The compound 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one (“rucaparib”) is a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP).

Rucaparib, and methods of making it, are described, e.g., in U.S. Pat. Nos. 6,495,541 and 7,323,562. U.S. Pat. No. 6,495,541 describes salts of rucaparib in general, and solid dosage forms in general (col. 9, lines 7-61), with broad dose ranges expressed as mg/kg body weight (col. 26, lines 7-20). The issue of dose loading, i.e., percent drug content of the formulation, is not addressed. Certain salts and polymorphs of rucaparib are disclosed in U.S. Pat. Nos. 7,351,701, 7,351,530 and 7,268,126, and in U.S. Patent Application Publication No. 2004-0248879. U.S. Pat. Nos. 7,351,701 and 7,351,530 describe the use of the phosphate salt of rucaparib. They refer to all dosage forms generally, including tablets ('701 patent, col. 6, lines 48-57; '530 patent, col. 6, lines 30-38), though the only working example is of a liquid formulation of unspecified content. Again, the issue of dose loading is not addressed, and in fact it is stated that “only very low doses . . . are needed” ('701 patent, col. 6, lines 21-24; lines '530 patent, col. 6, lines 3-6). Published Application 2004-0248879 describes the phosphate and glucuronate salts of rucaparib, and solid dosage forms thereof generally (Paragraphs 0035-0036), with doses described in terms of mg/kg body weight (Paragraph 0036). No specific formulations are exemplified or described, and the issue of dose loading is not addressed.
U.S. Pat. No. 8,754,072 (“the '072 patent”) discloses solid dosage forms of rucaparib maleate and rucaparib camsylate. The '072 patent states that of the pharmaceutically acceptable counter ions suitable for use with active ingredients, the maleate and camsylate salts of rucaparib were found to be less hygroscopic as compared to other salt forms (col. 11, lines 45-49), “making them particularly suitable in the preparation of solid dosage forms” (col. 11, lines 49-50). In addition, the maleate and camsylate salts of rucaparib were found to be more easily prepared and isolated than other salt forms (col. 11, lines 51-53). The '072 patent states very broadly that the compositions “will generally contain anywhere from about 0.001% by weight to about 99% by weight active ingredient,” with preferred ranges of from about 0.01% to about 5% and about 0.01% to 2% (col. 36, lines 41-47). Embodiments containing 10%-25% active ingredient are also disclosed (col. 3, line 65-col. 4, line 9; col. 5, line 60-col. 6, line 4). The only working example of a formulation (Example 13) relates to a formulation comprising 17.18% of the camsylate salt. Thus, the '072 patent does not specifically address the issue of a high dose rucaparib formulation, and indeed, like the prior art discussed above, teaches that a lower dose loading (i.e., under 25%) is preferable.
Clinical development of oral rucaparib camsylate was initiated with tablets of lower strength (40 mg and 60 mg). As individual dose requirements increased a higher dosage strength of 120 mg was developed employing 32% drug loading and a dry granulation manufacturing process. Formulation modification relative to lower strengths was required to prepare 120 mg tablets, suggesting that drug loading significantly higher than 32% would be difficult to achieve with a dry granulation process.
Clinical studies of rucaparib indicated the need for a high unit dose (200 mg-800 mg) of active ingredient. For convenient oral administration, generally the tablet weight should not exceed 800 mg. As the number of tablets required per dose can lead to compliance issues, it would be desirable to find a formulation that could be commercially made that resulted in fewer tablets required per dose with the resultant expectation that there would be improved patient compliance.
Thus, there is a need for developing tablet dosage forms containing a rucaparib salt that 1) has suitable size in order to allow the patient to easily swallow the tablet, 2) has a high load of rucaparib in order to minimize the number of tablets required per dose, 3) has suitable properties with respect to the release of the rucaparib from the tablet, and 4) has the pharmaceutical behavior that leads to the desired effect. In some embodiments, the dosage form can be a capsule.
The overall physical properties and manufacturability of low drug loading formulations is determined predominantly by the inactive ingredients or excipients in the formulation. However, at high drug loading, the contribution of the physical properties of the active pharmaceutical ingredient (“API”) to the manufacturability of a formulation becomes predominant. Not all APIs possess the necessary properties with respect to compressibility that are required in order to obtain a high load tablet using a dry granulation process.
Most small molecule API's, can be formulated in low dose forms because the physical properties of the excipients utilized in the formulations dominate the properties of the solid composition, rather than the physical properties of the API itself. As drug loading increases the physicochemical characteristics of the drug substance become increasing dominant in the tablet manufacturing process. It is common to include filler excipients in a single formulation that possess brittle characteristics and others that possess ductile/plastic characteristics. The combination of the brittle and plastic type materials in a given formulation are important to the “manufacturability” of that formulation. However, because API's can have a full spectrum of physical properties and are not selected based on these physical properties, it is not to be expected that a particular API would have the physical properties to favorably contribute to an overall formulation in terms of manufacturability and stability. In fact, it is not infrequent that it is the physical properties of the API that actually present the largest obstacle to creating a workable formulation. It is therefore surprising and unanticipated where it is found that an API can be formulated in a dry granulating manufacturing process with drug loads in excess of 45%. In fact, prior experience taught that it was likely not possible to create a formulation of rucaparib at a dose loading significantly exceeding 32%.
The ability to prepare rucaparib camsylate tablets at a drug loading in excess of 45% using a dry granulation process as described below is a surprising observation that is attributable to the unique physicochemical characteristics of the camsylate salt of rucaparib. In the current invention, no brittle filler excipients are necessary due to the unique and unexpected physicochemical characteristics of rucaparib camsylate.
As with hygroscopicity, and ease of manufacturing, the ability to form high dosage forms of an active ingredient may also be dependent on the specific salt form of the drug. However, hygroscopicity and ease of manufacturing at low dose loadings is not predictive of suitability for high dose formulations. This is demonstrated below, by the data presented herein showing that the maleate salt of rucaparib (showing favorable hygroscopicity and manufacturing properties in low dose formulations) cannot be formulated as a high dose form in a dry granulation manufacturing process.
In the present case, the inventors have surprisingly found that only one of the salt forms suitable for dry granulation manufacturing based on a constellation of physicochemical properties, such as hygroscopicity, brittle behavior and crystalline properties, would also have the appropriate physical properties for high dose formulations—i.e., the camsylate salt.
USPTO Backgrounds
USPTO Backgrounds