review is the
`absorption enhancers that are currently in development, and
`the companies pursuing them.
`
`THE NEED
`
`A number of advantages may be gained by maximizing
`systemic bioavailability after oral administration or administra-
`tion via a transmucosal (i.e., nasal, buccal, sublingual, and rectal)
`absorption site. First, these routes offer needle-free delivery,
`which is usually considered to be more acceptable than
`injections for patients taking a medicine chronically. Increased
`patient acceptance should result in improved compliance. Low
`bioavailability has been shown to be associated with large inter-
`subject variability in systemic exposure. The second advantage
`of increasing bioavailability is the reduction of intra- and inter-
`patient variability, thus improving the control of the drug’s
`intended and unintended actions. Finally, if an active drug
`substance is costly to manufacture, there is the economic
`advantage of reducing the waste of the drug material due to its
`lack of systemic absorption.
`
`Consider the types of compounds that could benefit from
`an absorption-enhancing technology. Table I lists some of the
`compounds for which absorption enhancement technologies
`have been proposed and tested, clinically in many cases. For
`the purpose of this discussion, these compounds are divided
`into three categories: (1) proteins, polypeptides, and peptides,
`(2) non-peptide macromolecules, and (3) hydrophilic small
`molecules.
`Many proteins and peptides have demonstrated highly
`potent and selective pharmacologic activities toward various
`therapeutic targets. While some of these have been devel-
`oped into marketed injectable products, there is clearly a
`need for non-injection alternatives, especially for compounds
`that are used chronically and require frequent dose adminis-
`tration. Insulin is an example of a protein that is administered
`by injection, and which is administered chronically to insulin-
`dependent diabetics. The term “insulin-dependent” indicates
`how beneficial this drug is for those in the growing diabetic
`population. The quest for non-injection insulin dosage forms
`has been ongoing for much of the nearly 100 years since the
`discovery of insulin. In addition to benefiting patient conve-
`nience, the oral route of insulin delivery could also have
`pharmacologic benefits, since it represents a more physiologic
`route of delivery. Insulin is normally secreted from the
`pancreas into the portal vein and is then highly extracted by
`the liver, binding to insulin receptors there. The potential
`clinical benefits of liver targeting of insulin via oral delivery
`
`Table I. Candidate Compounds for Oral and Transmucosal Absorption Enhancement Technologies
`
`Compound or compound family
`
`Uses
`
`Chemical properties
`
`Comments
`
`Peptides, proteins
`Calcitonin
`
`Desmopressin (DDAVP)
`
`Insulin
`
`Leuprolide
`
`Octreotide
`
`Non-peptide macromolecules
`Heparin
`
`Postmenopausal
`osteoporosis
`Diabetes insipidus,
`nocturnal enuresis
`Diabetes
`
`Endometriosis,
`prostate cancer
`Acromegaly,
`carcinoid tumors
`
`Anticoagulant
`
`Low-molecular weight
`heparin (enoxaparin)
`
`Prevention and treatment
`of thrombosis
`
`Fondaparinux
`
`Oligonucleotides
`
`Vancomycin
`
`Factor Xa inhibitor,
`anticoagulant
`
`Modulate various
`biological pathways
`Antibiotic
`
`Hydrophilic small molecules
`Aminoglycosides
`(e.g., amikacin, gentamycin)
`Amphotericin B
`
`Antibiotics
`
`Antifungal
`
`Bisphosphonates
`
`Osteoporosis
`
`32 amino acid peptide,
`MW ~3,455
`9 amino acid peptide,
`MW 1,183
`51 amino acid peptide,
`MW ~5,800, hexamer form
`9 amino acid peptide analog,
`MW ~1,200
`Cyclic octapeptide, MW ~1,000
`
`Highly sulfated polymer,
`MW 12,000–15,000
`MW ~4,500, sulfonate and
`carboxylate
`groups
`Pentasaccharide, MW ~1,727,
`sulfonate and carboxylate
`groups
`Hydrophilic, high MW
`
`Glycopeptide, MW 1,449
`
`MW ≥500
`
`MW 924, low log P, high-polar
`surface area
`Strongly acidic phosphonate
`groups, MW approx. 250–325
`
`Injection and nasal (F=3–5%)
`products are available
`Oral (F=0.16%) and nasal
`(F=5–10%) products
`Various injection products and
`one inhaled form available
`Solution and depot injections and
`implant forms available
`IV and SC injection use only
`(50–500 μg tid dose)
`
`IV and SC use only
`
`IV and SC use only, usually
`30–40 mg/day
`
`SC injection only, usually
`2.5–10 mg/day
`
`Emerging as potential parenteral
`products
`IV use, high doses, oral product
`for colitis only
`
`IV and IM use, high doses, some
`topical products
`IV use
`
`Oral bioavailability <1% for
`many in class
`
`

`

`12
`
`Aungst
`
`may include reduced hyperinsulinemia and risk of hypogly-
`cemia and improved weight control (5).
`In contrast to insulin, calcitonin is a peptide drug used to
`treat a condition, postmenopausal osteoporosis, for which there
`are already alternative therapeutic options not requiring
`injection. Calcitonin is available as a nasal spray, but the
`bioavailability when administered by that route is quite low,
`roughly 3–5%. In the case of calcitonin, the need is for a product
`that can be administered as conveniently as other available
`osteoporosis therapies, with adequate bioavailability, and with
`safety and effectiveness comparable to injectable calcitonin. The
`development of bioavailable, non-injection formulations of
`calcitonin could expand its use in the treatment and prevention
`of osteoporosis, as well as other potential indications.
`Absorption enhancement technologies have also been
`investigated for non-peptide macromolecules (MW>1,000)
`including heparin, low-molecular weight heparins, and some
`oligonucleotide drugs. Oligonucleotides as a structural class may
`see increased applications in the future, especially if the delivery
`issues associated with their use can be resolved. Also listed in
`Table I are a few groups of structurally related hydrophilic small
`molecules, in which one or more functional groups associated
`with pharmacologic activity also contributes significantly to
`poor membrane permeability characteristics. Examples include
`the aminoglycoside antibiotics and bisphosphonates.
`The compounds listed in Table I are, for the most part,
`approved drugs. The efficacy of each of these marketed agents
`has been proven, and a technology that enhances absorption
`may enable the development of a product that provides an
`alternative to the mainly injectable products already available.
`There are certainly many other pharmacologically active
`compounds which have not been developed as injectable
`products and for which inadequate bioavailability prevented
`their development into non-injection products. An example of a
`small molecule new chemical entity for which absorption
`enhancement was investigated during its development is
`DMP728, a cyclic peptide antagonist of the glycoprotein IIb/
`IIIa receptor (6,7). For compounds like this, with unproven
`human efficacy and safety, the development or application of an
`absorption-enhancing technology surely increases the risks
`involved in developing the compound. However, once absorp-
`tion-enhancing technologies have been proven and accepted
`into the market, it seems quite likely that an existing technology
`would be applied readily in the development of new chemical
`entities with less than optimal absorption properties.
`
`THE BARRIERS
`
`Potential routes of administration that have been con-
`sidered as alternatives to the injection route of drug delivery
`include oral, transmucosal, and transdermal. In this section,
`the nature of the barriers to drug delivery by the oral,
`transmucosal, and transdermal routes is briefly reviewed.
`Pulmonary delivery for systemic absorption has also been
`shown to represent an alternative to injection, and inhaled
`insulin has been introduced to the market. However, there is
`scarce literature on the need for, or the benefits of pulmonary
`absorption enhancers. So, pulmonary absorption enhance-
`ment will not be discussed further in this review.
`The first requirement for drug absorption is for the
`active ingredient to reach the absorbing membrane, which
`
`can occur by direct dermal or mucosal application, or in the
`case of intestinal absorption, the drug has to be delivered to
`the intestinal membrane surface intact. This may require
`controlling the release of
`the drug and the absorption-
`enhancing excipient as they pass through the acidic contents
`of the stomach and the digestive enzymes in the contents of
`the stomach and small intestine. As will be described later,
`special formulations have been designed to protect unstable
`drugs and to release drug and excipient simultaneous or in
`sequence within specific regions of the gastrointestinal tract.
`The intestinal epithelial membrane, which functions as the
`barrier to intestinal absorption, is comprised of a layer of
`columnar cells interconnected via tight junctions. The luminal
`surface of the intestinal membrane is covered by a layer of
`mucus, which is generally not a rate-limiting barrier to
`absorption. Most drugs are primarily absorbed transcellularly,
`permeating through the lipid bilayer that comprises the apical
`cell membrane. Transporters on the apical and basolateral cell
`membranes may move drug molecules either toward the cell
`interior or in a direction from the inside of the cell to the outside.
`Approaches to increasing absorption have included using
`excipients that inhibit secretory (efflux) drug transporters on
`the apical surface. For example, the common excipient polysor-
`bate 80 increased the oral bioavailability of digoxin in rats (8).
`Also, there have been successes in linking drugs to compounds
`that utilize transporters for active drug absorption and in
`designing drugs to be substrates for these transporters. An
`example of success of this approach is the prodrug valacyclovir,
`which is a substrate for the proton-linked intestinal peptide
`transporter and has three- to fivefold improved bioavailability
`relative to acyclovir in humans (9). However, transporters are
`not considered further in this review. In addition to transcellular
`permeation, drugs can be absorbed by a paracellular mecha-
`nism, and the tight junction structure represents the barrier to
`paracellular absorption. Once a drug molecule has passed
`through to the basolateral side of the intestinal epithelium,
`absorption into the blood is generally not restricted. Of course,
`peptides, polypeptides, and proteins may be subject to metab-
`olism before reaching the intestinal epithelium or during
`permeation of the intestinal membrane.
`Insulin, calcitonin, and other polypeptides and proteins
`have poor intestinal membrane permeability due to their large
`molecular weight relative to most orally administered drugs and
`due to the tendency of compounds with many hydrogen-
`bonding groups to permeate epithelial membranes poorly. The
`molecular size of non-peptide macromolecules, such as low-
`molecular weight heparins, is also not within the range usually
`associated with reasonable membrane permeability. In addition,
`many of these agents are very hydrophilic due to the presence of
`numerous functional groups that are charged at physiological
`pH, such as the sulfonates of heparin and its analogs. Strongly
`ionized, small molecule drugs, such as the bisphosphonates, are
`poorly permeable due to their inability to partition into the
`intestinal cell membrane, and paracellular absorption is also
`restricted when the molecular size is greater than the effective
`pore size of the paracellular channels.
`The membrane lining the nasal cavity consists of several
`different types of cells, but in general, the nasal epithelium is
`similar to the gastrointestinal epithelium in that
`it
`is a
`pseudostratified columnar epithelium, with a single layer of
`cells and interconnecting tight junctions presenting the main
`
`

`

`Absorption Enhancers
`
`13
`
`barriers to absorption. For nasal absorption, a drug formula-
`tion can be sprayed into the nasal cavity delivering the drug
`to the membrane surface. But ciliary movement at
`the
`membrane surface steadily moves materials from the anterior
`to the posterior portion of
`the nasal cavity where the
`materials are swallowed. Because ciliary action removes drug
`from the absorption site, nasal membrane permeation must
`be fairly rapid for bioavailability to be complete. Another
`limitation for nasal drug delivery is that generally only low
`volumes (a fraction of a milliliter) can be administered by this
`route; a larger volume will run out or be swallowed. So, the
`nasal route is useful only for potent compounds with good
`solubility in the dosing vehicle. An advantage versus oral
`delivery is that drugs absorbed by the nasal route are not
`subject to hepatic first-pass metabolism.
`The skin is a stratified squamous epithelium. The barrier
`to delivery through the skin is the stratum corneum, a layer of
`dead skin cells compressed into a matrix of intercellular
`lipids. The stratum corneum has been likened to a brick and
`mortar structure in which the cells are compactly stacked like
`bricks, and the intercellular spaces are filled with lipids,
`representing the mortar. Inside the stratified cells are keratin
`and other proteins that give the outer layer of skin its
`durability. The pathways for permeation of
`the stratum
`corneum are either through the multiple cell
`layers, the
`bricks, or through the intercellular lipids,
`the tortuous
`pathway through the mortar. The thickness of the stratum
`corneum barrier varies with location on the body, and skin
`permeability depends on the stratum corneum thickness.
`The buccal and sublingual membranes lining the mouth
`are similar to skin in being stratified squamous epithelia. The
`extent of keratinization varies within the region of the mouth,
`being greatest in the masticatory regions and hard palate. As
`with delivery via the nasal mucosa and skin, a drug
`formulation can be applied directly onto the membrane, and
`a drug that is absorbed from the mouth is not subject to
`hepatic first-pass metabolism.
`
`MECHANISMS OF ABSORPTION ENHANCEMENT
`
`Formulating a solution to an absorption problem requires
`defining the barriers to absorption for that compound as well as
`understanding the mechanisms by which absorption might be
`improved. An outline of the possible mechanisms of absorption
`enhancement is given in Table II. For many peptides and protein
`drugs, degradation and/or metabolism could occur at the
`absorption site or during delivery to the absorption site in the
`
`Table II. Mechanisms of Absorption Enhancement
`
`A. Preventing degradation/metabolism
`B. Enhancing membrane permeability
`Gastrointestinal and nasal membranes
`Transient opening of tight junction
`Disruption of lipid bilayer packing
`Complexation/carrier/ion pairing
`Skin, buccal, sublingual membranes
`Disruption of lipid packing in intercellular spaces
`Disruption of cellular protein structure
`Complexation/carrier/ion pairing
`Solvent drag
`
`case of oral delivery. For these compounds, one mechanism to
`improve bioavailability that may be applicable is the reduction
`of their degradation or metabolism. As examples described later
`will illustrate, this might be accomplished by encapsulation of
`the drug to protect it, by including a protease-inhibiting
`excipient in the formulation, or by controlling the pH of the
`environment where the drug is released.
`Compounds with poor membrane permeability may
`require the use of an excipient that modulates membrane
`permeability. The mechanism by which increased permeabil-
`ity is accomplished is likely to determine whether the increase
`in permeability is transient and non-cytotoxic. These factors
`are critical for the ultimate success of utilizing a permeation-
`enhancing excipient. Therefore, the most advanced perme-
`ation enhancers have been the subject of in-depth studies of
`the mechanisms of their effects on epithelial membranes.
`For gastrointestinal and nasal epithelial membranes, the
`movement of water and low-molecular weight solutes is
`physiologically regulated through the distension and constric-
`tion of the tight junctions, which alter paracellular porosity.
`Since the tight junctions open and close in response to
`physiological stimuli, regulating the permeabilities of at least
`some low-molecular weight compounds, it would seem possible
`that this mechanism might afford a relatively safe and reversible
`means of permeation enhancement. In their review of this
`subject, Hochman and Artursson (3) listed various types of tight
`junction modulators, including calcium chelators, protein kinase
`C activators, cytochalasins B or D, and Clostridium difficile
`toxin. More recently, some investigators have targeted specific
`proteins comprising the tight junction, such as claudin and
`occludin, and have described agents with potent and specific
`effects on these proteins and on tight junction permeability (10).
`Several companies have focused their research on the identifi-
`cation and design of tight junction modulators that could be used
`to enable drug delivery. Nastech scientists reported on the in
`vitro effects of tight junction-modulating lipids as well as a tight
`junction-modulating peptide (11). The drug delivery technology
`developed at Nastech has been acquired by Marina Biotech. An
`approach being pursued at Alba Therapeutics is based on the
`identification of a zonula occludens toxin protein, and subse-
`quently a peptide fragment thereof, that increased the intestinal
`absorption of several poorly absorbed compounds in rats
`through a mechanism targeting tight junction modulation (12).
`However, the selective targeting of tight junction elements is at
`an early stage relative to other absorption-enhancing technolo-
`gies, and less evidence of in vivo effects is available.
`The alternative mechanism of permeation enhancement
`involves promoting the transcellular permeation of drugs. This
`requires disrupting the structure of the cellular membrane. As
`reviewed by Swenson and Curatolo (2), surfactants can act as
`permeability enhancers by partitioning into the epithelial cell
`membrane and disrupting the packing of membrane lipids,
`forming structural defects that reduce membrane integrity.
`Surfactants can also extract proteins from the cellular mem-
`brane. Agents that alter cell membrane permeability in a way
`that disrupts the normal extracellular–intracellular ion gradients
`could be cytotoxic, since various cellular functions depend on
`maintaining transmembrane ion gradients. The important issues
`then are whether the permeabilization is transient, and if
`cytotoxicity occurs, whether the tissue can readily rejuvenate
`areas where cytotoxicity has occurred.
`
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`

`14
`
`Aungst
`
`As will be described later in this paper, some of the
`absorption-enhancing agents in advanced clinical trials are
`comprised of medium chain fatty acids or contain a medium
`chain alkyl functional group as part of their structure. For
`example, sodium caprate is already in use in a suppository
`product available in Japan and is currently being evaluated as
`an oral absorption enhancer. A consideration of the putative
`mechanisms by which this agent can enhance absorption may
`be useful. Sodium caprate was shown by microscopy to both
`dilate the tight junction (paracellular permeation enhance-
`ment) and to increase cell membrane penetration (trans-
`cellular permeation enhancement) of a fluorescent marker
`(3). The in vitro effects on drug permeation were more closely
`aligned with the effects on the tight junctions, suggesting that
`paracellular permeation enhancement may be more signifi-
`cant. However, sodium caprate can cause the release of
`membrane phospholipids in situ and can cause cytotoxicity in
`vitro (1), so it would seem that both paracellular and
`transcellular mechanisms of permeation enhancement may
`occur, depending on the caprate concentration, whether in
`vitro or in vivo, and other factors. Furthermore, the cytotox-
`icity associated with exposure to the structurally related
`enhancer, sodium laurate, was reduced by the presence of
`the amino acids taurine and L-glutamine (13). The cytotox-
`icity seen with sodium laurate exposure was associated with
`increased intracellular calcium resulting in apoptosis, and
`these effects were reduced by the amino acids. These studies
`are examples illustrating why it is important to understand
`the mechanisms of altered absorption and how this informa-
`tion might be used to optimize safety and efficacy.
`Another mechanism that has been proposed for enhanc-
`ing absorption is the formation of a membrane permeable
`complex, with one type of complex being an ion pair. The
`distinction must be made between using complexation to
`increase aqueous solubility, which is quite common, and to
`increase membrane permeability. A recently reported exam-
`ple designed to utilize ion pairing is the enhanced intestinal
`membrane permeability of two poorly permeable antivirals,
`zanamivir heptyl ester and guanidino oseltamivir, by inclusion
`of 1-hydroxy-2-naphthoic acid as a counter-ion (14). Sodium
`N-[8-(2-hydroxybenzoyl)amino]caprylate (also referred to as
`SNAC) is an absorption enhancer in late-stage clinical trials. As
`will be discussed in more depth later, several publications have
`provided evidence that this agent may act by forming an
`association with the drug in a way that increases the membrane
`permeation of the drug, but without permeabilizing the
`membrane.
`A hypothesis to generally describe the mechanisms of
`skin permeability enhancement referred to as the lipid–
`protein–partitioning (LPP) concept was proposed (15). This
`hypothesis proposes that skin permeation enhancers usually
`work by one or more of three mechanisms: by altering the
`stratum corneum lipids, proteins, or by increasing partitioning
`of the drug or another applied excipient into the stratum
`corneum. Lipids packed into well-organized structures con-
`stitute the intercellular spaces of the stratum corneum. Some
`skin permeation enhancers have been shown to disrupt the
`packed structure of stratum corneum lipids. An example is
`oleic acid, which was shown by differential scanning calorim-
`etry to alter the transition temperatures of stratum corneum
`lipids, with proportional effects on permeability (16). Other
`
`agents, such as non-ionic surfactants, cause changes in the
`intracellular proteins of stratum corneum and increase
`permeability by this mechanism. Increased partitioning can
`involve the formation of a drug–excipient association or
`increased penetration of the vehicle into skin with increased
`drug permeation by solvent drag (17).
`The available mechanisms for enhancing permeability of the
`buccal and sublingual membranes may be similar to those for
`skin, as summarized in the LPP concept. However, it has also
`been suggested that the lipids of the buccal mucosa are chemically
`and structurally different from those of the stratum corneum, and
`the mechanism of a particular permeation enhancer may differ
`between the skin and the buccal mucosa (18).
`
`THE DEVELOPMENT PROCESS
`AND REQUIREMENTS FOR SUCCESS
`
`Much of the published literature on permeation enhancers
`represent work that was performed at an early research stage.
`Typically, the initial work on absorption enhancement utilizes in
`vitro permeation studies with cell culture models or excised
`tissue membranes to identify agents that are effective in
`increasing permeation of the drug through the membrane
`targeted as the delivery route (e.g.,
`intestine, skin, etc.).
`Important components of the early in vitro evaluation are to
`define the effective concentration range of the enhancer, and the
`concentration range where membrane damage occurs, to
`identify a safety margin. In the case of intestinal delivery, it is
`also important to develop an understanding of how the effects of
`the enhancer vary in different locations of the intestinal tract. In
`addition,
`in vitro studies often provide useful
`information
`regarding the mechanism of permeation enhancement.
`As an absorption enhancement concept moves to the
`preclinical stage, the goal is to take what is known from the in
`vitro studies and apply it in a much more complex, whole
`animal system. One of the main challenges in establishing in
`vitro/in vivo correlations is that in a diffusion experiment
`conducted in vitro, the concentrations and environment of
`drug and enhancer can be precisely controlled, but in an
`animal, this may be difficult to accomplish. Formulations
`applied directly to an absorption site such as the nasal cavity
`or buccal mucosa will be diluted by the fluids present there
`and are subject to processes that tend to remove it from the
`application site. For intestinal delivery, the dilution effect can
`be tremendous and will be a function of gastric emptying and
`intestinal transit times. However, the aim is to deliver the
`drug and enhancer together to the surface of the absorbing
`membrane. This review will later describe some products that
`are in development and have used coatings, encapsulation, or
`other means of modifying the release of drug and enhancer
`for oral delivery. It is not surprising that the in vivo effects of
`absorption enhancers may not be as great as their in vitro
`effects on isolated membranes. Not only is this due to the
`dilution effect discussed above, but intact membranes may be
`more resilient to the insult of permeation enhancement than
`excised membranes or cultured cells.
`Preclinical development should include an evaluation of
`the safety of
`the permeation-enhancing technology. In
`addition to general safety indices, particular attention should
`be given to the targeted membrane or tissue. It is important
`to assess how long the state of enhanced permeability lasts;
`
`

`

`Absorption Enhancers
`
`15
`
`ideally the effect is transient and the tissue recovers quickly
`and completely. One might also question whether enhanced
`permeability allows unwanted foreign substances to be
`absorbed and what might be the consequences of that event.
`Finally, it is important to assess whether the extent of drug
`absorption is acceptable, with regard to average bioavailabil-
`ity as well as inter-subject variability. A successful perme-
`ation-enhancing formulation may increase bioavailability
`from negligible or very low levels to low or moderate levels.
`When bioavailability is incomplete, inter-subject variability
`can be expected. The question then is whether the drug safety
`margin can tolerate the level of inter-subject variability that
`might be seen with the absorption-enhancing formulation.
`
`PRODUCTS IN DEVELOPMENT
`
`This section will provide an update on some of the more
`advanced products in development that employ an absorp-
`tion-enhancing technology. This is not meant to be inclusive
`of all the technologies or products in development, especially
`since the most current information on development pipelines
`is not necessarily made available to the public. Table III
`provides a list of some of the companies utilizing absorption
`enhancers and their technologies and development candi-
`dates. Most commonly these companies control some form of
`intellectual property around a specific technology, and the
`technology is being applied to non-proprietary compounds, in
`addition to the possibility of licensing the technology or the
`products in development to partners. There may also be
`companies that recognized a need or potential application of
`an absorption-enhancing technology for their proprietary
`compounds or for a therapeutic area of particular interest
`
`and have initiated product development with non-proprietary
`absorption-en