WO2022115051A1

WO2022115051A1 - Direct compression method for non-micronised apixaban formulations

Info

Publication number: WO2022115051A1
Application number: PCT/TR2020/051184
Authority: WO
Inventors: Erol KIRESEPI; Ersin Yildirim
Original assignee: Santa Farma Ilac Sanayii A.S.
Priority date: 2020-11-27
Filing date: 2020-11-27
Publication date: 2022-06-02
Also published as: EP4251271A1

Abstract

The present invention relates to a pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using direct compression method to get desired dissolution profile wherein Apixaban particle size D90 value is more than 89 microns.

Description

DIRECT COMPRESSION METHOD FOR NON-MICRONISED APIXABAN

FORMULATIONS

FIELD OF INVENTION The present invention relates to a pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient manufactured by using direct compression method to get desired dissolution profile wherein Apixaban particle size D90 value is more than 89 microns. STATE OF ART

Apixaban is orally active, direct, selective inhibitor of the coagulation Factor Xa (FXa) which occupies a pivotal role in the clotting cascade when there is occurring to conversion from prothrombin to thrombin. Thrombin is a powerful platelet agonist and has multiple functions such as, converting fibrinogen to fibrin, promoting fibrin cross-linking by activating factor XIII, or activating thrombin-activatable fibrinolysis inhibitor to protect the clot from premature degradation. In other way, thrombin is central to the process of blood clotting and that includes both deep vein thrombosis and pulmonary embolism.

To diminish fibrin formation, and reduce coagulation and platelet activation, Factor Xa is blocked. Factor Xa causes to decrease the conversion of prothrombin to active thrombin. Thus, Apixaban is being co-developed by Bristol-Myers Squibb (BMS) and Pfizer as an anticoagulant and antithrombotic agent for the prevention and treatment of a wide range of thrombotic diseases.

Apixaban is a pyrazole derivative, is chemically described as l-(4-methoxyphenyl)-7-oxo-6- [4-(2-oxo-l-piperidinyl) phenyl]-4, 5, 6, 7-tetrahydro-lH-pyrazolo [3, 4-c] pyridine-3- carboxamide. The molecular formula of which is C25H25N5O4, its relative molecular mass 459.50 and its structural formula is shown in the Formula I.

Formula I Apixaban appears as a white to pale yellow, non-hygroscopic crystalline powder, with an aqueous solubility of 0.028 mg/ml at 24°C.

The molecule has no chiral central, therefore, no stereoisomers exist. It shows polymorphism and a number of hydrates and solvates were identified. However, only one form is consistently produced by the proposed synthetic process.

Apixaban was firstly commercially authorized by the European Medicines Agency on May 2011. The medicinal product of it been launched in the film-coated tablet form under the name of the ELIQUIS^® which is used for the treatment for preventing Venous thromboembolism in adults following elective knee or hip replacement surgery and for reducing the risk of stroke or systemic embolism in adults with non-valvular Atrial fibrillation.

ELIQUIS^® film coated tablets are available for oral administration in strengths of 2.5 mg and 5 mg of Apixaban with the following inactive ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. The film coating contains lactose monohydrate, hypromellose, titanium dioxide, triacetine, and yellow iron oxide for 2.5 mg tablets or red iron oxide for 5 mg tablets.

Apixaban is known to be a non-ionizable compound. The aqueous solubility of Apixaban is 0.04 mg/ml at 37°C over a pH range of 1.2 to 6.8. It is also classified as highly soluble for doses up to 10 mg in 250 ml. of physiological buffer.

The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Food does not affect the bioavailability of apixaban. Maximum concentrations (C_max) of apixaban appear 3 to 4 hours after oral administration. Apixaban is absorbed throughout the gastrointestinal tract with the distal small bowel and ascending colon contributing about 55% of apixaban absorption. Apixaban demonstrates linear pharmacokinetics with dose- proportional increases in exposure for oral doses up to 10 mg. At doses more than 25 mg, apixaban displays dissolution-limited absorption with decreased bioavailability.

Apixaban base and its pharmaceutically acceptable salts first have been declared in EP 1427415 by Bristol-Myers Squibb. In particular, Example 18 at the EP1427415 discloses the preparation of Apixaban base.

In the state of art there are many patents/patent applications which are summarized below.

EP2538925 relates to a pharmaceutical composition comprising crystalline Apixaban particles having a D90 equal to or less than 89 pm and a pharmaceutically acceptable diluent or carrier excipients wherein the prepared composition is manufactured by using a dry granulation process.

EP2538925 patent document has many divisional applications.

One of the divisional application EP3017811 discloses to the dry granulation process steps of the prepared pharmaceutical formulations comprising Apixaban and a pharmaceutically acceptable diluent or carrier excipients.

Another divisional application EP3251660 discloses to a pharmaceutical composition comprising crystalline Apixaban particles having a D90 less than 50 pm and a pharmaceutically acceptable diluent or carrier excipients.

Another divisional application EP3246021 discloses to a pharmaceutical composition exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein the dissolution test is performed in an aqueous media buffered to a pH range 1 to 7.4 and controlled at 37° C.

Another divisional application EP3257500 discloses to a pharmaceutical composition comprising crystalline Apixaban particles and a pharmaceutically acceptable diluent or carrier and a surfactant, wherein the surfactant is present in a concentration of 0.25% to 2% by weight, also wherein the composition is manufactured by using an air-jet milling process to reduce Apixaban particle size to the desired size and dry granulation.

Another divisional application EP3643301 discloses to a pharmaceutical composition exhibits dissolution properties such that an amount of the drug equivalent to at least 77% dissolves within 30 minutes, wherein the dissolution test is performed in 900 mL of dissolution medium containing 0.05 M sodium phosphate at pH 6.8 with 0.05% SDS at 37°C using USP Apparatus 2 (paddle) at a rotation speed of 50-75 rpm.

Another divisional application EP3662899 is rather close with the EP3643301 patent document wherein EP3662899 patent document discloses to the dose/solubility ratio of the Apixaban in the tablet which is less than 250 mL. The given dissolution properties are same with the EP3643301 patent document.

WO2018150286 relates to a pharmaceutical composition comprising Apixaban having a D90 more than 100 microns, a diluent, a surfactant, a disintegrant and a lubricant wherein the prepared composition is manufactured by using a wet granulation process. EP3405195 relates to a pharmaceutical composition comprising Apixaban or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable polymer wherein the polymer is graft copolymer of polyvinyl caprolactam, polyvinyl acetate and polyethylene glycol obtained by using of hot-melt method.

WO2019177318 relates to a pharmaceutical composition comprising Apixaban was prepared according to a preparation method comprising the steps of; mixing Apixaban and a water- soluble polymer to prepare a mixture; and wet kneading and vacuum drying of the mixture.

WO2017221209 relates to a pharmaceutical composition comprising the crystalline Apixaban particles having a D90 more than 100 microns and a pharmaceutically acceptable carrier wherein the crystalline Apixaban is Form M.

EP3243505 relates to a pharmaceutical composition comprising amorphous Apixaban or a salt thereof together with one or more pharmaceutically acceptable excipients or carriers, wherein the composition exhibits an in vitro dissolution profile measured in phosphate buffer at pH 6.8 containing 0.05 % weight/volume of sodium lauryl sulfate according to which: at least 30% of Apixaban is dissolved after 5 minutes and at least 60% of Apixaban is dissolved after 10 minutes.

EP2907507 relates to a pharmaceutical composition comprising Apixaban and a particularly selected polymer having low viscosity as binder.

W02017163170 relates to a pharmaceutical composition comprising Apixaban prepared by a non-aqueous wet granulation process wherein the composition releases at least 80% of Apixaban in 30 minutes.

EP3107530 relates to a pharmaceutical composition comprising Apixaban and a polymer having low viscosity as binder wherein the polymer is selected from the group consisting of povidone, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, copovidone, polyvinyl alcohol-polyethylene glycol graft copolymer, respectively having low viscosity, and a mixture thereof and wherein the composition prepared by wet granulation process.

W02017121340 relates to a pharmaceutical composition comprising non-micronized Apixaban and pharmaceutically acceptable excipients wherein the povidone is selected as binder as is dissolved in DMSO.

EP2554159 relates to a pharmaceutical composition comprising micronized Apixaban and a content uniformity enhancer manufactured by using direct compression. WO2017182908 relates to a pharmaceutical composition comprising micronized Apixaban and pharmaceutically acceptable excipients manufactured by using direct compression wherein the amount of the micronized Apixaban is present up to 20% of the total weight.

TR2017/17703 relates to a pharmaceutical composition comprising Apixaban or a pharmaceutically acceptable salt thereof manufactured by using wet granulation method wherein Apixaban is dispersed into the solvent or solvent mixture to prepare the granulating fluid.

Based on the prior art given in the above, the particle size of Apixaban effects on the dissolution and absorption rate. Thus, it is often formulated in a composition having a reasonable particle size using proper manufacturing process, to achieve and maintain relatively fine particles to obtain proper in vitro dissolution profiles.

However, the inventors of the present invention have surprisingly succeeded in formulating a pharmaceutical composition comprising crystalline Apixaban particles having a D90 value more than 89 microns and at least one pharmaceutically acceptable excipient manufactured by using direct compression method and at least 85% of Apixaban is dissolved in 30 minutes when measured by using USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm in 900 mL pH 6.8 phosphate buffer at 37°C temperature containing 0.05% weight/volume of sodium lauryl sulfate.

SUMMARY OF INVENTION

The object of this invention is to develop a solid oral pharmaceutical composition comprising a therapeutically effective amount of Apixaban or one of its pharmaceutically acceptable salts, and at least one pharmaceutically acceptable excipients.

It is an object of the present invention is to develop a solid oral pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salts, which is used for the treatment for preventing venous thromboembolism in adults following elective knee or hip replacement surgery and for reducing the risk of stroke or systemic embolism in adults with non-valvular atrial fibrillation.

The object of the present invention is to provide the pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and Apixaban that has a D90 value more than 89 microns either in particulate or crystalline form. Another object of the present invention is to provide a pharmaceutical composition comprising Apixaban which can be manufactured as solid oral dosage forms, such as tablets having desired dissolution profiles.

Another object of the present invention is to provide a solid oral pharmaceutical composition comprising crystalline Apixaban and one or more pharmaceutically acceptable excipients manufactured by using direct compression method.

Another object of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban manufactured by using direct compression method wherein provided for the manufacture of tablets containing the active ingredient, filler, disintegrant, lubricant, glidant and surfactant selected as to be the most suitable ones with respect to the targeted form of administration.

Another object of the present invention relates to provide direct compression method for preparing a solid oral pharmaceutical composition, direct compression method comprising the steps: i. Apixaban and Sodium lauryl sulfate are screened through a proper sieve and stirred, ii. Silicon dioxide and specified amount of Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. Croscarmellose sodium and specified amount of Microcrystalline cellulose are screened through a proper sieve and then added to the powder blend prepared in Step ii and stirred, iv. The rest of the Microcrystalline cellulose and Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step iii and stirred, v. Magnesium stearate is screened through a proper sieve and added to the powder blend prepared in Step iv and stirred to obtain a uniform final blend, vi. Tablet compression is performed with the final blend in Step v.

Another object of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban particles having a D90 value more than 89 microns and at least one pharmaceutically acceptable excipients manufactured by using direct compression method and at least 85% of Apixaban is dissolved in 30 minutes when measured by using USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm in 900 mL pH 6.8 phosphate buffer at 37°C temperature containing 0.05% weight/volume of sodium lauryl sulfate. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a solid oral pharmaceutical composition comprising an Apixaban and at least one pharmaceutically acceptable excipient is developed in the immediate release dosage form wherein the prepared composition is manufactured by using direct compression method to get desired dissolution profile.

The term an "immediate release tablet" refers to dosage forms undergo rapid disintegration to smaller granules and subsequent degradation to fine particles to release the medicaments. In the present invention, immediate release may be provided of an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not delay the rate of drug release and/or absorption.

In a preferred embodiment of the present invention is to provide a pharmaceutical composition for oral administration. Suitable solid oral dosage forms are selected from the group comprising tablets, capsules, granules, powders, and pellet or unit dose packets, preferably the solid oral dosage form is tablet. The term “apixaban” as used herein refers to apixaban in the form of free base or in the form of pharmaceutically acceptable salts, crystalline polymorph, solvates, hydrates, esters or in an amorphous form or mixtures thereof.

According to the literature knowledge, Apixaban is known to be highly water-soluble and relatively low oral bioavailability (about 50% for a single 10 mg dose) compound. However, one of its main document which is EP2538925 discloses a pharmaceutical composition comprising Apixaban lead to consistent in-vivo dissolution profiles which means that the particle size has an impact on Apixaban absorption rate when it has a D90 value equal or less than 89 microns. Moreover, it was also revealed that a prepared composition having a reasonable particle size of Apixaban using dry granulation process, to facilitate consistent in vitro dissolution.

Even if, there is a knowledge about the using large particles of Apixaban could result in less optimal exposures than micronized particles, in the present invention that the prepared pharmaceutical composition comprising Apixaban particles more than 89 microns exhibits a proper dissolution profile. Thus, in a preferred embodiment of the present invention is to provide the pharmaceutical composition comprising Apixaban particles having a D90 more than 89 microns and at least one pharmaceutical acceptable excipient. The ranges of particle size preferred for use in the present invention is more than 89 microns, preferably D90 value more than 100 microns, more preferably D90 value is 139.6 microns. The particle size distribution of apixaban particles as described in the specification is characterized by D90 values. The term “D90” is defined as 90% of the volume of particles having a diameter less than a specified diameter.

In the present invention, Apixaban is a low dose drug which is constituted less than 5% weight by the total weight of the composition. The mixing and formulation of low dose drugs can be difficult due to problem related to content uniformity. Thus, selection of proper manufacturing step is critical to develop a homogenous low dose drug. It is known that the manufacturing may be performed by the methods like direct compression, dry granulation or wet-granulation before tableting. In the present invention, the manufacturing method is selected as direct compression method.

The term “direct compression” refers to being a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug. The active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets. This type of mixing is believed to be essential in order to prepare “pharmaceutically acceptable” dosage forms.

The advantages of direct compression include uniformity of blend; few manufacturing steps, i.e., the overall process involves weighing of powders, blending and compression, hence less cost; elimination of heat and moisture, prime particle dissociation and physical stability.

In a preferred embodiment of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban having a D90 value more than 89 microns by using direct compression method which involves blending and compression. Moreover, the prepared pharmaceutically composition is also provided for the manufacture of tablets containing at least one pharmaceutically acceptable excipient is selected from fillers, disintegrants, binders, lubricants, surfactants and mixtures thereof.

In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable filler, preferably selected from which can be selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, mannitol, sugar's, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof. Preferably, filler is a combination of lactose anhydrous and microcrystalline cellulose.

In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable disintegrant preferably selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Preferably, the disintegrant is croscarmellose sodium.

In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable glidant preferably selected from colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate. Preferably, the glidant is colloidal silicon dioxide.

In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable lubricant preferably selected from sodium stearyl fumarate, magnesium stearate, calcium stearate tale, stearic acid and mixtures thereof. Preferably, the lubricant is magnesium stearate.

In a preferred embodiment, the pharmaceutical composition comprising at least one pharmaceutically acceptable surfactant preferably selected from polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, stearyl alcohol, poloxamers, potassium laureate, sodium lauryl sulfate, benzalkonium chloride and mixtures thereof. Preferably, the surfactant is sodium lauryl sulfate.

The embodiment in accordance with the present invention was designed with adjusted quantitative composition composed of pharmaceutically acceptable ingredients mentioned above by using direct compression method.

The embodiment. Example 1 is given in the below.

The proposed embodiment based on the invention provides an immediate release oral solid pharmaceutical composition wherein the amounts in w/w% of the total composition are as stated below: Example 1: Unit Formula

in this embodiment of the present invention, detailed manufacturing steps of a solid dosage form are presented below: i. Apixaban and Sodium lauryl sulfate are screened through a proper sieve and stirred, ii. Silicon dioxide and specified amount of Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. Croscarmellose sodium and specified amount of Microcrystalline cellulose were screened through a proper sieve and then added to the powder blend prepared in Step ii and stirred, iv. The rest of the Microcrystalline cellulose and Lactose anhydrous were screened through a proper sieve and then added to the powder blend prepared in Step iii and stirred, v. Magnesium stearate was screened through a proper sieve and is added to the powder granulation prepared in Step iv and are stirred to obtain a uniform final blend, vi. Tablet compression was performed with the final blend in Step v.

The obtained tablets were subjected to in vitro dissolution study and the dissolution conditions were designated considering the gastrointestinal pathway of orally applied solid dosage forms.

The dissolution test is carried out in pH 6.8 phosphate buffer medium containing sodium lauryl sulfate. Other conditions are defined as; volume of dissolution medium is 900 ml, temperature of study is 37°C±0.5, rotation speed is 75 rpm, apparatus is paddle and the duration of dissolution study is 60 minutes. Table 1: The results of dissolution study belongs to Example 1

Based on the results presented in Table 1 above, the in-vitro dissolution results of Example 1 were similar with the Reference drug product. In accordance with FDA regulations, similarity of two drug products can be compared based on the results of in vitro dissolution profile studies of these drug products by using a similarity factor f₂. The similarity factor Ϊ2 is the most common comparison index and if the estimated value is between 50 -100, the dissolution profiles of two drug products in comparison are concluded as similar. In the present invention, the similarity factor Ϊ2 of Example 1 was calculated as 55.0 which means the developed formulation was suitable and the prepared pharmaceutical composition is proper as it was intended.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. A solid oral pharmaceutical composition comprising Apixaban and at least one pharmaceutically acceptable excipient manufactured by using direct compression method, wherein Apixaban is in crystalline form having a D90 value more than 89 microns and at least 85% of Apixaban is dissolved in 30 minutes when measured by using USP Apparatus 2 (paddle) method at a rotation speed of 75 rpm in 900 mL pH 6.8 phosphate buffer at 37°C temperature containing 0.05% weight/volume of sodium lauryl sulfate.

2. A solid oral pharmaceutical composition according to Claim 1, wherein the Apixaban particles have a D90 value more than 100 microns, preferably D90 value is 139.6 micron.

3. A solid oral pharmaceutical composition according to Claim 1 or 2, wherein at least one pharmaceutically acceptable excipient is selected from fillers, disintegrants, glidant, surfactants, lubricants and mixtures thereof.

4. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a filler, preferably selected from calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, mannitol, sugars, sorbitol, sucrose, inorganic salts, primarily calcium salts and the like and mixtures thereof.

5. A solid oral pharmaceutical composition according to Claim 4, wherein the filler is a combination of lactose anhydrous and microcrystalline cellulose.

6. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a disintegrant, preferably selected from croscarmellose sodium, sodium starch g!yeo!ate, crospovidone, corn starch, pregelatinized starch, low -substituted hydroxypropyl cellulose and microcrystalline cellulose.

7. A solid oral pharmaceutical composition according to Claim 6, wherein the disintegrant is croscarmellose sodium.

8. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a glidant preferably selected from colloidal silicon dioxide, powdered cellulose, talc, tribasic calcium phosphate.

9. A solid oral pharmaceutical composition according to Claim 8, wherein the glidant is colloidal silicon dioxide.

10. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a lubricant preferably selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.

11. A solid oral pharmaceutical composition according to Claim 10, wherein the lubricant is magnesium stearate.

12. A solid oral pharmaceutical composition according to Claim 3, wherein at least one pharmaceutically acceptable excipient is a surfactant, preferably selected from polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, stearyl alcohol, poloxamers, potassium laureate, sodium lauryl sulfate, benzalkonium chloride and mixtures thereof.

13. A solid oral pharmaceutical composition according to Claim 12, wherein the surfactant is sodium lauryl sulfate.

14. A solid oral pharmaceutical composition according to any one of the preceding claims, comprising:

15. A direct compression method for preparing a solid oral pharmaceutical composition according to any one of the preceding claims, wherein the process comprising the steps of; i. Apixaban and Sodium lauryl sulfate are screened through a proper sieve and stirred, ii. Silicon dioxide and specified amount of Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step i and stirred, iii. Croscarmellose sodium and specified amount of Microcrystalline cellulose are screened through a proper sieve and then added to the powder blend prepared in Step ii and stirred, iv. The rest of the Microcrystalline cellulose and Lactose anhydrous are screened through a proper sieve and then added to the powder blend prepared in Step iii and stirred, v. Magnesium stearate was screened through a proper sieve and is added to the powder granulation prepared in Step iv and are stirred to obtain a uniform final blend, vi. Tablet compression was performed with the final blend in Step v.

16. A solid oral pharmaceutical composition according to any one of the preceding claims, wherein the composition is in the form of tablet.

17. A solid oral pharmaceutical composition according to any one of the preceding claims for use in the treatment of Venous thromboembolism in adults following elective knee or hip replacement surgery and for reducing the risk of stroke or systemic embolism in adults with non-valvular Atrial fibrillation.