Preliminary CommuniCation
`
`Restoration of rat colonic epithelium after
`in situ intestinal instillation of the absorption
`promoter, sodium caprate
`
`Background: Sodium caprate (C10) is an oral absorption promoter that is currently in clinical trials as a component
`of solid dosage forms for poorly permeable small molecules and peptides. Clinical data with zoledronic acid tablets
`suggest that significant delivery along with acceptable safety can be achieved from a once-a-week dosing regime.
`C10 has surfactant-like properties at the high doses used in vivo and therefore we examined its effects on rat intestinal
`epithelium following intestinal instillation. Results: Addition of 100 mM concentrations of C10 with the paracellular
`flux marker, fluorescein isothiocyanate-dextran 4 kDa, permitted a bioavailability of 33% to be achieved. When C10
`was added 10, 30 and 60 min in advance of fluorescein isothiocyanate-dextran 4 kDa, enhancement still occurred,
`but was progressively reduced. Histology revealed that the permeability increase was likely related in part to
`superficial epithelial damage caused in the first few minutes of exposure, which was rapidly repaired within 30–
`60 min. Conclusions: Design of optimized dosage forms containing C10 should corelease the payload and promoter
`close to the epithelium in high concentrations. While C10 induces some epithelial damage, its remarkable capacity
`for epithelial repair may render this effect insignificant in vivo.
`
`Xuexuan Wang1,
`Sam Maher1
`& David J Brayden†1
`1UCD School of Agriculture,
`Food Science and Veterinary
`Medicine and UCD Conway
`Institute, University College Dublin,
`Belfield, Dublin 4, Ireland
`Tel.: +353 1716 6013
`Fax: +353 1716 6219
`E-mail: david.brayden@ucd.ie
`
`One of the major challenges in drug delivery is
`the need for systems that improve oral bioavaila‑
`bility of poorly permeable molecules. Absorption
`promoters that increase epithelial permeability
`have been extensively studied, but to date none
`have been approved. One of the most advanced
`candidates in clinical trials is sodium caprate
`(C10), the sodium salt of the aliphatic saturated
`medium-chain fatty acid, capric acid (reviewed
`in [1]). C10 has been successfully formulated
`in antibiotic rectal suppositories, marketed in
`Scandanavia and Asia [2,3]. In preclinical stud-
`ies, C10 improved oral macromolecule permea-
`tion across Caco-2 monolayers [4], isolated rat
`and human intestinal mucosa [5], as well as in
`rat intestinal instillations and perfusions [6].
`Recently, the effect of the promoter on oral bio-
`availability has been successfully demonstrated in
`man for enteric-coated solid dosage forms with
`a range of actives including antisense oligonu-
`cleotides [7], bisphosphonates [8], low-molecular-
`weight heparin [9] and the gonadotropin-releasing
`hormone antagonist, acyline [10].
`The study of copresentation of promoter and
`cargo is important in designing solid dosage
`formulations in order to optimize delivery of
`payload across the intestinal epithelium. Study
`of contemporaneous and/or delayed release
`of C10 with its associated bioactive cargo may
`
`lead to improved designs. Furthermore, while
`C10 does not appear to lead to significant or
`irreversible mucosal toxicity, even at the high
`concentrations required for delivery in vivo,
`compromising the gastrointestinal barrier is
`often cited as a limitation to the potential use of
`intestinal promoters, at least in a repeat-dosing
`format [11,12]. There is a perception (real or oth-
`erwise) that increases in epithelial permeability,
`by either opening tight junctions through the
`paracellular pathway or, more significantly, by
`transcellular perturbation, may cause uninten-
`tional absorption of toxic dietary xenobiotics,
`microbial antigens or micro-organisms. It is
`notable that the size of the majority of these
`substances are far in excess of the molecular
`weight and diameter of the drugs whose per-
`meation have been enhanced by C10 to date, the
`one exception being the enabling of virus trans-
`port across cultured airway epithelia [13], which
`is an artificial model system. In vivo studies
`suggest that high millimolar concentrations of
`the agent required to enable delivery in animal
`models and human studies pertain more to
`surfactant-like transcellular mechanisms com-
`pared with paracellular effects triggered in vitro
`[1]. This is corroborated by studies in rodents
`where the promoter causes superficial mucosal
`injury [6]. Taking these data into consideration,
`
` 10.4155/TDE.10.5 © 2010 Future Science Ltd
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`Therapeutic Delivery (2010) 1(1), xxx–xxx
`
`ISSN 2041-5990
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`Preliminary CommuniCation | Wang, Maher & Brayden
`
`Key terms
`Oral absorption promoter:
`An agent that increases either
`epithelial permeation and/or
`solubility. These can be
`established excipients, ‘generally
`regarded as safe’ dietary agents
`or new chemical entities. None
`have yet been approved
`specifically as permeation
`enhancers.
`Oral bioavailability: The rate
`and extent of drug absorption in
`an unchanged format arriving in
`the systemic circulation from an
`oral dosage form. In practice,
`usually the extent is cited and
`compared with an optimized
`injected format.
`
`there is considerable interest in assessing the
`rate of recovery of the epithelial barrier fol-
`lowing enhancement by C10 in relevant in vivo
` intestinal models.
`The purpose of this study was therefore to
`examine the duration of C10’s promoting action
`on intact rat intestinal mucosa and the time
`taken for the epithelium to restore normal bar-
`rier function. We examined the kinetics of C10’s
`promoting action by measuring absorption of
`a marker molecule, fluorescein isothiocyanate
`(FITC)-dextran 4 kDa (FD4), in an in situ
`colonic instillation study in anesthetized rats.
`We used colon since it is particularly amenable
`to permeation enhancement by C10 compared
`with small intestine in this format [6]. Gross
`histology was used to give visual evidence of
`changes to morphology over time. This study
`confirms that the enhancement window of time
`with C10 is narrow, and that the compromised
`intestinal epithelial barrier of rats is rapidly
`restored to its native state within an hour.
`
`Experimental
` „ Animals
`All animal experimental protocols were approved
`by the University Animal Research Ethics
`Committee and were approved under animal
`license from the Irish Department of Health
`and Children (license reference B100/3709).
`Male Wistar rats (200–250 g) were purchased
`from Charles River Laboratories Inc. (Margate,
`UK). Animals were housed under controlled
`environmental conditions regarding humidity
`and temperature with a 12/12 h light/dark cycle.
`Rats received tap water and standard laboratory
`chow ad lib unless otherwise stated.
`
` „ Rat colonic instillations
`In situ intestinal absorption studies were carried
`out as previously described with minor modifi-
`cations [14]. The F of FD4 upon treatment with
`C10 was 14-fold higher in colonic instillation
`compared with jejunum (33 vs 2.3%; see [6]);
`because of this greater sensitivity, we selected
`the colon as our model to track changes in the
`transport-induced state. Rats were fasted for
`12 h and anesthesia was delivered by intraperi-
`toneal injection of ketamine (75 mg/kg) and
`xylazine (15 mg/kg). Anesthesia was main-
`tained with isoflurane (1–2%) vaporized in
`oxygen and administered at a rate of 1.5 l/min.
`Following midline laparotomy, C10 (100 mM;
`0.2 ml/100 g bodyweight) was instilled into
`the colonic lumen with a 30G microfine needle
`
`for 0, 10 or 30 min before instillation of FD4
`(5 mM) into the same segment. The concen-
`tration of C10 selected in this study was based
`on the average concentration of the promoter
`used in previous preclinical animal models [1].
`Each rodent was subjected to six blood sam-
`ples (~0.2 ml) over 2 h in order to measure a
`completed AUC for each animal. Blood sam-
`ples (~0.2 ml) were withdrawn into heparinized
`vials by cardiac puncture and centrifuged at
`5000 × g for 15 min at 4°C. Fluorescence inten-
`sity of FD4 (lex/lem 480/520 nm) was meas-
`ured in plasma samples diluted in borate buffer
`(0.1 M, pH 8.5) [15] in a spectrofluorimeter (MD
`Spectramax Gemini, Molecular Devices, UK).
`The concentration of FD4 was calculated from
`an external standard curve.
`The peak concentration (Cmax) and the time
`taken to reach Cmax (Tmax) were calculated
`from the plasma–concentration profiles and
`the area under the plasma-concentration curve
`(AUC0–2h) was calculated using WinNonLin
`5.2® (Pharsight Corporation, USA). The abso-
`lute bioavailability (F) of FD4 over the 2 h
`intestinal instillation (F0–2 h) was calculated
`as follows:
`
`^
`
`F
`0 2
`-
`
`h
`
`h
`
`^
`h
`%
`
`=
`
`^
`
`AUC
`0 2
`-
`
`h
`
`h
`
`^
`
`3
`h
`iv #
`AUC
`
`/
`
`100
`
`where AUC0–2 h was area under the plasma con-
`centration curve over the period (0–2 h) and
`AUCiv∞ the area under the plasma concentra-
`tion versus time (0-∞) after intravenous admin-
`istration of sterile filtered FD4 (40 mg/kg) in
`saline [15].
`
` „ Histology of intestinal mucosa
`Intestinal sections were immediately removed
`from euthanized rats and were opened longi-
`tudinally along the mesenteric border, pinned
`onto a sheet of Parafilm® to secure orientation,
`fixed in formalin (10% v/v), and embedded in
`paraffin wax. Tissue sections were cut at 5 µm
`on a microtome, mounted on adhesive-coated
`slides, stained with hematoxylin and eosin and
`examined under light microscopy.
`
` „ Data ana lysis
`Unless otherwise stated, all experiments were
`carried out on three independent occasions
`and data was expressed as the mean ± standard
`error of the mean. Statistical significance was
`measured by two-tailed Student’s t-tests using
`GraphPad Prism 5® software and was designated
`at the level of p < 0.05.
`
`2
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`Restoration of rat colonic epithelium after instillation of C10 | Preliminary CommuniCation
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`100
`
`FD4 [plasma] (µg/ml)
`
`10
`
`1
`
`logFD4 [plasma] (µg/ml)
`
`0.1
`
`0
`
`FD4 alone
`FDA and C10 (co-administration)
`FD4 and C10 (10 min pretreatment)
`FD4 and C10 (30 min pretreatment)
`FD4 and C10 (60 min pretreatment)
`
`0
`
`30
`
`60
`
`90
`
`120
`
`Time (min)
`
`FD4 alone
`FDA and C10 (co-administration)
`FD4 and C10 (10 min pretreatment)
`FD4 and C10 (30 min pretreatment)
`FD4 and C10 (60 min pretreatment)
`
`30
`
`60
`
`90
`
`120
`
`Time (min)
`
`Figure 1. Effect of sodium caprate (100 mM) pretreatment on the
`absorption of FD4 (5 mM) following rat colonic instillations. (A) Plasma
`concentration of FD4 (µg/ml) following either co administration (0 min) with, or
`pretreatment with, C10 for 10, 30 or 60 min and (B) log concentration of FD4 (µg/
`ml) in plasma. Each value represents the mean ± standard error of the mean of
`three independent experiments.
`C10: Sodium caprate; FD4: Fluorescein isothiocyanate-dextran 4 kDa.
`
`to that of the drug for corelease is therefore
`essential, otherwise they may never reach the
`intestinal mucosa together. The data in Figure 1
`& table 1 suggest that this disparity between the
`rates of release from a solid dosage form could
`ultimately lead to the promoter quickly reaching
`the intestinal epithelium, reversibly increasing
`permeability, but ahead of arrival of the payload,
`hence reducing overall efficacy. This suggests
`that formulations with C10 should be designed to
`achieve the highest concentration of coreleased
`promoter and cargo from onset of release.
`
`Results & discussion
`The capacity of C10 to promote the in situ
`absorption of poorly permeable solutes is widely
`reported across the GI tract of rats (reviewed
`in [1]). Basal F of FD4 (5 mM) after colonic
`instillation for 120 min was 1%, with a Cmax
`of 1.6 ± 0.8 µg/ml (Figure 1). Instillation of
`100 mM C10 with FD4 increased F by 33-fold to
`33% and increased the plasma Cmax by 44-fold to
`71.8 ± 8.3 µg/ml. In the majority of in situ drug-
`delivery models, the promoter and cargo are
`contemporaneously delivered to the epithelium
`as aqueous mixtures. Pretreatment of the intes-
`tinal epithelium with C10 for 10, 30 or 60 min
`followed by instillation of FD4 significantly and
`progressively reduced the enhancement effect of
`C10 as measured by F and enhancement ratios
`(table 1). Cmax averages for the 10, 30 or 60 min
`pretreatments of C10 were 5-, 8.9- and 8.4-fold
`lower than when FD4 and C10 were co-adminis-
`tered, respectively. Sequential instillations there-
`fore had less of an increase on the Cmax and F of
`FD4 than was observed with co-administration
`(table 1). There was an indication of greater
`enhancement at shorter intervals between addi-
`tion of the promoter and the payload (table 1).
`Staggered administration of FD4 10–60 min
`after C10 instillation still led to an increase in F
`(4- to 8.7-fold), despite the degree of enhance-
`ment dissipating at longer time gaps. These data
`indicate that the greatest promoting action of
`C10 in an anesthetized rat instillation model is
`best achieved when the promoter is copresented
`to the intestinal epithelium with FD4 and not
`when it is presented as a pretreatment. C10 was
`not flushed out of the intestinal lumen before
`addition of FD4 in this study, but results were
`not significantly different to when we attempted
`to flush the lumen (data not shown). This may
`be because C10 is rapidly absorbed with a Tmax
`of 10 min [16–18].
`Spreading of the promoter/cargo mix in
`the intestinal lumen may have an impact on
`enhancement potential [19], as could unpredict-
`able dilution effects in intestinal fluid volumes.
`This is particularly true in the small intestine
`of humans where, in addition to rapid absorp-
`tion of the promoter, the fluid volumes (fasted
`105 ml, fed 45 ml) have a considerable diluting
`effect compared with those of the large intestine
`(fasted 13 ml, fed 11 ml) and rectum (3 ml) [20].
`In addition, a rapid transit time could also pre-
`vent the optimal promoter/drug concentration
`being presented to the small intestinal epithe-
`lium [20–22]. Matching the promoter dissolution
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`Preliminary CommuniCation | Wang, Maher & Brayden
`
`Table 1. Pharmacokinetics of FD4 (5 mM) in rat colonic instillation following either
`co-administration with sodium caprate (100 mM) at 0 min or pretreatment with
`sodium caprate for 10–60 min.
`
`C10 (0 min)
`5
`
`C10 (-10 min)
`60
`
`PK parameter
`Tmax (min)
`Cmax (µg/ml)
`5146.3 ± 545.7 1363.0 ± 325.4
`AUC (µg/ml.min)
`33.0 ± 3.5
`8.7 ± 2.1
`F (%)
`Enhancement ratio 33
`8.7*
`
`71.8 ± 8.3
`
`14.1 ± 4.9
`
`C10 (-30 min)
`120
`
`C10 (-60 min) Control
`120
`60
`
`8.0 ± 3.4
`
`8.5 ± 3.6
`
`1.7 ± 0.8
`
`667.4 ± 210.7
`4.3 ± 1.4
`4.3**
`
`631.4 ± 191.6 156.1 ± 76.6
`4.0 ± 1.2
`1.0 ± 0.5
`4**
`1***
`
`*p = 0.002; **p = 0.001; ***p < 0.0001, compared with C10 at 0 min.
`AUC: Area under the curve; C10: Sodium caprate; Cmax: Maximum concentration; F: Bioavailability; FD4: Fluorescein
`isothiocyanate-dextran 4 kDa; PK: Pharmacokinetic; Tmax: Time to maximum concentration.
`
`The time for the intestinal epithelium to
`recover from increases in permeability and
`mucosal injury is under scrutiny since pro-
`longed enhancement could potentially allow
`xenobiotics, toxins and pathogen entry across
`the gut wall. In Caco-2 monolayers incubated
`with C10, there was a time and concentration
`relationship in recovery of transepithelial elec-
`trical resistance, a surrogate marker of epithe-
`lial permeability [23,24]. Monolayers treated
`with C10 (10 mM) for 60 min recovered tran-
`sepithelial electrical resistance values to 36%
`of maximum after 5 days, while at lower con-
`centrations recovery was considerably shorter
`[24]. Similarly, recovery time was considerably
`shorter, and the extent of recovery was greater
`when monolayers were incubated with C10 for
`10–20 min compared with 60 min [24]. In a
`separate study, the apparent permeability coeffi-
`cient of FD4 across Caco-2 monolayers was over
`sevenfold greater at 120 min compared with
`20 min in the presence of C10 [4], which further
`indicates the impact of the incubation time on
`the magnitude of the increase in transport. In
`a rat in situ jejunal loop study, promotion of
`phenol red absorption by C10 was diminished
`after just 30 min, perhaps due to rapid absorp-
`tion of the promoter itself [17]. This effect has
`also been described in colonic [17] and rectal [18]
`loops in rats. When cefazolin was coperfused
`in jejunum with C10 (50–100 mM) the plasma
`concentration of the antibiotic significantly
`increased [25]. Upon cessation of the C10 per-
`fusion, the plasma levels of cefazolin decreased
`within 15–30 min. However, this was not the
`case with sodium dodecyl sulfate (SDS), as the
`absorption of cefazolin continued to increase
`following removal of the promoter and did not
`significantly drop over the following 2 h. In a
`study of epithelial recovery after treatment with
`SDS it was shown that the epithelium can take
`
`up to 4 h to recover from an increase in trans-
`port [26]. Indeed, recovery of epithelial perme-
`ability from a transport-induced state has not
`been demonstrated with all promoting agents
`to the same extent; for example, in a rectal per-
`fusion with EDTA and poly(ethylene oxide),
`permeability to sulfanilic acid had recovered to
`only 50 and 66% of control, respectively, after
`120 min [27]. Even promoters that are in the
`same structural class as C10 do not behave in
`a consistent manner: both pre- and post-incu-
`bation of a medium-chain mono- di- and tri-
`glyceride mix of caprylate in the intestines of
`anesthetized rats for 10 min had no significant
`effect on cefmetazole absorption compared with
`copresentation [28]. In a canine study, enteric-
`coated formulations containing C10 led to an
`increase in the absorption of an oligonucleotide
`(ISIS 104838, antisense to TNF-a) [29]. The
`rapid absorption kinetics of C10 stimulated
`design of a pulsatile formulation, characterized
`by an immediate release of high concentra-
`tions of the promoter with the oligonucleotide
`cargo, followed by pulsed replenishment of C10
`to sustain the enhancement window. In human
`patients, the bioavailability of these formula-
`tions ranged from 7 to 12% [30].
`The most conclusive data demonstrating
`the reversibility of C10 action on permeability
`is from a lactulose:mannitol urinary excretion
`ratio (LMER) study in man [9]. Intrajejunal
`administration of C10 (500 mg) to human
`subjects increased the ratio up to 20 min after
`C10 administration, but not at 40–60 min. In
`the presence of gastrointestinal permeability
`enhancement technology (GIPET®, Merrion
`Pharmaceuticals Ltd, Dublin, Ireland), a number
`of poorly permeable drugs including zoledronic
`acid (Orazol®, Merrion Pharmaceuticals) have
`had their oral bioavailability increased in man,
`and this was associated with an increase in the
`
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`Restoration of rat colonic epithelium after instillation of C10 | Preliminary CommuniCation
`
`Key term
`Intestinal epithelial repair:
`Restoration is a coordinated
`response involving villous
`contraction, epithelial
`restitution and tight junction
`closure.
`
`LMER by 50% [9]. In comparison with LMER
`values seen with aspirin (146–760% [31]) and
`Crohn’s disease (520% [32]), the increase in epi-
`thelial permeability by C10 is smaller, reversible
`and disappears when it is absorbed or removed.
`There is a relationship between restoration
`of normal epithelial permeability and recovery
`from epithelial injury [33]. Indeed, a permeability
`recovery model has been used to quantify the
`damage caused by a surfactant in combination
`with morphology assessment [26]. In addition
`to the data on reversibility of the permeability
`increase induced by C10, we also assessed the
`effect of the promoter on gross histology of the
`epithelium. Instillation of saline into the colonic
`lumen had no effect on mucosal morphology
`and the epithelial surface of control mucosae
`was unperturbed with no noteworthy dam-
`age to enterocytes or goblet cells; there was no
`sign of damage to the sub-mucosa (Figure 2a).
`When the colonic mucosa was instilled with C10
`(100 mM) for 10 min, there was some damage
`to the mucosal surface, with continuous necro-
`sis, moderate cellular infiltration in the lamina
`propria and sub-mucosa (Figure 2b), confirming
`our previous data set at 5 and 10 min [6]. At
`the longer time points of 30 and 60 min post-
`administration of C10, damage to the intestinal
`mucosa was rapidly repaired (Figure 2C & D),
`and this was consistent with the FD4 perme-
`ability data (table 1). These data support similar
`
`conclusions made using the rat perfusion model
`for transport of phenol red in the presence of a
`detergent [26].
`The safety of C10 has been reviewed with
`the majority of studies examining toxicity at
`the experiment end point – a point at which
`there could be considerable epithelial repair [1].
`Such studies may be less informative because
`of the remarkable capacity of the intestinal epi-
`thelium to recover from injury [34], and even
`the most extreme cases of cellular damage and
`perturbation can be reversible [19]. There is often
`disparity between promoter studies, which is
`confounded by the concentration of the pro-
`moter, and the experimental methods of the
`selected gut permeability model. For example,
`absorption of a 6-kDa peptide with a proprie-
`tary enhancer platform was significantly greater
`when the intestinal segment was ligated [19].
`Nevertheless, the data from the current study
`and from previous reports suggest that C10 can
`cause mucosal perturbation, but that the bar-
`rier is rapidly repaired. This is not unique to
`C10; the intestinal mucosae can recover from
`injury caused by other transcellular promoters
`such as taurodeoxycholic acid, SDS and non-
`ylphenoxypolyoxyethylene [11,26,33]. However,
`recovery is often slower with surfactants that
`have a low critical micellar concentration and,
`furthermore, the safety profile of such agents
`when absorbed remains unclear. C10 itself,
`
`Figure 2. Representative light micrographs illustrating the effect of sodium caprate on
`morphology of the rat colonic epithelium. (A) Saline control, (B) sodium caprate (C10; 100 mM)
`after 10 min (C) C10 (100 mM) after 30 min and (D) C10 after 60 min. Horizontal bars = 250 µm.
`
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`Preliminary CommuniCation | Wang, Maher & Brayden
`
`while rapidly absorbed, is a dietary fatty acid
`that is recognized as safe for addition to foods
`for human consumption, indicating systemic
`toxicity is unlikely to be an important consid-
`eration [1]. The cytotoxicity of C10 reported in
`cell cultures has led to criticism of the clinical
`potential of the promoter. However, data from
`static in vitro models do not effectively trans-
`late to in vivo models because of the presence
`of relevant repair mechanisms in vivo and the
`propensity for rapid dilution of C10 in the gut.
`This information has aided in the selection of
`suitable candidate drugs for enhancement with
`C10. Clinical trials with oral weekly doses of
`zoledronic acid were to some extent designed
`so that the epithelium had considerable time to
`repair from any injury caused by the promoter
`between doses [1]. It will be interesting to see
`safety data from long-term oral daily dosing
`studies of C10 with other payloads. Finally, it
`is important to put the injury caused by C10
`in context with the damage caused by other
`dietary agents. Constituents of a healthy diet
`including food substances, drugs, drug for-
`mulations and even bile salts lead to mucosal
`injury, but cycles of damage and repair are
`normal physiological processes. Despite such
`a comprehensive number of studies involving
`C10, what is unknown is the exact nature of
`its interaction with intestinal mucosae. Despite
`in vitro data indicating a paracellular mode of
`action, it is more likely that the promoter acts
`through transcellular perturbation in vivo.
`Concentrations of C10 above its critical micel-
`lar concentration form supramolecular vesicles
`that could easily traffic the drug across the epi-
`thelium. Predicting how C10 behaves when in
`contact with the intestinal wall is difficult con-
`sidering the variability in composition of lumen
`fluid particularly pH, lumen salt concentration
`and the presence of other surfactants. Progress
`has been made with the development of fasted-
`state-simulating intestinal fluid and fed-state-
`simulating intestinal fluid, and these should be
`the starting points for studies to understand the
`interaction of the promoter with the intesti-
`nal epithelium, while in parallel attempting to
`understand the mechanism of mucosal injury
`and restitution.
`
`to the epithelium together and formulations
`should be designed to sustain the promoting
`window. Transiently increasing transmucosal
`permeability with C10 is accompanied by super-
`ficial mucosal injury. The intestinal epithelium
`has the capacity to rapidly recover from any
`mucosal damage sustained by treatment with
`C10. This provides further evidence that the
`enhancement action and damage caused by
`mild nonionic surfactants like C10 are closely
`related in vivo, but whether this is a significant
`safety issue is debatable.
`
`Future perspective
`Sodium caprate is currently one of the most
`advanced oral enhancers in clinical development
`for selected cargoes. It has generally been recog-
`nized as safe in dietary supplements and there
`is extensive knowledge from its widespread use
`as an excipient, which may suggest that it has
`fewer safety hurdles than new chemical entity-
`type promoters. As a surfactant at high doses
`used in man, it seems to temporarily damage
`the epithelium to an extent, an effect unrelated
`to the tight junction opening action seen at low
`concentrations in vitro. Future work will be
`focused on how the agent induces damage and
`how the restitution process takes place and is
`so effective. Even though C10 is in clinical tri-
`als, cargoes will have to be carefully selected
`in terms of target oral bioavailability and an
`acceptable intersubject variability. While there
`are a plethora of excipients at the preclinical
`stages of research, generally recognized as safe,
`innovative formulation design will be the key to
`progression to the clinic.
`
`Financial & competing interests disclosure
`David Brayden is a consultant to Merrion Pharmaceuticals
`Ltd and is in receipt of an Irish Council of Science and
`Engineering Grant part funded by the company. This
`work was also supported in part by Science Foundation
`Ireland Cluster Grant 07 SCR B1154. The authors have
`no other relevant affiliations or financial involvement
`with any organization or entity with a financial interest
`in or financial conflict with the subject matter or materials
`discussed in the manuscript apart from those disclosed.
`No writing assistance was utilized in the production of
`this manuscript.
`
`Conclusion
`The promoting action of C10 on permeabil-
`ity is concentration dependent and is rapidly
`reversed in rat colonic instillations. The pro-
`moter and cargo should ideally be delivered
`
`Ethical conduct of research
`The authors state that they have obtained appropriate
`insti tutional review board approval or have followed the
`princi ples outlined in the Declaration of Helsinki for all
`human or animal experimental investigations.
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`6
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`Therapeutic Delivery (2010) 1(1)
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`future science group
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`Restoration of rat colonic epithelium after instillation of C10 | Preliminary CommuniCation
`
`Executive summary
` „ Sodium caprate C10 improves the absorption of fluorescein isothiocyanate-dextran 4 kDa, a poorly absorbed molecule.
` „ The promoting action of C10 is rapidly reversed following rat colonic instillation.
` „ Copresentation of C10 with the selected cargo to the intestinal epithelium is essential for optimal promotion.
` „ Delivery platforms that synchronize release of high concentrations of C10 with cargo and maintain release of high promoter
`concentrations for a period could improve effectiveness.
` „ C10 causes mucosal injury in rat colonic instillation that is rapidly reversed.
` „ Increased intestinal permeability and the mucosal injury associated with surfactants are closely related events.
` „ The high capacity of the intestinal epithelium for repair suggests that damage caused by a promoter should be assessed over the entire
`time course of its promotion.
` „ Further studies are required in order to ascertain the in vivo mechanism of promotion and epithelial repair.
`
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