Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

• 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.
• laser tablet drilling can lead to throughput rates of up to 100,000 tablets/hour having the necessary dimensional tolerances and cosmetic appearance.
• 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”.
• WO 2012/100949 provides an oral dosage form for modified release comprising tofacitinib and a non-erodible material.
• 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.
• 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:
• An inner tablet comprising tofacitinib or a pharmaceutically acceptable salt
• 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.
• 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.
• 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.
• 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.
• the inner tablet contains at least one pH independent gelling control release polymer.
• 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.
• 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.
• 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.
• 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.
• the pH independent gelling control release polymer is the same for the inner and outer 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.
• 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.
• 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.
• 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.
• the mass ratio of the inner tablet: outer core may have an influence on the release rate.
• 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.
• the inner tablet and the outer tablet have the following compositions.
• the inner tablet comprises based on total weight of the inner tablet:
• said outer tablet comprises based on total weight of the outer tablet:
• pH independent gelling control release polymer preferably Hydroxypropyl methylcellulose in an amount of from 10% to 20% by weight
• the inner tablet and the outer tablet have the following compositions.
• the inner tablet comprises based on total weight of the inner tablet:
• Lactose in an amount of from 10 to 40% by weight
• said outer tablet comprises based on total weight of the outer tablet:
• pH independent gelling control release polymer preferably Hydroxypropyl methylcellulose in an amount of from 10% to 20% by weight
• MCC in an amount of from 25 to 45% by weight
• Lactose in an amount of from 25 to 45% by weight
• 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.
• 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.
• 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.
• 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 Controlled-release formulation consisting of a tablet-into-tablet dosage form containing HPMC 2208, 100 cP (Methocel 100K LV Premium®).
• 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.

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• 2019
  • 2019-05-14 WO PCT/EP2019/062390 patent/WO2019224058A1/en unknown
  • 2019-05-14 EA EA202092829A patent/EA202092829A1/ru unknown
  • 2019-05-14 EP EP19724469.2A patent/EP3810096A1/de active Pending

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