EP3810096A1

EP3810096A1 - Controlled release tofacitinib compositions

Info

Publication number: EP3810096A1
Application number: EP19724469.2A
Authority: EP
Inventors: Luis Nogueiras Nieto; Lisardo Alvarez Fernandez; Rohit Kumar
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2018-05-24
Filing date: 2019-05-14
Publication date: 2021-04-28
Also published as: EA202092829A1; WO2019224058A1

Abstract

The present invention relates to a tablet into tablet composition for oral administration of tofacitinib, or a pharmaceutically acceptable salt thereof.

Description

P1735PC00

CONTROLLED RELEASE TOFACITINIB COMPOSITIONS

BACKGROUND OF THE PRESENT INVENTION

Tofacitinib or (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-B- oxo-l-piperidinepropanenitrile, citrate salt (1:1), of the formula:

is a reversible inhibitor of the Janus kinase family of kinases (JAK1, JAK2, JAK3 and Tyrosine Kinase 2 (TyK2)). Tofacitinib has been disclosed in W02001042246.

Tofacitinib is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to

methotrexate. It is marketed as an extended release tablet under the brand name XELJANZ XR® (Pfizer Products Inc.). The tablets are based on osmotic pump technology, wherein the osmotic pressure is used to deliver the tofacitinib at controlled rate. The tablet insert for XELJANZ XR® tablet, describes the tablet as“a pink, oval, extended release film-coated tablet with a drilled hole at one end of the tablet band”.

XELJANZ XR® tablet is a controlled-release formulation, which provides more favourable pharmacokinetic profiles (e.g. reducing the peak variation of drug concentration levels), so reducing the side effects and achieving better patient compliance.

XELJANZ XR® drug release profile is very complicated combining different order kinetics. XELJANZ XR® formulation is described in WO2014147526; the formulation is an osmotic pump consisting of a semi-permeable coating made of an insoluble polymer, cellulose acetate, and a core containing tofacitinib citrate, sorbitol, hydroxyethyl cellulose, co-povidone and magnesium stearate. The solute concentration gradient, which provides the osmotic force driving the delivery of the drug through the drilled hole, can be maintained constant when solute saturation is present in the tablet core. As the tablet content comes out, solute concentration declines and as well the gradient and the osmotic force driving the drug release.

The typical orifice size in osmotic pumps ranges from about 600 pm to 1 mm. A nominal 600 pm hole usually has a ±100 pm tolerance on diameter, and an allowable ellipticity of 1.0 to 1.5. Although holes of these characteristics and tolerances can be obtained by mechanical means, there is no mechanical method able to work at high manufacturing rates consistent with pharmaceutical manufacturing processes.

In contrast, laser tablet drilling can lead to throughput rates of up to 100,000 tablets/hour having the necessary dimensional tolerances and cosmetic appearance. As a result, laser drilling has become the technology of choice for this type of orifice production.

This technology also requires accepted-rejected system in order to check if the drilled hole on the surface of the tablet meets the specifications. The reject mode is activated as soon as a failed tablet is sensed by the vision system, which causes one or two tablets ahead of the rejected unit to be expelled as well. The reject state only switches off when the system verifies that five tablets in a row meet pass criterion. An additional presence sensor downstream from the blow off verifies that no tablets are passing through the system when the reject condition is set to“on”.

Therefore, the required technology for the manufacturing of the osmotic pump delivery systems is significantly expensive, which is a disadvantage and an economic barrier for many companies. WO 2012/100949 provides an oral dosage form for modified release comprising tofacitinib and a non-erodible material. In this patent application a monolithic tablet containing a non-erodible material and other components such as pore formers is claimed. The main disadvantage of this type of delivery systems is the difficulties of the water to penetrate through the material, leading to slow hydration rates. This may lead as result the incomplete dissolution of the drug substance if the centre of the tablet core remains unwetted.

WO 2014/174073A1 discloses a sustained release formulation for oral administration comprising tofacitinib, a hydrophilic polymer and an alkalizing agent. The alkalizing agent is proposed for reducing API solubility in acidic pHs obtaining a non-pH dependent release formulation. Alkalizing the tablet core aims to reduce the release of the active ingredient at low pHs where it is more soluble; however the decrease of the active ingredient solubility by alkalizing the tablet core can limit the drug release at high pHs (for instances at the small intestine) impacting on the bioavailability of the drug substance.

There is still need of finding an additional oral formulation of tofacitinib which overcome the problems of the prior art and is bioequivalent to the commercial tofacitinib tablet XELJANZ XR®.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a tablet-into-tablet delivery system that is able to provide a similar dissolution release rate of tofacitinib than the commercial tables having an osmotic pump.

A first aspect of the invention relates to a controlled release pharmaceutical tablet comprising:

a) An inner tablet comprising tofacitinib or a pharmaceutically acceptable salt

thereof and a pH independent gelling control release polymer; b) An outer tablet surrounding said inner tablet comprising a pH independent gelling control release polymer;

wherein said outer layer does not contain tofacitinib or a pharmaceutically acceptable salt thereof.

The dissolution profile provided by the osmotic pump of tofacitinib marketed tablet is very complicated: initially it exhibits a short lag time where no drug release takes place. This short lag time corresponds with the diffusion of water through the semi-permeable membrane and the hydration of the tablet core. Afterwards, zero-order kinetic release occurs due to the sustained solute concentration gradient between the tablet core and the dissolution medium. The solute concentration gradient, which provides the osmotic force driving the delivery of the drug through the drilled hole, can be maintained constant whereas solute saturation takes place in the tablet core. As the tablet content come out the solute concentration declines and so the gradient and the osmotic force driving drug release. Ultimately, as a consequence of the decrease of the solute concentration in the tablet core, the dissolution profile shows first- order kinetic release after 3 hours.

The inventors have surprisingly found that this tablet-into tablet system can provide similar drug dissolution release than the osmotic pump system. Moreover, the technology required for the manufacturing of tablet-into-tablet drug delivery systems is cheaper than and as efficient as the one employed for obtaining osmotic pump systems.

The tablet-into-tablet system of the present invention combines two controlled release structures or mechanisms: there are two tablets comprising pH independent gelling control release polymer. Dissolution can be modulated to achieve the desired profile by choosing among these polymers; the inner tablet contains the tofacitinib or a salt thereof, preferably the citrate salt, and a pH independent gelling control release polymer. Covering this inner tablet there is an outer tablet that acts as external layer formulated as a placebo, this external layer contains a pH independent gelling control release polymer which determines the resulting lag time of the dissolution profile.

The inner tablet mainly alters the dissolution profile after 2 hours time. The content of the controlled release in the inner tablet modulates the dissolution rate of the active ingredient.

The inner tablet comprises the whole dose of tofacitinib. The word tofacitinib is used herein to refer to tofacitinib free base as well as its pharmaceutically acceptable salts.

A preferred salt to be use is the citrate salt.

Tofacitinib free base as well as its pharmaceutically acceptable salts, preferably tofacitinib citrate is preferably used in an amount of 10 to 80%, more preferably 15% to 70%, even more preferably 20 to 60% by weight based on the total inner tablet weight.

In the present invention tofacitinib is released from the formulation, in a controlled fashion so that at least 60% of tofacitinib is released at 4 hours and at least 80% of tofacitinib is released after 6 hours.

In the present invention the inner tablet contains at least one pH independent gelling control release polymer. The term pH independent gelling control release polymer means a control release polymer that forms a gel when in contact with water independently of the pH of the water. Such polymers are known in the art and include polyethylene oxide (for example (MW:900.000 g/mol; Polyox® 1105 WSR), hydroxypropyl methylcellulose (for example Methocel® K100 Premium low viscosity (LV) grade), hydroxypropyl cellulose, polyvinyl alcohol (for example Parteck® SRP 80), guar gum, carrageenan and combinations thereof. A preferred pH independent gelling control release polymers are soluble polymers such a polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol more preferably hydroxypropyl methyl cellulose and polyethylene oxide, even more preferably hydroxypropyl methyl cellulose. The amount of the pH independent gelling control release polymer in the inner tablet is preferably in an amount from 10% to 50%, more preferably from 20% to 40%, even more preferably 25% to 35% by weight based on the total inner tablet weight.

The pH independent gelling control release polymer of the present invention has preferably a viscosity of 10 cP or more, more preferably 25cP or more, even more preferably between 20 and 500cp, most preferred 24 to 300cP in a solution containing 2% of the polymer in distilled water at 22.5±0.5°C, measured using a Fungilab viscosimeter.

The inner tablet contains additional excipients such as diluents, lubricants, binders or buffering agents.

In the case that the inner tablet is made by granulation process these excipients can be present intragranularly or extragranularly.

Diluents are excipients that are used to increase the bulk volume of a tablet. By combining a diluent with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling. Binders hold the excipients that are present in a tablet together. Binders ensure that tablets and granules can be formed having the desired or required mechanical strength.

The inner tablet of the present invention preferably contains at least one diluent.

Diluents are preferably used in an amount of from 10% to 75% more preferably 20 to 65% even more preferably 25% to 50% by weight based on the total weight of the inner tablet. Suitable examples of diluents to be used in accordance with the present invention include lactose, starch, pregelatinized starch, microcrystalline cellulose(MCC), phosphates, and combinations thereof.

In a preferred embodiment of the present invention, the diluents to be used are lactose, microcrystalline cellulose or mixtures thereof. Binders which are suitable for use in accordance with the present invention include povidone, hydroxypropyl methylcellulose, hydroxy propylcellulose, and sodium carboxyl methylcellulose. Binders are preferably used intragranularly in an amount of from 1% to 5% by weight based on the total weight of the composition. A preferred binder is hydroxypropyl cellulose, povidone or co-povidone.

The inner tablet may also contain a lubricant and/or a glidant. Lubricants are generally used in order to reduce sliding friction. In particular, to decrease friction at the interface between a tablet’s surface and the die wall during ejection, and reduce wear on punches and dies. Suitable lubricants to be used in accordance with the present invention include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and sodium stearyl fumarate. Lubricants preferably are used in a total amount of from 0.05% to 5% by weight based on the total weight of the inner tablet. A preferred lubricant is magnesium stereate.

Glidants enhance product flow by reducing interparticulate friction. A suitable example is colloidal silicon dioxide. Glidants preferably are used in a total amount of from 0.05% to 5% by weight based on the total weight of the inner tablet.

The inner tablet may also contain one or more buffering agents. Buffering agents are generally used in order to maintain the pH constant. They may be acidic or basic agents. Suitable acidic buffering agents are tartaric acid, malic acid, maleic acid and citric acid. Suitable basic buffering agents are sodium carbonate, sodium acetate and potassium citrate.

In the present invention the outer tablet contains at least one pH independent gelling control release polymer. The pH independent gelling control release polymer in the outer tablet may be the same as or different from the pH independent gelling control release polymer in the inner tablet. In a preferred embodiment the pH independent gelling control release polymer is the same for the inner and outer tablet. As with the inner tablet the preferred polymer is a soluble polymer, more preferably hydroxypropyl methyl cellulose. The amount of the pH independent gelling control release polymer in the outer tablet is preferably in an amount from 3% to 35% more preferably from 5% to 25%, even more preferably 10% to 20%, most preferably 12% to 18% by weight to the total outer tablet.

The outer tablet may further contain additional pharmaceutical excipients as described above for the inner tablet, such as diluents, binders et cetera.

In a preferred embodiment at least one diluent as described above for the inner tablet is present in the outer tablet. Diluents are preferably used in an amount of from 10% to 95%, more preferably 30% to 90%, even more preferably 50% to 90% by weight based on the total weight of the outer tablet. In a preferred embodiment of the present invention, the diluents to be used are lactose, microcrystalline cellulose or mixtures thereof.

The outer tablet can also contain a lubricant and/or glidant as described above for the inner tablet.

Unlike the inner tablet, the outer tablet does not contain tofacitinib. It should be understood that this exclusion of the tofacitinib does not prohibit trace or otherwise accidental amounts of tofacitinib from being present in the outer tablet.

In addition to the pharmaceutical excipients, the mass ratio of the inner tablet: outer core may have an influence on the release rate. In a preferred embodiment, the mass ratio of the inner tablet to outer tablet is at least 1:1, respectively, more preferably in the range from 1:1 to 1:5, even more preferably from 1:2 to 1:4.

The inner tablet and the outer tablet are normally the same shape, preferably round including flat round or a convex round tablet shape.

In a preferred embodiment the inner tablet and the outer tablet have the following compositions. The inner tablet comprises based on total weight of the inner tablet:

a. Tofacitinib citrate in an amount of from 20 to 60% by weight; b. pH independent gelling control release polymer, preferably Hydroxypropyl methylcellulose, in an amount of from 20 to 40% by weight;

c. Diluents in an amount of from 25% to 50%by weight;

and wherein said outer tablet comprises based on total weight of the outer tablet:

a. pH independent gelling control release polymer, preferably Hydroxypropyl methylcellulose in an amount of from 10% to 20% by weight;

b. Diluents in an amount of from 50 to 90% by weight.

In a more preferred embodiment the inner tablet and the outer tablet have the following compositions.

The inner tablet comprises based on total weight of the inner tablet:

a. Tofacitinib citrate in an amount of from 20 to 60% by weight; b. pH independent gelling control release polymer, preferably Hydroxypropyl methylcellulose, in an amount of from 20% to 40% by weight;

c. MCC in an amount of from 10 to 40% by weight;

d. Lactose in an amount of from 10 to 40% by weight;

e. Optionally other pharmaceutical excipients;

b. MCC in an amount of from 25 to 45% by weight;

c. Lactose in an amount of from 25 to 45% by weight;

d. Optionally other pharmaceutical excipients. The inner and outer tablet can be made using conventional methods and equipment well-known in the art; direct compression, wet granulation or dry granulation. In a preferred embodiment the inner tablet is prepared by dry granulation process and the outer tablet via direct compression.

The tablet of the invention can be made by conventional tablet-into-tablet or compression techniques. The inner tablet is first made via any convenient tabletting technique such as direct compression or dry granulation, though dry granulation is preferred because it improves the flow properties of the final blend; additionally, this process does not require the use of solvents, which may be involved in chemical reactions reducing the stability of the drug susbtance. A pre -blend, which contains tofacitinib or a pharmaceutically acceptable salt thereof, preferably citrate salt, a pH independent gelling control release polymer, preferably hydroxypropyl methylcellulose, and optionally other pharmaceutical excipients are dry granulated. These pharmaceutically acceptable excipients may be chosen from diluents, preferably MCC and lactose, glidants preferably colloidal silicone dioxide and lubricants, preferably magnesium stereate. The granules are mixed with pharmaceutically acceptable excipients, for instance diluent(s) preferably lactose and MCC, glidants preferably colloidal silicone dioxide or lubricants, preferably magnesium stereate and are compressed to form the inner tablet. Then a second larger tablet punch is partially charged with a portion of an excipient composition containing at least one pH independent gelling control release polymer, preferably hydroxypropyl methylcellulose and optionally other pharmaceutically acceptable excipients as described above. The previously inner tablet is placed and centred in the partially charged punch; finally, then the second portion of the excipient composition is charged in the punch, covering the inner tablet, which will form the outer tablet and the whole material compressed to form a compression barrier layer around the inner tablet. Tablet presses allowing such a technique are known in the art as alternate tablet presses or tablet-into tablets presses.

The tablet composition in accordance with the present invention is bioequivalent in vitro and in vivo to the commercially available tofacitinib citrate tablets.

Figure 1 shows the manufacturing scheme of the formulation.

Figure 2 shows the in vitro dissolution profile of tablet compositions in accordance with the present invention as compared to commercially available tablets.

The present invention is illustrated by the following Example.

Example 1

In table 1 the pharmaceutical composition of example 1 is shown;

Example #1. Controlled-release formulation consisting of a tablet-into-tablet dosage form containing HPMC 2208, 100 cP (Methocel 100K LV Premium®).

2.66 grams of tofacitinib citrate, 2.25 grams of hydroxypropyl methyl cellulose (Methocel 100 K LV Premium®), 0.75 grams of microcrystalline cellulose, 0.75 grams of lactose monohydrate and 0.04 grams of anhydrous silicon dioxide were accurately weighed and sieved through 1.0 mm mesh for deagglomeration. Afterwards, the components were placed in a container and mixed at 72 rpm for 10 minutes using a diffusion blender obtaining a blend (1). 0.04 grams of magnesium stearate was accurately weighed and sieved through 0.5 mm mesh for deagglomeration. Then the blend (1) was mixed with the magnesium stearate at 72 rpm for 3 minutes using a diffusion blender to obtain a homogenous blend (2). The blend (2) was compressed to obtain slugs of approximately 650 mg. The slugs were then crushed and sieved through 1.0 mm mesh obtaining homogenous granules (3).

0.49 grams of microcrystalline cellulose and 0.49 grams of lactose monohydrate were accurately weighed and sieved through 1.0 mm mesh for deagglomeration. The components were placed in a container together with the granules (3) and mixed at 72 rpm for 10 minutes using a diffusion blender resulting in a homogenous blend (4). 0.04 grams of magnesium stearate were accurately weighed and sieved through 0.5 mm mesh for deagglomeration. Afterwards the magnesium stearate was mixed with the previous blend (4) at 72 rpm for 3 minutes using a diffusion blender resulting in a homogenous blend (5). Finally, this blend was compressed obtaining 50 mg, 5 mm round tablets (6).

6.75 g of hydroxypropyl methyl cellulose (Methocel 100 K LV Premium®), 7.76 grams of microcrystalline cellulose, 7.76 grams of lactose monohydrate and 0.11 grams of anhydrous silicon dioxide were accurately weighed and sieved through 1.0 mm mesh for deagglomeration. The components were placed in a container and mixed at 72 rpm for 10 minutes using a diffusion blender resulting in a blend (7). 0.11 grams of magnesium stearate were weighed, sieved through 0.5 mm mesh for deagglomeration and mixed with the previous blend (7) at 72 rpm for 3 minutes using a diffusion blender, resulting in a homogeneous blend (8).

The final compression consists of placing the previous 50 mg, 5 mm tablet (5) in between of 150 mg the previous blend (8), so that this blend (8) would correspond with the outer layer of the tablet-into-tablet formulation. Both the 5 mm tablets (5) and the blend (8) were compressed in order to obtain a 8 mm tablet-into-tablet.

Table 1.

*Intragranular components

The above formulation was made according to the process depicted in figure 1.

Claims

1. A controlled release pharmaceutical tablet comprising:

a) An inner tablet comprising tofacitinib or a pharmaceutically acceptable salt

thereof and a pH independent gelling control release polymer;

b) An outer tablet surrounding said inner tablet comprising a pH independent gelling control release polymer;

2. A controlled release pharmaceutical tablet according to claim 1 wherein tofacitinib is in the form of tofacitinib citrate.

3. A controlled release formulation according to claim 1 or 2 such that tofacitinib is

released from the formulation, in a controlled fashion so that at least 60% of tofacitinib citrate is released at 4 hours and at least 80% of tofacitinib citrate is released after 6 hours.

4. A tablet according to any one of the claims 1 to 3 wherein said tofacitinib is present in an amount of from 20 to 60% by weight based on the total inner tablet weight.

5. A tablet according to any one of the claims 1 to 4 wherein said pH independent gelling control release polymer is present in the outer tablet in an amount from 10% to 20% by weight to the total outer tablet weight.

6. A tablet according to any one of the claims 1 to 4 wherein said pH independent gelling control release polymer is present in the inner tablet in an amount from 20 to 40% by weight to the total inner tablet weight.

7. A tablet according to any one of the claims 1 to 6 wherein said pH independent gelling control release polymer in said inner tablet and in said outer tablet are each

independently selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene oxide, polyvinyl alcohol, and combinations thereof.

8. A tablet according to claim 6, wherein said pH independent gelling control release polymer in said inner tablet comprises hydroxypropyl methylcellulose.

9. A tablet according to claim 5, wherein said pH independent gelling control release polymer in said outer tablet comprises hydroxypropyl methylcellulose.

10. A tablet according to any one of the claims 1 to 9 wherein said inner tablet further comprises a diluent in an amount from 25-50% by weight based in the total weight of the inner tablet.

11. A tablet according to any one of the claims 1 to 10 wherein said outer tablet further comprises a diluent in an amount from 50-90% by weight based in the total weight of the outer tablet.

12. A tablet according to claim 10 and/or 11 wherein said diluent is selected from the group comprising microcrystalline cellulose, lactose, phosphates, hydroxypropyl cellulose, starch and combinations thereof.

13. A tablet according to any one of the claims 1 to 12 wherein said inner tablet and/or said outer tablet further comprises a lubricant.

14. A tablet according to any one of the claims 1 to 13;

wherein said inner tablet comprises based on total weight of the inner tablet:

a. Tofacitinib citrate in an amount of from 20 to 60% by weight;

b. Hydroxypropyl methylcellulose in an amount of from 20% to 40% by weight; c. Diluents in an amount of from 25% to 50% by weight;

a. Hydroxypropyl methylcellulose in an amount of from 10% to 20% by weight; b. Diluents in an amount of from 50 to 90% by weight.

15. A tablet according to claim 14 wherein the diluents are microcrystalline cellulose, lactose or combination thereof.

16. A tablet according to any one of the previous claims wherein the mass ratio of inner tablet to said outer tablet is within range 1:2 to 1:4.

17. A process for making the tablet according to claim 1-16, which comprises applying a compression barrier layer around a tablet having tofacitinib or a pharmaceutically acceptable salt thereof and a pH independent gelling polymer, to form an outer tablet surrounding said tablet, wherein the compression barrier layer comprises a pH independent gelling control release polymer.