Formulation comprising form b of avatrombopag maleate

Abstract

The invention relates to tablet composition comprising form B of avatrombopag maleate and a surfactant.

Description

[0001] FORMULATION COMPRISING FORM B OF AVATROMBOPAG MALEATE

[0002] BACKGROUND OF THE PRESENT INVENTION

[0003] Avatrombopag, l-(3-Chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-l- yl)-l,3-thiazol-2-yl]carbamoyl} pyridin-2-yl)piperidine-4-carboxylic acid, compound of formula (I), in the form of maleate salt (molar ratio 1:1; also called hydrogenmaleate) is a small molecule TPO-receptor agonist that is approved for the treatment of severe and primary chronic immune thrombocytopenia in adult patients under the brand name Doptelet®.

[0004] Avatrombopag was first disclosed in W02003062233 (Yamanouchi). Malate salt of avatrombopag was first disclosed in W02004029049 (Y amanouchi).

[0005] WO2013018362 (Astellas) discloses crystalline forms A, B and C of avatrombopag maleate. The document reports that form A crystals can morph depending on the scale of production and are therefore not suitable as drug substance for medicines. Furthermore, form B crystals were found to exhibit poor oral absorption even though they can be stably supplied in industrial production. Form C on the other hand was found to be devoid of these drawbacks. Form C of avatrombopag maleate is used in the commercial Doptelet® tablets marketed by Swedish Orphan Biovitrum. The aim of the present invention is to prepare the tablet formulation comprising form B of avatrombopag maleate, wherein the oral absorption of form B is improved resulting in a tablet formulation that is bioequivalent to commercial Dopteler® tablets. BRIEF DESCRIPTION OF THE INVENTION

[0006] The invention relates to the immediate release film-coated tablet comprising form B of avatrombopag maleate and intragranular surfactant, preferably pol oxamer or vitamin E TPGS.

[0007] BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts the manufacturing process of tablets according to the present invention.

[0008] Figure 2 depicts the defects on tablets obtained in reference example 1.

[0009] Figure 3 depicts the appearance of tablets obtained in example 1.

[0010] Figure 4 depicts the dissolution profile of tablets obtained in example 1 in comparison with commercially available Doptelet® tablets.

[0011] DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention relates to immediate release tablet formulation that comprises form B of avatrombopag maleate and an intragranular surfactant.

[0013] Form B can be characterized by xrpd pattern described in table 1:

[0014] Table 1

[0015] Surfactants are amphiphilic molecules that contain both hydrophilic and lipophilic groups. Surfactants may have several uses in pharmaceuticals, e.g. to solubilize hydrophobic drugs in aqueous media or to improve drug absorption and penetration. Surfactants are classified into ionic surfactants and non-ionic surfactants. Ionic surfactants are subclassified into anionic surfactants where the hydrophilic group dissociates into anions in aqueous solutions, cationic surfactants that dissociate into cations and amphoteric surfactants that dissociate in anions and cations often depending on pH. Examples of non-ionic surfactants are polyol esters including glycol and glycerol esters and sorbitan derivatives, polyoxyethylene esters including polyethylene glycol and poloxamers, which are non-ionic triblock copolymers composed of poly oxypropylene flanked by polyoxyethylene. Examples of ionic surfactants are sodium lauryl sulfate, docusate, alkyl ether phosphates and quartenary ammonium salts.

[0016] The hydrophile-lipophile balance (HLB) number is used as a measure of the ratio of the hydrophilic and lipophilic groups in the surfactant and defines the affinity for water or oil. HLB numbers above 10 indicate an affinity for water (hydrophilic) and below 10 an affinity for oil (lipophilic).

[0017] The selection of the surfactant type during oral formulation development requires an understanding of the interplay between surfactant characteristics and biopharmaceutical factors. However, there is a lack of comprehensive knowledge of how surfactant properties, such as HLB, digestibility, and the structure of the surfactant influences the in vivo performance. The tablets according to the invention improve the oral bioavailability of form B of avatrombopag maleate.

[0018] The present inventors have found that the oral absorption of crystalline form B of avatrombopag maleate can be improved when it is formulated into the tablet comprising the surfactant that has HTB value > 12. The surfactant to be used according to the invention is selected from poloxamer, preferably poloxamer 188, and D-a-Tocopherol polyethylene glycol succinate (also called vitamin E TPGS) or the mixtures thereof.

[0019] Poloxamers are a class of water-soluble nonionic block copolymers, consisting of poly(ethylene oxide)-poly(propylene oxide)-poly(ethyelene oxide) triblock copolymer. Preferably, poloxamer is used. Even more preferably poloxamer 188 is used as surfactant according to the invention. Poloxamer 188 is characterized by number average molar mass of 8760 g / mol and an ethylene oxide content of 81.8±1.9% (w / w). D-a-tocopheryl polyethylene glycol succinate is a water-soluble derivative of natural Vitamin E, which is formed by esterification of Vitamin E succinate with polyethylene glycol (PEG).

[0020] While developing the tablet comprising form B of avatrombopag maleate, the inventors have surprisingly found that when the surfactant is added in extragranular portion of the tablet formulation, defects are observed in the obtained tablets. Tablet defects impart financial burden on pharmaceutical companies and from a clinical perspective may result in therapeutic failure as well as reducing patient compliance.

[0021] The present invention relates to the immediate release tablet comprising avatrombopag maleate form B and at least one pharmaceutically acceptable excipient, wherein the tablet comprises the surfactant in intragranular portion of the tablet. The surfactant is preferably selected from poloxamer and vitamin E TPGS, more preferably poloxamer.

[0022] The amount of the surfactant in the formulation can be between 0.5 and 3% by weight relative to the tablet weight, preferably between 1 and 2.7% w / w, even more preferably between 1.5 and 2.5% w / w.

[0023] The amount of avatrombopag maleate in the formulation is preferably between 10-20% w / w.

[0024] The tablet compositions according to the present invention comprise, besides avatrombopag maleate form B and a surfactant, one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well-known and are those excipients which are conventionally used by the person skilled in the art. The pharmaceutically acceptable excipients are chosen from one or more diluents, binders, disintegrants, glidants or lubricants.

[0025] The pharmaceutical tablet composition according to the present invention comprises preferably 55-80% w / w of one or more diluents, 0-7% w / w of one or more binders, 2-10% w / w of one or more disintegrants, 0.25-1.0% w / w of one or more glidants and 0.5-2.5% w / w of one or more lubricants, all relative to the total tablet weight.

[0026] In another embodiment the tablet composition comprises 65-80% w / w of one or more diluents, 2-6% w / w of one or more disintegrants, 0.25-1.0% w / w of one or more glidants and 0.5-2.5% w / w of one or more lubricants, all relative to the total core tablet weight.

[0027] The diluent to be used in accordance with the present invention may be any diluent known to a person of ordinary skill in the art. Particularly, the diluent to be used in accordance with the present invention is an inorganic diluent, polysaccharide, mono- or disaccharide or sugar alcohol. Lactose and microcrystalline cellulose are particularly preferred diluents. In one embodiment of the present invention, the diluent is added as intragranular component. In another embodiment, the diluent is added partially to the intragranular phase and partially to the extragranular phase. In yet another embodiment lactose is added intragranularly, and microcrystalline cellulose is added in the extragranular portion.

[0028] The disintegrant to be used in accordance with the present invention may be any disintegrant known to a person of ordinary skill in the art. Suitable disintegrants to be used in accordance with the present invention are selected from the group consisting of croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose (HPC) or sodium starch glycolate. Crospovidone is a particularly preferred disintegrant. In one embodiment of the present invention, the disintegrant is added as to the intragranular phase. In the prefered embodiment, the disintegrant is added partially to the intragranular phase and partially to the extragranular phase.

[0029] The glidant to be used in accordance with the present invention may be any glidant known to a person of ordinary skill in the art. Colloidal silicon dioxide is a particularly preferred glidant. In the preferred embodiment of the present invention, the glidant is added as intragranular component. The lubricant to be used in accordance with the present invention may be any lubricant known to a person of ordinary skill in the art. Magnesium stearate is a particularly preferred lubricant. The lubricant may be added as extragranular component or it may be divided over the intragranular and extragranular phase. In a preferred embodiment, the lubricant is added partially to the intragranular phase and partially to the extragranular phase.

[0030] The tablets may be optionally further coated by a film-coat. The coating serves generally for cosmetic purposes. The coating material typically has no influence on the release rate, except of an inherent short initial delay in dissolution due to the time necessary to dissolve the coat. The coating may be selected from amongst one or more of those suitable coating materials known in the art.

[0031] The coating may be performed by applying one or more film forming polymers, with or without other pharmaceutically inert excipients, as a solution / suspension. Coating is done using any conventional coating technique known in the art, such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating.

[0032] The tablet composition according to the present invention is packaged in primary packaging material, e.g. blisters and bottles.

[0033] The pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.

[0034] EXAMPLES

[0035] Dissolution method used is USP Apparatus 2 at a paddle speed of 50 rpm in 900 mL of phosphate buffer, pH 6.8 containing 0.25% CTAB. Based on the FDA Product Quality Review(s), this dissolution method is proposed by the reference listed drug for batch release and stability testing of the drug product. Reference example 1: Immediate release film-coated tablet formulation containing avatrombopag maleate Form B and 1.0% w / w of the total core tablet weight of poloxamer 188 in the extragranular phase

[0036] 215.1 g of avatrombopag maleate, 1,098.4 g of lactose monohydrate, 30.0 g of crospovidone, 7.6 g of colloidal silicon dioxide were accurately weighed, sieved, and blended. 15.0 g if magnesium stearate were accurately weighed, sieved, and blended with the previous blend. The lubricated pre-granulation blend was dry granulated in a roller compactor with integrated milling system. 390.6 g of the resulting milled granulate was then blended with the extragranular excipients. 19.2 g of microcrystalline cellulose, 4.3 g of poloxamer 188, and 8.6 g of crospovidone were accurately weighed, sieved, and blended with the 390.6 g of milled granulate. 6.4 g of magnesium stearate were accurately weighed, sieved, and blended with the previous blend. The final blend was compressed in a power assisted tablet press and the resulting tablets were then film-coated.

[0037] The addition of poloxamer in the extragranular phase resulted in tablet appearance defects as presented in Figure 1.

[0038] Example 1: Immediate release film-coated tablet formulation containing avatrombopag maleate Form B and 1.0% w / w of the total tablet weight of poloxamer 188 in the extragranular phase

[0039] 436.04 g of avatrombopag maleate, 2,191 g of lactose monohydrate, 60.06 g of crospovidone, 45.00 g of poloxamer 188, and 15.07 g of colloidal silicon dioxide were accurately weighed and blended. The resulting blend was sieved and further blended. 30.01 g of magnesium stearate were accurately weighed, sieved, and blended with the previous blend. The lubricated pre-granulation blend was dry granulated in a roller compactor with integrated milling system. 2417 g of the resulting milled granulate was then blended with the extragranular excipients. 105 g of microcrystalline cellulose and 52 g of crospovidone were accurately weighed, sieved, and blended with the 2417 g of milled granulate. 39 g of magnesium stearate were accurately weighed, sieved, and blended with the previous blend. The final blend was compressed in a power assisted tablet press and the resulting tablets were then film-coated.

[0040] The composition of the prepared tablet is presented in table 2.

[0041] The process to prepare the tablets is presented in Figure 3.

[0042] As can be seen in Figure 2, tablets without any defects were obtained, when the surfactant was added intragranularly.

[0043] Table 2. Qualitative and quantitative composition of avatrombopag maleate (Form B)

[0044] 20 mg film-coated tablet.

[0045] 123.573 mg of avatrombopag maleate are equivalent to 20 mg of avatrombopag. The amount of avatrombopag maleate is compensated for its assay.

[0046] 2Opadry II 8F yellow is a combination of 40.00% (w / w) polyvinyl alcohol-partially hydrolyzed, 23.92%> (w / w) titanium dioxide, 20.20%> (w / w) macrogol / PEG, 14.80%> talc, and 1.08% (w / w) iron oxide yellow.

Claims

CLAIMS1. Immediate-release tablet formulation comprising form B of avatrombopag maleate and at least one pharmaceutically acceptable excipient, wherein the formulation comprises a surfactant.

2. The formulation according to claim 1, wherein the surfactant is in intragranular portion of the tablet formulation.

3. The formulation according to claims 1-2, wherein the surfactant is selected from poloxamer and vitamin E TPGS.

4. The formulation according to claim 3, wherein the surfactant is poloxamer 188.

5. The formulation according to claim 4, wherein the amount of poloxamer is between 0.5 and 3% by weight relative to the core tablet weight.

6. The formulation according to any of the preceding claims, wherein one or more pharmaceutically acceptable excipients are selected from diluents, disintegrants, glidants and lubricants.

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