Scoring of pharmaceutical tablets is well known. Scoring of pharmaceutical tablets produced in a layered fashion is also known, but has been employed less extensively. Scores into a tablet have not exceeded 1 mm in depth. Even though inaccurate breaking of scored tablets is a well-known problem, attention has not been paid to solving this problem by creating segmented (e.g., layered) tablets in a tablet press with a segment that provides some or most of said breaking region when the tablet is broken, and pari passu provides physical support for the part of the tablet with the deep score. The scope of the problem with tablet breaking may be summarized, in part, as follows: Many drugs require dosage adjustments, such as warfarin, the scored tablets of which are frequently broken. These dosage adjustments through tablet breaking by patients have been determined to be imprecise. As the following discussion demonstrates, for many years experts have called upon the pharmaceutical industry to improve the quality of tablet breaking, yet such has not been optimized until the current invention.
In 1984, Stimpel et al. (“Stimpel”), described the relative accuracy of breaking of various tablets for treatment of cardiovascular Problems. M. Stimpel et al., “Breaking Tablets in Half.” The Lancet (1984):1299. Even though breaking was performed by a sophisticated, dexterous person, Stimpel found that breaking was not accurate, and opined that real world use by patients would provide yet more unsatisfactory results. Stimpel called upon the pharmaceutical industry to improve the accuracy of splitting tablets: “Clearly any assumption that halving a tablet will not lead to inaccurate doses is invalid. This potential source of inaccuracy could be even more significant in clinical situations (our study was done under ideal conditions) and the pharmaceutical industry should tackle it, either by improving divisibility (as already has been done for lopressor and logroton) or, even better, by marketing a wider range of unscored tablets to provide all the doses that might be indicated clinically.”
Despite that finding and statement, and despite the issuance of various patents relating to optimizing a scoring pattern and/or tablet shape, Rodenhuis et al., (2004) noted that: “Improving the functioning of score lines may be a more practical approach than banning this dosage form.” N. Rodenhuis et al. (emphasis added), “The rationale of scored tablets as dosage form.” European J. of Pharmaceutical Sciences 21 (2004):305-308 (hereafter “Rodenhuis”) Rodenhuis observed that European regulatory authorities started a policy to discourage scoring of tablets in 1998, This policy change, according to Rodenhuis, likely related to “many recent reports of bad functioning score lines,” that “many scored tablets are difficult to break,” and that “many scored tablets show unsatisfactory mass uniformity of the subdivided halves.” The authors then go on to describe useful aspects of scoring tablets. For a comprehensive review article on this topic, see van Santen, E., Barends, D. M. and Frijlink, H. W. “Breaking of scored tablets: a review.” European J. of Pharmaceutics and Biopharmaceutics 53 (2002):139-145.
Some current studies that demonstrate the severity of the problem are described below.
Peek et al., (2002), studied tablet splitting by “elderly patients” aged 50-79. Peek, B. T., Al-Achi, A., Coombs, S. J. “Accuracy of Tablet Splitting by Elderly Patients.” The Journal of the American Medical Association 288 No. 4 (2002):139-145. Breaking scored tablets with mechanical tablet splitters without specific instruction led to highly unsatisfactory separating of the tablets. For example, warfarin 5 mg was on average split into 1.9 and 3.1 mg tablets. This potent anticoagulant has such a narrow therapeutic range that 2, 2.5, and 3 mg tablet doses are manufactured. Biron et al., (1999), demonstrated that warfarin 10 mg also often split to less than 4.25 or greater than 5.75 mg. Biron, C., Liczner, P., Hansel, S., Schved, J. F., “Oral Anticoagulant Drugs: Do Not Cut Tablets in Quarters.” Thromb Haemost 1201 (1999). In addition, they demonstrated that loss of mass due to crumbling or chipping or the breaking of the warfarin tablets was statistically significant. They also demonstrated that quartering of the tablets was grossly inaccurate.
McDevitt et al., (1998), found that 25 mg unscored hydrochlorothiazide (HCTZ) tablets were manually split badly enough that 12.4% deviated by more than 20% from ideal weight. McDevitt, J. T., Gurst, A. H., Chen, Y. “Accuracy of Tablet Splitting.” Pharmacotherapy 18 No. 1 (1998):193-197.77% of the test subjects stated that they would be willing to pay a premium for individually produced 12.5 mg HCTZ tablets rather than split unscored 25 mg tablets.
Rosenberg et al., (2002), studied pharmacist-dispensed split tablets. Rosenberg, J. M., Nathan, J. P., Plakogiannis, F. “Weight Variability of Pharmacist-Dispensed Split Tablets.” Journal of American Pharmaceutical Association 42 No. 2 (2002):200-205. They found that “tablet splitting resulted in an unacceptably high incidence of weight variation.” They recommended that “standards should be developed to ensure uniformity of split tablets.”
Teng et al., (2002), using a trained individual in a laboratory setting to split tablets, concluded that “the majority of the 11 drug products we tested, when assessed for their ability to be split into half-tablets of equal dose, failed a liberally interpreted USP (United States Pharmacopeia) uniformity test . . . . The practice of dividing tablets to save costs or to improve a dosage regimen . . . is not recommended for patients using drugs with more substantial toxicity and steep dose-response efficacy curves.” Teng, J., Song, C. K., Williams, R. L., Polli, J. E. “Lack of Medication Dose Uniformity in Commonly Split Tablets.” Journal of American Pharmaceutical Association 42 No. 2 (2002):195-199.
Rodenhuis reported that 31% of all tablets in one Netherlands study were subdivided before being swallowed. In the U.S., many “managed care” insurance organizations encourage tablet splitting by patients of tablets that are often unscored and that may be irregularly shaped.
Many drug products in the US are either unscored or are provided as capsules despite being able to be produced as tablets. The invention herein provides a solution for both scored and unscored tablets that provides an improved solution to the problems described above.
The current invention aims to ameliorate the above problem by providing, inter alia novel, deep scores into a segment of a tablet that contains an active ingredient for which enhanced precision of dosing with a dose less than that present in the whole tablet is desired, as well as providing novel use of pharmacologically inactive segments as part of a bilayer immediate release compressed tablet.
Embodiments of the invention describe an immediate release compressed pharmaceutical tablet with an outer segment (e.g., a layer) that is not provided with a pharmacologically effective amount of any active pharmaceutical ingredient, said tablet containing a segment having a pharmacologically effective quantity of an active pharmaceutical ingredient and a score to locate and aid tablet division. The prior art discloses outer layers of layered pharmaceutical tablets under only two circumstances: as part of a controlled-release product, as with Uroxatral®, or for specialized purposes in which a molded part of a tablet may be inactive, but said tablet is not provided with a score as it is not disclosed to be adapted to be split into a plurality of smaller dosage forms.
Published U.S. Application 2005/0019407A1 describes a composite dosage form which has first and second portions joined at an interface. These dosage forms have a first molded material and a second compressed material. There is no disclosure of any modification of the disclosed dosage forms that would facilitate the breaking of the dosage forms into any subdivided form.
The present invention is concerned with segmented pharmaceutical dosage forms that are adapted for breaking through more than one segment. Until now, a score in tablets has had practical limitations, because a deep score, such as one that extends through 85% of the height of a tablet, would tend to lead to structural instability of the tablets, so that they would tend not to survive intact the production and transport processes The invention has as a primary object utilizing a layered segment of a tablet that provides structural support for a segment of the tablet derived from a granulation provided with an active pharmaceutical agent.
USPTO Backgrounds
USPTO Backgrounds