Expert Opinion on Drug Delivery
`
`ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: http://www.tandfonline.com/loi/iedd20
`
`Promoting absorption of drugs in humans using
`medium-chain fatty acid-based solid dosage
`forms: GIPET™
`
`Thomas W Leonard, John Lynch, Michael J McKenna & David J Brayden
`
`To cite this article: Thomas W Leonard, John Lynch, Michael J McKenna & David J Brayden
`(2006) Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage
`forms: GIPET™, Expert Opinion on Drug Delivery, 3:5, 685-692, DOI: 10.1517/17425247.3.5.685
`To link to this article: https://doi.org/10.1517/17425247.3.5.685
`
`Published online: 01 Sep 2006.
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`

`

`1. Introduction
`
`2. GIPET™
`
`3. Phase I trials of GIPET™
`
`4. Safety studies of GIPET™ in
`preclinical models
`
`5. Safety studies of GIPET™ in
`clinical studies
`
`6. Conclusion
`
`7. Expert opinion
`
`Technology Evaluation
`Promoting absorption of drugs in
`humans using medium-chain fatty
`acid-based solid dosage forms:
`GIPET™
`
`Thomas W Leonard†, John Lynch, Michael J McKenna & David J Brayden
`†Merrion Pharmaceuticals USA, 219 Racine Drive, Suite D, Wilmington, NC 28403, USA
`
`One of the most important and challenging goals in drug delivery is over-
`coming the poor oral absorption of high-value therapeutics that include
`peptides. Gastrointestinal Permeation Enhancement Technology (GIPET™)
`attempts to address this question by safely delivering drugs across the small
`intestine in therapeutically relevant concentrations. GIPET is based primarily
`on promoting drug absorption through the use of medium-chain fatty
`acids, medium-chain fatty acid derivatives and microemulsion systems based
`on medium-chain fatty acid glycerides formulated in enteric-coated tablets
`or capsules. Importantly, these excipients are generally regarded as safe and
`the systems are formulated in such a way that there is no change in
`chemical composition of the active ingredient. More than 300 volunteers
`have been administered GIPET formulations in 16 Phase I studies of 6 sepa-
`rate drugs comprising both single- and repeat-dosing regimes. Oral bioa-
`vailability of alendronate, desmopressin and low-molecular-weight heparin
`in humans was increased using GIPET formulations compared with unformu-
`lated controls. GIPET was well tolerated by human subjects. Using fluxes of
`markers of epithelial permeability, the effects of GIPET on the human intes-
`tine were shown to be rapid, short-lived and reversible in vivo. These data
`suggest that GIPET formulations have genuine potential as a platform tech-
`nology for safe and effective oral drug delivery of a wide range of poorly
`permeable drugs.
`
`Keywords: bisphosphonates, epithelial permeation enhancers, intestinal absorption,
`low-molecular weight heparin, oral peptide delivery, sodium caprate
`
`Expert Opin. Drug Deliv. (2006) 3(5):685-692
`
`1. Introduction
`
`Most peptide-based molecules have properties that are not conducive to oral deliv-
`ery and must be injected at significant cost and inconvenience to patients. This
`technology gap currently limits the usefulness of a broad range of potential thera-
`peutics, of which peptides comprise a large component. Although there have been
`major advances in delivering poorly absorbable agents in humans by other routes,
`including the pulmonary delivery of insulin [1], oral delivery will, in most cases, be
`the preferred route of administration for systemic delivery. Due to a combination of
`improved compliance by patients and the generation of extended and entirely novel
`intellectual property, oral drug delivery represents a potential US$25 billion market.
`Some oral peptide formulations have been approved. These include a microemul-
`sion formulation of ciclosporin, as well as a desmopressin tablet (DDAVP®;
`sanofi-aventis). However, these examples are exceptions that are largely based on
`unique physicochemical characteristics of the two peptides.
`
`10.1517/17425247.3.5.685 © 2006 Informa UK Ltd ISSN 1742-5247
`
`685
`
`

`

`GIPET™
`
`Box 1. Composition of GIPET™ solid dose oral
`delivery technologies.
`
`GIPET I technology:
`
`• Medium-chain fatty acids and salts thereof (e.g., C10)
`(cid:127) Solid dosage forms (enteric-coated tablets)
`
`GIPET II technology:
`
`(cid:127) Mono/diglycerides of C8 and C10
`(cid:127) Solid dosage (enteric-coated soft gel/hard capsule shell)
`
`GIPET III technology (preclinical):
`
`(cid:127) Novel enhancers (not disclosed)
`
`C8: Caprylate; C10: Caprate; GIPET: Gastrointestinal Permeation
`Enhancement Technology™.
`
`In 1995, Amidon et al. described the biopharmaceutical clas-
`sification system for oral delivery of immediate release
`products [2]. The major outcome of the biopharmaceutical clas-
`sification system was to group major drug classes according to
`whether they had oral delivery issues related to solubility or per-
`meability issues, neither of these issues, or both. Technologies
`to address theses issues can also be described under the same
`headings. Thus, drugs that are insoluble but retain permeability
`(class II) can be better delivered with solubilising emulsion-type
`approaches [3], whereas soluble but poorly-absorbable drugs
`including most peptides (class III) are amenable to epithelial
`permeation enhancement [4]. There have been many attempts
`to promote oral absorption of poorly absorbed class III drugs
`over the past 15 years, but unfortunately the majority has
`failed. Reasons include the inability to deliver therapeutic levels
`by itself over a sustained period, the requirement for massive
`amounts of material, and safety issues regarding the long-term
`integrity of the intestinal epithelium. Additional pitfalls include
`the lack of reliable and predictive in vivo animal models, as well
`as the inability to follow through with practical and reproduci-
`ble solid dose formulations amenable to scaled-up manufactur-
`ing. Achieving a successful oral formulation of a poorly
`absorbable drug implies that there is access to the appropriate
`intestinal region for a sufficient amount of time, release of
`intact soluble drug and an acceptable but reversible degree of
`epithelial cell permeability. Once the targeted pharmacokinetic
`and pharmacodynamic profile is achieved in humans, the for-
`mulation must have a safety profile to allow it to be given to
`patients on a repeated basis, perhaps for an indefinite period.
`Current oral delivery technologies for class III drugs include
`permeation enhancers, mucoadhesive polymers, entrapment in
`particles and chemical conjugation. Some formulations con-
`tain combinations of the above, along with an in-built capacity
`to stabilise the drug against pH changes and metabolism. To
`the authors’ knowledge, the most advanced oral technologies
`for drugs that are difficult to deliver in Phase II human trials
`are the Eligen® carrier-based approach being developed by
`
`Emipshere [5], along with the RapidMist® spray system for
`oromucosal delivery being developed by Generex Biotechnol-
`ogy [6]. A different approach developed in Phase II trials by the
`Nobex Corporation involves peptide conjugation to pegylated
`alkyl amphiphilic polymers [7]. Preclinical research of note is
`the use of bioadhesive peptide-entrapped nanoparticles,
`including those made from sebacic acid/fumaric acid (Spher-
`ics) [8], as well as mini-tablets and microparticles comprising
`mucoadhesive thiolated polymeric excipients (ThioMatrix) [9].
`Gastrointestinal Permeation Enhancement Technology™
`(GIPET™) is a proprietary solid-dose/microemulsion-based
`medium-chain fatty acid technology by Merrion Pharmaceuti-
`cals. This short review provides an evaluation of the technology,
`with a particular emphasis on previously unpublished safety
`and efficacy data that has been achieved in Phase I human tri-
`als. Although rodent [10] and canine [11] oral delivery data with
`absorption-promoting technologies can indeed be impressive,
`significant species differences in intestinal physiology suggest
`that the only true species model for humans is humans [12].
`
`2. GIPET™
`
`The development of GIPET technologies (Box 1) was strongly
`influenced by research on medium-chain fatty acid permea-
`tion enhancers. In 1991 it was shown that paracellular absorp-
`tion of polar marker molecules across isolated rat colonic
`mucosae was increased by caprylate (C8) and caprate (C10) at
`selected concentrations in vitro [13]. Part of the mechanism of
`action of C10 in the in vitro human intestinal cell line Caco-2
`was to dilate intestinal epithelial tight junctions at a concen-
`tration of 13 – 16 mM, thereby effecting cytoskeletal changes
`favouring permeation of small polar molecules [14]. By the
`mid-1990s it was well known that millimolar concentrations
`of sodium salts of C6 (caproate), C8, C10 and C12 (laurate)
`could boost the flux of hydrophilic agents [15]. When C10 was
`incorporated at higher concentrations into a rectal triglyceride
`base suppository containing ampicillin, there was some evi-
`dence that paracellular route enhancement might not be the
`dominant mechanism at the required physiological concentra-
`tions required in vivo [16]. Although there are the complex
`issues of dose-related multiple mechanisms, the potential for
`delivering peptides to a significant level through pharmaco-
`logically opened tight junctions remains a research area of
`considerable interest [17].
`Although it is relatively simple to show enhanced permea-
`tion using isolated tissue mucosae or perfused rodent intestinal
`segments using solutions of excipients mixed with the active
`drug, it is an entirely another set of challenges to advance a pre-
`clinical concept to a practical solid-dose formulation that can
`be used in human patients. The drug must be protected from
`gastric acidity if it is sensitive to metabolism. Moreover, the
`absorption promoter and the drug should ideally be released
`together at the same rate and at appropriate concentrations
`close to the epithelium as the formulation moves down the
`small intestine by peristalsis. Thus, the spatial and temporal
`
`686
`
`Expert Opin. Drug Deliv. (2006) 3(5)
`
`

`

`Leonard, Lynch, McKenna & Brayden
`
`Table 1. Phase I oral bioavailability data with GIPET™.
`
`Drug (molecular weight, g/mol)
`
`GIPET
`
`% Oral bioavailability (CV%)
`
`Fold increase over oral control
`
`Alendronate (523)
`Desmopressin (1069)
`LMWH I (4400)
`LMWH II (6010)
`
`I
`II
`I
`I
`
`8.4 (59)
`2.4 (124)
`9.0 (63)
`8.0 (40)
`
`5
`13
`-
`-
`
`All human studies were carried out in fasted subjects. Bioavailability was calculated with reference to appropriate subcutaneous controls.
`CV%: Coefficient of variation; GIPET: Gastrointestinal Permeation Enhancement Technology™; LMWH: Low molecular weight heparin.
`
`relationships between cargo and promoter need to be opti-
`mised for delivery. Therefore, in the first format of GIPET
`(GIPET I), enteric-coated tablets comprising a pH-sensitive
`coating (e.g., Eudragit®; Röhm GmbH & Co. KG), a
`medium-chain fatty acid (e.g., C10) and a drug in selected
`ratios by weight were synthesised. The second variation of the
`technology (GIPET II) consisted of microemulsions of mono-
`and diglyceride mixtures of C8 and C10 entrapped with the drug
`in an enteric-coated soft gel capsule. Importantly, these excipi-
`ents were specifically selected due to their ‘generally regarded as
`safe’ status at an individual level in other pharmaceutical formu-
`lations. In addition, C10 is present in milk in millimolar concen-
`trations at a level comprising 2 – 3% of the total fatty acids [18],
`and it is approved as a food additive in the US and EU. GIPET I
`and II have been tested orally in rats, dogs and humans, prima-
`rily to establish safety profiles but also to demonstrate efficacy.
`Here, the authors evaluate human data from three separate
`Phase I clinical trials and discuss additional experiments in
`humans in support of the safety of the technology.
`
`3. Phase I trials of GIPET™
`
`GIPET has been tested in a range of doses with six
`poorly-absorbed drugs in a total of 16 Phase I studies. Table 1
`shows the human oral bioavailability data for four of those
`drugs in humans. Overall, oral bioavailabilities of 5 – 13%
`were achieved for compounds that normally have bioavailabil-
`ities of < 1 %. Detailed pharmacokinetics from human trials
`are described for three specific examples: alendronate, low
`molecular weight heparin (LMWH) and desmopressin.
`The bisphosphonate alendronate sodium is approved as
`both once-daily and once-weekly tablets for the treatment and
`prevention of postmenopausal osteoporosis in women, as well
`as for men requiring an increase in bone mass density. Another
`bisphosphonate, ibandronate sodium, was recently approved
`as a once-monthly oral medication. Oral bisphosphonates
`must be taken in the morning with a full glass of water on an
`empty stomach, and patients are required to remain standing
`for at least 30 min following administration, a regimen that
`impacts severely on compliance [19]. All of the current oral for-
`mulations are associated with dysphagia and oesophageal
`reflux. In a second disease indication, bisphosphonates such as
`pamidronate and zoledronic acid are used as chemotherapy for
`
`metastatic bone cancer [20]. These patients require a higher
`bioavailability than can currently be delivered from the oral
`route, and so they are injected intravenously, with some dis-
`comfort, albeit on a monthly basis. An oral formulation of
`bisphosphonates with significantly higher bioavailability
`would certainly benefit this subgroup of patients. Alendro-
`nate–GIPET I was given to a total of 16 healthy subjects as
`oral tablets comprising 17.5 mg active drug in a 200-mg
`enteric-coated GIPET-I tablet containing a selected concen-
`tration of C10. Oral bioavailability was compared with that
`achieved with alendronate sodium 35-mg tablets, resulting in
`a calculation of 8.4% for alendronate–GIPET. Urinary excre-
`tion data indicated that GIPET conferred a fivefold increase
`in the oral bioavailability of alendronate formulations over the
`reference compound (Figure 1).
`Subcutaneous injections of LMWH are typically used as a
`prophylactic anticoagulant treatment to prevent deep vein
`thrombosis or pulmonary embolism following hip or knee
`replacement surgery [21]. An oral formulation of LMWH
`would reduce healthcare costs, as it could be offered on an
`out-patient basis and would require less therapeutic monitoring
`than the typically prescribed standard therapy of oral warfarin.
`LMWH is poorly absorbed and an oral formulation would sat-
`isfy this significant medical need. LMWH–GIPET I was for-
`mulated in coated tablets containing 45,000 or 90,000 IU of
`LMWH with two levels of C10. Oral bioavailability was com-
`pared with the standard subcutaneous dose of 3200 IU follow-
`ing administration to 14 – 16 normal human subjects. Mean
`data over time is shown in Figure 2 and the overall data are
`summarised in Table 2. Oral bioavailability of 3.9 – 7.6% was
`achieved with
`subcutaneous administration. With
`the
`high-dose tablet of LMWH combined with high-dose caprate,
`levels of an indirect plasma surrogate marker for delivery of
`therapeutic levels was seen in all subjects, and the responses
`were sustained in most subjects with a similar time course to
`the subcutaneous route of delivery. Oral bioavailability of 8%
`in humans has also been achieved using GIPET II with another
`LMWH, dalteparin sodium, and up to 18% oral bioavailability
`was seen with LMWH in dogs with GIPET III (unpublished
`observations, TW Leaonard).
`Desmopressin is a synthetic structural stabilised peptide ana-
`logue of arginine vasopressin and it is used as an antidiuretic
`agent for the treatment of vasopressin-sensitive diabetes
`
`Expert Opin. Drug Deliv. (2006) 3(5)
`
`687
`
`

`

`4. Safety studies of GIPET™ in preclinical
`models
`
`Pharmaceutical products that include high concentrations of
`medium-chain fatty acids are already marketed; one example is
`a C10-based rectal suppository. There is well-known evidence
`of temporary mild abrasions associated with this product [16],
`but these are temporary and do not impact on long-term
`usage. Although the lead absorption-promoting fatty acid
`excipients of the GIPET technology are present in food addi-
`tives and are generally regarded as safe, several GIPET safety
`studies were carried out in rats, dogs and humans.
`There were four groups of three dogs that received daily oral
`doses of a GIPET I formulation comprising of C10 and C12 in
`ratios of 1:2 encased in gelatin capsules for up to 14 days. Doses
`were 0.1, 0.3 and 0.9 g/kg/day, given as 2, 6 and 18 tablets,
`respectively. Empty gelatin capsules were administered an equal
`number of times as the highest dose. Only at the highest dose
`was emesis seen in some dogs ∼ 1 h after administration,
`whereas occurrence was occasional and limited in other groups.
`The high-dose group also appeared to show a decrease in food
`consumption, resulting in loss of up to 0.5 kg in weight,
`although this is likely to have been due to the 18 tablets ingested
`each day. No unusual findings were seen for any dogs in any
`other group with respect to ECG, haematology, serum bio-
`chemistry and urinalysis. Gastrointestinal tissue histology
`revealed no micro- or macroscopic changes in any of the groups.
`A 1-week dose-ranging study comprising 0.33, 0.66 and
`1.0 g of C10 per day for 7 days, was also carried out. Although
`lipid-rich faeces were detected, all of the animals gained
`weight and no adverse events were apparent. A further safety
`study was carried out in three groups of eight dogs using
`enteric-coated or uncoated immediate-release GIPET I tablets
`containing high concentrations of C10 and LMWH. No
`adverse events (unusual behaviour or altered physiological
`functions) were reported in the 16 dogs that received the
`GIPET I tablets.
`A total of three groups of four dogs received daily oral doses
`of a size 12 gelatin capsules containing 0.4, 2.0 and 4.0 g
`GIPET II microemulsion per animal for 7 days. There was no
`evidence of clinical pathology, histopathology or body weight
`changes at
`these dose
`levels. In addition, a 28-day
`GIPET II/desmopressin study was also carried out in dogs.
`There were no overt toxicological changes, although salivation
`was seen in some animals. These canine data sets with
`GIPET II were consistent with that seen for GIPET 1, namely
`that solid dose formulations containing high concentrations of
`medium-chain fatty acids could be given to dogs on a daily
`basis without any signs of toxicity. In summary, the five separate
`canine daily tolerance studies revealed very encouraging safety
`data for selected components of the GIPET I and II technology.
`Published literature generally reveals the extensive safe use
`of C10 as an absorption promoter in several species. In Imai
`et al., 0.1% C10 was administered intra-colonically to rats
`with a solution of salmon calcitonin and histology revealed a
`
`REF
`
`GIPET A
`
`GIPET B
`
`GIPET C
`
`GIPET™
`
`2
`
`1
`
`0
`
`Dose in urine (%)
`
`Figure 1. Urinary excretion of alendronate from a single
`administration of GIPET™ solid dose formulations in humans.
`Groups are: REF (Fosamax® 35 mg); GIPET A (alendronate 17.5 mg with low
`concentrations of C10); GIPET B (alendronate 17.5 mg with low concentrations
`of C10-formulation variation of GIPET A); GIPET C (alendronate 17.5 mg with
`high concentrations of C10). n = 16 for each group.
`C10: Caprate; GIPET: Gastrointestinal Permeation Enhancement Technology™.
`
`Low-dose LMWH/
`high-dose GIPET™
`
`Subcutaneous reference
`drug, IU LMWH
`
`Low-dose LMWH/
`low-dose GIPET™
`
`0.70
`
`0.60
`
`0.50
`
`0.40
`
`0.30
`
`0.20
`
`0.10
`
`0.00
`
`Plasma activity (IU/ml)
`
`0
`
`6
`
`12
`
`Time (h)
`
`18
`
`24
`
`the oral delivery of
`Figure 2. Plasma profile of
`LMWH–GIPET I™ in humans. n = 14 – 16 subjects.
`LMWH: Low molecular-weight heparin. GIPET: Gastrointestinal Permeation
`Enhancement Technology™.
`
`insipidus, polyuria and polydypsia [22]. Oral bioavailability is
`low, ranging 1 – 3% and there is considerable intra-subject vari-
`ation. With a direct relationship between the amount absorbed
`and the pharmacodynamic response, an improved oral formula-
`tion could lead to better efficacy associated with a high level of
`compliance. When desmopressin was formulated in a GIPET
`solid dose format and administered orally to 18 human subjects,
`a bioavailability of 2.4% relative to the subcutaneous route was
`measured. Notably, this value was an improvement over the
`0.2% value seen in this study in subjects who were administered
`the currently marketed Minirin® tablet (desmopressin; Ferring
`Pharmaceuticals). It is worth noting that two subjects did not
`obtain measurable levels with the Minirin tablet. There was less
`variability in the GIPET tablet pharmacokinetic data than the
`subcutaneous route (Table 3, Figure 3).
`
`688
`
`Expert Opin. Drug Deliv. (2006) 3(5)
`
`

`

`Leonard, Lynch, McKenna & Brayden
`
`Table 2. Phase I oral bioavailability data: LMWH–GIPET™ I.
`
`PK
`
`Oral bioavailability (%)
`Coefficient of variation (%)
`Number of responders with
`levels > 0.1 IU/ml (%)
`Number of responders with
`levels > 0.1 IU/ml for > 6 h (%)
`Total duration > 0.1 IU/ml (h)
`
`Low/low
`
`3.9 ± 3.5
`89.1
`60
`(9/15)
`13
`(2/15)
`2.6 ± 3.6
`
`High/high
`
`7.6 ± 4.8
`62.9
`100
`(14/14)
`71
`(10/14)
`10.6 ± 5.4
`
`Subcutaneous reference
`
`NA
`NA
`100
`(16/16)
`81
`(13/16)
`7.1 ± 1.3
`
`GIPET: Gastrointestinal Permeation Enhancement Technology™; High/high: High-dose tablet of LMWH (Parnarpain®) combined with high-dose caprate;
`LMWH: Low molecular weight heparin; Low/low: Low-dose tablet of low molecular weight heparin combined with low-dose caprate; NA: Not available;
`PK: Pharmacokinetic parameters.
`
`further evidence of the safety of hydroxy propyl methyl cellu-
`lose-coated C10/antisense tablets in beagle dogs [25]. There
`were ∼ 0.33 g of C10 that was used in each tablet and the
`dogs received three per day orally for 7 days. The key safety
`data were that clinical chemistry and blood biochemistry was
`normal. The dogs tolerated the formulation well and there
`was normal weight gain. Canine intestinal issues were also
`judged to be normal following macroscopic examination at
`postmortem. These data are in stark contrast to some studies
`using in vitro human intestinal tissue culture monolayers
`where cell viability, measured by MTT assay, was reduced
`upon exposure to 10 mM sodium caprate [26]. The relevance
`of these in vitro models in predicting toxicity in vivo seems
`highly questionable, as the monolayers are in a static system,
`and are devoid of protective mucous and have a negligible
`cell turnover.
`There are several studies describing antipathogenic effects
`of C10 and other medium-chain fatty acids. These were dem-
`onstrated to be bacteriostatic at high concentrations against
`Helicobacter pylori [27]. In addition, one mechanism of action
`of the agent is to prevent expression of key regulator genes in
`salmonella for promoting invasion of intestinal epithelia [28].
`in vivo study with chickens,
`In an
`incorporation of
`medium-chain fatty acids including C10 in feed at a level of
`3 g/kg feed appeared to protect chickens from colonisation by
`Salmonella enterica [28]. Finally, capric acid has also been
`shown to have antifungal activities on Microsporium gypsum
`mycelia and spores in vitro [29].
`
`5. Safety studies of GIPET™ in clinical studies
`
`Phase I studies on the six drugs described here comprised
`800 exposures to a solid dosage form for GIPET in 300 volun-
`teers. In some studies, individuals have been safely dosed up to
`six times with GIPET formulations. A legitimate concern
`about the use of intestinal absorption-promoting technologies
`is that the epithelium may not have time to recover before the
`next dose. Although the clinical experience thus far has not
`suggested that this is an issue in vivo, intestinal permeability
`studies were carried out
`in human subjects following
`
`Table 3. Phase I oral bioavailability data:
`desmopressin–GIPET™ II.
`
`Treatment
`
`AUC
`(CV%)
`
`Desmopressin–GIPET
`(200 µg, p.o. capsule)
`Desmopressin (Minrin®;
`Ferring Phamaceuticals)
`(200-µg p.o. tablet)
`Desmopressin
`(4-µg s.c. reference drug)
`
`840 ± 729
`(87%)
`159 ± 383
`(241%)
`
`539 ± 517
`(96%)
`
`Relative
`bioavailability
`(CV%)
`
`2.4 ± 2.9
`(125%)
`0.2 ± 0.2
`(122%)
`
`Not available
`
`n = 18 in each group.
`CV%: Coefficient of variation; GIPET: Gastrointestinal Permeation Enhancement
`Technology™.
`
`Desmopressin–GIPET
`200-µg p.o. capsule
`Desmopressin 200-µg p.o.
`reference tablet
`
`Desmopressin 4-µg s.c.
`reference tablet
`
`500
`
`1000
`
`1500
`
`Time (h)
`
`200
`
`150
`
`100
`
`50
`
`0
`
`0
`
`Desmopressin (pg/ml)
`
`the oral delivery of
`Figure 3. Plasma profile of
`desmopressin–GIPET™ II in humans. n = 18 subjects.
`GIPET: Gastrointestinal Permeation Enhancement Technology™.
`
`normal colonic mucosa 9 h later [23]. Vervarcke et al.
`described the use of C10 as a promoter of antigen uptake by
`African catfish [24]. No adverse outcomes were reported from
`what is a particularly sensitive species. Raoof et al. provided
`
`Expert Opin. Drug Deliv. (2006) 3(5)
`
`689
`
`

`

`GIPET™
`
`Table 4. Timing of effect of C10 on human intestinal permeability using urinary excretion of polar sugars as a
`surrogate marker.
`
`Group
`
`A. Sugars
`B. C10 20 min before sugars
`C. C10 40 min before sugars
`D. C10 60 min before sugars
`E. Sugars
`
`LMER (CV %)
`
`0.02 ± 0.1 (66.3)
`0.03 ± 0.1 (70.4)*
`0.02 ± 0.1 (38.9)
`0.02 ± 0.1 (31.9)
`0.02 ± 0.0 (29.5)
`
`n
`
`24
`22
`22
`23
`22
`
`Statistics
`
`-
`p < 0.01
`NS
`NS
`NS
`
`Treatments were C10 0.5 g in 15-ml solution administered via perfusion tube to the jejunum in the presence and absence of mannitol 2 g /lactulose 5 g /glycerol 9 g
`administered as 100-ml solution orally at different time intervals. Statistical significance was assessed by paired t-test against group A. Group B was statistically different
`from baseline if two high responding outliers were removed from the analysis. Data from SJ Warrington, Hammersmith Medicines Research, Hammersmith Hospital,
`London.
`C10: Caprate; CV%: Coefficient of variation; LMER: Lactulose:mannitol urinary excretion ratio; NS: Non-significant.
`
`intra-jejunal administration of C10 followed by sugar molecules
`whose oral absorption is typically low and largely restricted to
`the tight junction route. The aim was to establish intestinal
`permeability recovery time in the presence of a typical fatty
`acid component of GIPET in a dose designed for the formula-
`tion. The polar sugar, mannitol (molecular weight 164 g/mol),
`is absorbed paracellularly across the gut and is excreted
`unchanged in the urine. Oral bioavailability of mannitol is
`∼ 25% and this amount is retrieved in the urine, as it is freely
`filtered and not reabsorbed by renal tubules. Another polar dis-
`accharide sugar, lactulose (molecular weight 342), is also
`absorbed paracellularly, but only to a level of 1% due to its
`larger molecular radius. The ratio of the two agents in urine is
`a well-established non-invasive indicator of human intestinal
`permeability in vivo [30].
`When the tight junctions are open or if the epithelium
`forms a less restrictive barrier, the urinary lactulose:mannitol
`excretion ratio should be increased, as the lactulose should be
`absorbed more easily. In an open-label partially randomised
`study using up to 24 human subjects, the marker molecules,
`mannitol (2 g) and lactulose (5 g) were given orally at 20, 40
`or 60 min following intra-jejunal instillation of 0.5 g C10.
`The data showed that only when the sugars were adminis-
`tered 20 min after the fatty acid was the urinary lactu-
`lose:mannitol excretion ratio increased (Table 4). Thus, in the
`subjects receiving three separate doses of C10, the effect of the
`agent on intestinal permeability was temporary and that
`increases in permeability were reversed at 40 and 60 min.
`Importantly, the three intra-jejunal doses of 0.5 g C10 was
`generally safe and well tolerated in the human subjects.
`Furthermore, studies testing the effects of C10 on increasing
`intestinal [14C]-PEG absorption in dogs were similarly sug-
`gestive of only a temporary effect of this major component of
`GIPET (data not shown). These data are not surprising, as
`17 billion enterocytes are normally replaced every day and
`the entire epithelium of the small intestine is replaced every
`5 days in humans [31].
`Having established that the effects of major GIPET
`components on the intestinal permeability are temporary, an
`
`additional concern was that the formulation might permit
`bystander absorption of pathogens from the lumen. How-
`ever, to the authors’ knowledge, decades of clinical experience
`with several NSAIDs with the potential to damage the intes-
`tinal epithelium does not suggest that such agents leave indi-
`viduals prone to either increased microbe absorption or
`opportunistic enteric infections. The lack of a potentially
`damaging physiological response from any co-absorbed
`material in cases of overt gut pathology and ulceration
`induced by some NSAIDS appears encouraging. Nonethe-
`less, use of GIPET or any other absorption-promoting tech-
`nology in subjects with inflammatory bowel disease would
`clearly be inadvisable.
`
`6. Conclusion
`
`GIPET is a maturing technology that has shown significant
`efficacy in human Phase I oral delivery studies of drugs that
`normally must be injected. The data show that a range of
`drugs of different structure can be delivered to therapeutic
`levels using two different solid dose GIPET formulations.
`The wide variety of poorly absorbed drug types that have
`now shown efficacy in Phase I trials through the use of the
`GIPET oral delivery formulations suggest that the delivery
`system is a platform technology that can be adapted for a
`range of biotechnology cargoes. Importantly, Phase I trials
`using 300 subjects revealed no toxicity of concern and, in
`addition, this was also manifest in subjects receiving multiple
`doses of GIPET. Additional human studies revealed that the
`absorption-promoting effects of GIPET were transient and
`complete in < 1 h. These data provided additional arguments
`suggesting that the absorption promoter and the active ingre-
`dient need to be formulated as an enteric-coated solid dosage
`form in which the ingredients are gradually co-released
`together to temporarily promote absorption as the formula-
`tion moves along the epithelium of the upper small intestine.
`In contrast to GIPET, simple mixing of solutions of promot-
`ers and active agents is therefore unlikely to be effective
`in vivo, as co-localised release is not present.
`
`690
`
`Expert Opin. Drug Deliv. (2006) 3(5)
`
`

`

`Leonard, Lynch, McKenna & Brayden
`
`7. Expert opinion
`
`One of the lessons from the GIPET development programme
`is that there is no substitute for human data. More than
`100 other oral delivery technologies have suggested potential
`in rodent studies, but only a few of them like GIPET actually
`make it to clinical trials. Apart from species differences in
`intestinal physiology [12], erroneous assumptions can also be
`made with regards to allosteric scaling of dosage [32], not to
`mention the additional challenge of redesigning the dosage
`form. Furthermore, there is little doubt that human intestinal
`monolayers have their limitations as prescreens for the in vivo
`use of absorption promoters [33]. Although the tight-junction
`opening effect of medium-chain fatty acid ingredients was
`apparent from early Caco-2 studies [14], higher concentrations
`and additional mechanisms could not be tested in vitro, as
`
`these monolayer systems are not robust enough in compari-
`son with the human intestine in vivo. This is hardly surpris-
`ing, as the human intestine is normally quite able to cope
`with regular doses of very challenging and occasionally nox-
`ious stimuli (typically food and drink). Perhaps it is just as
`well that GIPET appears not to operate exclusively through a
`junction-opening mechanism in vivo, as there
`tight
`is
`a strongly held view that this route of uptake represents only a
`small fraction of the
`intestinal epithelial surface area
`and therefore may offer limited uptake capacity for poorly
`absorbable biopharmaceuticals [34].
`
`Conflict of interest disclosure
`
`D Brayden is a consultant to Merrion Pharmaceuticals
`Ireland Ltd.
`
`7.
`
`8.
`
`9.
`
`(cid:127)
`
`10.
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