Breaking The Mould

Q: Accu-Break has used multilayer technology in an innovative way, could you please describe the reasoning behind the drug-free layer?

David Beach

We have developed two distinct multilayer tablet technologies, known as Accu-B and Accu-T, which incorporate a drug-free layer. With the Accu-B technology, the dosage form has two layers, one of which is drug-free. The second layer contains drug and is deeply scored. The drug-free layer provides several unique features: first and foremost, given the deep score in the drug layer, the drug-free layer forms a backbone that gives the finished dosage form mechanical strength to withstand packaging and shipping operations. Secondly, the drug-free layer is the fracture plane for the Accu-B tablet. The tablet can be broken through the score and the fracture occurs in the drug-free layer. Compared with a conventionally scored tablet, the Accu-B bilayer design ensures partial dosing accuracy and eliminates concerns over loss of mass. Using the Accu-B technology, scored tablets can be made that would satisfy the testing and data requirements for both the European Pharmacopeia's Monograph 0478 and the FDA's recently proposed Guidance for Industry, Tablet Scoring: Nomenclature, Labeling, and Data Evaluation.

Our Accu-T technology uses up to five layers in a taller-than-wide tablet, and the incorporation of drug-free layers serve one of two purposes:

• The drug-free layer provides a physical barrier between active ingredients. This barrier allows the formulation of incompatible actives with no worries about co-mixing and resultant physical or chemical stability issues. The technology utilises machinery that can produce tablets with up to five compressed layers so the use of more than one drug-free layer can facilitate a "poly pill" with three different API-containing formulations.

• A drug-free breaking layer is incorporated into the middle of an Accu-T tablet and can be used to separate the drug-containing layers. Since the drug-containing layers are physically located at the top and bottom of this taller-than-wide tablet, breaking the tablet through the middle drug-free layer separates the dose into exact halves. Unique fixed-dose combination (FDC) tablets can be made where the top and bottom layers contain different actives. In this configuration, the two different drug layers can be separated if desired by splitting the tablet through the middle-drug free layer. Patients taking antihypertensive FDCs can be confronted with side effects that result from one of the drugs within the FDC, resulting in prescription discontinuation. With the Accu-T FDC tablet design, a patient could suspend treatment with one of the drugs in the FDC by simply breaking the tablet through the middle drug-free layer. When appropriate, the patient could then resume taking the whole tablet, which allows some dose flexibility without having to stop the prescription entirely. The tablet could also be used to initiate treatment with a single agent and then add the second and, thus, efficiently transitioning the patient into a convenient FDC without the need for separate prescriptions during the titration phase.

Q: Does the use of a drug-free layer to separate incompatible APIs require further consideration specific to the choice of excipient(s)?

Excipient choices are broad and specific requirements are not unique to the technology, meaning common excipients are readily adaptable for use in Accu-Break technologies. For Accu-B tablets, the requirement for a strong backbone in the drug free layer necessitates the use of excipient materials with good compressibility (e.g., microcrystalline cellulose). Typical finished tablet hardnesses are more than 20 Kp. In addition, in an immediate release product, the desire to have the drug free layer separate rapidly from the active containing layer typically requires the use of higher levels of disintegrant in the drug-free layer.

Q: Why have fixed-dose combination (FDC) drugs been criticised in the past?

The largest historical criticism of FDCs has come from the lack of dose flexibility. Taking antihypertensive FDCs as an example, treatment is typically initiated with a single agent, which is titrated to a maximum tolerated dose. If the desired effect on lowering blood pressure is not achieved, a second agent is added, which also requires titration and can lead to lowering the dose of the first agent. A third agent is sometimes added to the mix, or substituted for one of the initial drugs. This process continues until the patient's blood pressure is within the target range, and then the physician looks for an option to transition the patient to an FDC that contains APIs at the effective dose for that patient. This is done of course to simplify the dosing regimen for the patient in an attempt to maintain adherence to the regimen. Problems arise when a dose adjustment is necessary due to the inflexibility of traditional FDCs. The convenience of a single dosage form is offset by the inability to manage dose adjustments without the need for new prescriptions. If a patient is transitioned to an FDC, inevitably an adjustment will be made to their dose(s), their regimen, the specific drugs being used, or all of the above. So, from that perspective, the criticism is justified. However, for those patients who are effectively managed using FDCs, the ability to take lower doses of two or more medications in a single dosage form is highly desired, especially if it is a once-a-day regimen.

David Beach is technical consultant for formulation development and manufacturing at Accu-Break Pharmaceuticals.