WO2024187416A1

WO2024187416A1 - Pharmaceutical composition comprising ruxolitinib

Info

Publication number: WO2024187416A1
Application number: PCT/CN2023/081661
Authority: WO
Inventors: Guanneng Yu; Jun Liu; Chunguang DAI; Zhiguo Zheng
Original assignee: Zhejiang Qizheng Pharmaceutical Co Ltd; Stada Arzneimittel AG
Current assignee: Zhejiang Qizheng Pharmaceutical Co Ltd; Stada Arzneimittel AG
Priority date: 2023-03-15
Filing date: 2023-03-15
Publication date: 2024-09-19
Anticipated expiration: 2025-09-15
Also published as: CN121175034A; WO2024189132A1

Abstract

Provided is a solid oral pharmaceutical composition comprising ruxolitinib as an active pharmaceutica ingredient wherein ruxolitinib is present in the form of its free base. Moreover, provided is the process for the preparation of the pharmaceutical composition according to the invention.

Description

Pharmaceutical composition comprising ruxolitinib

The present invention relates to a solid oral pharmaceutical composition comprising ruxolitinib as an active pharmaceutical ingredient.

Ruxolitinib is the International Nonproprietary Name (INN) for the drug molecule with the chemical name (R) -3- (4- (7H-pyrrolo [2, 3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropanenitrile. Ruxolitinib per se, i.e. Ruxolitinib in the form of its free base, has the following chemical structure:

Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2, that mediate the signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function. Ruxolitinib inhibits the JAK-STAT signalling and cell proliferation of cytokine-dependent cellular models of haematological malignancies, that play a role in regulating the development, proliferation, and activation of several immune cell types important for graft versus host disease pathogenesis.

In Europe ruxolitinib is marketed under the trade name is indicated for the treatment of myelofibrosis, polycythaemia vera and graft versus host disease.

is formulated as a filmless tablet that contains the drug molecule ruxolitinib in form of a phosphate salt. The Ruxolitinib phosphate salt is disclosed in EP 2 173 752 A2 that discloses also a maleic acid salt and a sulfuric acid salt of ruxolitinib. In EP 2 173 752 A2 it is stated that said ruxolitinib salts have a superior aqueous solubility, rate of dissolution and chemical stability compared with the free base form of ruxolitinib.

However, there is still a need to provide solid oral pharmaceutical compositions comprising ruxolitinib that are chemically stable with respect to ruxolitinib, e.g. in order to provide a relatively long high product quality, a relatively long shelf life of the composition and/or to permit more flexible storage conditions.

Thus, the object of the present invention is to provide a solid oral pharmaceutical composition comprising ruxolitinib as an active pharmaceutical ingredient that is relatively stable with respect to the chemical stability of ruxolitinib.

Surprisingly it has been found, that a relatively stable solid oral pharmaceutical composition comprising ruxolitinib can be provided if the ruxolitinib contained in the composition is present in the form of its free base.

Even it could be shown, that the solid oral pharmaceutical composition according to the invention is more stable with respect to the chemical stability of ruxolitinib compared to thecomposition.

Moreover, it has been found that the pharmaceutical composition according to the invention shows a sufficient solubility and dissolution rate to permit an effective oral bioavailability.

Furthermore, it has been found that the pharmaceutical composition according to the present invention can be formulated in a way that it is bioequivalent to theproduct.

As already said above the solid oral pharmaceutical compositions is relatively stable with respect to the chemical stability of ruxolitinib.

The term "stability" in this context is understood to mean the definition worked out by the Arbeitsgemeinschaft für pharmazeutische Verfahrenstechnik (APV) , according to which "stability" means the specification-suitable quality of the medicament up to the end of the shelf life fixed by the producer. The quality of the medicament is thus determined by the active ingredient content and the purity, the sensorially perceivable, physical-chemical and the microbiological properties, wherein the active ingredient content should not up to the end of the shelf life fall below 90 %of the declared value.

It is preferred that the pharmaceutical composition according to the present invention has at a temperature of 30 ℃ ± 2 ℃and a relative humidity RH of 65 %± 5 % (see committee for proprietary medicinal products (CPMP) , “guideline on stability testing: stability testing of existing active substances and related finished products” , CPMP/QWP/122/02, rev 1 corr of December 17, 2003) , a stability or shelf life of at least 1 year, preferably of at least 2 years, more preferably of at least 3 years, more preferably of at least 3.5 years, more preferably of at least 4 years, more preferably of at least 4.5 years and even more preferably of at least 5 years.

Moreover it is preferred that the pharmaceutical composition according to the present invention has at a temperature of 30 ℃ ± 2 ℃ and a relative humidity RH of 65 %± 5 % (see committee for proprietary medicinal products (CPMP) , “guideline on stability testing: stability testing of existing active substances and related finished products” , CPMP/QWP/122/02, rev 1 corr of December 17, 2003) , a stability or shelf life of up to 1 year, preferably of up to 2 years, more preferably of up to 3 years, more preferably of up to 3.5 years, more preferably of up to 4 years, more preferably of up to 4.5 years and even more preferably of up to 5 years.

As already stated above the present invention relates to a solid oral pharmaceutical composition comprising ruxolitinib as an active pharmaceutical ingredient wherein ruxolitinib is present in the form of its free base. This means that all of the ruxolitinib contained in the composition is in the form of the free base.

The pharmaceutical composition according to the invention can be formulated for immediate, modified, controlled, sustained, prolonged, extended or delayed release of the ruxolitinib drug. However, according to a preferred embodiment of the present invention the pharmaceutical composition is an immediate release composition. Immediate, modified, controlled, sustained, prolonged, extended or delayed release pharmaceutical compositions are well known in the prior art and belong including their preparation to the general common knowledge of the skilled person.

Beside ruxolitinib free base the pharmaceutical composition according to the invention may comprise one or more additional pharmaceutical active ingredients. But, according to another preferred embodiment of the present invention the pharmaceutical composition ruxolitinib is the only active pharmaceutical ingredient contained in the composition.

In particular the dissolution rate of ruxolitinib free base can be improved, if the invented composition comprises a water soluble polymer. Thus, according to a further preferred embodiment of the present invention the pharmaceutical composition contains the ruxolitinib free base in admixture with a water soluble polymer. According to a preferred embodiment of the present invention water-soluble polymers are defined as those polymers of which at least 1.0 gram and preferably 2.0 grams dissolve in 100 grams of water at 25℃ at a pH of 7.

The dissolution rate of ruxolitinib free base can be further improved, if the invented composition comprises a water soluble polymer in which the ruxolitinib free base is dispersed. Hence, according to a further preferred embodiment of the present invention the pharmaceutical composition contains the ruxolitinib free base dispersed in a water soluble polymer.

The dissolution rate of ruxolitinib free base can be improved even more, if the invented composition comprises a water soluble polymer in which the ruxolitinib free base is molecularly dispersed. So, according to a further preferred embodiment of the present invention the pharmaceutical composition contains the ruxolitinib free base molecularly dispersed in a water soluble polymer.

In addition, the dissolution rate of ruxolitinib free base can be improved even more, if the invented composition contains the ruxolitinib free base as a solid solution of ruxolitinib free base in a water soluble polymer. Thus, according to a further preferred embodiment of the present invention the pharmaceutical composition contains the ruxolitinib free base as a solid solution of ruxolitinib free base in a water soluble polymer.

According to another preferred embodiment of the present invention the invented pharmaceutical composition is prepared by means of a process that comprises the steps of

- dissolving ruxolitinib free base and a water soluble polymer in a solvent to obtain a solution, and

- removing the solvent from said solution.

The invented pharmaceutical composition prepared by the use of said preparation steps ensures a sufficient dissolution rate of ruxolitinib free base from the pharmaceutical composition. In this context as a solvent organic solvents like alcohols, water or mixtures thereof can be used. For example, said ruxolitinib free base/water soluble polymer-solution can be obtained by dissolving ruxolitinib free base in ethanol, by dissolving the water soluble polymer in water and by mixing the resulting two solutions to a final solution, from which the solvent has to be removed.

According to another preferred embodiment of the present invention the water soluble polymer is selected from the group consisting of hydroxypropylcellulose (HPC) , hydroxyethylcellulose (HEC) , hydroxypropylmethylcellulose (HPMC) , methylcellulose (MC) , hydroxyethyl methylcellulose (HEMC) , sodium carboxymethylcellulose (CMC) . hydroxyethylcarboxymethylcellulose (HECMC) , hydroxypropyl carboxymethylcellulose (HPCMC) , hydroxypropylmethycellulose acetate succinate, cellulose acetate trimellitate, acrylic and methacrylic polymers and their copolymers, methacrylic acid -methylmethacrylate copolymer, polyaminoalkyl methacrylate-methacrylic esters copolymer, dimethylaminoethyl methacrylate -butylmethacrylate-methylmethacrylatecopolymer, vinylpyrrolidone-vinyl acetate copolymer, methylvinylether-maleic acid copolymer, polyethyleneglycol-caprolactame-vinylpyrrolidone copolymer. Said water soluble polymers can significantly increase the dissolution rate of ruxolitinib free base and can act also as a binder in order to give the invented pharmaceutical composition sufficient mechanical stability. In particular hydroxypropylcellulose (HPC) is a preferred water-soluble polymer in the frame of the present invention.

In another preferred embodiment the pharmaceutical composition is free of cellulose ester derivatives, nitrogenous polymers and polymers with unsaturated bonds. Such polymers are not recommended, since they may negatively affect dissolution and stability.

Pursuant to another preferred embodiment of the present invention the weight ratio of ruxolitinib free base and the water soluble polymer in the composition is from 2.0 to 0.1.

In accordance with another preferred embodiment of the present invention the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient that can be chosen from, for example, diluents, binders, disintegrants, lubricants, and glidants.

Diluents are fillers which are used to increase the bulk volume of a pharmaceutical composition. By combining a diluent with the ruxolitinib free base, the final product is given adequate weight and size to assist in production and handling.

The pharmaceutical composition of the present invention preferably contains at least one diluent.

Diluents are preferably used in an amount of from 15%to 95%, preferably from 50%to 90%by weight based on the total weight of the composition. Suitable examples of diluents to be used in accordance with the present invention include microcrystalline cellulose and lactose monohydrate.

In a preferred embodiment of the present invention, the diluents to be used are microcrystalline cellulose, lactose monohydrate or mixtures thereof.

The pharmaceutical composition of the present invention may also contain a binder. Binders ensure that pharmaceutical compositions can be formed having the desired or required mechanical strength. Binders which are suitable for use in accordance with the present invention include povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxyl methylcellulose. Binders are preferably used in an amount of from 1%to 20%by weight based on the total weight of the composition.

As already explained above, the water soluble polymer that can be contained in the invented composition can already have a binder function.

The pharmaceutical composition of the present invention may optionally contain a disintegrant. Disintegrants are added to a pharmaceutical composition to promote the breakup of the composition into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the active pharmaceutical ingredient. Suitable examples of disintegrants to be used in accordance with the present invention include crospovidone, sodium starch glycolate, croscarmellose sodium, and mixtures of any of the foregoing. Disintegrants preferably are used in an amount of from 1%to 25%by weight based on the total weight of the composition. A preferred disintegrant in the context of the present invention is sodium starch glycolate, in a preferred amount of from 1%to 5%by weight based on the total weight of the composition.

The pharmaceutical composition of the present invention may also contain a lubricant. Lubricants are generally used in order to reduce sliding friction. In particular, to decrease the friction at the interface between the blend to be encapsulated and dosator of the encapsulation machine. Suitable lubricants to be used in accordance with the present invention include magnesium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, talc and glycerine fumarate. A preferred lubricant in the frame of the present invention is magnesium stearate. The lubricant is preferably used in an amount of from 0.01%to 5%by weight based on the total weight of the composition, more preferred in an amount of from 0.01%to 0.05%by weight.

The pharmaceutical composition of the invention may also contain a glidant. Glidants enhance product flow by reducing interparticulate friction. A suitable example is colloidal silicon dioxide.

The pharmaceutical composition according to the present invention is a solid and thus can be for example in the form of a tablet, capsule, pill, granulate, powder and so on. However, according to a preferred embodiment of the present invention the pharmaceutical composition is a tablet, in particular a filmless tablet.

Pursuant to another preferred embodiment of the present invention the pharmaceutical composition is free of povidone. This means that the composition includes less than 0.1 wt. -%, more preferably less than 0.01 wt. -%povidone and even more preferably absolutely no povidone based on the total weight of the composition. It has been found that the absence of povidone in the composition can improve the stability of ruxolitinib free base.

According to another preferred embodiment of the present invention the pharmaceutical composition contains ruxolitinib free base in the range from 2 mg to 50 mg, in particular 5 mg, 10 mg, 15 mg, 20 mg or 25 mg ruxolitinib free base.

The present invention relates also to a process for the preparation of a pharmaceutical composition according to the invention comprising the following steps:

a) dissolving ruxolitinib free base in a solvent, preferably in an alcohol, water or a mixture thereof, to obtain a solution;

b) applying said solution on at least one pharmaceutically acceptable excipient to obtain a wetted excipient;

c) drying the wetted excipient.

According to a preferred embodiment of the process of the present invention step a) further comprises the dissolution of a water soluble polymer in the solvent or solution.

Pursuant to another preferred embodiment of the process of the present invention the process in step b) comprises the granulation of the at least one pharmaceutically acceptable excipient to obtain a granulate by means of the solution of step a) as granulation liquid, and characterized in that step c) comprises the drying of the resultant granulate.

According to another preferred embodiment of the process of the present invention in step b) the solution is applied on a fluidized bed of the at least one pharmaceutically acceptable excipient at an elevated temperature, preferably at a temperature from 30℃ to 50℃.

Comparative example 1

As comparative example the marketed5, 10, 15, 20 and (20 + 5) mg tablets have been analyzed.

According to the summary of product characteristics ofthe tablets contain ruxolitinib in form of the phosphate salt (e.g. the 20 mg tablets contain 20 mg ruxolitinib (free base) in form of the phosphate salt) as well as microcrystalline cellulose, magnesium stearate, colloidal anhydrous silica, sodium starch glycolate, povidone, hydroxypropyl cellulose and lactose monohydrate as pharmaceutical excipients.

The in-vitro dissolution rate of ruxolitinib of said tablets was analyzed by means of the paddle method (apparatus 2) according to the provision in Eur. Ph. (European Pharmacopoeia, 8^th edition, 7^th supplement, 2.9.3 , , dissolution test for solid oral dosage forms “, p. 7367-7375 (German version) ) at 50 rpm in 900 ml buffer at 37 ℃ at pH values of 1.2 (hydrochloric acid solution) 4.5 (acetate sodium acetate buffer) and 6.8 (phosphoric acid buffer) .

The results of the dissolution tests are shown in the following tables, wherein the infinity data correspond to stirring at 150 rpm for 15 min after the 45 min time point.

Table 1: dissolution mean values of5 mg tablets at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablets) ; the values in brackets are the RSD [%] (relative standard deviation))

Table 2: dissolution mean values of10 mg tablets at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablets) ; the values in brackets are the RSD [%] (relative standard deviation))

Table 3: dissolution mean values of15 mg tablets at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablets) ; the values in brackets are the RSD [%] (relative standard deviation) )

Table 4: dissolution mean values of20 mg tablets at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablets) ; the values in brackets are the RSD [%] (relative standard deviation) )

Table 5: dissolution mean values of20 mg + 5 mg tablets (one20 mg tablet and one5 mg tablet) at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablet pairs) ; the values in brackets are the RSD [%] (relative standard deviation) )

Moreover, the stability of20 mg tablets was investigated in view of the chemical stability of ruxolitinib, namely the original value directly after purchase of the tablets as well after storage in aluminium-aluminium packages under accelerated condition at 40℃/75 %relative humidity/15 days or at 60℃/75 %relative humidity/15 days. The results of the stability study are shown in the following Table 6:

Table 6: Stability of20 mg tablets

The data in Table 6 have been determined by means of high performance liquid chromatography and evaluated by using the area normalization method. The high performance liquid chromatography was conducted with the following parameters:

High performance liquid chromatography, chromatographic conditions:

column: Zorbax Eclipse XDB C18, 3.5 μm (150×4.6 mm) ;

mobile phase: Awater, B acetonitrile, linear elution (below)

detection wavelength: 220 nm;

velocity of flow: 1.0 ml/min

column temperature: 30 ℃;

test solvent: acetonitrile -water (1: 1) ;

test concentration: 250 μg/ml

Example 1

Ruxolitinib tablets as one embodiment of the solid oral pharmaceutical composition according to the invention with the following constitution have been prepared:

These tablets (with 5 mg, 10 mg, 15 mg and 20 mg Ruxolotinib free base) have been prepared according to a preparation process according to the present invention. In the following the preparation of the 20 mg Ruxolotinib free base tablets is described.

A granulation liquid was prepared by dissolving 27.94 g ruxolitinib free base (dihydrate) in 100 g of 95%ethanol to obtain a first solution, by dissolving 20 g of the hydroxypropyl cellulose in 150 g of purified water to obtain a second solution and by mixing said first and second solution to obtain the granulation liquid in form of a solution.

Said granulation liquid was sprayed on a fluidized bed of the microcrystalline cellulose, lactose monohydrate and sodium carboxymethyl starch with an atomization pressure of 3.0 bar and an inlet air temperature of 40℃. After spraying of the granulation liquid, the pipelines have been washed with 50 g of a 40 %ethanol/water solution, wherein said solution is also sprayed on the fluidized bed.

The resulting granules have been dried in the fluidized bed at a temperature of 40 ℃ to a LOD of 2.3 %.

The dried granules are mixed with colloidal silica, milled, sieved, lubricated with magnesium stearate and pressed into tablets having the same shape and hardness as the tablets of the comparative example.

The in-vitro dissolution rate of ruxolitinib from said tablets according to the invention have been determined according to the provision and conditions as mentioned under the item “comparative example 1” .

The results of the dissolution tests are shown in the following Tables 7 -11:

Table 7: dissolution mean values of the 5 mg ruxolitinib free base tablets at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablets) ; the values in brackets are the RSD [%] (relative standard deviation) )

Table 8: dissolution mean values of the 10 mg ruxolitinib free base tablets at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablets) ; the values in brackets are the RSD [%] (relative standard deviation) )

Table 9: dissolution mean values of the 15 mg ruxolitinib free base tablets at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablets) ; the values in brackets are the RSD [%] (relative standard deviation) )

Table 10: dissolution mean values of the 20 mg ruxolitinib free base tablets at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablets) ; the values in brackets are the RSD [%] (relative standard deviation) )

Table 11: dissolution mean values of the 25 mg ruxolitinib free base tablets at different pH values (volume 900 ml; 50 rpm; N=3 (number of tablet pairs) ; the values in brackets are the RSD [%] (relative standard deviation) )

A comparison of the dissolution data of the comparative example 1 with the dissolution data of the present example according to the invention reveals that the dissolution rates of the composition according to the invention are significantly higher at all investigated pH values than those of the corresponding comparative prior art examples.

Moreover, the stability of tablets of the present example 1 was investigated in view of the chemical stability of ruxolitinib, namely the original value directly after the preparation of the tablets as well after storage in aluminium-aluminium packages under accelerated conditions at 40℃/75 %relative humidity/15 days or at 60℃/75 %relative humidity/15 days. The results of the stability study were determined by area normalization of peaks obtained by HPLC and are shown in the following Table 12:

Table 12: stability of 20 mg ruxolitinib free base formulation

The data in Table 12 have been determined and evaluated with methods as described in the above chapter “Comparative example 1” .

A comparison of the stability data of the comparative example 1 with the stability data of example 1 shows clearly that the stability of ruxolitinib is significantly higher in the composition according to the present invention. This comparison is also shown in Table 13 below.

Table 13: comparison of stability data

Claims

A solid oral pharmaceutical composition comprising ruxolitinib as an active pharmaceutical ingredient wherein ruxolitinib is present in the form of its free base.
The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is an immediate release composition.
The pharmaceutical composition according to one of the preceding claims, characterized in that ruxolitinib is the only active pharmaceutical ingredient contained in the composition.
The pharmaceutical composition according to one of the preceding claims, characterized in that the composition contains the ruxolitinib free base in admixture with a water soluble polymer.
The pharmaceutical composition according to one of the preceding claims, characterized in that the composition contains the ruxolitinib free base dispersed in a water soluble polymer.
The pharmaceutical composition according to one of the preceding claims, characterized in that the composition contains the ruxolitinib free base molecularly dispersed in a water soluble polymer.
The pharmaceutical composition according to one of the preceding claims, characterized in that the composition contains the ruxolitinib free base as a solid solution of ruxolitinib free base in a water soluble polymer.
The pharmaceutical composition according to one of the preceding claims, characterized in that the composition is prepared by means of a process that comprises the steps of

- dissolving ruxolitinib free base and a water soluble polymer in a solvent to obtain a solution, and

- removing the solvent from said solution.
The pharmaceutical composition according to one of the claims 4 to 8, characterized in that the water soluble polymer is selected from the group consisting of hydroxypropylcellulose (HPC) , hydroxyethylcellulose (HEC) , hydroxypropylmethylcellulose (HPMC) , methylcellulose (MC) , hydroxyethyl methylcellulose (HEMC) , sodium carboxymethylcellulose (CMC) .

hydroxyethylcarboxymethylcellulose (HECMC) , hydroxypropyl carboxymethylcellulose (HPCMC) , hydroxypropylmethycellulose acetate succinate, cellulose acetate trimellitate, acrylic and methacrylic polymers and their copolymers, methacrylic acid -methylmethacrylate copolymer, polyaminoalkyl methacrylate-methacrylic esters copolymer, dimethylaminoethyl methacrylate -butylmethacrylate-methylmethacrylatecopolymer, vinylpyrrolidone-vinyl acetate copolymer, methylvinylether-maleic acid copolymer, polyethyleneglycol-caprolactame-vinylpyrrolidone copolymer.
The pharmaceutical composition according to one of the preceding claims, characterized in that the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.
The pharmaceutical composition according to one of the preceding claims, characterized in that the pharmaceutical composition is a tablet.
The pharmaceutical composition according to one of the preceding claims, characterized in that the composition is free of povidone.
The pharmaceutical composition according to one of the preceding claims, characterized in that the composition contains ruxolitinib free base in the range from 2 mg to 50 mg.
The pharmaceutical composition according to one of the preceding claims, characterized in that the composition contains 5 mg, 10 mg, 15 mg, 20 mg or 25 mg ruxolitinib free base.
A process for the preparation of a pharmaceutical composition according to one of the preceding claims comprising the following steps:

d) dissolving ruxolitinib free base in a solvent to obtain a solution;

e) applying said solution on at least one pharmaceutically acceptable excipient to obtain a wetted excipient;

f) drying the wetted excipient.
The process according to one of the preceding claims, characterized in that step a) further comprises the dissolution of a water soluble polymer in the solvent or solution.
The process according to one of the preceding claims, characterized in that step b) comprises the granulation of the at least one pharmaceutically acceptable excipient to obtain a granulate by means of the solution of step a) as granulation liquid, and characterized in that step c) comprises the drying of the resultant granulate.
The process according to one of the preceding claims, characterized in that in step b) the solution is applied on a fluidized bed of the at least one pharmaceutically acceptable excipient at an elevated temperature.