DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

“PHARMACEUTICAL COMPOSITION OF APIXABAN”

ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company
Alembic Campus, Alembic Road, Gorwa, Vadodara-390 003, Gujarat, India

The following specification describes the invention:
TECHNICAL FIELD:

The present invention relates to a pharmaceutical composition comprising Apixaban having particle size more than 89 µm and process for preparation for the same. More particularly, it relates to a solid oral preparation of Apixaban which is easy to manufacture, stable and bioequivalent.

BACK GROUND:

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 filled Sep 17, 2002, has utility as a Factor Xa inhibitor, and is being developed for oral administration in a variety of indications like antithrombotic agent.

US9326945 (US’945) discloses, pharmaceutical composition of Apixaban having a D90 (90% of the volume) equal to or less than 89 microns (µm) which leads to optimum/desired dissolution (at physiologic pH), hence result in desired/optimum bioequivalence parameters like AUC and Cmax which lead to Factor Xa inhibition and consistency in therapeutic effect.

Further, US’945 discloses, tablets formulated by using a wet granulation process and having large particles of Apixaban drug substance resulted in less than the desired/optimum bioequivalence parameters like AUC, Cmax and dissolution, which can present quality control challenges.

Additionally US’945 discloses, tablets formulated using larger particles (D90 of 89 µm) had less than the desired/optimum bioequivalence parameters like AUC, Cmax and dissolution compared to tablets made using the same process (i.e. Dry/Wet granulation) but with particle size of D90 of 50 µm.

Hence as per US’945, in order to achieve bioequivalence, specific D90 particle size (i.e. D90 of less than 89 µm) is essential.

Inventors of the present invention have found that Apixaban particles having a D90 (90% of the volume) more than 89 microns (µm) lead to desired dissolution, hence desired/optimum bioequivalence parameters like AUC, Cmax and consistent Factor Xa inhibition.

Other aims of the present invention will become apparent to the skilled person from the foregoing and following remarks.
It has now been found that the pharmaceutical compositions, which are described in greater details herein, have particularly advantageous properties with Apixaban particles having a D90 (90% of the volume) more than 89 microns (µm).

SUMMARY OF THE INVENTION:

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) more 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 wet granulation process. Accordingly, the invention provides a pharmaceutical composition comprising crystalline apixaban particles having a D90 more than about 89 µm as measured by laser light scattering method, and a pharmaceutically acceptable diluent or carrier.

The present invention is directed to a pharmaceutical composition comprising Apixaban particles having a D90 (90% of the volume) more than 89 microns (µm) and one or more pharmaceutical excipients and process for preparation for the same.

In one embodiment, Apixaban is in the form of a crystalline anhydrate or hydrate or in the amorphous form.

Unless specifically noted, in the present context the term "Apixaban" is also intended to comprise any pharmaceutically acceptable salt thereof, crystal form, hydrate, solvate, diastereomer or enantiomer thereof.

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 size limit of more than 89 µm specified herein.

Reference to Apixaban particles having “a mean particle size” (herein also used interchangeably with “VMD” for “volume mean diameter”) more 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.

The term “Desired/Optimum dissolution” refers to Apixaban tablets had more than about 80% dissolved drug in 30 minutes and had AUC as well as Cmax values that met bioequivalence criteria.

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 about 80% 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 bufferred 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 (invivo) performance of the tablet, where invivo-invitro relationships (IVIVR) are established.

“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 in a range of 80-125% of the (corresponding) mean AUC and/or Cmax observed when the same cohort of subjects is dosed with reference product i.e. Eliquis® (Marketed by Bayer).

Use of AUCs, Cmax, and crossover studies is, of course otherwise well understood in the art.

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.

DETAILED DESCRIPTION OF THE INVENTION:

In an embodiment, the present invention is directed to a pharmaceutical composition (e.g. an oral solid dosage form, particularly a tablet) comprising Apixaban particles having a D90 (90% of the volume) more than 89 microns (µm) and one or more pharmaceutical excipients. It is noted the notation DX means that X % of the volume of particles have a diameter less than a specified diameter. Thus a D90 of more than 89 µm means that 90% of the volume of particles in an apixaban composition have a diameter more than 89 µm.

In an embodiment, The range of particle sizes preferred for use in the invention is D90 more than 89 µm, more preferably D90 more than 89 µm, and less than 500 µm, even more preferably D90 more than 89 µm, and less than 200 µm, most preferably D90 more than 89 µm and less than 150 µm. The particle sizes stipulated herein refer to particle sizes were determined using a laser light scattering technique.

In preferred embodiment particle size of Apixaban use in the invention is D90 90 µm, 95 µm, 100 µm, 105 µm, 110 µm, 120 µm, 130 µm, 140 µm.

In an embodiment, 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.

A pharmaceutical composition according to an embodiment of the present invention is intended for the treatment and/or prophylaxis of thromboembolic disorders.

In an embodiment, 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 composition comprising Apixaban particles having a D90 more than 89 µm as measured by laser light scattering, and a pharmaceutically acceptable carrier.

In one more embodiment, the present invention also provides a process for preparing a composition comprising Apixaban particles having a D90 more than 89 µm as measured by laser light scattering, and one or more pharmaceutically acceptable carrier.

As noted, average particle size can be determined by Malvern light scattering, a laser light scattering technique. The particle size for Apixaban drug substance was measured using a Malvern particle size analyzer.

The solid oral dosage forms of the present invention include but are not limited to tablets, capsules, granules, pellets and the like.

The pharmaceutical compositions like tablets, capsules and granules of this invention further comprise one or more diluents/Fillers, solubility enhancer and/or complexing agent Binder, disintegrants, lubricants and glidants.

In a more preferred embodiment, present invention provides the pharmaceutical composition comprising a solubility enhancer and/or complexing agent in the range selected from 0.1% to 20% by weight, preferably from 1% to 10% by weight, more preferably from 1 % to 5% by weight.

In a preferred embodiment solubility enhancer and/or complexing agent are selected from but not limited to sodium lauryl sulphate (SLS), soluplus, polyethylene Glycol (PEG), poloxamers, polysorbate 80, Cyclodextrin.

In a preferred embodiment, the pharmaceutical compositions of this invention comprise usually one or more diluents/fillers selected from but not limited to microcrystalline cellulose (MCC), lactose, D-mannitol, corn starch and/or pregelatinized starch.

In a preferred embodiment, the pharmaceutical compositions of this invention comprise usually one or more disintegrants selected from but not limited to croscarmellose sodium (CCS), sodium starch glycolate (SSG), crospovidone.

In a preferred embodiment, the pharmaceutical compositions of this invention comprise usually one or more binders selected from but not limited to Povidone, copovidone, Hypromellose (HPMC), hydroxypropyl cellulose (HPC).

In a preferred embodiment, the pharmaceutical compositions of this invention comprise usually one or more lubricants selected from but not limited to magnesium stearate, glyceryl benehate, calcium stearate.

In a preferred embodiment, the pharmaceutical compositions of this invention comprise usually a glident i.e colloidal anhydrous silica.

Suitably the pharmaceutical excipients used within this invention are conventional materials such as Lactose, microcrystalline cellulose as a filler/diluent, Hypromellose as a binder, croscarmellose sodium as a disintegrant, magnesium stearate as a lubricant and further said dosage form is optionally film-coated, preferred range of excipients shown in Table no. 1.

Table 1
Sr. No. Ingredients % of ingredient by weight of core tablet

1 Apixaban 0.1-10%
2 Filler/ Diluents (e.g. MCC, mannitol, Lactose) 55-90%
3 Solubility enhancer/ Complexing agents (e.g. SLS, soluplus, PEG, poloxamers, polysorbate 80, Cyclodextrin) 0.1-20%
4 Disintegrant (e.g. CCS, SSG, Crospovidone) 0-10%
5 Binder (e.g. HPMC, Povidone, Copovidone, HPC) 0.1-10%
6 Lubricant (e.g. Magnesium stearate) 0.1-10%
7 Optionally Film Coating Q.S

In a preferred embodiment the process for preparing a pharmaceutical composition comprising Apixaban particles having a D90 more than 89 µm and a pharmaceutically acceptable carrier according to this invention may be prepared by methods well-known to one skilled in the art includes but not limited to roller compaction, wet granulation and direct compression.

In a more preferred embodiment the process for preparing a composition comprising Apixaban particles having a D90 more than 89 µm and a pharmaceutically acceptable carrier by wet granulation method.

In another embodiment, the invention provides a drug product manufacturing process, comprising the steps:
1. Sift Intra granular materials and dry mix in suitable blender.
2. Add Apixaban & polymer in solvent system under stirring condition and stirring was continued to get clear solution/ homogeneous dispersion.
3. Load the material of Step no 1 in Fluid Bed Equipment.
4. Granulate the premix of step no.3 by top spray granulation process using the Drug-Binder solution of step no. 3.
5. Sift the dried granules of step no. 4 and mix with extra granular material.
6. Lubricate granules of step no.5 with magnesium stearate
7. Compress the tablets with approve tooling
8. Prepare the aqueous dispersion of coating material and film coat the tablets till desired weight gain.

Further details about the pharmaceutical composition of this invention, e.g. the ingredients, ratio of ingredients (such as e.g. ratio of apixaban and/or excipients), particularly with respect to special dosage forms (tablets) used within this invention as well as their preparation, become apparent to the skilled person from the disclosure hereinbefore and hereinafter (including by way of examples).

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, 15, 20, 30, and 45 from test initiation and analyzed for apixaban by HPLC at 280 nm. 0.05 M sodium phosphate pH 6.8 with 0.05% SLS solution has been used as dissolution medium during formulation development.

The selected dissolution method serve the purposes as quality control tests (with adequate discrimination ability), and in establishing IVIVR. A role of SLS (surfactant) in the 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 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 (eg, Cmax, AUC) are derived and compared with Eliquis® tablets (Marketed by Bayer)

The invention is further exemplified and disclosed by the following non-limiting examples:

Table 2 shows apixaban tablet compositions prepared using wet granulation process by different two strategies (i.e. FSI and FSII) that were evaluated in dissolution as well as bioequivalence study against Eliquis® tablets.

Table 2:
Name of the Ingredient % w/w % w/w
FS1 FSII
Intra granular Materials
Lactose Monohydrate 44.71 44.71
Microcrystalline Cellulose 39.42 39.42
Croscarmellose Sodium 1.92 1.92
Hypromellose 2.31 -
Sodium Lauryl Sulphate 0.96 0.96
Drug-Binder Solution
Apixaban 0.96 2.40
Hypromellose 1.54 3.85
Methylene Chloride qs -
Ethyl Alcohol Anhydrous qs -
Isopropyl alcohol - qs
Purified water - qs
Extra granular Materials
Apixaban 1.44 -
Croscarmellose Sodium 1.92 1.92
Magnesium Stearate 0.96 0.96
Film Coating
Opadry 3.85 3.85
Purified Water qs qs

Table 3 shows the dissolution data of FSI and FSII respectively that indicates that tablets made using Apixaban particles having a D90 more than 89 µm gives desired dissolution profile i.e. more than about 80% dissolved drug in 30 minutes.

Table 3 Dissolution data for the present invention
Media: pH 6.8 Phosphate Buffer + 0.05% SLS
Apparatus: Paddle Volume: 900 ml , RPM: 75
Formulation FSI FSII
Strength 5 mg 2.5 mg 5 mg 2.5 mg
Time (Min) Avg RSD Avg RSD Avg RSD Avg RSD
0 0 0 0 0 0 0 0 0
10 69 2.8 70 1.7 55 11.8 52 4.3
15 76 1.7 77 1.4 66 8.6 63 3.8
20 81 1 81 1.3 73 7.6 70 3
30 86 0.9 86 0.7 80 5.1 79 2.8
45 91 0.4 91 0.7 87 4.4 85 2.3

Table 4 shows the results of Bio equivalence study which demonstrate that, tablets prepared by two different strategies (i.e. FSI and FSII) and made using Apixaban particles having a D90 more than 89 µm and having dissolution rates more than about 80% in 30 min is bio equivalent to reference product Eliquis® (Batch no. AAK9857, Marketed by Bayer)
Table 4 BE data for the present invention
90% Confidence Interval Cmax
(ng/mL) AUCT
(ng.h/mL) AUCI
(ng.h/mL)
FSI Vs. R Lower 90.3 91.4 91.5
Upper 108.4 105.4 105.2
Power (%) 99.0 100.0 100.0
FSII Vs. R Lower 85.0 89.5 89.7
Upper 102.4 103.4 103.5
Power (%) 98.8 99.9 100.0

Dated this 29th day of June 2018
(Signature):

________________
(Dhaval Patel)
For Alembic Pharmaceuticals Limited

,CLAIMS:We claim:
Claim 1. A solid pharmaceutical composition comprising a therapeutically effective amount of apixaban and a pharmaceutically acceptable diluent or carrier, wherein the apixaban particles having D90 more than 89 µm.
Claim 2. A solid pharmaceutical composition comprising a therapeutically effective amount of apixaban and a pharmaceutically acceptable diluent or carrier, wherein solid pharmaceutical composition prepared by using apixaban particles having D90 more than 89 µm.
Claim 3. A solid pharmaceutical composition comprising a therapeutically effective amount of apixaban and a pharmaceutically acceptable diluent or carrier, wherein the apixaban particles have a D90 equal to or more than 89 µm, and wherein, as measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL, of a dissolution medium at 37° C., at least 80 wt % of apixaban in the pharmaceutical composition dissolves within 30 minutes in the dissolution medium, and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.
Claim 4. The composition as defined in claim 1, wherein the D90 is more than or equal to 120 µm.
Claim 5. The composition as defined in claim 3, which is a tablet.
Claim 6. The composition as defined in claim 4 prepared by using wet granulation method.
Claim 7. The composition as defined in claim 5, further comprising: from 2% to 6% by weight of a binder.
Claim 8. The composition as defined in claim 7, wherein the binder is cellulosic polymers.
Claim 9. The composition as defined in claim 7, further comprising: from 0.5% to 2% by weight of a surfactant.
Claim 10. The composition as defined in claim 9, wherein the surfactant is sodium lauryl sulfate.