WO2014174073A1

WO2014174073A1 - Sustained release formulations of tofacitinib

Info

Publication number: WO2014174073A1
Application number: PCT/EP2014/058448
Authority: WO
Inventors: Zrinka Abramovic; Uros Klancar; Bostjan MARKUN; Igor Legen; Klemen Naversnik
Original assignee: Sandoz Ag
Priority date: 2013-04-26
Filing date: 2014-04-25
Publication date: 2014-10-30

Abstract

Sustained release formulations comprising tofacitinib or a pharmaceutically acceptable salt thereof show reduced drug level fluctuation in plasma, pH independent release, mechanical robustness and no food effect and are suitable for once daily administration.

Description

SUSTAINED RELEASE FORMULATIONS OF TOFACITINIB

FIELD OF INDUSTRIAL APPLICABILITY

The present invention relates to sustained release formulations for oral administration comprising tofacitinib or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE DISCLOSURE

Tofacitinib, 3- {(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- amino]-piperidin-l -yl}3-oxo-propionitrile, is an inhibitor of the enzyme Janus Kinase 3 (JAK3) indicated for treatment of rheumatoid arthritis. Its synthetic preparation is disclosed in WO 02/096909 Al, WO 03/048162 Al and WO 2007/012953 A2.

The recommended dose is 5 mg given orally twice daily. The FDA label contains a black-box warning alerting about the risk of serious side effects, such as serious infections (tuberculosis, invasive fungal and viral infections), lymphoma and other malignancies. Serious concerns about the risk of malignancy with 10 mg dose were raised by the FDA and eventually this dosage was not approved. According to the prescription label the risk of serious side effects increases in a dose and time-dependant fashion. An increased frequency of side effects of drugs is usually observed when peak plasma concentrations exceed a certain level. Tofacitinib exhibits linear pharmacokinetics, with the systemic exposure (AUCM) and peak plasma concentration (Cmax) increasing in proportion to the dose in the dose range of 1 to 100 mg.

Therefore peak plasma concentrations of the 10 mg tofacitinib dose are approximately two times higher than those of the 5 mg dose and they may be too high for a safe drug administration.

Plasma concentration of Tofacitinib after oral administration is directly related to the release rate of the drug in the gastrointestinal tract. With an immediate release (IR) formulation a fast drug release is achieved giving rise to high peak plasma concentrations which are not sustained through a longer period of time.

Sustained peak plasma concentrations can theoretically be achieved by means of sustained release matrix systems. However, when such systems are made of hydrophilic polymers, they seldom provide pH independent drug release of pH-dependent soluble drugs and they are normally incapable of attaining zero-order release except for practically insoluble drugs. From FDA published data it can be seen that the aqueous solubility of Tofacitinib citrate is pH-dependent with higher solubility at low pH and drastically decreased solubility at pH above 3.9. pH dependent solubility can lead to pH-dependent in vivo drug release from sustained release matrices. Drug release varies as a function of movement through segments of the gastrointestinal tract with different pH. This can lead to inefficient drug delivery and bigger inter-subject variability, since pH in the gastrointestinal tract varies significantly between subjects. Sustained release formulations that would provide pH independent drug release throughout whole gastrointestinal tract are very desirable.

For extended release formulations, the robustness of drug release is also critical, since mechanical stress applied to matrix tablets during gastrointestinal transit may lead to faster disruption of the gel layer and influence the plasma drug concentrations over time. This can change the therapeutic efficacy and safety. Different mechanical stress can be exerted on matrix tablets due to variety of gastrointestinal conditions. In a fasting state, the stress on the tablet mainly depends on the migrating myoelectric complex (MMC), which cycles every 90 to 120 min and normally starts in the stomach. The movement of tablets during this phase is rapid and tablets are subject to increased mechanical stress, especially during gastric emptying. Additionally, gastrointestinal motility is elevated during and after food intake. This causes even greater mechanical stress on pharmaceutical compositions. There is also evidence that food intake stimulates the transport of gastrointestinal content from the terminal small intestine into the colon, a mechanism that is known as gastro-ileal or gastro-ileocecal reflex, which can again exert elevated mechanical stress on the matrix tablet.

WO 2012/100949 Al discloses oral dosage forms for modified release comprising Tofacitinib. Such formulations are disclosed in very general terms and give no direction to the skilled man for preparing sustained formulations with adequate release profile and properties. 10 examples of specific formulations are also provided, but no dissolution test results. When reproduced, such formulations showed poor release properties, liberating the active ingredient too fast for any practical application, and proved not to be resistant to mechanical stress.

There is thus still the need for Tofacitinib formulations that are mechanically robust and do not show a food effect. There is also the need for Tofacitinib formulations that attain a zero order release profile.

In addition there is still the need for Tofacitinib formulations that provide reduced drug level fluctuation in plasma, resulting in diminished side effects. There is also the need for an improved dosage regimen to increase patient compliance. SUMMARY OF THE DISCLOSURE

The present disclosure provides a sustained release formulation for oral administration comprising tofacitinib or a pharmaceutically acceptable salt thereof, a hydrophilic polymer and an alkalizing agent, wherein the pH at 25 °C of a 1% weight/volume water solution or dispersion of the formulation is between 5.5 and 11. It further provides a sustained release formulation for oral administration comprising tofacitinib or a pharmaceutically acceptable salt thereof and a polymer, wherein the hydrophilic polymer is either a cellulose derivative with a viscosity between 1000 and 150000 mPa-s, a carrageenan with a viscosity of 5 mPa-s or higher or a mixture thereof. A once daily dosage regimen of the formulations of the invention, preferably for the treatment of rheumatoid arthritis, is also disclosed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates simulated plasma profiles after twice daily administration of immediate release formulations containing 5 mg and 10 mg of tofacitinib (full and dashed line) and once daily administration of a sustained release formulation containing 11 mg of Tofacitinib (dotted line).

FIG. 2 illustrates the stability profile of Tofacitinib citrate at various pH.

FIG. 3 illustrates the dissolution test results of the formulations of example 1 (25% HPMC without alkalizing agent) - top - and example 15 (60 % of HEC without alkalizing agent) - bottom - using apparatus 2 at 100 rpm and dissolution media with different pH: dashed line at pH 1.2 + 6.8; full line at pH 6.8.

FIG. 4 illustrates the dissolution test results of the formulation of example 2 (25% HPMC with insoluble alkalizing agents) using apparatus 2 at 100 rpm and dissolution media with different pH: dashed line at pH 1.2 + 6.8; full line at pH 6.8.

FIG. 5 illustrates the dissolution test results of the formulations of example 3 (25% HPMC with 9 % sodium citrate) - top - and of example 5 (25%> HPMC with 48 % sodium citrate) - bottom -using apparatus 2 at 100 rpm and dissolution media with different pH: dashed line at pH 1.2 + 6.8; full line at pH 6.8.

FIG. 6 illustrates the dissolution test results of the formulation of example 8b (60% HEC with 25 % sodium citrate) using apparatus 2 at 100 rpm and dissolution media with different pH: dashed line at pH 1.2 + 6.8; full line at pH 6.8.

FIG. 7 illustrates the dissolution test results of the formulations of example 9 (25%> HPMC with calcium hydrogen phosphate dihydrate) - top - and 10 (25% HPMC with calcium sulphate) - bottom - using apparatus 2 at 100 rpm and dissolution media with different pH: dashed line at pH 1.2 + 6.8; full line at pH 6.8.

FIG. 8 illustrates the dissolution test results of the formulations of examples 11-13 (15 % circle, 25 % triangle and 35 > diamond HPMC) with (dotted lines) or without mechanical stress (full lines) using apparatus 1, 100 RPM, 900 ml of pH 6.8 medium.

FIG. 9 illustrates the dissolution test results of the formulations of examples 14 and 15 (30 % circle, 60% diamond HEC) with (dotted lines) or without mechanical stress (full lines) using apparatus 1, 100 RPM, 900 ml of pH 6.8 medium.

FIG. 10 illustrates the dissolution test results of the formulations of example 2 (25 % HPMC with insoluble alkalizing agents) with (dotted lines) or without mechanical stress (full lines) using apparatus 1 , 100 RPM, 900 ml of pH 6.8 medium.

FIG. 11 illustrates the dissolution test results of the formulations of example 17 (HEC + carrageenan) using apparatus 2 at 100 rpm and dissolution media with different pH (dotted line pH 1.2 + 6.8; full line 6.8 ) - top - and with (dotted line) or without mechanical stress (full line) using Apparatus 1, 100 RPM, 900 ml of pH 6.8 medium - bottom -.

FIG. 12 illustrates a schematic view of a hydrophilic matrix bilayer tablet comprising the active pharmaceutical ingredient (API) tofacitinib and a sustained release (SR) polymer.

DEFINITIONS

As used herein sustained release formulation refers to extended-release formulations as defined by the USP35-NF30 S2, Chapter 1151. Sustained release formulations make the active substance available over an extended period of time following ingestion. Sustained release formulations according to the invention release not more than 30% of Tofacitinib within 1 hour and at least 80 %> of tofacitinib between 4 and 18 hours using apparatus 2 USP at 100 rpm for 2 hours in 500 ml of 0.1 M hydrochloric acid medium with 2 g/1 of sodium chloride (pH= 1.2), followed by 900 ml of pH 6.8 medium.

As used herein hydrophilic polymer refers to water soluble polymeric materials that in contact with an aqueous environment swell and form a gel matrix. They are characterized by the presence of polar groups attached to the main polymer backbone of the molecule (see C.A. Finch: Hydrophilic polymers. In: R.W.Dyson (ed.) Specialty Polymers; Blackie&Son Ltd 1987).

As used herein alkalizing agent refers to any agent that counteracts or neutralizes acidity and/or increases the concentration of hydroxide anions (OH ) in water.

DETAILED DESCRIPTION OF THE DISCLOSURE

An ideal sustained release formulation releases the drug with a constant rate between 4 and 18 hours, preferably over 16 hours (zero-order release), and provides effective drug plasma concentration levels over a longer period of time, while at the same time not exceeding the peak plasma concentration of the immediate release formulation, as shown in FIG.l . This results in improved safety and efficacy of the drug product.

The plasma profiles in FIG.l were simulated by solving one-compartment pharmacokinetic differential equation - dA/dt = r_a(t)-k_eiA - where A is the amount of drug in plasma, r_a(t) in vivo dissolution/absorption rate and k_d elimination constant of drug from plasma. The plasma concentration is then obtained by dividing the amount of drug A by the volume of distribution V_d. The pharmacokinetic parameters were obtained from "NDA 203214 (Tofacitinib), Clinical Pharmacology and Biopharmaceutics Review (s), FDA": V_d=87 L, k_d=0.23/h I_m = 3 h). The drug is completely absorbed with about 20% of first-pass elimination. The absorption rate for the immediate release formulation is dictated by the transit of drug from the stomach into the intestine, where the absorption takes place. The dissolution rate for the sustained release formulation was chosen to mimic the preferred constant (i.e. zero-order) release over 16 hours.

Such sustained release formulation has to be carefully developed to provide drug release that would give optimal plasma concentrations and at the same time be robust enough to prevent dose dumping or a high burst effect. Both phenomena cause the premature and exaggerated release of a drug that can greatly increase its concentration in the body and thereby produce adverse effects. Dose dumping can be a consequence of poor sustained release formulation and several in vivo factors such as mechanical stress in the gastrointestinal tract (i.e. passage of formulation from the stomach into the duodenum and from the ileum to the colon), presence of food or alcohol in the stomach, differences in pH along the

gastrointestinal tract. Burst release is a phenomenon where an initial large bolus of drug is released before the release rate reaches a stable profile. It is related to some formulations (e.g. hydrophilic matrix systems) and well soluble drugs (S. B. Tiwari, A. R. Rajabi-Siahboomi, "Extended-release oral drug delivery technologies: Monolithic Matrix systems ", Methods in Molecular Biology, Drug Delivery Systems, Vol. 437, 217-243.).

Therefore one object of the present invention is the provision of Tofacitinib formulations causing reduced drug level fluctuation in plasma.

Another object of the present invention is the provision of formulations of Tofacitinib with reduced side effects.

Another object of the present invention is the provision of Tofacitinib formulations with pH independent release avoiding a burst at the acidic pH of the stomach.

Another object of the present invention is the provision of Tofacitinib formulations that are mechanically robust.

Another object of the present invention is the provision of Tofacitinib formulations that prevent dose dumping or a high burst effect.

Another object of the present invention is the provision of Tofacitinib formulations that do not show a food effect.

Another object of the present invention is the provision of Tofacitinib formulations with a zero order release profile.

Another object of the present invention is the provision of a dosage regimen for Tofacitinib with improved patient compliance.

One embodiment of the present invention is a sustained release formulation for oral administration comprising tofacitinib or a pharmaceutically acceptable salt thereof, a hydrophilic polymer and an alkalizing agent, wherein the pH at 25°C of a 1% weight/volume water solution or dispersion of the formulation is between 5.5 and 11.

Another embodiment of the present invention is a sustained release formulation for oral administration comprising tofacitinib or a pharmaceutically acceptable salt thereof and a hydrophilic polymer, wherein the hydrophilic polymer is either a cellulose derivative with a viscosity between 1000 and 150000 mPa-s, a carrageenan with a viscosity greater than 5 mPa-s or a mixture thereof.

Formulations of the invention are matrix formulations where a rate-controlling hydrophilic polymer forms a matrix through which the drug is dissolved or dispersed. Such formulations can be in the form of tablets, minitablets (that can be further inserted in capsules), pellets and granules, preferably in the form of tablets. Tablets can be monolayer or multilayer, with tofacitinib included in one or more layers. Tablets can be further coated with a functional or a non-functional coating.

In a preferred embodiment the formulations of the invention contain tofacitinib citrate. In a preferred embodiment the formulations of the invention comprise between 5 and 25 mg, more preferably between 20 and 22 mg or between 10 and 12 mg of tofacitinib or a pharmaceutically acceptable salt thereof, the amount being calculated based on tofacitinib free base.

In a preferred embodiment the formulations of the invention comprise tofacitinib or a pharmaceutically acceptable salt thereof in an amount between 10 and 12 mg expressed as tofacitinib free base and, wherein such formulations are administered once a day, the Cmax of tofacitinib measured in plasma is below 35 ng/ml, preferably between 25 and 35 ng/ml.

Hydrophilic polymers include natural gums and polysaccharides (such as alginates, xanthan, carrageenan, locust bean gum, chitosan, guar gum, pectin, crossed-linked high amylose starch, gelatine), semisynthetic materials (such as cellulose derivatives, propylene glycol alginate) and synthetic materials (such as polyethylene oxide and homo- and copolymers of acrylic acid). Preferred hydrophilic polymers are cellulose derivatives (such methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose sodium), carrageenan and mixtures thereof. Especially preferred hydrophilic polymers are hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), carrageenan and mixtures thereof.

The amount of hydrophilic polymer is preferably between 15 and 80%, preferably between 20 and 70%, more preferably between 25 and 60%> w/w, based on the total weight of the pharmaceutical composition excluding any coating. If the hydrophilic polymer is present in insufficient amounts the dissolution profile is either too fast or the drug release is more easily influenced by mechanical stress. If the hydrophilic polymer is present in excessive amounts, the drug release is too slow, e.g. it could take more than 24 hours to release the drug; in addition the manufacturing of the composition may be very difficult (see figures 8 and 9).

In a preferred embodiment the hydrophilic polymer is hydroxypropyl methylcellulose (HPMC) in an amount between 20 and 60%> w/w, more preferably between 25 and 50% w/w, based on the total weight of the pharmaceutical composition excluding any coating.

In another preferred embodiment the hydrophilic polymer is hydroxyethyl cellulose (HEC) in an amount between 30 and 70% w/w, more preferably between 40 and 60%> w/w, based on the total weight of the pharmaceutical composition excluding any coating.

In another preferred embodiment the hydrophilic polymer is a carrageenan in an amount between 20 and 70 %, more preferably between 40 and 60% w/w, based on the total weight of the pharmaceutical composition excluding any coating.

In a preferred embodiment the formulations of the invention comprise an alkalizing agent in order to control the solubility of the active substance and thus obtain a pH independent drug release. The alkalizing agents of the invention lower the dissolution rate at pH 1.2, thus preventing the burst release due to tofacitinib ^'s greater solubility in acidic media. Although tofacitinib citrate is a very stable substance in the solid state, its solution is sensitive to alkaline pH, especially at pH 10 and above (Figure 2). Due to such instability, alkalizing agents for tofacitinib formulations must be chosen very carefully during formulation development. In order to provide at the same time pH independent drug release and adequate stability of the drug substance, the pH at 25°C of a 1% weight/volume water solution or dispersion of the formulation must be between 5.5 and 11, preferably between 6 and 10.5.

The alkalizing agents may be soluble as well as insoluble. Examples of alkalizing agents are aluminum hydroxide, bentonite, kaolin, calcium carbonate, calcium silicate, calcium hydrogen phosphate, calcium sulphate, calcium chloride, calcium lactate, sodium hydrogen carbonate, sodium stearate, sodium citrate, sodium phosphate, sodium borate, sodium lactate, sodium hyaluronate, sodium acetate, monosodium glutamate, sodium tartrate, attapulgite, potassium citrate, potassium hydrogen carbonate, potassium chloride, potassium hydrogen phosphate, tromethamine, zinc oxide, magnesium silicate, magnesium aluminum silicate, magnesium oxide, magnesium hydroxide, magnesium citrate, magnesium gluconate, dextrin, carboxymethyl cellulose sodium, carrageenan, xanthan gum and starch.

Preferred alkalizing agents are selected from the group consisting of salts of inorganic and organic acids. More preferred alkalizing agents are selected from the group consisting of metal oxides, metal hydroxides, salts of weak acids and some polymers that give pH of solution/dispersion in stated range. Even more preferred alkalizing agents are selected from the group consisting of magnesium oxide, calcium carbonate, calcium silicate, potassium citrate and sodium citrate and mixtures thereof. Most preferred alkalizing agents are selected from the group consisting of magnesium oxide, calcium carbonate, sodium citrate and combinations thereof. In a particularly preferred embodiment, alkalizing agents are selected from the group consisting of potassium citrate, sodium citrate and combinations thereof.

The amount of alkalizing agent should be sufficient to increase pH of a tablet above 5.5 and thus decrease the drug release in acidic media while at the same time providing a stable formulation. Preferably such amount is between 5 and 60% w/w, more preferably between 8 and 50 %>, based on the total weight of the pharmaceutical composition excluding any coating. Tofacitinib release form hydroxypropyl methylcellulose matrix tablet is faster at pH 1.2 than at pH 6.8 (figure 3 - top). Similar drug release trend was observed also for Tofacitinib formulation with

hydroxyethylcellulose as a matrix forming polymer (figure 3 - bottom). This pH dependent drug release is most likely a consequence of pH dependent solubility of tofacitinib. Sustained release formulations that show pH independent drug release of tofacitinib citrate are prepared by incorporation of the alkalizing agents of the invention. By this approach the local pH within the tablet is modified and similar dissolution profiles are obtained in phosphate buffer at 6.8 pH and hydrochloric acid dissolution medium at pH 1.2.

Table 1 : pH and stability of tofacitinib formulations of the examples

The addition of the alkalizing agents of the invention successfully diminishes the initial burst release of tofacitinib from matrix formulations at pH 1.2 and a similar drug release is obtained regardless of the pH of the medium. In a particularly preferred embodiment, calcium carbonate, magnesium oxide and calcium silicate alone or in combination successfully prevent the burst release in acidic medium (figure 4, example 2). In another particularly preferred embodiment sodium citrate is used (figure 5 and 6). Formulations with different quantities (9-48 %) of sodium citrate (examples 3-5) enable comparable drug release regardless of the pH of the medium (Figure 5). On the other hand some formulations with calcium hydrogen phosphate or calcium sulfate do not show pH independent drug release (examples 9-10, Figure 7). This is unexpected since the pH of a 10% slurry of calcium sulfate is 7.3 for the dihydrate and 10.4 for anhydrous material and the pH of a calcium hydrogen phosphate dihydrate slurry is above 7 (both data according to Handbook of pharmaceutical excipients, 7th Ed.). Surprisingly, when dissolving the above mentioned formulations in water to reach a concentration of 1 % w/v on the solution/dispersion at 25 °C and measuring the pH of the resulting solution/dispersion, the pH of the formulation of example 10 is similar to that of an HPMC tablet without alkalizing agents (4.2 and 4.0 respectively) and the pH of the formulation of example 9 has a somewhat higher pH, but still below the one needed to obtain a pH independent release.

However a high pH within the tablet can negatively affect tofacitinib stability; therefore the stability of formulations with alkalizing agents was tested and compared to that of formulations without alkalizing agent (Table 1). Amounts of degradation products were measured at two stress conditions: 80°C and 60°C / 50% RH for one week. The stability of formulations containing sodium citrate was comparable to that of formulations without any alkalizing agents, thus making sodium citrate the most preferred alkalizing agent of the invention. Stability of formulations containing calcium carbonate, calcium silicate and magnesium oxide is slightly poorer, but acceptable long term stability can be expected notwithstanding a high pH of the tablet (10.5).

The viscosity of gel layer formed on the matrix in contact with water affects the erosion rate and consequently the drug release from the matrix formulation as well as determines the gel-layer robustness. The viscosity of the hydrophilic polymers determines the viscosity of the formed gel layer.

In a preferred embodiment the hydrophilic polymer is a cellulose polymer with a viscosity between 1000 and 150000 mPa-s, preferably between 2000 and 120000 mPa-s, most preferably between 2000 and 100000 mPa-s.

In a particularly preferred embodiment, the hydrophilic polymer is hydroxypropyl methylcellulose with a viscosity between 1000 and 140000 mPa-s. Such HPMC is available, for example, as Methocel® K4M or Kl 00M grade from Dow Chemical.

In a particularly preferred embodiment, the hydrophilic polymer is hydroxyethylcellulose with a viscosity between 1000 and 150000 mPa-s. Such HEC is available, for example, as Natrosol® 250 M, H or HH grade from Aqualon. In a particularly preferred embodiment the hydrophilic polymer is a carrageenan with a viscosity above 5 mPa-s, more preferably between 5 and 750 mPa-s. Most preferably lambda and iota carrageenans are used.

Table 2: Tofacitinib release from matrix tablets with the composition of example 12 where only the viscosity grade of HPMC is varied, with (MS) or without mechanical stress (No MS) using Apparatus 1 , 100 RPM, 900 ml of pH 6.8 medium.

It should be noted that in the reference example with 100 mPa-s HPMC (Methocel Kl 00 LV) more than 80 % of tofacitinib is released in 4 h.

Table 3: Tofacitinib release from hydrophilic cellulose matrix tablets with the composition of example 15 where only the viscosity grade of HEC is varied, with (MS) or without mechanical stress (No MS) using Apparatus 1, 100 RPM, 900 ml of pH 6.8 medium.

In a particularly preferred embodiment, the formulations of the invention show a pH independent drug release and are at the same time mechanically robust. The formulation of example 2 when tested according to discriminatory dissolution method for mechanical robustness shows that the addition of the alkalizing agents of the invention does not negatively effects the resistance of the formulation to mechanical stress (Figure 10).

Formulations prepared with mixtures of cellulose and carrageenan polymers are especially preferred. A particularly preferred embodiment of the present invention relates to formulations comprising hydroxyethylcellulose and carrageenan, which shows characteristics superior to those of other sustained release formulations, i.e. pH independent drug release, zero-order drug release and high robustness to mechanical stress.

The solubility of the drug in the polymeric matrix is a critical property that defines the drug release mechanism. For more soluble drugs the release is more diffusion controlled, for drugs with lower solubility the release is erosion controlled. Drug release profiles for hydrophilic matrices are first order for highly soluble drug or zero-order for practically insoluble drugs. To obtain more zero-like drug release also for more soluble drugs like tofacitinib is more challenging with matrix formulations. A particularly preferred embodiment consists of bilayer tablets. A hydrophilic polymer and Tofacitinib are combined in a first layer and an additional API free layer is applied on only one side of the first layer. The drug release from the first layer is restricted by the second layer and an initial burst effect is reduced. Several formulations of the invention were prepared with different hydrophilic polymers incorporated in the second layer to achieve a zero-order drug release.

For comparison and to evaluate the release mechanism we calculated Korsmeyer-Peppas exponent n and release rate constant k by fitting the dissolution curves into equation:

Q (t) = ktⁿ

Q (t) is the percentage of drug released at a given time point t, k is release rate constant.

The exponent n can be used as a criterion to evaluate the release-mechanism kinetics and usually assumed values between 0.45 and 0.89 (for cylindrical shapes). When n is equal to 0.89, the release kinetic is of zero order, and hence, with values for n approaching 0.89, the dissolution profile of a drug becomes progressively more linear. From calculated values n it is clearly evident that the release mechanism in case of bilayer tablets is more linear compared to standard HPMC matrix tablet, as in all bilayer tablets n is greater compared to basic HPMC matrix tablet. Drug release rate is also slower which is reflected in the calculated release rate constant k (Table 4).

Table 4: Exponent n and release rate constant k for different formulations

Formulation n k

Example 16 A 0.581 15.49

Example 16 B 0.707 12.60

Example 16 C 0.615 14.16

Example 12 0.501 24.98

Bilayer tablets were also tested for mechanical robustness. It is crucial from the safety aspect for patient that both layers are adhered well to each other and do not separate during tablet manipulation (packaging operation, taking form blister packaging or even in the gastrointestinal tract). Separation of both layers could lead to faster drug release and higher Cmax plasma concentrations. We have showed that mechanical stress during dissolution testing that simulates mechanical stress in the gastrointestinal tract does not affect the release of tofacitinib form tested tablets Table 5.

Table 5: Tofacitinib release from bilayer tablets of example 16 (25% HPMC in first layer) with different polymers in the second layer (A - HPMC, B - PEO, C - HEC) with (MS) or without mechanical stress (No MS) using apparatus 1, 100 RPM, 900 ml of pH 6.8 media

The formulations of the invention can be prepared either with wet or dry granulation or, in the case of tablets, with direct compression. In case of wet granulation low shear, high shear as well as fluid bed granulation techniques can be used. For wet granulation organic solvents, aqueous solution or pure water may be utilized to prepare granulating solution. The tablets were compressed using ordinary tableting equipment. The size of a tablet can range from 2 to 20 mm, preferably from 8 to 13 mm for normal tablets and from 2 to 5 mm for mini tablets. Tablets can be further coated. Coating can either modulate the drug release or just provide better tablet recognition by patient (non-functional coating). In case of mini tablet they can be optionally encapsulated.

Formulations of the invention can further comprise further excipients, preferably selected from the group consisting of fillers, disintegrants, binders, lubricants, glidants, coloring agents and coating agents.

Advantages

The formulations of the invention attain pH independent drug release avoiding a burst at the acidic pH of the stomach, are mechanically robust and do not show a food effect. They also prevent dose dumping or a high burst effect. They cause reduced drug level fluctuation in plasma and thus present reduced side effects. They are suitable for once-daily administration regimen and allow for improved patient compliance.

Viscosity measurement

As used herein the viscosity of a hydrophilic polymer refers to the viscosity of a water solution containing 2 % of the hydrophilic polymer calculated on a dry basis and measured with a Brookfield viscometer at 20°C, according to the method disclosed in the USP35-NF30 S2, Chapter Hypromellose.

As used herein the viscosity of a carrageenan refers to the viscosity of a water solution containing 1.5 % of the carrageenan and measured using a rotational viscometer at 75°C, according to the method disclosed in the USP35-NF30 S2, Chapter Carrageenan.

Drug release testing

To evaluate the mechanical susceptibility of matrix formulations, a discriminatory dissolution method was used, which simulates gastrointestinal mechanical stress and transition through pylorus and is thus suitable to detect burst release for extended release formulations. The test was performed using Apparatus 1 (basket method), 100 rpm and 900 ml phosphate buffer medium at pH 6.8. After lh 30 minutes from the beginning of the test formulations were transferred into plastic tubes containing 5 ml of medium and 15 glass beads of 8 mm diameter and were then shaken for 10 minutes on a laboratory shaker at 300 strokes per minute. Afterwards formulations were transferred back to baskets and the dissolution test continued through the remaining sampling time points. Dissolution profiles obtained from this test were compared to profiles obtained from an analogous test without the glass beads manipulation phase. To evaluate the influence of alkalizing agents, formulations were tested with a pH simulation test (pH 1.2

- pH 6.8) and the resulting dissolution profiles compared to the dissolution profiles of tests performed at pH 6.8 only. The smaller the difference between these 2 profiles, the bigger the alkalizing agent efficacy. Simulation test was performed using Apparatus 2 (paddle method) at 100 rpm with JP basket sinkers to prevent floating. The acid phase was performed for 2 hours in 500 ml of 0.1 M hydrochloric acid medium with 2 g/1 of sodium chloride (pH= 1.2). After 2 hours the medium was replaced with 900 ml of phosphate buffer at pH 6.8 and the test continued through the remaining time points.

Stability testing

Tofacitinib degradation products were followed by high performance liquid chromatography.

Formulations were dissolved in a mixture of 40 w/w% methanol in water to achieve a concentration of 0.2 mg/ml of tofacitinib. The sample solution was injected into an HPLC system with a HSS T3 column (1.7 micrometer particles) using binary gradient elution. Mobile phase A consisted of 0.1% trifluoroacetic acid in water and mobile phase B consisted of 50% vol. mixture of acetonitrile and mobile phase A. Gradient elution was performed according to the following program: mobile phase A (%) / time (min): 80%>/0min; 0%>/8min; 80%>/8.5min. The detector was set to a wavelength of 290 nm and impurities quantitated as area percentage with no response factors applied.

Stability of formulations was monitored by exposing them to two stress conditions:

- in a closed glass vial at 80°C for 7 days,

- in an open vial at 60°C and 50 % relative humidity for 7 days.

After storage in the above mentioned conditions, formulations were analyzed and the amounts of degradation products measured by HPLC. The extent of degradation was determined by subtracting the total amount of degradation products of a non-stressed (control) sample from the total amount of degradation of a stressed sample. pH stability profile of Tofacitinib citrate was determined in the following manner: one ml of tofacitinib citrate solution (2 mg/ml) was pipetted into a 10 ml beaker. To this solution, 2 ml of a buffer solution was added and left to stand overnight (20-25°C, dark). Samples were then neutralized (if needed), filled to the 10 ml mark with solvent and analyzed by HPLC under the conditions described for monitoring degradation products.

Tofacitinib plasma concentration measurement

Tofacitinib is extracted from sodium heparinized human plasma by 96-well solid phase extraction. Before the extraction, radiolabeled tofacitinib is added as an internal standard. The samples are eluted with 13% NH₄OH in methanol, evaporated to dryness and reconstituted with 50% methanol in water. The reconstituted sample is injected into an LC/MS/MS system using a Synergi Polar-RP column with a mobile phase of 40% 10 mM ammonium acetate and 60%> methanol (with 0.05%> formic acid).

The following non- limiting examples are illustrative of the disclosure.

EXAMPLES

Examples 1-2

Table 6: Hydrophilic cellulose (HPMC) matrix tablets without (example 1) and with (example 2) insoluble alkalizing agents

Core function example 1 example 2 mg/tablet mg/tablet

Tofacitinib citrate active 35.53 35.53

Hydroxypropyl methylcellulose matrix polymer 100.00 100.00

(type 2208 USP)*

Sprayed dried lactose filler 160.47 90.47

Microcrystalline cellulose filler 100.00 25.00

Calcium carbonate alkalizing agent - 112.00

Magnesium oxide alkalizing agent - 10.00

Calcium silicate alkalizing agent - 23.00

Magnesium stearate lubricant 4.00 4.00

Total 400.00 400.00

* 90 w/w % of 100000 mPa-s viscosity grade (Methocel K100M Premium CRT) and 10 w/w % of 3550 mPa-s viscosity grade (Methocel K4M Premium CR^®) were mixed.

All ingredients, except magnesium stearate, were mixed together and sieved through 0.75 mm mesh sieve. Then sieved (0.5 mm mesh size) magnesium stearate was added and the mixture was additionally blended. The final blend was compressed into tablets at compression forces ranging from 10 to 25 kN using round 10 or 11 mm punches.

Examples 3-5

Table 7: Hydrophilic cellulose (HPMC) matrix tablets with sodium citrate

Core function example 3 example 4 example 5 mg/tablet mg/tablet mg/tablet

Tofacitinib citrate active 35.53 35.53 35.53

Hydroxypropyl methylcellulose matrix polymer 100.00 100.00 100.00 (type 2208 USP)*

Sprayed dried lactose filler 176.22 90.47 45.47

Microcrystalline cellulose filler 48.00 25.00 25.00

Sodium citrate alkalizing agent 36.25 145.00 190.00

Magnesium stearate lubricant 4.00 4.00 4.00

Total 400.00 400.00 400.00

* 90% w/w of 100000 mPa-s viscosity grade (Methocel K100M Premium CR^®) and 10% w/w of 3550 mPa-s viscosity grade (Methocel K4M Premium CR^®) were mixed.

Sodium citrate was first sieved through a 0.5 mm sieve. Sprayed dried lactose, microcrystalline cellulose, hydroxypropyl methylcellulose and tofacitinib citrate were mixed together and sieved through a 0.75 mm mesh sieve. Sieved sodium citrate was added and blended for 3 minutes. Then sieved (0.5 mm mesh size) magnesium stearate was added and the mixture was additionally blended. The final blend was compressed into tablets at compression forces ranging from 9 to 17 kN using round 11 mm punches.

Examples 6-7

Table 8: Hydrophilic cellulose (HPMC) matrix tablets with insoluble alkalizing agents

Core function example 6 example 7 mg/tablet mg/tablet

Tofacitinib citrate active 35.53 35.53

Hydroxypropyl methylcellulose matrix polymer 100.00 100.00

(type 2208 USP)*

Sprayed dried lactose filler 90.47 94.47

Microcrystalline cellulose filler 88.00 26.00

Calcium carbonate alkalizing agent 80.00 -

Magnesium oxide alkalizing agent 2.00 -

Magnesium aluminum silicate alkalizing agent - 140.00

Magnesium stearate lubricant 4.00 4.00

Total 400.00 400.00

* 90% w/w of 100000 mPa-s viscosity grade (Methocel K100M Premium CR ) and 10% w/w of 3550 mPa-s viscosity grade (Methocel K4M Premium CR^®) were mixed.

Formulations were prepared according to the procedure described for examples 1 -2. Examples 8a and 8b

Table 9: Hydrophilic cellulose (HEC) matrix tablets with alkalizing ; agents

Core function example 8a example 8b mg/tablet mg/tablet

Tofacitinib citrate active 35.53 35.53

Hydroxyethylcellulose (Natrosol^® matrix polymer 240.00 240.00

250 HHX grade, 3500-5500 mPa-s)

Microcrystalline cellulose filler - 20.00

Calcium carbonate alkalizing agent 110.47 -

Magnesium oxide alkalizing agent 10.00 -

Sodium citrate alkalizing agent - 100.47

Magnesium stearate lubricant 4.00 4.00

Total 400.00 400.00

Formulations were prepared according to the procedure described for examples 1-2.

Examples 9-10

Table 10: Hydrophilic cellulose (HPMC) matrix tablets with inorganic alkalizing agents

Core function example 9 example 10 mg/tablet mg/tablet

Tofacitinib citrate active 35.53 35.53

Hydroxypropyl methyl cellulose matrix polymer 100.00 100.00

(type 2208 USP)*

Sprayed dried lactose filler - 78.97

Microcrystalline cellulose filler 100.00 21.50

Calcium hydrogen phosphate dihydrate alkalizing agent 160.47 -

Calcium sulfate alkalizing agent - 160.00

Magnesium stearate lubricant 4.00 4.00

Total 400.00

Formulations were prepared according to the procedure described for examples 1-2. Examples 11-13

Table 1 1 : Hydrophilic cellulose matrix tablets with different levels of HPMC

Core function example 11 example 12 example 13 mg/tablet mg/tablet mg/tablet

Tofacitinib citrate active 35.53 35.53 35.53

Hydroxypropyl methylcellulose matrix polymer 60.00 100.00 140.80

(type 2208 USP)*

Lactose filler 180.47 160.47 149.67

Microcrystalline cellulose filler 120.00 100.00 70.00

Magnesium stearate lubricant 4.00 4.00 4.00

Total 400.00 400.00 400.00

* 90 w/w % of 100000 mPa-s viscosity grade (Methocel K100M Premium CRT) and 10 w/w % of 3550 mPa- s viscosity grade (Methocel K4M Premium CR^®) were mixed.

Tofacitinib citrate is mixed with part of the hydroxypropyl methylcellulose, lactose and part of the microcrystalline cellulose. The mixture is granulated with water in a high shear mixer or fluid bed. The granulate is dried in oven or a fluid bed dryer. The dry mixture is sieved or milled through appropriate mesh size. The remaining microcrystalline cellulose and hydroxypropyl methylcellulose are mixed with the granulate. At the end sieved magnesium stearate is added and mixed together and tablets are compressed.

Examples 14-15

Table 12: Hydrophilic cellulose matrix tablets with different levels and viscosities of HEC

Core function example 14 example 15 mg/tablet mg/tablet

Tofacitinib citrate active 35.53 35.53

Hydroxyethylcellulose (Natrosol^® 250)* matrix polymer 120.00 240.00

Sprayed dried lactose or milled lactose filler 150.47 90.47 monohydrate

Microcrystalline cellulose filler 90.00 30.00

Magnesium stearate lubricant 4.00 4.00

Total 400.00 400.00

* In example 14 Natrosol 250 HX grade with viscosity 1500 - 2500 mPa s and in example 15 Natrosol 250 HHX grade with viscosity 3500 - 5500 mPa were used. Example 14: Sprayed dried lactose, microcrystalline cellulose, hydroxyethylcellulose and tofacitinib citrate were mixed together and sieved through 0.75 mm mesh sieve. Then sieved (0.5 mm mesh size) magnesium stearate was added and the mixture was additionally blended. The final blend was compressed at compression forces ranging from 15 to 23 kN into tablets using round 10 mm punches.

Example 15: Tofacitinib citrate is mixed with part of the hydroxyethylcellulose, lactose monohydrate and part of the microcrystalline cellulose. The mixture is granulated with water in a high shear mixer or fluid bed. The granulate is dried in oven or a fluid bed dryer. Dry mixture is sieved or milled through appropriate mesh size. Microcrystalline cellulose and the remaining hydroxyethylcellulose are mixed with the granulate. At the end sieved magnesium stearate is added and mixed together and tablets are compressed.

Example 16

Table 13 : Hydrophilic cellulose matrix bilayer tablets with different polymers in the second layer: A - HPMC, B - PEO and C - HEC

Core function Example 16 mg/tablet

First layer - API + hydrophilic polymer

Tofacitinib citrate active 35.53

Hydroxypropyl methylcellulose matrix polymer 100.00

(type 2208 USP)*

Lactose monohydrate filler 160.47

Microcrystalline cellulose filler 100.00

Magnesium stearate lubricant 4.00

Total first layer 400.00

Second layer - hydrophilic polymer

Hydroxypropyl methylcellulose (type 2208 USP; matrix polymer 100.00

Methocel K4M Premium CR, viscosity 3550

mPa-s), polyethylene oxide (Polyox WSR N-12K

400-800 mPa-s, 2 % solution) or

hydroxyethylcellulose (Natrosol 250 HHX grade)

Total tablet 500.00 * 90 w/w % of 100000 mPa-s viscosity grade (Methocel K100M Premium CR^®) and 10 w/w % of 3550 mPa-s viscosity grade (Methocel K4M Premium CR^®) were mixed. Tofacitinib is mixed with part of hydro xypropyl methylcellulose, lactose and part of microcrystalline cellulose. The mixture is granulated with water in a high shear mixer or fluid bed. The granulate is dried in oven or a fluid bed dryer. Dry mixture is sieved or milled through appropriate mesh size. Microcrystalline cellulose and the remaining hydroxypropyl methylcellulose and mixed with the granulate. At the end sieved magnesium stearate is added and mixed together to prepare final tableting mixture of first layer. Bilayer tablets are compressed. First API layer is filled into the die and slightly compressed at relatively low compression forces (for example 2 - 4 kN). Then the second layer is added into the die and the bilayer tablet is compressed with compression force ranging from 8 - 23 kN.

Example 17

Table 14: Hydrophilic cellulose matrix tablets with HEC + carrageenan

Core function example 17 mg/tablet

Tofacitinib citrate active 35.53

Lactose filler 90.47

Microcrystalline cellulose filler 30.00

Hydroxyethylcellulose matrix polymer 80.00

(Natrosol 250 HHX grade, 3500-5500 mPa-s

viscosity)

Carrageenan λ type (Viscarine^® GP-209NF) matrix polymer 80.00

Carrageenan ι type (Gelcarine^® GP-379NF) matrix polymer 80.00

Magnesium stearate lubricant 4.00

Total 400.00

Lactose, microcrystalline cellulose, hydroxyethylcellulose and tofacitinib citrate were mixed together and sieved through 0.75 mm mesh sieve. The mixture was granulated with water in a high shear mixer of fluid bed. The granulate was dried in oven or fluid bed dryer. The resulting dry mixture was sieved or milled through an appropriate sieve. Carrageenan and magnesium stearate were added and the mixture was additionally blended and tablets were compressed.

Reference examples 1-4

In order to show the advantages of the formulations of the invention, four formulations disclosed in WO 2012/100949 Alwere reproduced and analyzed according to the methods described above. Table 15 : Reference examples 1 - 4 corresponding respectively to example 1, 4, 5 and 9 of WO

2012/100949 Al

All ingredients in reference examples 1 and 2, except magnesium stearate, were sieved and blended. Then sieved magnesium stearate was added and mixture was additionally blended and compressed into tablets. In examples 3 and 4 tofacitinib citrate, Eudragit^® and lactose or cellulose microcrystalline were mixed and granulated with water. Granulate was dried at 40°C. The resulting granulate was sieved and Aerosil^® and magnesium stearate were mixed. The resulting mixture was compressed into tablets.

Reference examples 1 - 4 were tested according to discriminatory dissolution to evaluate mechanical susceptibility of matrix tablets. As it can be appreciated from table 16, drug release from reference samples was much faster under mechanical stress. Drug release from the formulation of reference example 3 was very fast even without mechanical stress so that such formulation cannot even be considered to be a sustained release formulation. Table 16: Drug release in dissolution medium with (MS) or without mechanical stress (No MS) using apparatus I, 100 RPM, 900 ml of pH 6.8 medium

All the tested reference formulations release tofacitinib too fast and would not provide a suitable plasma profile for a modified release formulation. Additionally all examples prepared did not show any mechanical robustness and thus possibly expose the patients to safety risks.

Claims

CLAIMS What is claimed is:

1. A sustained release formulation for oral administration comprising tofacitinib or a

pharmaceutically acceptable salt thereof, a hydrophilic polymer and an alkalizing agent, wherein the pH at 25°C of a 1% weight/volume water solution or dispersion of the formulation is between 5.5 and 11.

2. The formulation of claim 1, wherein the pharmaceutically acceptable salt of Tofacitinib is

Tofacitinib citrate.

3. The formulation of claims 1-2, wherein the pH of a 1% weight/volume water solution of the

formulation is between 6 and 10.5.

4. The formulation of claims 1-3, wherein the alkalizing agent is selected from the group consisting of magnesium oxide, calcium carbonate, calcium silicate, potassium citrate, sodium citrate and combinations thereof.

5. The formulation of claims 1 -4, wherein the alkalizing agent is selected from the group consisting of potassium citrate, sodium citrate and combinations thereof.

6. The formulation of claims 1-5, wherein the hydrophilic polymer is a cellulose derivative with a viscosity between 1000 and 150000 mPa-s, or a carrageenan with a viscosity greater than 5 mPa-s, or a mixture thereof.

7. A sustained release formulation for oral administration comprising tofacitinib or a

pharmaceutically acceptable salt thereof and a hydrophilic polymer, wherein the hydrophilic polymer is a cellulose derivative with a viscosity between 1000 and 150000 mPa-s, a carrageenan with a viscosity greater than 5 mPa-s, or a mixture thereof.

8. The formulation of any of the preceding claims, wherein the amount of hydrophilic polymer is between 15 and 80% based on the total weight of the pharmaceutical composition excluding any coating.

9. The formulation of any of the preceding claims, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxyethyl cellulose, carrageenan and mixtures thereof.

10. The formulation of claims 6-8, wherein such formulation contains a mixture of the cellulose

derivative and of the carrageenan.

11. The formulation of any of the preceding claims, wherein such formulation is a tablet.

12. The formulation of any of the preceding claims, wherein such formulation is a bilayer tablet.

13. The formulation of claims 1-12 for use as a medicament, wherein such formulation is

administered once a day.

14. The formulation of claims 1-12 for use in the treatment of rheumatoid arthritis, wherein such formulation is administered once a day.

15. A sustained release formulation for oral administration comprising tofacitinib or a

pharmaceutically acceptable salt thereof in an amount between 10 and 12 mg expressed as tofacitinib free base, wherein such formulation is administered once a day and the Cmax of tofacitinib measured in plasma is below 35 ng/ml, preferably between 25 and 35 ng/ml.