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Overcoming poor permeability:translating permeation enhancers fororal peptide deliverySam Maher, David J. Brayden*UCD School of Veterinary Medicine and UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland

Drug Discovery Today: Technologies Vol. 9, No. 2 2012

Editors-in-Chief

Kelvin Lam – Harvard University, USA

Henk Timmerman – Vrije Universiteit, The Netherlands

Formulation technologies to overcome poor drug-like properties

Demand for oral alternatives to parenteral delivery has

led to renewed interest in excipient-like intestinal per-

meation enhancers that improve oral drug bioavail-

ability. Oral delivery of macromolecules including

peptides and proteins is limited by pre-systemic degra-

dation and poor penetration across the gut wall.

Research on oral absorption enhancers that increase

gut permeability was first undertaken 50 years ago, yet

clinical success has yet to be achieved. Development

has been hampered by lack of adequate reproducible

efficacy as well as perceived safety concerns. We

review some selected permeation-enhancing excipi-

ents that are key components of peptide formulations

in advanced clinical development and assess why trans-

lation of such technologies is close to fruition.

Introduction

There is considerable interest in delivery platforms that

improve oral bioavailability of poorly absorbed peptides,

proteins and macromolecules. Not only does the oral route

improve patient compliance, but reformulation can also

extend intellectual property and reduce costs associated with

sterile manufacturing and use of healthcare professionals.

The oral route is also a more physiological means of deliver-

ing certain molecules to liver and intestinal cell targets (e.g.

insulin and glucagon-like peptide-1 (GLP-1)). There are over

*Corresponding author.: D.J. Brayden (David.Brayden@ucd.ie)

1740-6749/$ � 2011 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.ddtec.2011.11.006

Section editor:Max Zeller – addc GmbH, Fuellinsdorf, Switzerland.Tom Alfredson – Gilead Sciences, Foster City, CA, USA.

60 peptides and 180 biologics marketed worldwide and they

comprise a high percentage of candidates in pre-clinical

discovery [1–3]. The continued success of injectable peptides

and proteins is overshadowed on the oral side by suscept-

ibility to intestinal pre-systemic degradation. A bigger pro-

blem, due to relatively large molecular weights and

hydrophilicity, is poor penetration across the intestinal

epithelium (Fig. 1).

Absorption enhancers

One of the simplest approaches to overcome poor oral macro-

molecule permeability is use of absorption enhancers which

increase intestinal permeability as against impacting on

molecule solubility [4]. They do this by either opening epithe-

lial tight junctions (TJs) (paracellular route), mildly perturb-

ing the mucosal surface (transcellular permeation

enhancement), or by non-covalent complexation with the

payload. Several formulations that use enhancers have pro-

gressed to clinical trials to boost oral bioavailability of BCS1

Class III drugs (high solubility, low permeability). Some

enhancers have already been successfully used in non-oral

formats: topical (dimethyl sulfoxide in Pennsaid1, Covidien,

USA [6]), buccal (bile salts in Oral-Lyn1, Generex, Canada [7])

1 Biopharmaceutics Classification System: adopted by the FDA for bio-waivers for oralClass I molecules [5].

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Drug Discovery Today: Technologies | Formulation technologies to overcome poor drug-like properties Vol. 9, No. 2 2012

2 FDA nomenclature indicates that use of an excipient in a marketed product is‘allowed’ as against ‘approved’.

and rectal (sodium caprate (C10) in Doktacillin1, MEDA,

Sweden [8]). Despite 50 years of research, the hurdles to

progression of oral enhancers include low and variable

efficacy as well as safety concerns. Clinical data from several

specialised oral drug delivery companies that have pio-

neered such platforms for BCS Class III agents suggest that

some of these hurdles are now being addressed and 2012

could see the first oral peptide approval since cyclosporin

and desmopressin.

Oral macromolecule formulations

Oral formulations of peptides using enhancers have reached

clinical phases (Table 1). Other macromolecules in develop-

ment for oral delivery include heparins, antibiotics, anti-

cancer agents and ONS. Peptides are labile in gastrointestinal

fluids and they need protection from degradation by gastric

and pancreatic juice, and this can be achieved by enteric

coating with pH-dependent methacrylate-based polymers.

An entrapped formulation also enables co-release of pepti-

dase inhibitors, mucoadhesives or absorption enhancers in

specific intestinal regions. The latter works best when

released at the mucosal surface at the same time as the pay-

load, as the compromised barrier may otherwise ‘close’ before

the payload reaches the epithelium [9]. The majority of

enhancers in clinical trials are amphiphilic membrane per-

turbants. They increase flux by altering phospholipid packing

in plasma membranes at the concentrations required to

increase permeability. Some can cause a degree of cell lysis

and solubilisation, as reflected by superficial but reversible

mucosal injury.

Example I: acylcarnitines and bile salts

Tarsa Therapeutics (USA), under licence from Unigene

Laboratories (USA), have developed Oracal1, an oral salmon

calcitonin (sCT) formulation for osteoporosis containing

citric acid in vesicles in a Eudragit1 enteric coating [10–

12]. Oracal1 reached the primary endpoint of increasing

bone mass density at the lumbar spine in a recent Phase III

clinical trial of 565 postmenopausal women with estab-

lished osteoporosis; this citric acid formulation is the most

advanced oral peptide in clinical trials [13], and it seems

that the citric acid protects sCT and acts as a permeation

enhancer with an EDTA-like mechanism. Unigene’s oral

PTH (Enteripep1) based on a similar construct was also

effective in increasing bone mass growth and compared

well with a PTH injectable in a Phase II trial. Unlike their

sCT formulation, the oral PTH formulation contains an

additional and more established enhancer, lauroyl carni-

tine. Medium and long chain fatty acid esters of L-carnitine

have ideal properties for enhancement including rapid and

reversible action [14]. Another component in some of Uni-

gene’s oral formulations is the bile salt, sodium taurocho-

late [10,11]. Bile salts can routinely reach concentrations

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over 10 mM in the lumen in the fed state, which is high

enough to both increase intestinal permeability and

improve drug solubilisation [15]. Sodium taurocholate is

a constituent of the ‘allowed’2 excipient, sodium choleate

(derived from Ox bile extract, which also contains other bile

salts, glycocholate, deoxycholate and cholate). Sodium cho-

late is also present in the RapidMist1 spray being developed

for buccal delivery of insulin (Oral-lyn1, Generex) [7].

Actions of different bile salts often cause superficial mucosal

injury, but the barrier repairs within hours [16,17].

Example II: Eligen1

Emisphere Technologies Inc. (USA) has developed a family of

small carriers (Eligen1) that improve passage of hydrophilic

drugs across the intestinal epithelium by non-covalent com-

plexation [18]. In what is a controversial theory, the inter-

action helps protect the payload from digestive enzymes

and increases hydrophobicity so the moiety can passively

permeate, after which the complex dissociates into the

respective components. These formulations are therefore

not classed as new chemical entities (NCEs). The two

most advanced carriers are the acylated amino acids, SNAC

(n-(8-[2-hydroxybenzoyl]amino)caprylic acid) and 5-CNAC

(N-(5-chlorosalicyloyl)-8-aminocaprylic acid). Examples of

peptides that have been evaluated with SNAC in human

include GLP-1, sCT and PTH; non-peptides include fractio-

nated and unfractionated heparin. SNAC decreased transe-

pithelial electrical resistance (TEER) in Caco-2 monolayers,

which was accompanied by release of lactate dehydrogenase

(LDH), suggesting that transcellular enhancement might

also be part of its mechanism [19,20]. Despite suggestions

of in vitro cytotoxicity however, SNAC does not cause sig-

nificant pathology in rat intestinal instillations [19]. This is

further reflected in the paucity of side effects in clinical trials

as well as its provisional granting of generally regarded as safe

(GRAS) status.

The other advanced Eligen1 carrier, 5-CNAC, is licensed to

Novartis (Switzerland), who have performed clinical assess-

ments with Nordic Biosciences (Denmark). An enteric-coated

oral formulation for sCT containing 5-CNAC had greater

efficacy than the nasal format of the drug (Miacalcin1;

Novartis Ltd.) [21]. Unfortunately, there have been two failed

Phase III trials of oral 5-CNAC/sCT for osteoarthritis in 2011.

Whilst the Eligen1 formulation had some efficacy in both

trials, it was ineffective in the co-primary endpoint of joint

space narrowing. A recent proof-of-concept trial for oral

delivery of PTH with 5-CNAC failed several undisclosed end-

points and Novartis have terminated development. The

Phase III clinical programme with Eligen1-sCT for osteoporo-

sis is ongoing.

Vol. 9, No. 2 2012 Drug Discovery Today: Technologies | Formulation technologies to overcome poor drug-like properties

(a) (b)

(c)mucusgel

microvilli

epithelialcell

basementmembrane

laminapropria

blood vessel

liversinusoid

hepatocyte

Kupffer cells

liver(d)

Drug Discovery Today: Technologies

Figure 1. Barriers to the oral absorption of macromolecules. Gastric juice released from the stomach wall inactivates acid- and protease-labile drugs;

protection can be achieved by enteric coating or entrapment in micro- or nano-particulates. After leaving the stomach, the formulation enters the small

intestinal lumen (a) where the elevated pH causes dissolution of pH-dependent enteric coatings. Peptide-based macromolecules require protection from

pancreatic juice, achieved either by using citric acid to lower the optimal pH for enzymatic activity and/or by incorporation of a protease inhibitor. If

adequate protection is provided, the cargo reaches the small intestinal epithelium (b) which consists primarily of enterocytes and goblet cells. All BCS Class

III molecules require assistance with permeation to pass across the epithelial surface (c). Absorption enhancers can reversibly increase epithelial

permeability by the paracellular or transcellular routes, or by a combination of both. Macromolecules then enter sub-mucosal capillaries through endothelia

which drain into the hepatic portal vein, where the first pass effect may further reduce the fraction absorbed (d). If a macromolecule is encapsulated in a

nano- or micro-particulate, further barriers to absorption are the basement membrane, the endothelium of capillaries, the hepatic portal vein and the

Kupffer cells that line sinusoids. Figures (a) and (b) were produced using Servier Medical Art.

Example III: C10

Medium chain fatty acids have a long history of safe use as

dietary constituents in human, and have been extensively

studied as oral enhancers. C10 remains the only enhancer that

has been used clinically in the intestine for that purpose, albeit

in rectal suppositories [8]. It is one of the principal constituents

of gastrointestinal permeation enhancement technology

(GIPETTM; Merrion Pharmaceuticals, Ireland), an enteric-

coated solid dosage form currently designed to boost permea-

tion ofLMWH,pemetrexed,bisphosphonates andacyline [22].

GIPETTM is currently licensed to NovoNordisk (Denmark) for

oral formats of insulin and GLP-1 analogues. Isis Pharma (USA)

has also designed a different enteric-coated formulation of

C10 to improve bioavailability of antisense ONS. These were

effective in dogs and pigs as well as in preliminary clinical

studies [23]. The ISIS oral formulation comprises immediate

bolus release of payload and C10 followed by further gradual

release of C10 to extend the enhancement window [24], but

delivery of ONS has the disadvantage of requiring even higher

concentrations of C10 than that required for other molecules.

Numerous efforts have been made to determine the mechan-

ism that C10 increases gut permeability (reviewed in [8]). Low

concentrations increase paracellular permeability by activa-

tion of phospholipase C, calmodulin and myosin light chain

kinase, which leads to contraction of scaffolding proteins

required to maintain TJ integrity. However, the higher con-

centrations that are required for optimal enhancement in

animals and human, lead to transcellular perturbation as a

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Drug Discovery Today: Technologies | Formulation technologies to overcome poor drug-like properties Vol. 9, No. 2 2012

Table 1. Selected candidate oral absorption promoters in clinical trials

Candidate enhancer(s) Company(s) Proprietary name Most advanced phase

Citric acid � lauroylcarnitine Tarsa, USA (Unigene, USA) PeptelligenceTM Phase III complete (sCT)

SNAC, 5-CNAC Emisphere, USA Eligen1 Phase III (sCT)

Bile acids/salts (e.g. sodium cholate),

C10, formulated with alkyl-PEG–peptide

conjugates

Biocon, India IN-105 Phase III (insulin)

Sodium caprate in matrix tablets Merrion Pharma, Ireland GIPET1 Phase II (bisphosphonate)

Sodium caprylate in hydrophobic suspensions Chiasma, Israel TPE Phase I (octreotide)

Salts of EDTA Oramed Pharma, USA ORMD-0801

ORMD-0901

Phase I (exenatide/insulin)

Hydrophilic aromatic alcohols (e.g. phenoxy-,

benzyl- and phenyl-alcohols)

Proxima Concepts, UK Capsulin1 Capcitonin1 Phase I (insulin/sCT)

Alkylsaccharides (e.g. TDM and DDM) Aegis Therapeutics, USA Intravail1 Oral pre-clinical (octreotide);

Phase I (nasal, GLP-1 analogues)

result of its surfactant properties. In vivo this perturbative

action causes only mild mucosal injury that is rapidly reversed

and seems to be of little toxicological consequence to date. To

date, Merrion have administered GIPETTM to several hundred

patients without any major toxicity issues.

Example IV: transient permeability enhancer (TPE)

TPE (Chiasma, Israel) is an enteric-coated formulation con-

taining sodium caprylate (C8) in hydrophilic microparticles

that are mixed with castor oil or medium chain glyceride

(MCG) and/or caprylic acid, yielding an oily suspension [25].

Chiasma was granted orphan status by the FDA for their oral

format of the octapeptide, octreotide (Octreolin1). In a

Phase I trial of 12 individuals, octreolin1 performed simi-

larly to SC injection and had no adverse effects [26]. The

most effective molecular weight range of macromolecules

that TPE can deliver is 4–10 kDa [25]. Staggering the admin-

istration of TPE and cargo (FD4) gradually reduced the

window for enhancement, similar to other oral enhancers

(e.g. C10 [27]), the reasons being rapid intestinal epithelium

repair and likely absorption of the enhancer [17]. Increased

permeability with C8 is accompanied by altered membrane

fluidity of brush border membrane vesicles (BBMV) and

release of proteins from cells, both of which suggest trans-

cellular path enhancement [28]. Whilst the promoting

action of C8 is less than that of C10 and C12 per se, the

inventive step is its combination with other excipients in

an emulsion format to yield TPE and that format provides

increased oral bioavailability over that achieved with simple

admixed formats.

Example V: alcohol derivatives

Proxima Concepts (UK) is using food additives with GRAS

status and/or pharmacopoeia-listed excipients as absorption

enhancers [29]. Capsulin1 and Capcitonin1 are oral formats

of insulin and calcitonin containing enhancers that are being

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evaluated under license by Diabetology Ltd. (UK) and Bone

Medical (Australia), respectively. Components include phe-

noxyethanol, benzyl- and phenyl-alcohols. These alcohol

derivatives are normally used as formulation preservatives

and solvents [30]. The Capsulin1 (150–300 IU) formulation

increased the glucose infusion rate when measured in

patients using the glucose clamp technique, although it

did not increase serum insulin level to the same degree as

the SC (12 IU) insulin counterpart [31].

Case VI: EDTA

Oramed Pharmaceuticals (USA) has tested oral and rectal

formulations for insulin (ORMD-0801) and GLP-1 analogues

(ORMD-0901) [32,33]. Assessment of five undisclosed ORMD-

0801 formulations showed reduction in baseline serum glu-

cose and c-met levels in eight patents [34]. An oral version of

exenatide (Eli Lilly, USA) demonstrated improved absorption

as indicated by a 28% increase in post-prandial serum insulin

[35]. Oramed’s enteric-coated oral formats contain a carrier

(e.g. omega-3 fatty acid), a protease inhibitor (e.g. soya bean

trypsin inhibitor) and an absorption enhancer (e.g. sodium

EDTA). Salts of EDTA are BCS Class III enhancers charac-

terised by strong-to-moderate enhancement with relatively

slow recovery of the barrier [14]. They increase paracellular

permeability by chelating the calcium that is required to form

intercellular junctions [36]. Sodium EDTA has widespread use

in topical, oral and parenteral formulations at concentrations

of 0.01–0.1% (w/v) [37]. It is considered non-toxic and non-

irritant at ‘allowable’ levels and is listed in the US Pharma-

copoeia-National Formulary (USP-NF). Oramed’s oral peptide

formulations were well tolerated in patients with only mild

gastrointestinal events. Although there are safety considera-

tions for some EDTA salts [38], the estimated daily acceptable

level of disodium EDTA is 2.5 mg/kg, and this is likely to be

much higher than the concentrations in Oramed’s oral for-

mulations.

Vol. 9, No. 2 2012 Drug Discovery Today: Technologies | Formulation technologies to overcome poor drug-like properties

Case VII: alkyl maltosides

Aegis Therapeutics (USA) use alkylmaltoside enhancers (col-

lectively termed Intravail1) that improve nasal and oral

delivery of macromolecules [39]. The most common enhan-

cers in Intravail1 are the amphiphilic surfactants, tetradecyl-

maltoside (TDM) and dodecylmaltoside (DDM). Whilst TDM

has been the more studied of the two enhancers for nasal

delivery, there are data showing improved oral delivery of

octreotide in rodents with DDM [40]. Intravail1 also

improved delivery of the synthetic peptide [D-Leu-4]-OB3

in rodents with an oral bioavailability of 47% relative to

SC [41]. Although ingredients of Intravail1 are GRAS-listed,

they probably cause some level of transcellular enhancement

as they are surfactants. This is reflected in studies showing

that increased nasal insulin bioavailability with DDM was

accompanied by mild morphological change [42].

Status of paracellular-specific peptide-based enhancers

Paracellular enhancers open the gaps between adjacent

epithelial cells by either (i) activating signalling cascades,

(ii) directly scrambling homophilic interactions between TJ

proteins or (iii) proteolytic cleavage of the extracellular por-

tions of TJ proteins [43–45]. By contrast, transcellular enhan-

cers may non-specifically affect the TJ by removing weakly

packed proteins or by directly perturbing the intestinal muco-

sae. In some cases the reversible opening of TJ is thought to be

a safer alternative than transcellular perturbation with sur-

factants. Nevertheless, for those that do not damage the

intestinal mucosa in pre-clinical animal models (e.g. C-term-

inal of Clostridium perfringens enterotoxin (C-CPE) [46]),

safety remains a key drawback. For instance, toxicological

assessment of C-CPE showed that whilst systemic delivery did

not increase biochemical markers of liver or kidney injury, it

caused an undesired immune response [47]. There are also

questions about whether specific TJ modulation can achieve

significant efficacy in human given the low overall surface

area in the intestine. Many are peptides or proteins them-

selves, and are likely to be digested in the GI lumen. The most

advanced specific TJ opening candidates to date are AT1002,

AT1006 and AT3227 (Alba Therapeutics, USA), which are

products of structure–function analysis of Zonula occludens

toxin (Zot), an enterotoxin produced by strains of Vibrio

cholera (reviewed in [48]). To our knowledge, no peptide-

based enhancer acting at TJs is currently in the clinic for oral

peptide delivery.

Hurdles to progression: efficacy considerations

A key issue in development of oral enhancer/macromolecule

formats is that oral bioavailability remains low and variable.

Low bioavailability is acceptable once the format can repro-

ducibly reach a threshold efficacy which is still cost effective:

this is the case with desmopressin, which has an oral bioa-

vailability of 0.16%. Traditionally, it was not financially

feasible to use 10- to 100-fold more peptide for oral delivery,

but there has been significant reduction in the cost of pro-

duction. For example, 0.8 mg of sCT was used in Phase III

clinical trials with 5-CNAC, which is almost 5000 times

higher than the current nasal dose (200 IU; 0.167 mg Miacal-

cin1; Novartis). Furthermore, the added cost of higher

amounts of active drug required when switching parenteral

peptides to oral formats can be partially offset by removing

the requirement for sterile injectable manufacturing and

increased revenue from new oral formulation patents.

In contrast to closed compartments like the nasal route, co-

presentation of the payload and enhancer at the intestinal

epithelium for a sufficient period is unpredictable because of

variability in intestinal transit, residence time, dilution in

intestinal fluids, diet and absorption of the enhancer itself.

Residence time in the small intestine is variable due to

wide-ranging peristaltic flow rates, so the enhancer and cargo

may have only short contact time with the wall [49]. Mucoad-

hesive polymers may slow formulation transit, although this

approach is limited by the high rate of mucous turnover [50].

Pharmacological inhibition of small intestinal peristalsis using

muscarinic antagonists [51], may improve understanding of

the contribution of residence time on efficacy of oral peptide

formulations. Furthermore, fluid volume in the small intestine

ranges from 45–320 ml (fasted) to 20–150 ml (fed) [52], so the

enhancer might never reach the threshold concentration for

enhancement, unless it is localised using novel formulation

design. The volume of solvent in which the formulation is

administered with also influences oral absorption: for 5-

CNAC/sCT, 50 ml water was more effective than 200 ml in

clinical studies [21]. A more concerted effort to understand the

effect of fluid volume and diet on enhancer action will assist

development of more effective oral platforms.

Another approach that could help overcome some of the

macromolecule permeability problems presented by the

small intestine is to target the colon, which is often shown

to be a more effective region for enhancement. When DDM

was formulated in colon-specific capsules, relative bioavail-

ability of carboxyflourescein (CF) in rats was 68.4% compared

with 16.9% and 29.3% in solution and uncoated gelatin

capsules, respectively [53]. Regional differences could be as

a result of (i) solvent drag effects in colon, (ii) differential

susceptibility to surfactants because the small intestine must

withstand regular exposure to bile salts and mixed micelles,

(iii) lower fluid volume in colon (4–13 ml), (iv) greater colonic

residence time (18–72 hours) and (v) reduced colonic pro-

teolysis [52–54]. A potential safety issue in targeting the colon

is the issue of increasing permeability in this bacteria-rich

environment.

Hurdles to progression: safety considerations

Since the first documented study on the use of intestinal

absorption enhancers, there has been concern about their

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safety. Progression of enhancers that are either entirely NCEs

and/or have pharmacological actions are of greater toxico-

logical risk than substances with a history of safe use in

human. The FDA guidelines state that ‘if an excipient is

found to be pharmacologically active, this information

can influence subsequent development,’ so such substances

are likely to require a full battery of toxicological assess-

ments. Some paracellular enhancers have undesirable phar-

macology, for example, cytochalasin D which causes

hepatotoxicity [55] and C. perfringens enterotoxin (CPE),

which causes food poisoning [56]. These first-generation

TJ modulators helped delineate the structure and function

of epithelial TJs, and ultimately aided design of more selec-

tive second-generation paracellular enhancers which are

considered selective and potentially safer [43–45], although

their safety in human is unknown. Taking into account the

heavy financial investment developing the drug of interest,

Pharma has therefore focused on simple enhancers that have

a history of safe use including those with food additive status

or use of ‘allowed’ excipients that can be cheaply manufac-

tured. It is not yet clear whether these candidates will receive

any toxicological dispensation by regulatory authorities, but

their risk of failure because of unknown toxicity is signifi-

cantly reduced.

Of the candidate enhancers listed in Table 1, most have

demonstrated some capacity to superficially abrade the

intestinal mucosa. However, dilution, spreading and absorp-

tion of the enhancer itself prevent prolonged exposure in vivo.

Combined with the high turnover of enterocytes means that

the abrasive actions of enhancers are relatively mild [17].

Drugs (NSAIDs), established excipients (e.g. suppository

bases) and dietary constituents (alcohol, fatty and spicy

foods) can all cause mucosal injury, as do bile and gastric

secretions [15,16,57]. Aspirin causes gastrointestinal side

effects including ulceration and bleeding, but its damaging

action results from both mucosal perturbation and systemic

effects that are exacerbated by interference in mucosal repair

[58]. Whilst no such actions have been reported with enhan-

cers in recent clinical trials, repeated superficial mucosal

injury might be an issue for daily dosing regimes.

The possibility of bystander absorption during the

enhancement window is a valid concern. Taking into account

the precise conditions required for permeation enhance-

ment, as well as the difference in the molecular weight

between effective payloads (<10 kDa) and dangerous luminal

bystanders (�100 kDa), this concern may well be overstated.

Reversibility studies performed with C10 in human using the

lactulose:mannitol urinary excretion ratio (LMER), showed

that following intra-jejunal administration to human sub-

jects, the enhancer only increased permeability over the first

20 min and that the change in permeability is several orders

of magnitude lower than disease states [59]. Further studies

that rule out adverse events caused by bystander absorption

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(both local and systemic) will improve the safety profile of the

candidate enhancer.

Conclusions and prospects

Oral formulations using absorption enhancers for poorly

absorbed peptides have matured with several technologies

progressing to clinical development. The positive outcome

from the Phase III trial of Tarsa’s Oracal1 sCT formulation

could result in the first oral peptide approval since cyclos-

porin and desmopressin. The most successful approaches

reaching clinical development are enteric-coated formula-

tions that encapsulate a peptide drug (<10 kDa) with protec-

tive carrier, peptidase inhibitors and an absorption enhancer

capable of rapidly and reversibly increasing epithelial perme-

ability. The most suitable enhancers are those with a history

of safe use in human either as food additives or ‘allowed’

pharmaceutical excipients that can be easily scaled to man-

ufacture and do not adversely affect peptide physicochemical

properties. The future is likely to see greater emphasis on

optimised micro- and nano-particulates with enhancers that

provide an added level of protection from degradation and

assist co-localised release. Achieving an adequate level of oral

efficacy is likely to be a bigger constraint than toxicity,

although safety of daily and long-term oral administration

regimes must be assessed.

Acknowledgements

Merrion Pharmaceuticals part-fund a PhD student and Novo-

Nordisk funds a postdoc in the lab of DB. Work in the lab is

mainly funded by Science Foundation Grant SRC/07/B1154

(The Irish Drug Delivery Network). SM is funded by Food-For-

Health Ireland.

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