Enhancing Dosage Flexibility in Combination Therapy

Hypertension was identified early on as an entity for which pharmacologic therapy with 2 or more agents would be required for most patients. The study designed by Freis that proved the benefits of antihypertensive therapy used a combination tablet of reserpine and hydrochlorothiazide plus a tablet of hydralazine. ¹ This later became the basis for the commercial triple combination, Ser‐Ap‐Es.

Combination drug therapy is not new. Nevertheless, combinations were frowned upon in much of the 20th century because the prevailing philosophy was to seek a single “silver bullet” to treat a disease entity rather than prescribe multicomponent formulations to be dispensed by pharmacists or physicians, indeed, “generations of medical graduates from the 1960s, 1970s and 1980s were presented with a view that polypharmacy was dangerous therapeutics and indefensible practice. Most fixed‐dose combination tablets were viewed with suspicion.” ²

By the 1960s, antimicrobial, antituberculosis, and antihypertensive medications were being combined. JNC VI ³ was the first hypertension guideline to mention combination therapy as a choice. JNC 7 fully endorsed the concept. ⁴ At present, numerous combinations are available for treatment of hypertension, diabetes, lipid disorders, human immunodeficiency virus, and other infections, and additional combination products—including a “polypill” to reduce cardiovascular risk—have been proposed. ⁵ , ⁶

COMBINATION THERAPY AND THERAPEUTIC INERTIA

Combination drug therapy of hypertension has become more widely used to achieve the lower blood pressure goals currently recommended, especially for patients with diabetes mellitus and chronic kidney disease. When fixed‐dose combination products are used, there may be an additional disincentive to perform drug dose titration when indicated because of what has been termed clinical inertia or therapeutic inertia. ⁷ , ⁸ This is the result, in part, of the need to write a new prescription for a higher dose combination product and the possible lack of flexibility of dose forms. In addition, the physician cannot easily titrate one component without changing the other(s). If a patient has an adverse effect, it is not possible to stop the allegedly responsible component (at least temporarily) while continuing the other without writing a new prescription, many of which are never filled.

Physicians tend not to bring patients to target blood pressure if doing so requires additional action. Most titration to goal blood pressure should be accomplished after initiation of a new medication, but later titration (either upward or downward) often becomes necessary as conditions change. The temptation, especially if the patient is fairly close to goal, is to ignore the need for additional medication. Alternatively, one must take the action of writing a new prescription or writing multiple prescriptions. All of this takes time and effort.

NEW TYPES OF TABLETS: POTENTIAL BENEFITS IN ACHIEVING GOAL BP

New types of tablets are under development. While being designed to be used whole without being broken, they nevertheless may be broken easily to allow novel dose flexibility. In the tablet types discussed below, the tablet is manufactured with a drug‐free layer that serves as the break region if a partial dose is desired.

Split‐Drug Configurations

The tablet in Figure 1 was developed to provide the essential benefits of traditional fixed‐dose combination therapy—enhanced compliance and one copay—with the traditional advantage of 2 separate dosage forms, namely, dosage flexibility. This tablet is manufactured so that each of 2 drugs is placed at opposite ends of the tablet with a drug‐free (inactive) layer placed in between. Drug “A” is separated from drug “B” by the inactive layer (“A‐I‐B”). The inactive area will generally be scored. The tablet is shaped and sized both for easy breaking and easy swallowing as a whole tablet. As long as a break through the inactive layer does not impinge on either the “A” or “B” layer, the tablet can break irregularly by mass, yet each half tablet (or “tablette”) will contain the full dose of each drug. Each layer has its unique color and code marking. If a patient were prescribed a combination tablet in this format and the physician wanted to double the dose of only one of the drugs, the patient could be instructed to break another tablet and take the appropriate half tablet plus a whole tablet. If a patient were taking a diuretic combination and needed a “diuretic holiday” for any reason, the patient could be instructed to continue to take the half tablet with the nondiuretic drug only for a period of rime and then to resume taking the whole tablet when instructed.

Figure 1.

. “A‐I‐B” combination tablet. Drug “A” (blue layer) may be separated from drug “B” (red layer) by breaking the tablet through the scored drug‐free middle layer (off‐white part).

Another use allows a patient who will likely need a combination product to achieve goal to start with only 1 of the 2 drugs as a test by beginning with 1 tablette created from the intact tablet. In addition, 1 of the 2 tablettes can itself have a score (not shown). This will allow a half dose of that drug to be created after the whole tablet is broken.

Successful titration can be achieved without writing a new prescription or writing multiple prescriptions. The tablets are color coded to allow for common colorblind patterns and marked so that instructions can be given by telephone just as one does with modifying the dose of other medications. Patients who self‐medicate despite having cognitive dysfunction or who cannot see clearly may not be suitable recipients for this novel tablet.

Configurations for Accurate Dose Division for Fixed Combination Products

Another manufacturing option that is particularly suitable to fixed‐dose combination drugs is one that places the combination of drugs at each end with the inactive zone in between as in the split‐drug example displayed in Figure 2. This “AB‐I‐AB” tablet permits giving the combination as a half dose, a whole dose, a whole plus a half dose, and then a double dose if needed. As described above, one of the active drug zones can be scored to be split in half after the whole tablet has been broken, thus allowing the combination dose first to be halved and then halved again to create a quarter dose. This gives additional flexibility.

Figure 2.

. “AB‐I‐AB” combination drug tablet. Drugs “A” and “B” are combined in equal proportions at both ends of the tablet (blue parts) and separated by a scored drug‐free break layer (off‐white part). An equal half‐dose of both drug “A” and drug “B” can be obtained if desired by breaking through the drug‐free layer. Breaking need not be accurate to ensure precise dosing.

In another manufacturing version, a bilayer tablet can be produced in which a layer containing the active drugs is divided into discrete, separate segments, all of which rest on a drug‐free layer. The scores extend up to or preferably into this drug‐free layer so that even if the tablet breaks unevenly, the dosing should remain precisely as desired. The tablet can be scored as desired, such as bisected, trisected, or quadrisected. As is the case with the other tablet configurations, the tablet is designed to be of a convenient size to be swallowed whole, and the tablet shape is elongated to allow easy grasping and breaking (Figure 3).

Figure 3.

. Bilayer combination drug tablets. Drugs “A” and “B” are combined uniformly in the blue layer, which is scored through to the drug‐free layer (peach). This design creates predivided quarter doses of the combination, allowing one to easily obtain a one‐quarter, one‐half, or one‐third dose by splitting the tablet at the score lines. The dose of subparts is not compromised as the breaking occurs in the drug‐free layer.

It will be apparent that the tablets depicted in Figure 2 and Figure 3 could also contain a single drug rather than a combination of 2 or more drugs in each active segment. This could provide benefits if applied to a variety of antihypertensive agents, both for initial dose titration and to allow dosage adjustments during ongoing medical treatment.

Ease of Use

Physicians and patients are expected to find that the tablets are easy for patients to grasp and break. A tablet cutter is not required. Appropriate labeling of these novel tablets will help to ensure that patients as well as their physicians realize the full benefits of these tablets.

Combinations of 3 or More Drugs

This new technology can be used for many combinations of drugs—even those that are chemically incompatible. For example, Mahmud and Feely took one‐quarter of a tablet each of amlodipine 5 mg, atenolol 50 mg, bendroflumethiazide 2.5 mg, and captopril 100 mg and combined them in an opaque capsule. The researchers demonstrated that the combination capsule was more efficacious for blood pressure reduction than the full dose of any of the monotherapies. ⁹ The tablet concepts described herein could in theory permit the manufacture of a single tablet that contains 3 or 4 low‐dose antihypertensive agents of different classes, yet allows easy and accurate splitting off of any one or more of the components by having each drug be in its own layer separated by a breakable drug‐free layer (Figure 4). The physician would have the flexibility of instructing the patient to break off and discard a component suspected of causing an adverse effect (eg, a cough from an angiotensin‐converting enzyme inhibitor) while retaining the benefit of the other 3 drugs.

Figure 4.

. “A‐I‐B‐I‐C” combination drug tablet. Drugs “A,”“B,” and “C” are separated by a drug‐free layer. All 3 drugs can be ingested by swallowing the intact tablet. If appropriate, any one of the drugs can be broken out cleanly and the other 2 drugs can be ingested.

The possibilities extend far beyond hypertension. Treatment of diabetes and dyslipidemias may someday be enhanced by the use of this type of tablet. Patient adherence to treatment may be improved, as might the ease of getting to goal. Proof of these concepts will require further study.

LIMITATIONS

While this concept is now far along in development, no product made with this tablet technology is currently marketed. Multiple patents are pending and the processes dictated by regulatory agencies have been initiated. Patient education brochures and package inserts must be created to maximize the potential benefits of these tablets and to minimize the risks of misunderstanding and miscommunication to as close to zero as possible. Cost should not be an issue in that the manufacturing costs are low and patients will save one or more copays on each prescription. Furthermore, the total number of prescriptions for care of the patient should be reduced. All of these concepts need to be tested and those trials are in planning stages or in progress.

CONCLUSIONS

The blood pressure control goal for Healthy People 2000 was not met and the 2010 goal (50% blood pressure control rate) may also not be met, at least in part because of therapeutic inertia. Despite the many advantages of fixed‐dose combinations, one disadvantage is difficulty in dose regulation and removal of one of the components either as a therapeutic measure or to cope with a potential adverse reaction. Another disadvantage is that very few combination products are scored. The new breakable combination tablet technology may, if successfully implemented, provide a simple method to improve dose flexibility and reduce therapeutic inertia.

Disclosures: These data were presented as posters at the American Society of Hypertension Scientific Meeting, Chicago, IL, May 21, 2007, Dr Materson is a member of the Scientific Advisory Board and holds stock options in ACCU‐BREAK Pharmaceuticals, Inc, Plantation, FL. Dr Marvin Moser, Editor in Chief of The Journal of Clinical Hypertension, is Chairman of the Scientific Advisory Board of ACCU‐BREAK Pharmaceuticals, Inc and has not reviewed, commented on, or otherwise been involved in the preparation of this article.