FORMULATIONS

FIELD OF INVENTION

The present invention relates to a pharmaceutical composition comprising Apixaban or one of its pharmaceutically acceptable salt thereof has a D90 less than 20 microns and at least one pharmaceutically acceptable excipient manufactured by using wet granulation method wherein Apixaban is in non-hydrolyzed form.

STATE OF ART

Apixaban is novel, orally active, selective inhibitor of the coagulation factor Xa (FXa) which directly and reversibly binds to the active site of FXa, and decreases the conversion of prothrombin to thrombin due to exerting antithrombotic and anticoagulant effects.

The chemical name of Apixaban is 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 drug substance is a white to pale yellow, non-hygroscopic crystalline powder and a non-ionizable compound which means that, any changes in pH does not affect to the aqueous solubility of Apixaban.

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 in 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.

Absorption of apixaban is approximately 50%. Peak plasma concentrations are observed around 3 to 4 hours post dose after oral following administration. 87% of Apixaban is bound to the plasma proteins. By being prolonged absorption, the pharmacokinetics of Apixaban are complicated. Its short clearance half-life is about 6 hours, but the apparent half-life during following dose is about 12 hours. Thus, it continues the anticoagulation effective for at least a day, even when the drug is stopped for surgery. Its absorption takes place throughout the gastrointestinal tract. Food does not significantly affect bioavailability of Apixaban, thus; it can be taken without to food.

Apixaban was co-developed by Bristol-Myers Squibb (BMS) and Pfizer as an anticoagulant and antithrombotic agent.

Apixaban base and its pharmaceutically acceptable salts first have been declared in EP1427415. 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 (paddles) 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.

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 value more than 89 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.

EP3582777 relates to a pharmaceutical composition comprising Apixaban having a D90 particle size of more than 100 microns, a diluent, a surfactant, a disintegrant and a lubricant manufactured by using wet granulation method wherein Apixaban is dispersed in the binder solution.

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 solution.

Based on the prior art given in the above, many formulation strategies have been carried out to overcome the solubility and bioavailability problem of Apixaban by determining proper particle size and manufacturing process. However, there still exists a need in the art for an improved pharmaceutical composition and dosage form comprising apixaban and improved technological process for the preparation thereof.

In the present invention, pharmaceutical composition comprising Apixaban particles having a D90 value less than 20 microns and at least one pharmaceutically acceptable excipient is developed in the immediate release oral solid dosage form with improved solubility by using wet granulation method wherein Apixaban is in non-hydrolyzed form.

SUMMARY OF INVENTION

The object of this invention is to develop an immediate release solid oral pharmaceutical composition comprising a therapeutically effective amount of Apixaban, which is a novel, orally active, selective, direct, reversible inhibitor of the coagulation factor Xa.

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 a solid oral pharmaceutical composition comprising Apixaban and pharmaceutically acceptable excipients, wherein the Apixaban is in particulate and crystalline form and has a D90 value less than 20 microns.

Another object of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban which can be manufactured into 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 wet granulation method. Another object of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban manufactured by using wet granulation method wherein provided for the manufacture of tablets containing the active ingredient, filler, disintegrant, binder, lubricant, surfactant and solvent selected as to be the most suitable ones with respect to the intended form of administration.

Also present invention particularly relates to a process for the preparation of a pharmaceutical composition manufactured by using wet granulation method, including the steps of: a. Apixaban, Lactose monohydrate, Croscarmellose sodium, Microcrystalline cellulose and specified amount of Povidone are screened through a proper sieve, transferred into the high shear mixer through screening with a proper sieve and stirred, b. Poloxamer is dissolved in a sufficient amount of the deionized water till to dissolve completely, c. The rest amount of the Povidone is added into the granulation solution prepared in Step b and stirred till to obtain homogenous mixture, d. The solution in Step c is added into the powder blend prepared in Step a to perform granulation process, e. The granule prepared in Step d is dried in solution bed dryer and shifted through a proper sieve, f. Magnesium stearate is screened through a proper sieve and added to the powder granulation prepared in Step e and are stirred to obtain a uniform final blend, g. Tablet compression was performed with the final blend in Step f.

Another object of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban particles having a D90 value less than 20 microns and at least one pharmaceutically acceptable excipients manufactured by using wet granulation method and Apixaban is in non-hydrolyzed form.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a pharmaceutical composition comprising Apixaban and at least one pharmaceutically acceptable excipient is developed in the immediate release dosage form wherein the prepared composition is manufactured by using wet granulation method to get desired dissolution properties.

Based on the prior art, even if Apixaban is classified as BCS (Biopharmaceutics Classification System) class III compound which means that it exhibits high solubility and low permeability less than 10 mg Apixaban, it acts as being poor solubility in water as 0.028 mg/mL at 24°C. Thus, the stated particle size with proper manufacturing method becomes an essential and important issue to get completed and desired dissolution profile.

In the present invention relates to a pharmaceutical composition comprising Apixaban and at least one pharmaceutically acceptable excipients wherein Apixaban particles have a D90 value less than 20 microns.

The term “D90” is defined as 90% of the volume of particles having a diameter less than a specified diameter. The value of D90 refers to the particle size distribution of Apixaban particles. In the present invention, Apixaban particles having D90 doesn’t exceed the 20 microns, preferably D90 is less than 17 microns, more preferably D90 is less than 15 microns.

In the present invention, Apixaban is present as a low dose drug as constituting less than 5% w/w by the total weight of the composition. Thus, to eliminate the forming of the non-uniform content in the tablet composition, proper manufacturing method should be selected. Conventionally, manufacturing methods are composed of direct compression, dry granulation and wet granulation methods. In the present invention, the manufacturing step is selected as wet granulation method.

Wet granulation method refers to convert a powder blend into granules with having suitable flow and cohesive properties for tableting. The procedure consists of preparing the granulating solution of a binder or any other excipient dissolved in suitable solvent; mixing the powders in a suitable blender wherein the active ingredient and at least one other pharmaceutically excipient present and adding/spraying the granulating solution onto to the powder blend, usually high shear or fludizied bed to obtain a granulation. In the present invention, the granulation takes place in the high shear granulator. The advantages of wet granulation include improvement of the cohesiveness and compressibility of powders, a good distribution and uniform content of micronized or finely milled low-dosage drugs. In a preferred embodiment of the present invention is to provide a solid oral pharmaceutical composition comprising Apixaban having a D90 less than 20 microns by using wet granulation method.

Moreover, the prepared pharmaceutically composition is also provided for the manufacture of tablets containing the active ingredient, filler, disintegrant, binder, lubricant, surfactant and solvent for the immediate release solid dosage form.

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

In a preferred embodiment, the pharmaceutical composition comprising at least one disintegrant which can be selected from croscarmei!ose sodium, sodium starch glycolate, crospovidone, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Preferably, the disintegrant is croscarmellose sodium.

In a preferred embodiment, the pharmaceutical composition comprises at least a binder which can be selected from hypromeliose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is povidone.

In a preferred embodiment, the pharmaceutical composition comprising at least one lubricant which can be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. Preferably, the lubricant is magnesium stearate.

The choice of the granulating solvent is one of the critical step for the granulation. Typical granulation solutions usually selected as water, ethanol, isopropanol and methylene chloride either alone or in combination. Also, it can be used alone or, more usually, as a solvent containing a dissolved binder/suspension/gelatinized binder to ensure particle adhesion once the granule is dry.

In the present invention, preferred solvent in the granulation solution is selected as water. Moreover, in the present invention, preferred solvent in the granulation solution contains binder and surfactant. Surfactant is used in tablet formulation to increase the dissolution rate or active ingredient release amount by increasing hydrophilicity within the tablet matrix.

In a preferred embodiment, the pharmaceutical composition comprising at least one suitable surfactant which is 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 poloxamer.

One of the preferred embodiment, the pharmaceutical composition of the present invention is manufactured by using wet granulation method, wherein the process comprised the steps of: a. Co-sifting Apixaban, filler, disintegrant and specified amount of the binder through a proper sieve and stir to prepare the powder blend, b. Dissolving the surfactant in the granulation solution, c. Preparing the binder solution by adding it into the prepared granulation solution in Step b, d. Adding the binder solution into the prepared pow'der blend in Step a to preform granulation process, e. Drying the granules in fludizied bed dryer and sifting the dried granules through a proper sieve, f. Sifting the lubricant through a proper sieve and adding to the prepared granule in Step e, g, Compressing the final blend in Step f.

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

The embodiment, Example 1 was given in the Table- 1 below. The proposed embodiment based on the invention provides an immediate release oral solid pharmaceutical composition wherein the amounts in w/w% by w'eight of the total composition are as stated below: Table 1: Unit Formula of Example 1

Further in a preferred embodiment, the process for the preparation of a pharmaceutical composition manufactured by using wet granulation method, including the steps of: a. Apixaban, Lactose monohydrate, Croscarmellose sodium, Microcrystalline cellulose and specified amount of Povidone are screened through a proper sieve, transferred into the high shear mixer and stirred, b. Poloxamer is dissolved in a sufficient amount of the deionized water till to dissolve completely, c. The rest amount of the Povidone is added into the granulation solution prepared in Step b and stirred till to obtain homogenous mixture, d. The solution in Step c is added into the powder blend prepared in Step a to perform granulation process, e. The granule prepared in Step d is dried in fludizied bed dryer and shifted through a proper sieve, f. Magnesium stearate is screened through a proper sieve and added to the powder granulation prepared in Step e and are stirred to obtain a uniform final blend, g. Tablet compression is performed with the final blend in Step f.

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 at pH 6.8 phosphate buffer containing 0.05% sodium lauryl sulfate. Other conditions are defined as; volume of dissolution media is 900 ml, temperature is 37°C±0.5°C, rotation speed is 75 rpm, apparatus is paddle and the duration of dissolution study is 60-minute. Table 2: The results of dissolution study of 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 f ₂ . The similarity factor f ₂ is the most common comparison index and if the estimated value is in the range from 50 to 100, the dissolution profiles of two drug products in comparison are concluded as similar. In the present invention, the similarity factor f ₂ of Example 1 was calculated as 78.0, wherein the first sample was taken after 10 minutes, which means the developed formulation was suitable and the prepared pharmaceutical composition is proper as it was intended.

Finally, the proper dissolution profile was obtained which was developed in the immediate release dosage form comprising Apixaban having a D90 value less than 20 microns and at least one pharmaceutical excipient manufactured by using wet granulation method, wherein Apixaban was only present in the powder blend and binder solution was made of dissolved povidone and poloxamer which enable the aqueous povidone-based binder solution to decrease the interfacial tension between the poorly soluble Apixaban particles.

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.