Flamel’s Micropump® Technology: Oral Delivery of Small Molecule Drugs

Flamel’s Micropump® technology is a controlled-release system which permits either extended, or both delayed and extended delivery, of small molecule drugs. It is suitable in particular to drugs with a narrow window of absorption from the upper part of the small intestine.

Flamel’s Novel Solution for the Delivery of Small Molecules Best Absorbed in the Small Intestine

More than 70% of small molecule drugs are absorbed almost exclusively in the small intestine, with a transit time duration limited to 3 to 4 hours. In order to extend the time of action of these drugs, it is necessary to increase the duration of absorption by maintaining the drugs longer in the stomach or in the small intestine.

Some companies have developed gastro-retentive systems with sizable tablets. Among the specific problems inherent to these monolithic systems, large tablets are generally not authorized to treat children and present swallowing problem for elderly people.

Flamel has designed Micropump® I and II to maintain small molecule drugs longer in the small intestine. The size of Micropump® microparticles allows formulation of suspensions/syrups for children and sachets for elderly patients.

Description

Flamel’s Micropump® technology consists of a multiple-dose system containing 5,000 to 10,000 microparticles per capsule or tablet. The 200-500 microns diameter-sized microparticles are released in the stomach and pass into the small intestine, where each microparticle, operating as a miniature delivery system, releases the drug by osmotic pressure at an adjustable rate (controlled for Micropump® I or delayed for Micropump® II) and over an extended period of time.



The design of the Micropump® microparticles allows an extended transit time in the small intestine with a plasma mean residence time extended up to 24 hours, which is especially suitable for short-lived drugs known to be absorbed only in the small intestine.

The Micropump® microparticles’ design can be adapted to each drugs’ specific characteristics by modifying the coating thickness and composition (including the excipients encapsulated with the drug) for improved efficacy (i.e., extending therapeutic coverage), reduced toxicity and/or side effects (i.e., reduced C_max or peak drug concentration in the plasma) and improved patient compliance (once-a-day regimen). Such adaptations can be particularly useful in the context, for example, of chrono-therapy.

Performance

• Permits the extended delivery of drugs with a narrow window of absorption, i.e., Micropump® I (up to 24 hours) or, both delayed and extended delivery of these drugs, i.e., Micropump® II (up to 12 hours following the drug uptake and for a release over an additional 12 hours);
• Allows the controlled-release of poorly soluble (< 0.01mg/L) as well as highly soluble (> 500g/L) drugs; and,
• Applicable to low doses(4 mg) or high dose (1,000 mg) drugs.

From Pediatric to Geriatric Uses

• Using Micropump®, Flamel has developed suspensions for pediatric applications (a therapeutic need and a large market);

Only a few controlled release applications have been approved for pediatric applications. The main reason is that large tablets are not generally authorized for children and large particle-based controlled release systems do not allow stable suspension.

By using small particle formulations (e.g., 200-500 microns diameter), Flamel has created Micropump®-enabled formulations of different drugs. These formulations carry the additional advantage of taste masking.

• Using Micropump®, Flamel is also currently developing sachets for geriatric applications.

The geriatric market is increasing and it is more and more complex to treat elderly people due to the number and quantity of drugs in a daily regimen. In addition, elderly patients have difficulty swallowing large tablets. Flamel’s sachet formulation is the ideal solution for giving high dosage drugs less frequently, such as for Metformin XL, i.e. 2 grams once-a-day.

Advantages

• Easy to swallow (due to the microparticles’ size);
• Taste masking;
• Good tolerability;
• Avoids dose dumping;
• Reduces intra- and inter-variability;
• Allows combination of different drugs whose release can be controlled separately;
• Easy to scale up to industrial high-volume production (based on fluidized bed spray coating and granulation);
• Cost effective process; and,
• Strong intellectual property position (over 40 patents incl. US Patent N° 6,022,562 granted on Feb. 8, 2000)

Current Products Pipeline

Flamel has proven in human studies (up to and including Phase III clinical trials) the extension of the release of four small molecule drugs, known to be only absorbed in the upper part of the small intestine:

Proton pump inhibitors for the treatment of gastroesophageal conditions, including heartburn and other symptoms of gastroesophageal reflux disease (GERD);

Genvir™, acyclovir for the treatment of Acute Genital Herpes (positive results in Phase III);

Metformin XL, an anti-diabetic for the treatment of type II diabetes (positive results in Phase I);

An undisclosed ACE inhibitor co-developed with Servier Monde (confidential); and,

Augmentin SR, an antibiotic (confidential).

Flamel developed COREG CR™ for GSK using the MICROPUMP^® technology.
GSK launched the drug in the USA for treatment of three key cardiovascular conditions on March 22, 2007 (see the press release by Flamel Technologies)