Kaletra enters Europe with non-freeze tablet formulation
medications known as protease inhibitors, has won the thumbs up
from the European Commission with a melt extrusion formulation
which enhances solubility, requires fewer processing steps, and,
crucially, does not need to be refrigerated.
The commercialisation approval makes Kaletra the first co-formulated pharmaceutical compound available in Europe to be successfully tableted using a proprietary melt extrusion process, combining its two anti-HIV protease inhibitors, lopinavir and ritonavir.
Melt extrusion, whose industrial application dates back to the 1930s, has been used in a wide range of medical applications, from stents to ophthalmic implants, but its application to the manufacturing of tablets is relatively new, complex, and technically challenging.
Melt extrusion is the process of converting a thermoplastic raw material into a product of uniform shape and density by forcing it through a die.
Over the past fifteen years, only four pharmaceutical products have been successfully formulated into tablets through melt extrusion technology, including Isoptin (verapamil) and a fast-acting version of ibuprofen, both of which are manufactured by Abbott.
The Illinois drugmaker decided the technology can be used to replace Kaletra's soft capsules with tablets that need a lower pill count, show stability at room temperature and eliminate the need to plan mealtimes around the medication's schedule.
Reformulation is a controversial area for Abbott, as the company is currently engaged in an acrimonious legal battle with generic manufacturers who allege the drugmaker has changed formulations of its cholesterol drug TriCor so many times, it has violated US antitrust laws.
"Kaletra's reformulation is about the huge benefits this formulation can have for patients," Abbott spokeswoman Tracy Sorrentino told In-PharmaTechnologist.com, stressing that there is no patent dispute or expiration in this case.
"Apart from reducing the pill count from six to four a day and having no food requirements, this medication will be a big deal for developing countries in Africa, where refrigeration is a big problem."
Many developing countries require documentation of European approval as part of the filing process for the new tablet formulation, so the latest development has been welcomed as a step forward in the fight against AIDS in Africa.
One of the preferred methods of delivery for insoluble drugs such as Kaltana has been the soft gel capsule (SGC), where a semi-solid vehicle is encapsulated in an outer shell, often in the presence of a lipophilic compound, such as a fatty acid, to aid absorption inside the gastrointestinal tract.
However, SGC poses several problems, such that chemical instability can arise between the drug, the vehicle and the capsule shell, resulting in physical and even chemical changes. Sometimes the active ingredient can crystallise out of solution, reducing bioavailability.
What is more, traditional approaches used in tablet formulation, such as incorporation of surfactants or acids, have failed to adequately increase the bioavailability of these solid formulations.
Melt extrusion technology overcomes these challenges by uniformly dissolving Kaletra's active ingredients lopinavir and ritonavir throughout a hydrophilic polymeric matrix, ensuring a constant release of active ingredient as it is dissolved in the gastrointestinal tract.
Thus, this solid formulation of the drug provides the critical level of bioavailability that previous experimental tablet formulations have failed to achieve.
For manufacturers the new formulation also means high throughput, fewer processing steps with no time-steps and no restrictions on the compressibility of the active ingredients.
Meltrex, the proprietary melt extrusion technology used for the manufacture of Kaletra tablets, was designed and operated by Soliqs, the drug delivery business of Abbott.
The extruder used has a twin-screw design which offers short-residence time, self-wiping screws and versatility.
A single Kaletra tablet will now be composed of 200mg lopinavir and 50mg ritonavir, as compared to 133.3mg lopinavir and 33.3mg ritonavir in the previously introduced soft capsule.
