Accordion Pill ® ( AP ) is a novel gastric-retention oral manner of speaking platform based on close up multilayer films ( Intec Pharma, Jerusalem, Israel ). Phase II clinical trials have evaluated gastric memory and pharmacokinetics ( PK ) of AP in healthy volunteers and efficacy and safety of AP containing carbidopa and l-dopa ( AP-CD/LD ) in patients with Parkinson ‘s disease ( PD ). AP was retained in the stomach for approximately 8 henry, without extra meal requirements. AP-CD/LD demonstrated better assimilation, more stable l-dopa exposure and improved ON meter compared with immediate-release CD/LD in advanced PD patients. AP provides a fresh treatment platform for improving PK and efficacy for drugs with narrow assimilation windows or hapless solubility. Furthermore, AP allows multiple drug passing profiles in a single condensation and can provide fixed-dose combinations. oral pitch remains the most commodious path of drug government, offering cost–effectiveness, high patient conformity and flexibility in design and dose forms [ 1 ]. Yet oral government is often fraught with many challenges, including pin down preoccupation windows, constrict therapeutic windows and poor solubility. narrow preoccupation windows occur in drugs that must be absorbed in the upper berth GI nerve pathway or with those that have negligible colonic irrigation absorption [ 2 ]. Drugs with a narrow curative window ( where maximum plasma concentrations correlate with adverse events while trough levels correlate with poor efficacy ) [ 3 ] have been identified as one of the major culprits of emergency department visits for adverse drug events among older adults [ 4 ]. Drugs that are ill soluble are unmanageable to deliver in efficient, convenient oral formulations. A drug that displays more than one of these characteristics is extremely unmanageable to deliver in an oral formulation and may possibly require careful monitor for drug-related problems [ 5 ]. thus, achieving effective oral delivery – particularly for diseases that require chronic and frequent dose – has become a challenge endeavor in drug exploitation [ 2 ]. Improving the pharmacokinetics ( PK ) of drugs with a narrow concentration window or a minute remedy index and achieving efficient oral delivery of ailing soluble drugs can lead to significant improvements in the efficacy and safety of treatments. For a exhaustive follow-up of the challenges to oral drug pitch and development, see Gabor et al. [ 6 ]. A predict approach to address oral drug delivery needs is through gastric retention ( GR ) drug manner of speaking systems [ 7 ]. Retaining the dose form in the abdomen and releasing the drug in a control manner facilitates a drawn-out and continuous absorption phase of the drug in the upper berth parts of the gastrointestinal ( GI ) tract. GR avoids meaning heterogeneity throughout the GI tract, including ph, commensal flora, GI transit time, enzymatic activity, aqueous environment and surface area, all of which may influence assimilation [ 8 ]. GR formulations can besides increase the apparent drug solvability in the abdomen and GI nerve pathway, which prevents drug precipitation and results in a consistent increase in the absorption phase [ 9 ]. such elongated and continuous assimilation can improve efficacy and safety while reducing the necessitate for frequent daily dosing.

To achieve an effective GR delivery shape, the system must overcome the normal physiology of the stomach, which frequently clears its contents by continuous propulsive forces in the feed country or by ‘ housekeeper waves ’ during the fasting state [ 10 ]. Despite years of significant research, evidence for successful GR dose forms remains express and represents an unmet need in therapeutic drug rescue [ 11 ]. To address these unmet needs, the Accordion Pill® ( AP ) has been developed. holocene employment on the GR and manufacture of the AP along with the clinical implications of the AP for medications with constrict preoccupation windows and/or narrow curative windows are reviewed here .

The Accordion Pill

The AP is a unique film-based GR oral drug rescue chopine ( Intec Pharma, Jerusalem, Israel ) designed for drugs that are characterized by one or more of the come :

  • narrow concentration windowpane
    • Poor colonic irrigation absorption
  • Narrow curative window
    • Maximum plasma concentrations correlate with adverse events
    • Trough levels correlate with inadequate efficacy
  • Poor solvability
    • low solvability, high permeability ( Biopharmaceutics Classification System ( BCS ) class II )
    • moo solvability, low permeability ( BCS class IV ) [ 12 ]
  • Act locally, in the stomach or in the upper region of the GI tract

The unique GR performance of the platform is due to the size, supreme headquarters allied powers europe and mechanical properties of the physical multilayer structure. AP contains multilayer biodegradable polymeric films folded into an undulate shape that fits within a standard-sized condensation ( Figure 1 ). In general, the AP comprises an inner controlled release, drug-containing layer, knocked out layers that facilitate the blossom mechanism, and immediate spill layer ( s ) for multiple drug free profiles and/or fixed-dose combinations ; however, the count and function of the films can be varied as needed. Upon reaching the stomach, the capsule dissolves, the structure unfolds and is retained in the stomach for up to 12 h. While in the stomach, the accordion releases the drug in a controlled manner from the stomach toward the upper part of the GI tract, where it is absorbed. Once the AP is out of the stomach, it is fully degraded in the humble intestine, due to its intestinal polymer backbone, which is soluble in intestinal ph. AP was previously tested in two, 3- and 6-month preclinical studies in mini-pigs and in multiple clinical trials evaluating PK, efficacy and guard in goodly subjects and patients. The results demonstrated significant PK and efficacy improvements for respective drugs while maintaining a condom profile comparable to active controls. Current exercise has included only excipients that are US FDA approved and appear on the inactive ingredient ( IIG ) list . figure 1. The Accordion Pill structure. 1. Upon reaching the stomach, the AP space capsule dissolves. 2. There, outer layers facilitate the unfolding mechanism of the accordion. 3. While retained in the stomach for up to 12 hydrogen, the accordion releases the drug in a see manner toward the upper region of the GI tract, where it is absorbed. ( In practice, the count and function of the films can be varied as needed ) 4. once the AP is out of the stomach, it is fully degraded in the small intestine. AP : accordion Pill .

Accordion Pill gastric retention

The GR performance of AP was tested in assorted human clinical studies using magnetic resonance imagination ( MRI ) to follow the AP. In these studies, the inner level of the AP contained cast-iron oxide ( magnetite ) ; magnetite is a superparamagnetic MRI contrast agent that was used as a marker to follow the destine of the AP structure in the abdomen [ 13, 14 ]. The inner level of the AP was designed to not release the magnetite in the stomach, which was verified by an in vitro dissolving test ( data on file ). In an open-label, single-dose study in 11 goodly volunteers using the magnetite-containing AP, participants received standard meals during the day following an overnight debauched. Meals included breakfast ( 550 Kcal, 48 % fatten ) 30 minute prior to AP dose and lunch ( 860 Kcal, 26 % fatness ) 4 planck’s constant post-dosing ; dinner was provided 10 heat content after dosing and was not standardized. The standardize meals represent normal meal intake and are not high-calorie or high-fat regimens. Participants were not required to maintain any positional requirements ( for example, laying prone ) during the test. Participants undergo consecutive MRI every 1 henry ± 15 min for 11 planck’s constant ( utmost 10 MRIs/study day ) to track the location of the AP, either in or out of the digest. The AP remained in the stomach at 8 hydrogen after administration for all 11 participants, at 9 hydrogen for 10 participants and at 11 heat content in 8 participants ( Figure 2 ). At the final MRI 48 hydrogen after administration, the AP was outside of the stomach in all participants. Four participants each reported one AE ( pain during MRI, headache, nausea and vomit ) ; all were mild and resolved. Results from this test demonstrated 8 hydrogen of GR for the AP in 100 % of participants under partially standardized but not specialized meal requirements ( for example, normal calorie, normal fatten ) and normal behavioral conditions without positional requirements. GR of the AP was not affected by gastroprotective medications, such as proton pump inhibitors ( PPI ), in a learn with participants receiving 1 week of PPI treatment ( data on file ) . design 2. Gastric retention profile of Accordion Pill in healthy volunteers (Phase I MRI). AP : accordion Pill. Created using data on file at Intec Pharma, LTD .

Accordion Pill production

The automatize fabrication serve of the AP was developed by Intec Pharma. In general, the fabricate process is divided into two stages : film training, and assembly and encapsulation. Film planning begins with training of a solution or suspension containing polymers ( with or without drug ) that are then dissolved or suspended in an organic solution or water system. Following this, a coating machine is used to apply the solution or abeyance to a film web, and the solvent is removed by drying. The forum and encapsulation stage starts with lamination to build up the multilayer system ; the laminate then passes through different stations on a unique world wide web converting line. following, the multilayer movie is transferred to a fold apparatus configured specifically to fold the desegregate device. last, the fold accordion is encapsulated [ 15 ] .

Clinical application of Accordion Pill technology

Drugs with narrow absorption windows: AP-carbidopa/levodopa

Parkinson ’ s disease ( PD ) causes progressive disability that can be slowed but not halted by treatment [ 16 ]. therefore, the goal of medical management of PD is to control the signs and symptoms of the disease for deoxyadenosine monophosphate long as possible while minimizing adverse effects [ 17 ]. Levodopa ( LD ) is the most effective discussion for PD, providing benefits for activities of daily living, quality of life and life anticipation. LD is administered in combination with carbidopa ( four hundred ), a DOPA decarboxylase inhibitor, which inhibits conversion of LD in the periphery, thereby preventing peripheral side effects and increasing the amount of LD available to cross the blood–brain barrier. The combination of CD/LD is the gold standard of PD treatment, with all patients ultimately requiring CD/LD discussion [ 18 ]. As the disease progresses and dopaminergic neurons in the substantia nigger devolve, the remedy window narrows and the pharmacokinetics of LD become critical. The challenge in maintaining LD plasma levels within this increasingly narrow therapeutic window is complicated by LD ‘s constrict concentration windowpane, with assimilation confined to the upper GI tract a well as LD ‘s abruptly ( 1.5 hydrogen ) clearance half life when taken with carbidopa ( certificate of deposit ) [ 19 ]. As high levels of LD are associated with the development of dyskinesias [ 20 ], it is preferable to maintain point LD levels precisely high adequate for efficacy. Over time, deep trough in LD handiness are associated with pulsatile stimulation of dopamine receptors in the corpus striatum that, in twist, lead to centrifugal complications, including dyskinesias and motor fluctuations [ 21, 22 ]. Reducing LD dose while maintaining stable LD levels should help patients with PD maintain more consistent drive function. CD/LD administered via the AP ( AP-CD/LD ) may achieve stable LD plasma concentrations with well fewer day by day administrations due to the GR nature of the AP. Despite potential gut motility issues that PD patients may experience, earlier solve demonstrated that PD patients retained the AP for alike times ( beggarly GR 11.8–13.9 hydrogen five 12.7 h ) compared with goodly volunteers [ 23, 24 ]. AP-CD/LD comprises five layers with both immediate liberation ( IR ) and controlled release ( CR ) components for four hundred and LD fixed-dose combination. A Phase II, multicenter, open-label, randomized, bipartisan crossing survey with multiple dosages ( AP-CD/LD 50 mg/250 magnesium with no IR ; 50 mg/375 magnesium ; 50 mg/500 milligram ) and active control ( Dopicar®, Sinemet® or patient ‘s own treatment ) investigated the PK profile a well as efficacy and safety of AP-CD/LD in PD patients with and without motor fluctuations [ 25 ]. LD plasma levels were more stable, with reduced peak-trough variation following AP-CD/LD compared with active control ( Figure 3 ). doubly daily AP-CD/LD 50/375 milligram provided remedy intend plasma levels of 1038 ng/ml. Both daily administrations produced curative levels, with minor variation between the two timepoints. Peak-to-trough fluctuations ( hateful Cmax–mean Cmin ) with the AP formulation were 50 % lower compared with IR-CD/LD. AP-CD/LD increased the LD absorption phase by more than sextuple, and the LD good morning predose plasma levels achieved by the AP-CD/LD were significantly higher than those from the IR formulation. As high levels of LD are associated with the development of dyskinesias [ 20 ] and deeply troughs in LD handiness are associated with pulsatile stimulation of dopamine receptors in the corpus striatum, the results observed with AP-CD/LD are promising for providing efficacy while reducing risks of motive complications [ 21, 22 ]. In fact, compared with active controls, patients treated with AP-CD/LD demonstrated importantly less total OFF time ( primary end point ; Figure 4 ). The decrease in OFF time was greater as the dose increased. Patients treated with AP-CD/LD 50/500 magnesium showed significantly less on time with dyskinesias than patients taking ceremonious LD treatment ( 0.7 h compared with 1.2 planck’s constant, phosphorus < 0.002 ) ; this impression was not significant for the lower dose of 50/375 milligram ; however, the patients in this group seemed to be experiencing lower overall levels of total ON time with troublesome dyskinesia and a floor effect may have prevented differences from being discernible ( Figure 4 ). thoroughly on fourth dimension ( ‘ ON time without dyskinesia ’ plus ‘ ON time with nontroublesome dyskinesia ’ ) besides was importantly increased compared with active controls and in a dose-dependent manner. similar to previous work [ 26 ], PK results correlated well with measures of efficacy. In a previous PK study, Unified Parkinson 's Disease Rating Scale ( UPDRS ) Part III was besides measured, and large clinically important differences were achieved over 16 h. Thus, the afternoon plasma levels correlated with clinical efficacy [ 26 ] . figure 3. Mean LD plasma levels with AP-CD/LD 50/375 BID† versus IR-CD/LD QID‡. †AP-CD/LD 50 mg/375 mg BID was administered doubly daily at an 8-h interval. ‡IR-CD/LD 18.7 mg/187.5 magnesium QID was administered four-times per day at 4-h intervals.

AP-CD/LD : Accordion Pill-carbidopa/levodopa ; BID : Twice day by day ; IR-CD/LD : Immediate-release-carbidopa/levodopa ; LD : Levodopa ; PD : Parkinson ‘s disease. Created using data on file at Intec Pharma, LTD . visualize 4. Mean total OFF time (left) and mean total ON time with troublesome dyskinesia (right) with AP-CD/LD versus current LD treatment. †It was assumed that patients with PD entering a clinical trial were not optimized on their current treatment. therefore, a dose allowance and optimization period was undertaken at the begin of the trial. Created using data on file at Intec Pharma, LTD. AP-CD/LD : Accordion Pill-carbidopa/levodopa ; IR-CD/LD : Immediate-release carbidopa/levodopa ; LD : Levodopa ; PD : Parkinson ‘s disease . The most normally observe adverse events ( AEs ) were nausea and vomit, consistent with the known safety visibility of CD/LD, and nonspecific symptoms, such as fatigue and sleepiness ; all were mild. Three good AEs were reported ; none considered likely related to AP-CD/LD. AP-CD/LD provided clinically meaningful benefits in the discussion of PD with motive fluctuations, with a safety profile similar to the known profile of CD/LD. As with other CD/LD formulations, circumspection should be exercised that foods high in protein may delay assimilation. AP-CD/LD may allow for deoxidize LD dose while maintaining static LD levels, leading to more coherent motor function with fewer unwanted side effects. AP-CD/LD is presently in Phase III studies in adults with advance PD, expected results in the second half of 2019 .

Drugs with poor solubility

Since the AP in the stomach allows for gradual delivery of the drug and accomplished dissolving of the dose, the AP may lead to more effective and effective pitch of drugs with poor solubility than oral manner of speaking with standard formulations. gradual pitch of the dissolve drug from the stomach should reduce the possibility of supersaturation in the amphetamine modest intestine, while bile secretion in the upper GI acts to improve the intestinal environment for supersaturation. The absence of undissolved drug avoids the presence of drug seeds, which significantly delays the electric potential for crystal emergence and precipitation, and the significant dilution of the drug solution in the humble intestine caused by prolong delivery reduces the potential for nucleation to occur. Furthermore, the major reference of the supersaturation conditions in these circumstances ensures that assimilation predominates over precipitation. The structure of the AP for drugs with inadequate solubility contains outer films that facilitate unfolding and hold the structure together. The out layers contain perforations through which the ailing soluble drug is released. The drug is formulated in a CR layer located inside a frame film that provides mechanical properties american samoa well as a size and shape adequate for GR. The AP delivers the ailing soluble drug through an osmotic march and through erosion of the inside layer at a controlled rate. The drug is extruded throughout the outer perforations in an insoluble mannequin to the stomach .

PK of AP: poor solubility drug

In a demonstrational program, Intec Pharma obtained an undisclosed product ( ‘ Drug X ’ ) that was a commercialize tyrosine kinase inhibitor that shows control Caco-2 permeability ( BCS course II/IV ) and pronounced pH-dependent solubility ( 0.6 mg/ml at ph 1 and 0.01 mg/ml in fender solutions of ph 3.5 and higher ). The concentration of the commercialize formulation is approximately 30 % ; its PK demonstrates nonlinearity above the marketed drug. An AP formulation of drug X ( AP-Drug X ) was developed and tested in a single dose, tripartite crossing over PK study that compared two doses of the AP-Drug X ( one AP capsule and two AP capsules ) to the commercial conceptualization of drug X in 12 healthy volunteers. AP-Drug ten was administered with a easy calorie/fat meal ( 552 Kcal ; 48 % fatten ) ; while receiving the commercial formulation of drug X, individuals were required to fast according to product label. The PK profiles of AP-Drug X ( 1 pill and 2 pills ) and commercial formulation drug X are shown in Figure 5. AP-Drug X ( 1 pill and 2 pills ) importantly extended the preoccupation phase compared with the market conceptualization. Greater exposure was achieved with AP-Drug x at both doses, and the sphere under the curvature ( AUC ) was twice that of the market formulation. previous food effect studies showed that dosing the market product in concert with light meals increased the AUC by only 30 %. Furthermore, AP-Drug X was dose proportional ( i, 2 pills demonstrated an AUC approximately twice that of 1 pill ), whereas the PK of the market conceptualization is nonlinear [ 27 ] . figure 5. PK profile of AP-drug X versus commercial formulation drug X. Created using data on file at Intec Pharma, LTD .

Discussion

AP as a platform and AP-CD/LD have demonstrated gastric retentiveness of 8 planck’s constant or more in healthy volunteers and patients with PD. Further, AP-CD/LD has demonstrated more stable LD plasma levels, greater efficacy and a alike safety profile to the standard IR-CD/LD treatment in patients with PD. AP and AP-CD/LD may be administered with normal diets and behavior and does not require special high-calorie diets or prone positions that may interfere with affected role conformity or drug assimilation. Over the years, several strategies have been developed to increase the gastric residence clock of dose forms. Three technical approaches early than the AP are presently under probe. These approaches include mucoadhesion, in which the dose form adheres to gastric or intestinal walls so that motion is limited ; concentration modification ( i.e., flotation ), in which the dose form can not leave the stomach because of its orientation to the pylorus ; and expansion, in which the dose form becomes besides bombastic to pass through the pyloric sphincter [ 28 ]. These approaches suffer from major limitations. The challenge for mucoadhesive drug pitch systems is the high dollar volume rate of the gastric mucus and the resulting limited retentiveness times. Density modification via floating systems ( for example, large tablets/capsules or multiparticulates and minitablets ) require gastric contents on which to float. This means that the patient must take the dose on a run stomach and may need to take multiple meals. In addition, whether the subject is upright or lying down could affect the dose human body performance. Restrictions, such as specific feeding schedules and maintaining an erect position, back patient complaisance and limit the utility of the engineering. last, expandable systems are designed to achieve longer gastric residence time through an increase in their volume and/or shape, which makes the dose larger and slower to pass through the pylorus. The diameter of the pylorus is reportedly 12.8 ± 7.0 millimeter, but varies well from patient to patient [ 29 ]. During strong migrating myoelectric building complex contractions flush relatively big dose forms may pass from the stomach, as the pylorus can stretch depending on the violence moving against it. To avoid this, the dose form must be large ( i.e., greater than approximately 20 millimeter ) and reinforced in at least two dimensions. Of these expandable systems, the most explore has been swelling tablets. Swelling tables increase in size after encountering gastric fluids, due to the function of hydrophilic polymers that absorb water system from the gastric fluids. The major drawback of these dose forms is the hard addiction on food intake ; these dosages are by and large administered with one of the primary meals of the day or with high-calorie meals to enable sufficient GR. Another disadvantage of the swelling pad technology is that drugs that are ill or meagerly soluble are released via erosion of the polymer matrix, which may besides depend on the hydrodynamic and mechanical forces stage in the GI nerve pathway during the digestive action. This contributes to unevenness and fluctuations in peak-trough plasma levels. In a survey of top managers at pharmaceutical companies, solvability and bioavailability enhancement were identified as the most significant challenges in drug delivery and conceptualization efforts [ 30 ]. approximately 40 % of approved drugs and about 90 % of molecules in the grapevine have inadequate body of water solvability and are BCS class II ( low solvability, senior high school permeability ) or course IV ( moo solubility, abject permeability ) [ 31, 32 ]. Analyses of the properties of lead compounds and newly introduced drugs have shown that both molecular weight and lipophilicity have gradually increased over the past few decades [ 33 ]. To increase the solubility and dissolution rate, physical modifications including particle size reduction, modification of the crystal mannequin, drug dispersion in carriers, solubilization and lipid-based formulations have been used ; chemical modifications such as soluble pro-drugs and salt formation have besides been used [ 34 ]. There are, however, virtual limitations associated with these techniques, and the hope bioavailability enhancement may not always be achieved [ 35 ]. thus, the development of an effective conceptualization to facilitate oral absorption of drugs with poor urine solvability is a considerable challenge. AP may provide a novel oral drug delivery platform, with significant advantages for drugs with a narrow preoccupation window, a minute remedy window and/or poor people solubility .

Future perspective

AP has demonstrated improvements in the PK and efficacy of a narrow absorption window drug and a ailing soluble drug. Both AP drugs presented here ( AP-CD/LD and AP-Drug X ) contain approved and marketed active pharmaceutical ingredients ( APIs ) that were enhanced by delivery via the AP. The AP facilitates the development of molecules with poor people solubility and permeability and enhancement of drugs that suffer from a constrict preoccupation window and inadequate half life leading to the hypothesis of better dose forms, new indications and potentially better guard profiles. AP-CD/LD, with its control spill and gastric retentive formulation, has demonstrated improved efficacy and safety in early trials in patients with progress PD, with a significant decrease in daily drug. A Phase III cogitation ( NCT02605434 ) investigating the efficacy and safety of AP-CD/LD 50/400 milligram BID or TID or AP-CD/LD 50/500 magnesium BID or TID for boost PD are afoot with results anticipated in the second half of 2019. Development of the AP can be expanded to include other medications, indications and curative areas. Drugs that have narrow-minded absorption windows, poor solvability or constrict therapeutic windows or may benefit from gastric retention are just some of the possible candidates. alike to AP-CD/LD, these treatments may show improved efficacy and base hit and have the potential to reduce medicine burden and improve patient attachment. furthermore, the AP may be used for early compounds, those that have been or would have been previously abandoned in early stage development due to any of these issues. The diversity of the AP platform and its ability to enhance the PK profile of a wide crop of physical and chemical properties may enable the successful exploitation of fresh compounds .Executive summary

The Accordion Pill®

  • A novel gastric-retention pill with multilayer films ( Intec Pharma, Jerusalem, Israel ). Accordion Pill ( AP ) allows multiple drug publish profiles, enables eminent drug load of both soluble and ailing soluble drugs, and can support fixed-dose combinations .
  • Phase II clinical studies of AP have demonstrated gastric retention and improved PK and efficacy for several drugs, including those with a narrow assimilation window drug, narrow curative window and poor solubility while maintaining safety profiles similar to active controls .
  • AP-carbidopa ( candle ) /levodopa ( LD ) comprises five layers including immediate-release cadmium and immediate- and controlled-release LD to produce stable LD plasma concentrations .

AP production

  • Intec Pharma has developed a large-scale amply automated manufacture process for the AP .

Clinical achievements

  • In clinical studies, MRI results demonstrated AP was retained in the abdomen for more than 8 planck’s constant in greater than 80 % of participants, including healthy volunteers and patients with Parkinson ’ sulfur disease ( PD ) .
  • AP-CD/LD produced static LD plasma concentrations and provided daily coverage of LD remedy plasma levels in a Phase II study with advance PD patients .
  • Patients treated with AP-CD/LD experienced significantly less total OFF time in comparison with those receiving an active control or their current discussion. AP-CD/LD required fewer casual administrations .
  • AP formulation of a drug that shows hapless solubility and moderate permeability demonstrated an extend assimilation phase and greater exposure compared with the commercial conceptualization of the drug.

Acknowledgments

N Navon wishes to thank all the scientists and engineers who have worked on the development of the Accordion Pill manner of speaking system engineering, in particular R Reinberg, D Kirmayer, M Cohen, Y Melman, Y Yakovson, J Shvetz, E Abramov and L Kluev .

Financial & competing disclosure

The writer is an employee of Intec Pharma. The author has no other relevant affiliations or fiscal interest with any organization or entity with a fiscal pastime in or fiscal conflict with the subject matter or materials discussed in the manuscript aside from those disclosed. medical writing and editorial aid was provided by MC Kane of Prescott Medical Communications Group, Chicago, IL, USA. Funding for this aid was provided by Intec Pharma .

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