The Accordion Pill^®: unique oral delivery to enhance pharmacokinetics and therapeutic benefit of challenging drugs

Oral delivery remains the most convenient route of drug administration, offering cost–effectiveness, high patient compliance and flexibility in design and dosage forms [1]. Yet oral administration is often fraught with many challenges, including narrow absorption windows, narrow therapeutic windows and poor solubility. Narrow absorption windows occur in drugs that must be absorbed in the upper GI tract or with those that have negligible colonic absorption [2]. Drugs with a narrow therapeutic 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 poorly soluble are difficult to deliver in efficient, convenient oral formulations. A drug that displays more than one of these characteristics is exceedingly difficult to deliver in an oral formulation and may possibly require careful monitoring for drug-related problems [5]. Thus, achieving efficient oral delivery – particularly for diseases that require chronic and frequent dosing – has become a challenging endeavor in drug development [2].

Improving the pharmacokinetics (PK) of drugs with a narrow absorption window or a narrow therapeutic index and achieving efficient oral delivery of poorly soluble drugs can lead to significant improvements in the efficacy and safety of treatments. For a thorough review of the challenges to oral drug delivery and development, see Gabor et al. [6].

A promising approach to address oral drug delivery needs is through gastric retention (GR) drug delivery systems [7]. Retaining the dosage form in the stomach and releasing the drug in a controlled manner facilitates a prolonged and continuous absorption phase of the drug in the upper parts of the gastrointestinal (GI) tract. GR avoids significant heterogeneity throughout the GI tract, including pH, commensal flora, GI transit time, enzymatic activity, aqueous environment and surface area, all of which may influence absorption [8]. GR formulations can also increase the apparent drug solubility in the stomach and GI tract, which prevents drug precipitation and results in a consistent increase in the absorption phase [9]. Such prolonged and continuous absorption can improve efficacy and safety while reducing the need for frequent daily dosing.

To achieve an efficient GR delivery form, the system must overcome the normal physiology of the stomach, which often clears its contents by continuous propulsive forces in the fed state or by ‘housekeeper waves’ during the fasting state [10]. Despite years of substantial research, evidence for successful GR dosage forms remains limited and represents an unmet need in therapeutic drug delivery [11]. To address these unmet needs, the Accordion Pill^® (AP) has been developed. Recent work on the GR and manufacture of the AP along with the clinical implications of the AP for medications with narrow absorption windows and/or narrow therapeutic windows are reviewed here.

The Accordion Pill

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

• Narrow absorption window

  • Poor colonic absorption

• Narrow therapeutic window

  • Maximum plasma concentrations correlate with adverse events

  • Trough levels correlate with poor efficacy

• Poor solubility

  • Low solubility, high permeability (Biopharmaceutics Classification System (BCS) class II)

  • Low solubility, low permeability (BCS class IV) [12]

• Act locally, in the stomach or in the upper part of the GI tract

The unique GR performance of the platform is due to the size, shape and mechanical properties of the physical multilayer structure. AP contains multilayer biodegradable polymeric films folded into an undulated shape that fits within a standard-sized capsule (Figure 1). In general, the AP comprises an inner controlled release, drug-containing layer, outer layers that facilitate the unfolding mechanism, and immediate release layer(s) for multiple drug release profiles and/or fixed-dose combinations; however, the number 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 small intestine, due to its enteric 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 safety in healthy subjects and patients. The results demonstrated significant PK and efficacy improvements for various drugs while maintaining a safety profile comparable to active controls. Current work has included only excipients that are US FDA approved and appear on the inactive ingredient (IIG) list.

Accordion Pill gastric retention

The GR performance of AP was tested in various human clinical studies using magnetic resonance imaging (MRI) to follow the AP. In these studies, the inner layer of the AP contained iron oxide (magnetite); magnetite is a superparamagnetic MRI contrast agent that was used as a marker to follow the fate of the AP structure in the stomach [13,14]. The inner layer of the AP was designed to not release the magnetite in the stomach, which was verified by an in vitro dissolution test (data on file).

In an open-label, single-dose study in 11 healthy volunteers using the magnetite-containing AP, participants received standard meals during the day following an overnight fast. Meals included breakfast (550 Kcal, 48% fat) 30 min prior to AP dosing and lunch (860 Kcal, 26% fat) 4 h post-dosing; dinner was provided 10 h after dosing and was not standardized. The standardized meals represent normal meal intake and are not high-calorie or high-fat regimens. Participants were not required to maintain any positional requirements (e.g., laying prone) during the testing. Participants underwent sequential MRI every 1 h ± 15 min for 11 h (maximum 10 MRIs/study day) to track the location of the AP, either in or out of the stomach. The AP remained in the stomach at 8 h after administration for all 11 participants, at 9 h for 10 participants and at 11 h in 8 participants (Figure 2). At the final MRI 48 h after administration, the AP was outside of the stomach in all participants. Four participants each reported one AE (pain during MRI, headache, nausea and vomiting); all were mild and resolved. Results from this trial demonstrated 8 h of GR for the AP in 100% of participants under partially standardized but not specialized meal requirements (e.g., normal calorie, normal fat) 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 study with participants receiving 1 week of PPI treatment (data on file).

Accordion Pill production

The automated manufacturing process of the AP was developed by Intec Pharma. In general, the manufacturing process is divided into two stages: film preparation, and assembly and encapsulation. Film preparation begins with preparation of a solution or suspension containing polymers (with or without drug) that are then dissolved or suspended in an organic solvent or water. Following this, a coating machine is used to apply the solution or suspension to a film web, and the solvent is removed by drying. The assembly and encapsulation stage starts with lamination to build up the multilayer system; the laminate then passes through different stations on a unique web converting line. Next, the multilayer film is transferred to a folding apparatus configured specifically to fold the integrated device. Finally, the folded 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 as long as possible while minimizing adverse effects [17]. Levodopa (LD) is the most effective treatment for PD, providing benefits for activities of daily living, quality of life and life expectancy. LD is administered in combination with carbidopa (CD), 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 treatment [18]. As the disease progresses and dopaminergic neurons in the substantia nigra degenerate, the therapeutic window narrows and the pharmacokinetics of LD become critical. The challenge in maintaining LD plasma levels within this progressively narrowing therapeutic window is complicated by LD's narrow absorption window, with absorption confined to the upper GI tract as well as LD's short (1.5 h) clearance half-life when taken with carbidopa (CD) [19]. As high levels of LD are associated with the development of dyskinesias [20], it is preferable to maintain peak LD levels just high enough for efficacy. Over time, deep troughs in LD availability are associated with pulsatile stimulation of dopamine receptors in the striatum that, in turn, lead to motor complications, including dyskinesias and motor fluctuations [21,22]. Reducing LD dosage while maintaining stable LD levels should help patients with PD maintain more consistent motor function.

CD/LD administered via the AP (AP-CD/LD) may achieve stable LD plasma concentrations with considerably fewer daily administrations due to the GR nature of the AP. Despite potential gut motility issues that PD patients may experience, earlier work demonstrated that PD patients retained the AP for similar times (mean GR 11.8–13.9 h vs 12.7 h) compared with healthy volunteers [23,24]. AP-CD/LD comprises five layers with both immediate release (IR) and controlled release (CR) components for CD and LD fixed-dose combination. A Phase II, multicenter, open-label, randomized, two-way crossover study with multiple dosages (AP-CD/LD 50 mg/250 mg with no IR; 50 mg/375 mg; 50 mg/500 mg) and active control (Dopicar^®, Sinemet^® or patient's own treatment) investigated the PK profile as 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 fluctuation following AP-CD/LD compared with active control (Figure 3). Twice daily AP-CD/LD 50/375 mg provided therapeutic mean plasma levels of 1038 ng/ml. Both daily administrations produced therapeutic levels, with minor variation between the two timepoints. Peak-to-trough fluctuations (mean C_max–mean C_min) with the AP formulation were 50% lower compared with IR-CD/LD. AP-CD/LD increased the LD absorption phase by more than sixfold, and the LD 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 deep troughs in LD availability are associated with pulsatile stimulation of dopamine receptors in the striatum, the results observed with AP-CD/LD are promising for providing efficacy while reducing risks of motor complications [21,22]. In fact, compared with active controls, patients treated with AP-CD/LD demonstrated significantly 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 mg showed significantly less ON time with dyskinesias than patients taking conventional LD treatment (0.7 h compared with 1.2 h, p < 0.002); this effect was not significant for the lower dosage of 50/375 mg; 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 observable (Figure 4). Good ON time (‘ON time without dyskinesia’ plus ‘ON time with nontroublesome dyskinesia’) also was significantly 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 also measured, and large clinically important differences were achieved over 16 h. Thus, the afternoon plasma levels correlated with clinical efficacy [26].

The most commonly observed adverse events (AEs) were nausea and vomiting, consistent with the known safety profile of CD/LD, and nonspecific symptoms, such as fatigue and somnolence; all were mild. Three serious AEs were reported; none considered likely related to AP-CD/LD. AP-CD/LD provided clinically meaningful benefits in the treatment of PD with motor fluctuations, with a safety profile similar to the known profile of CD/LD. As with other CD/LD formulations, caution should be exercised that foods high in protein may delay absorption. AP-CD/LD may allow for reduced LD dosage while maintaining stable LD levels, leading to more consistent motor function with fewer unwanted side effects. AP-CD/LD is currently in Phase III studies in adults with advanced 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 complete dissolution of the dose, the AP may lead to more effective and efficient delivery of drugs with poor solubility than oral delivery with standard formulations. Gradual delivery of the dissolved drug from the stomach should reduce the possibility of supersaturation in the upper small bowel, 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 potential for crystal growth and precipitation, and the significant dilution of the drug solution in the small bowel caused by prolonged delivery reduces the potential for nucleation to occur. Furthermore, the major extension of the supersaturation conditions in these circumstances ensures that absorption predominates over precipitation.

The structure of the AP for drugs with poor solubility contains outer films that facilitate unfolding and hold the structure together. The outer layers contain perforations through which the poorly soluble drug is released. The drug is formulated in a CR layer located inside a frame film that provides mechanical properties as well as a size and shape adequate for GR. The AP delivers the poorly soluble drug through an osmotic process and through erosion of the inner layer at a controlled rate. The drug is extruded throughout the outer perforations in an insoluble form to the stomach.

PK of AP: poor solubility drug

In a demonstrational program, Intec Pharma obtained an undisclosed product (‘Drug X’) that was a marketed tyrosine kinase inhibitor that shows moderate Caco-2 permeability (BCS class II/IV) and pronounced pH-dependent solubility (0.6 mg/ml at pH 1 and 0.01 mg/ml in buffer solutions of pH 3.5 and higher). The absorption of the marketed formulation is approximately 30%; its PK demonstrates nonlinearity above the marketed dose. An AP formulation of drug X (AP-Drug X) was developed and tested in a single dose, three-way crossover PK study that compared two doses of the AP-Drug X (single AP capsule and two AP capsules) to the commercial formulation of drug X in 12 healthy volunteers. AP-Drug X was administered with a light calorie/fat meal (552 Kcal; 48% fat); 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) significantly extended the absorption phase compared with the marketed formulation. Greater exposure was achieved with AP-Drug X at both doses, and the area under the curve (AUC) was twice that of the marketed formulation. Previous food effect studies showed that dosing the marketed product together with light meals increased the AUC by only 30%. Furthermore, AP-Drug X was dose proportional (i.e., 2 pills demonstrated an AUC approximately twice that of 1 pill), whereas the PK of the marketed formulation is nonlinear [27].

Discussion

AP as a platform and AP-CD/LD have demonstrated gastric retention of 8 h or more in healthy volunteers and patients with PD. Further, AP-CD/LD has demonstrated more stable LD plasma levels, greater efficacy and a similar 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 patient compliance or drug absorption.

Over the years, several strategies have been developed to increase the gastric residence time of dosage forms. Three technological approaches other than the AP are currently under investigation. These approaches include mucoadhesion, in which the dosage form adheres to gastric or intestinal walls so that motility is limited; density modification (i.e., flotation), in which the dosage form cannot leave the stomach because of its orientation to the pylorus; and expansion, in which the dosage form becomes too large to pass through the pyloric sphincter [28]. These approaches suffer from major limitations. The challenge for mucoadhesive drug delivery systems is the high turnover rate of the gastric mucus and the resulting limited retention times. Density modification via floating systems (e.g., large tablets/capsules or multiparticulates and minitablets) require gastric contents on which to float. This means that the patient must take the dosage on a fed stomach and may need to take multiple meals. In addition, whether the subject is upright or lying down could affect the dosage form performance. Restrictions, such as specific feeding schedules and maintaining an upright stance, hinder patient compliance and limit the usefulness of the technology. Lastly, expandable systems are designed to achieve longer gastric residence time through an increase in their volume and/or shape, which makes the dosage larger and slower to pass through the pylorus. The diameter of the pylorus is reportedly 12.8 ± 7.0 mm, but varies considerably from patient to patient [29]. During strong migrating myoelectric complex contractions even relatively large dosage forms may pass from the stomach, as the pylorus can stretch depending on the force moving against it. To avoid this, the dosage form must be large (i.e., greater than approximately 20 mm) and reinforced in at least two dimensions. Of these expandable systems, the most explored has been swelling tablets. Swelling tables increase in size after encountering gastric fluids, due to the use of hydrophilic polymers that absorb water from the gastric fluids. The major drawback of these dosage forms is the strong dependence on food intake; these dosages are generally administered with one of the primary meals of the day or with high-calorie meals to enable sufficient GR. Another disadvantage of the swelling tablet technology is that drugs that are poorly or sparingly soluble are released via erosion of the polymer matrix, which may also depend on the hydrodynamic and mechanical forces present in the GI tract during the digestive process. This contributes to variability and fluctuations in peak-trough plasma levels.

In a survey of top managers at pharmaceutical companies, solubility and bioavailability enhancement were identified as the most significant challenges in drug delivery and formulation efforts [30]. Approximately 40% of approved drugs and nearly 90% of molecules in the pipeline have poor water solubility and are BCS class II (low solubility, high permeability) or class IV (low solubility, low 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 form, drug dispersion in carriers, solubilization and lipid-based formulations have been used; chemical modifications such as soluble pro-drugs and salt formation have also been used [34]. There are, however, practical limitations associated with these techniques, and the desired bioavailability enhancement may not always be achieved [35]. Thus, the development of an effective formulation to facilitate oral absorption of drugs with poor water solubility is a considerable challenge. AP may provide a novel oral drug delivery platform, with significant advantages for drugs with a narrow absorption window, a narrow therapeutic window and/or poor solubility.

Future perspective

AP has demonstrated improvements in the PK and efficacy of a narrow absorption window drug and a poorly 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 solubility and permeability and enhancement of drugs that suffer from a narrow absorption window and short half-life leading to the possibility of better dosage forms, new indications and potentially better safety profiles. AP-CD/LD, with its controlled release and gastric retentive formulation, has demonstrated improved efficacy and safety in early trials in patients with advanced PD, with a significant reduction in daily dosing. A Phase III study (NCT02605434) investigating the efficacy and safety of AP-CD/LD 50/400 mg BID or TID or AP-CD/LD 50/500 mg BID or TID for advanced PD are underway with results anticipated in the second half of 2019. Development of the AP can be expanded to include other medications, indications and therapeutic areas. Drugs that have narrow absorption windows, poor solubility or narrow therapeutic windows or may benefit from gastric retention are just some of the possible candidates. Similar to AP-CD/LD, these treatments may show improved efficacy and safety and have the potential to reduce medication burden and improve patient adherence. Furthermore, the AP may be used for other 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 range of physical and chemical properties may enable the successful development of new compounds.