Effervescent route to improved solubility

Effervescence is generally used in pharmaceutical formulation to make it easier to administer drugs by mouth, but it may also have a role in improving the absorption of drugs that have poor bioavailability.

A US patent (No 6,641,838) awarded to drug delivery specialist CIMA Laboratories describes a means of using an effervescent formulation as a penetration enhancer for drugs to improve their solubility.

It also covers the use of various coatings and other systems to delay the effervescence until the tablet reaches a particular portion of the gastrointestinal tract, such as the oesophagus, stomach, duodenum or colon. This could be used, for example, to direct the drug to the area of the GI tract where it has the best chance of being absorbed.

Many orally-administered drugs display poor bioavailability when administered in conventional dosage forms, i.e., the rate and extent to which the drugs are absorbed is less than desirable. With several drugs, absorption may be as little as 30 per cent or less of the orally administered dose. Specific examples of drugs in this bracket include the widely-used immunosuppressant cyclosporine, doxorubicin for cancer and the asthma drug terbutaline.

To compensate for this effect, a very large dose is often administered so that absorption of the therapeutically required quantity of the drug can occur. This technique may prove costly with expensive drugs, and the non-absorbed drug may also have undesirable side effects within the gastrointestinal tract.

In addition, poorly absorbed drugs often display a great deal of variability between patients in bioavailability, and this can create dosing problems. For example, the Parkinson's disease treatment methyldopa has an average bioavailability of 25 per cent, but this can be anything between 8 per cent and 62 per cent, depending on the patient.

Penetration enhancers are often employed to overcome this problem, but many of them damage the absorbing tissues and thus are not a practical solution to the problem of poor bioavailability. In fact, it has been suggested that the damage to the mucosa caused by these agents may be the factor responsible for the improved absorption.

Other techniques which have been employed to improve bioavailability include using enteric coated tablets in tandem with effervescence to rapidly dissolve or disperse the dosage form in the stomach.

Effervescence leads to an increase in absorption of drugs in a number of ways, according to the patent. These include reducing the thickness and/or the viscosity of the mucus layer which is present adjacent to the gastrointestinal mucosa, loosening so-called tight junctions between cells, causing a change in the cell membrane structure to promote absorption absorption into and through the cells, and increasing the hydrophobic environment within the cellular membrane.

CIMA's patent covers dosage forms that contain materials that can lead to site-specific delivery. Various mechanisms to achieve this are described in the patent. For instance, the material may be metabolised by enzymes present in a specific part of the gut, thus releasing the drug in that section. Coatings can also be used to prevent absorption higher up the GI tract, it notes.

CIMA is set to be acquired by US biotechnology firm Cephalon in a $515 million (€449m) cash deal.