Patent Application
20170202825
This invention relates to apixaban pharmaceutical formulations comprising crystalline apixaban particles having a maximum size cutoff, and methods of using them, for example, for the treatment and/or prophylaxis of thromboembolic disorders.
Apixaban is a known compound having the structure:
The chemical name for apixaban is 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (CAS name) or 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (IUPAC name).
Apixaban is disclosed in U.S. Pat. No. 6,967,208 (based on U.S. application Ser. No. 10/245,122, filed Sep. 17, 2002), which is herein incorporated by reference in its entirety, has utility as a Factor Xa inhibitor, and is being developed for oral administration in a variety of indications that require the use of an antithrombotic agent.
The aqueous solubility (40 μg/mL at all physiological pH) of apixaban suggests that the tablets with less than 10 mg apixaban (dose/solubility ratio=250 mL) should not demonstrate dissolution rate limited absorption since dissolution rate limitations are only expected when the dose/solubility ratio is greater than 250 mL. Based on this dose and solubility consideration, the particle size of the compound should not be critical for achieving consistent plasma profiles, according to the prediction based on the Biopharmaceutics Classification System (BCS; Amidon, G. L. et al., Pharmaceutical Research, 12: 413-420 (1995)). However, it was determined that formulations that were made using a wet granulation process as well as those using large particles of apixaban drug substance resulted in less than optimal exposures, which can present quality control challenges.
Surprisingly and unexpectedly, it has been found that compositions for tablets comprising up to 5 mg, apixaban particles having a D90 (90% of the volume) less than 89 microns (μm) lead to consistent in vivo dissolution in humans (at physiologic pH), hence, consistent exposure and consistent Factor Xa inhibition that will lead to consistency in therapeutic effect. Consistent exposure is defined as that where in vivo exposure from tablets is similar to that from a solution and not affected by the differences in dissolution rates. The compositions were prepared using a dry granulation process. Accordingly, the invention provides a pharmaceutical composition comprising crystalline apixaban particles having a D90 equal to or less than about 89 μm, as measured by laser light scattering method, and a pharmaceutically acceptable diluent or carrier. It is preferred that the apixaban particles in the composition have a D90 not exceeding 89 μm. It is noted the notation Dx means that X % of the volume of particles have a diameter less than a specified diameter D. Thus, a D90 of 89 μm means that 90% of the volume of particles in an apixaban composition have a diameter less than 89 μm.
The range of particle sizes preferred for use in the invention is D90 less than 89 μm, more preferably D90 less than 50 μm, even more preferably D90 less than 30 μm, and most preferably D90 less than 25 μm. The particle sizes stipulated herein and in the claims refer to particle sizes determined using a laser light scattering technique.
The invention further provides the pharmaceutical composition further comprising a surfactant from 0.25% to 2% by weight, preferably from 1% to 2% by weight. As regards the surfactant, it is generally used to aid in wetting of a hydrophobic drug in a tablet formulation to ensure efficient dissolution of the drug, for example, sodium lauryl sulfate, sodium stearate, polysorbate 80 and poloxamers, preferably sodium lauryl sulfate.
The invention further provides a method for the treatment or prophylaxis of thromboembolic disorders, comprising administering to a patient in need of such treatment or prophylaxis a therapeutically effective amount of a composition comprising crystalline apixaban particles having a D90 equal to or less than about 89 μm as measured by laser light scattering, and a pharmaceutically acceptable carrier.
The present invention also provides a dry granulation process for preparing a composition comprising crystalline apixaban particles having a D90 equal to or less than about 89 μm as measured by laser light scattering, and a pharmaceutically acceptable carrier.
The formulations of this invention are advantageous because, inter alia, as noted above, they lead to consistent human in-vivo dissolution. The invention is surprising in this respect, however, in that exposures are variable even though apixaban has adequate aqueous solubility that would allow the drug to dissolve rapidly. That is, one would expect dissolution rate for a drug that has high solubility (as defined by the Biopharmaceutical Classification System) would not be limited by the particle size. It has surprisingly been found, however, that the particle size that impacts apixaban absorption rate is about a D90 of 89 μm. Thus, apixaban can be formulated in a composition having a reasonable particle size using dry granulation process, to achieve and maintain relatively fine particles to facilitate consistent in vivo dissolution.
In a relative bioavailability study where various apixaban formulations were evaluated, it was determined that formulations made using a wet granulation process resulted in lower exposures compared to the exposures obtained from a dry granulation process. Additionally, tablets made using larger particles (D90 of 89 μm) had lower exposures compared to tablets made using the same process but with particle size of D90 of 50 μm. In a dry granulation process, water is not used during manufacturing to develop granules containing apixaban and the excipients.
Formulations according to this invention, when dissolution tested in vitro preferably exhibit the following dissolution criteria. That is, the formulation exhibits dissolution properties such that, when an amount of the drug equivalent to 77% therein dissolves within 30 minutes. Usually the test result is established as an average for a pre-determined number of dosages (e.g., tablets, capsules, suspensions, or other dosage form), usually 6. The dissolution test is typically performed in an aqueous media buffered to a pH range (1 to 7.4) observed in the gastrointestinal tract and controlled at 37° C. (±1° C.), together maintaining a physiological relevance. It is noted that if the dosage form being tested is a tablet, typically paddles rotating at 50-75 rpm are used to test the dissolution rate of the tablets. The amount of dissolved apixaban can be determined conventionally by HPLC, as hereinafter described. The dissolution (in vitro) test is developed to serve as a quality control tool, and more preferably to predict the biological (in vivo) performance of the tablet, where in vivo-in vitro relationships (IVIVR) are established.
The term “particles” refers to individual drug substance particles whether the particles exist singly or are agglomerated. Thus, a composition comprising particulate apixaban may contain agglomerates that are well beyond the size limit of about 89 μm specified herein. However, if the mean size of the primary drug substance particles (i.e., apixaban) comprising the agglomerate are less than about 89 μm individually, then the agglomerate itself is considered to satisfy the particle size constraints defined herein and the composition is within the scope of the invention.
Reference to apixaban particles having “a mean particle size” (herein also used interchangeably with “VIVID” for “volume mean diameter”) equal to or less than a given diameter or being within a given particle size range means that the average of all apixaban particles in the sample have an estimated volume, based on an assumption of spherical shape, less than or equal to the volume calculated for a spherical particle with a diameter equal to the given diameter. Particle size distribution can be measured by laser light scattering technique as known to those skilled in the art and as further disclosed and discussed below.
“Bioequivalent” as employed herein means that if a dosage form is tested in a crossover study (usually comprising a cohort of at least 10 or more human subjects), the average Area under the Curve (AUC) and/or the Cmax for each crossover group is at least 80% of the (corresponding) mean AUC and/or Cmax observed when the same cohort of subjects is dosed with an equivalent formulation and that formulation differs only in that the apixaban has a preferred particle size with a D90 in the range from 30 to 89 μm. The 30 μm particle size is, in effect, a standard against which other different formulations can be compared. AUCs are plots of serum concentration of apixaban along the ordinate (Y-axis) against time for the abscissa (X-axis). Generally, the values for AUC represent a number of values taken from all the subjects in a patient population and are, therefore, mean values averaged over the entire test population. Cmax, the observed maximum in a plot of serum level concentration of apixaban (Y-axis) versus time (X-axis) is likewise an average value.
Use of AUCs, Cmax, and crossover studies is, of course, otherwise well understood in the art. The invention can indeed be viewed in alternative terms as a composition comprising crystalline apixaban particles having a mean particle size equal to or less than about 89 μm, as measured by Malvern light scattering, and a pharmaceutically acceptable carrier, said composition exhibiting a mean AUC and/or mean Cmax which are at least 80% of the corresponding mean AUC and/or Cmax values exhibited by a composition equivalent thereto (i.e., in terms of excipients employed and the amount of apixaban) but having an apixaban mean particle size of 30 μm. Use of the term “AUC” for purposes of this invention implies crossover testing within a cohort of at least 10 healthy subjects for all compositions tested, including the “standard” 30 μm particle size composition.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. Thus, the above embodiments should not be considered limiting. Any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. Each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment. In addition, the present invention encompasses combinations of different embodiment, parts of embodiments, definitions, descriptions, and examples of the invention noted herein.
As previously stated, apixaban in any form which will crystallize can be used in this invention. Apixaban may be obtained directly via the synthesis described in U.S. Pat. No. 6,967,208 and/or U.S. 2006/0069258 A1 (based on U.S. application Ser. No. 11/235,510, filed Sep. 26, 2005), herein incorporated by reference.
Form N-1 (neat) and Form H2-2 (hydrate) of apixaban may be characterized by unit cell parameters substantially equal to the following shown in Table 1.
Characteristic X-ray diffraction peak positions (degrees 2θ±0.1) at room temperature, based on a high quality pattern collected with a diffractometer (CuKα) with a spinning capillary with 2θ calibrated with a NIST suitable standard are shown in Table 2 below.
It will be appreciated by those skilled in the art of manufacturing and granulation processes that there are numerous known methods which can be applied to producing apixaban solid dosage forms. The feature of this invention, however, involves processes that produce apixaban dosage forms with an ability to produce primary particles at the site of dissolution with a D90<89 μm. Examples of such methods include dry granulation or wet granulation by low or high-shear techniques.
The dry granulation process that produces crystalline apixaban particles having a mean particle size equal to or less than about 89 μm is believed to be novel, and is accordingly provided as a further feature of the invention. Thus, the invention provides a drug product manufacturing process, comprising the following steps:
In another embodiment, the invention provides a drug product manufacturing process, comprising the following steps:
In a preferred embodiment, a dry granulation process is employed.
In a preferred embodiment, the surfactant (SLS) in the composition serves as a wetting aid for inherently hydrophobic apixaban drug substance (contact angle=54° with water), further exacerbated as part of air-jet milling process that is used to reduce apixaban particle size to the desired size.
The amount of apixaban contained in a tablet, capsule, or other dosage form containing a composition of this invention will usually be between 2.5 and 5 mg, usually administered orally twice a day, although amounts outside this range and different frequencies of administration are feasible for use in therapy as well. As previously mentioned, such dosage forms are useful, inter alia, in the prevention and/or treatment of thromboembolic disorders, for example, deep vein thrombosis, acute coronary syndrome, stroke, and pulmonary embolism, as disclosed in U.S. Pat. No. 6,967,208.
As noted, average particle size can be determined by Malvern light scattering, a laser light scattering technique. In the examples below, the particle size for apixaban drug substance was measured using a Malvern particle size analyzer.
Upon measurement completion, the sample cell was emptied and cleaned, refilled with suspending medium, and the sampling procedure repeated for a total of three measurements.
The dissolution test is performed in 900 mL of dissolution medium at 37° C., using USP Apparatus 2 (paddles) method at a rotation speed of 75 rpm. Samples are removed after 10, 20, 30, 45, and 60 minutes from test initiation and analyzed for apixaban by HPLC at 280 nm. 0.1 N HCl or 0.05 M sodium phosphate pH 6.8 with 0.05% SDS solution has been used as dissolution medium during formulation development. While both methods serve the purposes as quality control tests (with adequate discrimination ability), and in establishing IVIVR, the latter was preferred from the standpoint of method robustness. A role of SDS (surfactant) in the latter dissolution medium is as a wetting aid to facilitate complete dissolution of hydrophobic apixaban from tablets, rather than to increase the solubility of apixaban. Dissolution data from both the tests are included in this invention record and unless otherwise specified, the results reported were averages of values from six tablets.
Blood samples are drawn at predetermined time points following drug administration as specified in the clinical study protocol. Concentrations of the samples are measured using a validated analytical method (Liquid Chromatography with Tandem Mass Spectrometry). Individual subject pharmacokinetic parameters (e.g., Cmax, AUC, T-HALF) are derived by non-compartmental methods using Kinetica® software from the time-concentration profiles.
The invention is further exemplified and disclosed by the following non-limiting examples:
Table 3 shows apixaban tablet compositions prepared using the dry granulation process that were evaluated in the bioequivalence (BE) study.
Table 4 shows apixaban tablet compositions prepared using the wet granulation process that were evaluated in the BE study.
Table 5 and Table 5a show the dissolution data that indicates that using a dry granulation process will result in faster dissolution compared to that using a wet granulation process. As shown in Table 5, the 20 mg tablets made using a dry granulation process had 79% apixaban dissolved in 30 minutes versus 62% apixaban dissolved at 30 minutes for the 20 mg tablets made using a wet granulation process. Dissolution test in 0.1 N HCl also indicated a similar behavior of faster dissolution from tablets made using dry granulation process (58% in 30 min), compared to wet granulation process (45% in 30 min).
Table 6 and Table 6a provide the dissolution data from tablets made with different manufacturing processes (wet and dry granulation) and drug substance different particle sizes. As shown Table 6, apixaban tablets that had 77% dissolved in 30 minutes or 86% dissolved in 30 minutes both had AUC values that met bioequivalence criteria (Confidence Interval between 80% to 125%) when compared to the tablets that had 89% dissolved at 30 minutes. Similar rank order of the dissolution rates were observed for these tablets (A, B & C) when tested in 0.1 N HCl.
The results of clinical studies demonstrated that, for tablets with similar dissolution rates (89% and 86% at 30 min in pH 6.8 phosphate buffer containing 0.05% SLS), Cmax and AUC of the coated Phase 3 tablet (C) relative to the uncoated Phase 2 tablet (A) met bioequivalence criteria. Tablets with different dissolution rates (77% and 86% at 30 min) had similar AUCs, but did not meet equivalence criteria for Cmax. The lower boundary of the 90% confidence interval of the ratio of geometric mean Cmax was 0.788, indicating the rate of absorption, as defined by Cmax, was lower for the slower dissolving tablet (77% at 30 min). Since the oral bioavailability from these tablets is shown to be comparable to that from solution (see
This application is a continuation of U.S. Patent Application No. 15/086,447, filed Mar. 31, 2016, which is a continuation of U.S. patent application Ser. No. 13/579,796, now U.S. Pat. No. 9,326,945, which was the National Stage of International Application No. PCT/US2011/025994, filed Feb. 24, 2011, which claims the benefit of U.S. Provisional Application No. 61/308,056, filed Feb. 25, 2010. U.S. patent application Ser. Nos. 13/579,796 and 15/086,447 are incorporated herein by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61308056 | Feb 2010 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15086447 | Mar 2016 | US |
| Child | 15474264 | US | |
| Parent | 13579796 | Oct 2012 | US |
| Child | 15086447 | US |
