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  Exploratory Clinical Trials  
     
 

Gastric Retentive Profile

 
     

Radiology Trials

 

The company conducted a series of exploratory trials in humans that compared the gastric retention times of six novel Accordion Pill™ products with different sizes, polymeric constituents and mechanical properties. Intec performed radiology experiments during which human subjects were given the Accordion Pill™ in a standard Gelatin capsule. The location of the Accordion Pill™ was visualized by X-ray imaging at specific time intervals.

 
 

The purpose of these trials was to:
1. confirm that the system is indeed gastric-retentive;
2. test whether the system is retained in the stomach for an extended period of time;
3. investigate the possibility of controlling the gastric retention profile by modifying the composition of polymers and mechanical properties

  
     
Radiology Trial Highlights:  
 
  • 82 healthy human volunteers
  • No reported adverse side effects
  • Demonstrated ability to control duration of gastric retention
  • Gastric retention achieved even with low calorie meal
 
     
  For a more detailed report on this trial see publication; Klausner et al., Novel Gastroretentive Dosage Forms: Evaluation of Gastroretentivity and Its Effect on Levodopa Absorption in Humans. Pharmaceutical Research; Vol. 20, No. 9, September 2003.  
     
  MRI Trial  
 

In order to study the kinetics and dynamics of the drug dosage form in the stomach, the Accordion Pill™ was developed with a drug reservoir containing magnetite, an MRI contrasting agent. Human volunteers were dosed with the magnetite-labeled Accordion Pill™ after eating a light breakfast (282 kcal). The retained dosage forms were visualized with MRI at various intervals. The Accordion Pill™'s retention and movement within the gastric compartment were observed over time, documenting that the danger of blocking the pylorus is minimal due to the constant movement of the DF in the stomach (see figure below).

 
     
   
 

MRI images of magnetite-labeled Accordion Pill™ in a human volunteer, administered after a light breakfast. At various time intervals the system is positioned in different loci in the stomach.

 
     
MRI Trial Highlights:  
  Significant gastric retention was achieved with the Accordion Pill™ even after a low calorie meal. The system moved within the stomach, reducing the possibility of interfering with physiological gastric emptying. For a more detailed description of these trials see publication - Afargan et al., Delivery Technology September 2006 Vol 6 No 8.  
     
  The Accordion Pill™: Overcoming the Absorption Limit in the GI Tract

 
 

Gamma scintigraphy trials

 
  An important safety concern with any expandable gastric-retentive dosage form is the possible hindrance of gastric emptying of food or of other drugs. To evaluate this, the Accordion Pill™ was labeled with an 111 In - marker and administered with 99m Tc - labeled food. The food and the Accordion Pill™ could therefore be followed simultaneously by a g-camera. A large non-disintegrating tablet, also labeled with 111 In, was used as a comparator arm with the labeled food in this study. The trial was carried out in a random cross-over design in eight healthy volunteers.  
     
   
     
   
     
 

The images obtained with gamma scintigraphy, showing the meal in the 99m Tc channel and the Accordion Pill™ in the 111 In channel.
In this trial, the mean T50 and T90 for food evacuation from the stomach were 0.77 (+ 0.12) hour and 1.43 (+ 0.13) hours for the Accordion Pill™, while the control scores were 0.71 (+ 0.13) hour and 1.51 (+ 0.21) hour, respectively.

 
     

Results:

 
 
  • The Accordion Pill™ did not affect food emptying.
  • The unique movement of the Accordion Pill™ within the stomach during its retention was also confirmed in this trial and supports the lack of interference with food emptying
  • The trial also confirmed the significant gastric retention as previously observed with MRI.
 
     

Pharmacokinetic Profile
The Accordion Pill™ doubles the absolute bioavailability

 
 

Riboflavin (RF) is a well-known "narrow absorption window" marker for evaluating the significance of the gastric retention approach. Following oral administration, it is poorly absorbed (25%) through specific carriers that are over expressed in the upper part of the GI. Following absorption, its circulating half-life is relatively short (2 hours).

 
     

Experimental Approach

 
 

Riboflavin was formulated in the Accordion Pill™ for an in-vitro release rate of 75mg for 10 hours - the same range of time that the Accordion Pill™ was shown to be retained in the stomach. In a double cross-over trial, the Accordion Pill™ was administered after a light breakfast to seven volunteers, and compared to an immediate release (IR) formulation.

 
     
   
     

Results:

 
 
  • The Accordion Pill™ doubled the absorption phase and bioavailability of Riboflavin
  • Equal Cmax values were observed for the Accordion Pill™ and the IR
  • Tmax was delayed by 2 hours by the Accordion Pill™
  • A three-fold increase in Capical duration above the IR was observed
  
 

This clinical trial confirmed that retaining the drug reservoir in the stomach while releasing it over the same period of time can effectively improve the bioavailability even when absorption is limited by saturation of a specific transporter.